| 馬場 英司（ばば えいし） | データ更新日：2023.09.28 |
教授 ／
医学研究院
附属総合コホートセンター
社会環境医学講座 連携社会医学分野
| 1. | 磯部 大地, 柴田 義宏, 在田 修二, 内野 慶太, 牧山 明資, 瀧井 康, 草場 仁志, 馬場 英司, 中野 修治, 原田 実根, 居石 克夫, 八尾 隆史, 消化器原発進行小細胞癌に対する全身化学療法の検討, 日本消化器病学会雑誌, 103, 臨増大会, A927-A927, 2006.09. |
| 2. | 磯部 大地, 内野 慶太, 牧山 明資, 在田 修二, 柴田 義宏, 草場 仁志, 馬場 英司, 中野 修治, CPT-11/CDDP不応性の進行・再発胃癌に対する二次療法としてのDTX/TS-1療法の実施可能性, 日本癌治療学会誌, 41, 2, 397-397, 2006.09. |
| 3. | 内野 慶太, 平野 元, 白川 剛, 磯部 大地, 牧山 明資, 在田 修二, 柴田 義宏, 草場 仁志, 馬場 英司, 中野 修治, 胃腸癌細胞におけるNanog偽遺伝子8発現(Nanog pseudogene 8 expression in gastrointestinal cancer cells), 日本癌学会総会記事, 66回, 302-302, 2007.08. |
| 4. | 在田 修二, 馬場 英司, 柴田 義宏, 新納 宏明, 磯部 大地, 下田 慎治, 平野 元, 牧山 明資, 内野 慶太, 草場 仁志, 中野 修治, 原田 実根, B細胞から放出されるエクソソームHLAはNF-κBにより産生調節される(Exosomal HLA production of B cells is regulated by NF-κB signaling), 日本癌学会総会記事, 66回, 156-156, 2007.08. |
| 5. | 薦田 正人, 白川 剛, 磯部 大地, 平野 元, 牧山 明資, 内野 慶太, 在田 修二, 柴田 義宏, 平川 直也, 草場 仁志, 馬場 英司, 赤司 浩一, 耳下腺癌術後再発に対してCAP療法が奏効した一例, 日本癌治療学会誌, 43, 2, 675-675, 2008.10. |
| 6. | 白川 剛, 薦田 正人, 磯部 大地, 平野 元, 牧山 明資, 内野 慶太, 在田 修二, 柴田 義宏, 瀧井 康, 草場 仁志, 馬場 英司, 中野 修治, 赤司 浩一, TC(DC)療法、CPT-11療法が奏効した腹膜癌症例の検討, 日本癌治療学会誌, 43, 2, 437-437, 2008.10. |
| 7. | 磯部 大地, 馬場 英司, 在田 修二, 薦田 正人, 内野 慶太, 白川 剛, 平野 元, 牧山 明資, 草場 仁志, 赤司 浩一, B細胞におけるTSAP6によるエクソゾームHLA産生及びアポトーシス誘導の調節(TSAP6 regulates exosomal HLA secretion and apoptosis induction in B cells), 日本癌学会総会記事, 67回, 436-436, 2008.09. |
| 8. | 白川 剛, 田村 真吾, 薦田 正人, 平野 元, 磯部 大地, 内野 慶太, 有山 寛, 草場 仁志, 小田代 敬太, 馬場 英司, 当科で経験した心臓悪性腫瘍4例の後方視的検討, 日本癌治療学会誌, 44, 2, 788-788, 2009.09. |
| 9. | 牧山 明資, 藤本 千夏, 在田 修二, 江崎 泰斗, 織田 信弥, 田中 吏佐, 三ツ木 健二, 薦田 正人, 白川 剛, 磯部 大地, 内野 慶太, 有山 寛, 草場 仁志, 馬場 英司, 赤司 浩一, 切除不能・進行再発大腸癌に対するセツキシマブ使用経験(KRAS検査実施症例を交えて), 日本癌治療学会誌, 44, 2, 580-580, 2009.09. |
| 10. | 磯部 大地, 馬場 英司, 在田 修二, 薦田 正人, 白川 剛, 内野 慶太, 有山 寛, 草場 仁志, 赤司 浩一, STEAP3は細胞内鉄貯蔵量を調節し、鉄欠乏環境での腫瘍増殖生存を維持する(STEAP3 maintains tumor cell proliferation and survival by regulating intracellular iron storage), 日本癌学会総会記事, 68回, 280-281, 2009.08. |
| 11. | 薦田 正人, 馬場 英司, 磯部 大地, 新納 宏昭, 在田 修二, 有山 寛, 草場 仁志, 赤司 浩一, Exosomeを介した細胞間small RNA輸送(Intercellular transfer of functional small RNA via exosomes), 日本癌学会総会記事, 68回, 210-210, 2009.08. |
| 12. | 薦田 正人, 馬場 英司, 磯部 大地, 新納 宏昭, 在田 修二, 草場 仁志, 内野 慶太, 白川 剛, 田村 真吾, 赤司 浩一, 癌患者末梢血中エクソソームに含まれるmiRNAの検出と機能解析(Detection and functional analysis of miRNA in peripheral blood exosomes from cancer patients), 日本癌学会総会記事, 69回, 380-380, 2010.08. |
| 13. | 藤本 千夏, 熊谷 穂積, 牧山 明資, 在田 修二, 江崎 泰斗, 磯部 大地, 田村 真吾, 薦田 正人, 白川 剛, 内野 慶太, 草場 仁志, 馬場 英司, 赤司 浩一, 三ツ木 健二, 田中 吏佐, 切除不能進行・再発大腸癌の高齢患者に対するBevacizumab併用化学療法の検討, 日本癌治療学会誌, 45, 2, 815-815, 2010.09. |
| 14. | 磯部 大地, 馬場 英司, 在田 修二, 薦田 正人, 田村 真吾, 白川 剛, 平野 元, 内野 慶太, 牧山 明資, 草場 仁志, 植木 隆, 赤司 浩一, STEAP3によって調節される癌細胞内貯蔵鉄量(The uptake of iron, crucial for cellular proliferation and survival, maintained by STEAP3 in cancer), 日本癌学会総会記事, 69回, 82-83, 2010.08. |
| 15. | 白川 剛, 内野 慶太, 草場 仁志, 田村 真吾, 薦田 正人, 磯部 大地, 馬場 英司, 赤司 浩一, In vivo selection systemを用いた骨髄転移細胞内のがん幹細胞の解析(Analysis of cancer stem cells in bone marrow metastasis by use of in vivo selection system), 日本癌学会総会記事, 69回, 488-488, 2010.08. |
| 16. | 白川 剛, 田村 真吾, 薦田 正人, 磯部 大地, 高石 繁生, 草場 仁志, 馬場 英司, 赤司 浩一, 骨髄微小環境により選択された乳癌幹細胞はNotch1、CD44、CD49fを高発現する(Breast cancer stem cells selected by bone marrow microenvironment highly express Notch1, CD44 and CD49f), 日本癌学会総会記事, 70回, 228-228, 2011.09. |
| 17. | 白川 剛, 田村 真吾, 薦田 正人, 磯部 大地, 高石 繁生, 草場 仁志, 馬場 英司, 赤司 浩一, 骨髄微小環境により選択された乳癌幹細胞の解析と治療への可能性, 日本癌治療学会誌, 46, 2, 465-465, 2011.09. |
| 18. | 白川 剛, 中野 倫孝, 田村 真吾, 薦田 正人, 磯部 大地, 熊谷 穂積, 高石 繁生, 草場 仁志, 馬場 英司, 赤司 浩一, 腫瘍内科にて化学療法を施行する患者に合併する精神疾患の実態調査, 日本癌治療学会誌, 46, 2, 702-702, 2011.09. |
| 19. | 中野 倫孝, 森崎 裕子, 相良 浩輔, 白川 剛, 熊谷 穂積, 田村 真吾, 薦田 正人, 磯部 大地, 高石 繁生, 草場 仁志, 馬場 英司, 赤司 浩一, 肺結核との鑑別を要した空洞性病変を伴う大腸がん肺転移の2例, 日本癌治療学会誌, 46, 2, 841-841, 2011.09. |
| 20. | 白川 剛, 田村 真吾, 薦田 正人, 磯部 大地, 熊谷 穂積, 高石 繁生, 草場 仁志, 馬場 英司, 赤司 浩一, 当科にて緩和的放射線治療を施行した症例の後方視的調査による緩和的放射線治療の現状と問題点の検討, 日本緩和医療学会学術大会プログラム・抄録集, 16回, 298-298, 2011.06. |
| 21. | 白川 剛, 中野 倫孝, 田村 真吾, 薦田 正人, 磯部 大地, 熊谷 穂積, 高石 繁生, 草場 仁志, 小田代 敬太, 馬場 英司, 赤司 浩一, がん化学療法中に生じる心血管系有害事象のretrospective studyとその予測・対策, 日本癌治療学会誌, 46, 2, 688-688, 2011.09. |
| 22. | 田村 真吾, 磯部 大地, 馬場 英司, 中野 倫孝, 薦田 正人, 高石 繁生, 草場 仁志, 植木 隆, 赤司 浩一, 大腸癌においてはE-Cadherin陽性細胞、陰性細胞ともにがん幹細胞性をもつ(Both E-Cadherin-positive and negative cells of colorectal cancer stem cell population possess tumor initiating potential), 日本癌学会総会記事, 71回, 244-244, 2012.08. |
| 23. | 中野 倫孝, 有山 寛, 奥村 祐太, 田村 真吾, 磯部 大地, 宮脇 恒太, 草場 仁志, 植木 隆, 馬場 英司, 赤司 浩一, TGF-B刺激によるEMTを介したCD44陽性大腸がん幹細胞の可塑性 ex vivo培養システムに基づく検討(Plasticity of CD44+ colorectal cancer stem cells depends on TGF-beta-induced epithelial mesenchymal transition (EMT)), 日本癌学会総会記事, 73回, J-1093, 2014.09. |
| 24. | 田村 真吾, 磯部 大地, 有山 寛, 中野 倫孝, 植木 隆, 高石 繁生, 草場 仁志, 馬場 英司, 赤司 浩一, 大腸がん幹細胞分画におけるE-カドヘリン陽性細胞とE-カドヘリン陰性細胞の病理学的差異についての検討, 日本癌学会総会記事, 74回, J-1124, 2015.10. |
| 25. | Tsuchihashi Kenji, Okazaki Shogo, Yoshikawa Momoko, Seishima Ryo, Sampetrean Oltea, Onishi Nobuyuki, Wakimoto Hiroaki, Furnari Frank, Baba Eishi, Akashi Koichi, Saya Hideyuki, Nagano Osamu, xCT promotes malignant phenotypes in EGFR-expressing glioma, CANCER RESEARCH, 10.1158/1538-7445.AM2017-LB-334, 77, 2017.07. |
| 26. | Tomoyasu Yoshihiro, Kenta Nio, Kenji Tsuchihashi, Hiroshi Ariyama, Kenichi Kohashi, Nobuhiro Tsuruta, Fumiyasu Hanamura, Kyoko Inadomi, Mamoru Ito, Kosuke Sagara, Yuta Okumura, Michitaka Nakano, Shuji Arita, Hitoshi Kusaba, Yoshinao Oda, Koichi Akashi, Eishi Baba, Pancreatic acinar cell carcinoma presenting with panniculitis, successfully treated with FOLFIRINOX: A case report., Molecular and clinical oncology, 10.3892/mco.2017.1240, 6, 6, 866-870, 2017.06, Pancreatic acinar cell carcinoma (PACC) is a rare tumor of the exocrine pancreas, representing only 1% of all pancreatic malignancies. A 50-year-old man presented with edema of the thumb joints bilaterally, followed by an appearance of masses in the bilateral lower extremities and fever (38°C). The masses were diagnosed as panniculitis by skin biopsy, and multiple intraperitoneal masses were incidentally detected on pelvic magnetic resonance imaging performed to investigate the leg abnormalities. The patient was referred to the Kyushu University Hospital for further investigation, and fluorodeoxyglucose-positron emission tomography/computed tomography (CT) revealed high-uptake tumors in the pancreatic tail, in the periphery of the liver, and in the pelvis. Laboratory examinations revealed high serum concentrations of pancreatic exocrine enzymes, such as lipase, trypsin, elastase 1 and pancreatic phospholipase A2. Histological examination of a bioptic specimen obtained from a hepatic lesion revealed proliferation of atypical cells arranged in a tubular or glandular pattern. Immunohistochemical staining revealed that the atypical cells were positive for cytokeratin (CK)7, CK19 and lipase, but negative for CK20 and thyroid transcription factor-1, leading to a final diagnosis of acinar cell carcinoma of the pancreatic tail (T4bN0M1, stage IV according to the 7th edition of the TNM Classification of Malignant Tumors). Combined chemotherapy with oxaliplatin, irinotecan and fluorouracil (FOLFIRINOX) was administered and fever was soon alleviated. The serum levels of lipase also declined and panniculitis completely resolved. As of the start of the 8th course of chemotherapy, the levels of the pancreatic exocrine enzymes were within normal ranges and CT revealed partial response. Therefore, the severe lipase hypersecretion syndrome was well controlled by the FOLFIRINOX regimen and shrinkage of the mass was also achieved. Thus, the FOLFIRINOX regimen may represent an effective treatment option for advanced PACC.. |
| 27. | Hirofumi Ohmura, Kyoko Yamaguchi, Fumiyasu Hanamura, Mamoru Ito, Akitaka Makiyama, Keita Uchino, Hozumi Shimokawa, Taito Esaki, Kenji Mitsugi, Yoshihiro Shibata, Hisanobu Oda, Kenji Tsuchihashi, Hiroshi Ariyama, Hitoshi Kusaba, Koichi Akashi, Eishi Baba, Activation of central/effector memory T cells in advanced gastric cancer patients treated with antiprogrammed death-1 antibody., Journal of Clinical Oncology, 10.1200/jco.2019.37.4_suppl.54, 37, 4_suppl, 54-54, 2019.02, 54 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances antitumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 (PD-L1) and has shown efficacy for advanced gastric cancer (AGC) in the salvage line. However, specific subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood mononuclear cells of 20 AGC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). The proportion of immune cell subsets were systematically analyzed by flow cytometry, including the expression of costimulatory and coinhibitory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T cell antigen-4 (CTLA-4), CD28, OX40, and inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were analyzed. Results: Median progression free survival (PFS) of the whole patients was 51 days (95% CI 35–83). After a single course of nivolumab, patients showed a significant increase in activated effector memory and activated effector subsets of CD4+/CD8+ T cells (p = 0.018, 0.018, 0.032, 0.024). At the time of PD, proportions of myeloid dendritic cell, IgM memory B cell and Tfh-Th1/17 cell subsets decreased (p = 0.024, 0.013, 0.0039). On the other hand, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells increased at the time of PD (p = 0.013, 0.032, 0.042, 0.042). Significant positive correlations were found between PFS and the proportion of LAG3 positive CD4+/CD8+ T cells (p = 0.0056, 0.0054), OX 40 positive CD4+/CD8+ T cells (p = 0.0034, 0.0006) prior to the initial nivolumab therapy. Conclusions: Nivolumab therapy enhances activation of effector memory and effector subsets of CD4+/CD8+ T cells. The expression level of LAG3 and OX40 on T cells might be correlated with efficacy of nivolumab therapy.. |
| 28. | 有山 寛, 山口 享子, 吉弘 知恭, 大村 洋文, 有水 耕平, 山家 覚, 赤司 浩一, 馬場 英司, 微小管阻害薬に関するバイオマーカーの同定, 日本癌学会総会記事, 79回, OJ18-3, 2020.10. |
| 29. | 中野 倫孝, 菊繁 吉謙, 宮脇 恒太, 水野 晋一, 鶴田 展大, 花村 文康, 山口 享子, 山内 拓司, 磯部 大地, 有山 寛, 草場 仁志, 中村 雅史, 前田 高宏, 馬場 英司, 赤司 浩一, がん幹細胞の根源を探る RHAMM陽性大腸癌がん幹細胞分画の同定, 日本癌学会総会記事, 79回, S1-6, 2020.10. |
| 30. | T. Yoshino, G. Pentheroudakis, S. Mishima, M.J. Overman, K.-H. Yeh, E. Baba, Y. Naito, F. Calvo, A. Saxena, L.-T. Chen, M. Takeda, A. Cervantes, H. Taniguchi, K. Yoshida, Y. Kodera, Y. Kitagawa, J. Tabernero, H. Burris, J.-Y. Douillard, JSCO—ESMO—ASCO—JSMO—TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions, Annals of Oncology, 10.1016/j.annonc.2020.03.299, 31, 7, 861-872, 2020.07. |
| 31. | 吉弘 知恭, 有山 寛, 磯部 大地, 赤司 浩一, 馬場 英司, IGF1受容体シグナル阻害は大腸癌細胞株においてエリブリンによるDNA損傷を増強する, 日本癌学会総会記事, 79回, PJ14-1, 2020.10. |
| 32. | 倉田 加奈子, 久保 真, 永井 俊太郎, 藤田 逸人, 土橋 賢司, 有山 寛, 永吉 絹子, 貞苅 良彦, 川地 眸, 甲斐 昌也, 伊東 守, 山元 英崇, 小田 義直, 馬場 英司, 中村 雅史, FoundationOne CDxによる進行大腸癌患者の遺伝子変異解析, 日本外科学会定期学術集会抄録集, 120回, SF-5, 2020.08. |
| 33. | Kenta Nio, Kenji Tsuchihashi, Keisuke Taguchi, Tomoyasu Yoshihiro, Kyoko Yamaguchi, Mamoru Ito, Shohei Moriyama, Mitsuhiro Fukata, Toshifumi Fujiwara, Nokitaka Setsu, Makoto Endo, Yoshihiro Matsumoto, Yasuharu Nakashima, Takahiro Wakasaki, Ryuji Yasumatsu, Hiroshi Ariyama, Hitoshi Kusaba, Junji Kishimoto, Koichi Akashi, Eishi Baba, Exploratory retrospective study of risk factors for thromboembolism treated with multi-kinase inhibitor pazopanib or lenvatinib, INTERNATIONAL JOURNAL OF SURGERY-ONCOLOGY, 10.1097/IJ9.0000000000000089, 5, 4, 2020.08, Tyrosine kinase inhibitors (TKI) work against various types of cancer by inhibiting angiogenic signaling. Little is understood about the incidence, characteristics, and risk factors associated with thromboembolism induced by TKI in routine clinical practice. We retrospectively analyzed data derived from 29 patients with thyroid cancer or soft tissue sarcoma (STS) treated with lenvatinib (n=10) and pazopanib (n=19). Eight (arterial n=4; venous n=4) thromboembolic events developed in 6 (20%) patients. Thromboembolisms occurred during a mean of 149 (range, 42-847) days from starting TKI. The primary disease progressed in all patients with thromboembolism. The overall survival durations of patients with and without improved thromboembolism were 572 [95% confidence interval (CI), 225- 918] and 176 (95% CI, 84-394) days, respectively, which did not significantly differ (P=0.33). Patients with and without improved thromboembolism survived after onset for 122 (95% CI, 71-173) versus 27 (95% CI, 21-42) days (P=0.049), which significantly differed. Univariate analysis and variate selection for multivariate analysis selected a history of thromboembolism as the most powerful risk factor for new thromboembolism. In summary, the frequency of thromboembolism in clinical practice was higher than that in previous clinical trials. Furthermore, a history of thromboembolism was a risk factor for the development of new thromboembolism in patients treated with TKI. Thromboembolism developed particularly as the primary disease progressed. Our findings require validation in a large-scale study.. |
| 34. | Hirofumi Ohmura, Kyoko Yamaguchi, Fumiyasu Hanamura, Tanoue Kenrou, Shiho Kawagoe, Kohei Arimizu, Yuzo Matsushita, Tatsuhiro Kajitani, Shingo Tamura, Hozumi Shimokawa, Keita Uchino, Hisanobu Oda, Yudai Shinohara, Mamoru Ito, Kenji Tsuchihashi, Taichi Isobe, Hiroshi Ariyama, Hitoshi Kusaba, Koichi Akashi, Eishi Baba, Activation of memory/effector T cells and association between prognosis and OX40-positive T cells in advanced head and neck cancer patients treated with anti-programmed death-1 antibody., Journal of Clinical Oncology, 10.1200/jco.2020.38.5_suppl.35, 38, 5_suppl, 35-35, 2020.02, 35 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances anti-tumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 and has shown efficacy for platinum-refractory recurrent or advanced head and neck cancer (HNC). However, subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for HNC and specifically associated with the prognosis have not been clarified. Methods: Peripheral blood mononuclear cells of 15 HNC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). We performed comprehensive analysis of the proportion of immune cell subsets by flow cytometry, including the expression of coinhibitory and costimulatory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), B and T lymphocyte attenuator (BTLA), CD28, OX40, inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were also analyzed. Results: Median progression free survival (PFS) of the whole patients was 96 days (95% CI 70–308). After a single course of nivolumab, patients showed a significant increase in activated central memory and effector subsets of CD4+/CD8+ T cells and activated helper T1 cells (p = 0.0039, 0.0078, 0.0273, 0.0391, 0.0391). A trend of increase of activated effector memory CD4+/CD8+ T cell was observed (p = 0.4961, 0.3594). At the time of PD, effector regulatory T cells, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells and BTLA positive CD4+/CD8+ T cells significantly increased. Significant positive correlations were found between PFS and the proportion of OX40 positive CD4+/CD8+ T cells before nivolumab therapy (p = 0.0239, 0.0134). Conclusions: Nivolumab therapy enhances activation of central memory and effector subsets of CD4+/CD8+ T cells. The expression level of OX40 on T cells was correlated with efficacy of nivolumab therapy in HNC patients.. |
| 35. | Fumiaki Jinnouchi, Takuji Yamauchi, Ayano Yurino, Takuya Nunomura, Michitaka Nakano, Chika Iwamoto, Teppei Obara, Kohta Miyawaki, Yoshikane Kikushige, Koji Kato, Takahiro Maeda, Toshihiro Miyamoto, Eishi Baba, Koichi Akashi, Katsuto Takenaka, A human SIRPA knock-in xenograft mouse model to study human hematopoietic and cancer stem cells, Blood, 10.1182/blood.2019002194, 135, 19, 1661-1672, 2020.05, In human-to-mouse xenogeneic transplantation, polymorphisms of signal-regulatory protein α (SIRPA) that decide their binding affinity for human CD47 are critical for engraftment efficiency of human cells. In this study, we generated a new C57BL/6.Rag2nullIl2rgnull (BRG) mouse line with Sirpahuman/human (BRGShuman) mice, in which mouse Sirpa was replaced by human SIRPA encompassing all 8 exons. Macrophages from C57BL/6 mice harboring Sirpahuman/human had a significantly stronger affinity for human CD47 than those harboring SirpaNOD/NOD and did not show detectable phagocytosis against human hematopoietic stem cells. In turn, Sirpahuman/human macrophages had a moderate affinity for mouse CD47, and BRGShuman mice did not exhibit the blood cytopenia that was seen in Sirpa−/− mice. In human to mouse xenograft experiments, BRGShuman mice showed significantly greater engraftment and maintenance of human hematopoiesis with a high level of myeloid reconstitution, as well as improved reconstitution in peripheral tissues, compared with BRG mice harboring SirpaNOD/NOD (BRGSNOD). BRGShuman mice also showed significantly enhanced engraftment and growth of acute myeloid leukemia and subcutaneously transplanted human colon cancer cells compared with BRGSNOD mice. BRGShuman mice should be a useful basic line for establishing a more authentic xenotransplantation model to study normal and malignant human stem cells.. |
| 36. | Mamoru Ito, Eishi Baba, [Development of Cancer Genomic Medicine in Kyushu Region and the Roles of Kyushu University Hospital as a Core Hospital for Cancer Genomic Medicine]., Gan to kagaku ryoho. Cancer & chemotherapy, 48, 7, 873-877, 2021.07, Kyushu University Hospital has been designated as a Core Hospital for Cancer Genomic Medicine since February 2018. Our institution promotes cancer genomic medicine collaborating with 10 Cooperative Hospitals for Cancer Genomic Medicine among Kyushu region. Over 500 solid tumor cases have been examined by cancer genomic profiling tests and the results have been intensively evaluated and discussed in the expert panel meetings. To expand cancer genomic medicine for Kyushu region, we have started a consultation desk for the cancer patients in the local community and began educating programs as cancer genomic medicine seminars for the medical staff of Cooperative Hospitals for Cancer Genomic Medicine. A consultation system has been established to discuss the indication of"Patient requested medical care system". Kyushu University Hospital is now focusing on rare cancer care and medical genetics. Thus close cooperation with cancer genomic medicine and each department has been started. We would like to look back on current progress and issues of cancer genomic medicine in Kyushu University Hospital.. |
| 37. | Kenro Tanoue, Shingo Tamura, Hitoshi Kusaba, Yudai Shinohara, Mamoru Ito, Kenji Tsuchihashi, Tsuyoshi Shirakawa, Taiga Otsuka, Hirofumi Ohmura, Taichi Isobe, Hiroshi Ariyama, Sakuya Koreishi, Yuzo Matsushita, Hozumi Shimokawa, Risa Tanaka, Kenji Mitsugi, Koichi Akashi, Eishi Baba, Predictive impact of C-reactive protein to albumin ratio for recurrent or metastatic head and neck squamous cell carcinoma receiving nivolumab., Scientific reports, 10.1038/s41598-021-82448-1, 11, 1, 2741-2741, 2021.02, Although the neutrophil to lymphocyte ratio (NLR) was reported to be a predictive biomarker for clinical outcomes in various types of cancer, including recurrent or metastatic head and neck cancer (R/M HNSCC) treated with nivolumab, the usefulness of the pretreatment C-reactive protein/albumin ratio (CAR) as a prognostic marker remains to be clarified. This study aimed to analyze the clinical usability of the CAR in comparison with that of the NLR. 46 R/M HNSCC patients treated with nivolumab were retrospectively analyzed. The optimal cutoff value for the CAR was calculated using receiver operating characteristic curve analysis. The optimal cutoff value for the CAR was set to 0.30. On multivariate analyses, a high CAR was significantly associated with poor overall survival (adjusted HR, 2.19; 95% CI, 1.42-3.47; p |
| 38. | Shohei Ueno, Masato Uenomachi, Hitoshi Kusaba, Mamoru Ito, Kunihiro Suzuki, Hirofumi Ohmura, Kenji Tsuchihashi, Hiroshi Ariyama, Koichi Akashi, Eishi Baba, Improvement in recurring nivolumab-induced pneumonitis with repetitive administration of infliximab in a patient with head and neck cancer: A case report., Molecular and clinical oncology, 10.3892/mco.2021.2379, 15, 4, 221-221, 2021.10, Severe pneumonitis induced by nivolumab, an anti-programmed cell death-1 monoclonal antibody, is a rare but potentially fatal immune-related adverse event. In cases of steroid-refractory pneumonitis, an appropriate therapeutic strategy using anti-tumor necrosis factor-α (TNF-α) antibody has not been established. A 59-year-old female was diagnosed with hypopharyngeal squamous cell carcinoma. Previous therapies including chemoradiotherapy and throat laryngectomy were performed, but metastatic recurrence appeared in the intrapulmonary and mediastinal lymph nodes. The patient was administered nivolumab. On the 14th day of nivolumab administration, the patient experienced dyspnea and computed tomography of the chest showed multiple consolidations in the right lung. She was diagnosed with nivolumab-induced pneumonitis. Because the pneumonitis was refractory to steroid therapy, she was administered infliximab, and the pneumonitis improved. On the 72nd and 101st days of nivolumab administration, nivolumab-induced pneumonitis re-appeared with an elevated serum TNF-α concentration. In each occurrence of pneumonitis, repetitive administration of infliximab improved the pneumonitis. Repetitive administration of infliximab may be effective for treating recurrent nivolumab-induced pneumonitis that is associated with an increased serum TNF-α concentration.. |
| 39. | 吉弘 知恭, 有山 寛, 土橋 賢司, 磯部 大地, 赤司 浩一, 馬場 英司, IGF1受容体の核内移行は大腸癌細胞株においてエリブリン抵抗性を付与する, 日本癌学会総会記事, 80回, [P14-6], 2021.09. |
| 40. | Eijiro Shimada, Makoto Endo, Yoshihiro Matsumoto, Kenji Tsuchihashi, Mamoru Ito, Hitoshi Kusaba, Akira Nabeshima, Tomoya Nawata, Akira Maekawa, Tomoya Matsunobu, Nokitaka Setsu, Toshifumi Fujiwara, Keiichiro Iida, Makoto Nakagawa, Takeshi Hirose, Masaya Kanahori, Ryunosuke Oyama, Taichi Isobe, Hiroshi Ariyama, Kenichi Kohashi, Hidetaka Yamamoto, Yoshinao Oda, Yukihide Iwamoto, Koichi Akashi, Eishi Baba, Yasuharu Nakashima, Does the Use of Peripheral Immune-Related Markers Indicate Whether to Administer Pazopanib, Trabectedin, or Eribulin to Advanced Soft Tissue Sarcoma Patients?, Journal of clinical medicine, 10.3390/jcm10214972, 10, 21, 2021.10, Pazopanib, trabectedin, and eribulin are administered for the treatment of soft tissue sarcomas (STSs); however, there is little consensus on which agent should be preferentially used in a clinical setting. This study assessed whether peripheral immune-related markers served as a useful reference when selecting pazopanib, trabectedin, or eribulin. This study included 63 patients who were administered pazopanib, trabectedin, or eribulin for advanced STSs between March 2015 and December 2020. Patients were divided into three groups based on the first drug administered among these three drugs. Differences in overall survival (OS) or progression-free survival (PFS) among the three groups were analyzed. OS showed no significant differences among the drugs administered first. For patients with low neutrophil-to-lymphocyte ratio (NLR), the OS of patients administered pazopanib as the first choice was shorter than the others (hazard ratio [HR] = 9.53, 95% confidence interval [CI] = 1.94-18.13, p = 0.0018). In the low platelet-to-lymphocyte ratio (PLR) subgroup, the OS of the patients administered eribulin for the first choice was longer than that of the others (HR = 0.32, 95%CI = 0.10-0.98, p = 0.046). Therefore, NLR and PLR might be used as prognostic indicators to dictate whether STS patients receive pazopanib, trabectedin, or eribulin.. |
| 41. | Kohei Shitara, Eishi Baba, Kazumasa Fujitani, Eiji Oki, Satoshi Fujii, Kensei Yamaguchi, Discovery and development of trastuzumab deruxtecan and safety management for patients with HER2-positive gastric cancer., Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 10.1007/s10120-021-01196-3, 24, 4, 780-789, 2021.07, Approximately 12-15% of gastric cancers (GCs) are human epidermal growth factor receptor-2 (HER2)-positive (HER2 immunohistochemistry 3 + or 2 + /in situ hybridization + [ERBB2/CEP17 ≥ 2.0]). While the anti-HER2 monoclonal antibody trastuzumab, in combination with chemotherapy, is the standard treatment for HER2-positive GC, other HER2-targeted therapies have not demonstrated survival benefits in patients with GC, despite showing efficacy in patients with HER2-positive breast cancer. This indicates that there are unique challenges to the use of currently available HER2-targeted therapies for the treatment of HER2-positive GC. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 human monoclonal IgG1 antibody with the same amino acid sequence as trastuzumab, an enzymatically cleavable peptide-based linker, and DXd, a novel topoisomerase I inhibitor, as its released payload. T-DXd has a high drug-antibody ratio (approximately 8) and a demonstrated bystander antitumor effect. It has demonstrated significant efficacy when compared with standard therapies and is approved as third- or later-line treatment for HER2-positive GC in Japan and second- or later-line treatment in the US. T-DXd treatment is associated with gastrointestinal and hematological adverse events, and a risk of interstitial lung disease (ILD), with the ILD risk being higher in Japan than in countries other than Japan. However, most adverse events, including ILD, can be managed with proactive monitoring and T-DXd dose modification, and initiation of adequate treatment. In this review, we summarize the discovery and development of T-DXd and provide guidance for T-DXd safety management, including ILD monitoring, for patients with HER2-positive GC.. |
| 42. | 土橋 賢司, 平田 雄紀, 山崎 淳太郎, 推名 健太郎, 田ノ上 絢郎, 八戸 敏文, 増田 健太, 馬場 英司, 赤司 浩一, 北川 雄光, 佐谷 秀行, 永野 修, 食道癌における自然な上皮間葉転換可塑性の存在とその意義(Presence and its role of spontaneous epithelial-mesenchymal plasticity in esophageal cancer), 日本癌学会総会記事, 81回, E-2042, 2022.09. |
| 43. | 遠藤 誠, 松本 嘉寛, 土橋 賢司, 馬場 英司, 中島 康晴, 悪性軟部腫瘍の希少性と多様性に対して、われわれはどう対峙すべきか 多職種連携の重要性と地域希少がんセンターに求められる役割, 日本整形外科学会雑誌, 96, 6, S1295-S1295, 2022.06. |
| 44. | 遠藤 誠, 土橋 賢司, 松本 嘉寛, 坂本 節子, 鍋島 央, 飯田 圭一郎, 藤原 稔史, 伊東 守, 磯部 大地, 有山 寛, 赤司 浩一, 馬場 英司, 中島 康晴, 希少がんの治療戦略 信頼と絆に基づく肉腫のチーム医療, 日本癌治療学会学術集会抄録集, 60回, WS15-3, 2022.10. |
| 45. | 大村 洋文, 有山 寛, 馬場 英司, 【外来で行う消化器がん薬物療法のコツ-専門医からのアドバイス】がん診療におけるがん薬物療法の位置づけ 胃がん, 臨床消化器内科, 37, 11, 1404-1409, 2022.09, ＜文献概要＞胃がんは,わが国で罹患率,死亡者数ともに高い悪性腫瘍の一つである.胃がんに対するがん薬物療法は,治癒切除例における再発予防目的および切除不能・再発症例に対する延命・症状緩和目的で選択される.近年薬物療法の開発が進み,pStage III症例に対する術後補助化学療法としてS-1+ドセタキセル(DTX)併用療法の有効性が示された.また切除不能・再発症例の一次治療でニボルマブが化学療法との併用でup-frontに使用されるようになり,またHER2陽性例に対するトラスツズマブ・デルクステカンなど,三次治療においても延命効果が期待される薬剤が開発されている.胃がんにおける薬物療法について解説していく.. |
| 46. | 磯部 大地, 馬場 英司, 【がんに対する新しい治療法と未来型医療】新しいがん治療法 抗体薬物複合体(ADC), 腫瘍内科, 29, 5, 535-543, 2022.05. |
| 47. | Kenji Tsuchihashi, Yuki Hirata, Juntaro Yamasaki, Kentaro Suina, Kenro Tanoue, Toshifumi Yae, Kenta Masuda, Eishi Baba, Koichi Akashi, Yuko Kitagawa, Hideyuki Saya, Osamu Nagano, Presence of spontaneous epithelial-mesenchymal plasticity in esophageal cancer., Biochemistry and biophysics reports, 10.1016/j.bbrep.2022.101246, 30, 101246-101246, 2022.07, Epithelial-mesenchymal plasticity (EMP) refers to the reversible cellular transition between epithelial and mesenchymal status. Spontaneous EMP is also reported in breast and prostate cancer, leading to the acquisition of stem-cell properties and chemoresistance. However, the presence of spontaneous EMP is still not reported in esophageal cancer. We screened 11 esophageal squamous cancer cell (ESCC) cell lines by CD44 isoform expression. KYSE520 was found to comprise heterogenous populations consisting of CD44v+ and CD44v- subpopulations. CD44v+ and CD44v- cells showed the expression of epithelial and mesenchymal markers, respectively. Single-cell sorting of CD44v+ and CD44v- cells revealed both cells gave rise to cell populations consisting of CD44v+ and CD44v- cells, indicating CD44v+ epithelial-like and CD44v- mesenchymal-like cells can generate counterparts, respectively. The ablation of Epithelial splicing regulatory protein 1 (ESRP1), a major regulator of CD44 mRNA splicing, resulted in the shift from CD44v+ to CD44v- cells in KYSE520. However, the expression of epithelial-mesenchymal transition (EMT)-related markers or transcriptional factors were almost not affected, suggesting ESRP1 functions downstream of EMP. Our results revealed the presence of spontaneous EMP in esophageal cancer and KYSE520 is useful model to understand spontaneous EMP.. |
| 48. | Kyoko Yamaguchi, Tomoyasu Yoshihiro, Hiroshi Ariyama, Mamoru Ito, Michitaka Nakano, Yuichiro Semba, Jumpei Nogami, Kenji Tsuchihashi, Takuji Yamauchi, Shohei Ueno, Taichi Isobe, Koji Shindo, Taiki Moriyama, Kenoki Ohuchida, Masafumi Nakamura, Yoshihiro Nagao, Tetsuo Ikeda, Makoto Hashizume, Hiroyuki Konomi, Takehiro Torisu, Takanari Kitazono, Tomohiro Kanayama, Hiroyuki Tomita, Yoshinao Oda, Hitoshi Kusaba, Takahiro Maeda, Koichi Akashi, Eishi Baba, Potential therapeutic targets discovery by transcriptome analysis of an in vitro human gastric signet ring carcinoma model., Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 10.1007/s10120-022-01307-8, 25, 5, 862-878, 2022.06, BACKGROUND: Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. METHODS: To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). RESULTS: CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. CONCLUSIONS: E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.. |
| 49. | Mamoru Ito, Michitaka Nakano, Hiroshi Ariyama, Kyoko Yamaguchi, Risa Tanaka, Yuichiro Semba, Takeshi Sugio, Kohta Miyawaki, Yoshikane Kikushige, Shinichi Mizuno, Taichi Isobe, Kenro Tanoue, Ryosuke Taguchi, Shohei Ueno, Takahito Kawano, Masaharu Murata, Eishi Baba, Koichi Akashi, Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions., Cancer letters, 10.1016/j.canlet.2022.215597, 532, 215597-215597, 2022.04, Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45+CD14+ CAMs transdifferentiated into CD45-CD90+ fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45-CD90+ fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFβ signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFβ and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.. |
| 50. | Akiko Tozawa, Fuminori Kimura, Yasushi Takai, Takeshi Nakajima, Kimio Ushijima, Hiroaki Kobayashi, Toyomi Satoh, Miyuki Harada, Kohei Sugimoto, Shigehira Saji, Chikako Shimizu, Kyoko Akiyama, Hiroko Bando, Akira Kuwahara, Tatsuro Furui, Hiroshi Okada, Koji Kawai, Nobuo Shinohara, Koichi Nagao, Michio Kitajima, Souichi Suenobu, Toshinori Soejima, Mitsuru Miyachi, Yoko Miyoshi, Akihiro Yoneda, Akihito Horie, Yasushi Ishida, Noriko Usui, Yoshinobu Kanda, Nobuharu Fujii, Makoto Endo, Robert Nakayama, Manabu Hoshi, Tsukasa Yonemoto, Chikako Kiyotani, Natsuko Okita, Eishi Baba, Manabu Muto, Iwaho Kikuchi, Ken-Ichirou Morishige, Koichiro Tsugawa, Hiroyuki Nishiyama, Hajime Hosoi, Mitsune Tanimoto, Akira Kawai, Kazuhiko Sugiyama, Narikazu Boku, Masato Yonemura, Naoko Hayashi, Daisuke Aoki, Nao Suzuki, Yutaka Osuga, Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2., International journal of clinical oncology, 10.1007/s10147-021-02076-7, 27, 2, 281-300, 2022.02, The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer.. |
| 51. | Miyuki Harada, Fuminori Kimura, Yasushi Takai, Takeshi Nakajima, Kimio Ushijima, Hiroaki Kobayashi, Toyomi Satoh, Akiko Tozawa, Kohei Sugimoto, Shigehira Saji, Chikako Shimizu, Kyoko Akiyama, Hiroko Bando, Akira Kuwahara, Tatsuro Furui, Hiroshi Okada, Koji Kawai, Nobuo Shinohara, Koichi Nagao, Michio Kitajima, Souichi Suenobu, Toshinori Soejima, Mitsuru Miyachi, Yoko Miyoshi, Akihiro Yoneda, Akihito Horie, Yasushi Ishida, Noriko Usui, Yoshinobu Kanda, Nobuharu Fujii, Makoto Endo, Robert Nakayama, Manabu Hoshi, Tsukasa Yonemoto, Chikako Kiyotani, Natsuko Okita, Eishi Baba, Manabu Muto, Iwaho Kikuchi, Ken-Ichirou Morishige, Koichiro Tsugawa, Hiroyuki Nishiyama, Hajime Hosoi, Mitsune Tanimoto, Akira Kawai, Kazuhiko Sugiyama, Narikazu Boku, Masato Yonemura, Naoko Hayashi, Daisuke Aoki, Yutaka Osuga, Nao Suzuki, Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 1., International journal of clinical oncology, 10.1007/s10147-021-02081-w, 27, 2, 265-280, 2022.02, In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).. |
| 52. | Tomoyasu Yoshihiro, Hiroshi Ariyama, Kyoko Yamaguchi, Takashi Imajima, Satoru Yamaga, Kenji Tsuchihashi, Taichi Isobe, Hitoshi Kusaba, Koichi Akashi, Eishi Baba, Inhibition of insulin-like growth factor-1 receptor enhances eribulin-induced DNA damage in colorectal cancer., Cancer science, 10.1111/cas.15558, 113, 12, 4207-4218, 2022.09, Microtubule targeting agents (MTAs) such as taxanes are broadly used for the treatment of patients with cancer. Although MTAs are not effective for treatment of colorectal cancer (CRC), preclinical studies suggest that a subset of patients with CRC, especially those with cancers harboring the BRAF mutation, could benefit from such agents. However, two MTAs, eribulin (Eri) and vinorelbine, have shown limited clinical efficacy. Here, we report that insulin-like growth factor 1 receptor (IGF-1R) signaling is involved in Eri resistance. Using CRC cell lines, we showed that Eri induces activation and subsequent translocation of IGF-1R to the nucleus. When the activation and/or nuclear translocation of IGF-1R was inhibited, Eri induced DNA damage and enhanced G2 /M arrest. In a xenograft model using the Eri-resistant SW480 cell line, the combination of Eri and the IGF-1R inhibitor linsitinib suppressed tumor growth more efficiently than either single agent. Thus, our results indicated that combination dosing with Eri and an IGF-1R inhibitor could overcome Eri resistance and offer a therapeutic opportunity in CRC.. |
| 53. | Hitoshi Kusaba, Shohei Moriyama, Michinari Hieda, Mamoru Ito, Hirofumi Ohmura, Taichi Isobe, Kenji Tsuchihashi, Mitsuhiro Fukata, Hiroshi Ariyama, Eishi Baba, IMPROVE bleeding score predicts major bleeding in advanced gastrointestinal cancer patients with venous thromboembolism., Japanese journal of clinical oncology, 10.1093/jjco/hyac103, 52, 10, 1183-1190, 2022.10, BACKGROUND: The incidence of venous thromboembolism has been reported as 20% in cancer patients. Anticoagulation therapy is the standard treatment for venous thromboembolism. On the other hand, bleeding should be carefully managed, because advanced cancer, particularly gastrointestinal cancer, carries a high risk of bleeding. However, the optimal management for cancer-associated thromboembolism remains to be clarified. METHODS: We retrospectively examined patients with advanced gastrointestinal cancer, including gastric cancer and colorectal cancer, who were treated with chemotherapy between 2014 and 2018 for the incidence and characteristics of venous thromboembolism and bleeding. RESULTS: In total, 194 patients (120 men, 74 women) were enrolled in this study. The underlying pathology was gastric cancer in 74 cases and colorectal cancer in 120 cases. Of the 194 patients, 40 patients (20.6%) were diagnosed with venous thromboembolism and 10 patients (5.2%) were diagnosed with concomitant pulmonary thromboembolism. Conversely, bleeding was observed in 29 patients (15%). The location of bleeding was the primary tumor in 17 cases, metastatic tumor in 9 and hemorrhagic gastric ulcer in 3. Within the venous thromboembolism group (n = 40), bleeding was observed in 10 patients (25%). Multivariate analysis showed that International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding score ≥7 correlated significantly with major bleeding (P = 0.01). In patients with a low risk of bleeding, major bleeding was observed in only three patients. CONCLUSIONS: IMPROVE bleeding score may predict the risk for bleeding in gastrointestinal cancer patients with venous thromboembolism. Selecting patients with a low risk of bleeding using with IMPROVE bleeding score is expected to contribute to the safer management of anticoagulation therapy for cancer-associated thromboembolism.. |
| 54. | Michio Nakamura, Taro Funakoshi, Shigeki Kataoka, Takahiro Horimatsu, Yoshitaka Nishikawa, Takeshi Matsubara, Takuro Mizukami, Tomoyuki Goto, Kenji Tsuchihashi, Eishi Baba, Takehiko Tsumura, Yoshiaki Mihara, Tetsuya Hamaguchi, Motoko Yanagita, Manabu Muto, Decision making for anti-VEGF inhibitor continuation: dip stick? or urine protein/creatinine ratio? (VERSiON UP study)., BMC cancer, 10.1186/s12885-022-09611-3, 22, 1, 515-515, 2022.05, BACKGROUND: Monitoring proteinuria is important for the management of patients with cancer treated with anti-vascular endothelial growth factor (VEGF) or anti-VEGF receptor (VEGFR) inhibitors (VEGF/Ri). Here we investigated the difference between the urine protein/creatinine ratio (UPCR) and a qualitative value test (QV) on the decision making of treatment continuation and the usefulness of UPCR testing in patients with gastrointestinal cancer treated with anti-VEGF/Ri. METHODS: From January 2017 to December 2018, a survey was conducted based on the medical records of patients with gastrointestinal cancer with a QV of ≥2+ during the use of anti-VEGF/Ri at seven Japanese institutions participating in the Onco-nephrology Consortium. The primary endpoint was the ratio of the worst UPCR |
| 55. | Akiko Tozawa, Fuminori Kimura, Yasushi Takai, Takeshi Nakajima, Kimio Ushijima, Hiroaki Kobayashi, Toyomi Satoh, Miyuki Harada, Kohei Sugimoto, Shigehira Saji, Chikako Shimizu, Kyoko Akiyama, Hiroko Bando, Akira Kuwahara, Tatsuro Furui, Hiroshi Okada, Koji Kawai, Nobuo Shinohara, Koichi Nagao, Michio Kitajima, Souichi Suenobu, Toshinori Soejima, Mitsuru Miyachi, Yoko Miyoshi, Akihiro Yoneda, Akihito Horie, Yasushi Ishida, Noriko Usui, Yoshinobu Kanda, Nobuharu Fujii, Makoto Endo, Robert Nakayama, Manabu Hoshi, Tsukasa Yonemoto, Chikako Kiyotani, Natsuko Okita, Eishi Baba, Manabu Muto, Iwaho Kikuchi, Ken-Ichirou Morishige, Koichiro Tsugawa, Hiroyuki Nishiyama, Hajime Hosoi, Mitsune Tanimoto, Akira Kawai, Kazuhiko Sugiyama, Narikazu Boku, Masato Yonemura, Naoko Hayashi, Daisuke Aoki, Nao Suzuki, Yutaka Osuga, Correction to: Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2., International journal of clinical oncology, 10.1007/s10147-022-02137-5, 27, 3, 635-637, 2022.03. |
| 56. | Kazuo Nishikawa, Shuichi Hironaka, Takashi Inagaki, Azusa Komori, Satoshi Otsu, Kenji Mitsugi, Akitaka Makiyama, Koichiro Watanabe, Shingo Tamura, Yuta Okumura, Hitoshi Kusaba, Taito Esaki, Eishi Baba, Kuniaki Shirao, A multicentre retrospective study comparing site-specific treatment with empiric treatment for unfavourable subset of cancer of unknown primary site, Japanese Journal of Clinical Oncology, 10.1093/jjco/hyac143, 52, 12, 1416-1422, 2022.09, Abstract Background Patients with cancer of unknown primary site are divided into two distinct groups, favourable and unfavourable subsets. For the unfavourable subset, empiric treatment or site-specific treatment is recommended, but limited knowledge exists about the efficacy of site-specific treatment compared with empiric treatment in clinical practice. Methods In this multicentre retrospective study, we reviewed the medical records of patients with cancer of unknown primary site treated with chemotherapy (or chemoradiotherapy) as first-line treatment from eight institutions during 2006–18. We investigated the workup modality and categorized the patients into favourable and unfavourable subsets, which were further divided into site-specific and empiric treatment groups. Site-specific treatment is defined as a standard chemotherapy for an estimated primary site. We examined the efficacy in the favourable and unfavourable subsets and performed multivariable analysis for estimating the overall survival in the unfavourable subset. Results Of 177 patients with cancer of unknown primary site, 33 and 144 were categorized into favourable and unfavourable subsets, respectively. In the unfavourable subset, 84 patients (58.3%) received empiric therapy, and 60 patients (41.7%) received site-specific treatment. Median overall survival was 10.0 and 10.1 months in site-specific and empiric treatment groups, respectively, with no significant difference (hazard ratio 1.01, 95% confidence interval 0.70–1.45, P = 0.95). Multivariable analysis revealed performance status, number of metastatic sites and hypoalbuminaemia as independent prognostic factors for overall survival in the unfavourable subset. Conclusions Overall survival in site-specific and empiric treatment groups was similar in the unfavourable cancer of unknown primary site subset in this study. Further research is needed to prolong overall survival in patients in the unfavourable cancer of unknown primary site subset.. |
| 57. | Michitaka Nakano, Taguchi R, Kikushige Y, Taichi Isobe, Kohta Miyawaki, Mizuno S, Tsuruta N, Hanamura F, Yamaguchi K, Yamauchi T, Hiroshi Ariyama, Kusaba H, Nakamura M, Maeda T, Kuo CJ, Eishi Baba, Akashi K, RHAMM marks proliferative subpopulation of human colorectal cancer stem cells., Cancer science, 10.1111/cas.15795, 2023.03, The cancer stem cell (CSC) theory features typically rare self-renewing subpopulation that reconstitute the heterogeneous tumor. Identification of molecules which characterize the feature of CSCs is a key imperative for further understanding of tumor heterogeneity and for the development of novel therapeutic strategies. However, the use of conventional markers of CSCs is still insufficient for the isolation of bona fide CSCs. We investigated organoids which are miniature forms of tumor tissues with reconstructing cellular diversity to identify specific marker to characterize CSCs in heterogeneous tumors. Here, we report that receptor for hyaluronan-mediated motility (RHAMM) expresses in a subpopulation of CD44+ conventional human colorectal CSC fraction. Single-cell transcriptomics of organoids highlighted RHAMM positive proliferative cells that revealed distinct characteristics among the various cell types. Prospectively isolated RHAMM+ CD44+ cells from the human colorectal cancer tissues showed highly proliferative character with self-renewal ability in comparison with the other cancer cells. Furthermore, inhibition of RHAMM strongly suppressed organoids formation in vitro and inhibited the tumor growth in vivo. Our findings suggest that RHAMM is a potential therapeutic target because it is a specific marker of the proliferative subpopulation within the conventional CSC fraction.. |
| 58. | Koki Uehara, Kenro Tanoue, Kyoko Yamaguchi, Hirofumi Ohmura, Mamoru Ito, Yuzo Matsushita, Kenji Tsuchihashi, Shingo Tamura, Hozumi Shimokawa, Taichi Isobe, Yoshihiro Shibata, Hiroshi Ariyama, Risa Tanaka, Hitoshi Kusaba, Hidetaka Yamamoto, Yoshinao Oda, Koichi Akashi, Eishi Baba, Preferential B cell differentiation by combined immune checkpoint blockade for renal cell carcinoma is associated with clinical response and autoimmune reactions., Cancer immunology, immunotherapy : CII, 10.1007/s00262-023-03505-4, 2023.08, Combined immune checkpoint blockade (ICB) is effective therapy for renal cell carcinoma (RCC). However, the dynamic changes in circulating B cells induced by combined ICB have not been clarified. The present study prospectively examined 22 patients scheduled to receive ICB for unresectable or metastatic RCC between March 2018 and August 2021. Eleven patients received combined therapy with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab), and the other 11 patients received nivolumab monotherapy. Comprehensive phenotypes of circulating immune cells obtained prior to and after ICB therapy were analyzed by flow cytometry. Although the proportion of naïve B cells among total B cells was significantly decreased, that of switched memory B cells was significantly increased after combined therapy. In responders, the proportion of B cells among peripheral blood mononuclear cells was significantly higher prior to ICB therapy, and the proportion of switched memory B cells among total B cells tended to increase after ICB therapy. Of note, the proportion of plasmablasts among total B cells was significantly increased after ICB therapy in patients who developed severe immune-related adverse events (irAEs), and the proportion of B cells among peripheral blood decreased significantly. Furthermore, in four of five patients who developed immune-related hypophysitis following combined therapy, anti-pituitary antibody was detected in the serum. These results suggested that immune-related hypophysitis was closely related to the increase in circulating plasmablasts. Collectively, this study suggests that combined ICB promotes the differentiation of B cell populations, which is associated with efficient tumor suppression and development of irAEs.. |
| 59. | Taichi Isobe, Eishi Baba, Shuji Arita, Masato Komoda, Hiroaki Niiro, Gen Hirano, Keita Uchino, Akitaka Makiyama, Yoshihiro Shibata, Hiroshi Ariyama, Hitoshi Kusaba, Koichi Akashi, TSAP6 regulating intracellular iron content maintains tumor cell survival in iron-depleted condition., CANCER RESEARCH, 69, 2009.05. |
| 60. | Michitaka Nakano, Hiroshi Ariyama, Shingo Tamura, Taichi Isobe, Kohta Miyawaki, Yuta Okumura, Hitoshi Kusaba, Eishi Baba, Koichi Akashi, Plasticity of CD44+colorectal cancer stem cells depends on TGF-beta-induced epithelial mesenchymal transition(EMT): Evidences from an ex vivo culture, CANCER RESEARCH, 10.1158/1538-7445.AM2014-1947, 74, 19, 2014.10. |
| 61. | Shingo Tamura, Yuzo Matsushita, Mamoru Tanaka, Hozumi Kumagai, Shuji Arita, Hiroshi Ariyama, Hitoshi Kusaba, Eishi Baba, Koichi Akashi, IFOSFAMIDE AND ETOPOSIDE AS A SALVAGE CHEMOTHERAPY FOR SMALL ROUND CELL SARCOMA, ANNALS OF ONCOLOGY, 10.1093/annonc/mdu435.18, 25, 2014.10. |
| 62. | Eiji Iwama, Koichi Takayama, Taishi Harada, Isamu Okamoto, Eishi Baba, Yoshinao Oda, Yoichi Nakanishi, Highly sensitive and quantitative detection of EGFR T790M mutationin tumor samples by nanofluidic digital PCR, JOURNAL OF CLINICAL ONCOLOGY, 32, 15, 2014.05. |
| 63. | Mamoru Tanaka, Hozumi Kumagai, Junji Kishimoto, Satomi Mukaide, Hisanobu Oda, Kenji Mitsugi, Akitaka Makiyama, Masato Komoda, Hitoshi Kusaba, Eishi Baba, EXPLORATORY ANALYSIS OF A PROGNOSIS PREDICTIVE MODEL FOR METASTATIC COLORECTAL CANCER TREATED WITH CHEMOTHERAPY, ANNALS OF ONCOLOGY, 10.1093/annonc/mdu435.121, 25, 2014.10. |
| 64. | Kenji Tsuchihashi, Osamu Nagano, Toshifumi Yae, Takatsugu Ishimoto, Takeshi Motohara, Momoko Yoshikawa, Go J. Yoshida, Takeyuki Wada, Takashi Masuko, Kaoru Mogushi, Hiroshi Tanaka, Tsuyoshi Osawa, Yasuharu Kanki, Takashi Minami, Hiroyuki Aburatani, Mitsuyo Ohmura, Akiko Kubo, Makoto Suematsu, Kazuhisa Takahashi, Eishi Baba, Koichi Akashi, Hideyuki Saya, ESRP1 regulated alternative splicing of CD44mRNA enhances lung colonization of metastatic cancer cell, CANCER RESEARCH, 10.1158/1538-7445.AM2014-4967, 74, 19, 2014.10. |
| 65. | Kenji Tsuchihashi, Kotoe Takayoshi, Keita Uchino, Tsuyoshi Shirakawa, Hozumi Kumagai, Shingo Tamura, Masato Komoda, Taichi Isobe, Shigeo Takaishi, Hitoshi Kusaba, Shinichi Aishima, Koichi Akashi, Eishi Baba, Systemic chemotherapy for metastatic non-mucinous appendiceal adenocarcinoma: a case report and literature review, International Cancer Conference Journal, 10.1007/s13691-012-0060-z, 2, 1, 36-40, 2013.01. |
| 66. | Kentaro Yamazaki, Michitaka Nagase, Hiroshi Tamagawa, Shinya Ueda, Takao Tamura, Kohei Murata, Takashi Tsuda, Eishi Baba, Masahiro Tsuda, Toshikazu Moriwaki, Taito Esaki, Yasushi Tsuji, Kei Muro, Koichi Taira, Tadamichi Denda, Takahiro Tsushima, Masahiko Ando, Satoshi Morita, Narikazu Boku, Ichinosuke Hyodo, A randomized phase III trial of mFOLFOX6 plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment for metastatic colorectal cancer: West Japan Oncology Group study 4407G (WJOG4407G)., JOURNAL OF CLINICAL ONCOLOGY, 10.1200/jco.2014.32.15_suppl.3534, 32, 15, 2014.05. |
| 67. | Tsuyoshi Shirakawa, Tomoko Hara, Kojiro Hata, Kimitaka Suetsugu, Hideki Kakimoto, Kentaro Ogata, Yousuke Ikari, Hidenori Sasaki, Makoto Takahashi, Masaru Fukahori, Miyuki Uoi, Taito Esaki, Mikako Hiraike, Toshinobu Hayashi, Akira Tokunaga, Norio Ureshino, Tsuneo Kuwamura, Hitoshi Kusaba, Kenji Mitsugi, Eishi Baba, Analysis of a Questionnaire Survey regarding Current Conditions against Exposure to Anticancer Drugs and Reports of Cancer Chemotherapy at Outpatient Departments in Japan, Pharmacology & Pharmacy, 140-152, 2017.08. |
| 68. | Horimatsu T, Nakayama N, Moriwaki T, Hirashima Y, Fujita M, Asayama M, Moriyama I, Nakashima K, Baba E, Kitamura H, Tamura T, Hosokawa A, Yoshimura K, Muto M, A phase II study of 5-FU/l-LV/oxaliplatin (mFOLFOX6) in Japanese patients with metastatic or unresectable small bowel adenocarcinoma., Int J Clin Oncol, 10.1007/s10147-017-1138-6., 2017.05. |
| 69. | Nobuhiro Tsuruta, Kenji Tsuchihashi, Hirofumi Ohmura, Kyoko Yamaguchi, Mamoru Ito, Hiroshi Ariyama, Hitoshi Kusaba, Koichi Akashi, Eishi Baba, RNA N6-methyladenosine demethylase FTO regulates PD-L1 expression in colon cancer cells, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2020.06.153, 530, 1, 235-239, 2020.09. |
| 70. | Kenji Tsuchihashi, Hitoshi Kusaba, Tomoyasu Yoshihiro, Toshifumi Fujiwara, Nokitaka Setsu, Makoto Endo, Yoshihiro Matsumoto, Takashi Imajima, Yudai Shinohara, Mamoru Ito, Satoru Yamaga, Kenro Tanoue, Kohei Arimizu, Hirofumi Ohmura, Fumiyasu Hanamura, Kyoko Yamaguchi, Taichi Isobe, Hiroshi Ariyama, Yasuharu Nakashima, Koichi Akashi, Eishi Baba, Eribulin as a first-line treatment for soft tissue sarcoma patients with contraindications for doxorubicin, Scientific Reports, 10.1038/s41598-020-77898-y, 10, 1, 2020.12, |
| 71. | 遠藤 誠, 土橋 賢司, 松本 嘉寛, 薛 宇孝, 藤原 稔史, 飯田 圭一郎, 鍋島 央, 木村 敦, 島田 英二郎, 金堀 将也, 吉弘 知恭, 草場 仁志, 赤司 浩一, 馬場 英司, 中島 康晴, ドキソルビシン投与不適の進行軟部肉腫患者に対する一次治療としてのエリブリンの使用経験, 整形外科と災害外科, 70, Suppl.1, 89-89, 2021.05. |
| 72. | Tomomi Kashiwada, Katsunori Shinozaki, Shohei Ueno, Hirofumi Kawanaka, Futoshi Uno, Yoshihiro Okita, Masaru Fukahori, Hidenobu Matsushita, Yasunori Emi, Mototsugu Shimokawa, Akitaka Makiyama, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Masaki Mori, Eishi Baba, Safety and efficacy of S-1 plus oxaliplatin 130 mg/m2 combination therapy in patients with previously untreated HER2-negative unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: a phase II trial (KSCC1501A)., International journal of clinical oncology, 10.1007/s10147-020-01803-w, 26, 2, 345-354, 2021.02, BACKGROUND: In a randomized pivotal global phase III study, S-1 and oxaliplatin 100 mg/m2 (SOX100) combination chemotherapy was as effective as S-1 and cisplatin for advanced gastric cancer (AGC) and showed a favorable safety profile. In this phase II study, we analyzed survival outcomes to assess the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) in AGC. METHODS: Patients with HER2-negative AGC received 80 mg/m2/day S-1 orally on days 1-14 and 130 mg/m2 oxaliplatin intravenously on day 1 of each 21-day cycle until the criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the null hypothesis of RR in the current trial was 45%. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were recorded according to CTCAE version 4.0. RESULTS: Seventy-one patients were enrolled from June 2015 to November 2016, but eight were excluded for ineligibility. Therefore, all final analyses were conducted with 63 patients. The confirmed RR was 46.0% (90% confidence interval [CI]: 36.1-56.3), and the disease control rate was 77.8% (90% CI: 68.1-85.1). The median PFS and OS were 4.9 (95% CI: 4.2-7.1) and 14.8 (95% CI: 11.1-18.9) months, respectively. Incidences of grade 3-4 AEs > 10% were anorexia (19.0%), peripheral neuropathy (12.7%), nausea (11.1%), and thrombocytopenia (11.1%). CONCLUSIONS: This study represents the first evaluation of SOX130 in patients with HER2-negative AGC. SOX130 showed an acceptable safety profile, but the prespecified statistical efficacy targets were not achieved.. |
| 73. | Hitomi Kawaji, Makoto Kubo, Nami Yamashita, Hidetaka Yamamoto, Masaya Kai, Atsuko Kajihara, Mai Yamada, Kanako Kurata, Kazuhisa Kaneshiro, Yurina Harada, Saori Hayashi, Akiko Shimazaki, Hitomi Mori, Sayuri Akiyoshi, Eiji Oki, Yoshinao Oda, Eishi Baba, Masaki Mori, Masafumi Nakamura, Comprehensive molecular profiling broadens treatment options for breast cancer patients, Cancer Medicine, 10.1002/cam4.3619, 10, 2, 529-539, 2021.01, © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Precision oncology with next generation sequencing (NGS) using tumor tissue with or without blood has begun in Japan. Tumor molecular profiling tests are available, including the OncoGuide™ NCC Oncopanel System and FoundationOne® CDx (F1CDx). Our purpose was to identify potentially actionable genetic alterations in breast cancer with this comprehensive tumor profiling test. We enrolled 115 patients with pathologically diagnosed advanced or metastatic breast cancer. Comprehensive tumor genomic profiling, microsatellite instability, and tumor mutational burden (TMB) were determined using F1CDx. Testing was successful in 109/115 cases (94.8%). Clinically actionable alterations were identified in 76% of advanced breast cancer patients. The most frequent short variants were in TP53 (48.6%), PIK3CA (38.5%), GATA3 (11.0%), PTEN (11.0%), and BRCA1 (10.1%), and structural variants were in ERBB2 (24.8%), MYC (21.1%), RAD21 (21.1%), CCND1 (11.9%), FGF19 (10.1%), and PTEN (10.1%). Regarding human epidermal growth factor receptor (HER)2 status, 106/109 samples (97.2%) were concordant between F1CDx and HER2 testing with immunohistochemistry/fluorescence in situ hybridization. However, ERBB2 amplification was newly detected in four samples and ERBB2 mutations were detected in five HER2-negative breast cancer samples. Oncogenic BRCA mutations were found in three samples with F1CDx among 27 germline testing-negative samples. The mean TMB in all samples was 6.28 mut/Mb and tended to be higher in luminal B and triple-negative breast cancer (mean = 8.1 and 5.9 mut/Mb, respectively) compared with other subtypes. In conclusion, we established a system for precision oncology and obtained preliminary data with NGS as the first step. The information in this clinical sequencing panel will help guide the development of new treatments for breast cancer patients.. |
| 74. | 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, Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (edition 2.1)., International journal of clinical oncology, 10.1007/s10147-020-01831-6, 26, 2, 233-283, 2021.02, 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.. |
| 75. | Hirofumi Ohmura, Kyoko Yamaguchi, Fumiyasu Hanamura, Mamoru Ito, Akitaka Makiyama, Keita Uchino, Hozumi Shimokawa, Shingo Tamura, Taito Esaki, Kenji Mitsugi, Yoshihiro Shibata, Hisanobu Oda, Kenji Tsuchihashi, Hiroshi Ariyama, Hitoshi Kusaba, Yoshinao Oda, Koichi Akashi, Eishi Baba, OX40 and LAG3 are associated with better prognosis in advanced gastric cancer patients treated with anti-programmed death-1 antibody, British journal of cancer, 10.1038/s41416-020-0810-1, 122, 10, 1507-1517, 2020.05, [URL], Background: Anti-PD-1 monoclonal antibody, nivolumab, has shown efficacy for advanced gastric cancer (AGC). However, the specific immune cell subsets predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood of 30 AGC patients treated with nivolumab was prospectively obtained before the initial and second administrations and at the time of progressive disease (PD). The proportions of immune cell subsets and the serum concentrations of cytokines were systematically analysed by flow cytometry. Associations of subsets and serum cytokines with therapeutic effects were evaluated. Results: After the initial administration, significant increases in activated central/effector memory, activated effector T cells, and activated T-helper 1 subsets were observed. At the time of PD, activated regulatory T cells, LAG3-positive CD4+/CD8+ T cells, and TIM3-positive CD4+/CD8+ T cells increased significantly. Significant positive correlations were shown between progression-free survival and proportions of LAG3-positive CD4+/CD8+ T cells and of OX40-positive CD4+/CD8+ T cells (log-rank p = 0.0008, 0.0003, 0.0035 and 0.0040). Conclusions: Nivolumab therapy enhances activation of central/effector memory and effector subsets of CD4+/CD8+ T cells. The expression levels of LAG-3 and OX40 on T cells correlated with the efficacy of nivolumab therapy and could be reasonable biomarkers for anti-PD-1 therapy.. |
| 76. | Takanobu Nobori, Masumi Kawamura, Ryosuke Yoshida, Taisei Joichi, Kenta Kamino, Akihiro Kishimura, Eishi Baba, Takeshi Mori, Yoshiki Katayama, Fluorescence Signal Amplification by Using β-Galactosidase for Flow Cytometry; Advantages of an Endogenous Activity-Free Enzyme, Analytical chemistry, 10.1021/acs.analchem.9b04471, 92, 4, 3069-3076, 2020.02, [URL], We previously proposed using a hydrolysis enzyme for fluorescent signal amplification in flow cytometric detection of antigen proteins, which was named the catalyzed reporter penetration (CARP) method. In this method, antigen proteins are labeled with enzyme-modified antibodies, and then fluorophore-modified substrates stain cells by penetrating the cell membrane upon hydrolysis of the substrate. We proved the concept by using alkaline phosphatase (AP) as the hydrolysis enzyme. However, a required prior inactivation process of endogenous AP activity on the cell surface risked disrupting recognition of antigen proteins by antibodies. In this report, the CARP method was extended to β-galactosidase (β-gal) as an amplification enzyme, which circumvented the requirement of an initial inactivation process because endogenous β-gal activity on the surface of examined cells was found to be negligible. The substrate structure for β-gal was optimized and used for the CARP method. The CARP method showed significantly higher fluorescent signals than a conventional method using fluorophore-modified antibodies. Moreover, the degree of amplification of the fluorescence signal was higher for antigens with low expression levels, showing that the CARP method is a suitable signal amplification method over current conventional approaches.. |
| 77. | Saori Mishima, Hiroya Taniguchi, Kiwamu Akagi, Eishi Baba, Yutaka Fujiwara, Akira Hirasawa, Masafumi Ikeda, Osamu Maeda, Kei Muro, Hiroshi Nishihara, Hiroyki Nishiyama, Tadao Takano, Katsuya Tsuchihara, Yasushi Yatabe, Yasuhiro Kodera, Takayuki Yoshino, Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition, International Journal of Clinical Oncology, 10.1007/s10147-019-01498-8, 25, 2, 217-239, 2020.02, [URL], Background: Novel therapeutic agents have improved survival outcomes in patients with advanced solid tumors. In parallel, the development of predictive biomarkers to identify patients who are likely to benefit from a certain treatment has also contributed to the improvement of survival. Recently, clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. In Japan, a PD-1 inhibitor for dMMR advanced solid tumors, regardless of the primary tumor site, has been approved. However, there are some issues related to administering immune checkpoint inhibitors in the clinical practice setting, making it necessary to develop the guidelines. Methods: Clinical questions (CQs) regarding medical care were formulated for patients with dMMR advanced solid tumors, and evidence to the CQs was collected by manual search to prepare recommendations. Then, the committee members voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other factors. Results: The current guideline, which we consider a provisional clinical opinion at this point, describes the 11 requirements to be considered in terms of patients for whom dMMR testing is recommended, the timing and methods of dMMR testing, and clinical care systems required to perform dMMR testing properly and to administer immune checkpoint inhibitors safely. Conclusion: This provisional clinical opinion proposes the requirements for performing dMMR testing properly to select patients who are likely to benefit from immune checkpoint inhibitors and administering them safely.. |
| 78. | Kyoko Yamaguchi, Mamoru Ito, Hirofumi Ohmura, Fumiyasu Hanamura, Michitaka Nakano, Kenji Tsuchihashi, Shuntaro Nagai, Hiroshi Ariyama, Hitoshi Kusaba, Hidetaka Yamamoto, Yoshinao Oda, Masafumi Nakamura, Koichi Akashi, Eishi Baba, Helper T cell-dominant tertiary lymphoid structures are associated with disease relapse of advanced colorectal cancer, OncoImmunology, 10.1080/2162402X.2020.1724763, 9, 1, 2020.01, [URL], Tertiary lymphoid structures (TLSs), clusters of immune cells found around tumor tissue, have been shown to be associated with anti-tumor immunity, but the cellular composition within each TLS and whether the cellular composition of a TLS affects a patient’s prognosis are poorly understood. In the present study, each TLS was categorized according to its cellular composition determined by a system of multiplex immunohistochemical staining and quantitative analysis, and the correlation between the category and prognosis was examined. Sixty-seven patients with curatively resected stage II/III colorectal cancer (CRC) were enrolled. A TLS, consisting of germinal center B cells, follicular dendritic cells, T helper (Th) cells, B cells, cytotoxic T cells, and macrophages, was confirmed in the tumor tissue of 58 patients (87%). The densities of Th cells and macrophages were significantly higher in relapsed patients than in not-relapsed patients (p = .043 and p = .0076). A higher ratio of Th cells was the most significant independent risk factor for disease relapse on multivariate analysis. The subset increasing in Th cells was GATA3+ Th2. A total of 353 TLSs was divided into five clusters according to immune cell composition. Among them, the Th-rich type TLS was significantly increased (p = .0009) in relapsed patients. These data suggest the possibility that Th cell-dominant composition might disturb the anti-tumor immune response, and the function of each TLS might differ depending on its composition.. |
| 79. | Hirofumi Ohmura, Mamoru Ito, Keita Uchino, Chihiro Okada, Shigeki Tanishima, Yuichi Yamada, Seiya Momosaki, Masato Komoda, Miyuki Kuwayama, Kyoko Yamaguchi, Yuta Okumura, Michitaka Nakano, Kenji Tsuchihashi, Taichi Isobe, Hiroshi Ariyama, Hitoshi Kusaba, Yoshinao Oda, Koichi Akashi, Eishi Baba, Methylation of drug resistance-related genes in chemotherapy-sensitive Epstein–Barr virus-associated gastric cancer, FEBS Open Bio, 10.1002/2211-5463.12765, 10, 1, 147-157, 2020.01, [URL], Epstein–Barr virus (EBV)-associated gastric cancer (GC) is associated with a high degree of DNA methylation. However, the association between chemotherapy susceptibility and tumor DNA methylation in advanced diseases remains unclear. The comprehensive DNA methylation status of GC cells obtained from an advanced EBV-associated GC (EBVGC) case, in which complete response to S-1 plus cisplatin chemotherapy was achieved, was analyzed using a DNA methylation microarray. We compared DNA methylation of GC cells with public data and identified genes with higher methylation in EBVGC cell lines than in normal gastric cells, and genes in which methylation was increased by EBV. Of these genes, ABCG2, AHNAK2, BCL2, FZD1, and TP73 are associated with published evidence for resistance to 5-fluorouracil and cisplatin. Silencing of these genes may be associated with hypersensitivity to chemotherapy.. |
| 80. | Shiho Kawagoe, Masahiro Nakano, Keita Uchino, Kohei Arimizu, Tatsuhiro Kajitani, Hozumi Shimokawa, Tetsuya Kusumoto, Koji Ikejiri, Eishi Baba, Analysis of response evaluation criteria in solid tumors reduction ratio of primary chemotherapy in unresectable advanced or recurrent colorectal cancer, Molecular and Clinical Oncology, 10.3892/mco.2019.1894, 11, 3, 243-251, 2019.09, [URL], Response Evaluation Criteria in Solid Tumors (RECIST) is used to assess the objective response of solid tumors to treatment. However, it remains unclear to what extent the response rate assessed by RECIST reflects a reduction of tumor size in multiple organs in patients with unresectable advanced or recurrent colorectal cancer (CRC) with multiple organ metastases. It is also unclear whether the management of liver metastases with systemic chemotherapy in CRC patients with multiple organ metastases improves their prognosis, although surgical resection has been shown to be the most effective treatment approach to CRC cases with liver metastases. A total of 38 CRC patients who underwent systemic chemotherapy in Kyushu Medical Center Hospital between January 2013 and April 2016 were examined. The patients had measurable lesions in multiple organs, including the liver, and did not undergo curative surgery for metastatic lesions after initiation of chemotherapy. The association between the total reduction ratio (TRR) of all lesions and liver lesion reduction ratio (LRR) was retrospectively analyzed. A total of 18 patients (47%) had H3 liver metastases, and the median liver lesion occupancy rate in the sum of the measured lesions with RECIST was 76%. TRR and LRR were strongly correlated, regardless of the volume of the liver metastases. Although a TRR of >30% was significantly associated with improved overall survival (OS), this improvement was not observed in patients with H3 liver metastases. TRR was correlated with LRR and was associated with a better OS. CRC patients with both multiple organ and H3 liver metastases exhibited poor survival, even with a high reduction ratio by chemotherapy.. |
| 81. | Kotoe Takayoshi, Hitoshi Kusaba, Tomomi Aikawa, Sakuya Koreishi, Kosuke Sagara, Michitaka Nakano, Masato Komoda, Mihoko Kono, Mitsuhiro Fukata, Takeshi Arita, Taito Esaki, Koichi Akashi, Eishi Baba, Hypoalbuminemia for the prediction of venous thromboembolism and treatment of direct oral anticoagulants in metastatic gastric cancer patients, Gastric Cancer, 10.1007/s10120-019-00930-2, 22, 5, 988-998, 2019.09, [URL], Background: Venous thromboembolism (VTE) is highly associated with advanced gastric cancer (AGC) and is sometimes lethal. Predictors of VTE have not been identified, and the efficacy and safety of direct oral anticoagulants (DOACs) for AGC-associated VTE remain to be clarified. Methods: A total of 188 AGC patients who started chemotherapy during the period from January 2014 to December 2017 in our institutions were retrospectively examined for the incidence of VTE, risk factors for VTE, and the efficacy and safety of DOAC-based anticoagulant therapy for VTE. Results: Thirty-four patients (18%) were diagnosed with VTE at the start or during the course of chemotherapy (VTE group). More VTE group patients had a history of abdominal surgery and had moderate–severe ascites (32% versus 17%, 32% versus 14%, respectively) than non-VTE group patients (NVTE group). The mean serum albumin concentrations in the VTE group were significantly lower than NVTE group (3.38 mg/dL vs 3.65 mg/dL, respectively). Multivariate analysis showed that hypoalbuminemia was significantly correlated with VTE (P = 0.012). In the VTE group, 29 patients (85%) received anticoagulant therapy, including 24 patients treated with DOACs. No lethal VTE was observed in any patients. Thirteen patients (45%) terminated DOACs because of anemia or bleeding events, of whom eleven developed major bleeding. Median overall survivals of the VTE and NVTE groups were 9.63 months and 11.5 months, respectively (P = 0.262). Conclusion: Hypoalbuminemia appears to be a risk factor for AGC-associated VTE. DOACs are effective to AGC-associated VTE, but careful observation of bleeding events is required.. |
| 82. | Tomoyasu Yoshihiro, Hitoshi Kusaba, Akitaka Makiyama, Kazuma Kobayashi, Masato Uenomachi, Mamoru Ito, Yasuhiro Doi, Kenji Mitsugi, Tomomi Aikawa, Kotoe Takayoshi, Taito Esaki, Hozumi Shimokawa, Kenji Tsuchihashi, Hiroshi Ariyama, Koichi Akashi, Eishi Baba, Efficacy and safety of ramucirumab plus modified FOLFIRI for metastatic colorectal cancer, International Journal of Clinical Oncology, 10.1007/s10147-018-01391-w, 24, 5, 508-515, 2019.05, [URL], Background: Dose modification of chemotherapy for metastatic colorectal cancer (MCRC) is often needed, especially in second-line and later-line treatments due to adverse events of previous treatment and poor patient condition. No study has focused on ramucirumab plus modified dose of FOLFIRI for MCRC, and whether low relative dose intensity (RDI) affects treatment efficacy has not been clarified. Methods: MCRC patients who received ramucirumab plus FOLFIRI, which consisted of 150 mg/m 2 of irinotecan, at six institutions were retrospectively analyzed. Results: A total of 43 patients were assessed. Median age was 63 years, and 22 patients (51%) were women. Twenty-six patients (60%) were given ramucirumab plus FOLFIRI as second-line therapy, and 17 (40%) as third or later-line. The median relative dose intensity (RDI) of irinotecan was 60.6%, which is lower than that in the pivotal phase 3 study (RAISE), and other agents showed the same trend. Median progression-free survival was 4.8 [95% confidence interval (CI) 3.2–5.7] months for all patients, 5.4 (95% CI 3.5–7.2) months for second-line patients, and 2.8 (95% CI 1.6–5.8) months for third or later-line patients. Median overall survival was 17.3 (95% CI 11.5–22.4) months for all patients. Patients with irinotecan RDI less than 60% showed similar treatment efficacy. Hematological toxicities of grade 3 or worse were observed in 21 patients, but all were manageable. Conclusion: Low RDI did not compromise the treatment efficacy of ramucirumab plus modified FOLFIRI for MCRC patients.. |
| 83. | Yoshihiko Fujita, Masataka Taguri, Kentaro Yamazaki, Junji Tsurutani, Kazuko Sakai, Takahiro Tsushima, Michitaka Nagase, Hiroshi Tamagawa, Shinya Ueda, Takao Tamura, Yasushi Tsuji, Kohei Murata, Koichi Taira, Tadamichi Denda, Toshikazu Moriwaki, Sadao Funai, Takako Eguchi Nakajima, Kei Muro, Akihito Tsuji, Motoki Yoshida, Koichi Suyama, Takuya Kurimoto, Naotoshi Sugimoto, Eishi Baba, Nobuhiko Seki, Mikio Sato, Takaya Shimura, Narikazu Boku, Ichinosuke Hyodo, Takeharu Yamanaka, Kazuto Nishio, aCGH Analysis of Predictive Biomarkers for Response to Bevacizumab plus Oxaliplatin- or Irinotecan-Based Chemotherapy in Patients with Metastatic Colorectal Cancer, Oncologist, 10.1634/theoncologist.2018-0119, 24, 3, 327-337, 2019.03, [URL], Background: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC. Materials and Methods: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG). Results: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p =.07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p =.134 for RR; interaction test, p =.102 for PFS and p =.003 for OS) and 8q24.2 (Fisher's exact test, p =.179 for RR; interaction test, p =.144 for PFS and p =.002 for OS). Conclusion: Chromosome 8q24.1–q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC. Implications for Practice: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1–p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.. |
| 84. | Michitaka Nakano, Yoshikane Kikushige, Kohta Miyawaki, Yuya Kunisaki, Shinichi Mizuno, Katsuto Takenaka, Shingo Tamura, Yuta Okumura, Mamoru Ito, Hiroshi Ariyama, Hitoshi Kusaba, Masafumi Nakamura, Takahiro Maeda, Eishi Baba, Koichi Akashi, Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer, Oncogene, 10.1038/s41388-018-0480-0, 38, 6, 780-793, 2019.02, [URL], Cancer stem cells (CSCs) possess the capacity for self-renewal and the potential to differentiate into non-CSCs. The recent discoveries of dynamic equilibrium between CSCs and non-CSCs revealed the significance of acquiring CSC-like properties in non-CSCs as an important process in progression of cancer. The mechanism underlying acquisition of CSC-like properties has mainly been investigated in the context of epithelial–mesenchymal transition. Here, we demonstrate the dedifferentiation process may be an alternative mechanism in acquisition of CSC-like properties in human colorectal cancer cells. By exploring the single-cell gene expression analysis of organoids developed from CD44 + CSCs, we identified TWIST1 as a key molecule for maintaining the undifferentiated state of cancer cells. Consistent with the finding, we found that TGF-beta signaling pathway, a regulator of TWIST1, was specifically activated in the undifferentiated CD44 + CSCs in human colorectal cancer using microarray-based gene expression analysis and quantitative pathology imaging system. Furthermore, we showed that external stimulation with TGF-beta and the induction of TWIST1 converted CD44 − non-CSCs into the undifferentiated CD44 + CSCs, leading to the significant increment of CSCs in xenograft models. This study strongly suggests dedifferentiation driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer.. |
| 85. | K. Muro, E. Van Cutsem, Y. Narita, G. Pentheroudakis, E. Baba, J. Li, M -H Ryu, W I Wan Zamaniah, W -P Yong, K -H Yeh, K. Kato, Z. Lu, B.C. Cho, I.M. Nor, M. Ng, L -T Chen, T.E. Nakajima, K. Shitara, H. Kawakami, T. Tsushima, T. Yoshino, F. Lordick, E. Martinelli, E.C. Smyth, D. Arnold, H. Minami, J. Tabernero, J -Y Douillard, Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: a JSMO–ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS, Annals of Oncology, 10.1093/annonc/mdy502, 30, 1, 19-33, 2019.01, [URL]. |
| 86. | K. Muro, F. Lordick, T. Tsushima, G. Pentheroudakis, E. Baba, Z. Lu, B. C. Cho, I. M. Nor, M. Ng, L. T. Chen, K. Kato, J. Li, M. H. Ryu, W. I. Wan Zamaniah, W. P. Yong, K. H. Yeh, T. E. Nakajima, K. Shitara, H. Kawakami, Y. Narita, T. Yoshino, E. Van Cutsem, E. Martinelli, E. C. Smyth, D. Arnold, H. Minami, J. Tabernero, J. Y. Douillard, Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic oesophageal cancer A JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS, Annals of Oncology, 10.1093/annonc/mdy498, 30, 1, 34-43, 2019.01, [URL], The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and covered the management and treatment of local/ locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.. |
| 87. | Kentaro Suina, Kenji Tsuchihashi, Juntaro Yamasaki, Shohei Kamenori, Subaru Shintani, Yuki Hirata, Shogo Okazaki, Oltea Sampetrean, Eishi Baba, Koichi Akashi, Yoichiro Mitsuishi, Fumiyuki Takahashi, Kazuhisa Takahashi, Hideyuki Saya, Osamu Nagano, Epidermal growth factor receptor promotes glioma progression by regulating xCT and GluN2B-containing N-methyl-d-aspartate-sensitive glutamate receptor signaling., Cancer science, 10.1111/cas.13826, 109, 12, 3874-3882, 2018.12, [URL], Autocrine and paracrine factors, including glutamate and epidermal growth factor (EGF), are potent inducers of brain tumor cell invasion, a pathological hallmark of malignant gliomas. System xc(-) consists of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. We previously showed that the EGF receptor (EGFR) interacts with xCT and thereby promotes the activity of system xc(-) in a kinase-independent manner, resulting in enhanced glutamate release in glioma cells. However, the molecular mechanism underlying EGFR-mediated glioma progression in a glutamate-rich microenvironment has remained unclear. Here we show that the GluN2B subunit of the N-methyl-d-aspartate-sensitive glutamate receptor (NMDAR) is a substrate of EGFR in glioma cells. In response to EGF stimulation, EGFR phosphorylated the COOH-terminal domain of GluN2B and thereby enhanced glutamate-NMDAR signaling and consequent cell migration in EGFR-overexpressing glioma cells. Treatment with the NMDAR inhibitor MK-801 or the system xc(-) inhibitor sulfasalazine suppressed EGF-elicited glioma cell migration. The administration of sulfasalazine and MK-801 also synergistically suppressed the growth of subcutaneous tumors formed by EGFR-overexpressing glioma cells. Furthermore, shRNA-mediated knockdown of xCT and GluN2B cooperatively prolonged the survival of mice injected intracerebrally with such glioma cells. Our findings thus establish a central role for EGFR in the signaling crosstalk between xCT and GluN2B-containing NMDAR in glioma cells.. |
| 88. | Kenji Tsuchihashi, Mamoru Ito, Toshikazu Moriwaki, Shota Fukuoka, Hiroya Taniguchi, Atsuo Takashima, Yosuke Kumekawa, Takeshi Kajiwara, Kentaro Yamazaki, Taito Esaki, Akitaka Makiyama, Tadamichi Denda, Hironaga Satake, Takeshi Suto, Naotoshi Sugimoto, Kenji Katsumata, Toshiaki Ishikawa, Tomomi Kashiwada, Eiji Oki, Yoshito Komatsu, Hiroyuki Okuyama, Daisuke Sakai, Hideki Ueno, Takao Tamura, Kimihiro Yamashita, Junji Kishimoto, Yasuhiro Shimada, Eishi Baba, Role of Predictive Value of the Modified Glasgow Prognostic Score for Later-line Chemotherapy in Patients With Metastatic Colorectal Cancer., Clinical colorectal cancer, 10.1016/j.clcc.2018.07.004, 17, 4, e687-e697-e697, 2018.12, [URL], BACKGROUND: Assessment of patient factors is essential for selecting later-line chemotherapy in patients with metastatic colorectal cancer (mCRC). The efficacy, prognosis, and safety of each treatment regimen according to nutritional and inflammatory status still remain to be elucidated. PATIENTS AND METHODS: A total of 550 patients with mCRC who were registered in the REGOTAS study (Regorafenib versus TAS-102 as Salvage-line in patients with colorectal cancer refractory to standard chemotherapies: a multicenter observational study, UMIN 000020416) and treated with trifluridine/tipiracil (TFTD) or regorafenib as a later-line therapy were retrospectively stratified according to the modified Glasgow Prognostic Score (mGPS), which divided patients into mGPS 0 to 2 by serum albumin and C-reactive protein, and compared. RESULTS: The median overall survival (OS) of patients with mGPS 0, 1, and 2 was 10.0 months (95% confidence interval [CI], 9.2-11.6 months), 6.5 months (95% CI, 5.3-7.1 months), and 3.9 months (95% CI, 3.3-4.9 months), respectively. The median progression-free survival (PFS) with mGPS 0, 1, and 2 was 2.5 months (95% CI, 2.1-3.0 months), 2.0 months (95% CI, 1.9-2.3 months), and 1.7 months (95% CI, 1.4-1.9 months), respectively. There were significant differences by mGPS in both OS and PFS (all P |
| 89. | Michitaka Nakano, Mamoru Ito, Risa Tanaka, Hiroshi Ariyama, Kenji Mitsugi, Akitaka Makiyama, Keita Uchino, Taito Esaki, Nobuhiro Tsuruta, Fumiyasu Hanamura, Kyoko Yamaguchi, Yuta Okumura, Kosuke Sagara, Kotoe Takayoshi, Kenta Nio, Kenji Tsuchihashi, Shingo Tamura, Hozumi Shimokawa, Shuji Arita, Kohta Miyawaki, Hitoshi Kusaba, Koichi Akashi, Eishi Baba, Epithelial-mesenchymal transition is activated in CD44-positive malignant ascites tumor cells of gastrointestinal cancer., Cancer science, 10.1111/cas.13777, 109, 11, 3461-3470, 2018.11, [URL], Disseminated cancer cells in malignant ascites possess unique properties that differ from primary tumors. However, the biological features of ascites tumor cells (ATC) have not been fully investigated. By analyzing ascites fluid from 65 gastrointestinal cancer patients, the distinguishing characteristics of ATC were identified. High frequency of CD44+ cells was observed in ATC using flow cytometry (n = 48). Multiplex quantitative PCR (n = 15) showed higher gene expression of epithelial-mesenchymal transition (EMT)-related genes and transforming growth factor beta (TGF-beta)-related genes in ATC than in the primary tissues. Immunohistochemistry (n = 10) showed that ATC also had much higher expression of phosphorylated SMAD2 than that in the corresponding primary tissues. TGF-beta 1 was detected in all cases of malignant ascites by enzyme-linked immunoassay (n = 38), suggesting the possible interaction of ATC and the ascites microenvironment. In vitro experiments revealed that these ATC properties were maintained by TGF-beta 1 in cultured ATC(n = 3). Here, we showed that ATCrevealed high frequencies of CD44 and possessed distinct EMT features from primary tissues that were mainly maintained by TGF-beta 1 in the ascites.. |
| 90. | Yamaguchi K, Mishima K, Ohmura H, Hanamura F, Ito M, Nakano M, Tsuchihashi K, Ota SI, Wada N, Uchi H, Ariyama H, Kusaba H, Niiro H, Akashi K, Baba E, Activation of central/effector memory T cells and T-helper 1 polarization in malignant melanoma patients treated with anti-programmed death-1 antibody., Cancer science, 10.1111/cas.13758, 109, 10, 3032-3042, 2018.10, [URL]. |
| 91. | Tsuchihashi K, Arita S, Fujiwara M, Iwasaki K, Hirano A, Yoshihiro T, Nio K, Koga Y, Esaki M, Ariyama H, Kusaba H, Moriyama T, Ohuchida K, Nagai E, Nakamura M, Oda Y, Akashi K, Baba E, Metastatic esophageal carcinosarcoma comprising neuroendocrine carcinoma, squamous cell carcinoma, and sarcoma: A case report., Medicine, 10.1097/MD.0000000000012796, 97, 41, e12796, 2018.10, [URL]. |
| 92. | A. Hosokawa, K. Yamazaki, C. Matsuda, S. Ueda, H. Fujii, E. Baba, S. Okamura, M. Tsuda, T. Tamura, K. Shinozaki, T. Tsushima, T. Tsuda, T. Shirakawa, H. Yamashita, S. Morita, K. Muro, Morphologic response to chemotherapy containing bevacizumab in patients with colorectal liver metastases (CLM) A post hoc analysis of the WJOG4407G phase III study, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy281.058, 29, viii171, 2018.10, [URL]. |
| 93. | Y. Kito, T. Yamada, T. Matsumoto, H. Yasui, K. Murata, A. Makiyama, H. Hara, E. Baba, K. Nishio, K. Yoshimura, S. Hironaka, K. Muro, K. Yamazaki, Randomized phase II study of FOLFIRI plus ramucirumab (Rmab) versus FOLFOXIRI plus Rmab as first-line treatment for patients with metastatic colorectal cancer (mCRC) WJOG9216G, Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdy281.151, 29, viii201, 2018.10, [URL]. |
| 94. | Kyoko Yamaguchi, Hitoshi Kusaba, Akitaka Makiyama, Kenji Mitsugi, Keita Uchino, Shingo Tamura, Yoshihiro Shibata, Taito Esaki, Mamoru Ito, Kotoe Takayoshi, Kenji Tsuchihashi, Shuji Arita, Hiroshi Ariyama, Koichi Akashi, Eishi Baba, The risk factors for oxaliplatin-induced peripheral sensory neuropathy and thrombocytopenia in advanced gastric cancer., Cancer chemotherapy and pharmacology, 10.1007/s00280-018-3652-2, 82, 4, 625-633, 2018.10, [URL], PURPOSE: Peripheral sensory neuropathy (PSN) and thrombocytopenia are the main dose-limiting toxicities of oxaliplatin for the treatment of advanced gastric cancer (AGC). Because the risk factors for those toxicities in practice have not been clarified, we conducted this prospective study. METHODS: AGC patients who received oxaliplatin-based therapy at any of seven institutions participating in the Kyushu Medical Oncology Group were assessed after we obtained written informed consent. RESULTS: A total of 60 patients including 39 males and 21 females were examined. The median age was 66 years. The numbers of patients receiving oxaliplatin as the first, second, or third and later lines of therapy were 39, 16, and 5, respectively. An initial dose of 130, 100, or |
| 95. | Akitaka Makiyama, Kenji Kunieda, Masaaki Noguchi, Takeshi Kajiwara, Takao Tamura, Koji Takeda, Junko Sugiyama, Keiko Minashi, Toshikazu Moriwaki, Naotoshi Sugimoto, Michitaka Nagase, Yuji Negoro, Takashi Tsuda, Hideki Shimodaira, Naohiro Okano, Akihito Tsuji, Daisuke Sakai, Kazuhiro Yanagihara, Shinya Ueda, Shingo Tamura, Satoshi Otsu, Takuya Honda, Yuzo Matsushita, Tatsuya Okuno, Tomomi Kashiwada, Akira Nozaki, Masahide Ebi, Hiroyuki Okuda, Mototsugu Shimokawa, Shuichi Hironaka, Ichinosuke Hyodo, Eishi Baba, Narikazu Boku, Kei Muro, Taito Esaki, First-line chemotherapy with S-1 alone or S-1 plus cisplatin for elderly patients with advanced gastric cancer: a multicenter propensity score matched study, Gastric Cancer, 10.1007/s10120-018-0797-y, 1-10, 2018.01, [URL], Background: Fluoropyrimidine and platinum combination is the standard treatment for advanced or recurrent gastric cancer (AGC). However, fluoropyrimidine monotherapy is commonly used for elderly patients with AGC because of its good tolerability. Methods: In this multicenter retrospective study, we collected clinical data of AGC patients aged 70 years or older, treated with S-1 alone or S-1 plus cisplatin (SP) as the first-line treatment between January 2009 and December 2011. Propensity score matched cohorts (PSMC) were used for reducing the confounding effects to compare efficacy and safety between the two treatment groups. Cox regression analysis was performed to clarify the prognostic factors. Results: PSMC (n = 109 in each group) were selected from among 444 eligible patients (S-1 group, 210 SP group, 234) the S-1 group included more patients deemed unfit for intensive chemotherapy than the SP group (e.g., higher age, poorer PS, poor renal function). In the PSMC, patients’ characteristics were comparable between groups, except the male ratio (S-1 group, 64.2% SP group, 77.1% p = 0.04). No significant differences were observed in either overall survival [hazard ratio (HR) 0.93, p = 0.63] or progression-free survival (HR 1.09, p = 0.61). Severe adverse events (AEs) and hospitalization due to AEs were more frequent in the SP group than in the S-1 group (p < 0.001 each). Conclusion: Our findings do not support the survival benefit of SP over S-1 in elderly patients with AGC. We are now conducting a prospective comparative study to optimize treatment strategy and explore applicability of the geriatric assessment for these patients.. |
| 96. | Nakano M, Ito M, Tanaka R, Yamaguchi K, Ariyama H, Mitsugi K, Yoshihiro T, Ohmura H, Tsuruta N, Hanamura F, Sagara K, Okumura Y, Nio K, Tsuchihashi K, Arita S, Kusaba H, Akashi K, Baba E, PD-1+ TIM-3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer., Cancer science, 10.1111/cas.13723, 109, 9, 2986-2992, 2018.09, [URL]. |
| 97. | Tamura S, Isobe T, Ariyama H, Nakano M, Kikushige Y, Takaishi S, Kusaba H, Takenaka K, Ueki T, Nakamura M, Akashi K, Baba E, E‑cadherin regulates proliferation of colorectal cancer stem cells through NANOG., Oncology reports, 10.3892/or.2018.6464, 40, 2, 693-703, 2018.08, [URL]. |
| 98. | Hozumi Kumagai, Hitoshi Kusaba, Takeharu Yamanaka, Kenta Nio, Kyoko Inadomi, Kotoe Takayoshi, Mamoru Ito, Shingo Tamura, Akitaka Makiyama, Chinatsu Makiyama, Gen Hirano, Yoshihiro Shibata, Tsuyoshi Shirakawa, Kenji Mitsugi, Hiroshi Ariyama, Taito Esaki, Koichi Akashi, Eishi Baba, A phase 2 study of fosaprepitant combined with high-dose dexamethasone for Japanese cancer patients receiving highly emetogenic chemotherapy., Medicine, 10.1097/MD.0000000000011042, 97, 25, e11042, 2018.06, [URL], PURPOSE: Combination therapy of fosaprepitant, dexamethasone (DEX) and a serotonin (5-HT3) receptor antagonist is a standard antiemetic prophylaxis for patients receiving highly emetogenic chemotherapy (HEC). However, the appropriate dose of DEX has not been established in Japan. This study determined the efficacy and safety of triplet antiemetic prophylaxis in Japanese patients receiving HEC when administered the same doses of DEX as those given in a previous international phase 3 study on this drug. METHODS: To assess the efficacy and safety of a sufficient dose of DEX (12 mg on day 1, 8 mg on day 2, 16 mg on days 3 and 4) in combination with intravenous fosaprepitant and granisetron, we prospectively examined patients receiving HEC including cisplatin (≥50 mg/m). The primary endpoint was to determine the percentage of patients who had achieved a complete response (CR), which was defined as no vomiting and no rescue therapy during the entire treatment course. RESULTS: Between February 2013 and January 2015, 44 patients were enrolled with a median age of 65 years (range, 30-75). There were 34 males (77.3%) in the study. Most of the patients had upper gastrointestinal cancers. The CR rate during the treatment course was 70% (95% confidence interval [CI]: 55%-83%) in the overall phase and 91% (95% CI: 78%-97%) in the acute phase and 70% (95% CI: 55%-83%) in the delayed phase. Appreciable severe toxicities related to the antiemetic therapy were not observed. CONCLUSIONS: These results suggest that a sufficient dose of DEX in combination with fosaprepitant and granisetron is optimal as an antiemetic prophylaxis for Japanese patients receiving HEC.. |
| 99. | Makiyama A, Arimizu K, Hirano G, Makiyama C, Matsushita Y, Shirakawa T, Ohmura H, Komoda M, Uchino K, Inadomi K, Arita S, Ariyama H, Kusaba H, Shinohara Y, Kuwayama M, Kajitani T, Oda H, Esaki T, Akashi K, Baba E, Irinotecan monotherapy as third-line or later treatment in advanced gastric cancer, Gastric Cancer, 10.1007/s10120-017-0759-9., 464-472, 2017.08, [URL]. |
| 100. | Kotoe Takayoshi, Goro Doi, Nobuhiro Tsuruta, Tomoyasu Yoshihiro, Kenta Nio, Kenji Tsuchihashi, Hiroshi Ariyama, Jun Odawara, Shinji Shimoda, Kenichi Kohashi, Yoshinao Oda, Shinji Itoh, Norifumi Harimoto, Yoshihiko Maehara, Hitoshi Kusaba, Koichi Akashi, Eishi Baba, Successful chemotherapeutic treatment for metastatic littoral cell angioma: A case report, Medicine (United States), 10.1097/MD.0000000000010378, 97, 15, e0378, 2018.04, [URL], Rationale:Metastatic littoral cell angioma (LCA) is extremely rare. No standard therapeutic strategy has been established, and the impact of chemotherapy has not yet been evaluated.Patient concerns:A 61-year-old woman was admitted because of bicytopenia. She had a splenectomy for LCA of the spleen 10 years earlier. Bone marrow aspiration was normal, and a computed tomography (CT) scan showed hepatomegaly with multiple liver tumors. Diagnoses:Liver biopsy samples showed macrophage-like cell infiltration in the hepatic sinusoids. Metastatic LCA was diagnosed based on immunohistochemistry, imaging tests, and the clinical course.Interventions:Immunosuppressive agents, such as prednisolone and cyclosporine, were ineffective. Next, cytotoxic agents, such as etoposide, paclitaxel, and vincristine, were administered.Outcomes:Cytotoxic agents showed a prominent effect against LCA. CT showed improvement of the hepatomegaly, and fluoro-deoxyglucose (FDG) uptake decreased markedly at a follow-up FDG- positron emission tomography (PET) scan.Lessons:Chemotherapeutic treatment based on hemophagocytic syndrome or angiosarcoma might have anti-tumor activity against metastatic LCA. Analysis of the molecular characteristics of this tumor is needed to develop better treatment options.. |
| 101. | Taro Funakoshi, Takahiro Horimatsu, Michio Nakamura, Koichi Shiroshita, Koichi Suyama, Masashi Mukoyama, Takuro Mizukami, Tsutomu Sakurada, Eishi Baba, Kazuhiko Tsuruya, Akira Nozaki, Kensei Yahata, Yukinori Ozaki, Yoshifumi Ubara, Hisateru Yasui, Akihiro Yoshimoto, Shingo Fukuma, Naoya Kondo, Takeshi Matsubara, Kazuo Matsubara, Shunichi Fukuhara, Motoko Yanagita, Manabu Muto, Chemotherapy in cancer patients undergoing haemodialysis A nationwide study in Japan, ESMO Open, 10.1136/esmoopen-2017-000301, 3, 2, 2018.02, [URL], Background Cancer is a major cause of death in patients undergoing haemodialysis. However, information about the actual clinical practice of chemotherapy for patients with cancer undergoing haemodialysis is lacking. We conducted a nationwide survey using questionnaires on the clinical practice of chemotherapy for such patients. Patients and methods The nationwide survey included patients undergoing haemodialysis who were subsequently diagnosed with cancer in 20 hospitals in Japan from January 2010 to December 2012. We reviewed their clinical data, including cancer at the following primary sites: kidney, colorectum, stomach, lung, liver, bladder, pancreas and breast. The questionnaires consisted of the following subjects: (1) patient characteristics; (2) regimen, dosage and timing of chemotherapy; and (3) clinical outcome. Results Overall, 675 patients were registered and assessed for main primary cancer site involvement. Of 507 patients with primary site involvement, 74 patients (15%) received chemotherapy (44 as palliative chemotherapy and 30 as perioperative chemotherapy). The most commonly used cytotoxic drugs were fluoropyrimidine (15 patients), platinum (8 patients) and taxane (8 patients), and the dosage and timing of these drugs differed between institutions; however, the dosage of molecular targeted drugs (24 patients) and hormone therapy drugs (15 patients) was consistent. The median survival time of patients receiving palliative chemotherapy was 13.0 months (0.1-60.3 months). Three patients (6.8%) died from treatment-related causes and nine patients (20%) died of causes other than cancer. Of the 30 patients who received perioperative chemotherapy, 6 (20%) died of causes other than cancer within 3 years after the initiation of chemotherapy. Conclusion Among the haemodialysis patients with cancer who received chemotherapy, the rates of mortality from causes other than cancer might be high for both palliative and perioperative chemotherapy. Indications for the use of chemotherapy in patients undergoing haemodialysis should be considered carefully.. |
| 102. | Takanobu Nobori, Kenta Tosaka, Akira Kawamura, Taisei Joichi, Kenta Kamino, Akihiro Kishimura, Eishi Baba, Takeshi Mori, Yoshiki Katayama, Alkaline Phosphatase-Catalyzed Amplification of a Fluorescence Signal for Flow Cytometry., Analytical chemistry, 10.1021/acs.analchem.7b03893, 90, 2, 1059-1062, 2018.01, [URL], Despite the expanding use of flow cytometry, its detection limit is not satisfactory for many antigen proteins with low copy numbers. Herein, we describe an alkaline phosphatase (AP)-based technique to amplify the fluorescence signal for cell staining applications. We designed a fluorescent substrate that acquires membrane permeability upon dephosphorylation by AP. By using the substrate, the fluorescence signal of cells in flow cytometry could be successfully amplified to give a much stronger signal than the cells labeled using a conventional fluorophore-modified antibody.. |
| 103. | Toshikazu Moriwaki, Shota Fukuoka, Hiroya Taniguchi, Atsuo Takashima, Yusuke Kumekawa, Takeshi Kajiwara, Kentaro Yamazaki, Taito Esaki, Chinatsu Makiyama, Tadamichi Denda, Hironaga Satake, Takeshi Suto, Naotoshi Sugimoto, Masanobu Enomoto, Toshiaki Ishikawa, Tomomi Kashiwada, Masahiko Sugiyama, Yoshito Komatsu, Hiroyuki Okuyama, Eishi Baba, Daisuke Sakai, Tomoki Watanabe, Takao Tamura, Kimihiro Yamashita, Masahiko Gosho, Yasuhiro Shimada, Propensity Score Analysis of Regorafenib Versus Trifluridine/Tipiracil in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapy (REGOTAS): A Japanese Society for Cancer of the Colon and Rectum Multicenter Observational Study., The oncologist, 10.1634/theoncologist.2017-0275, 23, 1, 7-15, 2018.01, [URL], BACKGROUND: This study compared the efficacy of regorafenib and trifluridine/tipiracil (TFTD) in patients with metastatic colorectal cancer (mCRC) who are refractory to standard chemotherapy, because despite their clinical approval, it still remains unclear which of these two drugs should be used as initial treatment. MATERIALS AND METHODS: The clinical data of patients with mCRC who were treated with regorafenib or TFTD and those of drug-naive patients, between June 2014 and September 2015, were retrospectively collected from 24 institutions in Japan. Overall survival (OS) was evaluated using the Cox's proportional hazard models based on propensity score adjustment for baseline characteristics. RESULTS: A total of 550 patients (223 patients in the regorafenib group and 327 patients in the TFTD group) met all criteria. The median OS was 7.9 months (95% confidence interval [CI], 6.8-9.2) in the regorafenib group and 7.4 months (95% CI, 6.6-8.3) in the TFTD group. The propensity score adjusted analysis showed that OS was similar between the two groups (adjusted hazard ratio [HR], 0.96; 95% CI, 0.78-1.18). In the subgroup analysis, a significant interaction with age was observed. Regorafenib showed favorable survival in patients aged |
| 104. | Hiroshi Saeki, Yasunori Emi, Eiji Oki, Shoji Tokunaga, Yoshihiro Kakeji, Yoshito Akagi, Hideo Baba, Eishi Baba, Yoshihiko Maehara, Study protocol of a phase II clinical trial (KSCC1501A) examining oxaliplatin + S-1 for treatment of HER2-negative advanced/recurrent gastric cancer previously untreated with chemotherapy., BMC cancer, 10.1186/s12885-017-3937-6, 18, 1, 57-57, 2018.01, [URL], BACKGROUND: Oxaliplatin + S-1 is a recognized treatment regimen in Japan, but there are no Japanese clinical data on an oxaliplatin dose of 130 mg/m2. The current research involves a single-arm, prospective, phase II clinical trial to examine the efficacy and safety of oxaliplatin + S-1 with an oxaliplatin dose of 130 mg/m2 to treat HER2-negative advanced/recurrent gastric cancer previously untreated with chemotherapy in Japan. METHODS/DESIGN: The primary endpoint of this trial will be the response rate, and the secondary endpoints will be the safety profile of oxaliplatin + S-1, progression-free survival, the response rate in subjects under the age of 75, overall survival, time to treatment failure, duration of treatment, time to failure of strategy, and dose intensity. The threshold response rate is 45% and the expected response rate is 60%. Assuming that a one-tailed score test will be performed with an α of 0.05, 68 patients are needed to ensure a statistical power of 80%. Planned enrollment is 70 subjects and the total duration of this trial is expected to be 3 years. DISCUSSION: Since replacing cisplatin with oxaliplatin should provide the same level of therapeutic efficacy while limiting adverse events and simplifying treatment, oxaliplatin + S-1 may be increasingly used to treat gastric cancer in Japan. Verifying the efficacy and safety of oxaliplatin + S-1 with an oxaliplatin dose of 130 mg is an important task that the current trial has set out to achieve. TRIAL REGISTRATION: The protocol was registered at the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID UMIN000017550) on May 29, 2015. The details are available at the following web address: http://www.umin.ac.jp/ctr/ .. |
| 105. | Kenji Tsuchihashi, Tomoyasu Yoshihiro, Tomomi Aikawa, Kenta Nio, Kotoe Takayoshi, Taku Yokoyama, Mitsuhiro Fukata, Shuji Arita, Hiroshi Ariyama, Yukiko Shimizu, Yuichiro Yoshida, Takehiro Torisu, Motohiro Esaki, Keita Odashiro, Hitoshi Kusaba, Koichi Akashi, Eishi Baba, Metastatic esophageal cancer presenting as shock by injury of vagus nerve mimicking baroreceptor reflex: A case report, Medicine (United States), 10.1097/MD.0000000000008987, 96, 49, 2017.12, [URL], Rationale: Neurogenic shock is generally typified by spinal injury due to bone metastases in cancer patients, but continuous disturbance of the vagus nerve controlling the aortic arch baroreceptor can cause shock by a reflex response through the medulla oblongata. Patient concerns: A 43-year-old woman with dysphagia presented to our hospital. Computed tomography showed a primary tumor adjacent to and surrounding half the circumference of the descending aorta, and multiple cervical lymph node metastases, including a 55 × 35-mm lymph node overlapping the root of the left vagus nerve. Squamous esophageal cancer (T4bN3M1, stage IV) was diagnosed. Whereas shock status initially appeared soon after left cervical pain, suggesting pain-induced neutrally-mediated syncope, sustained bradycardia and hypotension occurred even after alleviation of pain by opioids. Diagnosis: Disturbance of the left vagus nerve associated with the aortic arch baroreceptor by a large left cervical lymph node metastasis was considered as the cause of shock, pathologically mimicking the baroreceptor reflex. Interventions: Systemic steroid administration was performed, and radiotherapy for both the primary site and lymph node metastasis was started 2 days after initiating steroid treatment. Outcomes: Four days after initiating steroid administration, hypotension and bradycardia were improved and stable. Lessons: Disturbance of the vagus nerve controlling the aortic arch baroreceptor should be kept in mind as a potential cause of neurogenic shock in cancer patients, through a pathological reflex mimicking the baroreceptor reflex.. |
| 106. | Tatsuhiro Kajitani, Akitaka Makiyama, Shuji Arita, Hozumi Shimokawa, Hisanobu Oda, Tsuyoshi Shirakawa, Eishi Baba, Taito Esaki, Anti-Epidermal Growth Factor Receptor Antibody Readministration in Chemorefractory Metastatic Colorectal Cancer, ANTICANCER RESEARCH, 10.21873/anticanres.12101, 37, 11, 6459-6468, 2017.11, [URL], Background/Aim: Readministration of anti-epidermal growth factor receptor (EGFR) antibody for metastatic colorectal cancer (mCRC) after disease progression remains to be determined. Patients and Methods: Readministration of anti-EGFR antibody in mCRC patients previously refractory to anti-EGFR antibody was prospectively observed. Results: A total of thirteen patients with a median age of 60-years old and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, were enrolled. The median number of previous chemotherapies was 3 (range 2-5). Prior anti-EGFR antibody in combination with cytotoxic drugs was administered in 12 patients. Anti-EGFR antibody readministration regimens were cetuximab/panitumumab plus capecitabine/S-1 (seven patients), panitumumab plus FOLFOX (three patients), cetuximab plus irinotecan (two patients), and panitumumab monotherapy (one patient). Seven patients showed stable disease following readministration and six patients showed progressive disease. The median overall survival (OS) following readministration was 228 days and the median PFS was 102 days. Patients with intervals longer than 90 days between anti-EGFR therapies exhibited more favorable survival than those with intervals shorter than 90 days. Switching of anti-EGFR antibody between treatments was observed to contribute survival. Conclusion: Anti-EGFR antibody readministration could show a modest survival benefit in mCRC patients, with the length of therapy interval and switching of antibody being important contributory factors.. |
| 107. | Tomoyasu Yoshihiro, Kenji Tsuchihashi, Kenta Nio, Shuji Arita, Takafumi Nakano, Ryuji Yasumatsu, Rina Jiroumaru, Hiroshi Ariyama, Hitoshi Kusaba, Yoshinao Oda, Koichi Akashi, Eishi Baba, Lingual alveolar soft part sarcoma responsive to pazopanib: A case report, MEDICINE, 10.1097/MD.0000000000008470, 96, 44, 2017.11, [URL], Rationale:The multi-targeted tyrosine kinase inhibitors such as cediranib, sunitinib and pazopanib have been reported to be effective for alveolar soft part sarcoma (ASPS). The efficacy of pazopanib for the patient with lingual ASPS has yet to be reported.Patient concerns:A 23-year old man presented with articulation disorder and swelling of the tongue. Diagnosis of lingual ASPS was made after incisional biopsy and complete excision of the mass was performed. Three months later, he presented with a protruding mental region.Diagnoses:Computed tomography revealed mental region mass and lung metastasis.Interventions:After the failure of combination therapy of doxorubicin and ifosfamide, pazopanib was administered.Outcomes:Shrinkage of both the mental region and lung mass continued for more than two months, but regrowth was confirmed at the fourth month.Lessons:Lingual ASPS is an exceedingly rare subset of ASPS with distinct molecular and histological characteristics and appropriate therapy remains to be established. Our findings suggest a possible therapeutic strategy for lingual ASPS.. |
| 108. | Takahiro Horimatsu, Norisuke Nakayama, Toshikazu Moriwaki, Yoshinori Hirashima, Mikio Fujita, Masako Asayama, Ichiro Moriyama, Koji Nakashima, Eishi Baba, Hiroshi Kitamura, Takao Tamura, Ayumu Hosokawa, Kenichi Yoshimura, Manabu Muto, A phase II study of 5-fluorouracil/L-leucovorin/oxaliplatin (mFOLFOX6) in Japanese patients with metastatic or unresectable small bowel adenocarcinoma, INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY, 10.1007/s10147-017-1138-6, 22, 5, 905-912, 2017.10, [URL], Several studies have suggested that chemotherapy prolonged survival in patients with metastatic or recurrent small bowel adenocarcinoma (SBA); however, there is still no standard chemotherapy regimen. Here, we evaluated the efficacy and safety of a 5-fluorouracil (5-FU)/L-leucovorin (l-LV)/oxaliplatin (mFOLFOX6) protocol as a first-line therapy for patients with SBA. This was a multicenter, single-arm, open-label phase II study. Eligibility criteria included histologically confirmed adenocarcinoma, age 20-80 years, and an Eastern Cooperative Oncology Group performance status (PS) of 0-2. The primary endpoint was 1-year progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), overall survival (OS), overall PFS, and safety. Between April 2010 and November 2012, 24 patients were enrolled from 12 institutions. The median age of the patients was 63 years (range 31-79) and there was a male/female ratio of 18/6. The number of PS 0/1 patients was 17/7 and locally advanced/metastatic disease was seen in 2/22 patients, respectively. The primary tumor site was the duodenum in 14 patients (58%) and jejunum in 10 patients (42%). The median follow-up time was 14.7 months (3.7-40.3). The 1-year PFS was 23.3%. The ORR was 9/20 (45%). The median PFS and OS times were 5.9 months (95% confidence interval [CI] 3.0-10.2) and 17.3 months (95% CI 11.7-19.0), respectively. Major grade 3/4 toxicities were neutropenia (38%), anemia/peripheral neuropathy (25%), and stenosis (17%). There were no treatment-related deaths. Although the primary endpoint was not met, mFOLFOX6 showed effective and good tolerance as a first-line treatment for SBA.. |
| 109. | Kenta Nio, Kenji Tsuchihashi, Hitoshi Kusaba, Tomoyasu Yoshihiro, Shuji Arita, Hiroshi Ariyama, Takeshi Arita, Keita Odashiro, Koichi Akashi, Eishi Baba, A retrospective analysis for thromboembolic events associated with multikinase inhibitors, ANNALS OF ONCOLOGY, 28, ix77, 2017.10, [URL]. |
| 110. | Kenji Tsuchihashi, Hozumi Shimokawa, Kotoe Takayoshi, Kenta Nio, Tomomi Aikawa, Yuzo Matsushita, Iori Wada, Shuji Arita, Hiroshi Ariyama, Hitoshi Kusaba, Koh-Hei Sonoda, Koichi Akashi, Eishi Baba, Regorafenib-induced retinal and gastrointestinal hemorrhage in a metastatic colorectal cancer patient with liver dysfunction: A case report, MEDICINE, 10.1097/MD.0000000000008285, 96, 42, 2017.10, [URL], Rationale:Regorafenib is effective for metastatic colorectal cancer but its toxicity such as hemorrhage should be considered. The safety of regorafenib for the patient with the liver disease is not known.Patient concerns:Seventy-one-year old man of colon cancer had myodesopsia and blood stool after 14 days from the initiation of regorafenib administration with 50% dose reduction due to liver dysfunction.Diagnoses:Fundus examination revealed hemorrhage of the retinal vein.Interventions:Regorafenib treatment was discontinued and observational therapy was pursued.Outcomes:Retinal and gastrointestinal hemorrhage resolved in 1 week.Lessons:Retinal hemorrhage should be considered as the differential diagnosis of myodesopsia in the patient treated by regorafenib. Safety and pharmacokinetic of continuous regorafenib administration for patients with liver dysfunction remains to be clarified.. |
| 111. | Kotoe Takayoshi, Hitoshi Kusaba, Masato Uenomachi, Kenji Mitsugi, Chinatsu Makiyama, Akitaka Makiyama, Keita Uchino, Tsuyoshi Shirakawa, Yoshihiro Shibata, Yudai Shinohara, Kyoko Inadomi, Kenji Tsuchihashi, Shuji Arita, Hiroshi Ariyama, Taito Esaki, Koichi Akashi, Eishi Baba, Suggestion of added value by bevacizumab to chemotherapy in patients with unresectable or recurrent small bowel cancer, CANCER CHEMOTHERAPY AND PHARMACOLOGY, 10.1007/s00280-017-3371-0, 80, 2, 333-342, 2017.08, [URL], Purpose Standard therapy for advanced small bowel adenocarcinoma (SBA) has not yet been established. The present study assessed the efficacy and safety of chemotherapy (CT) in association with molecular targeting approaches for SBA. Methods The histories of 33 advanced SBA patients from six different institutions in Japan, who received CT from 2008 to 2016, were retrospectively examined for background, clinical course and outcome. Results Median patient age was 65 years (range 39-83). Primary tumor was located in the duodenum in 21 patients (67%), the ampulla of Vater in three patients (9%), the jejunum in seven patients (21%) and the ileum in one patient (3%). Histologically, well-to-moderately and poorly differentiated adenocarcinoma were identified in 20 (61%) and nine (27%) patients, respectively. Thirteen patients received a single CT regimen, seven patients received two types of CT regimen, and 13 patients received three or more CT regimens. As first-line CT, modified FOLFOX6, capecitabine plus oxaliplatin, and S-1 plus cisplatin were employed in 13, 1, and 4 patients, respectively. The response rate (RR) and median progression-free survival (PFS) were 25% and 6.0 months, respectively. Median overall survival (OS) was 13.0 months. Nine out of the 33 patients received bevacizumab-containing CT and three received cetuximab-containing CT. Median OS of bevacizumab-containing CT patients was 21.9 months. No unexpected serious adverse events were observed. Conclusions The analysis indicates that combination CT for advanced SBA is associated with modest efficacy and safety, and bevacizumab-containing CT may contribute to favorable outcome in these patients.. |
| 112. | Noriko Hidaka, Eiji Iwama, Naoki Kubo, Taishi Harada, Kohta Miyawaki, Kentaro Tanaka, Isamu Okamoto, Eishi Baba, Koichi Akashi, Hiroyuki Sasaki, Yoichi Nakanishi, Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non-small cell lung cancer, LUNG CANCER, 10.1016/j.lungcan.2017.02.019, 108, 75-82, 2017.06, [URL], Objectives: The T790M and C797S mutations of the epidermal growth factor receptor gene (EGFR) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR. C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerise chain reaction (dPCR)-based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation). Materials and Methods: Seven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations. Results: The median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M-positive alleles was 97.1% (range, 90.0-100%). Confirmatory analysis by next-generation sequencing yielded a corresponding value of 96.7% (range, 89.1-99.5%). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner. Conclusions: Almost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR-TKI treatment. (C) 2017 Elsevier B.V. All rights reserved.. |
| 113. | Kyoko Inadomi, Hitoshi Kusaba, Yuzo Matsushita, Risa Tanaka, Kenji Mitsugi, Kohei Arimizu, Gen Hirano, Akitaka Makiyama, Hirofumi Ohmura, Keita Uchino, Fumiyasu Hanamura, Yoshihiro Shibata, Miyuki Kuwayama, Taito Esaki, Kotoe Takayoshi, Shuji Arita, Hiroshi Ariyama, Koichi Akashi, Eishi Baba, Efficacy and Safety Analysis of Oxaliplatin-based Chemotherapy for Advanced Gastric Cancer, ANTICANCER RESEARCH, 10.21873/anticanres.11614, 37, 5, 2663-2671, 2017.05, [URL], Background: Significant efficacy of oxaliplatin-based chemotherapy has been demonstrated for advanced gastric cancer (AGC). However, the appropriate dose of oxaliplatin, and the efficacy and toxicity of administration of oxaliplatin subsequent to cisplatin therapy still remain unclear. Patients and Methods: In total, 55 patients with AGC that were scheduled to receive oxaliplatin-based chemotherapy were prospectively examined. Results: The median age was 67 years and oxaliplatin was administered to 39 (71%) patients as first-line and in 16 (29%) patients as second-line therapy. An initial dose of 130 or 100 mg/m(2) of oxaliplatin was administered to 11 and 36 patients, respectively. The overall response rates (ORR) and median progression free survival (mPFS) were 86 and 33%, and 7.2 and 7.8 months, respectively. Compared to 100 mg/m(2), the relative dose intensity was significantly lower and severe toxicity tended to increase with oxaliplatin at 130 mg/m(2). A total of 10 patients (18%) had a prior cisplatin-based therapy. The ORR of the patients pretreated with cisplatin was 14% and the mPFS was 6.1 months. Conclusion: An initial oxaliplatin dose of 130 mg/m(2) resulted in a good response, but tended to increase the risk of toxicity. Subsequent oxaliplatin-based therapy after cisplatin exhibited modest efficacy, especially in cases with cisplatin intolerance.. |
| 114. | Kotoe Takayoshi, Keita Uchino, Masahiro Nakano, Koji Ikejiri, Eishi Baba, Weight Loss During Initial Chemotherapy Predicts Survival in Patients With Advanced Gastric Cancer, Nutrition and Cancer, 10.1080/01635581.2017.1267774, 69, 3, 408-415, 2017.04, [URL], Background: Patients with advanced gastric cancer (AGC) often suffer weight loss, which can be used to predict prognosis. Few reports have assessed the correlation between weight loss during chemotherapy and survival in patients with AGC. Methods: Fifty-three patients with histologically proven AGC, who started systemic chemotherapy from September 2010 to March 2014, were retrospectively examined for body weight, inflammatory status, and survival. Correlation analyses were performed between weight change and survival. Correlations between weight loss and the patient characteristics were analyzed by stepwise multiple regression analyses. Results: The mean age of the patients was 64.4 years; 64% of the patients were males. Initial chemotherapy included fluoropyrimidine plus cisplatin (62%), fluoropyrimidine alone (26%), and other medications (12%); 72% of the patients exhibited weight loss during the initial therapy. Poorer mean overall survival and mean progression-free survival were observed in patients with weight loss of higher-than-average values than in those with weight loss of lower-than-average values. Serum C-reactive protein levels were significantly correlated with weight loss. Conclusions: Weight loss during initial chemotherapy for AGC may predict survival. Systemic inflammation is suggested to be associated with weight loss.. |
| 115. | Mamoru Ito, Hitoshi Kusaba, Satomi Mukaide, Junji Kishimoto, Hozumi Shimokawa, Shingo Tamura, Akitaka Makiyama, Gen Hirano, Hisanobu Oda, Tsuyoshi Shirakawa, Masato Komoda, Keita Uchino, Risa Tanaka, Kenji Mitsugi, Taito Esaki, Shuji Arita, Hiroshi Ariyama, Koichi Akashi, Eishi Baba, Early tumor shrinkage indicates a favorable response to bevacizumab-based first-line chemotherapy for metastatic colorectal cancer, ANTI-CANCER DRUGS, 10.1097/CAD.0000000000000562, 28, 10, 1166-1173, 2017.11, [URL], A close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined. Seventy-three patients were enrolled and 61 patients were evaluable for survival by simple regression analysis. Bevacizumab-based chemotherapies were administered to 40 (66%) patients. The median EETS, DPR, progression-free survival, and OS were 16.1%, 27.2%, 8.0 months, and 19.5 months, respectively. Progression-free survival showed a positive correlation with OS (R-2= 0.429), whereas EETS and DPR were less correlated with OS (R-2= 0.0682, 0.186). EETS was well correlated with DPR (R-2=0.659). Patients with EETS greater than 16.12% were predicted to achieve tumor shrinkage of more than 30% at the maximum response. EETS in bevacizumab-treated mCRC showed a close correlation with DPR, which suggested that EETS might be useful, indicating a favorable response in treatment with bevacizumab-based chemotherapy. Copyright (c) 2017 Wolters Kluwer Health, Inc. All rights reserved.. |
| 116. | Nobuhiro Tsuruta, Kotoe Takayoshi, Shuji Arita, Tomomi Aikawa, Hiroshi Ariyama, Hitoshi Kusaba, Kenoki Ohuchida, Eishi Nagai, Kenichi Kohashi, Minako Hirahashi, Kyoko Inadomi, Mamoru Tanaka, Kosuke Sagara, Yuta Okumura, Kenta Nio, Michitaka Nakano, Masafumi Nakamura, Yoshinao Oda, Koichi Akashi, Eishi Baba, Systemic chemotherapy with pronounced efficacy and neutropenia in a granulocyte-colony stimulating factor-producing advanced gastric neuroendocrine carcinoma, ONCOLOGY LETTERS, 10.3892/ol.2017.6299, 14, 2, 1500-1504, 2017.08, [URL], An advanced granulocyte-colony stimulating factor (G-CSF)-producing tumor is rare, and it exhibits leukocytosis in association with high serum G-CSF levels. A 67-year-old male with a 1-month history of bloody emesis and black stools was revealed to exhibit leukocytosis, anemia and a high serum concentration of G-CSF. During a gastrointestinal endoscopy, an ulcerating tumor was identified in the stomach. Computed tomography and a fluorodeoxyglucose-positron emission tomography scan demonstrated direct invasion of the gastric tumor into the transverse colon, regional lymphadenopathy, lung nodules and diffuse high uptake of FDG in bone marrow. The histological diagnosis was a G-CSF-producing neuroendocrine carcinoma (NEC) (tumor 4b, node 2, metastasis 1, pulmonary, clinical stage IV). Systemic chemotherapy consisting of cisplatin and irinotecan was started. Common terminology criteria of adverse events grade 3 tumor lysis syndrome and gastric penetration appeared. Grade 4 neutropenia lasted for 10 days despite intensive G-CSF administration. Prominent shrinkage of the primary and the metastatic tumors was observed subsequent to 3 cycles of chemotherapy. Total gastrectomy and resection of the transverse colon were subsequently performed. Systemic chemotherapy was effective for a G-CSF-producing advanced gastric NEC with careful monitoring and appropriate supportive care for severe adverse events.. |
| 117. | Hanamura F, Shibata Y, Shirakawa T, Kuwayama M, Oda H, Ariyama H, Taguchi K, Esaki T, Baba E, Favorable control of advanced colon adenocarcinoma with severe bone marrow metastasis: A case report., Molecular and clinical oncology, 10.3892/mco.2016.1029, 5, 5, 579-582, 2016.11, [URL]. |
| 118. | Tsuyoshi Shirakawa, Michitaka Nakano, Kenta Nio, Shingo Tamura, Masato Komoda, Hozumi Kumagai, Keita Uchino, Keita Odashiro, Shuji Arita, Yoshihiro Shibata, Hiroshi Ariyama, Hitoshi Kusaba, Koichi Akashi, Eishi Baba, Retrospective analysis of cardiovascular diseases related to chemotherapies for advanced solid tumor patients, ANTI-CANCER DRUGS, 10.1097/CAD.0000000000000392, 27, 9, 891-898, 2016.10, [URL], Appropriate management of cardiovascular diseases (CVDs) related to chemotherapy for solid tumors is important for safe oncologic treatment. However, prediction of the onset and progression of CVDs has not generally been established in Japan. We carried out a retrospective analysis of advanced or recurrent solid tumor patients who received chemotherapies in a single institution. Patient characteristics, chemotherapy regimens, adverse events, CVDs before chemotherapy, and diagnosis of CVDs in association with chemotherapy were assessed. During the period from April 2006 to March 2012, 394 patients were examined. Cardiac diseases (CDs), hypertension (HT), or arterial thrombosis or venous thromboembolism were prevalent in 37 (9.4%), 22 (5.6%), five (1.3%), and 14 (3.5%) cases, respectively. HT (14.5%) and venous thrombosis (5.8%) were frequent in patients who received bevacizumab-containing chemotherapy. Four cases with left ventricular dysfunction experienced a decrease of ejection fraction and early filling/atrial filling (E/A) and E/A tended to decrease before ejection fraction. Ninety (62.1%) of 145 cases showed an increase in the d-dimer (DD) level before chemotherapy, and a further increase in DD level was found when venous thrombosis occurred. Relative risks of the disease progression of HT, CD, and thromboembolism because of chemotherapy were 1.3, 1.9, and 3.6, respectively. A decrease in E/A and an increase in DD were suggested to be valuable for early diagnosis of the respective onsets of left ventricular dysfunction and venous thrombosis related to chemotherapy. We conclude that patients with previous CD tend to have disease progression of CD during chemotherapy.. |
| 119. | K Yamazaki, M Nagase, H Tamagawa, S Ueda, T Tamura, K Murata, T Eguchi Nakajima, E Baba, M Tsuda, T Moriwaki, T Esaki, Y Tsuji, K Muro, K Taira, T Denda, S Funai, K Shinozaki, H Yamashita, N Sugimoto, T Okuno, T Nishina, M Umeki, T Kurimoto, T Takayama, A Tsuji, M Yoshida, A Hosokawa, Y Shibata, K Suyama, M Okabe, K Suzuki, N Seki, K Kawakami, M Sato, K Fujikawa, T Hirashima, T Shimura, K Taku, T Otsuji, F Tamura, E Shinozaki, K Nakashima, H Hara, T Tsushima, M Ando, S Morita, N Boku, I Hyodo, Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G)., Annals of oncology : official journal of the European Society for Medical Oncology, 10.1093/annonc/mdw206, 27, 8, 1539-46, 2016.08, [URL], BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.. |
| 120. | Kyoko Inadomi, Hozumi Kumagai, Shuji Arita, Nobuhiro Tsuruta, Kotoe Takayoshi, Koji Mishima, Shun-Ichiro Ota, Mamoru Tanaka, Yuta Okumura, Kosuke Sagara, Kenta Nio, Michitaka Nakano, Hiroshi Uchi, Hidetaka Yamamoto, Hiroshi Ariyama, Hitoshi Kusaba, Hiroaki Niiro, Yoshinao Oda, Koichi Akashi, Eishi Baba, Bi-cytopenia possibly induced by anti-PD-1 antibody for primary malignant melanoma of the esophagus A case report, MEDICINE, 10.1097/MD.0000000000004283, 95, 29, 2016.07, [URL], Background: Anti-programmed cell death 1 antibody nivolumab is a promising agent for various cancers. Immune-related adverse events are recognized; however, bi-cytopenia with nivolumab has not been reported. Case presentation: A 73-year-old man was diagnosed with advanced primary malignant melanoma of the esophagus with liver, lung, and lymph node metastases. Previous therapies including dacarbazine and radiation of 39 Gy to the esophageal region were performed, but the liver metastases deteriorated. The patient was then administered nivolumab (2 mg/kg, every 3 weeks). After 3 cycles, the esophageal tumor and lymph nodes showed marked reductions in size, the lung metastases disappeared, and the liver metastases shrank partially. The treatment continued with 7 cycles for 4 months. However, severe anemia and thrombocytopenia appeared in the 6th cycle, and intermittent blood transfusions were required. The patient received high-dose intravenous methylprednisolone therapy for bi-cytopenia, but it was ineffective. Seven months after the initiation of nivolumab, the patient died of tumor. Although the mechanisms of bi-cytopenia were unclear, it could have been induced by nivolumab. Conclusion: The present case shows a rare but serious life-threatening bi-cytopenia possibly associated with nivolumab and suggests the importance of awareness of hematological adverse events during nivolumab therapy.. |
| 121. | Nio K, Higashi D, Kumagai H, Arita S, Shirakawa T, Nakashima K, Shibata Y, Esaki M, Manabe T, Nagai S, Ueki T, Nakano M, Ariyama H, Kusaba H, Hirahashi M, Oda Y, Esaki T, Mitsugi K, Futami K, Akashi K, Baba E, Efficacy and safety analysis of chemotherapy for advanced colitis-associated colorectal cancer in Japan., Anti-cancer drugs, 10.1097/CAD.0000000000000338, 27, 5, 457-463, 2016.06, [URL]. |
| 122. | Mutsunori Murahashi, Yasuki Hijikata, Kazunari Yamada, Yoshihiro Tanaka, Junji Kishimoto, Hiroyuki Inoue, Tomotoshi Marumoto, Atsushi Takahashi, Toshihiko Okazaki, Kazuyoshi Takeda, Masakazu Hirakawa, Hiroshi Fujii, Shinji Okano, Masaru Morita, Eishi Baba, Kazuhiro Mizumoto, Yoshihiko Maehara, Masao Tanaka, Koichi Akashi, Yoichi Nakanishi, Koji Yoshida, Takuya Tsunoda, Kazuo Tamura, Yusuke Nakamura, Kenzaburo Tani, Phase I clinical trial of a five-peptide cancer vaccine combined with cyclophosphamide in advanced solid tumors, CLINICAL IMMUNOLOGY, 10.1016/j.clim.2016.03.015, 166, 48-58, 2016.05, [URL], We designed a phase I trial to investigate the safety, immune responses and clinical benefits of a five-peptide cancer vaccine in combination with chemotherapy. Study subjects were patients positive for HLA-A2402 with locally advanced, metastatic, and/or recurrent gastrointestinal, lung or cervical cancer. Eighteen patients including nine cases of colorectal cancer were treated with escalating doses of cyclophosphamide 4 days before vaccination. Five HLA-A2402-restricted, tumor-associated antigen (TAA) epitope peptides from KOC1, TTK, URLC10, DEPDC1 and MPHOSPH1 were injected weekly for 4 weeks. Treatment was well tolerated without any adverse events above grade 3. Analysis of peripheral blood lymphocytes showed that the number of regulatory T cells dropped from baseline after administration of cyclophosphamide and confirmed that TAA-specific T cell responses were associated significantly with longer overall survival. This phase I clinical trial demonstrated safety and promising immune responses that correlated with vaccine-induced T-cell responses. Therefore, this approach warrants further clinical studies. (C) 2016 Elsevier Inc. All rights reserved.. |
| 123. | Kenji Tsuchihashi, Shogo Okazaki, Mitsuyo Ohmura, Miyuki Ishikawa, Oltea Sampetrean, Nobuyuki Onishi, Hiroaki Wakimoto, Momoko Yoshikawa, Ryo Seishima, Yoshimi Iwasaki, Takayuki Morikawa, Shinya Abe, Ayumi Takao, Misato Shimizu, Takashi Masuko, Motoo Nagane, Frank B. Furnari, Tetsu Akiyama, Makoto Suematsu, Eishi Baba, Koichi Akashi, Hideyuki Saya, Osamu Nagano, The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-), Cancer Research, 10.1158/0008-5472.CAN-15-2121, 76, 10, 2954-2963, 2016.05, [URL], Extracellular free amino acids contribute to the interaction between a tumor and its microenvironment through effects on cellular metabolism and malignant behavior. System xc(-) is composed of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. Here, we show that the EGFR interacts with xCT and thereby promotes its cell surface expression and function inhumanglioma cells. EGFR-expressing glioma cells manifested both enhanced antioxidant capacity as a result of increased cystine uptake, as well as increased glutamate, which promotes matrix invasion. Imaging mass spectrometry also revealed that brain tumors formed in mice by human glioma cells stably overexpressing EGFR contained higher levels of reduced glutathione compared with those formed by parental cells. Targeted inhibition of xCT suppressed the EGFR-dependent enhancement of antioxidant capacity in glioma cells, as well as tumor growth and invasiveness. Our findings establish a new functional role for EGFR in promoting the malignant potential of glioma cells through interaction with xCT at the cell surface.. |
| 124. | Arita S, Shirakawa T, Matsushita Y, Shimokawa HK, Hirano G, Makiyama A, Shibata Y, Tamura S, Esaki T, Mitsugi K, Ariyama H, Kusaba H, Akashi K, Baba E, Efficacy and Safety of TAS-102 in Clinical Practice of Salvage Chemotherapy for Metastatic Colorectal Cancer., Anticancer research, 36, 4, 1959-1966, 2016.04. |
| 125. | Iwama E, Okamoto I, Yabuuchi H, Takayama K, Harada T, Matsuo Y, Tokunaga S, Baba E, Nakanishi Y, Characteristics of Smoking Patients with Lung Cancer with Emphysematous Bullae., Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 10.1016/j.jtho.2016.04.024, 11, 9, 1586-90, 2016.09, [URL]. |
| 126. | Hitoshi Kusaba, Hozumi Kumagai, Kyoko Inadomi, Tomoya Matsunobu, Katsumi Harimaya, Kotoe Takayoshi, Shuji Arita, Hiroshi Ariyama, Koichi Akashi, Eishi Baba, Efficacy analysis of the aprepitant-combined antiemetic prophylaxis for non-round cell soft-tissue sarcoma patients received adriamycin and ifosfamide therapy, MEDICINE, 10.1097/MD.0000000000005460, 95, 49, e5460, 2016.12, [URL], Appropriate antiemetic prophylaxis for moderately emetogenic chemotherapy in patients with non-round cell soft-tissue sarcomas (NRC-STS) remains unclear. We retrospectively investigated efficacy and safety of aprepitant-combined antiemetic prophylaxis in patients with NRC-STS receiving adriamycin plus ifosfamide (AI) therapy. Forty NRC-STS patients were enrolled, their median age was 50 years (range 18-74), and 13 (32.5%) were female. Median cycle number of AI therapy was 4. Twenty patients received the doublet antiemetic prophylaxis (5-hydroxytryptamine-3 receptor antagonist and dexamethasone), and 20 received triplet (5-hydroxytryptamine-3 receptor antagonist, dexamethasone, and aprepitant). In the overall period, complete response rate for nausea and emesis in the triplet group was significantly higher than that in the doublet group (70% vs 35%; P=0.027). Patients with no-emesis in the overall period were more frequently observed in the triplet group than in the doublet group (90% vs 65%; P=0.058). All toxicities other than emesis were almost equivalent in both the groups. These results suggest that a triplet antiemetic prophylaxis may be optimal in the treatment with AI therapy for NRC-STS.. |
| 127. | Miyuki Kuwayama, Keita Uchino, Kotoe Takayoshi, Masato Komoda, Motoyuki Kohjima, Makoto Nakamuta, Seiya Momosaki, Hitoshi Kusaba, Koichi Akashi, Eishi Baba, Immunosuppressant therapy successfully improved regorafenib-induced severe hepatic injury in a patient with metastatic gastrointestinal stromal tumor: A case report, ONCOLOGY LETTERS, 10.3892/ol.2015.3853, 11, 1, 85-88, 2016.01, [URL], A 75-year-old man diagnosed with ileal gastrointestinal tumor with peritoneal dissemination was subjected to salvage treatment with regorafenib at 120 mg/day. Following the initiation of the treatment, liver dysfunction appeared on day 28, and continued to worsen despite termination of the treatment. Since no increase in the levels of serum immunoglobulins of the patient was observed, and negative results were obtained for the analysis of viral markers and autoantibodies, a diagnosis of regorafenib-induced hepatitis was suggested. In consequence, the patient received steroid pulse therapy and continuous administration of prednisolone, without sufficient improvement. Liver biopsy revealed interface hepatitis with prominent plasma cell infiltration, suggesting regorafenib-induced autoimmune hepatitis. The patient was then administered azathioprine and prednisolone, which improved the hepatic injury. The present case represents the first report of successful treatment of regorafenib-induced severe hepatic injury by the use of an immunosuppressant.. |
| 128. | Kotoe Takayoshi, Hiroshi Ariyama, Shingo Tamura, Shunsuke Yoda, Takeshi Arita, Toshihiro Yamaguchi, Keigo Ozono, Hidetaka Yamamoto, Kyoko Inadomi, Hozumi Kumagai, Mamoru Tanaka, Yuta Okumura, Kosuke Sagara, Kenta Nio, Michitaka Nakano, Shuji Arita, Hitoshi Kusaba, Keita Odashiro, Yoshinao Oda, Koichi Akashi, Eishi Baba, Intraluminal superior vena cava metastasis from adenosquamous carcinoma of the duodenum: A case report, ONCOLOGY LETTERS, 10.3892/ol.2015.3938, 11, 1, 605-609, 2016.01, [URL], In 2013, a 76-year-old male with a cardiac pacemaker was diagnosed with adenosquamous carcinoma of the duodenum. SubSequently, a pancreatoduodenectomy and lymph node dissection were performed, and 12 cycles of adjuvant chemotherapy (modified FOLFOX6 regimen), which consisted of fluorouracil, leucovorin and oxaliplatin, were administered via a central venous catheter. At 5 months after the completion of adjuvant chemotherapy, the patient experienced the sudden onset of severe pain at the back right of the ear, edema of the right side of the face and right jugular vein dilatation. Computed tomography (CT) revealed filling defects in the superior vena cava (SVC) and right brachiocephalic vein, indicating catheter-induced venous thrombosis. Although the catheter was removed and anti-coagulation therapy, aspiration of the thrombosis and ballooning dilatation were performed immediately, the patient's symptoms were not ameliorated. Notably, histological examination following thrombus aspiration revealed metastatic cancer cells, and fluorodeoxyglucose-positron emission tomography/CT identified metabolically active nodules in the SVC at locations consistent with the initial duodenal tumors detected by CT and in the first thoracic vertebrae. The tumor thrombus rapidly increased in size and resulted in worsening dyspnea. Subsequently, radiotherapy was performed, followed by chemotherapy, which relieved the systemic symptoms and suppressed the tumor growth. Adenosquamous carcinoma of the duodenum is extremely rare, and to the best of our knowledge, intraluminal SVC metastasis as a result of adenosquamous carcinoma of the duodenum has not been reported previously. The placement of a cardiac pacemaker, central venous catheter and tumor cells possessing high metastatic potential are hypothesized to have contributed to this rare case of metastasis.. |
| 129. | Kyoko Inadomi, Hozumi Kumagai, Kotoe Takayoshi, Hiroshi Ariyama, Hitoshi Kusaba, Akihiro Nishie, Hidetaka Yamamoto, Ken Takase, Mamoru Tanaka, Kosuke Sagara, Yuta Okumura, Kenta Nio, Michitaka Nakano, Shuji Arita, Yoshinao Oda, Koichi Akashi, Eishi Baba, Successful combination chemotherapy for metastatic inflammatory myofibroblastic tumor: A case report, ONCOLOGY LETTERS, 10.3892/ol.2015.3708, 10, 5, 2981-2985, 2015.11, [URL], A 64-year-old male presented with increased abdominal fullness and fever. Radiological examination revealed moderate ascites, a tumor with a diameter of 12.5 cm in the mesenteric region, as well as multiple tumors in the thoracic and abdominal para-aortic regions and in the left supraclavicular regions. Pathohistological findings of the biopsy specimen revealed atypical spindle cells accompanied by infiltration of lymphocytes. The plasmacytes were positive for CD68, murine double minute 2 and S-100, while they were negative for a-smooth muscle actin, cyclin-dependent kinase 4 and anaplastic lymphoma kinase. Clinically, the patient presented systemic symptoms and laboratory results indicated an elevation in the inflammatory response, while the CT and MRI findings were consistent with an inflammatory myofibroblastic tumor (IMT). Based on the clinical and histological findings, the patient was diagnosed with IMT. In total, 4 cycles of combination chemotherapy with doxorubicin and ifosfamide were administered. Tumor size reduction by 50% was achieved subsequent to the 4th chemotherapy cycle. In conclusion, successful control of this rare metastatic IMT was achieved by systemic chemotherapy.. |
| 130. | M. H. Ryu, on behalf of the SOS study investigators, E. Baba, K. H. Lee, Y. I. Park, N. Boku, I. Hyodo, B. H. Nam, T. Esaki, C. Yoo, B. Y. Ryoo, E. K. Song, S. H. Cho, W. K. Kang, S. H. Yang, D. Y. Zang, D. B. Shin, S. R. Park, K. Shinozaki, T. Takano, Yoon-Koo Kang, Comparison of two different S-1 plus cisplatin dosing schedules as first-line chemotherapy for metastatic and/or recurrent gastric cancer: A multicenter, randomized phase III trial (SOS), Annals of Oncology, 10.1093/annonc/mdv316, 26, 10, 2097-2101, 2015.10, [URL], Background: Five-weekly S-1 plus cisplatin (SP5) is one of the standard first-line regimens for advanced gastric cancer (GC), proven in a Japanese phase III study. To enhance the dose intensity of cisplatin, 3-weekly S-1 plus cisplatin (SP3) was developed. Patients and methods: This multicenter, randomized, open-label, phase III study evaluated whether SP3 (S-1 80 mg/ m2/day on days 1-14 and cisplatin 60 mg/m2 on day 1) was noninferior/superior to SP5 (S-1 80-120 mg/day on days 1-21 and cisplatin 60 mg/m2 on day 1 or 8) in terms of progression-free survival (PFS). Chemotherapy-naive patients with metastatic, recurrent gastric or gastroesophageal junction adenocarcinoma were randomized 1 : 1 to receive either SP3 or SP5. The trial is registered at ClinicalTrials.gov (NCT00915382). Results: Between February 2009 and January 2012, 625 patients were randomized at 42 sites in Korea and Japan. With a median follow-up duration of 32.4 months (range, 13.3-48.6 months) in surviving patients, SP3 was not only noninferior but also superior to SP5 in terms of PFS [median 5.5 versus 4.9 months hazard ratio (HR) = 0.82 95% confidence interval (CI) 0.68-0.99 P = 0.0418 for superiority). There was no difference in overall survival (OS) between the groups (median 14.1 versus 13.9 months HR = 0.99 95% CI 0.81-1.21 P = 0.9068). In patients with measurable disease, the response rates were 60% in the SP3 arm and 50% in the SP5 arm (P = 0.065). Both regimens were generally well tolerated, but grade 3 or higher anemia (19% versus 9%) and neutropenia (39% versus 9%) were more frequent in SP3. Conclusions: SP3 is superior to SP5 in terms of PFS. However, since the improvement in PFS was only slight and there was no difference in OS, both SP3 and SP5 can be recommended as first-line treatments for patients with advanced GC.. |
| 131. | Kotoe Takayoshi, Kosuke Sagara, Keita Uchino, Hitoshi Kusaba, Naotaka Sakamoto, Atsushi Iguchi, Eishi Baba, A case of metastatic renal cell carcinoma and bile duct carcinoma treated with a combination of sunitinib and gemcitabine, BMC CANCER, 10.1186/s12885-015-1443-2, 15, 2015.05, [URL], Background: Metastatic renal cell carcinoma (mRCC) had been a chemo-refractory disease, but recent advances in multiple kinase inhibitors such as sunitinib have dramatically changed the clinical course of mRCC. Sunitinib is used for mRCC chemotherapy based on the favorable results of a recent clinical trial, but specific biomarkers predicting efficacy and safety are not yet available. Locally advanced bile duct carcinoma (BDC) has generally been treated with single agent gemcitabine or as doublet therapy with cisplatin. Concomitant occurrence of mRCC and BDC is extremely rare, and a standard therapeutic strategy has not been established. Case presentation: A 65-year-old woman was diagnosed as having multiple mRCC and intercurrent, locally advanced BDC. A single course of combination therapy with sunitinib (25 mg/day, day2-15) and gemcitabine (750 mg/m(2), days 1, 8) was administered, and this showed obvious effects, with partial response for mRCC and stable disease for BDC. However, the patient also experienced severe adverse events, including hematological and various non-hematological toxicities; the combination therapy was then terminated on day 13 after its initiation. She recovered on day 28 and is alive 3.5 years after the diagnosis. The plasma trough levels of sunitinib and its active metabolite SU12662 on day 13 were 91.5 ng/mL and 19.2 ng/mL, respectively, which were relatively higher than in previous reports. Analysis of her single nucleotide polymorphisms (SNPs) detected TC in ABCB1 3435C/T, TC in 1236C/T and TT in 2677G/T, suggesting a possible TTT haplotype. Conclusion: A rare case of double cancer of mRCC and BDC was treated by combination chemotherapy. Although unknown synergistic mechanisms of these agents may be involved, severe toxicities might be possibly associated with high sunitinib exposure. Further exploration of combination therapy with sunitinib and gemcitabine is required.. |
| 132. | Eishi Baba, Koichi Akashi, The fundamental concept of cancer stem cell and the progress in cancer stem cell research, Nippon rinsho. Japanese journal of clinical medicine, 73, 5, 721-725, 2015.05, Stem cell is defined as the cell having the ability of self-renew and differentiation. Due to the development of flow cytometric analysis and immunodeficient mouse model, stem cell research had dramatically progressed. Based on the knowledge of normal stem cell, concept of cancer stem cell, which have self-renewal ability and tumorigenic potential in immunodeficient mouse, have been established. Cancer stem cell population in various cancers has been identified using cell surface markers, such as CD44, and therapeutic strategies have been developing. Moreover, as accumulating the knowledge of cancer stem cell, it has revealed that cancer stem cell has high plasticity. We introduce here the evolving cancer stem cell concept.. |
| 133. | Nio K, Arita S, Isobe T, Kusaba H, Kohashi K, Kajitani T, Tamura S, Hirano G, Mitsugi K, Makiyama A, Esaki T, Ariyama H, Oda Y, Akashi K, Baba E, Amrubicin monotherapy for patients with extrapulmonary neuroendocrine carcinoma after platinum-based chemotherapy., Cancer chemotherapy and pharmacology, 10.1007/s00280-015-2706-y, 75, 4, 829-835, 2015.04, [URL]. |
| 134. | Taniguchi H, Yamazaki K, Yoshino T, Muro K, Yatabe Y, Watanabe T, Ebi H, Ochiai A, Baba E, Tsuchihara K, Japanese Society of Medical Oncology, Japanese Society of Medical Oncology Clinical Guidelines: RAS (KRAS/NRAS) mutation testing in colorectal cancer patients., Cancer science, 10.1111/cas.12595, 106, 3, 324-327, 2015.03, [URL]. |
| 135. | Hozumi Kumagai, Hitoshi Kusaba, Eishi Baba, Anti-vascular endothelial growth factor antibody, Nihon rinsho. Japanese journal of clinical medicine, 73, 229-234, 2015.02. |
| 136. | Hitoshi Kusaba, Eishi Baba, Platinum drugs, Nippon rinsho. Japanese journal of clinical medicine, 73, 143-145, 2015.02. |
| 137. | Eiji Iwama, Koichi Takayama, Taishi Harada, Isamu Okamoto, Fumihiko Ookubo, Junji Kishimoto, Eishi Baba, Yoshinao Oda, Yoichi Nakanishi, Highly sensitive and quantitative evaluation of the EGFR T790M mutation by nanofluidic digital PCR, ONCOTARGET, 6, 24, 20466-20473, 2015.08, [URL], The mutation of T790M in EGFR is a major mechanism of resistance to treatment with EGFR-TKIs. Only qualitative detection (presence or absence) of T790M has been described to date, however. Digital PCR (dPCR) analysis has recently been applied to the quantitative detection of target molecules in cancer with high sensitivity. In the present study, 25 tumor samples (13 obtained before and 12 after EGFR-TKI treatment) from 18 NSCLC patients with activating EGFR mutations were evaluated for T790M with dPCR. The ratio of the number of T790M alleles to that of activating mutation alleles (T/A) was determined. dPCR detected T790M in all 25 samples. Although T790M was present in all pre-TKI samples from 13 patients, 10 of these patients had a low T/A ratio and manifested substantial tumor shrinkage during treatment with EGFR-TKIs. In six of seven patients for whom both pre-and post-TKI samples were available, the T/A ratio increased markedly during EGFR-TKI treatment. Highly sensitive dPCR thus detected T790M in all NSCLC patients harboring activating EGFR mutations whether or not they had received EGFR-TKI treatment. Not only highly sensitive but also quantitative detection of T790M is important for evaluation of the contribution of T790M to EGFR-TKI resistance.. |
| 138. | Hirano G, Makiyama A, Makiyama C, Esaki T, Oda H, Uchino K, Komoda M, Tanaka R, Matsushita Y, Mitsugi K, Shibata Y, Kumagai H, Arita S, Ariyama H, Kusaba H, Akashi K, Baba E, Reduced dose of salvage-line regorafenib monotherapy for metastatic colorectal cancer in Japan., Anticancer research, 35, 1, 371-377, 2015.01. |
| 139. | Hiroaki Ikesue, Toshikazu Tsuji, Koujiro Hata, Hiroyuki Watanabe, Kazuto Mishima, Mayako Uchida, Nobuaki Egashira, Toshihiro Miyamoto, Eishi Baba, Koichi Akashi, Koichi Takayama, Yoichi Nakanishi, Eriko Tokunaga, Tatsuro Okamoto, Yoshihiko Maehara, Akira Yokomizo, Seiji Naito, Makoto Kubo, Masao Tanaka, Satohiro Masuda, Time Course of Calcium Concentrations and Risk Factors for Hypocalcemia in Patients Receiving Denosumab for the Treatment of Bone Metastases From Cancer, ANNALS OF PHARMACOTHERAPY, 10.1177/1060028014539919, 48, 9, 1159-1165, 2014.09, [URL], Background:Severe hypocalcennia sometimes develops during denosumab treatment for bone metastases from cancer and is, therefore, an important issue. However, limited information is available on the risk factors for hypocalcemia and the appropriate interval for monitoring serum calcium concentration. Objective: The present study aimed to identify the risk factors for grade >= 2 hypocalcennia and to investigate the time course of serum calcium concentrations in patients receiving denosumab for bone metastases from cancer. Method: The medical records of 66 cancer patients treated with denosumab between April 2012 and August 2013 were retrospectively reviewed. Result: Of the 66 enrolled patients, 11, 5, and 1 developed grade 1, 2, and 3 hypocalcemia, respectively. All 4 patients with a baseline estimated glomerular filtration rate (eGFR) of <30 mL/min developed hypocalcemia. Hypocalcemia occurred in only 20%, 24%, and 15% of patients with an eGFR of 30 to 59, 60 to 89, and >= 90 mL/min, respectively. Multivariate logistic regression analysis revealed that lower eGFR values (odds ratio, 1.72 per 10 mL/min decrease, P = 0.02) were significantly associated with grade >= 2 hypocalcemia. In 11 patients who developed hypocalcemia during the first treatment course, the mean calcium concentrations decreased from 9.8 mg/dL at baseline to 8.4 mg/dL during the first week and reached a nadir of 8.1 mg/dL during the second week. Conclusion: Our results support more frequent monitoring of serum calcium concentrations at baseline and during the first 2 weeks of treatment in patients receiving denosumab, especially those with an eGFR <30 mL/min.. |
| 140. | Kosuke Sagara, Kotoe Takayoshi, Eiji Kusumoto, Keita Uchino, Taisei Matsumura, Hitoshi Kusaba, Seiya Momosaki, Koji Ikejiri, Eishi Baba, Favorable control of rapidly progressive retroperitoneal pleomorphic leiomyosarcoma with multimodality therapy: A case report, BMC Research Notes, 10.1186/1756-0500-7-377, 7, 1, 2014.06, [URL], Background: Retroperitoneal sarcomas (RPS), such as pleomorphic leiomyosarcoma, often invade or displace vital organs in the abdominal cavity and exhibit an aggressive clinical course. Complete surgical resection of the tumor and preoperative radiotherapy and chemotherapies can be used for non-metastatic RPS. However, in case of huge retroperitoneal sarcoma fully occupying the abdominal cavity, surgical resection tends to be insufficient, resulting in poor outcomes. This report describes a case of rapidly progressive retroperitoneal pleomorphic leiomyosarcoma that was favorably controlled by debulking surgery followed by combination chemotherapy and radiotherapy. Case presentation. A 65-year-old Japanese woman developed abdominal discomfort due to a huge retroperitoneal tumor fully occupying the abdominal cavity. The immunohistochemical diagnosis was pleomorphic leiomyosarcoma with high-grade malignancy and aggressive proliferative features. Debulking surgery could be performed, but the small residual tumor had rapidly grown to an approximately 22 cm in length on the major axis within 38 days after the operation. The patient's general condition progressively declined. Combination chemotherapy, consisting of doxorubicin and ifosfamide, was successfully administered for six cycles while maintaining dose intensity. The best objective response was a partial response, and the chemotherapy was well tolerated. Approximately 50 Gy of radiotherapy was delivered to the remaining tumor. This multimodal strategy resulted in progression-free survival for more than 17 months and achieved sustained symptomatic relief. Conclusions: Multimodal therapy with debulking surgery, combination chemotherapy and radiotherapy controlled a rapidly progressive retroperitoneal pleomorphic leiomyosarcoma. Maintaining dose intensity of the chemotherapy and radiotherapy might contribute to overall tumor control. © 2014 Sagara et al. licensee BioMed Central Ltd.. |
| 141. | Keita Uchino, Eishi Baba, Primary and secondary prophylactic administration of granulocyte-colony stimulating factor (G-CSF) for febrile neutropenia, Japanese Journal of Cancer and Chemotherapy, 41, 6, 691-693, 2014.06, The Japanese guidelines for the proper use of granulocyte-colony stimulating factor (G-CSF) have been revised on the basis of the current international guidelines and latest evidence. The guidelines for primary and secondary prophylactic administration of G-CSF are clearly defined in the revised version. Primary prophylactic administration is recommended as per the incidence of febrile neutropenia (FN): it is highly recommended for patients with an FN rate > 20%, but selectively recommended for patients with an FN rate |
| 142. | Taichi Isobe, Keita Uchino, Chinatsu Makiyama, Hiroshi Ariyama, Shuji Arita, Shingo Tamura, Masato Komoda, Hitoshi Kusaba, Tsuyoshi Shirakawa, Taito Esaki, Kenji Mitsugi, Shigeo Takaishi, Koichi Akashi, Eishi Baba, Analysis of Adverse Events of Bevacizumab-containing Systemic Chemotherapy for Metastatic Colorectal Cancer in Japan, ANTICANCER RESEARCH, 34, 4, 2035-2040, 2014.04, Background: Bevacizumab (BV) is widely used in chemotherapy for metastatic colorectal cancer (mCRC). Although specific adverse events have been observed, their risk factors have not been clarified. Patients and Methods: 178 mCRC patients who underwent chemotherapy were retrospectively examined and correlations between possible risk factors and adverse events were analyzed. Results: 87 out of 178 patients were treated with BV-containing chemotherapy. Possible risk factors for BV-related adverse events were: remaining primary tumor, current bleeding, history of arterial thromboembolism (ATE), hypertension, and proteinuria, and these were observed in 22%, 2%, 7%, 16%, and 8% of patients, respectively. Patients with hypertension prior to chemotherapy developed significantly worse hypertension (p=0.018). Gastrointestinal bleeding occurred in 3 out of 18 patients with residual primary tumor (16.7%) and 6 out of 63 patients with no primary tumor (8.7%) (p=0.385). Conclusion: Pre-existing hypertension appears to be a risk factor for BV-related deterioration of hypertension.. |
| 143. | Hozumi Kumagai, Kenta Nio, Yuta Okumura, Masato Komoda, Tsuyoshi Shirakawa, Hitoshi Kusaba, Shioto Yasuda, Keita Odashiro, Shuji Arita, Hiroshi Ariyama, Yuichi Yamada, Hidetaka Yamamoto, Yoshinao Oda, Katsumasa Nakamura, Koichi Akashi, Eishi Baba, Successful chemoradiotherapy for undifferentiated malignant neoplasm arising from the left pulmonary artery, Case Reports in Oncology, 10.1159/000365387, 7, 2, 484-490, 2014.03, [URL], Undifferentiated malignant neoplasms, which occur primarily in the pulmonary artery, are extremely rare and associated with poor outcomes as there is no effective therapy. A 67-year-old woman visited our hospital with complaints of dry cough and dyspnea on exertion. A contrast-enhanced chest computed tomography revealed an intravascular tumor obstructing the left pulmonary artery and a pedunculated lesion extending to the main and right pulmonary artery. Multiple metastases in the lung, bones and bilateral adrenal glands were identified by fluorodeoxyglucose-positron emission tomography. A small sample was obtained by catheter aspiration biopsy of the intravascular tumor, and examination revealed undifferentiated small atypical cells. The tumor was diagnosed as an undifferentiated neoplasm arising from the pulmonary artery based on immunohistochemical findings, including the absence of expressions of organ-specific markers. Systemic chemotherapy (paclitaxel and carboplatin) and concurrent radiation were performed as treatment for the primary tumor. Marked shrinkage of the intravascular tumor was achieved, and no serious adverse events were observed during therapy. Chemotherapy was continued for 5 months, but the patient died because of tumor progression 9 months after the initial diagnosis. Chemoradiotherapy has efficacy against undifferentiated neoplasm of the pulmonary artery.. |
| 144. | Hozumi Kumagai, Hitoshi Kusaba, Yuta Okumura, Masato Komoda, Michitaka Nakano, Shingo Tamura, Mayako Uchida, Kenichiro Nagata, Shuji Arita, Hiroshi Ariyama, Shigeo Takaishi, Koichi Akashi, Eishi Baba, Efficacy and safety of an increased-dose of dexamethasone in patients receiving fosaprepitant chemotherapy in Japan, Asian Pacific Journal of Cancer Prevention, 10.7314/APJCP.2014.15.1.461, 15, 1, 461-465, 2014.01, [URL], Background: Antiemetic triplet therapy including dexamethasone (DEX) is widely used for patients receiving highly emetogenic chemotherapy (HEC). In Japan, the appropriate dose of DEX has not been established for this combination. Materials and Methods: To assess the efficacy and safety of increased-dose DEX, we retrospectively examined patients receiving HEC with antiemetic triplet therapy. Results: Twenty-four patients (fosaprepitant group) were given an increased-dose of DEX (average total dose: 45.8mg), fosaprepitant, and 5-HT3 antagonist. A lower-dose of DEX (33.6mg), oral aprepitant, and 5-HT3 antagonist were administered to the other 48 patients (aprepitant group). The vomiting control rates in the fosaprepitant and aprepitant groups were 100% and 85.4% in the acute phase, and were 75.0% and 64.6% in the delayed phase. The incidences of toxicity were similar comparing the two groups. Conclusions: Triplet therapy using an increased-dose of DEX is suggested to be safe and effective for patients receiving HEC.. |
| 145. | Shingo Tamura, Hitoshi Kusaba, Naoki Kubo, Kayo Ijichi, Kenji Tsuchihashi, Masato Komoda, Keita Uchino, Hiroshi Ariyama, Koichi Akashi, Eishi Baba, Interstitial pneumonia during bevacizumab-based chemotherapy for colorectal cancer, MEDICAL ONCOLOGY, 10.1007/s12032-014-0856-0, 31, 3, 2014.03, [URL], Bevacizumab is a widely used agent for treatment for colorectal cancer. Though it relates to several adverse events, a few cases have been reported of drug-induced interstitial lung damage in bevacizumab-based chemotherapy for advanced colorectal cancer. In this study, we retrospectively reviewed a consecutive series of 72 patients with advanced colorectal cancer who received bevacizumab-based chemotherapy and identified five cases (6.9 %) who developed interstitial pneumonia (IP). The median age was 68 years, all five were male, and four of five patients were smokers. Three cases were asymptomatic, and they immediately recovered by withdrawal of chemotherapeutic drugs. On the other hand, two severe cases were required high-dose infusion of corticosteroid. It is suggested that early diagnosis of IP contributes to prevent exacerbation of the event and results in better outcomes. IP may have been associated with systemic chemotherapy, suggesting that a caution should be raised for pulmonary damage by bevacizumab-based chemotherapy.. |
| 146. | Michitaka Nakano, Hitoshi Kusaba, Akitaka Makiyama, Hiroshi Ariyama, Shuji Arita, Hisanobu Oda, Taito Esaki, Kotoe Takayoshi, Keita Uchino, Shingo Tamura, Hozumi Kumagai, Eiji Iwama, Tsuyoshi Shirakawa, Kenji Mitsugi, Shigeo Takaishi, Koichi Akashi, Eishi Baba, Pemetrexed Combined with Platinum-based Chemotherapy for Advanced Malignant Peritoneal Mesothelioma: Retrospective Analysis of Six Cases, ANTICANCER RESEARCH, 34, 1A, 215-220, 2014.01, Background: Malignant peritoneal mesothelioma (PM) is an extremely rare disease. Pemetrexed and platinum have been used for advanced PM following malignant pleural mesothelioma (PLM). Because PM differs considerably from PLM in clinical features, the efficacy and safety of these therapies have yet to be established. Patients and Methods: Six Japanese patients with PM who had been treated with pemetrexed-based chemotherapy in four Institutions were retrospectively identified. Treatment response, progression-free survival, and overall survival were examined. Toxicities of therapy were also evaluated. Results: Three patients with mild ascites achieved clinical benefits (one with partial response and two with stable disease). Treatments with reduced cisplatin or carboplatin for patients with massive ascites were safely performed. Median PFS and OS were 7.2 and 13.1 months, respectively. Grade 3 hematological toxicities appeared in two patients with massive ascites. Conclusion: Selection of chemotherapy based on the patient's condition, such as ascites, might be important for advanced PM.. |
| 147. | 岩間 映二, 髙山 浩一, 馬場 英司, 中西 洋一, 非小細胞肺癌における個別化治療, 福岡医学雑誌 = Fukuoka acta medica, 10.15017/1446200, 105, 3, 57-66, 2014.03, 肺癌は小細胞肺癌と非小細胞肺癌の大きく二つに分けられる．非小細胞肺癌は肺癌の約85%を占め，腺癌，扁平上皮癌，大細胞癌に分けられる．非小細胞肺癌に対する治療は手術，放射線，化学療法の大きく三つに分けられるが，近年における化学療法の進歩は目覚ましく，その大きな要因は個別化治療の進歩にあると考えられる．本稿では非小細胞肺癌における化学療法の進歩について個別化治療を中心に概説する．. |
| 148. | Yamaguchi K, Sawaki A, Doi T, Satoh T, Yamada Y, Omuro Y, Nishina T, Boku N, Chin K, Hamamoto Y, Takiuchi H, Komatsu Y, Saji S, Koizumi W, Miyata Y, Sato A, Baba E, Tamura T, Abe T, Ohtsu A, Efficacy and safety of capecitabine plus cisplatin in Japanese patients with advanced or metastatic gastric cancer: subset analyses of the AVAGAST study and the ToGA study., Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 10.1007/s10120-012-0167-0, 16, 2, 175-182, 2013.04, [URL]. |
| 149. | Kensei Yamaguchi, Akira Sawaki, Toshihiko Doi, Taroh Satoh, Yasuhide Yamada, Yasushi Omuro, Tomohiro Nishina, Narikazu Boku, Keisho Chin, Yasuo Hamamoto, Hiroya Takiuchi, Yoshito Komatsu, Shigehira Saji, Wasaburo Koizumi, Yoshinori Miyata, Atsushi Sato, Eishi Baba, Takao Tamura, Takashi Abe, Atsushi Ohtsu, Erratum: Efficacy and safety of capecitabine plus cisplatin in Japanese patients with advanced or metastatic gastric cancer: Subset analyses of the AVAGAST study and the ToGA study (Gastric Cancer DOI: 10.1007/s10120-012-0167-0), Gastric Cancer, 10.1007/s10120-012-0205-y, 16, 2, 183-184, 2013.04, [URL]. |
| 150. | Kusaba H, Esaki T, Kishimoto J, Uchino K, Arita S, Kumagai H, Mitsugi K, Akashi K, Baba E, Phase I study of bevacizumab combined with irinotecan and S-1 as second-line chemotherapy in patients with advanced colorectal cancer., Cancer chemotherapy and pharmacology, 10.1007/s00280-012-2023-7, 71, 1, 29-34, 2013.01, [URL]. |
| 151. | Toshikazu Moriwaki, Hideaki Bando, Atsuo Takashima, Kentaro Yamazaki, Taito Esaki, Keishi Yamashita, Mutsumi Fukunaga, Yasuhiro Miyake, Kenji Katsumata, Satoshi Kato, Taroh Satoh, Mitsuharu Ozeki, Eishi Baba, Shigemasa Yoshida, Narikazu Boku, Ichinosuke Hyodo, Bevacizumab in combination with irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) in patients with metastatic colorectal cancer who were previously treated with oxaliplatin-containing regimens: a multicenter observational cohort study (TCTG 2nd-BV study), MEDICAL ONCOLOGY, 10.1007/s12032-011-0151-2, 29, 4, 2842-2848, 2012.12, [URL], The efficacy of bevacizumab combined with infusional 5-fluorouracil/leucovorin (5-FU/LV) plus irinotecan (FOLFIRI) as the second-line treatment for metastatic colorectal cancer (mCRC) has not been fully clarified, although bevacizumab combined with infusional 5-FU/LV plus oxaliplatin (FOLFOX) in the second-line setting has demonstrated a survival benefit. We investigated the efficacy of bevacizumab plus FOLFIRI in mCRC patients who failed oxaliplatin-containing regimens without bevacizumab. Patients who received bevacizumab plus FOLFIRI or bevacizumab plus FOLFOX as second-line chemotherapy between July 2007 and March 2008 were registered (trial registration: UMIN000001547). Patient background data and progression-free survival (PFS), overall survival (OS), response, and bevacizumab-related adverse events were prospectively collected every 6 months. A total of 195 patients were enrolled from 26 institutions. Among them, 115 patients received bevacizumab plus FOLFIRI after failure of oxaliplatin and fluoropyrimidine (FOLFIRI+BV after OX/FU group), and 45 patients received bevacizumab plus FOLFOX after failure of irinotecan and fluoropyrimidine (FOLFOX+BV after IRI/FU group). Median PFS was 8.3 months (95% confidence interval [CI], 6.7-9.9) for the FOLFIRI+BV after OX/FU group and 7.8 months (95% CI, 5.8-9.7) for the FOLFOX+BV after IRI/FU group. Median OS was 21.6 months (95% CI, 17.6-25.6) and 16.5 months (95% CI, 11.8-21.2), respectively. Overall response rates were 25 and 29%, respectively. The most common grade a parts per thousand yen3 bevacizumab-related adverse events were hypertension (5.0%) and bleeding (3.8%). FOLFIRI+BV after OX/FU showed comparable efficacy to FOLFOX+BV after IRI/FU.. |
| 152. | Okita NT, Esaki T, Baba E, Sakai D, Tokunaga S, Takiuchi H, Mizunuma N, Nagashima K, Kato, A multicenter phase II study of the stop-and-go modified FOLFOX6 with bevacizumab for first-line treatment of patients with metastatic colorectal cancer, Investigational New Drugs, 10.1007/s10637-011-9779-1, 30, 5, 2026-2031, 2012.10, [URL]. |
| 153. | Keita Uchino, Gen Hirano, Minako Hirahashi, Taichi Isobe, Tsuyoshi Shirakawa, Hitoshi Kusaba, Eishi Baba, Masazumi Tsuneyoshi, Koichi Akashi, Human Nanog pseudogene8 promotes the proliferation of gastrointestinal cancer cells, EXPERIMENTAL CELL RESEARCH, 10.1016/j.yexcr.2012.04.011, 318, 15, 1799-1807, 2012.09, [URL], There is emerging evidence that human solid tumor cells originate from cancer stem cells (CSCs). In cancer cell lines, tumor-initiating CSCs are mainly found in the side population (SP) that has the capacity to extrude dyes such as Hoechst 33342. We found that Nanog is expressed specifically in SP cells of human gastrointestinal (GI) cancer cells. Nucleotide sequencing revealed that NanogP8 but not Nanog was expressed in GI cancer cells. Transfection of NanogP8 into GI cancer cell lines promoted cell proliferation, while its inhibition by anti-Nanog siRNA suppressed the proliferation. lmmunohistochemical staining of primary GI cancer tissues revealed NanogP8 protein to be strongly expressed in 3 out of 60 cases. In these cases, NanogP8 was found especially in an infiltrative part of the tumor, in proliferating cells with Ki67 expression. These data suggest that NanogP8 is involved in Cl cancer development in a fraction of patients, in whom it presumably acts by supporting CSC proliferation. (C) 2012 Elsevier Inc. All rights reserved.. |
| 154. | Hozumi Kumagai, Kenta Nio, Tsuyoshi Shirakawa, Keita Uchino, Hitoshi Kusaba, Taichi Isobe, Masato Komoda, Shingo Tamura, Ryo Maeyama, Eishi Nagai, Koichi Akashi, Eishi Baba, Improvement of quality of life and survival using self-expandable metal stent placement for severe malignant stenosis of the gastric body A case report, Journal of Medical Case Reports, 10.1186/1752-1947-6-315, 6, 2012.09, [URL], Introduction. Advanced gastric carcinoma often decreases quality of life because of upper gastrointestinal tract stenosis. Self-expandable metal stents have been thought to be an effective, minimally invasive treatment for stenosis. However, the effectiveness of self-expandable metal stent placement for carcinomatous stenosis of the gastric body and antrum has not been clarified, and there have been few reports of such cases. Case presentation. A 74-year-old Japanese woman developed stenosis of the gastric body and antrum caused by advanced gastric cancer during first-line chemotherapy. She developed weight loss and poor nutrition due to inadequate intake. Self-expandable metal stent placement for stenosis of the gastric body and antrum ameliorated her symptoms rapidly and improved her general condition and quality of life. Eight days after self-expandable metal stent placement, second-line chemotherapy could be administered safely. Oral intake and nutritional status were maintained for 117 days after self-expandable metal stent placement, and she died of gastric cancer 176 days after self-expandable metal stent placement and initiation of second-line chemotherapy. Conclusions: Self-expandable metal stent placement for carcinomatous stenosis in the gastric body and antrum could be an effective therapeutic strategy for patients with inadequate oral uptake. It may provide rapid improvement of the patients general condition and oral intake with minimal complications, comparatively long-term symptom relief, and a survival benefit by allowing second-line chemotherapy.. |
| 155. | Akira Sawaki, Yasuo Ohashi, Yasushi Omuro, Taroh Satoh, Yasuo Hamamoto, Narikazu Boku, Yoshinori Miyata, Hiroya Takiuchi, Kensei Yamaguchi, Yasutsuna Sasaki, Tomohiro Nishina, Atsushi Satoh, Eishi Baba, Takao Tamura, Takashi Abe, Kiyohiko Hatake, Atsushi Ohtsu, Efficacy of trastuzumab in Japanese patients with HER2-positive advanced gastric or gastroesophageal junction cancer: a subgroup analysis of the Trastuzumab for Gastric Cancer (ToGA) study, GASTRIC CANCER, 10.1007/s10120-011-0118-1, 15, 3, 313-322, 2012.07, [URL], The Trastuzumab for Gastric Cancer (ToGA) study is the first international trial to include Japanese patients with human epidermal growth factor 2 (HER2) positive advanced/metastatic gastric or gastroesophageal junction cancer. ToGA showed that trastuzumab plus chemotherapy (capecitabine/cisplatin or 5-fluorouracil/cisplatin) improved overall survival in the overall population (hazard ratio 0.74). Regional differences in outcome in favor of Japanese populations were observed in other studies; therefore, subgroup analyses of ToGA may contribute to the evaluation of the potential benefits of this regimen in Japanese patients. We performed subgroup analyses on 101 Japanese patients enrolled into ToGA (trastuzumab plus chemotherapy, n = 51; chemotherapy, n = 50). Median overall survival in the Japanese subgroup was 15.9 months (95% confidence interval 12-25) for trastuzumab plus chemotherapy and 17.7 months (95% confidence interval 12-24) for chemotherapy (hazard ratio 1.00; 95% confidence interval 0.59-1.69). After adjusting for prespecified covariates, the estimated hazard ratio for overall survival was 0.68 (95% confidence interval 0.36-1.27). Further post hoc and exploratory examinations supported the robustness of the adjusted hazard ratios. After adjusting for imbalanced patient backgrounds between arms, overall survival of Japanese patients with human epidermal growth factor 2 positive advanced/metastatic gastric or gastroesophageal junction cancer who received trastuzumab plus chemotherapy was improved compared with patients who received chemotherapy alone.. |
| 156. | Hiroaki Niiro, Siamak Jabbarzadeh-Tabrizi, Yoshikane Kikushige, Takahiro Shima, Kumiko Noda, Shun-ichiro Ota, Hirofumi Tsuzuki, Yasushi Inoue, Yojiro Arinobu, Hiromi Iwasaki, Shinji Shimoda, Eishi Baba, Hiroshi Tsukamoto, Takahiko Horiuchi, Tadayoshi Taniyama, Koichi Akashi, CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells, BLOOD, 10.1182/blood-2011-04-351965, 119, 10, 2263-2273, 2012.03, [URL], The aberrant regulation of B-cell receptor (BCR) signaling allows unwanted B cells to persist, thereby potentially leading to autoimmunity and B-cell malignancies. Casitas B-lineage lymphoma (Cbl) proteins suppress BCR signaling; however, the molecular mechanisms that control Cbl function in human B cells remain unclear. Here, we demonstrate that CIN85 (c-Cbl interacting protein of 85 kDa) is constitutively associated with c-Cbl, Cbl-b, and B-cell linker in B cells. Experiments using CIN85-overexpressing and CIN85-knockdown B-cell lines revealed that CIN85 increased c-Cbl phosphorylation and inhibited BCR-induced calcium flux and phosphorylation of Syk and PLC gamma 2, whereas it did not affect BCR internalization. The Syk phosphorylation in CIN85-overexpressing and CIN85-knockdown cells was inversely correlated with the ubiquitination and degradation of Syk. Moreover, CIN85 knockdown in primary B cells enhanced BCR-induced survival and growth, and increased the expression of BcLxL, A1, cyclin D2, and myc. Following the stimulation of BCR and Toll-like receptor 9, B-cell differentiation-associated molecules were up-regulated in CIN85-knockdown cells. Together, these results suggest that CIN85 is required for Cbl-mediated regulation of BCR signaling and for downstream events such as survival, growth, and differentiation of human B cells. (Blood. 2012;119(10): 2263-2273). |
| 157. | Baba E, Fujishima H, Makiyama A, Uchino K, Tanaka R, Esaki T, Kusaba H, Mitsugi K, Nakano S, Akashi K, Phase 2 study of modified irinotecan and bolus 5-fluorouracil/l-leucovorin in Japanese metastatic colorectal cancer patients., Advances in therapy, 10.1007/s12325-012-0002-3, 29, 3, 287-296, 2012.03, [URL]. |
| 158. | Baba E, Kusaba H, Nakano S, [Development trends for therapeutic antibody]., Nihon rinsho. Japanese journal of clinical medicine, 70, 2098-2103, 2012.12. |
| 159. | Taichi Isobe, Eishi Baba, Shuji Arita, Masato Komoda, Shingo Tamura, Tsuyoshi Shirakawa, Hiroshi Ariyama, Shigeo Takaishi, Hitoshi Kusaba, Takashi Ueki, Koichi Akashi, Human STEAP3 maintains tumor growth under hypoferric condition, EXPERIMENTAL CELL RESEARCH, 10.1016/j.yexcr.2011.07.022, 317, 18, 2582-2591, 2011.11, [URL], Iron is essential in cellular proliferation and survival based on its crucial roles in DNA and ATP synthesis. Tumor cells proliferate rapidly even in patients with low serum iron, although their actual mechanisms are not well known. To elucidate molecular mechanisms of efficient tumor progression under the hypoferric condition, we studied the roles of six-transmembrane epithelial antigen of the prostate family member 3 (STEAP3), which was reported to facilitate iron uptake. Using Raji cells with low STEAP3 mRNA expression, human STEAP3-overexpressing cells were established. The impact of STEAP3 expression was analyzed about the amount of iron storage, the survival under hypoferric conditions in vitro and the growth of tumor in vivo. STEAP3 overexpression increased ferritin, an indicator of iron storage, in STEAP3-overexpressing Raji cells. STEAP3 gave Raji cells the resistance to iron deprivation-induced apoptosis. These STEAP3-overexpressing Raji cells preserved efficient growth even in hypoferric mice, while parental Raji cells grew less rapidly. In addition, iron deficiency enhanced S7EAP3 mRNA expression in tumor cells. Furthermore, human colorectal cancer tissues exhibited more S7EAP3 mRNA expression and iron storage compared with normal colon mucosa. These findings indicate that STEAP3 maintains iron storage in human malignant cells and tumor proliferation under the hypoferric condition. (C) 2011 Elsevier Inc. All rights reserved.. |
| 160. | Hideya Onishi, Takashi Morisaki, Eishi Baba, Mitsunari Nakamura, Syoichi Inaba, Hideo Kuroki, Kotaro Matsumoto, Mitsuo Katano, Long-term Vaccine Therapy with Autologous Whole Tumor Cell-pulsed Dendritic Cells for a Patient with Recurrent Rectal Carcinoma, ANTICANCER RESEARCH, 31, 11, 3995-4005, 2011.11, We performed continuous dendritic cells (DCs) vaccination to treat a patient with chemotherapy-resistant recurrent rectal carcinoma and lung and bone metastases. A patient has received a total of 66 DC vaccinations at 14-day intervals for 3 years until his death. Necrotic whole tumor. cells (WTC) were selected as the tumor-associated antigen source because they showed a greater capacity for DC maturation and interleukin-12 secretion than both necrotic tumor lysate alone and necrotic tumor cell fragment alone. After the sixth vaccination, both skin test and interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISPOT) response by peripheral blood T-cells to WTC-pulsed DCs were positive. Importantly, T-cell responses were positive towards DCs pulsed with several synthetic peptides including Carcinoembryonic antigen (CEA), Melanoma associated antigen (MAGE)1 and MAGE3. A biopsy specimen collected from the pelvic bone metastasis after the 6th vaccination showed marked necrotic change of the carcinoma cells, with many infiltrating mononuclear cells. The patient did not show any particular adverse reactions to vaccination such as autoimmune phenomena. Our experience of this case suggests that continuous long-term vaccination with autologous WTC-pulsed DCs can elicit in vivo T-cell response against multiple tumor-associated antigens and induce tumor regression in disease that has proven resistant to intensive chemo- or radiation therapy.. |
| 161. | Baba E, Esaki T, Ariyama H, Mitsugi K, Morikita T, Fujishima H, Kusaba H, Nakano S, Akashi K, Phase II study of sequential treatment with S-1 and cisplatin for metastatic gastric cancer., Cancer chemotherapy and pharmacology, 10.1007/s00280-010-1529-0, 68, 3, 611-617, 2011.09, [URL]. |
| 162. | Kusaba H, Esaki T, Futami K, Tanaka S, Fujishima H, Mitsugi K, Sakai K, Ariyama H, Tanaka R, Kinugawa N, Ueki T, Mibu R, Baba E, Nakano S, Akashi K, Phase I/II study of a 3-week cycle of irinotecan and S-1 in patients with advanced colorectal cancer., Cancer science, 10.1111/j.1349-7006.2010.01728.x, 101, 12, 2591-2595, 2010.12, [URL]. |
| 163. | Shibata Y, Baba E, Ariyama H, Arita S, Isobe T, Kusaba H, Mitsugi K, Nakano S, Akashi K, Irinotecan-based combination chemotherapy for metastatic small intestinal adenocarcinoma., Oncology letters, 10.3892/ol_00000074, 1, 3, 423-426, 2010.05, [URL]. |
| 164. | hiroshi ariyama, Hitoshi Kusaba, Eishi Baba, Cetuximab for patients with metastatic colorectal cancer - From the result of recent clinical trials, Japanese Journal of Cancer and Chemotherapy, 37, 5, 782-786, 2010, Cetuximab is a monoclonal antibody that inhibits human epidermal growth factor receptor, and was approved for metastatic advanced colorectal cancer (mCRC) in 2008 in Japan. Evidences confirming the efficacy of cetuximab have been accumulated in western countries. As the first- and second-line therapy, cetuximab plus chemotherapy showed longer survival compared with chemotherapy alone. As a third-line chemotherapy, among various anti-cancer agents for mCRC, only cetuximab could exhibit survival benefits in monotherapy or combination therapy with irinotecan. Recent studies suggest that the status of KRAS mutation is a predictive marker in colorectal cancer patients treated with cetuximab, and these findings lead to personalized cancer treatment.. |
| 165. | Yasunobu Abe, Tetsuhide Ito, Eishi Baba, Koji Nagafuji, Ken Kawabe, Ilseung Choi, Yoshiyuki Arita, Toshihiro Miyamoto, Takanori Teshima, Shuji Nakano, Mine Harada, Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation as Immunotherapy for Pancreatic Cancer, PANCREAS, 10.1097/MPA.0b013e3181b576ee, 38, 7, 815-819, 2009.10, [URL], Objective: Advanced unresectable pancreatic cancer has an extremely poor prognosis despite intensive chemotherapy. As a new therapeutic modality, we investigated nonmyeloablative allogeneic hematopoietic stem cell transplantation from a related donor. Methods: Five patients with chemotherapy-resistant pancreatic cancer received allogeneic peripheral blood stem cell transplantation after a conditioning regimen consisting of low-dose total body irradiation and fludarabine. The prophylaxis for graft-versus-host disease consisted of mycophenolate mofetil and cyclosporine. Results: The median age of the 5 patients was 54 years, and the median duration from diagnosis to nonmyeloablative allogeneic hematopoietic stem cell transplantation was 10 months. Three of the 5 patients achieved complete donor chimerism of peripheral T cells, at a median time of day 42. Acute graft-versus-host disease developed in 3 patients: grade 2 in 2 patients and grade 1 in 1. Tumor reduction was observed in 2 patients: 1 patient showed disappearance of the pancreatic tumor, and the other patient showed approximately 20% reduction of the tumor. Marked elevation of tumor necrosis factor alpha was observed as the tumor regressed. Conclusions: Although advanced pancreatic cancer progresses rapidly, some graft-versus-tumor effects and pivotal role of tumor necrosis factor alpha were suggested. To obtain the durable response, patient selection and new strategies become important.. |
| 166. | Shibata Y, Ariyama H, Baba E, Takii Y, Esaki T, Mitsugi K, Tsuchiya T, Kusaba H, Akashi K, Nakano S, Oxaliplatin-induced allergic reaction in patients with colorectal cancer in Japan., International journal of clinical oncology, 10.1007/s10147-009-0883-6, 14, 5, 397-401, 2009.10, [URL]. |
| 167. | Baba E, Fujishima H, Kusaba H, Esaki T, Ariyama H, Kato K, Tanaka R, Mitsugi K, Shibata Y, Harada M, Nakano S, Phase I study of the sequential administration of S-1 and cisplatin for metastatic gastric cancer., Anticancer research, 29, 5, 1727-1732, 2009.05. |
| 168. | Makiyama A, Qin B, Uchino K, Shibata Y, Arita S, Isobe T, Hirano G, Kusaba H, Baba E, Akashi K, Nakano S, Schedule-dependent synergistic interaction between gemcitabine and oxaliplatin in human gallbladder adenocarcinoma cell lines., Anti-cancer drugs, 10.1097/CAD.0b013e3283218080, 20, 123-130, 2009.02, [URL]. |
| 169. | Siamak Jabbarzadeh Tabrizi, Hiroaki Niiro, Mariko Masui, Goichi Yoshimoto, Tadafumi Iino, Yoshikane Kikushige, Takahiro Wakasaki, Eishi Baba, Shinji Shimoda, Toshihiro Miyamoto, Toshiro Hara, Koichi Akashi, T Cell Leukemia/Lymphoma 1 and Galectin-1 Regulate Survival/Cell Death Pathways in Human Naive and IgM(+) Memory B Cells through Altering Balances in Bcl-2 Family Proteins, JOURNAL OF IMMUNOLOGY, 182, 3, 1490-1499, 2009.02, [URL], BCR signaling plays a critical role in purging the self-reactive repertoire, or in rendering it anergic to establish self-tolerance in the periphery. Differences in self-reactivity between human naive and IgM(+) memory B cells may reflect distinct mechanisms by which BCR signaling dictates their survival and death. Here we demonstrate that BCR stimulation protected naive B cells from apoptosis with induction of prosurvival Bcl-2 family proteins, Bcl-x(L) and Mcl-1, whereas it rather accelerated apoptosis of IgM(+) memory B cells by inducing proapoptotic BH3-only protein Bim. We found that BCR-mediated PI3K activation induced the expression of Mcl-1, whereas it inhibited Bim expression in B cells. Phosphorylation of Akt, a downstream molecule of PI3K, was more sustained in naive than IgM(+) memory B cells. Abundant expression of T cell leukemia/lymphoma 1 (Tell), an Akt coactivator, was found in naive B cells, and enforced expression of Tell induced a high level of Mcl-1 expression, resulting in prolonged B cell survival. In contrast, Galectin-1 (Gal-1) was abundantly expressed in IgM(+) memory B cells, and inhibited Akt phosphorylation, leading to Bim up-regulation. Enforced expression of Gal-1 induced accelerated apoptosis in B cells. These results suggest that a unique set of molecules, Tell and Gal-1, defines distinct BCR signaling cascades, dictating survival and death of human naive and IgM(+) memory B cells. The Journal of Immunology, 2009, 182: 1490-1499.. |
| 170. | Tsukasa K, Fujimoto C, Ariyama H, Esaki T, Murakawa M, Syoji T, Baba E, Hiranuma S, [A case of bone marrow carcinosis from gastric cancer that presented hypocalcemia caused by zoledronic acid during the treatment of methotrexate/5-fluorouracil sequential therapy]., Gan to kagaku ryoho. Cancer & chemotherapy, 36, 3, 489-492, 2009.03. |
| 171. | Y. Kanda, Y. Omuro, E. Baba, K. Oshima, K. Nagafuji, Y. Heike, Y. Takaue, T. Sasaki, H. Sakamaki, M. Harada, Allo-SCT using reduced-intensity conditioning against advanced pancreatic cancer: A Japanese survey, Bone Marrow Transplantation, 10.1038/bmt.2008.94, 42, 2, 99-103, 2008.07, [URL], Pancreatic cancer is a frequent cause of cancer-related mortality and has an extremely poor prognosis. To evaluate the efficacy of allogeneic hematopoietic SCT with reduced-intensity conditioning (RICT) against pancreatic cancer, we analyzed the clinical data of 22 patients. After a fludarabine-based conditioning regimen followed by the infusion of PBSCs, all but two achieved engraftment. Complete, partial and minor response was observed in 1, 2 and 2 patients, respectively, with an overall response rate of 23%. Median survival was only 139 days and the major cause of death was tumor progression. Poor performance status before RICT and a lower number of infused CD34-positive cells were associated with shorter survival after RICT. Patients who developed chronic GVHD tended to survive longer than those who did not. These findings support the investigation of a novel treatment strategy to enhance the immunological effect against pancreatic cancer.. |
| 172. | Hitoshi Kusaba, Masahiko Fujihara, Ryuichi Nagashima, Yoshikazu Kaji, Eishi Baba, Shuji Nakano, Systemic chemotherapy of TS-1 and cisplatin for gastric signet-ring cell carcinoma presenting as cardiac tamponade, Medical Oncology, 10.1007/s12032-007-9010-6, 25, 2, 241-244, 2008.06, [URL], A 59-year-old man complaining of dyspnea, anterior chest oppression, and hypotension was diagnosed to have cardiac tamponade due to massive pericardial effusion. A cytological analysis of the pericardial effusion disclosed adenocarcinoma. An endoscopic study revealed gastric cancer in the lesser curvature wall of the middle body of the stomach, and signet-ring cell carcinoma was confirmed histologically. The gastric cancer was complicated by malignant pericardial effusion, and metastasis to the mediastinal lymph nodes. The patient was treated with pericardiocentesis followed by systemic chemotherapy consisting of TS-1 and cisplatin (CDDP). After 5 months, pericardial effusion disappeared and the primary gastric tumor decreased in size. Our experience suggests that the systemic chemotherapy of TS-1 and CDDP may be effective for controlling advanced gastric signet-cell carcinoma accompanied by malignant pericardial effusion.. |
| 173. | Shuji Arita, Eishi Baba, Yoshihiro Shibata, Hiroaki Niiro, Shinji Shimoda, Taichi Isobe, Hitoshi Kusaba, Shuji Nakano, Mine Harada, B cell activation regulates exosomal HLA production, EUROPEAN JOURNAL OF IMMUNOLOGY, 10.1002/eji.200737694, 38, 5, 1423-1434, 2008.05, [URL], Exosomes are nanovesicles produced constitutively and inducibly by several types of cells. They are generated as intraluminal vesicles of multivesicular bodies and express MHC and several endosomal/lysosomal proteins. In spite of their potential role in cellular immunity, the regulatory mechanisms of exosome production are largely unknown. In this study, we have established a novel ELISA system to quantify exosomal HLA using a combination of anti-HLA class I and anti-HLA-DR mAb. We found that exosomal HLA production of B cells was enhanced by contact with CD4(+) T cells. Neutralizing anti-CD154 (CD40L) mAb inhibited this effect, and a soluble CD40L significantly increased production of exosomal HLA in B cells. In addition, B cell stimulation via BCR and TLR9 enhanced their production while IL-4 stimulation alone failed to do so. Strikingly, an inhibitor of the classical NF-kappa B pathway drastically inhibited exosomal HLA production in stimulated B cells, indicating that the classical NF-kappa B pathway is critical for exosomal HLA production in B cells. Together, these findings suggest a pivotal role of B cell activation in exosomal HLA production in vivo.. |
| 174. | Nozomi Tomiyama, Yusushi Higashiuesato, Takaya Oda, Eishi Baba, Mine Harada, Momoyo Azuma, Tomoko Yamashita, Kazuhiro Uehara, Akiko Miyazato, Kazuhiro Hatta, Yuzuke Ohya, Kunitoshi Iseki, Yoshihiro Jinno, Shuichi Takishita, MEFV mutation analysis of familial Mediterranean fever in Japan, Clinical and Experimental Rheumatology, 26, 1, 13-17, 2008.01, Background: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever with serosal inflammation. FMF gene (MEFV) mutations have been identified primarily in patients from Mediterranean populations. Although several clinical cases have been reported in Japan, there have been few reports to date on mutation analysis. We studied FMF patients and their relatives to examine the clinical and genetic features of this disease in the Japanese population. Methods: Twelve Japanese FMF patients who met the Tel Hashomer criteria and a total of 17 relatives from 5 of 10 families underwent molecular genetic studies to detect MEFV mutations. The characteristics of these Japanese FMF patients and geno-phenotypical correlations were examined. Results: Almost all of our patients had been suffering for a long time from fever of unknown origin and one patient also had systemic amyloidosis. In our 12 FMF patients, we detected the substitutions E84K, L110P, E148Q, R761H and M694I. We also newly diagnosed 2 relatives as having FMF based on clinical symptoms and the existence of FMF mutations. One patient was homozygous for E148Q, the patient with systemic amyloidosis was a homozygote for M694I and 4 patients from 3 families were compound heterozygotes for E148Q and M694I. Three patients in one family were compound heterozygotes for E148Q, L110P and M694I. There were 3 patients who were heterozygous for E84K, L110P-E148Q or M694I and had no other nucleotide changes in the exons of MEFV. On the other hand, 2 relatives who had never experienced symptoms of FMF were homozygous for L110P-E148Q as well as compound heterozygous for E148Q/ E148Q-R761H. E148Q and M694I were the most frequently detected substitutions in our study. Conclusions: MEFV mutations occur in Japanese FMF patients though FMF is rare in Japan. The identification of MEFV mutations could be a reliable diagnostic test for FMF. The results of genetic analyses on 14 Japanese FMF patients in this study revealed that E148Q and M694I are frequent alleles. © Copyright Clinical and Experimental Rheumatology 2008.. |
| 175. | Shibata Y, Baba E, Ariyama H, Miki R, Ogami N, Arita S, Qin B, Kusaba H, Mitsugi K, Noshiro H, Yao T, Nakano S, Metastatic basaloid-squamous cell carcinoma of the esophagus treated by 5-fluorouracil and cisplatin., World journal of gastroenterology : WJG, 13, 3634-3637, 2007.07, [URL]. |
| 176. | Hitoshi Kusaba, Yoshihiro Shibata, Shuji Arita, Hiroshi Ariyama, Eishi Baba, Kenji Mitsugi, Mine Harada, Shuji Nakano, Infusional 5-fluorouracil and cisplatin as first-line chemotherapy in patients with carcinoma of unknown primary site, Medical Oncology, 10.1007/BF02698049, 24, 2, 259-264, 2007.06, [URL], A combination chemotherapy of 5-fluorouracil (5-FU) and cisplatin (CDDP) has demonstrated activities in various malignancies, including head and neck, lung, esophageal, gastric, and pancreatic cancers. We reviewed our experience of 11 patients diagnosed as carcinoma of unknown primary site (CUPS), who were treated with infusional 5-FU and CDDP between January 1998 and December 2005. The median number of cycles administered was three (range: 1-12). All patients had measurable disease. Six partial responses were obtained (response rate: 54.5%, 95% confidence interval: 23.4-83.3%). The median survival time for all patients was 10 mo (range, 2-37 mo). The median time to disease progression was 3 mo (range, 1-6 mo). This regimen was well tolerated, with grade 3-4 neutropenia (two patients), febrile neutropenia (one patient), grade 3 nausea/vomiting (one patient), and grade 3 stomatitis (two patients). Grade 2 leukoencephalopathy was observed in one patient. No treatment-related death was observed. The combination chemotherapy of infusional 5-FU and CDDP was feasible and tolerated with promising activity for CUPS.. |
| 177. | Qin B, Ariyama H, Baba E, Tanaka R, Kusaba H, Harada M, Nakano S, Activated Src and Ras induce gefitinib resistance by activation of signaling pathways downstream of epidermal growth factor receptor in human gallbladder adenocarcinoma cells., Cancer chemotherapy and pharmacology, 10.1007/s00280-006-0219-4, 58, 577-584, 2006.11, [URL]. |
| 178. | Qin B, Tanaka R, Ariyama H, Shibata Y, Arita S, Kusaba H, Baba E, Harada M, Nakano S, In-vitro differential metabolism and activity of 5-fluorouracil between short-term, high-dose and long-term, low-dose treatments in human squamous carcinoma cells., Anti-cancer drugs, 10.1097/01.cad.0000203380.22361.6c, 17, 439-443, 2006.04, [URL]. |
| 179. | Qin B, Tanaka R, Shibata Y, Arita S, Ariyama H, Kusaba H, Baba E, Harada M, Nakano S, In-vitro schedule-dependent interaction between oxaliplatin and 5-fluorouracil in human gastric cancer cell lines., Anti-cancer drugs, 10.1097/01.cad.0000198912.98442.cd, 17, 445-453, 2006.04, [URL]. |
| 180. | Ariyama H, Qin B, Baba E, Tanaka R, Mitsugi K, Harada M, Nakano S, Gefitinib, a selective EGFR tyrosine kinase inhibitor, induces apoptosis through activation of Bax in human gallbladder adenocarcinoma cells., Journal of cellular biochemistry, 10.1002/jcb.20678, 97, 724-734, 2006.03, [URL]. |
| 181. | Shinji Shimoda, Fumihiko Ishikawa, Takashi Kamihira, Atsumasa Komori, Hiroaki Niiro, Eishi Baba, Kenichi Harada, Kumiko Isse, Yasuni Nakanuma, Hiromi Ishibashi, M. Eric Gershwin, Mine Harada, Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory, GASTROENTEROLOGY, 10.1053/j.gastro.2006.05.056, 131, 2, 606-618, 2006.08, [URL], Background & Aims: Autoreactive T cells that proliferate in response to autoantigens are found in both autoimmune disease and controls but have important qualitative differences in relative activation states, costimulation signal requirements, and pathogenetic significance. Understanding the mechanism for activation of autoreactive T cells will be critical in the treatment of autoimmune diseases. Methods: To understand the differences between autoreactive T cells in primary biliary cirrhosis (PBC) versus controls, we have developed autoreactive T-cell clones (TCCs) from patients with PBC and healthy controls and have used a peptide corresponding to the CD4 major auto-epitope to define the relative proliferative and cytokine response. Results: Using an enzyme-linked immunosorbent spot assay, peripheral blood mononuclear cells (PBMCs) from PBC, but not from controls, produce interferon (IFN)-gamma regardless of whether costimulation-competent or -incompetent antigen-presenting cells (APC) were used. In contrast, a significant number of IFN-gamma-producing cells were found in PBMCs from controls but only if costimulation-competent PBMCs presented an autoantigenic peptide. In addition, costimulation-dependent autoreactive TCCs became anergic after a single round of stimulation in the presence of APC that did not provide a costimulatory signal, whereas some costimulation-independent autoreactive TCCs required repeated stimulation to become anergic and the others did not become anergic. Finally, anergic TCCs produced interleukin-10, but no IFN-gamma, and exhibited regulatory functions in an antigen-dependent, cell contact-independent, and partially interleukin-10-mediated manner. Conclusions: These data relate specifically to the functional characteristics of autoreactive T cells in PBC but are also generically important for understanding the mechanisms for generating pathogenetic autoreactive T cells.. |
| 182. | Qin B, Kato K, Mitsugi K, Nakamura M, Tanaka R, Baba E, Ariyama H, Kuroiwa T, Harada M, Nakano S, Feasibility study of ambulatory continuous infusion of 5-fluorouracil followed by cisplatin through hepatic artery for metastatic colorectal cancer., Cancer chemotherapy and pharmacology, 10.1007/s00280-005-0021-8, 57, 114-119, 2006.01, [URL]. |
| 183. | Hideya Onishi, Takashi Morisaki, Hideo Kuroki, Kotaro Matsumoto, Eishi Baba, Hirotaka Kuga, Masao Tanaka, Mitsuo Katano, Evaluation of a dysfunctional and short-lived subset of monocyte-derived dendritic cells from cancer patients, Anticancer Research, 25, 5, 3445-3451, 2005.09, Monocyte-derived dendritic cells (Mo-DCs) were generated from peripheral blood monocytes of 12 healthy volunteers (hMo-DCs) and 11 patients (pMo-DCs) with malignancies by culture for 7 days with granulocyte-macrophage colony-stimulating factor and interleukin-4. In this study, we focused on the cytogram pattern by FACS analysis. A gate (R1) was set up by which more than 95% of hMo-DCs were contained. Mo-DCs having lower side scatter than the R1 (R2) comprised 4.5% of hMo-DCs and 24.2% of pMo-DCs. Expressions of antigen presentation-related molecules and phagocytic ability in the R2 of pMo-DCs were lower than those in the R1 population. The R2, but not R1, in pMo-DCs decreased in number between days 7 and 14, and expression levels of antigen presentation-related molecules in the living pMo-DCs on day 14 increased. The 11 patients received dendritic cell vaccine therapy with autologous, tumor-pulsed mature Mo-DCs (day 7). The low R2 group (R2< 10%, 3 patients) had a significantly higher positive delayed-type hypersensitivity reaction against autologous tumor-pulsed Mo-DCs than that of the high R2 group (R2> 10%, 8 patients) (p< 0.001). These results indicate that the R2 of pMo-DCs may be a dysfunctional and short-lived subset.. |
| 184. | Tanaka R, Takii Y, Shibata Y, Ariyama H, Qin B, Baba E, Kusaba H, Mitsugi K, Harada M, Nakano S, In vitro sequence-dependent interaction between nedaplatin and paclitaxel in human cancer cell lines., Cancer chemotherapy and pharmacology, 10.1007/s00280-004-0991-y, 56, 279-285, 2005.09, [URL]. |
| 185. | Tanaka R, Ariyama H, Qin B, Shibata Y, Takii Y, Kusaba H, Baba E, Mitsugi K, Harada M, Nakano S, Synergistic interaction between oxaliplatin and SN-38 in human gastric cancer cell lines in vitro., Oncology reports, 14, 683-688, 2005.09. |
| 186. | Akihiko Numata, Keiko Yasuda, Takahiro Fukuda, Eishi Baba, Satoshi Yamasaki, Ken Takase, Toshihiro Miyamoto, Koji Nagafuji, Shuji Nakano, Mine Harada, Non-myeloablative allogeneic haemopoietic stem-cell transplantation for treatment of metastatic invasive thymoma, Lancet Oncology, 10.1016/S1470-2045(05)70285-0, 6, 8, 626-628, 2005.08, [URL]. |
| 187. | Tanaka R, Ariyama H, Qin B, Takii Y, Baba E, Mitsugi K, Harada M, Nakano S, In vitro schedule-dependent interaction between paclitaxel and oxaliplatin in human cancer cell lines., Cancer chemotherapy and pharmacology, 10.1007/s00280-004-0966-z, 55, 595-601, 2005.06, [URL]. |
| 188. | KAWANO N, Efficient engraftment of primary adult T-cell leukemia cells in newborn NOD/SCID/β2-microglobulin null mice, Leukemia, 10.1038/sj.leu.2403829, 19, 8, 1384-1390, 2005.01, [URL]. |
| 189. | Hideya Onishi, Hideo Kuroki, Kotaro Matsumoto, Eishi Baba, Nobuhiko Sasaki, Hirotaka Kuga, Masao Tanaka, Mitsuo Katano, Takashi Morisaki, Monocyte-derived dendritic cells that capture dead tumor cells secrete IL-12 and TNF-α through IL-12/TNF-α/NF-κB autocrine loop, Cancer Immunology, Immunotherapy, 10.1007/s00262-004-0568-y, 53, 12, 1093-1100, 2004.12, [URL], This study focused on the question of how monocyte-derived dendritic cells (Mo-DCs) that capture dead tumor cells (Mo-DCs-Tum) secrete interleukin 12 (IL-12) and tumor necrosis factor α (TNF-α). Mo-DCs-Tum showed higher secretions of IL-12 and TNF-α than were shown by Mo-DCs. Enhanced nuclear factor-kappa B (NF-κB) activation was also induced in MoDCs-Tum within 6 h. The NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), suppressed both IL-12 and TNF-α secretions from Mo-DCs-Tum. Administration of recombinant TNF-α or IL-12 enhanced IL-12 or TNF-α secretion respectively in Mo-DCs-Tum. Addition of anti-TNF-α or anti-IL-12 neutralizing antibody decreased NF-κB activation and IL-12 or TNF-α secretion in Mo-DCs-Tum. These results suggest that TNF-α or IL-12 secretion induces NF-κB activation, and it stimulates further TNF-α and IL-12 secretions, i.e., an IL-12/TNF-α/NF-κB autocrine loop, in Mo-DCs-Tum. Thus, Mo-DCs-Tum secrete a large amount of IL-12 and TNF-α through accelerated NF-κB activation induced by the IL-12/TNF-α/NF- κB autocrine loop. © Springer-Verlag 2004.. |
| 190. | Kotaro Matsumoto, Takashi Morisaki, Hideo Kuroki, Makoto Kubo, Hideya Onishi, Katsuya Nakamura, Chihiro Nakahara, Hirotaka Kuga, Eishi Baba, Masafumi Nakamura, Kazuho Hirata, Masao Tanaka, Mitsuo Katano, Exosomes secreted from monocyte-derived dendritic cells support in vitro naive CD4+ T cell survival through NF-κB activation, Cellular Immunology, 10.1016/j.cellimm.2004.11.002, 231, 1-2, 20-29, 2004.09, [URL], We investigated the effect of exosomes secreted from human monocyte-derived dendritic cells (Mo-DCs), which are generated from PBMCs in response to treatment with GM-CSF and IL-4, on naive CD4+ T cell survival in vitro. Exosomes isolated from culture supernatants of Mo-DCs (> 90% purity) were purified with anti-HLA-DP, -DQ, -DR-coated paramagnetic beads. Purified exosomes prolonged the survival of naive CD4+ T cells (> 98% purity) in vitro. Treatment with neutralizing mAb against HLA-DR significantly decreased the supportive effect of purified exosomes on CD4+ T cell survival. Exosomes increased nuclear translocation of NF-κB in naive CD4+ T cells, and NF-κB activation was significantly suppressed by anti-HLA-DR mAb or NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). In addition, PDTC inhibited the effect of exosomes on naive CD4+ T cell survival. Thus, exosomes secreted by Mo-DCs appear to support naive CD4+ T cell survival via NF-κB activation induced by interaction of HLA-DR and TCRs. © 2004 Elsevier Inc. All rights reserved.. |
| 191. | Mitsugi K, Nakamura T, Kashiwabara N, Ariyama H, Tanaka R, Baba E, Nakamura M, Harada M, Nakano S, Protection against methotrexate toxicity by a soybean protein- and omega-3 fatty acid-containing diet: comparative study with a casein-containing diet., Oncology reports, 12, 41-45, 2004.07. |
| 192. | Fujishima H, Kikuchi I, Miyanaga O, Ueda A, Baba E, Mitsugi K, Harada M, Nakano S, Phase I study of CPT-11 and bolus 5-FU/ l-leucovorin in patients with metastatic colorectal cancer., International journal of clinical oncology, 10.1007/s10147-003-0371-3, 9, 2, 92-97, 2004.04, [URL]. |
| 193. | Akira Tasaki, Naoki Yamanaka, Makoto Kubo, Kotaro Matsumoto, Hideo Kuroki, Katsuya Nakamura, Chihiro Nakahara, Hideya Onishi, Hirotaka Kuga, Eishi Baba, Masao Tanaka, Takashi Morisaki, Mitsuo Katano, Three-dimensional two-layer collagen matrix gel culture model for evaluating complex biological functions of monocyte-derived dendritic cells, Journal of Immunological Methods, 10.1016/j.jim.2004.01.014, 287, 1-2, 79-90, 2004.04, [URL], Dendritic cell-like cells (Mo-DCs) generated from peripheral blood monocytes with interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used as tools to treat cancer patients (DC-vaccines). Because Mo-DCs have multiple antigen presentation-related functions, including phagocytosis, migration, cytokine production, and T cell stimulation, establishment of a method for simultaneously evaluating the various functions of Mo-DCs is important. We developed a new in vitro three-dimensional two-layer collagen matrix culture model that consists of a collagen gel containing Mo-DCs as the lower layer and a collagen gel containing necrotic GCTM-1 tumor cells and/or T cells as the upper layer. We used this system to observe simultaneously multiple functions of Mo-DCs by phase-contrast or fluorescence microscopy and to assess IL-12 secretion during more than 2 weeks of culture. We also observed interactions between Mo-DCs and necrotic GCTM-1 or T cells on an individual cell basis by time-lapse videomicroscopy. In addition, we collected Mo-DCs from the collagen gels by collagenase treatment and analyzed the expression of antigen presentation-related molecules such as HLA-DR, CD80, CD83, and CD86 on Mo-DCs. This model may be a useful tool for evaluation of the various functions of Mo-DCs used as DC vaccines and for studies of the complex behaviors of Mo-DCs in vivo. © 2004 Elsevier B.V. All rights reserved.. |
| 194. | Takashi Morisaki, Kotaro Matsumoto, Hideya Onishi, Hideo Kuroki, Eishi Baba, Akira Tasaki, Makoto Kubo, Mitsunari Nakamura, Syoichi Inaba, Koji Yamaguchi, Masao Tanaka, Mitsuo Katano, Dendritic cell-based combined immunotherapy with autologous tumor-pulsed dendritic cell vaccine and activated T cells for cancer patients rationale, current progress, and perspectives., Human cell : official journal of Human Cell Research Society, 10.1111/j.1749-0774.2003.tb00151.x, 16, 4, 175-182, 2003.12, [URL], Effective adoptive cancer immunotherapy depends on an ability to generate tumor-antigen-presenting cells and tumor-reactive effector lymphocytes and to deliver these effector cells to the tumor. Dendritic cells (DCs) are the most potent antigen-presenting cells, capable of sensitizing T cells to new and recall antigens. Many studies have shown that tumors express unique proteins that can be loaded on DCs to trigger an immune response. The current experimental and clinical statuses of adoptive transfer of tumor antigen-pulsed DCs and vaccine-primed activated T cells are summarized herein. Clinical trials of antigen-pulsed DCs have been conducted in patients with various types of cancer, including non-Hodgkin lymphoma, multiple myeloma, prostate cancer, renal cell carcinoma, malignant melanoma, colorectal cancer, and non-small cell lung cancer. These studies have shown that antigen-loaded DC vaccination is safe and promising for the treatment of cancer. In addition, tumor vaccine-primed T cells have been shown to induce antitumor activity in vivo. Several clinical studies are being conducted on the use of vaccine-primed T cells such as tumor-drainage lymph node. It is reasonable to consider using both tumor antigen-pulsed DCs and vaccine-primed lymphocytes as adjuvants. We are now investigating the use of autologous whole tumor antigen-pulsed DCs and the DC vaccine-primed activated lymphocytes in patients with multiple metastasis of solid tumors.. |
| 195. | Makoto Kubo, Takashi Morisaki, Hideo Kuroki, Akira Tasaki, Naoki Yamanaka, Kotaro Matsumoto, Katsuya Nakamura, Hideya Onishi, Eishi Baba, Mitsuo Katano, Combination of Adoptive Immunotherapy with Herceptin for Patients with HER2-expressing Breast Cancer, Anticancer Research, 23, 6 A, 4443-4449, 2003.11, Clinical use of Herceptin (trastuzumab), which is a humanized monoclonal antibody against HER2, started for patients with HER2-overexpressing breast cancer. To potentiate the efficacy of the Herceptin therapy, this study focused on the combination of Herceptin with activated immune lymphocytes. We used peripheral blood mononuclear cells (PBMCs) as effector cells and used HER2-unexpressing K562 cells, HER2-weakly-expressing breast carcinoma cells (Breast-M), or HER2-strongly-expressing breast carcinoma cells (BT-474) as target cells. Interleukin-2 (IL-2)-activated PBMCs, IL-2/OKT-3-activated PBMCs and a streptococcal preparation OK-432-activated PBMCs were generated and used as effector cells. Cytotoxic activity was determined with 4-hour 51Cr release assay. Both fresh PBMCs and activated PBMCs exhibited Herceptin-dependent cytotoxicity. Importantly, Herceptin-dependent cytotoxicity was found even at a lower effector to target cell ratio (E/T ratio) than that of Herceptin-independent cytotoxicity. In addition, Herceptin-dependent cytotoxicity by these activated PBMCs was observed even in HER2-weakly-expressing Breast-M cells. Since γ-globulin or anti-CD16 antibody abrogated Herceptin-dependent cytotoxicity, it seems likely that antibody-dependent cellular cytotoxicity (ADCC) plays an important role in the Herceptin-dependent cytotoxicity. We present a recurrent breast cancer patient with malignant pleural effusion, in which HER2-strongly-expressing tumor cells were present, who was undergoing Herceptin therapy. Cluster formation between tumor cells and intrapleural mononuclear cells was induced 24 hours after intravenous injection of Herceptin (4 mg/kg). Mononuclear cells bound specifically to HER2-strongly-expressing tumor cells but not to other cells, such as mesothelial cells, suggested a Herceptin-mediated binding like ADCC in vivo. Taken together, these findings suggest that the combination of Herceptin with various types of activated lymphocytes may be a new therapeutic strategy, not only for HER2-strongly-expressing breast cancer but also for HER2-weakly-expressing cancer.. |
| 196. | T Morisaki, K Matsumoto, H Kuroki, M Kubo, E Baba, H Onishi, A Tasaki, M Nakamura, S Inaba, M Katano, Combined immunotherapy with intracavital injection of activated lymphocytes, monocyte-derived dendritic cells and low-dose OK-432 in patients with malignant effusion, ANTICANCER RESEARCH, 23, 6A, 4459-4465, 2003.11, We have conducted a pilot study with combined immunotherapy using autologous lymphocytes activated ex vivo and monocyte-derived dendritic cells in combination with low-dose OK-432, a streptococcal preparation, in five patients with peritoneal or pleural carcinomatosis who were resistant to standard chemotherapy. All patients were given 3 to 10 courses of the combined immunotherapy. No severe adverse reactions occurred. Effusion production was decreased in all of the patients. Significant decreases in tumor markers of both effusions and sera as well as effusion volume occurred in all of the patients. Cytological examinations revealed a marked decrease or disappearance of cancer cells in those effusions. Three patients showed increase in IFN-gamma levels in the effusions. The overall prognosis of the patients was acceptable and the mean survival time was more than 9 months. The locoregional immunotherapy seems to be encouraging in view of therapeutic modality in patients who are resistant to standard chemotherapy. Our study provides a new protocol for immunotherapy and warrants further phase I/II clinical study for chemo-resistant patients with malignant effusion.. |
| 197. | Chihiro Nakahara, Katsuya Nakamura, Naoki Yamanaka, Eishi Baba, Morimasa Wada, Hisashi Matsunaga, Hirokazu Noshiro, Masao Tanaka, Takashi Morisaki, Mitsuo Katano, Cyclosporin-A Enhances Docetaxel-Induced Apoptosis through Inhibition of Nuclear Factor-κB Activation in Human Gastric Carcinoma Cells, Clinical Cancer Research, 9, 14, 5409-5416, 2003.11, Purpose: We sought to determine whether cyclosporin-A (CsA) enhances docetaxel [Taxotere (TXT)]-induced apoptosis in human gastric carcinoma cells, and, if so, to determine the relation between this apoptosis and nuclear factor-κB (NF-κB) activation. Experimental Design: Two human gastric carcinoma cell lines (GCTM-1 and MK-1), a human embryonic pulmonary fibroblast cell line, and human umbilical vein endothelial cells were used as drug targets. Apoptotic cell death was verified morphologically by nuclear fragmentation assay with Hoechst staining. Electrophoretic mobility shift assays were performed to check for nuclear translocation of NF-κB. The therapeutic effects of a combination of TXT and CsA were assessed in a mouse peritoneal dissemination model. Results: A combination of CsA (5 μM) and TXT (10 nM) significantly enhanced apoptotic cell death in both carcinoma cell lines but not in nonmalignant cell lines in comparison with the single-agent treatment alone. This effect was not related to drug uptake, efflux, or MDR1 expression. These effects were also observed in freshly obtained TXT-resistant gastric carcinoma cells isolated from a patient with malignant ascites. TXT alone induced NF-κB activation in both carcinoma cell types, and this activation was suppressed by CsA. A combination of TXT and NF-κB decoy, a well-known NF-κB inhibitor, also enhanced apoptotic cell death in the carcinoma cells. A combination of CsA and TXT significantly suppressed peritoneal dissemination in vivo relative to the single-agent effect. Conclusions: Treatment with CsA and TXT in combination may be an effective therapeutic strategy for patients with gastric carcinoma.. |
| 198. | Hideo Kuroki, Takashi Morisaki, Kotaro Matsumoto, Hideya Onishi, Eishi Baba, Masao Tanaka, Mitsuo Katano, Streptococcal preparation OK-432: A new maturation factor of monocyte-derived dendritic cells for clinical use, Cancer Immunology, Immunotherapy, 10.1007/s00262-003-0394-7, 52, 9, 561-568, 2003.09, [URL], For vaccinations based on dendritic cells (DCs), maturation of DCs is critical to the induction of T-cell responses. We tested the efficacy of streptococcal preparation OK-432 as a Good Manufacturing Practice (GMP)-grade maturation agent. OK-432 is currently used in Japan as a cancer immunotherapy drug. Immature monocyte-derived dendritic cells (imMo-DCs) isolated from human peripheral blood monocytes stimulated with granulocyte-macrophage colony stimulating factor and interleukin-4 were exposed to maturation factors, i.e., lipopolysaccharide (LPS), tumor necrosis factor α (TNF-α) plus prostaglandin E2 (PGE2), and OK-432 for 2 days. OK-432 increased expression of activation- and maturation-related molecules such as HLA-DR, CD80, CD83, and CD86 in imMo-DCs at levels similar to that of TNF-α plus PGE2, and higher than that of LPS. All agents examined induced allogeneic T-cell proliferation at a similar level. Only OK-432 caused significant production of interleukin-12 (IL-12) p70 and interferon γ (IFN-γ) at both the mRNA and protein levels in imMo-DCs. Neutralizing antibody against IL-12 p70 blocked IFN-γ secretion from OK-432-stimulated Mo-DCs. IL-12 p70 produced by OK-432-stimulated imMo-DCs induced secretion of IFN-γ by CD4+ T cells. OK-432 and LPS activated nuclear factor κ B (NF-κB) in imMo-DCs. Both secretion of IL-12 p70 and IFN-γ and activation of NF-κB induced by OK-432 were suppressed when imMo-DCs were pretreated with cytochalasin B. These results indicate that uptake of OK-432 by imMo-DCs is an early critical event for IL-12 p70 production and that NF-κB activation induced by OK-432 also contributes partially to IL-12 p70 production. In conclusion, OK-432 is a GMP-grade maturation agent and may be a potential tool for DC-based vaccine therapies.. |
| 199. | Takashi Kamihira, Shinji Shimoda, Kenichi Harada, Akira Kawano, Mizuki Handa, Eishi Baba, Koichi Tsuneyama, Minoru Nakamura, Hiromi Ishibashi, Yasuni Nakanuma, M. Eric Gershwin, Mine Harada, Distinct Costimulation Dependent and Independent Autoreactive T-Cell Clones in Primary Biliary Cirrhosis, Gastroenterology, 10.1016/j.gastro.2003.07.013, 125, 5, 1379-1387, 2003.01, [URL], Background & Aims: Previous work has suggested that CD4+ CD28- or costimulation-independent T cells are increased in autoimmune diseases. In this study, we compared frequency and qualitative characteristics of autoreactive costimulation-independent or CD4+ CD28- T cells in primary biliary cirrhosis (PBC) by taking advantage of the well-defined immunodominant autoepitope of the E2 component of pyruvate dehydrogenase (PDC-E2). Methods: We determined the frequency of costimulation-independent autoreactive T cells that respond to PDC-E2 163-176 and the frequency of CD4+ CD28- T cells. Finally, we determined the role of biliary epithelial cells (BEC) as both an antigen-presenting cell or, alternatively, as a target cell for T-cell-mediated cytotoxicity. Results: The precursor frequency of costimulation-independent CD4+ T cells that respond to PDC-E2 163-176 and the frequency of CD4+ CD28- T cells were dramatically elevated in PBC. Furthermore, 2 types of T-cell clones that respond to PDC-E2 163-176 emerged from this study. One type was costimulation dependent and the other costimulation independent. Both types of clones lyse BEC in a similar effector target (E/T) ratio distribution. However, BEC did not help the proliferation of any T-cell clones. Furthermore, costimulation-independent T-cell clones do not become anergic by BEC. Conclusions: In PBC, costimulation-independent autoreactive T cells, which do not become anergic, increase and maintain the autoimmune response. In controls, although autoantigens are expressed on BEC and autoantigen-reactive T cells exist around BEC, autoantigen-reactive T cells are costimulation dependent and will become anergic and maintain peripheral tolerance.. |
| 200. | Hideya Onishi, Takashi Morisaki, Eishi Baba, Hirotaka Kuga, Hideo Kuroki, Kotaro Matsumoto, Masao Tanaka, Mitsuo Katano, Dysfunctional and short-lived subsets in monocyte-derived dendritic cells from patients with advanced cancer, Clinical Immunology, 10.1006/clim.2002.5293, 105, 3, 286-295, 2002.12, [URL], Dendritic cells (DCs) are antigen-presenting cells specialized for the induction of the primary T-cell response. Tumor immunotherapy using DCs loaded with tumor antigens is under way for patients with several types of advanced malignancies. In this study, DC-like cells (Mo-DCs) were generated from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor and interleukin-4. The antigen-presenting abilities, including capture of apoptotic tumor cells, IL-12 secretion, expression of antigen-presentation-related molecules (HLA-ABC, HLA-DR, and CD80), and mixed leukocyte reaction, of Mo-DCs from 37 patients with advanced cancer (pMo-DCs) were compared to those of 20 healthy volunteers (hMo-DCs). Seven days after the initial culture, no significant difference was found in either the number or the size of Mo-DC-forming colonies between the two groups. However, most of the antigen-presenting abilities of pMo-DCs were weaker than those of hMo-DCs on day 7. On day 14, both number and size of colonies were significantly decreased in pMo-DCs but not in hMo-DCs. Interestingly, the antigen-presenting abilities of the remaining pMo-DCs gradually strengthened with time and by day 14 no significant difference was observed between pMo-DCs and hMo-DCs. These results indicate that pMo-DCs contain dysfunctional and short-lived Mo-DC subsets. © 2002 Elsevier Science (USA).. |
| 201. | K. Nakamura, H. Kuga, T. Morisaki, E. Baba, N. Sato, K. Mizumoto, K. Sueishi, M. Tanaka, Mitsuo Katano, Simulated microgravity culture system for a 3-D carcinoma tissue model, BioTechniques, 33, 5, 1068-1076, 2002.11, An in vitro organotypic culture model is needed to understand the complexities of carcinoma tissue consisting of carcinoma cells, stromal cells, and extracellular matrices. We developed a new in vitro model of carcinoma tissue using a rotary cell culture system with four disposable vessels (RCCS™-4D) that provides a simulated microgravity condition. Solid collagen gels containing human pancreatic carcinoma NOR-P1 cells and fibroblasts or minced human pancreatic carcinoma tissue were cultured under a simulated microgravity condition or a static 1g condition for seven days. NOR-P1 cultures subjected to the simulated microgravity condition showed greater numbers of mitotic, cycling (Ki-67-positive), nuclear factor-κ B-activating cells, and a lower number of apoptotic cells than were shown by cultures subjected to the static 1g condition. In addition, human pancreatic carcinoma specimens cultured under the simulated microgravity condition maintained the heterogeneous composition and cellular activity (determined by the cycling cell ratio and mitotic index) of the original carcinoma tissue better than static culture conditions. This new 3-D rotary cell culture system with four disposal vessels may be useful for in vitro studies of complex pancreatic carcinoma tissue.. |
| 202. | E Baba, Y Takahashi, J Lichtenfeld, R Tanaka, A Yoshida, K Sugamura, N Yamamoto, Y Tanaka, Functional CD4 T cells after intercellular molecular transfer of OX40 ligand, JOURNAL OF IMMUNOLOGY, 167, 2, 875-882, 2001.07, [URL], OX40/OX40 ligand (OX40L) proteins play critical roles in the T cell-B cell and T cell-dendritic cell interactions. Here we describe the intercellular transfer of OX40L molecules by a non-Ag specific manner. After 2-h coculture of activated CD4(+) T cell (OX40L(-), OX40(+)) with FLAG peptide-tagged OX40L (OX40L-flag) protein-expressing COS-1 cells, the OX40L-flag protein was detected on the cell surface of the CD4(+) T cells by both anti-OX40L and anti-FLAG mAbs. The intercellular OX40L transfer was specifically abrogated by pretreatment of the COS-1 cells with anti-OX40L mAb, 5A8. The OX40L transfer to OX40-negative cells was also observed, indicating an OX40-independent pathway of OX40L transfer. HUVECs, allostimulated monocytes, and human T cell leukemia virus type I-infected T cells, which all express OX40L, can potentially act as the donor cells of OX40L. The entire molecule of OX40L was transferred and stabilized on the recipient cell membrane with discrete punctate formation. The transferred OX40L on normal CD4(+) T cells was functionally active as they stimulated latent HIV-1-infected cells to produce viral proteins via OX40 signaling. Therefore, these findings suggest that the intercellular molecular transfer of functional OX40L may be involved in modifying the immune responses.. |
| 203. | E Baba, R Erskine, JE Boyson, GB Cohen, DM Davis, P Malik, O Mandelboim, HT Reyburn, JL Strominger, N-linked carbohydrate on human leukocyte antigen-C and recognition by natural killer cell inhibitory receptors, HUMAN IMMUNOLOGY, 10.1016/S0198-8859(00)00184-1, 61, 12, 1202-1218, 2000.12, [URL], The possible role of carbohydrate in the interaction of HLA-C with a human inhibitory natural Killer cell Immunoglobulin-like Receptor with two Ib domains, KIR2DL1, was investigated. Transfectants of 721.221 (a class I MHC-negative human B cell line) expressing only HLA-Cw4 or -Cw6 or their respective non-glycosylated mutants (N86Q, S88A) were made. The binding of a KIR2DL1-Ig fusion protein to the non-glycosylated mutant HLA-Cw4- or -Cw6-expressing cells was markedly decreased compared to the wild type-expressing cells. The ability to induce an inhibitory signal in the NK tumor line YTS transfected with KIR2DL1 was also impaired in the nonglycosylated mutant expressing cells. Furthermore, in a second functional assay, mutant HLA-Cw I and -Cw6 molecules had impaired ability to induce signal transduction in BW cells expressing a KIR2DL1-CD3 zeta chain chimeric protein. Thus, the deletion of the N-linked glycosylation signal in HLA-Cw4 and -Cw6 greatly reduced recognition by KIR2DL1. Alternative interpretations of the data are discussed. (C) American Society for Histocompatibility and Immunogenetics, 2000. Published by Elsevier Science Inc.. |
| 204. | P Malik, E Baba, JL Strominger, Biotinylation of class I MHC molecules abrogates recognition by W6/32 antibody, TISSUE ANTIGENS, 53, 6, 576-579, 1999.06, [URL], W6/32 is one of the most common monoclonal antibodies (mAb) used to characterize human class I major histocompatibility complex (MHC) molecules. It recognizes a conformational epitope on the intact MWC molecule containing both beta(2)-microglobulin (beta(2)-m) and the heavy chain. Labelling proteins by biotinylation is a very useful technique of for their detection, purification and analysis A common method for biotinylating proteins is through the use of N-hydroxysuccinimide (NHS) biotin or Sulfo-NHS-biotin where the free amino groups on the protein are used for coupling the biotin moiety. However, W6/32 was unable to effectively immunoprecipitate biotinylated human class I MHC molecules including the human non-classical HLA-G molecule. FACScan analysis confirmed that biotinylating human class I MHC and HLA-G molecules prevents the recognition of these molecule by W6/32. In contrast, the recognition by another conformation-dependent monoclonal antibody, ME1, specific to HLA-B27 molecules, remained totally unaffected.. |
| 205. | DM Davis, O Mandelboim, Luque, I, E Baba, J Boyson, JL Strominger, The transmembrane sequence of human histocompatibility leukocyte antigen (HLA)-C as a determinant in inhibition of a subset of natural killer cells, JOURNAL OF EXPERIMENTAL MEDICINE, 10.1084/jem.189.8.1265, 189, 8, 1265-1274, 1999.04, [URL], Molecular interactions with the extracellular domains of class I major histocompatibility complex proteins are major determinants of immune recognition that have been extensively studied both physically and biochemically. However, no immunological function has yet been placed on the transmembrane or cytoplasmic amino acid sequences of these proteins despite strict conservation of unique features within each class I major histocompatibility complex locus. Here we report that lysis by a subset of natural killer (NK) cells inhibited by target cell expression of human histocompatibility leukocyte antigen (HLA)-Cw6 or -Cw7 was not inhibited by expression of chimeric proteins consisting of the extracellular domains of HLA-C and the COOH-tenninal portion of HLA-G. Assays using transfectants expressing a variety of HLA-Cw6 mutants identified the transmembrane sequence and, in particular, cysteine at position 309 as necessary for inhibition of 68% (25/37) of NK cell lines and 23% (33/145) of NK clones tested. Moreover, these NK clones inhibited by target cell expression of HLA-Cw6 and dependent upon the transmembrane sequence were found not to express or to only dimly express NK inhibitory receptors (NKIR1) that are EB6/HP3E4-positive. Furthermore, assays using monoclonal antibody blocking suggest that an NK receptor other than NKIR1 or CD94 is responsible for recognition dependent upon the transmembrane sequence of HLA-Cw6.. |
| 206. | Kenji Yamasaki, Jun-Ichi Kira, Yoshio Koyanagi, Yuji Kawano, Naoko Miyano-Kurosaki, Minoru Nakamura, Eishi Baba, Jun Suzuki, Akifumi Yamamoto, Naoki Yamamoto, Takuro Kobayashi, Long term, high dose interferon-alpha treatment in HTLV-I-associated myelopathy/tropical spastic paraparesis: A combined clinical, virological and immunological study, Journal of the Neurological Sciences, 10.1016/S0022-510X(96)05319-1, 147, 2, 135-144, 1997.04, [URL], The efficacy of long-term, high dose interferon-α (IFN-α) therapy was studied in seven patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). IFN-α was administered at a dose of 6 x 106 international units daily for the initial 2 weeks and thereafter 3 times a week for the following 22 weeks. Five patients showed a sustained improvement in motor performance during and up to 6 months after the completion of IFN-a. The other patient who responded to IFN-α initially dropped out at 3 months because of depression, while another patient first deteriorated and thereafter dropped out. In the six responders,the absolute number of peripheral blood lymphocytes (PBL) harboring the HTLV-I genome as evaluated by the quantitative polymerase chain reaction method decreased significantly during the therapy period (28.6 ± 16.6% reduction, P=0.0083), whereas the one deteriorated patient showed a 2.5-fold increase in HTLV-I-infected cells. The autoproliferation of CD4+ T clone cells from a single cell culture was markedly depressed even after the cessation of IFN-α in the responders who completed long-term IFN-α therapy. In addition, the CD8+DR+ T cells in the peripheral blood and soluble IL-2 receptor levels in the sera increased significantly during the therapy in all patients (P=0.0431 and P=0.0041, respectively). Therefore, the results of our study suggested that both the reduction of HTLV-I proviral DNA load and immunomodulation by long-term IFN-α therapy contributed to its sustained clinical benefits.. |
| 207. | Jun Suzuki, Jun Ichi Kira, Eishi Baba, Minoru Nakamura, Yoshio Koyanagi, Tatsufumi Nakamura, Yuji Kawano, Kenji Yamasaki, Susumu Shirabe, Naoya Hatano, Kenshi Hayashi, Naoki Yamamoto, Takuro Kobayashi, The association of antibodies against human T cell lymphotropic virus type I (HTLV-I) pX gene mutant products with HTLV-I-associated myelopathy/tropical spastic paraparesis, Journal of Infectious Diseases, 10.1093/infdis/173.5.1115, 173, 5, 1115-1122, 1996.01, [URL], Antibodies specific for the products of the human T cell lymphotropic virus type 1 (HTLV-I) pX frame-shift mutants were studied by ELISA. The serum IgG antibodies to the synthetic peptide corresponding to one nucleotide insertion at position 7784 were significantly more common in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients than in HTLV-I carriers who had neither HAM/TSP nor adult T cell leukemia (39% vs. 5%). The seropositivities to the other synthetic peptides, which corresponded to the one nucleotide deletion at position 7475 and the internal deletion of nt 7754-7819 and nt 7853-7936, were rare. A genetic study confirmed the presence of the responsible mutation of the pX gene in peripheral blood mononuclear cells and central nervous system tissue from HTLV-I-infected subjects with and without HAM/TSP. These results suggest that HTLV-I pX frame-shift mutants are expressed in vivo in HTLV-I carriers; they also induce antibodies, especially in those with HAM/TSP.. |
| 208. | E BABA, M NAKAMURA, K OHKUMA, J KIRA, Y TANAKA, S NAKANO, Y NIHO, A PEPTIDE-BASED HUMAN T-CELL LEUKEMIA-VIRUS TYPE-I VACCINE CONTAINING T-CELL AND B-CELL EPITOPES THAT INDUCES HIGH TITERS OF NEUTRALIZING ANTIBODIES, JOURNAL OF IMMUNOLOGY, 154, 1, 399-412, 1995.01, We have recently identified the principal linear neutralizing B cell epitopes of human T cell leukemia virus type (HTLV-I) on the envelope protein gp46, amino acids (aa) 187-199, by using a number of human mAbs. We therefore propose that this region would be a good candidate for a peptide-based HTLV-I vaccine. To develop a peptide-based vaccine that can induce a high titer of neutralizing Abs against HTLV-I, we first synthesized peptides of various lengths containing aa187-199. Because the addition of gp46 aa181-186 or aa200-210 to either the N-terminus or C-terminus of SP187-199 did not alter the antigenicity of the principal neutralizing determinant, we prepared two peptide-based vaccines, MAP181-203 and MAP181-210, by conjugating SP181-203 and SP181-210 with a branched polylysine oligomer. In rabbits, x4 to x8 and x8 to x64 titers of the neutralizing Abs were induced by immunization with MAP181-203 and MAP181-210, respectively. Furthermore, high titers of neutralizing Abs (x40 to x320) were elicited in five different strains of rats by immunization with MAP181-210. We also identified the major T cell epitope on gp46 aa194-210 in various Strains of rats immunized with MAP181-210. Furthermore, the peripheral T lymphocytes obtained from the majority of HTLV-I-infected patients including HTLV-1-associated myelopathy/tropical spastic paraparesis, adult T cell leukemia/lymphoma, and healthy carriers, proliferated in response to the peptides containing aa194-210. These results indicated that MAP181-210 contains a T cell helper epitope on aa194-210 not only in rats and rabbits, but also in humans with various HLA haplotypes. It is therefore possible that MAP181-210 could become one of the candidates for a peptide-based HTLV-I vaccine for human use.. |
| 209. | Masumoto N, Nakano S, Esaki T, Tatsumoto T, Fujishima H, Baba E, Nakamura M, Niho Y, Sequence-dependent modulation of anticancer drug activities by 7-ethyl-10-hydroxycamptothecin in an HST-1 human squamous carcinoma cell line., Anticancer research, 15, 2, 405-409, 1995.03. |
| 210. | Nakano S, Tatsumoto T, Esaki T, Nakamura M, Baba E, Kimura A, Ohshima K, Niho Y, Characterization of a newly established human gallbladder carcinoma cell line., In vitro cellular & developmental biology. Animal, 30A, 11, 729-732, 1994.11, [URL]. |
| 211. | Yuetsu Tanaka, Reiko Tanaka, Eiji Terada, Yoshio Koyanagi, Naoko Miyano-Kurosaki, Naoki Yamamoto, Eishi Baba, Minoru Nakamura, Hisatoshi Shida, Induction of antibody responses that neutralize human T-cell leukemia virus type I infection in vitro and in vivo by peptide immunization, Journal of Virology, 68, 10, 6323-6331, 1994.10, In order to define neutralization regions on the envelope antigen of human T-cell leukemia virus type I (HTLV-I), we have generated a number of new anti-envelope gp46 monoclonal antibodies from rats and mice. Epitopes recognized by new monoclonal antibodies which could neutralize HTLV-I in syncytium and transformation inhibition assays were localized to sequences in gp46 from amino acids 186 to 193, 190 to 195, 191 to 195, 191 to 196, and 194 to 199. Ovalbumin-conjugated synthetic gp46 peptides containing these neutralization epitopes, pep190-199 (a synthetic gp46 peptide containing amino acids 190 to 199) and pep180-204, but not pep185-194 or pep194-203, could give rise to HTLV-I-neutralizing antibody responses in rabbits. These immune or nonimmune rabbits were then challenged with HTLV-I by intravenous inoculation with 5 x 107 live HTLV-I-producing ILT-8M2 cells. By a PCR assay, it was revealed that HTLV-I provirus was detected in peripheral blood lymphocytes from nonimmune and pep288-312-immunized rabbits, whereas the provirus was not detected in peripheral blood lymphocytes from pep190-199- and pep180-204-immunized rabbits over an extended period. These results suggest that the induction of anti-gp46 neutralizing antibody responses by immunization with synthetic peptides has the potential to protect animals against HTLV-I infection in vivo.. |
| 212. | Jun‐ichi ‐i Kira, Yoshio Koyanagi, Takeshi Yamada, Yasuto Itoyama, Jun Tateishi, Shin‐ichiro ‐i Akizuki, Masao Kishikawa, Eishi Baba, Minoru Nakamura, Jun Suzuki, Tatsufumi Nakamura, Naomi Nakamura, Naoki Yamamoto, Ikuo Goto, Sequence heterogeneity of HTLV‐I proviral DNA in the central nervous system of patients with HTLV‐I–associated myelopathy, Annals of Neurology, 10.1002/ana.410360206, 36, 2, 149-156, 1994.08, [URL], The nucleotide sequence of human T‐lymphotropic virus type I (HTLV‐I) in central nervous system tissue was determined in 3 autopsy cases with HTLV‐I–associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and 1 seropositive carrier without HAM/TSP but with multiple sclerosis. All HAM/TSP samples (3 spinal cords and 2 brains) and the sample from the seropositive carrier without HAM/TSP (brain) were positive for HTLV‐I env (5146–6681), pX5′ (6549–7494), and pX3′ (7354–8276) regions by the two‐step polymerase chain reaction method. A nucleotide sequence analysis of the pX5′ and pX3′ polymerase chain reaction products from nucleotides 6631 to 8259 revealed heterogeneity of the HTLV‐I genome in all cases. It is notable that 13 of 50 clones derived from the pX3′ polymerase chain reaction products were defective in the tax open reading frame while 7 were defective in the rex open reading frame in the HAM/TSP samples. All 17 clones from 1 HAM/TSP case were defective in the pX open reading frame II. One nucleotide insertion at 7784 creating a frame shift in both tax and rex was seen in all 3 HAM/TSP cases but not in the HTLV‐I carrier without HAM/TSP. The pX‐defective mutants found frequently in the central nervous system may contribute to the neural damage, since the pX gene products are essential for the transactivation of various cellular genes as well as for viral replication.. |
| 213. | E. Baba, M. Nakamura, Y. Tanaka, M. Kuroki, Y. Itoyama, S. Nakano, Y. Niho, Multiple neutralizing B-cell epitopes of human T-cell leukemia virus type 1 (HTLV-1) identified by human monoclonal antibodies A basis for the design of an HTLV-1 peptide vaccine, Journal of Immunology, 151, 2, 1013-1024, 1993.01, We have generated 153 human mAb reacting with natural envelope glycoprotein-gp46 of human T-cell leukemia virus type-1 (HTLV-1) by the EBV- transformation of B lymphocytes obtained from patients with HTLV-1-associated myelopathy (HAM)/Tropical spastic paraparesis (TSP). Twenty-four of these mAb had neutralizing activity of HTLV-1 as determined by an HTLV-1-induced syncytium formation inhibition assay in vitro. The reactivity of these neutralizing mAb was studied by using 9 different synthetic peptides covering immunodominant regions of the gp46. Thirteen out of these 24 neutralizing mAb reacted with gp46 peptide 175-199, whereas one mAb reacted with gp46 213-236 and another one with gp46 288-317. The other 9 neutralizing mAb did not react with any of these peptides. Fine epitope mapping of the mAb reacting with gp46 peptide 175-199 revealed the presence of 4 distinct neutralizing B-cell epitopes on this region; (1) 187-193, (2) 191-196, (3) 193-199, and (4) continuous conformational B-cell epitope. The competitive antibody-binding inhibition experiments by soluble phase synthetic peptides showed that the binding activity of these neutralizing mAb to the corresponding synthetic peptides is equal to or a little lower than that to native gp46 protein, suggesting that synthetic peptides can form structure very similar to the neutralizing epitopes on native gp46 protein. The present study is the first systematic demonstration of multiple neutralizing B-cell epitopes of HTLV-1 in human HTLV-1 infection. It would be possible to prepare a synthetic peptide vaccine against HTLV-1 based on these newly identified multiple linear neutralizing B-cell epitopes of HTLV-1.. |
| 214. | M. Kuroki, M. Nakamura, Y. Itoyama, Y. Tanaka, H. Shiraki, E. Baba, T. Esaki, T. Tatsumoto, S. Nagafuchi, S. Nakano, Y. Niho, Identification of new epitopes recognized by human monoclonal antibodies with neutralizing and antibody-dependent cellular cytotoxicity activities specific for human T cell leukemia virus type 1, Journal of Immunology, 149, 3, 940-948, 1992.01, We have generated a number of EBV-transformed B cell lines producing human mAb against human T cell leukemia virus type 1 (HTLV-1) from the peripheral blood B lymphocytes obtained from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. Various synthetic peptides corresponding to antigenic regions of HTLV-1 gag and env proteins were used for the screening of antibodies in ELISA. In our study, four IgG mAb to the gag p19 amino acids 100 to 130, and 5 IgG mAb to the env p46 amino acids 175 to 199 were characterized. An immunofluorescence assay showed that all of these mAb specifically bound to the surface of HTLV-1-bearing cell lines. Among these mAb, one anti-gp46 mAb, designated KE36-11, neutralized the infectivity of HTLV-1 as determined by both the inhibition of HTLV-1-induced syncytium formation and transformation assays in vitro. An antibody-binding assay using overlapping oligopeptides revealed that KE36-11 recognized a new epitope locating between the gp46 amino acid sequence 187-193 (Ala-Pro-Pro- Leu-Leu-Pro-His). Another anti-gp46 mAb, designated KE36-7, showed antibody- dependent cellular cytotoxicity against HTLV-1-bearing cell line. KE36-7 bound strongly to the 10-mer peptide-gp46 187-196, and weakly to peptides containing the gp46 amino acid sequence 191-196 (Leu-Pro-His-Ser-Asn-Leu). These two epitopes, which are associated with HTLV-1 neutralization and antibody-dependent cellular cytotoxicity, are thus the first epitopes identified in human HTLV-1 infection. It is possible that passive immunization of humans with these two human mAb are effective on the protection of HTLV-1 infection in vivo.. |
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