593 results on '"Motohiro Kato"'
Search Results
2. Adverse prognostic impact of KIT exon 17 mutations despite negative flow cytometric measurable residual disease in pediatric acute myeloid leukemia with RUNX1::RUNX1T1
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Shota Kato, Shin-Ichi Tsujimoto, Jun Matsubayashi, Shotaro Iwamoto, Hidefumi Hiramatsu, Yusuke Okuno, Tatsuya Kamitori, Kentaro Ohki, Takao Deguchi, Nobutaka Kiyokawa, Motohiro Kato, Junko Takita, Shiro Tanaka, Souichi Adachi, Daisuke Tomizawa, and Norio Shiba
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Not available.
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- 2024
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3. Treatments and outcomes of neonatal disseminated intravascular coagulation with and without neonatal asphyxia: A retrospective study using nationwide data in Japan
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Hiroki Kitaoka, Takaaki Konishi, Yoshihiko Shitara, Atsushi Ito, Kohei Kashima, Yohei Hashimoto, Hiroki Matsui, Motohiro Kato, Naoto Takahashi, and Hideo Yasunaga
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bloodcoagulationdisorders ,neonatal asphyxia ,neonatology ,preterm birth ,Pediatrics ,RJ1-570 - Abstract
Background: Although neonatal disseminated intravascular coagulation (DIC) is associated with high mortality and severe complications, few studies have reported its clinical course. We aimed to describe the characteristics, treatments, and outcomes of neonatal DIC by using a national inpatient database. Methods: Using the Japanese Diagnosis Procedure Combination database, we identified 5533 patients with neonatal DIC who were admitted to neonatal intensive care units between July 2010 and March 2020. We categorized the patients into those with asphyxia (n = 2911) and those without asphyxia (n = 2622). We investigated the patient characteristics, treatments, and outcomes. We further categorized neonates with asphyxia according to its severity. Results: The gestational age of neonates with asphyxia was significantly lower than that of neonates without asphyxia (P
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- 2024
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4. Ventriculosubgaleal shunt placement for hydrocephalus in osteogenesis imperfecta with novel compound heterozygous CRTAP variants
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Shintaro Nakamura, Kyosuke Ibi, Hiroyuki Tanaka, Hirokazu Takami, Keita Okada, Nao Takasugi, Motohiro Kato, Naoto Takahashi, and Takanobu Inoue
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Genetics ,QH426-470 ,Life ,QH501-531 - Abstract
Abstract Osteogenesis imperfecta is characterized by frequent fractures, bone deformities, and other systemic symptoms. Severe osteogenesis imperfecta may progress to hydrocephalus; however, treatment strategies for this complication remain unclear. Here, we describe severe osteogenesis imperfecta in an infant with symptomatic hydrocephalus treated with ventriculosubgaleal shunt placement. Targeted next-generation sequencing revealed novel compound heterozygous CRTAP variants, i.e., NM_006371.5, c.241 G > T, p.(Glu81*) and NM_006371.5, c.923-2_932del. We suggest that ventriculosubgaleal shunt placement is an effective and safe treatment for hydrocephalus in patients with severe osteogenesis imperfecta.
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- 2024
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5. A case of inherited glycosylphosphatidylinositol deficiency caused by PGAP3 variant with uniparental isodisomy on chromosome 17
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Takeo Mukai, Shota Kato, Hiroyuki Tanaka, Yukiko Kuroda, Hiroki Kitaoka, Atsushi Ito, Yoshihiko Shitara, Kohei Kashima, Hirokazu Takami, Naoto Takahashi, and Motohiro Kato
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chromosome 17 ,HPMRS ,inherited glycosylphosphatidylinositol deficiency ,PGAP3 ,uniparental isodisomy ,Genetics ,QH426-470 - Abstract
Abstract Background Inherited glycosylphosphatidylinositol (GPI) deficiency is an autosomal recessive disease and a set of syndromes caused by different genes involved in the biosynthesis of phosphatidylinositol characterized by severe cognitive disability, elevated serum alkaline phosphatase (ALP) levels, and distinct facial features. This report presents a patient with inherited GPI deficiency caused by a homozygous frameshift variant of PGAP3 due to uniparental isodisomy (UPiD) on chromosome 17. Method Clinical characteristics of the patient were collected. Microarray analysis followed by adaptive sampling sequencing targeting chromosome 17 was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. Results The patient was born at 38 weeks of gestation with a birthweight of 3893 g. He had a distinctive facial appearance with hypertelorism, wide nasal bridge, and cleft soft palate. Postnatal head magnetic resonance imaging revealed a Blake's pouch cyst. The serum ALP level was 940 IU/L at birth and increased to 1781 IU/L at 28 days of age. Microarray analysis revealed region of homozygosity in nearly the entire region of chromosome 17, leading to the diagnosis of UPiD. Adaptive sampling sequencing targeting chromosome 17 confirmed the homozygous variant NM_033419:c.778dupG (p.Val260Glyfs*14) in the PGAP3 gene, resulting in a diagnosis of inherited GPI deficiency. Conclusion This is the first report of inherited GPI deficiency caused by UPiD. Inherited GPI deficiency must be considered in patients with unexplained hyperphosphatasemia.
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- 2024
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6. Usefulness and difficulties with the thiopurine pharmacogenomic NUDT15 genotyping test: Analysis of real-world data in Japan
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Yoichi Kakuta, Motohiro Kato, Yusuke Shimoyama, Takeo Naito, Rintaro Moroi, Masatake Kuroha, Hisashi Shiga, Yoshitaka Kinouchi, and Atsushi Masamune
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NUDT15 ,Pharmacogenetics ,Azathioprine ,6-Melcaptopurine ,Thiopurine ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The usefulness of NUDT15 genotyping as a pharmacogenomic test for thiopurine has been established. The first such test developed to date, NUDT15 genotyping was approved for reimbursement in Japan in February 2019 for all indicated patients. We retrospectively examined claims data in Japan and confirmed that the proportion of patients who undergo genotyping before initiating a new thiopurine regimen has increased; furthermore, genotyping has improved the rate of treatment continuation and reduced on-treatment hospitalization. However, the genotyping rate before thiopurine induction was >50% for patients with inflammatory bowel disease and
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- 2023
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7. Case Report: Tuberous sclerosis complex-associated hemihypertrophy successfully treated with mTOR inhibitor sirolimus
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Konomi Shimoda, Hiroyuki Iwasaki, Yoko Mizuno, Masafumi Seki, Masakazu Mimaki, Motohiro Kato, Aya Shinozaki-Ushiku, Harushi Mori, Seishi Ogawa, and Masashi Mizuguchi
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tuberous sclerosis complex ,hemihypertrophy ,limb overgrowth ,somatic mutation ,loss of heterozygosity ,pharmacological treatment ,Pediatrics ,RJ1-570 - Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by a mutation in either of the two tumor suppressor genes, TSC1 and TSC2. Due to dysregulated activity of the mammalian target of rapamycin (mTOR) pathway, hamartomas or benign tumors frequently occur in many organs and are often treated with mTOR inhibitors. Hemihypertrophy is a rare complication of TSC. Although not being a tumor, progressive overgrowth of the affected limb may cause cosmetic and functional problems, for which the efficacy of mTOR inhibitors has not been reported previously. We herein report a case of TSC-associated hemihypertrophy. In this case, genetic studies revealed TSC1 loss of heterozygosity as the cause of hemihypertrophy. Clinically, pharmacological treatment with an mTOR inhibitor sirolimus successfully ameliorated cosmetic and functional problems with no intolerable adverse effects.
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- 2024
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8. Prevalence of pathogenic variants in cancer‐predisposing genes in second cancer after childhood solid cancers
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Masanori Yoshida, Kazuhiko Nakabayashi, Wentao Yang, Aiko Sato‐Otsubo, Shin‐ichi Tsujimoto, Hiroko Ogata‐Kawata, Tomoko Kawai, Keisuke Ishiwata, Mika Sakamoto, Kohji Okamura, Kaoru Yoshida, Ryota Shirai, Tomoo Osumi, Chikako Kiyotani, Yoko Shioda, Keita Terashima, Sae Ishimaru, Yuki Yuza, Masatoshi Takagi, Yuki Arakawa, Toshihiko Imamura, Daisuke Hasegawa, Akiko Inoue, Takako Yoshioka, Shuichi Ito, Daisuke Tomizawa, Katsuyoshi Koh, Kimikazu Matsumoto, Nobutaka Kiyokawa, Seishi Ogawa, Atsushi Manabe, Akira Niwa, Kenichiro Hata, Jun J. Yang, and Motohiro Kato
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cancer predisposition ,childhood solid cancer ,second malignant neoplasms ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Second malignant neoplasms (SMNs) are one of the most severe late complications after pediatric cancer treatment. However, the effect of genetic variation on SMNs remains unclear. In this study, we revealed germline genetic factors that contribute to the development of SMNs after treatment of pediatric solid tumors. Methods We performed whole‐exome sequencing in 14 pediatric patients with SMNs, including three brain tumors. Results Our analysis revealed that five of 14 (35.7%) patients had pathogenic germline variants in cancer‐predisposing genes (CPGs), which was significantly higher than in the control cohort (p
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- 2023
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9. A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1
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Masashi Numata, Noriyasu Haginoya, Machiko Shiroishi, Tsuyoshi Hirata, Aiko Sato-Otsubo, Kenji Yoshikawa, Yoshimi Takata, Reina Nagase, Yoshinori Kashimoto, Makoto Suzuki, Nina Schulte, Gernot Polier, Akiko Kurimoto, Yumiko Tomoe, Akiko Toyota, Tomoko Yoneyama, Emi Imai, Kenji Watanabe, Tomoaki Hamada, Ryutaro Kanada, Jun Watanabe, Yoshiko Kagoshima, Eri Tokumaru, Kenji Murata, Takayuki Baba, Taeko Shinozaki, Masami Ohtsuka, Koichi Goto, Tsuyoshi Karibe, Takao Deguchi, Yoshihiro Gocho, Masanori Yoshida, Daisuke Tomizawa, Motohiro Kato, Shinji Tsutsumi, Mayumi Kitagawa, and Yuki Abe
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Menin-MLL1 inhibitor ,MLL1-r or NPM1c acute leukemia ,Leukemia-initiating cells ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Background Mixed lineage leukemia 1-rearranged (MLL1-r) acute leukemia patients respond poorly to currently available treatments and there is a need to develop more effective therapies directly disrupting the Menin‒MLL1 complex. Small-molecule–mediated inhibition of the protein‒protein interaction between Menin and MLL1 fusion proteins is a potential therapeutic strategy for patients with MLL1-r or mutated-nucleophosmin 1 (NPM1c) acute leukemia. In this study, we preclinically evaluated the new compound DS-1594a and its salts. Methods We evaluated the preclinical efficacy of DS-1594a as well as DS-1594a·HCl (the HCl salt of DS-1594a) and DS-1594a·succinate (the succinic acid salt of DS-1594a, DS-1594b) in vitro and in vivo using acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) models. Results Our results showed that MLL1-r or NPM1c human leukemic cell lines were selectively and highly sensitive to DS-1594a·HCl, with 50% growth inhibition values
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- 2023
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10. Genome-wide assessment of genetic risk loci for childhood acute lymphoblastic leukemia in Japanese patients
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Mayumi Hangai, Takahisa Kawaguchi, Masatoshi Takagi, Keitaro Matsuo, Soyoung Jeon, Charleston W.K. Chiang, Andrew T. Dewan, Adam J. de Smith, Toshihiko Imamura, Yasuhiro Okamoto, Akiko M. Saito, Takao Deguchi, Michiaki Kubo, Yoichi Tanaka, Yoko Ayukawa, Toshinari Hori, Kentaro Ohki, Nobutaka Kiyokawa, Takeshi Inukai, Yuki Arakawa, Makiko Mori, Daisuke Hasegawa, Daisuke Tomizawa, Hiroko Fukushima, Yuki Yuza, Yasushi Noguchi, Yuichi Taneyama, Setsuo Ota, Hiroaki Goto, Masakatsu Yanagimachi, Dai Keino, Kazutoshi Koike, Daisuke Toyama, Yozo Nakazawa, Kozue Nakamura, Koichi Moriwaki, Yujin Sekinaka, Daisuke Morita, Shinsuke Hirabayashi, Yosuke Hosoya, Yuri Yoshimoto, Hiroki Yoshihara, Miwa Ozawa, Shinobu Kobayashi, Naho Morisaki, Tshewang Gyeltshen, Osamu Takahashi, Yukinori Okada, Makiko Matsuda, Toshihiro Tanaka, Johji Inazawa, Junko Takita, Yasushi Ishida, Akira Ohara, Catherine Metayer, Joseph L. Wiemels, Xiaomei Ma, Shuki Mizutani, Katsuyoshi Koh, Yukihide Momozawa, Keizo Horibe, Fumihiko Matsuda, Motohiro Kato, Atsushi Manabe, and Kevin Y. Urayama
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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11. Serum polyethylene glycol-specific IgE and IgG in patients with hypersensitivity to COVID-19 mRNA vaccines
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Mariko Mouri, Mitsuru Imamura, Shotaro Suzuki, Tatsuya Kawasaki, Yoshiki Ishizaki, Keiichi Sakurai, Hiroko Nagafuchi, Norihiro Matsumura, Marina Uchida, Takayasu Ando, Kohei Yoshioka, Seido Ooka, Takahiko Sugihara, Hiroshi Miyoshi, Masaaki Mori, Tomoyuki Okada, Masao Yamaguchi, Hiroyuki Kunishima, Motohiro Kato, and Kimito Kawahata
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COVID-19 mRNA vaccines ,PEG-specific IgE ,PEG-specific IgG ,Polyethylene glycol ,Polysorbate ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Background: The mechanism of allergic reactions to COVID-19 mRNA vaccines has not been clarified. Polyethylene glycol (PEG) is a potential antigen in the components of vaccines. However, there is little evidence that allergy after COVID-19 mRNA vaccination is related to PEG. Furthermore, the role of polysorbate (PS) as an antigen has also not been clarified. The objective of this study was to investigate whether PEG and PS allergies are reasonable causes of allergic symptoms after vaccination by detecting PEG-specific and PS-specific antibodies. Methods: Fourteen patients who developed immediate allergic reactions to BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccines and nineteen healthy controls who did not present allergic symptoms were recruited. Serum PEG-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) and PS-specific IgE and IgG were measured by enzyme-linked immunosorbent assay. Skin tests using PEG-2000 and PS-80 were applied to five patients and three controls. Results: Serum levels of PEG-specific IgE and IgG in patients with immediate allergic reactions to the COVID-19 mRNA vaccine were higher than those in the control group. Serum levels of PS-specific IgE in patients with allergy to the vaccine were higher than those in patients of the control group. Intradermal tests using PEG verified the results for PEG-specific IgE and IgG. Conclusions: The results suggest that PEG is one of the antigens in the allergy to COVID-19 mRNA vaccines. Cross-reactivity between PEG and PS might be crucial for allergy to the vaccines. PEG-specific IgE and IgG may be useful in diagnosing allergy to COVID-19 mRNA vaccines.
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- 2022
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12. Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia
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Tomoya Isobe, Masatoshi Takagi, Aiko Sato-Otsubo, Akira Nishimura, Genta Nagae, Chika Yamagishi, Moe Tamura, Yosuke Tanaka, Shuhei Asada, Reina Takeda, Akiho Tsuchiya, Xiaonan Wang, Kenichi Yoshida, Yasuhito Nannya, Hiroo Ueno, Ryo Akazawa, Itaru Kato, Takashi Mikami, Kentaro Watanabe, Masahiro Sekiguchi, Masafumi Seki, Shunsuke Kimura, Mitsuteru Hiwatari, Motohiro Kato, Shiro Fukuda, Kenji Tatsuno, Shuichi Tsutsumi, Akinori Kanai, Toshiya Inaba, Yusuke Shiozawa, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Rishi S. Kotecha, Mark N. Cruickshank, Fumihiko Ishikawa, Tomohiro Morio, Mariko Eguchi, Takao Deguchi, Nobutaka Kiyokawa, Yuki Arakawa, Katsuyoshi Koh, Yuki Aoki, Takashi Ishihara, Daisuke Tomizawa, Takako Miyamura, Eiichi Ishii, Shuki Mizutani, Nicola K. Wilson, Berthold Göttgens, Satoru Miyano, Toshio Kitamura, Susumu Goyama, Akihiko Yokoyama, Hiroyuki Aburatani, Seishi Ogawa, and Junko Takita
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Science - Abstract
The molecular heterogeneity of KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) remains poorly characterised. Here, the authors perform multi-omics analysis for 84 ALL patients and suggest 5 distinct subgroups for risk stratification and personalised treatment.’
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- 2022
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13. Nonconditioned ADA-SCID gene therapy reveals ADA requirement in the hematopoietic system and clonal dominance of vector-marked clones
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Toru Uchiyama, Sirirat Takahashi, Kazuhiko Nakabayashi, Kohji Okamura, Kaori Edasawa, Masafumi Yamada, Nobuyuki Watanabe, Emi Mochizuki, Toru Yasuda, Akane Miura, Motohiro Kato, Daisuke Tomizawa, Makoto Otsu, Tadashi Ariga, and Masafumi Onodera
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ADA-SCID ,retroviral vector ,nonconditioned gene therapy ,clonal dominance ,ADA activity ,insertional mutagenesis ,Genetics ,QH426-470 ,Cytology ,QH573-671 - Abstract
Two patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (ADA-SCID) received stem cell-based gene therapy (SCGT) using GCsapM-ADA retroviral vectors without preconditioning in 2003 and 2004. The first patient (Pt1) was treated at 4.7 years old, and the second patient (Pt2), who had previously received T cell gene therapy (TCGT), was treated at 13 years old. More than 10 years after SCGT, T cells showed a higher vector copy number (VCN) than other lineages. Moreover, the VCN increased with differentiation toward memory T and B cells. The distribution of vector-marked cells reflected variable levels of ADA requirements in hematopoietic subpopulations. Although neither patient developed leukemia, clonal expansion of SCGT-derived clones was observed in both patients. The use of retroviral vectors yielded clonal dominance of vector-marked clones, irrespective of the lack of leukemic changes. Vector integration sites common to all hematopoietic lineages suggested the engraftment of gene-marked progenitors in Pt1, who showed severe osteoblast (OB) insufficiency compared to Pt2, which might cause a reduction in the stem/progenitor cells in the bone marrow (BM). The impaired BM microenvironment due to metabolic abnormalities may create space for the engraftment of vector-marked cells in ADA-SCID, despite the lack of preconditioning.
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- 2021
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14. Establishment of multiplex RT-PCR to detect fusion genes for the diagnosis of Ewing sarcoma
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Hitomi Ueno-Yokohata, Hajime Okita, Keiko Nakasato, Chikako Kiyotani, Motohiro Kato, Kimikazu Matsumoto, Nobutaka Kiyokawa, Atsuko Nakazawa, and Takako Yoshioka
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Ewing sarcoma ,Multiplex RT–PCR ,Genetic diagnosis ,Fusion gene ,EWSR1 ,Transcription factor ,Pathology ,RB1-214 - Abstract
Abstract Background Detection of the tumor-specific EWSR1/FUS-ETS fusion gene is essential to diagnose Ewing sarcoma. Reverse transcription–polymerase chain reaction (RT–PCR) and fluorescence in situ hybridization are commonly used to detect the fusion gene, and assays using next-generation sequencing have recently been reported. However, at least 28 fusion transcript variants have been reported, making rapid and accurate detection difficult. Methods We constructed two sets of multiplex PCR assays and evaluated their utility using cell lines and clinical samples. Results EWSR1/FUS-ETS was detected in five of six tumors by the first set, and in all six tumors by the second set. The fusion gene detected only by the latter was EWSR1-ERG, which completely lacked exon 7 of EWSR1. The fusion had a short N-terminal region of EWSR1 and showed pathologically atypical features. Conclusions We developed multiplex RT–PCR assays to detect EWSR1-ETS and FUS-ETS simultaneously. These assays will aid the rapid and accurate diagnosis of Ewing sarcoma. In addition, variants of EWSR1/FUS-ETS with a short N-terminal region that may have been previously missed can be easily detected.
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- 2021
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15. Genetic features of B‐cell lymphoblastic lymphoma with TCF3‐PBX1
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Ryota Shirai, Tomoo Osumi, Aiko Sato‐Otsubo, Kazuhiko Nakabayashi, Takeshi Mori, Masanori Yoshida, Kaoru Yoshida, Mika Kohri, Takashi Ishihara, Shiho Yasue, Toshihiko Imamura, Mikiya Endo, Satoshi Miyamoto, Kentaro Ohki, Masashi Sanada, Nobutaka Kiyokawa, Seishi Ogawa, Takako Yoshioka, Kenichiro Hata, Masatoshi Takagi, and Motohiro Kato
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6q LOH ,B‐cell lymphoblastic lymphoma ,KMT2D ,TCF3‐PBX1 ,whole exome sequencing ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are categorized as the same entity under precursor lymphoid neoplasms in the World Health Organization classification. However, compared to B‐cell ALL, the molecular genetic makeup of B‐cell LBL remains to be understood, mainly due to its rarity. We performed whole exome sequencing (WES) on seven patients with TCF3‐PBX1‐positive B‐cell LBL. Methods WES was performed using DNA extracted from tumor specimens and paired blood samples at remission for six patients, and tumor‐only analysis was performed for one patient whose remission sample was not available. For one patient, a relapsed sample was also analyzed. Results KMT2D variants and 6q LOH were found as recurrent alterations. Somatic variants of KMT2D were identified in three of the seven patients. Of note, the two patients with heterozygous nonsense variant of KMT2D were at stage III, without bone marrow infiltration. 6q LOH was also identified in two others, out of the seven patients. The common 6q deleted region of the two patients ranged from 6q12 to 6q16.3. Both patients had bone marrow infiltration. Analysis of recurrent case also revealed that the relapsed clone might be derived from a minor clone of the bone marrow at diagnosis. Conclusion In this study, through WES for seven patients with TCF3‐PBX1‐positive B‐LBL, we identified KMT2D mutations and 6q LOH as recurrent alterations. In order to elucidate the relationship between these recurrent alterations and disease specificity or outcomes, further studies comparing with TCF3‐PBX1‐positive B‐ALL are required.
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- 2022
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16. NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir
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Rina Nishii, Takanori Mizuno, Daniel Rehling, Colton Smith, Brandi L. Clark, Xujie Zhao, Scott A. Brown, Brandon Smart, Takaya Moriyama, Yuji Yamada, Tatsuo Ichinohe, Makoto Onizuka, Yoshiko Atsuta, Lei Yang, Wenjian Yang, Paul G. Thomas, Pål Stenmark, Motohiro Kato, and Jun J. Yang
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Science - Abstract
Nucleoside analogs (NNA), such as acyclovir (ACV) and ganciclovir (GCV), are widely used as anti-virals to treat herpes virus infection. Here, Nishii et al. show that diphosphatase NUDT15 hydrolyzes ACV and GCV, therewith reducing NNA activity in vitro and link NUDT15 variation to inter-patient variability in ACV and GCV therapeutic effects.
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- 2021
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17. Current status of intensive end-of-life care in children with hematologic malignancy: a population-based study
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Nobuyuki Yotani, Daisuke Shinjo, Motohiro Kato, Kimikazu Matsumoto, Kiyohide Fushimi, and Yoshiyuki Kizawa
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Quality of life ,ICU admission ,Cardiopulmonary resuscitation ,Extra-corporeal membrane oxygenation ,Intravenous chemotherapy ,Mechanical ventilation ,Special situations and conditions ,RC952-1245 - Abstract
Abstract Background Adult patients with hematologic malignancies are less likely to receive palliative care and more likely to accept intensive anti-cancer treatments until end-of-life than those with solid tumors, but limited data are available regarding the quality of end-of-life care (EOLC) for children with hematologic malignancies. To improve the quality of EOLC for children with hematologic malignancies, the aims of this study were (i) to compare intensive EOLC between children with hematologic malignancies and those with solid tumors; and (ii) to describe factors associated with intensive EOLC in children with hematologic malignancies. Methods We retrospectively reviewed 0- to 18-year-old patients with cancer, who died in hospital between April 2012 and March 2016 in Japan using the Diagnosis Procedure Combination per-diem payment system. Indicators of intensive inpatient EOLC were defined as intensive care unit admission, cardiopulmonary resuscitation (CPR), intubation and/or mechanical ventilation, hemodialysis, or extra-corporeal membrane oxygenation in the last 30 days of life, or intravenous chemotherapy in the last 14 days. We determined factors associated with intensive EOLC using regression models. Data regarding use of blood transfusion were also obtained from the database. Results Among 1199 patients, 433 (36%) had hematological malignancies. Children with hematologic malignancies were significantly more likely than those with solid tumors to have intubation and/or mechanical ventilation (37.9% vs. 23.5%), intensive care unit admission (21.9% vs. 7.2%), CPR (14.5% vs. 7.7%), hemodialysis (13.2% vs. 3.1%) or extra-corporeal membrane oxygenation (2.5% vs. 0.4%) in their last 30 days, or intravenous chemotherapy (47.8% vs. 18.4%; all P
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- 2021
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18. Genetic features of precursor B‐cell phenotype Burkitt leukemia with IGH‐MYC rearrangement
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Masanori Yoshida, Daisuke Tomizawa, Satoshi Yoshimura, Tomoo Osumi, Kazuhiko Nakabayashi, Hiroko Ogata‐Kawata, Keisuke Ishiwata, Aiko Sato‐Otsubo, Yui Kimura, Shuichi Ito, Kimikazu Matsumoto, Takao Deguchi, Nobutaka Kiyokawa, Takako Yoshioka, Kenichiro Hata, and Motohiro Kato
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FBXO11 ,IGH‐MYC ,KRAS ,preBLL ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background An atypical form of Burkitt leukemia/lymphoma (BL), BL with a phenotype of precursor B‐cells (preBLL), is listed in the WHO Classification. Recent reports suggested that preBLL and classical BL could be distinguished by the differences in IG‐MYC translocation architecture and an additional mutated genes profile. The characteristics of classical BL are IG‐MYC by aberrant somatic hypermutation or class switch recombination, and BL‐specific gene mutations such as MYC, ID3, and CCND3. Meanwhile, preBLL is characterized by IG‐MYC due to aberrant VDJ recombination and mutations in NRAS and KRAS. However, it is not clear whether all preBLL cases can be differentiated. This report investigated the molecular characteristics of an infant preBLL case, with a more advanced stage of maturity than typical preBLL. Case The patient showed BL‐like morphology with IGH‐MYC rearrangement. In the immunophenotyping, CD20 and surface immunoglobulin were negative, whereas other markers were consistent with BL. To evaluate the genetic contribution, we performed whole‐exome sequencing. The breakpoint analysis revealed the IG‐MYC occurred due to an aberrant VDJ recombination. Meanwhile, additional somatic mutations were detected in FBXO11, one of the mutant genes specific to BL. In the analysis of the specimen in complete remission, mutation in KRAS, frequently mutated in preBLL, was detected with low frequency, suggesting somatic mosaicism. Conclusion The present case showed the characteristics of both typical preBLL and classical BL. Because preBLL includes atypical cases such as the present case, further studies are required to elucidate preBLL features.
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- 2022
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19. BRAF V600E-positive cells as molecular markers of bone marrow disease in pediatric Langerhans cell histiocytosis
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Ko Kudo, Tsutomu Toki, Rika Kanezaki, Tatsuhiko Tanaka, Takuya Kamio, Tomohiko Sato, Shinya Sasaki, Masaru Imamura, Chihaya Imai, Kumiko Ando, Harumi Kakuda, Takehiko Doi, Hiroshi Kawaguchi, Masahiro Irie, Yoji Sasahara, Akihiro Tamura, Daiichiro Hasegawa, Yosuke Itakura, Kenichiro Watanabe, Kenichi Sakamoto, Yoko Shioda, Motohiro Kato, Kazuko Kudo, Reiji Fukano, Atsushi Sato, Hiroshi Yagasaki, Hirokazu Kanegane, Itaru Kato, Katsutsugu Umeda, Souichi Adachi, Tatsuki Kataoka, Akira Kurose, Atsuko Nakazawa, Kiminori Terui, and Etsuro Ito
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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20. Case Report: Rotavirus Vaccination and Severe Combined Immunodeficiency in Japan
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Kay Tanita, Yoshiki Kawamura, Hiroki Miura, Noriko Mitsuiki, Takahiro Tomoda, Kento Inoue, Akihiro Iguchi, Masafumi Yamada, Taro Yoshida, Hideki Muramatsu, Norimasa Tada, Toshihiro Matsui, Motohiro Kato, Katsuhide Eguchi, Masataka Ishimura, Shouichi Ohga, Kohsuke Imai, Tomohiro Morio, Tetsushi Yoshikawa, and Hirokazu Kanegane
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severe combined immunodeficiency ,hematopoietic cell transplantation ,rotavirus ,vaccination ,T-cell receptor excision circles (TREC) ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Severe combined immunodeficiency (SCID) is an inborn error of immunity that occurs in approximately 1 in 50,000 births, mainly due to impaired lymphocyte differentiation. Without curative treatment, such as hematopoietic cell transplantation (HCT) or gene therapy, severe infection in the first year of life could make this condition fatal. The results of HCT are poor when patients have active infections, thus requiring early diagnosis before onset of infection. In five cases of SCID diagnosed in Japan, the oral rotavirus vaccine had been administered before diagnosis. In this study, we demonstrated that the rotavirus from their stools was a vaccine-derived strain. In some cases, severe gastroenteritis triggered the diagnosis of SCID. However, newborn screening for SCID is available before the first rotavirus vaccination using assays for the detection of T-cell receptor excision circles (TRECs). Therefore, to improve the prognosis of patients with SCID in Japan, we should establish a screening system of TRECs for newborns throughout Japan.
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- 2022
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21. Comparison of child and family reports of health-related quality of life in pediatric acute lymphoblastic leukemia patients after induction therapy
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Shohei Nakajima, Iori Sato, Takafumi Soejima, Katsuyoshi Koh, Motohiro Kato, Yasuhiro Okamoto, Toshihiko Imamura, Miho Maeda, Yasushi Ishida, Atsushi Manabe, and Kiyoko Kamibeppu
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Agreement ,Dyadic analysis ,Neoplasms ,Patient reported outcome measures ,Pediatric hospitals ,Quality of life ,Pediatrics ,RJ1-570 - Abstract
Abstract Background This study aims at determining the health-related quality of life (HRQOL) of children with acute lymphoblastic leukemia (ALL) after the induction therapy, assessing the agreement between child self-reports and family proxy-reports HRQOL, and determining the factors related to this agreement, especially child age, family attendance, and children’s social relationships beyond the family. Methods We analyzed questionnaire data (2012–2017) from the Japanese Pediatric Leukemia/Lymphoma Study Group’s clinical study (ALL-B12). Participants were children with B-cell precursor ALL aged 5–18 and their family members, who mostly took care of the child during hospitalization. Participants answered the Pediatric Quality of Life Inventory™ (PedsQL™) Generic Core Scales (PedsQL-G), and Cancer Module (PedsQL-C) to measure pediatric HRQOL. We calculated the differences between child self-reported and family proxy-reported subscale scores along with intraclass correlation coefficients (ICC). We conducted multiple regression analyses according to all participant pairs and age groups (young children, school age, and adolescents), with ICCs for all PedsQL-G subscales (ICC-G) and all PedsQL-C subscales (ICC-C) as the outcome variables. Results Five hundred twenty-two pairs of children and their families were analyzed. We observed a moderate level of agreement on most PedsQL subscales between child self-reports and family proxy-reports; however, worry had the weakest agreement for all PedsQL subscales (ICC = .32, 95% confidence interval = .24–.40). The agreement of ICC-C was positively related to family attendance in the hospitalization, only for the young children group (B = .185, p = .003). Conclusions We observed some differences between child self-reports and family proxy-reports of HRQOL of children with ALL. Both child self-reports and family proxy-reports captured HRQOL in the induction therapy. We suggest that attending to young children’s hospitalization affects the level of agreement between reports on their HRQOL.
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- 2020
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22. Case Report: Treatment of Extremely Preterm Infants With Birthweight Below 300 g: Case Series
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Yoshihiko Shitara, Satsuki Kakiuchi, Takeo Mukai, Kohei Kashima, Motohiro Kato, and Naoto Takahashi
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extremely preterm infants ,extremely low birthweight infants ,birthweight below 300 g ,fetal growth restriction ,en caul delivery ,obstetric complications ,Pediatrics ,RJ1-570 - Abstract
Reports on the birth of infants weighing
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- 2021
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23. An international retrospective study for tolerability of 6-mercaptopurine on NUDT15 bi-allelic variants in children with acute lymphoblastic leukemia
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Yoichi Tanaka, Allen Eng Juh Yeoh, Takaya Moriyama, Chi-Kong Li, Ko Kudo, Yuki Arakawa, Jassada Buaboonnam, Hui Zhang, Hsi-Che Liu, Hany Ariffin, Zhiwei Chen, Shirley K.Y. Kham, Rina Nishii, Daisuke Hasegawa, Junya Fujimura, Dai Keino, Kensuke Kondoh, Atsushi Sato, Takahiro Ueda, Masaki Yamamoto, Yuichi Taneyama, Moeko Hino, Masatoshi Takagi, Akira Ohara, Etsuro Ito, Katsuyoshi Koh, Hiroki Hori, Atsushi Manabe, Jun J. Yang, and Motohiro Kato
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2021
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24. A female case of pleuropulmonary blastoma type 1 whose pulmonary cystic lesion was followed since neonate
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Michinobu Ohno, Toshiko Takezoe, Toshihiko Watanabe, Kazunori Tahara, Tomoro Hishiki, Akihiro Fujino, Motomi Matsuo, Masataka Higuchi, Kazuteru Kawasaki, Yoko Shioda, Motohiro Kato, Chikako Kiyotani, Kimikazu Matsumoto, Emi Takakuwa, Rie Irie, Takako Yoshioka, Shunsuke Kimura, Masafumi Seki, Junko Takita, and Yutaka Kanamori
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Pleuropulmonary blastoma type 1 ,Cystic lung disease ,CPAM ,DICER1 ,Pediatrics ,RJ1-570 ,Surgery ,RD1-811 - Abstract
Pleuropulmonary blastoma (PPB) is a rare malignant mesenchymal tumor. It is classified into 3 subgroups, and PPB type 1 is known to be a cystic lesion with good prognosis. Here, we report a case of PPB type 1 seen in a 1-year-old girl whose pulmonary cystic lesion had been followed-up as a congenital pulmonary airway malformation since neonate. The cyst had been diagnosed as congenital pulmonary airway malformation before surgery but the final diagnosis was type 1 PPB. The tumor had a somatic mutation in exon 25 of the DICER 1 gene whereas no germline mutation was found.
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- 2017
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25. Clinical and molecular characteristics of MEF2D fusion-positive B-cell precursor acute lymphoblastic leukemia in childhood, including a novel translocation resulting in MEF2D-HNRNPH1 gene fusion
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Kentaro Ohki, Nobutaka Kiyokawa, Yuya Saito, Shinsuke Hirabayashi, Kazuhiko Nakabayashi, Hitoshi Ichikawa, Yukihide Momozawa, Kohji Okamura, Ai Yoshimi, Hiroko Ogata-Kawata, Hiromi Sakamoto, Motohiro Kato, Keitaro Fukushima, Daisuke Hasegawa, Hiroko Fukushima, Masako Imai, Ryosuke Kajiwara, Takashi Koike, Isao Komori, Atsushi Matsui, Makiko Mori, Koichi Moriwaki, Yasushi Noguchi, Myoung-ja Park, Takahiro Ueda, Shohei Yamamoto, Koichi Matsuda, Teruhiko Yoshida, Kenji Matsumoto, Kenichiro Hata, Michiaki Kubo, Yoichi Matsubara, Hiroyuki Takahashi, Takashi Fukushima, Yasuhide Hayashi, Katsuyoshi Koh, Atsushi Manabe, Akira Ohara, and for the Tokyo Children’s Cancer Study Group (TCCSG)
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Fusion genes involving MEF2D have recently been identified in precursor B-cell acute lymphoblastic leukemia, mutually exclusive of the common risk stratifying genetic abnormalities, although their true incidence and associated clinical characteristics remain unknown. We identified 16 cases of acute lymphoblastic leukemia and 1 of lymphoma harboring MEF2D fusions, including MEF2D-BCL9 (n=10), MEF2D-HNRNPUL1 (n=6), and one novel MEF2D-HNRNPH1 fusion. The incidence of MEF2D fusions overall was 2.4% among consecutive precursor B-cell acute lymphoblastic leukemia patients enrolled onto a single clinical trial. They frequently showed a cytoplasmic μ chain-positive pre-B immunophenotype, and often expressed an aberrant CD5 antigen. Besides up- and down-regulation of HDAC9 and MEF2C, elevated GATA3 expression was also a characteristic feature of MEF2D fusion-positive patients. Mutations of PHF6, recurrent in T-cell acute lymphoblastic leukemia, also showed an unexpectedly high frequency (50%) in these patients. MEF2D fusion-positive patients were older (median age 9 years) with elevated WBC counts (median: 27,300/ml) at presentation and, as a result, were mostly classified as NCI high risk. Although they responded well to steroid treatment, MEF2D fusion-positive patients showed a significantly worse outcome, with 53.3% relapse and subsequent death. Stem cell transplantation was ineffective as salvage therapy. Interestingly, relapse was frequently associated with the presence of CDKN2A/CDKN2B gene deletions. Our observations indicate that MEF2D fusions comprise a distinct subgroup of precursor B-cell acute lymphoblastic leukemia with a characteristic immunophenotype and gene expression signature, associated with distinct clinical features.
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- 2019
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26. B-lymphoblastic lymphoma with TCF3-PBX1 fusion gene
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Mari Kubota-Tanaka, Tomoo Osumi, Shouko Miura, Hiroshi Tsujimoto, Toshihiko Imamura, Akira Nishimura, Kentaro Oki, Kozue Nakamura, Satoshi Miyamoto, Kento Inoue, Maiko Inoue, Takahiro Kamiya, Masakatsu Yanagimachi, Tsubasa Okano, Noriko Mitsuiki, Takeshi Isoda, Kohsuke Imai, Hirokazu Kanegane, Tomohiro Morio, Shinji Kounami, Mikiya Endo, Motohiro Kato, and Masatoshi Takagi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2019
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27. ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype
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Shinsuke Hirabayashi, Kentaro Ohki, Kazuhiko Nakabayashi, Hitoshi Ichikawa, Yukihide Momozawa, Kohji Okamura, Akinori Yaguchi, Kazuki Terada, Yuya Saito, Ai Yoshimi, Hiroko Ogata-Kawata, Hiromi Sakamoto, Motohiro Kato, Junya Fujimura, Moeko Hino, Akitoshi Kinoshita, Harumi Kakuda, Hidemitsu Kurosawa, Keisuke Kato, Ryosuke Kajiwara, Koichi Moriwaki, Tsuyoshi Morimoto, Kozue Nakamura, Yasushi Noguchi, Tomoo Osumi, Kazuo Sakashita, Junko Takita, Yuki Yuza, Koich Matsuda, Teruhiko Yoshida, Kenji Matsumoto, Kenichiro Hata, Michiaki Kubo, Yoichi Matsubara, Takashi Fukushima, Katsuyoshi Koh, Atsushi Manabe, Akira Ohara, and Nobutaka Kiyokawa
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384. Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3-ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384-positive patients, but was significantly distinct from that of TCF3-PBX1-positive and ZNF384-fusion-negative patients. However, clinical features of TCF3-ZNF384-positive patients are markedly different from those of EP300-ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384-positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.
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- 2017
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28. Genomic profiling of adult acute lymphoblastic leukemia by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric acute lymphoblastic leukemia
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Ryoko Okamoto, Seishi Ogawa, Daniel Nowak, Norihiko Kawamata, Tadayuki Akagi, Motohiro Kato, Masashi Sanada, Tamara Weiss, Claudia Haferlach, Martin Dugas, Christian Ruckert, Torsten Haferlach, and H. Phillip Koeffler
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Differences in survival have been reported between pediatric and adult acute lymphoblastic leukemia. The inferior prognosis in adult acute lymphoblastic leukemia is not fully understood but could be attributed, in part, to differences in genomic alterations found in adult as compared to in pediatric acute lymphoblastic leukemia.Design and Methods We compared two different sets of high-density single nucleotide polymorphism array genotyping data from 75 new diagnostic adult and 399 previously published diagnostic pediatric acute lymphoblastic leukemia samples. The patients’ samples were randomly acquired from among Caucasian and Asian populations and hybridized to either Affymetrix 50K or 250K single nucleotide polymorphism arrays. The array data were investigated with Copy Number Analysis for GeneChips (CNAG) software for allele-specific copy number analysis.Results The high density single nucleotide polymorphism array analysis of 75 samples of adult acute lymphoblastic leukemia led to the identification of numerous cryptic and submicroscopic genomic lesions with a mean of 7.6 genomic alterations per sample. The patterns and frequencies of lesions detected in the adult samples largely reproduced known genomic hallmarks detected in previous single nucleotide polymorphism-array studies of pediatric acute lymphoblastic leukemia, such as common deletions of 3p14.2 (FHIT), 5q33.3 (EBF), 6q, 9p21.3 (CDKN2A/B), 9p13.2 (PAX5), 13q14.2 (RB1) and 17q11.2 (NF1). Some differences between adult and pediatric acute lymphoblastic leukemia were identified when the pediatric data set was partitioned into hyperdiploid and non-hyperdiploid cases and then compared to the nearly exclusively non-hyperdiploid adult samples. In this analysis, adult samples had a higher rate of deletions of chromosome 17p (TP53) and duplication of 17q.Conclusions Our analysis of adult acute lymphoblastic leukemia cases led to the identification of new potential target lesions relevant for the pathogenesis of acute lymphoblastic leukemia. However, no unequivocal pattern of submicroscopic genomic alterations was found to separate adult acute lymphoblastic leukemia from pediatric acute lymphoblastic leukemia. Therefore, apart from different therapy regimen, differences of prognosis between adult and pediatric acute lymphoblastic leukemia are probably based on genetic subgroups according to cytogenetically detectable lesions but not focal genomic copy number microlesions.
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- 2010
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29. Congenital cytomegalovirus infection in a preterm infant with 22q11.2 deletion syndrome and immunological abnormalities.
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Yoshihiko Shitara, Etsushi Toyofuku, Hideki Doi, Takeo Mukai, Kohei Kashima, Satsuki Kakiuchi, Motohiro Kato, and Naoto Takahashi
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DIGEORGE syndrome ,IMMUNOLOGIC diseases ,CYTOMEGALOVIRUS diseases ,CONGENITAL disorders ,PREMATURE infants - Abstract
The 22q11.2 deletion syndrome has many complications; one of them is immunodeficiency. However, the time of onset and the degree of immunodeficiency can vary. We report a case of a preterm infant with congenital cytomegalovirus infection complicated with 22q11.2 deletion syndrome and immunological abnormalities. Ultrasonography revealed pulmonary atresia, ventricular septal defect, major aortopulmonary collateral artery, and thymic hypoplasia. His serum chemistry tests on admission revealed immunoglobulin G, A, and M levels of 1,547 mg/dL, 70 mg/dL, and 274 mg/dL, respectively. A surface antigen analysis of the peripheral lymphocytes using flow cytometry revealed the following: relatively low CD4-positive T-cell levels (18.1%; 1,767/μL), very high CD8-positive T-cell levels (58.9%; 5,751/μL), and CD4/CD8 ratio of 0.31. The level of T-cell receptor excision circles was relatively low at 17.5 copies/μL. After birth, the CD8-positive T-cell level began to gradually decrease, whereas the CD4/CD8 ratio began to increase. Thrombocytopenia, neutropenia, and skin petechiae were observed on admission. However, the condition improved. Treatment for congenital cytomegalovirus infection was not provided due to the absence of viremia. Unfortunately, the patient died suddenly on the 158th day of life, and the cause of death was unknown. To the best of our knowledge, no association between 22q11 deletion syndrome and cCMV has been described in the recent medical literature. According to the calculation, around one newborn infant who have both 22q11 deletion syndrome and cCMV infection will be born each year in Japan. Healthcare providers should pay more attention to this medical situation in the future. [ABSTRACT FROM AUTHOR]
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- 2024
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30. Minimal residual disease detection by mutation-specific droplet digital PCR for leukemia/lymphoma
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Ryota Shirai, Tomoo Osumi, Dai Keino, Kazuhiko Nakabayashi, Toru Uchiyama, Masahiro Sekiguchi, Mitsuteru Hiwatari, Masanori Yoshida, Kaoru Yoshida, Yuji Yamada, Daisuke Tomizawa, Seido Takae, Nobutaka Kiyokawa, Kimikazu Matsumoto, Takako Yoshioka, Kenichiro Hata, Toshinori Hori, Nao Suzuki, and Motohiro Kato
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Hematology - Abstract
Minimal residual disease (MRD) is usually defined as the small number of cancer cells that remain in the body after treatment. The clinical significance of MRD kinetics is well recognized in treatment of hematologic malignancies, particularly acute lymphoblastic leukemia (ALL). Real time quantitative PCR targeting immunoglobulin (Ig) or T-cell receptor (TCR) rearrangement (PCR-MRD), as well as multiparametric flow cytometric analysis targeting antigen expression, are widely used in MRD detection. In this study, we devised an alternative method to detect MRD using droplet digital PCR (ddPCR), targeting somatic single nucleotide variants (SNVs). This ddPCR-based method (ddPCR-MRD) had sensitivity up to 1E-4. We assessed ddPCR-MRD at 26 time points from eight T-ALL patients, and compared it to the results of PCR-MRD. Almost all results were concordant between the two methods, but ddPCR-MRD detected micro-residual disease that was missed by PCR-MRD in one patient. We also measured MRD in stored ovarian tissue of four pediatric cancer patients, and detected 1E-2 of submicroscopic infiltration. Considering the universality of ddPCR-MRD, the methods can be used as a complement for not only ALL, but also other malignant diseases regardless of tumor-specific Ig/TCR or surface antigen patterns.
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- 2023
31. Reduced-intensity conditioning is effective for allogeneic hematopoietic stem cell transplantation in infants with MECOM-associated syndrome
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Masahiro Irie, Tetsuya Niihori, Tomohiro Nakano, Tasuku Suzuki, Saori Katayama, Kunihiko Moriya, Hidetaka Niizuma, Nobu Suzuki, Yuka Saito-Nanjo, Masaei Onuma, Takeshi Rikiishi, Atsushi Sato, Mayumi Hangai, Mitsuteru Hiwatari, Junji Ikeda, Reo Tanoshima, Norio Shiba, Yuki Yuza, Nobuyuki Yamamoto, Yoshiko Hashii, Motohiro Kato, Junko Takita, Miho Maeda, Yoko Aoki, Masue Imaizumi, and Yoji Sasahara
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Hematology - Abstract
Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae.
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- 2022
32. Recent progress in pediatric lymphoblastic leukemia
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Motohiro Kato
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Hematology - Abstract
The probability of long-term survival for children with lymphoblastic leukemia has improved dramatically over recent decades, mainly owing to advances in genomic analysis techniques, which have improved our understanding of the nature of leukemic cells and prognostic prediction based on the evaluation of precise treatment response. Risk-adjusted chemotherapy based on these advances has simultaneously reduced relapse rates and minimized complications. In addition, recent genomic analyses have deepened our understanding of the pathogenesis of leukemia and revealed the involvement of germline variations in the clinical course of leukemia treatment. Additionally, advances in minimal residual disease assays and the introduction of immunotherapy are expected to further improve therapeutic analyses. Further advances in clinical and translational research are anticipated to improve survival to 100% in a healthy state.
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- 2022
33. Identification of the ultrahigh-risk subgroup in neuroblastoma cases through DNA methylation analysis and its treatment exploiting cancer metabolism
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Kentaro Watanabe, Shunsuke Kimura, Masafumi Seki, Tomoya Isobe, Yasuo Kubota, Masahiro Sekiguchi, Aiko Sato-Otsubo, Mitsuteru Hiwatari, Motohiro Kato, Akira Oka, Katsuyoshi Koh, Yusuke Sato, Hiroko Tanaka, Satoru Miyano, Tomoko Kawai, Kenichiro Hata, Hiroo Ueno, Yasuhito Nannya, Hiromichi Suzuki, Kenichi Yoshida, Yoichi Fujii, Genta Nagae, Hiroyuki Aburatani, Seishi Ogawa, and Junko Takita
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Cancer Research ,N-Myc Proto-Oncogene Protein ,DNA methylation ,Arginine ,Cancer metabolism ,Gene Expression Regulation, Neoplastic ,Paediatric cancer ,Neuroblastoma ,Mechanisms of disease ,Targeted therapies ,Cell Line, Tumor ,Genetics ,Serine ,Humans ,Molecular Biology ,Cell Proliferation - Abstract
Neuroblastomas require novel therapies that are based on the exploitation of their biological mechanism. To address this need, we analyzed the DNA methylation and expression datasets of neuroblastomas, extracted a candidate gene characterizing the aggressive features, and conducted functional studies. Based on the DNA methylation data, we identified a subgroup of neuroblastoma cases with 11q loss of heterozygosity with extremely poor prognosis. PHGDH, a serine metabolism-related gene, was extracted as a candidate with strong expression and characteristic methylation in this subgroup as well as in cases with MYCN amplification. PHGDH inhibition suppressed neuroblastoma cell proliferation in vitro and in vivo, indicating that the inhibition of serine metabolism by PHGDH inhibitors is a therapeutic alternative for neuroblastoma. Inhibiting the arginine metabolism, which is closely related to serine metabolism using arginine deiminase, had a combination effect both in vitro and in vivo, especially on extracellular arginine-dependent neuroblastoma cells with ASS1 deficiency. Expression and metabolome analyses of post-dose cells confirmed the synergistic effects of treatments targeting serine and arginine indicated that xCT inhibitors that inhibit cystine uptake could be candidates for further combinatorial treatment. Our results highlight the rational therapeutic strategy of targeting serine/arginine metabolism for intractable neuroblastoma., 神経芽腫の新たな診断法と治療戦略を創出 --がん細胞の生存戦略「がん代謝」を逆用する--. 京都大学プレスリリース. 2022-11-02.
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- 2022
34. Cord Blood Transplantation in 2 Infants Presenting Monosomy 7 Clonal Hematopoiesis: SAMD9/SAMD9L Germline Mutation
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Maiko Hirai, Hiroshi Yagasaki, Koji Kanezawa, Masaru Ueno, Katsuyoshi Shimozawa, Kohsuke Imai, Tomohiro Morio, Motohiro Kato, Yoshihiro Gocho, Satoshi Narumi, Yasuhiro Ebihara, and Ichiro Morioka
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Oncology ,Pediatrics, Perinatology and Child Health ,Hematology - Published
- 2022
35. Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors
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Yoichi Naito, Saori Mishima, Kiwamu Akagi, Naomi Hayashi, Akira Hirasawa, Tomoro Hishiki, Ataru Igarashi, Masafumi Ikeda, Shigenori Kadowaki, Hiroaki Kajiyama, Motohiro Kato, Hirotsugu Kenmotsu, Yasuhiro Kodera, Keigo Komine, Takafumi Koyama, Osamu Maeda, Mitsuru Miyachi, Hiroshi Nishihara, Hiroyuki Nishiyama, Shouichi Ohga, Wataru Okamoto, Eiji Oki, Shigeru Ono, Masashi Sanada, Ikuo Sekine, Tadao Takano, Kayoko Tao, Keita Terashima, Katsuya Tsuchihara, Yasushi Yatabe, Takayuki Yoshino, and Eishi Baba
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Oncology ,Surgery ,Hematology ,General Medicine - Abstract
Background Clinical trials have reported the efficacy of tropomyosin receptor kinase (TRK) inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors. The accumulated evidence of tumor-agnostic agent has made since TRK inhibitors were approved and used in clinical practice. Therefore, we have revised the ‘Japan Society of Clinical Oncology (JSCO)/Japanese Society of Medical Oncology (JSMO)-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese Society of Pediatric Hematology/Oncology (JSPHO)’. Methods Clinical questions regarding medical care were formulated for patients with NTRK fusion-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by JSCO, JSMO, and JSPHO voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. Results The current guideline describes 3 clinical questions and 14 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. Conclusion The committee proposed 14 recommendations for performing NTRK testing properly to select patients who are likely to benefit from TRK inhibitors.
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- 2023
36. Quantitative assessment of copy number alterations by liquid biopsy for neuroblastoma
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Ryota Shirai, Tomoo Osumi, Aiko Sato‐Otsubo, Kazuhiko Nakabayashi, Keisuke Ishiwata, Yuji Yamada, Masanori Yoshida, Kaoru Yoshida, Yoko Shioda, Chikako Kiyotani, Keita Terashima, Daisuke Tomizawa, Nao Takasugi, Junko Takita, Osamu Miyazaki, Nobutaka Kiyokawa, Akihiro Yoneda, Yutaka Kanamori, Tomoro Hishiki, Kimikazu Matsumoto, Kenichiro Hata, Takako Yoshioka, and Motohiro Kato
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N-Myc Proto-Oncogene Protein ,Neuroblastoma ,Cancer Research ,DNA Copy Number Variations ,Liquid Biopsy ,Genetics ,Humans ,DNA, Neoplasm ,Cell-Free Nucleic Acids - Abstract
Liquid biopsy, a method of detecting genomic alterations using blood specimens, has recently attracted attention as a noninvasive alternative to surgical tissue biopsy. We attempted quantitative analysis to detect amplification of MYCN (MYCNamp) and loss of heterozygosity at 11q (11qLOH), which are clinical requisites as prognostic factors of neuroblastoma (NB). In this study, cell-free DNA (cfDNA) was extracted from plasma samples from 24 NB patients at diagnosis. Copy numbers of MYCN and NAGK genes were quantitatively analyzed by droplet digital PCR (ddPCR). 11qLOH was also assessed by detecting allelic imbalances of heterozygous single nucleotide polymorphisms in the 11q region. The results obtained were compared to those of specimens from tumor tissues. The correlation coefficient of MYCN copy number of cfDNA and tumor DNA was 0.88 (p 0.00001). 11qLOH was also accurately detected from cfDNA, except for one case with localized NB. Given the high accuracy of liquid biopsy, to investigate components of cfDNA, the proportion of tumor-derived DNA was estimated by examining the variant allele frequency of tumor-specific mutations in cfDNA. The proportion of tumor-derived DNA in cfDNA was 42.5% (range, 16.9%-55.9%), suggesting sufficient sensitivity of liquid biopsy for NB. In conclusion, MYCN copy number and 11qLOH could be quantitatively analyzed in plasma cfDNA by ddPCR assay. These results suggest that plasma cfDNA can be substituted for tumor DNA and can also be applied for comprehensive genomic profiling analysis.
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- 2022
37. Data from Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation
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Motohiro Kato, Susumu Goyama, Nobutaka Kiyokawa, Kenichiro Hata, Kimikazu Matsumoto, Toshio Kitamura, Seishi Ogawa, Takeshi Inukai, Junko Takita, Kentaro Ohki, Masafumi Seki, Ryota Shirai, Hitomi Ueno-Yokohata, Hiroe Kizawa, Toru Uchiyama, Hiroko Ogata-Kawata, Masahiro Migita, Kazuko Hamamoto, Shohei Yamamoto, Tsukasa Hori, Hiroyuki Takahashi, Akihiro Watanabe, Daisuke Tomizawa, Masanori Yoshida, Kohji Okamura, Kazuhiko Nakabayashi, Meri Uchiyama, Moe Tamura, Shin-ichi Tsujimoto, and Tomoo Osumi
- Abstract
Translocations of retinoic acid receptor-α (RARA), typically PML–RARA, are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of RARA, we focused here on APL cases without RARA translocation to elucidate the molecular etiology of RARA-negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without RARA translocations. Four of five RARA-negative APL cases had translocations involving retinoic acid receptor-β (RARB) translocations, and TBL1XR1–RARB was identified as an in-frame fusion in three cases; one case had an RARB rearrangement detected by FISH, although the partner gene could not be identified. When transduced in cell lines, TBL1XR1–RARB homodimerized and diminished transcriptional activity for the retinoic acid receptor pathway in a dominant-negative manner. TBL1XR1–RARB enhanced the replating capacity of mouse bone marrow cells and inhibited myeloid maturation of human cord blood cells as PML–RARA did. However, the response of APL with RARB translocation to retinoids was attenuated compared with that of PML–RARA, an observation in line with the clinical resistance of RARB-positive APL to ATRA. Our results demonstrate that the majority of RARA-negative APL have RARB translocations, thereby forming a novel, distinct subgroup of APL. TBL1XR1–RARB as an oncogenic protein exerts effects similar to those of PML–RARA, underpinning the importance of retinoic acid pathway alterations in the pathogenesis of APL.Significance: These findings report a novel and distinct genetic subtype of acute promyelocytic leukemia (APL) by illustrating that the majority of APL without RARA translocations harbor RARB translocations. Cancer Res; 78(16); 4452–8. ©2018 AACR.
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- 2023
38. Data from MYC Amplification as a Prognostic Marker of Early-Stage Lung Adenocarcinoma Identified by Whole Genome Copy Number Analysis
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Jun Yokota, Seishi Ogawa, Masayuki Noguchi, Koji Tsuta, Kouya Shiraishi, Motohiro Kato, Takashi Kohno, and Reika Iwakawa
- Abstract
Purpose: Even in small-sized (≤2 cm in greatest dimension) and/or pathologic stage I lung adenocarcinoma (ADC), a considerable proportion of the patients will relapse within 5 years and show poor prognosis. The purpose of this study was to identify genetic alterations that define prognosis of patients with early-stage lung ADC.Experimental Design: Regions of copy number alterations in 65 small-sized lung ADCs and 40 ADC cell lines were determined by using GeneChip Human Mapping 10-K and 250-K single-nucleotide polymorphism (SNP) arrays, respectively. A copy number assay based on real-time genomic PCR (RT-G-PCR) was done for 60 small-sized lung ADCs and 162 stage I lung ADCs.Results: Several regions on chromosomes 5p, 7p, 8q, and 14q were frequently (>10%) amplified in both small-sized ADCs and lung ADC cell lines. In particular, the MYC gene was mapped in the minimum common region at chromosome 8q24.21, and therefore was indicated to be a target of gene amplification in lung ADCs. MYC amplification correlated with poor prognosis (P = 0.031) of patients with small-sized ADCs. MYC amplification detected by SNP array analysis was well reproduced by RT-G-PCR analysis. Therefore, to investigate the utility of MYC amplification as a prognostic marker for early-stage lung ADCs, 162 stage I lung ADCs were subjected to the analysis. MYC amplification was associated with relapse-free survival in these patients (P = 0.013 by multivariate Cox proportional hazard model analysis).Conclusions: These results strongly indicate that MYC amplification is a prognostic marker of patients with early-stage lung ADCs. Clin Cancer Res; 17(6); 1481–9. ©2010 AACR.
- Published
- 2023
39. Supplementary Information from Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation
- Author
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Motohiro Kato, Susumu Goyama, Nobutaka Kiyokawa, Kenichiro Hata, Kimikazu Matsumoto, Toshio Kitamura, Seishi Ogawa, Takeshi Inukai, Junko Takita, Kentaro Ohki, Masafumi Seki, Ryota Shirai, Hitomi Ueno-Yokohata, Hiroe Kizawa, Toru Uchiyama, Hiroko Ogata-Kawata, Masahiro Migita, Kazuko Hamamoto, Shohei Yamamoto, Tsukasa Hori, Hiroyuki Takahashi, Akihiro Watanabe, Daisuke Tomizawa, Masanori Yoshida, Kohji Okamura, Kazuhiko Nakabayashi, Meri Uchiyama, Moe Tamura, Shin-ichi Tsujimoto, and Tomoo Osumi
- Abstract
Supplementary Methods: IRB approval, Genomic analysis, Identification of translocations and determination of their breakpoints, Plasmids Construct, Cell line and reagent, Co-immunoprecipotation and immunoblotting analysis, Luciferase assay, Retrovirus production and transduction, FCM and Morphologic analysis, Human CB cell culture, and Colony replating assay. Supplementary Tables: Table 1. Clinical characteristics of RARA translocation negative APL cases. Table 2. BAC clones for FISH used in this study. Table 3. Primer sequences. Table 4. Somatic mutations observed in RARA-negative APL cases. Supplementary Figures: Figure 1. Morphologic feature and FISH analyisis for RARB translocations. Figure 2. Event-free survival of RARA-negative APL. Figure 3. Determination of TBL1XR1 mutated allele by allele-specific PCR. Figure 4. Constructs of TBL1XR1-RARB and other RARA fusions. Figure 5. Morphologic change in U937. Figure 6. Colony replating assay with mouse bone marrow. Figure 7. Colony replating assay with human cord blood.
- Published
- 2023
40. Supplementary Data from MYC Amplification as a Prognostic Marker of Early-Stage Lung Adenocarcinoma Identified by Whole Genome Copy Number Analysis
- Author
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Jun Yokota, Seishi Ogawa, Masayuki Noguchi, Koji Tsuta, Kouya Shiraishi, Motohiro Kato, Takashi Kohno, and Reika Iwakawa
- Abstract
Supplementary Figure S1; Supplementary Table S1.
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- 2023
41. Supplementary Tables from Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma
- Author
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Junko Takita, Seishi Ogawa, Satoru Miyano, Kenichiro Hata, Yukichi Tanaka, Masashi Sanada, Akira Oka, Hajime Hosoi, Tomoko Iehara, Chikako Kiyotani, Takao Deguchi, Tsuyoshi Ito, Akiko Inoue, Junya Fujimura, Masaharu Akiyama, Tomoaki Taguchi, Asahito Hama, Akihiro Iguchi, Motohiro Kato, Teppei Shimamura, Hiroko Tanaka, Kenichi Chiba, Tomoko Kawai, Yusuke Sato, Keisuke Kataoka, Hiromichi Suzuki, Nobuyuki Kakiuchi, Akira Yokoyama, Yoshikage Inoue, Misa Yoshida, Shunsuke Kimura, Yuichi Shiraishi, Yusuke Shiozawa, Masahiro Sekiguchi, Kenichi Yoshida, Masafumi Seki, and Tomoya Isobe
- Abstract
Supplementary Tables S1-S13. Supplementary Table S1. Clinical information and the summary of experiments performed on each sample. Supplementary Table S2. List of genes and regions captured for targeted deep sequencing. Supplementary Table S3. dbSNP ID list for which target baits were designed. Supplementary Table S4. Non-silent mutations detected in a validation cohort by targeted deep sequencing. Supplementary Table S5. Validated non-silent somatic mutations by PCR-based deep sequencing. Supplementary Table S6. Validated silent/non-silent somatic mutations used for clonal analysis of multiple samples from PBL001. Supplementary Table S7. Significantly hypo-/hyper-methylated gene sets in PBL compared to normal pancreas. Supplementary Table S8. Fusion genes detected by whole transcriptome sequencing in PBL. Supplementary Table S9. Genes with a significant differential expression between PBL and normal pancreatic samples. Supplementary Table S10. Significant gene set enrichment in comparison between PBL and normal pancreas. Supplementary Table S11. List of differentially expressed genes in each gene cluster identified by hierarchical clustering. Supplementary Table S12. Top 20 significantly enriched pathways in each gene cluster. Supplementary Table S13. Gene coefficients of PC1 and PC2.
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- 2023
42. Data from Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma
- Author
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Junko Takita, Seishi Ogawa, Satoru Miyano, Kenichiro Hata, Yukichi Tanaka, Masashi Sanada, Akira Oka, Hajime Hosoi, Tomoko Iehara, Chikako Kiyotani, Takao Deguchi, Tsuyoshi Ito, Akiko Inoue, Junya Fujimura, Masaharu Akiyama, Tomoaki Taguchi, Asahito Hama, Akihiro Iguchi, Motohiro Kato, Teppei Shimamura, Hiroko Tanaka, Kenichi Chiba, Tomoko Kawai, Yusuke Sato, Keisuke Kataoka, Hiromichi Suzuki, Nobuyuki Kakiuchi, Akira Yokoyama, Yoshikage Inoue, Misa Yoshida, Shunsuke Kimura, Yuichi Shiraishi, Yusuke Shiozawa, Masahiro Sekiguchi, Kenichi Yoshida, Masafumi Seki, and Tomoya Isobe
- Abstract
Pancreatoblastoma is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multiomics study of whole-exome and RNA sequencing as well as genome-wide copy number and methylation analyses of ten pancreatoblastoma cases. The pancreatoblastoma genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of heterozygosity (CN-LOH) of APC (10%). In addition, imprinting dysregulation of IGF2 as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) was universally detected. At the transcriptome level, pancreatoblastoma exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for pancreatoblastoma and highlight rational therapeutic targets for its treatment.Significance: Molecular genetic analysis of a rare untreatable pediatric tumor reveals Wnt/IGF2 aberrations and features of early pancreas progenitor-like cells, suggesting cellular origins and rational strategies for therapeutic targeting. Cancer Res; 78(4); 865–76. ©2017 AACR.
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- 2023
43. Supplementary Figures from Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma
- Author
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Junko Takita, Seishi Ogawa, Satoru Miyano, Kenichiro Hata, Yukichi Tanaka, Masashi Sanada, Akira Oka, Hajime Hosoi, Tomoko Iehara, Chikako Kiyotani, Takao Deguchi, Tsuyoshi Ito, Akiko Inoue, Junya Fujimura, Masaharu Akiyama, Tomoaki Taguchi, Asahito Hama, Akihiro Iguchi, Motohiro Kato, Teppei Shimamura, Hiroko Tanaka, Kenichi Chiba, Tomoko Kawai, Yusuke Sato, Keisuke Kataoka, Hiromichi Suzuki, Nobuyuki Kakiuchi, Akira Yokoyama, Yoshikage Inoue, Misa Yoshida, Shunsuke Kimura, Yuichi Shiraishi, Yusuke Shiozawa, Masahiro Sekiguchi, Kenichi Yoshida, Masafumi Seki, and Tomoya Isobe
- Abstract
Supplementary Figures S1-S10. Supplementary Figure S1. Depths and coverages of targeted deep sequencing. Supplementary Figure S2. Sequencing coverages and numbers of mutations detected by WES. Supplementary Figure S3. Tumor subclonal populations in multiple samples from PBL001 estimated by PyClone. Supplementary Figure S4. Mutational signatures of primary and metastatic PBL. Supplementary Figure S5. SNP array-based copy number analysis of PBL. Supplementary Figure S6. Targeted deep sequencing based allele-specific copy number analysis of chromosome 11. Supplementary Figure S7. Bisulfite Sanger sequencing of ICR1 on chromosome 11p15.5. Supplementary Figure S8. Relative expression levels of IGF2 in CN-LOH-negative samples. Supplementary Figure S9. Aberrant activation of Wnt signaling pathway in PBL009. Supplementary Figure S10. Global DNA methylation profile of PBL.
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- 2023
44. Data from Biallelic DICER1 Mutations in Sporadic Pleuropulmonary Blastoma
- Author
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Junko Takita, Seishi Ogawa, Yasuhide Hayashi, Satoru Miyano, Takashi Igarashi, Akira Oka, Toshiaki Ishida, Myoung-Ja Park, Yuko Nomura, Ryoji Hanada, Motohiro Kato, Keisuke Kato, Hiroko Tanaka, Kenichi Chiba, Yusuke Okuno, Riki Nishimura, Yusuke Sato, Teppei Shimamura, Yuichi Shiraishi, Kenichi Yoshida, and Masafumi Seki
- Abstract
Pleuropulmonary blastoma (PPB) is a rare pediatric malignancy whose pathogens are poorly understood. Recent reports suggest that germline mutations in the microRNA-processing enzyme DICER1 may contribute to PPB development. To investigate the genetic basis of this cancer, we performed whole-exome sequencing or targeted deep sequencing of multiple cases of PPB. We found biallelic DICER1 mutations to be very common, more common than TP53 mutations also found in many tumors. Somatic ribonuclease III (RNase IIIb) domain mutations were identified in all evaluable cases, either in the presence or absence of nonsense/frameshift mutations. Most cases had mutated DICER1 alleles in the germline with or without an additional somatic mutation in the remaining allele, whereas other cases displayed somatic mutations exclusively where the RNase IIIb domain was invariably affected. Our results highlight the role of RNase IIIb domain mutations in DICER1 along with TP53 inactivation in PPB pathogenesis. Cancer Res; 74(10); 2742–9. ©2014 AACR.
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- 2023
45. Supplementary Figures 1 - 6, Tables 1 - 7 from Biallelic DICER1 Mutations in Sporadic Pleuropulmonary Blastoma
- Author
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Junko Takita, Seishi Ogawa, Yasuhide Hayashi, Satoru Miyano, Takashi Igarashi, Akira Oka, Toshiaki Ishida, Myoung-Ja Park, Yuko Nomura, Ryoji Hanada, Motohiro Kato, Keisuke Kato, Hiroko Tanaka, Kenichi Chiba, Yusuke Okuno, Riki Nishimura, Yusuke Sato, Teppei Shimamura, Yuichi Shiraishi, Kenichi Yoshida, and Masafumi Seki
- Abstract
PDF file - 1805KB, Supplementary Table S1. List of primers used for validation of somatic mutations detected by whole-exome sequencing. Supplementary Table S2. Primers for DICER1 sequencing of all coding exons. Supplementary Table S3. Primers for DICER1 sequencing of all coding exons in paraffin embedded samples. Supplementary Table S4. Primers for TP53, UBA2, PDCD2L, CTNNB1, and GPR182. Supplementary Table S5. List of mutated genes detected by whole-exome sequencing. Supplementary Table S6. Allele frequency of DICER1 mutations in cases with unknown somatic status. Supplementary Table S7. Recurrent mutations detected by whole-exome sequencing. Supplementary Figure S1. Analyzing processes using Genomon. Supplementary Figure S2. Mean coverage of whole-exome sequencing in primary tumor, relapse tumor, and control samples. Supplementary Figure S3. Mean coverage of whole exome sequencing with GC contents in primary tumor, relapse tumor and control samples. Supplementary Figure S4. Detected mutations of DICER1 by Sanger sequencing. Supplementary Figure S5. Distribution of genetic lesions with 14 samples in PPB cases. Supplementary Figure S6. Common amplification lesion at 19q13.11.
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- 2023
46. Factors affecting in-hospital mortality among pediatric patients with myocarditis treated with mechanical circulatory support
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Susumu Urata, Nobuaki Michihata, Ryo Inuzuka, Hiroki Matsui, Kiyohide Fushimi, Miho Ishimaru, Motohiro Kato, and Hideo Yasunaga
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Cardiology and Cardiovascular Medicine - Published
- 2023
47. Novel TENM3–ALK fusion is an alternate mechanism for ALK activation in neuroblastoma
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Mitsuteru Hiwatari, Masafumi Seki, Ryosuke Matsuno, Kenichi Yoshida, Takeshi Nagasawa, Aiko Sato-Otsubo, Shohei Yamamoto, Motohiro Kato, Kentaro Watanabe, Masahiro Sekiguchi, Satoru Miyano, Seishi Ogawa, and Junko Takita
- Subjects
Cancer Research ,Oncogene Proteins, Fusion ,Membrane Proteins ,Receptor Protein-Tyrosine Kinases ,Nerve Tissue Proteins ,Translocation, Genetic ,Mice ,Neuroblastoma ,Cell Transformation, Neoplastic ,Mice, Inbred NOD ,Cell Line, Tumor ,NIH 3T3 Cells ,Genetics ,Animals ,Humans ,Anaplastic Lymphoma Kinase ,Molecular Biology ,Cell Proliferation - Abstract
The identification of molecular events underlying the pathogenesis of neuroblastoma can likely result in improved clinical outcomes for this disease. In this study, a translocation within chromosome 2p and 4q was found to bring about the formation of an in-frame fusion gene that was composed of portions of the teneurin transmembrane protein 3 (TENM3, also known as ODZ3) gene and the anaplastic lymphoma kinase (ALK) gene in tumor cells from patients with neuroblastoma. Expression of the full length TENM3-ALK cDNA in NIH-3T3 cells led to the formation of a fusion protein that: (1) possesses constitutive tyrosine kinase activity, (2) induces strong activation of the downstream targets of extracellular signal-regulated kinase (ERK), protein kinase B (a.k.a. AKT), and signal transducer and activator of transcription 3 (STAT3), (3) provokes oncogenic transformation in NOD.Cg-Prkdc
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- 2022
48. Ponatinib in pediatric patients with Philadelphia chromosome-positive leukemia: a retrospective survey of the Japan Children’s Cancer Group
- Author
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Yuichi Kodama, Atsushi Sato, Keisuke Kato, Hirotoshi Sakaguchi, Motohiro Kato, Hirohide Kawasaki, Hidefumi Hiramatsu, Itaru Kato, Takashi Taga, and Hiroyuki Shimada
- Subjects
Adult ,Male ,Adolescent ,Imidazoles ,Antineoplastic Agents ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Pyridazines ,Japan ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Humans ,Female ,Philadelphia Chromosome ,Child ,Protein Kinase Inhibitors ,Retrospective Studies - Abstract
Ponatinib is effective in adults with Philadelphia chromosome-positive (Ph+) leukemia, resistant or intolerant to second-generation tyrosine kinase inhibitors, but there are limited data on its use in children. The clinical courses of nine pediatric patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL) and four with chronic myeloid leukemia (CML) who received ponatinib therapy were retrospectively reviewed. The median age at the start of ponatinib therapy was 12 years (range 8-16 years). Nine patients were male and four were female. Six patients received ponatinib alone, three received ponatinib with prednisolone, one received ponatinib with rituximab intrathecal therapy, and one received ponatinib with conventional chemotherapy. Two patients received ponatinib both alone and in combination with chemotherapy. The median dose and duration of ponatinib were 16.9 mg/m
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- 2022
49. Prognostic factors of children and adolescents with T‐cell acute lymphoblastic leukemia after allogeneic transplantation
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Hisashi Ishida, Motohiro Kato, Yuta Kawahara, Sae Ishimaru, Yuho Najima, Shinichi Kako, Maho Sato, Mitsuteru Hiwatari, Maiko Noguchi, Keisuke Kato, Katsuyoshi Koh, Keiko Okada, Fuminori Iwasaki, Ryoji Kobayashi, Shunji Igarashi, Shoji Saito, Yoshiyuki Takahashi, Atsushi Sato, Junji Tanaka, Yoshiko Hashii, Yoshiko Atsuta, Hirotoshi Sakaguchi, and Toshihiko Imamura
- Subjects
Adult ,Cancer Research ,Transplantation Conditioning ,Adolescent ,T-Lymphocytes ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,Hematology ,General Medicine ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Young Adult ,Oncology ,Recurrence ,Humans ,Transplantation, Homologous ,Child ,Retrospective Studies - Abstract
Acute lymphoblastic leukemia (ALL) is the most common cancer during childhood, and some high-risk patients with ALL require hematopoietic stem cell transplantation (HSCT). Mainly due to small patient numbers, studies focusing specifically on children and adolescents with T-cell ALL (T-ALL) are limited. Using a nationwide registry, we retrospectively analyzed data from patients under 20 years old who underwent their first HSCT for T-ALL between 2000 and 2018. As a result, total 484 patients were included, and their median follow-up period was 6.9 years after HSCT for survivors. While patients receiving HSCT at first complete remission (CR) showed relatively good 5-year leukemia free survival (5yLFS, 73.5%), once relapse occurred, their prognosis was much worse (44.4%) even if they attained second remission again (p 0.001). Among patients receiving HSCT at CR1, grade II-IV acute graft versus host disease was associated with worse overall and LFS than grade 0-I (5yLFS 69.5% vs. 82.1%, p = 0.026) mainly due to high non-relapse mortality. Among those patients, patients receiving related bone marrow transplantation, unrelated bone marrow transplantation, or unrelated cord blood transplantation showed similar survival (5yLFS, 73.2%, 76.3%, and 77.0%, respectively). For patients undergoing cord blood transplantation at CR1, total-body irradiation-based myeloablative conditioning was associated with better 5yLFS than other conditioning regimens (85.4% vs. 62.2%, p = 0.044), as it reduced the risk of relapse. These results indicate that relapsed patients have much less chance of cure, and that identifying patients who require HSCT for cure and offering them HSCT with optimal settings during CR1 are crucial for children and adolescents with T-ALL.
- Published
- 2022
50. A Pediatric Case of Leadless Pacemaker Implantation
- Author
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Kaname Satoh, Toshiya Kojima, Akiharu Omori, Yosuke Ogawa, Yu Tanaka, Kazuhiro Shiraga, Hitomi Masuda, Susumu Urata, Hikoro Matsui, Miyuki Shibata, Yasutaka Hirata, Minoru Ono, Motohiro Kato, and Ryo Inuzuka
- Subjects
Complementary and alternative medicine ,Pharmaceutical Science ,Pharmacology (medical) - Published
- 2022
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