881 results on '"Murakami, A."'
Search Results
2. The hepatic niche leads to aggressive natural killer cell leukemia proliferation through the transferrin–transferrin receptor 1 axis
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Kameda, Kazuaki, Yanagiya, Ryo, Miyatake, Yuji, Carreras, Joaquim, Higuchi, Hiroshi, Murayama, Hiromichi, Ishida, Takashi, Ito, Asahi, Iida, Shinsuke, Fukuhara, Noriko, Harigae, Hideo, Fujioka, Yuki, Takahashi, Naoto, Wada, Hidenori, Ishida, Fumihiro, Nakazawa, Hideyuki, Ishihara, Rei, Murakami, Yuki, Tagawa, Hiroyuki, Matsuura, Tadashi, Nakagawa, So, Iwabuchi, Sadahiro, Hashimoto, Shinichi, Imadome, Ken-Ichi, Nakamura, Naoya, Ishizawa, Kenichi, Kanda, Yoshinobu, Ando, Kiyoshi, and Kotani, Ai
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- 2023
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3. An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis
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Zoref-Lorenz, Adi, Murakami, Jun, Hofstetter, Liron, Iyer, Swaminathan, Alotaibi, Ahmad S., Mohamed, Shehab Fareed, Miller, Peter G., Guber, Elad, Weinstein, Shiri, Yacobovich, Joanne, Nikiforow, Sarah, Ebert, Benjamin L., Lane, Adam, Pasvolsky, Oren, Raanani, Pia, Nagler, Arnon, Berliner, Nancy, Daver, Naval, Ellis, Martin, and Jordan, Michael B.
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- 2022
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4. Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma
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Battistello, Elena, Katanayeva, Natalya, Dheilly, Elie, Tavernari, Daniele, Donaldson, Maria C., Bonsignore, Luca, Thome, Margot, Christie, Amanda L., Murakami, Mark A., Michielin, Olivier, Ciriello, Giovanni, Zoete, Vincent, and Oricchio, Elisa
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- 2018
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5. Integrated molecular profiling of juvenile myelomonocytic leukemia
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Murakami, Norihiro, Okuno, Yusuke, Yoshida, Kenichi, Shiraishi, Yuichi, Nagae, Genta, Suzuki, Kyogo, Narita, Atsushi, Sakaguchi, Hirotoshi, Kawashima, Nozomu, Wang, Xinan, Xu, Yinyan, Chiba, Kenichi, Tanaka, Hiroko, Hama, Asahito, Sanada, Masashi, Ito, Masafumi, Hirayama, Masashi, Watanabe, Arata, Ueno, Toshihide, Kojima, Seiji, Aburatani, Hiroyuki, Mano, Hiroyuki, Miyano, Satoru, Ogawa, Seishi, Takahashi, Yoshiyuki, and Muramatsu, Hideki
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- 2018
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6. The Optimized HLH Inflammatory Index Is Associated with a Higher Stage of Lymphoma, but an Unexpected High Mortality Associated with Inflammation
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Adi Zoref-Lorenz, Jun Murakami, Liron Hofstetter, Uri Abadi, Swaminathan P. Iyer, Shehab Fareed Mohamed, Abd El Haleem Natour, Shiri Weinstein, Joanne Yacobovich, Shai Izraeli, Sarah Nikiforow, Ronit Gurion, Inbar Cohen, Oren Pasvolsky, Pia Raanani, Arnon Nagler, Nancy Berliner, Naval Daver, Martin H. Ellis, Gaurav Goyal, and Michael B Jordan
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
7. JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis
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Grisouard, Jean, Li, Sai, Kubovcakova, Lucia, Rao, Tata Nageswara, Meyer, Sara C., Lundberg, Pontus, Hao-Shen, Hui, Romanet, Vincent, Murakami, Masato, Radimerski, Thomas, Dirnhofer, Stephan, and Skoda, Radek C.
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- 2016
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8. Prospective Study of the Usefulness of Liquid Biopsy in Patients with Unknown Fever Suspected of Malignant Lymphoma
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Okamoto, Akinao, primary, Sanada, Masashi, additional, Yasuda, Takahiko, additional, Kato, Seiichi, additional, Satou, Akira, additional, Matsue, Kosei, additional, Hosoi, Hiroki, additional, Yoshida, Masahiro, additional, Murakami, Satsuki, additional, Kondo, Eisei, additional, Masaki, Yasufumi, additional, Suzuki, Yasuhiro, additional, Miyazaki, Kana, additional, Kajiguchi, Tomohiro, additional, Hiraga, Junji, additional, Kurahashi, Shingo, additional, Inagaki, Yuichiro, additional, Ozeki, Kazutaka, additional, Saito, Shigeki, additional, Terao, Toshiki, additional, Iba, Sachiko, additional, Hattori, Keiko, additional, Yamamoto, Hideyuki, additional, Goto, Naoe, additional, Iriyama, Chisako, additional, Okamoto, Masataka, additional, and Tomita, Akihiro, additional
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- 2022
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9. Calcineurin Inhibitors Inhibit Tolerance Induction By Suppressing Terminal Differentiation of Donor Exhausted T Cells after Allogeneic SCT
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Senjo, Hajime, primary, Hashimoto, Daigo, additional, Kubota, Shinpei, additional, Tanaka, Yuki, additional, Harada, Shinpei, additional, Yoneda, Kazuki, additional, Zhang, Zixuan, additional, Chen, Xuanzhong, additional, Kikuchi, Ryo, additional, Hasegawa, Yuta, additional, Ohigashi, Hiroyuki, additional, Ara, Takahide, additional, Hasegawa, Yoshinori, additional, Murakami, Masaaki, additional, and Teshima, Takanori, additional
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- 2022
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10. Detailed Analysis of the Impact of Clonal Hematopoiesis on the Risk of Severe COVID-19 Infection
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Saiki, Ryunosuke, primary, Namkoong, Ho, additional, Edahiro, Ryuya, additional, Sonehara, Kyuto, additional, Wang, Qingbo S, additional, Hasegawa, Takanori, additional, Momozawa, Yukihide, additional, Makishima, Hideki, additional, Nannya, Yasuhito, additional, Kakiuchi, Nobuyuki, additional, Terao, Chikashi, additional, Shiraishi, Yuichi, additional, Chiba, Kenichi, additional, Tanaka, Hiroko, additional, Matsuda, Koichi, additional, Morisaki, Takayuki, additional, Murakami, Yoshinori, additional, Kamatani, Yoichiro, additional, Kubo, Michiaki, additional, Kimura, Akinori, additional, Imoto, Seiya, additional, Miyano, Satoru, additional, Kanai, Takanori, additional, Fukunaga, Koich, additional, Okada, Yukinori, additional, and Ogawa, Seishi, additional
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- 2022
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11. ORIHIME II Study: Background, Treatment Status, and Outcomes of Patients with Acquired Hemophilia A with Low Activities of Daily Living Scores or Undergoing Rehabilitation - a Japanese Health Claims Database Analysis
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Ogawa, Yoshiyuki, primary, Amano, Kagehiro, additional, Ioka, Akiko, additional, Nosaka, Daisuke, additional, Murakami, Yoichi, additional, Adachi, Hiroki, additional, and Nogami, Keiji, additional
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- 2022
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12. Cell Mass and Stiffness As Integrative Biomarkers of Cell State in Mantle Cell Lymphoma
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Debaize, Lydie, primary, Zhang, Ye, additional, Langenbucher, Adam, additional, Liu, Huiyun, additional, Ramseier, Michelle, additional, Mulugeta, Nolawit, additional, Senhaji, Nezha, additional, Redd, Robert A., additional, Aryee, Martin J., additional, Shalek, Alex K., additional, Weinstock, David M., additional, Manalis, Scott R., additional, and Murakami, Mark A., additional
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- 2022
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13. Dysfunctional Clusterin-Positive Hematopoietic Stem Cells Expand with Aging
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Koide, Shuhei, primary, Oshima, Motohiko, additional, Nishiyama, Akira, additional, Murakami, Koichi, additional, Itokawa, Naoki, additional, Nakajima-Takagi, Yaeko, additional, Zheng, Zhiqian, additional, Yusa, Nozomi, additional, Yokoyama, Kazuaki, additional, Tojo, Arinobu, additional, Tamura, Tomohiko, additional, and Iwama, Atsushi, additional
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- 2022
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14. The Optimized HLH Inflammatory Index Is Associated with a Higher Stage of Lymphoma, but an Unexpected High Mortality Associated with Inflammation
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Zoref-Lorenz, Adi, primary, Murakami, Jun, additional, Hofstetter, Liron, additional, Abadi, Uri, additional, Iyer, Swaminathan P., additional, Mohamed, Shehab Fareed, additional, Natour, Abd El Haleem, additional, Weinstein, Shiri, additional, Yacobovich, Joanne, additional, Izraeli, Shai, additional, Nikiforow, Sarah, additional, Gurion, Ronit, additional, Cohen, Inbar, additional, Pasvolsky, Oren, additional, Raanani, Pia, additional, Nagler, Arnon, additional, Berliner, Nancy, additional, Daver, Naval, additional, Ellis, Martin H., additional, Goyal, Gaurav, additional, and Jordan, Michael B, additional
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- 2022
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15. Dysfunctional Clusterin-Positive Hematopoietic Stem Cells Expand with Aging
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Shuhei Koide, Motohiko Oshima, Akira Nishiyama, Koichi Murakami, Naoki Itokawa, Yaeko Nakajima-Takagi, Zhiqian Zheng, Nozomi Yusa, Kazuaki Yokoyama, Arinobu Tojo, Tomohiko Tamura, and Atsushi Iwama
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
16. Detailed Analysis of the Impact of Clonal Hematopoiesis on the Risk of Severe COVID-19 Infection
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Ryunosuke Saiki, Ho Namkoong, Ryuya Edahiro, Kyuto Sonehara, Qingbo S Wang, Takanori Hasegawa, Yukihide Momozawa, Hideki Makishima, Yasuhito Nannya, Nobuyuki Kakiuchi, Chikashi Terao, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Koichi Matsuda, Takayuki Morisaki, Yoshinori Murakami, Yoichiro Kamatani, Michiaki Kubo, Akinori Kimura, Seiya Imoto, Satoru Miyano, Takanori Kanai, Koich Fukunaga, Yukinori Okada, and Seishi Ogawa
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
17. ORIHIME II Study: Background, Treatment Status, and Outcomes of Patients with Acquired Hemophilia A with Low Activities of Daily Living Scores or Undergoing Rehabilitation - a Japanese Health Claims Database Analysis
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Yoshiyuki Ogawa, Kagehiro Amano, Akiko Ioka, Daisuke Nosaka, Yoichi Murakami, Hiroki Adachi, and Keiji Nogami
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
18. Cell Mass and Stiffness As Integrative Biomarkers of Cell State in Mantle Cell Lymphoma
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Lydie Debaize, Ye Zhang, Adam Langenbucher, Huiyun Liu, Michelle Ramseier, Nolawit Mulugeta, Nezha Senhaji, Robert A. Redd, Martin J. Aryee, Alex K. Shalek, David M. Weinstock, Scott R. Manalis, and Mark A. Murakami
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
19. Calcineurin Inhibitors Inhibit Tolerance Induction By Suppressing Terminal Differentiation of Donor Exhausted T Cells after Allogeneic SCT
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Hajime Senjo, Daigo Hashimoto, Shinpei Kubota, Yuki Tanaka, Shinpei Harada, Kazuki Yoneda, Zixuan Zhang, Xuanzhong Chen, Ryo Kikuchi, Yuta Hasegawa, Hiroyuki Ohigashi, Takahide Ara, Yoshinori Hasegawa, Masaaki Murakami, and Takanori Teshima
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
20. Toward rational therapy for mantle cell lymphoma
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Murakami, Mark A.
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- 2023
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21. Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane
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Nanua, Suparna, Murakami, Mark, Xia, Jun, Grenda, David S., Woloszynek, Jill, Strand, Marie, and Link, Daniel C.
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- 2011
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22. Unraveling Heterogeneity of Aged Hematopoietic Stem Cells By Single-Cell RNA Sequence Analysis
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Koide, Shuhei, primary, Oshima, Motohiko, additional, Nishiyama, Akira, additional, Murakami, Koichi, additional, Yamada, Yuta, additional, Itokawa, Naoki, additional, Nakajima-Takagi, Yaeko, additional, Zheng, Zhiqian, additional, Tamura, Tomohiko, additional, and Iwama, Atsushi, additional
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- 2021
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23. Prospective Comparison Study of Prognostic Value of MRD Detected By 8-Color MFC (EuroFlow-NGF) and NGS in Patients with Multiple Myeloma in ASCT Setting
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Yoroidaka, Takeshi, primary, Takamatsu, Hiroyuki, additional, Itagaki, Mitsuhiro, additional, Yoshihara, Satoshi, additional, Sato, Kota, additional, Takezako, Naoki, additional, Ozaki, Shuji, additional, Suzuki, Kazuhito, additional, Kohno, Kentaro, additional, Matsumoto, Morio, additional, Terasaki, Yasushi, additional, Yamashita, Takeshi, additional, Fuchida, Shin-ichi, additional, Urushihara, Ryota, additional, Hiragori, Yuji, additional, Suzuki, Kenshi, additional, Murakami, Hirokazu, additional, Nakao, Shinji, additional, Durie, Brian G.M., additional, and Shimizu, Kazuyuki, additional
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- 2021
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24. Leveraging Pathway-Interference to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia
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Chan, Lai N., primary, Murakami, Mark A., additional, Hurtz, Christian, additional, Kume, Kohei, additional, Lee, Jaewoong, additional, Cosgun, Kadriye Nehir, additional, Geng, Huimin, additional, Izraeli, Shai, additional, Weinstock, David M., additional, and Müschen, Markus, additional
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- 2021
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25. Hikoboshi Study: Remaining Burden and Current Medical Care Status of Patients with Congenital Hemophilia a: A Study Using Two Japanese Medical Information Databases
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Nagao, Azusa, primary, Ioka, Akiko, additional, Nakamura, Takao, additional, Murakami, Yoichi, additional, Makishima, Misako, additional, Okada, Norihiro, additional, and Sakai, Michio, additional
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- 2021
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26. Orihime Study: Real World Treatment Patterns and Clinical Outcomes of 338 Patients with Acquired Hemophilia a from a Japanese Health Claims Database
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Ogawa, Yoshiyuki, primary, Amano, Kagehiro, additional, Matsuo-Tezuka, Yukari, additional, Okada, Norihiro, additional, Murakami, Yoichi, additional, Nakamura, Takao, additional, Yamaguchi-Suita, Haruko, additional, and Nogami, Keiji, additional
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- 2021
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27. A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL in Adults
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Luskin, Marlise R., primary, Stevenson, Kristen E., additional, Mendez, Lourdes M., additional, Wang, Eunice S., additional, Wadleigh, Martha, additional, Garcia, Jacqueline S., additional, Stone, Richard M., additional, An, Hyun Hwan, additional, Hagopian, Ella, additional, Galinsky, Ilene, additional, Rae, Lindsey, additional, Leonard, Rebecca, additional, DeAngelo, Daniel J., additional, and Murakami, Mark A., additional
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- 2021
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28. An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis
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Naval Daver, Ahmad S. Alotaibi, Adi Zoref-Lorenz, Adam Lane, Nancy Berliner, Oren Pasvolsky, Liron Hofstetter, Shehab F. Mohamed, Pia Raanani, Arnon Nagler, Joanne Yacobovich, Swaminathan P. Iyer, Shiri Weinstein, Peter Miller, Michael B. Jordan, Sarah Nikiforow, Jun Murakami, Elad Guber, Benjamin L. Ebert, and Martin Ellis
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Male ,endocrine system ,medicine.medical_specialty ,Immunology ,Context (language use) ,Malignancy ,Biochemistry ,Lymphohistiocytosis, Hemophagocytic ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Mortality prediction ,Aged ,Retrospective Studies ,Hemophagocytic lymphohistiocytosis ,Receiver operating characteristic ,business.industry ,Hazard ratio ,Interleukin-2 Receptor alpha Subunit ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Confidence interval ,Survival Rate ,Hematologic Neoplasms ,Cohort ,Ferritins ,Female ,business ,Follow-Up Studies - Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. Classification and regression tree and receiver-operating curve analyses were used to identify the most useful diagnostic and prognostic parameters and to optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3900 U/mL) and ferritin (>1000 ng/mL) best identified HLH-2004–defining features (sensitivity, 84%; specificity, 81%). Moreover, this combination, which we term the optimized HLH inflammatory (OHI) index, was highly predictive of mortality (hazard ratio, 4.3; 95% confidence interval, 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk who were not defined as having HLH according to HLH-2004/HScore. Finally, the OHI index shows diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies patients with HM and an inflammatory state associated with a high mortality risk and warrants further prospective validation.
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- 2021
29. Targeting SF3B1 in High-Risk B-Cell Acute Lymphoblastic Leukemia
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Murakami, Yuki, Konishi, Hiroaki, Tepper, Cliff, McPherson, John, and Satake, Noriko
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- 2023
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30. DNA Polymerases Pol θ/Pol η Involved in Error-Prone DNA Repair Are Highly Expressed in Multiple Myeloma and Upregulated By DNA Damage
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Sunaga, Masanobu, primary, Oda, Tsukasa, additional, Yamane, Eiko, additional, Ishihara, Rei, additional, Murakami, Yuki, additional, Watanabe, Saki, additional, Asao, Yuta, additional, Masuda, Yuta, additional, Takei, Hisashi, additional, Kobayashi, Nobuhiko, additional, Osaki, Yohei, additional, Nanami, Gotoh, additional, Kasamatsu, Tetsuhiro, additional, Koiso, Hiromi, additional, Takizawa, Makiko, additional, Shimizu, Hiroaki, additional, Ishizaki, Takuma, additional, Ogawa, Yoshiyuki, additional, Yokohama, Akihiko, additional, Tsukamoto, Norifumi, additional, Saitoh, Takayuki, additional, Murakami, Hirokazu, additional, and Handa, Hiroshi, additional
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- 2019
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31. P53 Pathway Activation Mediated High c-MAF Expression Is Associated with Overall and Post-Progression Survival in Multiple Myeloma
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Yamane, Eiko, primary, Oda, Tsukasa, additional, Sunaga, Masanobu, additional, Murakami, Yuki, additional, Ishihara, Rei, additional, Asao, Yuta, additional, Masuda, Yuta, additional, Watanabe, Saki, additional, Kobayashi, Nobuhiko, additional, Takei, Hisashi, additional, Osaki, Yohei, additional, Nanami, Gotoh, additional, Kasamatsu, Tetsuhiro, additional, Shimizu, Hiroaki, additional, Ishizaki, Takuma, additional, Koiso, Hiromi, additional, Takizawa, Makiko, additional, Ogawa, Yoshiyuki, additional, Yokohama, Akihiko, additional, Tsukamoto, Norifumi, additional, Saitoh, Takayuki, additional, Murakami, Hirokazu, additional, and Handa, Hiroshi, additional
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- 2019
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32. Inherited glycosylphosphatidylinositol defects cause the rare Emm-negative blood phenotype and developmental disorders
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Duval, Romain, primary, Nicolas, Gaël, additional, Willemetz, Alexandra, additional, Murakami, Yoshiko, additional, Mikdar, Mahmoud, additional, Vrignaud, Cedric, additional, Megahed, Hisham, additional, Cartron, Jean-Pierre, additional, Masson, Cecile, additional, Wehbi, Samer, additional, Koehl, Bérengere, additional, Hully, Marie, additional, Siquier, Karine, additional, Chemlay, Nicole, additional, Rotig, Agnes, additional, Lyonnet, Stanislas, additional, Colin, Yves, additional, Barcia, Giulia, additional, Cantagrel, Vincent, additional, Le Van Kim, Caroline, additional, Hermine, Olivier, additional, Kinoshita, Taroh, additional, Peyrard, Thierry, additional, and Azouzi, Slim, additional
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- 2021
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33. Negative regulation of the SH2-homology–containing protein-tyrosine phosphatase-1 (SHP-1) P2 promoter by the HTLV-1 Tax oncoprotein
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Cheng, Jihua, Kydd, Andre R., Nakase, Koichi, Noonan, Kristin M., Murakami, Akikazu, Tao, Hong, Dwyer, Markryan, Xu, Chen, Zhu, Quan, and Marasco, Wayne A.
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- 2007
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34. Splenic CD19−CD35+B220+ cells function as an inducer of follicular dendritic cell network formation
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Murakami, Takaya, Chen, Xin, Hase, Koji, Sakamoto, Ayako, Nishigaki, Chie, and Ohno, Hiroshi
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- 2007
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35. A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL in Adults
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Jacqueline S. Garcia, Rebecca Leonard, Marlise R. Luskin, Kristen E. Stevenson, Martha Wadleigh, Eunice S. Wang, Daniel J. DeAngelo, Ilene Galinsky, Ella Hagopian, Richard Stone, Mark A. Murakami, Hyun Hwan An, Lindsey Rae, and Lourdes M. Mendez
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Phase i study ,Dasatinib ,Bcr abl1 ,Prednisone ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Introduction Oral tyrosine kinase inhibitors (TKIs) that inhibit the constitutively active ABL1 kinase have improved outcomes for BCR-ABL1+ acute lymphoblastic leukemia (ALL) and decreased reliance on cytotoxic chemotherapy (ctx). Later generation, more potent TKIs such as dasatinib (DAS) are particularly effective (Foa et al. Blood 2011; Foa et al. N Eng J Med 2020). ABL001 (asciminib) is a STAMP (Specifically Targeting the ABL Myristoyl Pocket) allosteric inhibitor of ABL1 that binds to a site spatially distinct from all approved ATP-competitive TKIs. Combination treatment with an allosteric and an ATP-competitive TKI may deepen clinical responses and limit mutational resistance as supported by a cell line xenograft model of CML (Wylie et al. Nature 2017) and patient-derived xenograft models of BCR-ABL1+ ALL. We hypothesized that dual ABL blockade with catalytic domain and allosteric inhibitors would be tolerable and effective in BCR-ABL1+ ALL. Methods This is an investigator initiated, phase I study (NCT03595917) of ABL001 in combination with DAS plus prednisone in BCR-ABL1+ ALL. The study employs a 3+3 dose escalation design with an expansion cohort with the primary objective to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Secondary objectives include defining the depth and durability of responses. Patients (pts) ≥ 50 years (yrs) and younger unfit pts (18-49 yrs) with untreated BCR-ABL+ ALL or pts ≥ 18 yrs with relapsed/refractory ALL (no prior DAS or ABL001) are eligible. Pts are treated with DAS 140 mg daily and prednisone 60 mg/m2 days (d) 1-24 (max 120 mg daily, tapered d 25-32) with escalating doses of ABL001 once/d administered fasting (DL1: 40 mg; DL2: 80 mg; DL3: 160 mg). DAS plus ABL001 are given in 28-day cycles. Pts receive CNS prophylaxis with intrathecal ctx. Bone marrow transplant (BMT)-eligible pts may be consolidated with BMT after d85; BMT-ineligible pts may remain on therapy if deriving clinical benefit. Dose-limiting toxicity (DLT) was initially defined as CTCAEv4 non-heme toxicity grade (gr) 3+; the study has since been amended to assess DLT via CTCAEv5. Correlative science aims to identify biomarkers of response to combined ABL1 blockade and to define targetable biological programs enriched in minimal residual disease. Results The study has enrolled 12 pts (7 male/5 female). All 12 had untreated BCR-ABL1+ ALL. The median age at registration was 66 yrs (range 53 - 86; 4 pts 70+). DL1 (ABL001 40 mg/d) enrolled 3 pts without DLT; all have discontinued therapy (1 pt personal decision - C5, 2 pts to BMT- C5). DL2 (ABL001 80 mg daily) enrolled 3 pts without DLT (1 pt remains on study - C32, 1 pt discontinued for DAS pulmonary toxicity - C4, 1 pt discontinued for ALL progression - C11). DL3 (ABL001 160 mg daily) enrolled 3 pts with 2 pts developing asymptomatic CTCAEv4 Gr 3 amylase elevation during C1 meeting original DLT criteria (3 rd pt discontinued C2 due to DAS pulmonary toxicity and inadequate response). A 4th pt was enrolled on DL3 under protocol amendment defining asymp CTCAEv4 gr 3 amylase/lipase elevations persisting Conclusion Dual ABL1 kinase inhibition with asciminib and DAS plus prednisone in BCR-ABL1+ ALL is feasible. Primary toxicity is asymptomatic amylase and lipase elevation. Enrollment continues at DL2 under CTCAEv5 to further define safety profile and determine MTD. An expansion cohort of 10 pts (age ≥18 yrs) at the RP2D is planned. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Takeda: Consultancy, Honoraria, Other: Advisory board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Garcia: Pfizer: Research Funding; Prelude: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stone: AbbVie Inc, Actinium Pharmaceuticals Inc, Aprea Therapeutics, BerGenBio ASA, ElevateBio, Foghorn Therapeutics, GEMoaB, GlaxoSmithKline, Innate Pharma, Syndax Pharmaceuticals Inc, Syros Pharmaceuticals Inc, Takeda Oncology: Other: Advisory Committee; Agios Pharmaceuticals Inc, Novartis;: Research Funding; ACI Clinical, Syntrix Pharmaceuticals, Takeda Oncology: Other: Data Safety & Monitoring. DeAngelo: Autolus: Consultancy; Incyte Corporation: Consultancy; Forty-Seven: Consultancy; Agios: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; GlycoMimetics: Research Funding; Jazz: Consultancy; Shire: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Blueprint Medicines Corporation: Consultancy.
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- 2021
36. Unraveling Heterogeneity of Aged Hematopoietic Stem Cells By Single-Cell RNA Sequence Analysis
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Akira Nishiyama, Naoki Itokawa, Tomohiko Tamura, Atsushi Iwama, Motohiko Oshima, Zhiqian Zheng, Yaeko Nakajima-Takagi, Yuta Yamada, Shuhei Koide, and Koichi Murakami
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Haematopoiesis ,medicine.anatomical_structure ,Immunology ,Cell ,RNA Sequence ,medicine ,hemic and immune systems ,Cell Biology ,Hematology ,Stem cell ,Biology ,Biochemistry ,Cell biology - Abstract
During aging, hematopoietic stem cells (HSCs) alter quantitatively as well as qualitatively due to accumulating damages induced by intrinsic and extrinsic stresses. Functional decline of HSCs causes deregulated hematopoiesis resulting in anemia, immune dysfunction, and increased risk of hematologic malignancies. The absolute number of HSCs in aged mice evidently increases compared to young mice. In addition, aged HSCs show abnormal hematopoiesis such as myeloid-biased differentiation accompanied by low production of lymphocytes. However, the molecular mechanisms underlying age-associated changes in hematopoiesis remain largely unknown. In this study, we performed single-cell RNA sequence analysis (scRNA-seq) of HSCs from young (10-week-old), middle-aged (12-month-old) and aged (20-month-old) mice to gain insight into the dynamics of HSC aging. scRNA-seq analysis revealed three major clusters (A, B, C) and three minor clusters (D, E, F) in young HSCs. Of interest, aged HSCs also showed similar cluster formation. One of the minor clusters was characterized by gene signature associated with inflammatory response and significantly increased with age, while the remaining two minor clusters, which showed cell cycle gene signature, did not change in proportion. One of the major clusters, Cluster C, which showed the strongest expression of HSC-specific gene sets compared with other clusters, moderately increased with age. Our scRNA-seq analysis confirmed upregulation of age-related genes previously reported, such as Selp, Mt1, and Vwf, in a considerable portion of aged HSCs. von Willebrand factor (Vwf) encodes a blood glycoprotein produced by megakaryocytes and endothelial cells. Several groups have reported that Vwf-expressing HSCs show myeloid/platelet-biased differentiation (Joana C et al., Nature 2013; Sandra P et al., Developmental Cell 2018). Importantly, our scRNA-seq data identified that Clusterin (Clu) is rarely expressed in young HSCs and is dramatically upregulated in aged HSCs. Clu expression was predominantly increased in one of the major clusters, Cluster C. Clusterin encodes a secreted chaperone involved in clearance of cellular debris and regulation of apoptosis. We hypothesized that Clu would be useful as a marker of a unique subpopulation of aged HSCs, and thus conducted further analysis by using Clu reporter mice with Clu BAC clone, in which an EGFP reporter gene was inserted at the initiating ATG codon of the Clu gene so that EGFP expression is driven by the regulatory sequences of the BAC gene. Clu/GFP was preferentially expressed in HSCs and at lower frequencies in MPP1 than HSCs in Lineage -Sca-1 +c-Kit + (LSK) cell fraction. Clu-positive HSCs expressed high levels of CD150 and were detected in 10% and 60% of HSCs in 10-week-old young mice and 8-month-old middle-aged mice, respectively, indicating that Clu-positive HSCs increase with aging. We next assessed the function of Clu-positive HSCs in young mice. Clu-positive young HSCs established significantly lower chimerism than Clu-negative young HSCs and preferentially differentiated into myeloid cells in competitive transplantation assays. RNA-seq analysis of Clu-positive and Clu-negative HSCs from young mice confirmed that Clu-positive HSCs show the gene signature of myeloid-biased HSCs. Characterization of Clu-positive and negative subpopulations in aged HSCs is currently underway. These results suggest that Clu-positive HSCs represent myeloid-biased HSCs which expand with aging, thus Clu expression serves as a novel marker to monitor the alterations in HSC heterogeneity with aging. Disclosures Iwama: Nissan Chemical Corporation: Research Funding.
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- 2021
37. Hikoboshi Study: Remaining Burden and Current Medical Care Status of Patients with Congenital Hemophilia a: A Study Using Two Japanese Medical Information Databases
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Michio Sakai, Takao Nakamura, Misako Makishima, Azusa Nagao, Akiko Ioka, Norihiro Okada, and Yoichi Murakami
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business.industry ,Immunology ,medicine ,Medical information ,Cell Biology ,Hematology ,Medical emergency ,medicine.disease ,business ,Biochemistry ,Medical care - Abstract
Introduction: FVIII prophylaxis for hemophilia A (HA) has reduced the bleeding frequency in patients and enabled the prevention of hemophilic arthropathy and severe bleeding. However, the treatment/disease burden remains a concern, as evidenced by requiring intravenous injections two/three times a week; regular hospital visits to receive a prescription for medication, as drug delivery is not a provision in Japan; and frequent hospital visits because of complications, like bleeding. Moreover, there is no national patient registry for hemophilia in Japan, and few studies have examined the state of medical care and patient burden due to symptoms and medical practices. Herein, data from medical information databases (DBs) were assessed to investigate the state of medical care and patient burden for HA patients in Japan. Methods: The DBs of health insurance subscribers provided by JMDC Inc. (JMDC-DB) and of electronic medical care records provided by Real World Data Co., Ltd. (RWD-DB) were reviewed. Two DBs were used because the differences between them, such as data source for HA patients, may lead to intergroup differences in the characteristics and traceability of each patient. The targets of analysis were HA patients (ICD-10 code: D66) prescribed FVIII concentrates, emicizumab, or bypassing agents. The definition of targets in this analysis was deemed appropriate in a separate validation study. The occurrence rates of intracranial hemorrhage, ischemic heart disease, hospitalizations, emergency visits, and outpatient visits were calculated to evaluate patient burden. Further, data on the number of hospitals visited and prescribed amounts of FVIII concentrates per month were tabulated and descriptive statistics, applied. Table 1 shows the outcome measures. Results: The number of patients included, based on the target period and inclusion criteria, was 459 from JMDC-DB (January 2005 to March 2020) and 229 from RWD-DB (January 1985 to March 2020). Both DBs had a large proportion of patients aged 0-9 years (23.09% in JMDC-DB and 47.16% in RWD-DB) and a small proportion of patients aged ≥60 years (2.61% in JMDC-DB and 5.68% in RWD-DB). The mean (standard deviation [SD]) and median values for the monthly prescribed amount of FVIII concentrate were 10526.36 IU (11260.42) and 8594.91 IU in JMDC-DB and 12569.11 IU (54846.02) and 1514.35 IU in RWD-DB, respectively. The yearly trends of monthly prescribed amounts of FVIII concentrate for patients in JMDC-DB were analyzed. The median values for every 3 years since 2007 were as follows: 1916.67 IU (2007), 3375.00 IU (2010), 7229.17 IU (2013), 8614.58 IU (2016), and 10000.00 IU (2019), indicating an increasing trend in recent years. The occurrence rates (95% confidence intervals [CIs]) of intracranial hemorrhage, ischemic heart disease, and hospitalizations were 2.61% (1.36-4.52), 0.00%, and 32.68% (28.40-37.18) in JMDC-DB and 4.42% (2.14-7.99), 0.44% (0.01-2.44), and 57.08% (50.35-63.62) in RWD-DB, respectively. The age-stratified occurrence rates (95% CIs) of intracranial hemorrhage in JMDC-DB and RWD-DB were 9.43% (4.62-16.67) for 0-9 years, 1.67% (0.04-8.94) for 40-49 years, and 4.00% (0.10-20.35) for 50-59 years and 3.70% (1.02-9.21) for 0-9 years, 13.04% (2.78-33.59) for 10-19 years, 9.09% (1.12-29.16) for 30-39 years, and 6.67% (0.17-31.95) for 40-49 years, respectively. The overall occurrence rates of intracranial hemorrhage were similar in the two DBs: 2.61% (JMDC-DB) vs. 4.42% (RWD-DB). Additional results of our analysis will be presented at the conference. Conclusions: The prescription of FVIII concentrates for Japanese patients with HA is increasing, probably because FVIII prophylaxis in the clinical setting has become more common. The widespread use of FVIII has many benefits for HA patients. However, there are still treatment burdens that should be considered, such as the need for several drug prescriptions and severe bleeding, such as intracranial hemorrhage. Figure 1 Figure 1. Disclosures Nagao: CHUGAI PHARMACEUTICAL CO., LTD.: Consultancy, Honoraria, Speakers Bureau; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Bayer Yakuhin, Ltd.: Honoraria, Research Funding; Sanofi K.K.: Honoraria; Fujimoto Pharmaceutical Corporation: Honoraria; KM Biologics Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Japan Blood Products Organization: Honoraria; Novo Nordisk Pharma Ltd.: Honoraria; CSL Behring K.K.: Honoraria. Ioka: Chugai Pharmaceutical, Co., Ltd.: Current Employment. Nakamura: Chugai Pharmaceutical Co., Ltd.: Current Employment. Murakami: Chugai Pharmaceutical Co., Ltd.: Current Employment. Makishima: Chugai Pharmaceutical, Co., Ltd.: Current Employment. Okada: Chugai Pharmaceutical Co., Ltd.: Current Employment. Sakai: Bayer Yakuhin, Ltd.: Consultancy, Speakers Bureau; Novo Nordisk Pharma Ltd.: Consultancy, Speakers Bureau; CSL Behring K.K.: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau; CHUGAI PHARMACEUTICAL CO., LTD.: Speakers Bureau; Sanofi K.K.: Speakers Bureau.
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- 2021
38. Leveraging Pathway-Interference to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia
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Shai Izraeli, Christian Hurtz, Huimin Geng, David M. Weinstock, Kohei Kume, Kadriye Nehir Cosgun, Lai N. Chan, Mark A. Murakami, Jaewoong Lee, and Markus Müschen
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business.industry ,Lymphoblastic Leukemia ,Immunology ,Cancer research ,Medicine ,Cell Biology ,Hematology ,Drug resistance ,business ,Interference (genetic) ,Biochemistry - Abstract
Background: The concept of multi-step carcinogenesis (Fearon and Vogelstein 1990) suggests that acquisition of mutations in addition to an existing set of mutations invariably accelerates tumor-progression. In colorectal cancer and many other cancer types, activation of multiple distinct oncogenic pathways is required for the development of invasive cancer. Here, we examined this paradigm for genetic lesions in B-ALL and 13 other cancer types. Bioinformatic approaches: To broadly study how oncogenic drivers across multiple signaling pathways interact, we developed a bioinformatic platform to map interactions between genetic lesions that cause oncogenic activation of eight oncogenic pathways, including PI3K, STAT5, NF-κB, Hippo, Notch, WNT, RAS-ERK and TGFβ-Smad pathways. Plotting of interaction scores between 56 pathway pairs in a matrix for 14 cancer types revealed that 12 of the 14 cancer types showed a pattern of globally synergistic pathway interactions, consistent with the Fearon and Vogelstein model of cooperation of multiple pathways to drive malignant transformation. Strikingly, B-ALL and gliomas showed the opposite behavior with largely antagonistic pathway interactions. Results. Unlike the vast majority of cancer types, B-ALL and gliomas are driven by one principal oncogenic pathway at a time. While the reasons for negative pathway interactions in glioma are unknown, we focused on functional analyses on pathway interference patterns in 1,148 cases of B-ALL. Genetic lesions leading to STAT5- or ERK-pathway activation are frequently found in B-ALL. Interestingly, activating lesions of both pathways co-occurred in only 3% of the cases studied, suggesting that co-activation of STAT5- and ERK-occurs much less frequently than expected by chance (odds ratio 0.13, P=2e-16, Figure, left). Unbiased interaction mapping analyses of mutational co-occurrence indicated strong negative selection for dual activation of both STAT5- and ERK-pathways (Figure, middle). Importantly this inter-pathway aversion is much stronger than intra-pathway effects, reflecting incompatibility rather than redundancy. Even in rare cases of co-occurrence in the same sample, single-cell mutation and phosphoprotein analyses revealed that STAT5- and ERK-activating mutations were mutually exclusive and reflected two competing clones. STAT5- and ERK-pathways engage conflicting transcriptional and biochemical programs, resulting in "friction", when both pathways are concurrently activated. In agreement with pathway interference, we demonstrated that Cre-mediated deletion of divergent pathway components - Erk2 fl/fl in a STAT5-driven model of B-ALL and Stat5 fl/fl in an ERK-driven B-ALL model - dramatically accelerated initiation of fatal leukemia in vivo. While Cre-mediated deletion of divergent pathway components precipitated leukemia-initiation, these findings suggest that reactivation of divergent signaling pathways represents a powerful barrier against malignant transformation. Interestingly, our preclinical studies suggested that pharmacological reactivation of divergent (suppressed) pathways can be leveraged for therapeutic benefit: The DUSP6 small molecule inhibitor BCI-215 functions as powerful activator of ERK and suppresses STAT5-phosphorylation, i.e. the principal pathway in STAT5-driven B-ALL (Figure, right). Likewise, DPH, a small molecule STAT5-agonist interferes with ERK-phosphorylation, the principal oncogenic driver in RAS-pathway B-ALL (Figure, right). Both BCI-215 and DPH significantly prolonged overall survival of NSG mice transplanted with refractory STAT5- and ERK-driven B-ALL PDX, respectively. Conclusions: We propose that a diverse spectrum of signaling input reflects interactions of normal cells with their environment, while convergence on one centralized pathway is a hallmark of cancer. Tracking early stages of leukemia-initiation, we identified convergence on one principal oncogenic driver and inactivation of diverging pathways as an early critical step. Pharmacological reactivation of divergent signaling pathways to subvert transformation was achievable by STAT5- and ERK-agonists. Proof-of-concept studies in patient-derived B-ALL cells revealed that pharmacological reactivation of suppressed divergent circuits can be leveraged as a previously unrecognized strategy to overcome drug-resistance. Figure 1 Figure 1. Disclosures Izraeli: Roche: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; sightDx: Consultancy. Weinstock: ASELL: Consultancy; SecuraBio: Consultancy; Bantam: Consultancy; AstraZeneca: Consultancy; Abcuro: Research Funding; Verastem: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Travera: Other: Founder/Equity; Ajax: Other: Founder/Equity.
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- 2021
39. Prospective Comparison Study of Prognostic Value of MRD Detected By 8-Color MFC (EuroFlow-NGF) and NGS in Patients with Multiple Myeloma in ASCT Setting
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Yasushi Terasaki, Kenshi Suzuki, Shin-ichi Fuchida, Brian G.M. Durie, Takeshi Yoroidaka, Kentaro Kohno, Kazuyuki Shimizu, Kazuhito Suzuki, Shuji Ozaki, Naoki Takezako, Yuji Hiragori, Hirokazu Murakami, Kota Sato, Morio Matsumoto, Takeshi Yamashita, Ryota Urushihara, Mitsuhiro Itagaki, Shinji Nakao, Satoshi Yoshihara, and Hiroyuki Takamatsu
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,EuroFlow ,Internal medicine ,Comparison study ,medicine ,In patient ,business ,Value (mathematics) ,Multiple myeloma - Abstract
Background: Novel agents capable of inducing deeper responses dramatically improve the prognosis of patients with multiple myeloma (MM). Innovative technologies such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) are utilized to assess minimal residual disease (MRD) for further stratification of patients who achieve a complete response (CR). EuroFlow-next-generation flow (EuroFlow-NGF) is one of the gold standard MFC methods. Recently, both NGF and NGS have been used in many clinical trials to assess MRD levels associated with progression-free survival (PFS) and overall survival (OS). The present study prospectively assessed MRD levels by both NGF and NGS to elucidate the prognostic impact of both methods and clarify their characteristics in MM patients in an autologous stem cell transplantation (ASCT) setting. Methods: We prospectively assessed the response in Japanese patients with newly diagnosed MM who underwent ASCT and lenalidomide-based maintenance therapy at multiple Japanese medical centers between September 2016 and July 2021. The diagnosis of MM and patients' responses to therapy were assessed using the IMWG criteria. Only patients with CR or stringent CR on days 100-365 post-ASCT were included, and bone marrow (BM) samples were obtained to assess MRD. Four milliliters of BM was divided equally. Cells derived from 2 mL BM were analyzed by the NGF method (Flores-Montero et al., Leukemia 2017) at Kanazawa University, and DNA extracted from the remaining 2 mL BM cells was processed by Adaptive Biotechnologies' standardized NGS-MRD assay (Seattle, WA) (Ching et al., BMC Cancer 2020) to assess MRD levels. MRD levels in BM were also monitored at 1-year (± 20 days) and 2-year (± 20 days) post-ASCT. The prognostic value of MRD levels in BM was assessed, and their correlation between NGF and NGS was compared at a cut-off value of 1×10 -5. Sustained MRD negativity was defined as the maintenance of MRD negativity in the BM for more than 6 months. BM cells were analyzed for high-risk cytogenetics (del(17p), t(4;14), and t(14;16)) by FISH. Results: A total of 60 patients (male = 29, female = 31) underwent bortezomib-based induction therapy, ASCT conditioned with high-dose melphalan, and lenalidomide-based maintenance. The median age was 62 years at the ASCT (range 36-71; ISS 1 [n = 13], 2 [n = 24], and 3 [n = 23]). Thirty-three percent of patients showed high-risk chromosomal abnormalities (del17p (n=11), t(4;14) (n=10), t(14;16) (n=2)), 3 patients had double hit diseases, and five patients had extramedullary diseases. With a median follow-up of 3 years, the 3-year progression-free survival (PFS) and 3-year overall survival (OS) rates were 69.2% and 94.2%, respectively. In total, 148 samples were analyzed using NGF and 138 were analyzed using NGS. The rates of MRD negativity at least once using NGF and NGS were 80% and 61%, respectively. The patients who achieved at least one MRD negativity exhibited significantly better 3-year PFS (82.9% by NGF; 84.8% by NGS) than those who did not (P < 0.0001, 0% by NGF; P = 0.005, 49.1% by NGS). Patients who sustained MRD negativity for more than 6 months also showed significantly better 3-year PFS (96.7% by NGF; 92.3% by NGS) compared with those without sustained MRD negativity (Figure; P < 0.0001, 37.1% by NGF; P < 0.01, 50.9% by NGS). The MRD levels between the NGF and NGS methods were significantly correlated with each other (r = 0.9295, P < 0.0001). Among the 17 patients who developed PD after ASCT, seven cases showed discrepancies in the MRD results and two cases in which one case was MRD-positive and the other was MRD-negative by both methods progressed with extramedullary diseases. Five of the seven cases were MRD-positive by NGS and MRD-negative by NGF. Conclusions: In this prospective comparison study of MRD assessment in BM cells using EuroFlow-NGF and NGS approaches, MRD levels highly correlated with each other, and MRD negativity and sustained MRD negativity were significantly associated with prolonged PFS. Multiple MRD assessments by NGF or NGS are essential for predicting durable remission and prolonged clinical outcomes. Figure 1 Figure 1. Disclosures Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies, Eisai: Honoraria; SRL: Consultancy; Janssen: Consultancy, Honoraria, Research Funding. Yoshihara: Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Matsumoto: Sanofi: Honoraria; Janssen: Honoraria; Ono: Honoraria; Bristol-Myers Squibb: Honoraria. Yamashita: Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; celgene: Honoraria; Takeda: Honoraria. Fuchida: Takeda Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria. Hiragori: BML: Current Employment. Suzuki: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; ONO: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Abie: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Nakao: Symbio: Consultancy; Kyowa Kirin: Honoraria; Novartis Pharma: Honoraria; Alexion Pharma: Research Funding. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy.
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- 2021
40. Orihime Study: Real World Treatment Patterns and Clinical Outcomes of 338 Patients with Acquired Hemophilia a from a Japanese Health Claims Database
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Yukari Matsuo-Tezuka, Yoshiyuki Ogawa, Norihiro Okada, Yoichi Murakami, Haruko Yamaguchi-Suita, Kagehiro Amano, Keiji Nogami, and Takao Nakamura
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medicine.medical_specialty ,Health claims on food labels ,business.industry ,Family medicine ,Immunology ,Acquired hemophilia ,Medicine ,Cell Biology ,Hematology ,business ,Biochemistry ,health care economics and organizations - Abstract
Introduction: Acquired hemophilia A (AHA) is a rare disorder characterized by severe, spontaneous bleeding caused by autoantibodies against factor (F)VIII (inhibitors). It is known that onset of AHA is triggered by malignancy, autoimmune disease, dermatological disease, and pregnancy/delivery. As the standard therapy, immunosuppressive therapy (IST) should be started immediately to eliminate inhibitors and hemostatic therapy is also necessary in case of bleeding. Many patients require prolonged bed rest because of the bleeding risk; therefore, it is difficult to determine the best time to start rehabilitation. Additionally, the early deaths and high thrombotic rates are frequently reported in AHA. Since it is a rare disorder, the actual situation has not been fully clarified. This study was to describe the epidemiology and clinical practice of AHA in the real world using a large health claims database in Japan. Methods: This was a retrospective observational study using a health claims database provided by Medical Data Vision Co., Ltd. The data period was Apr. 2008-Mar. 2020. Patients who met all of the following criteria were included; patients with disease diagnosis of AHA; patients were hospitalized on the day of AHA diagnosis; and patients had immunosuppressants on/after the date of the first hospitalization. The first date of hospitalization was set as an Index date. Patients with disease diagnosis code of antiphospholipid syndrome, lupus anticoagulant, acquired factor XIII deficiency, acquired von Willebrand disease, or acquired factor V deficiency were excluded. Treatment/procedure patterns (IST, hemostatic therapy, and rehabilitation) and clinical outcome (Activities of Daily Living [ADL], death, and thromboembolism in the hospitalization) in AHA patients were investigated. Results: The study population of 338 patients (214 males: 124 females) was with the mean age of 75.7 (21-96) years. A total of 105 patients (pts) (31.1%) had concurrent diseases, including malignancy (61 pts, 18.0%), autoimmune diseases (40 pts, 11.8%), and dermatological diseases (18 pts, 5.3%). In bypassing agent use (153 pts, 45.3%), recombinant activated factor VII (rFVIIa) was the most frequently used (129 pts, 38.2%) followed by activated prothrombin complex concentrate (aPCC) (36 pts, 10.7%), and plasma-derived factor VIIa and factor X (FVIIa/FX) (14 pts, 4.1%). FVIII agent uses (8 pts) were very few. Median duration of treatment for bypassing agents ranged from 2.5 (FVIIa/FX) to 6.0 (aPCC) days. Steroids alone were used predominantly in the first line for immunosuppression (292 pts, 86.4 %) and oral prednisolone was the most frequently used. The category of rehabilitation most commonly implemented in AHA patients was disuse syndrome (104 pts, 30.8%) followed by locomotor (73 pts, 21.6%) and cerebrovascular (49 pts, 14.5%). Median time (days) from Index date to initiating rehabilitation was 16.5 for disuse syndrome, 23.0 for locomotor, 19.0 for cerebrovascular. In the total ADL scores (Barthel Index) in 196 patients with all 10 items, the proportions of patients with less than 70 points were high at both initial admission and final discharge (47.4% and 38.8%, respectively). The median number of times and length of hospitalization were 1.0 time and 62.0 days, respectively. Of evaluable population (328 pts), thromboembolism during hospitalization was recorded in 15 patients, by type of which disseminated intravascular coagulation (10 pts, 3.0%) was the most frequently recorded. Acute coronary syndrome (3 pts, 0.9%), pulmonary embolism and other (1 pt, 0.3%, each) were fewly recorded. The proportion of deaths during hospitalization was 18.6% (63 pts). Table 1 shows study result summary. Conclusions: This was the first study in a large AHA population using a health claims database in Japan. From an epidemiological point of view, the number of male patients was slightly larger and the mean age was slightly higher compared to the demographics in previous reports. The possible reason is regional variance or data source, whereas, the treatment patterns and the proportion of deaths during hospitalization are mostly aligned with the previous studies. Also this was the first report publishing the data on ADL and rehabilitation in AHA patients. The results showed that it took median 2-3 weeks to start rehabilitation. Further development of treatment strategies to enable early start of rehabilitation is awaited. Figure 1 Figure 1. Disclosures Ogawa: Chugai Pharmaceutical Co., Ltd.: Consultancy. Amano: Chugai Pharmaceutical Co., Ltd.: Consultancy, Speakers Bureau; KM Biologics Co., Ltd.: Research Funding, Speakers Bureau; Bioverativ Inc.: Speakers Bureau; Bayer AG: Speakers Bureau; Shire Plc: Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Speakers Bureau; Sanofi S.A.: Speakers Bureau; Novo Nordisk A/S: Speakers Bureau; CSL Behring: Speakers Bureau; Pfizer Inc.: Speakers Bureau; Japan Blood Products Organization: Speakers Bureau. Matsuo-Tezuka: Chugai Pharmaceutical Co., Ltd.: Current Employment. Okada: Chugai Pharmaceutical Co., Ltd.: Current Employment. Murakami: Chugai Pharmaceutical Co., Ltd.: Current Employment. Nakamura: Chugai Pharmaceutical Co., Ltd.: Current Employment. Yamaguchi-Suita: Chugai Pharmaceutical Co., Ltd: Current Employment. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk A/S: Honoraria, Research Funding, Speakers Bureau; Bayer AG: Honoraria, Research Funding, Speakers Bureau; Sanofi S.A.: Honoraria, Research Funding, Speakers Bureau; KM Biologics Co., Ltd.: Honoraria, Research Funding, Speakers Bureau. OffLabel Disclosure: Data on the uses of cyclophosphamide, cyclosporin A, and rituximab for acquired hemophilia may be included in the poster presentation. However, with regard to these drugs, treatments for other diseases may also be included because this study was conducted with a secondary use of a health claims database. Off-label drug use is explained in the poster.
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- 2021
41. A Novel Inflammatory Index Is Sufficient to Identify Hemophagocytic Lymphohistiocytosis in Adult Patients with Hematologic Malignancies
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Zoref-Lorenz, Adi, primary, Murakami, Jun, additional, Hofstetter, Liron, additional, Iyer, Swaminathan P, additional, Alotaibi, Ahmad S., additional, Miller, Peter, additional, Guber, Elad, additional, Weinstein, Shiri, additional, Yacobovich, Joanne, additional, Nikiforow, Sarah, additional, Ebert, Benjamin L., additional, Pasvolsky, Oren, additional, Raanani, Pia, additional, Nagler, Arnon, additional, Berliner, Nancy, additional, Daver, Naval, additional, Ellis, Martin H, additional, and Jordan, Michael B., additional
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- 2020
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42. Loss of Tie2 receptor compromises embryonic stem cell–derived endothelial but not hematopoietic cell survival
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Hamaguchi, Isao, Morisada, Tohru, Azuma, Masaki, Murakami, Kyoko, Kuramitsu, Madoka, Mizukami, Takuo, Ohbo, Kazuyuki, Yamaguchi, Kazunari, Oike, Yuichi, Dumont, Daniel J., and Suda, Toshio
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- 2006
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43. A Novel Inflammatory Index Is Sufficient to Identify Hemophagocytic Lymphohistiocytosis in Adult Patients with Hematologic Malignancies
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Oren Pasvolsky, Shiri Weinstein, Naval Daver, Elad Guber, Nancy Berliner, Pia Raanani, Sarah Nikiforow, Joanne Yacobovich, Liron Hofstetter, Peter Miller, Arnon Nagler, Martin Ellis, Michael B. Jordan, Swaminathan P. Iyer, Adi Zoref-Lorenz, Ahmad S. Alotaibi, Jun Murakami, and Benjamin L. Ebert
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medicine.medical_specialty ,education.field_of_study ,Hemophagocytic lymphohistiocytosis ,Index (economics) ,business.industry ,Immunology ,Population ,Context (language use) ,Retrospective cohort study ,Cell Biology ,Hematology ,Disease ,medicine.disease ,Biochemistry ,Exact test ,Family medicine ,Cohort ,medicine ,education ,business ,health care economics and organizations - Abstract
Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory syndrome which may occur in adults with hematologic malignancies (HM). The diagnosis of HLH in this context (HM-HLH) is hindered by a number of factors. First, the currently used HLH 2004 diagnostic criteria are derived from pediatric patients commonly with HLH-associated genetic lesions, a very different population than adults with cancer. Second, most parameters used for diagnosis of HLH are directly impacted by the underlying HM and may reflect the presence of the malignant clone itself rather than an inflammatory process. Finally, appropriate diagnostic cutoff values for laboratory abnormalities in HM-HLH have not been defined. In this study we determine the diagnostic value of the laboratory components of the HLH 2004 diagnostic criteria and establish optimal cutoffs for the diagnosis of HM-HLH in HM patients. Methods: This is a multicenter, retrospective study of adult patients with a hematologic malignancy in whom sCD25 was measured because of clinically suspected HM-HLH or as part of routine screening of patients with a newly diagnosed hematologic malignancy, between January 2012 and March 2020. We considered patients fulfilling the five of eight of the HLH 2004 diagnostic criteria to have HM-HLH. Patients fulfilling fewer than five criteria were assigned to the HM group. These cohorts were well balanced in terms of disease distribution. We established the optimal cutoffs for laboratory parameters used for the diagnosis of HM-HLH using receiver operating curves (ROC) in a discovery cohort and tested their performance in a validation cohort. In order to improve the results obtained using the individual ROC, we then created a combined ROC using parameters demonstrating the highest individual performance (highest area under the curve (AUC)), in order to develop a diagnostic index. Finally, we examined the performance of each parameter in each cohort by using a contingency table and Chi-square and Fisher's exact test to determine the positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity and likelihood ratio (LR) of disease for each parameter. Results: 212 adults with HM with or without HLH in whom testing for HLH was performed were included in the study. HMs were: B cell lymphoma (41%), T cell lymphoma (26%), Hodgkin lymphoma (9%), acute myeloid leukemia (8%), myelodysplastic syndrome (8%), myeloproliferative neoplasms (5%) and chronic lymphocytic leukemia (4%). 99 (47%) patients had HM-HLH. Despite considerable overlap in laboratory values between the patient groups, all parameters apart from fibrinogen were able to distinguish HM-HLH from HM alone, with ferritin and sCD25 having the greatest discriminatory power. ROC analysis revealed an optimal cutoff value of >5,600 U/mL for sCD25 (sensitivity/specificity 76%/78%, AUC=0.83) and >1,300 ng/ml for ferritin (sensitivity/specificity 76%/76%, AUC=0.83). Combining the two markers to create a novel inflammatory index (HM-INFL) yielded superior diagnostic ability (AUC =0.86). Using HLH 2004 cutoff levels the HM-INFL index had a sensitivity of 94% and NPV of 94% and when using the optimal cutoff levels, it had a specificity of 92% and PPV of 90% (Table 1). Conclusions: HM-INFL is an index comprising only ferritin and sCD25. Using the original HLH 2004 cutoffs the index is an effective screening tool. Using our newly defined cutoff levels obtained by ROC analysis it is highly specific and can be used as a confirmatory test for the diagnosis of HLH in HM patients. These findings also support the hypothesis that HLH in the context of HM is an inflammatory condition associated with immune dysregulation. Disclosures Miller: Foundation Medicines, Inc.: Consultancy. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jordan:Sobi: Consultancy.
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- 2020
44. Th1 Cytokine Polymorphism Gene: TNF-Alpha -857C/T Affects the Pathogenesis and Progression of Acute Myeloid Leukemia
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Soma, Kana, primary, Nanami, Gotoh, additional, Kasamatsu, Tetsuhiro, additional, Murakami, Yuki, additional, Ishihara, Rei, additional, Awata, Maaya, additional, Yamane, Eiko, additional, Sunaga, Masanobu, additional, Asao, Yuta, additional, Hashimoto, Nao, additional, Ogawa, Yoshiyuki, additional, Shimizu, Hiroaki, additional, Ishizaki, Takuma, additional, Yokohama, Akihiko, additional, Tsukamoto, Norifumi, additional, Handa, Hiroshi, additional, Sakura, Toru, additional, Takada, Satoru, additional, and Saitoh, Takayuki, additional
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- 2019
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45. Impact of Continuous and Maintenance Therapy on Survival Outcome in Patients with Newly Diagnosed Multiple Myeloma: A Multicenter Retrospective Collaborative Study of the Japanese Society of Myeloma
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Ozaki, Shuji, primary, Handa, Hiroshi, additional, Saitoh, Takayuki, additional, Sunami, Kazutaka, additional, Ishida, Tadao, additional, Suzuki, Kenshi, additional, Narita, Tomoko, additional, Iida, Shinsuke, additional, Nakamura, Yuichi, additional, Suzuki, Kazuhito, additional, Nishimura, Noriko, additional, Murakami, Hirokazu, additional, and Shimizu, Kazuyuki, additional
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- 2019
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46. A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for Untreated BCR-ABL1-Positive ALL in Older Adults
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Luskin, Marlise, primary, Murakami, Mark A., additional, Stevenson, Kristen E., additional, Wadleigh, Martha, additional, McMasters, Malgorzata, additional, Winter, Peter, additional, Weinstock, David M., additional, Stone, Richard, additional, and DeAngelo, Daniel J., additional
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- 2019
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47. Cage Transcriptome Analysis Reveals BCL2A1 Upregulation in FLT3-ITD/D835 Dual Mutated AML Cells Harboring Complex Co-Mutations
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Yamatani, Kotoko, primary, Ai, Tomohiko, additional, Saito, Kaori, additional, Yang, Haeun, additional, Suzuki, Koya, additional, Hori, Atsushi, additional, Murakami-Tonami, Yuko, additional, Zhang, Weiguo, additional, Carter, Bing Z, additional, Kinjo, Sonoko, additional, Ikeo, Kazuho, additional, Kazuhiro, Katayama, additional, Harada, Hironori, additional, Miida, Takashi, additional, Shah, Neil P., additional, Konopleva, Marina Y, additional, Hayashizaki, Yoshihide, additional, Andreeff, Michael, additional, and Tabe, Yoko, additional
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- 2019
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48. DNA Methylation As a Biomarker of Outcome in JMML: An International Effort Towards Clinical Implementation
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Meyer, Julia, primary, Schönung, Maximillian, additional, Flotho, Christian, additional, Olshen, Adam B., additional, Hartmann, Mark, additional, Plass, Christoph, additional, Okuno, Yusuke, additional, Takahashi, Yoshiyuki, additional, Murakami, Norihiro, additional, Wakamatsu, Manabu, additional, Loh, Mignon L., additional, Niemeyer, Charlotte M., additional, Muramatsu, Hideki, additional, Lipka, Daniel B., additional, and Stieglitz, Elliot, additional
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- 2019
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49. Elevated Serum Soluble Interleukin-2 Receptor Level Is a Useful Prognostic Factor for Disease-Specific Overall Survival in Patients with Newly Diagnosed Follicular Lymphoma before Initiation of Treatment
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Nozaki, Kenji, primary, Sugahara, Hiroyuki, additional, Ueda, Shuji, additional, Ishikawa, Jun, additional, Fuji, Shigeo, additional, Masaie, Hiroaki, additional, Tada, Yuma, additional, Suga, Makiko, additional, Tsutsumi, Kazuhito, additional, Shibata, Kumi, additional, Kida, Shuhei, additional, Karasuno, Takahiro, additional, Sata, Hiroshi, additional, Yasumi, Masato, additional, Iida, Masato, additional, Mitsui, Hideki, additional, Kamae, Tsuyoshi, additional, Saito, Norimitsu, additional, Murakami, Hiraku, additional, Moriyama, Yasuhiro, additional, Kawakami, Manabu, additional, Kato, Ruri, additional, Nakae, Yoshiki, additional, Kida, Toru, additional, Kosugi, Satoru, additional, and Shibayama, Hirohiko, additional
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- 2019
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50. Oxphos Inhibition Induces Formation of Tunneling Nanotubes in AML Cells and Facilitates Mitochondrial Transfer from BM Stroma to AML That Contributes to Microenvironment-Mediated Drug-Resistance of AML
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Yang, Haeun, primary, Tabe, Yoko, primary, Saito, Kaori, primary, Yamatani, Kotoko, primary, Jacamo, Rodrigo, primary, Ma, Helen, primary, Ruvolo, Vivian, primary, Zhang, Qi, primary, Kuruvilla, Vinitha Mary, primary, Baran, Natalia, primary, Imoto, Junichi, primary, Ikeo, Kazuho, primary, Moriya, Kaori, primary, Murakami-Tonami, Yuko, primary, Suzuki, Koya, primary, Miida, Takashi, primary, Andreeff, Michael, primary, Vellano, Christopher P, primary, Marszalek, Joseph, primary, and Konopleva, Marina Y, primary
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- 2019
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