81 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. 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
31. Current status of intensive end-of-life care in children with hematologic malignancy: a population-based study
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Yoshiyuki Kizawa, Daisuke Shinjo, Kimikazu Matsumoto, Nobuyuki Yotani, Motohiro Kato, and Kiyohide Fushimi
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Quality of life ,Pediatrics ,medicine.medical_specialty ,Palliative care ,Blood transfusion ,Adolescent ,medicine.medical_treatment ,Extra-corporeal membrane oxygenation ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Intravenous chemotherapy ,Mechanical ventilation ,law ,030225 pediatrics ,medicine ,Humans ,Cardiopulmonary resuscitation ,Child ,Retrospective Studies ,Terminal Care ,ICU admission ,business.industry ,Palliative Care ,Infant, Newborn ,Infant ,RC952-1245 ,General Medicine ,Intensive care unit ,Intensive Care Units ,Hospice Care ,Special situations and conditions ,030220 oncology & carcinogenesis ,Child, Preschool ,Hematologic Neoplasms ,Hemodialysis ,business ,End-of-life care ,Research Article - 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 Conclusion Children with hematologic malignancies are more likely to receive intensive EOLC compared to those with solid tumors. A younger age and shorter hospital stay might be associated with intensive EOLC in children with hematologic malignancies.
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- 2021
32. Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (edition 2.1)
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Itaru Matsumura, Toru Furukawa, Shinji Kohsaka, Masayuki Takeda, Ichiro Kinoshita, Kuniko Sunami, Hiroyuki Aburatani, Motohiro Kato, Naomi Kiyota, Yuji Miura, Tetsu Hayashida, Natsuko Okita, Katsutoshi Oda, Yoshiaki Nakamura, Toraji Amano, Yoichi Naito, Eiso Hiyama, Eishi Baba, Kazuto Nishio, Atsushi Natsume, Shinichi Toyooka, Naoyuki Oda, Shinichi Yachida, Hideaki Takahashi, Takayuki Yoshino, Hideki Ueno, Takashi Kohno, Masashi Kanai, Keigo Komine, Kumiko Oseto, Katsuya Tsuchihara, Sadakatsu Ikeda, and Shimon Tashiro
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0301 basic medicine ,medicine.medical_specialty ,Clinical practice guidance ,Medical Oncology ,03 medical and health sciences ,Special Article ,0302 clinical medicine ,Surgical oncology ,Cancer genome ,Neoplasms ,medicine ,Genomic medicine ,Humans ,Medical physics ,Precision Medicine ,Reimbursement ,Clinical Oncology ,business.industry ,Patient Selection ,Solid cancer ,Cancer ,High-Throughput Nucleotide Sequencing ,Hematology ,General Medicine ,medicine.disease ,Test (assessment) ,Clinical Practice ,030104 developmental biology ,Oncology ,Cancer genomic profiling test ,030220 oncology & carcinogenesis ,Next-generation sequencing ,Surgery ,business - Abstract
Background To promote precision oncology in clinical practice, the Japanese Society of Medical Oncology, the Japanese Society of Clinical Oncology, and the Japanese Cancer Association, jointly published “Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment” in 2017. Since new information on cancer genomic medicine has emerged since the 1st edition of the guidance was released, including reimbursement for NGS-based multiplex gene panel tests in 2019, the guidance revision was made. Methods A working group was organized with 33 researchers from cancer genomic medicine designated core hospitals and other academic institutions. For an impartial evaluation of the draft version, eight committee members from each society conducted an external evaluation. Public comments were also made on the draft. The finalized Japanese version was published on the websites of the three societies in March 2020. Results The revised edition consists of two parts: an explanation of the cancer genomic profiling test (General Discussion) and clinical questions (CQs) that are of concern in clinical practice. Particularly, patient selection should be based on the expectation that the patient's post-test general condition and organ function will be able to tolerate drug therapy, and the optimal timing of test should be considered in consideration of subsequent treatment plans, not limited to treatment lines. Conclusion We expect that the revised version will be used by healthcare professionals and will also need to be continually reviewed in line with future developments in cancer genome medicine.
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- 2020
33. 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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Takafumi Soejima, Kiyoko Kamibeppu, Shohei Nakajima, Motohiro Kato, Miho Maeda, Atsushi Manabe, Katsuyoshi Koh, Yasushi Ishida, Yasuhiro Okamoto, Toshihiko Imamura, and Iori Sato
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Quality of life ,Parents ,Adolescent ,Psychometrics ,Intraclass correlation ,Pediatric hospitals ,media_common.quotation_subject ,Agreement ,03 medical and health sciences ,0302 clinical medicine ,Pediatric Acute Lymphoblastic Leukemia ,030225 pediatrics ,Induction therapy ,Neoplasms ,Surveys and Questionnaires ,Medicine ,Humans ,Family ,030212 general & internal medicine ,Child ,media_common ,Pediatric leukemia ,Health related quality of life ,business.industry ,Attendance ,lcsh:RJ1-570 ,lcsh:Pediatrics ,Dyadic analysis ,Induction Chemotherapy ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Patient reported outcome measures ,humanities ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Worry ,business ,Clinical psychology ,Research Article - 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
34. Phase II/III study in children and adolescents with newly diagnosed B-cell precursor acute lymphoblastic leukemia: protocol for a nationwide multicenter trial in Japan
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Atsushi Manabe, Akiko Kada, Katsuyoshi Koh, Keizo Horibe, Motohiro Kato, Yasuhiro Okamoto, Akiko Saito, Hirohide Kawasaki, and Toshihiko Imamura
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Male ,Cancer Research ,Vincristine ,Asparaginase ,medicine.medical_specialty ,Adolescent ,Endpoint Determination ,Clinical Trial Note ,randomization ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Maintenance therapy ,Japan ,Multicenter trial ,Internal medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Child ,acute lymphoid leukemia ,Dexamethasone ,business.industry ,trial protocol ,Infant ,hemic and immune systems ,General Medicine ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Minimal residual disease ,Acute toxicity ,Clinical trial ,Treatment Outcome ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Child, Preschool ,Sample Size ,Female ,business ,030215 immunology ,medicine.drug - Abstract
We are conducting a nationwide multicenter Phase II/III trial in children and adolescents with newly diagnosed B-cell precursor acute lymphoblastic Leukemia in Japan., B-cell precursor acute lymphoblastic leukemia is the most common pediatric malignancy, but its treatment needs to be modified to cause low acute toxicity and few late complications with a high cure rate. In this trial, we will stratify patients with B-cell precursor acute lymphoblastic leukemia into standard, intermediate and high risk groups according to prognostic factors. In addition, we will establish an evaluation system for minimal residual disease that will enable us to stratify patients based on minimal residual disease in subsequent clinical trials. We will clarify the impact of dexamethasone/vincristine pulse therapy during maintenance therapy in the standard risk group, and intensive l-asparaginase therapy in the intermediate risk group. In the high risk group, usefulness of vincristine intensification will be assessed. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000009339 [http://www.umin.ac.jp/ctr/].
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- 2018
35. Clonal evolution mechanisms in NT5C2 mutant relapsed acute lymphoblastic leukemia
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Alberto Ambesi-Impiombato, Hossein Khiabanian, Mignon L. Loh, Gannie Tzoneva, Koichi Oshima, Chelsea L. Dieck, Giuseppe Basso, Maria Luisa Sulis, Julie M. Gastier-Foster, Maddalena Paganin, Ilaria Iacobucci, Chioma J. Madubata, Adolfo A. Ferrando, Esmé Waanders, Jiangyan Yu, Raul Rabadan, Charles G. Mullighan, Marta Sanchez-Martin, Motohiro Kato, Katsuyoshi Koh, and Renate Kirschner-Schwabe
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0301 basic medicine ,Male ,medicine.medical_treatment ,Mutant ,Drug Resistance ,medicine.disease_cause ,Somatic evolution in cancer ,Mice ,0302 clinical medicine ,IMP Dehydrogenase ,Recurrence ,hemic and lymphatic diseases ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,Receptor, Notch1 ,Cytotoxicity ,5-Nucleotidase ,5'-Nucleotidase ,Cancer ,Pediatric ,Mutation ,Multidisciplinary ,Guanosine ,Mercaptopurine ,Lymphoblast ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Phenotype ,3. Good health ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Gain of Function Mutation ,Female ,Development of treatments and therapeutic interventions ,Receptor ,Pediatric Cancer ,Childhood Leukemia ,General Science & Technology ,Biology ,Article ,Clonal Evolution ,03 medical and health sciences ,Rare Diseases ,All institutes and research themes of the Radboud University Medical Center ,Nucleotidase ,medicine ,Genetics ,Animals ,Humans ,Cell Proliferation ,Chemotherapy ,Notch1 ,Animal ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,030104 developmental biology ,HEK293 Cells ,Drug Resistance, Neoplasm ,Purines ,Disease Models ,Cancer research ,Neoplasm - Abstract
Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.
- Published
- 2018
36. Regional evaluation of childhood acute lymphoblastic leukemia genetic susceptibility loci among Japanese
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Kozue Nakamura, Yuichi Taneyama, Motohiro Kato, Yasushi Ishida, Toshihiro Tanaka, Kevin Y. Urayama, Yujin Sekinaka, Yasushi Noguchi, Johji Inazawa, Kazutoshi Koike, Takeshi Inukai, Dai Keino, Yozo Nakazawa, Yuki Arakawa, Katsuyoshi Koh, Shuki Mizutani, Daisuke Hasegawa, Hidemitsu Kurosawa, Keitaro Matsuo, Takashi Kaneko, Masatoshi Takagi, Akira Ohara, Yoichi Tanaka, Takahisa Kawaguchi, Daisuke Morita, Yuki Yuza, Setsuo Ota, Masakatsu Yanagimachi, Daisuke Toyama, Yoko Ayukawa, Fumihiko Matsuda, Atsushi Manabe, Junko Takita, Koichi Moriwaki, and Hiroaki Goto
- Subjects
Male ,0301 basic medicine ,Linkage disequilibrium ,Adolescent ,lcsh:Medicine ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Article ,Ikaros Transcription Factor ,Young Adult ,03 medical and health sciences ,Asian People ,Japan ,Humans ,SNP ,Genetic Predisposition to Disease ,Child ,lcsh:Science ,Childhood Acute Lymphoblastic Leukemia ,Genotyping ,Genetic association ,Genetics ,Multidisciplinary ,lcsh:R ,Infant, Newborn ,Infant ,CEBPE ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,DNA-Binding Proteins ,Phosphotransferases (Alcohol Group Acceptor) ,030104 developmental biology ,Genetic Loci ,Child, Preschool ,Female ,lcsh:Q ,Genome-Wide Association Study ,Transcription Factors - Abstract
Genome-wide association studies (GWAS) performed mostly in populations of European and Hispanic ancestry have confirmed an inherited genetic basis for childhood acute lymphoblastic leukemia (ALL), but these associations are less clear in other races/ethnicities. DNA samples from ALL patients (aged 0–19 years) previously enrolled onto a Tokyo Children’s Cancer Study Group trial were collected during 2013–2015, and underwent single nucleotide polymorphism (SNP) microarray genotyping resulting in 527 B-cell ALL for analysis. Cases and control data for 3,882 samples from the Nagahama Study Group and Aichi Cancer Center Study were combined, and association analyses across 10 previous GWAS-identified regions were performed after targeted SNP imputation. Linkage disequilibrium (LD) patterns in Japanese and other populations were evaluated using the varLD score based on 1000 Genomes data. Risk associations for ARID5B (rs10821936, OR = 1.84, P = 6 × 10−17) and PIP4K2A (rs7088318, OR = 0.76, P = 2 × 10−4) directly transferred to Japanese, and the IKZF1 association was detected by an alternate SNP (rs1451367, OR = 1.52, P = 2 × 10−6). Marked regional LD differences between Japanese and Europeans was observed for most of the remaining loci for which associations did not transfer, including CEBPE, CDKN2A, CDKN2B, and ELK3. This study represents a first step towards characterizing the role of genetic susceptibility in childhood ALL risk in Japanese.
- Published
- 2018
37. ATRT-11. PREVALENCE OF GERMLINE VARIANTS IN SMARCB1 INCLUDING SOMATIC MOSAICISM IN AT/RT AND OTHER RHABDOID TUMORS
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Meri Uchiyama, Tomoro Hishiki, Shinichi Tsujimoto, Keita Terashima, Dai Keino, Masahiro Sekiguchi, Yoko Shioda, Takao Deguchi, Shuichi Ito, Kentaro Ohki, Chikako Kiyotani, Daisuke Tomizawa, Hideki Ogiwara, Takako Yoshioka, Hitomi Ueno-Yokohata, Junko Takita, Tomoo Osumi, Toru Uchiyama, Kaoru Yoshida, Motohiro Kato, Kenichiro Watanabe, Nobutaka Kiyokawa, Seishi Ogawa, Masanori Yoshida, Kimikazu Matsumoto, Ryota Shirai, and Hajime Okita
- Subjects
Genetics ,Cancer Research ,Rhabdoid tumors ,Atypical Teratoid/Rhabdoid Tumors ,Single-nucleotide polymorphism ,Biology ,Genome ,Germline ,chemistry.chemical_compound ,Oncology ,Somatic mosaicism ,chemistry ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,Neurology (clinical) ,SMARCB1 ,Gene ,DNA - Abstract
BACKGROUND Genetic hallmark of atypical teratoid/rhabdoid tumor (AT/RT) is loss-of-function variants or deletions in SMARCB1 gene on 22q11.2 chromosome, which is common to extracranial malignant rhabdoid tumors (MRT). Previous studies demonstrated that approximately one-thirds of AT/RT and extracranial MRT patients harbored germline SMARCB1 variants as the rhabdoid tumor predisposing syndrome. We studied herein intensive analysis of the SMARCB1 gene in AT/RT and extracranial MRT patients focusing on prevalence of germline genetic variants. PROCEDURE: In total, 16 patients were included. Both tumor-derived DNA and germline DNA were obtained from all patients. First, screening for SMARCB1 alterations in the tumor specimens was done by direct sequencing, ddPCR and SNP array analysis. Then, analysis of germline DNA samples focusing on the genomic abnormalities detected in the paired tumors in each case was performed. RESULTS In eight of 16 cases (50%), genomic alterations observed in the tumor-derived DNA were also detected in the germline DNA. It is worth noting that three patients had germline mosaicism. Two of three patients had mosaic deletion, including SMARCB1 region, and the average copy number of the deleted region in the SMARCB1 gene in the germline was 1.60 and 1.76. For another patient, the fraction of SMARCB1 variants in normal cells was as low as 1.7%. CONCLUSIONS Approximately half the MRT cases in this study had SMARCB1 germline alterations. Considering the presence of low-frequency mosaicisms which conventional methods might overlook, inherited germline variants in predisposition genes are more important than previously assumed for the pathogenesis of pediatric cancers.
- Published
- 2020
38. A female case of pleuropulmonary blastoma type 1 whose pulmonary cystic lesion was followed since neonate
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Motohiro Kato, Yutaka Kanamori, Kazuteru Kawasaki, Michinobu Ohno, Masafumi Seki, Toshihiko Watanabe, Shunsuke Kimura, Akihiro Fujino, Toshiko Takezoe, Kimikazu Matsumoto, Junko Takita, Masataka Higuchi, Motomi Matsuo, Emi Takakuwa, Rie Irie, Kazunori Tahara, Yoko Shioda, Chikako Kiyotani, Tomoro Hishiki, and Takako Yoshioka
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,lcsh:Surgery ,Pleuropulmonary blastoma ,DICER1 ,03 medical and health sciences ,Cystic lesion ,0302 clinical medicine ,Germline mutation ,CPAM ,medicine ,Cyst ,business.industry ,Cystic lung disease ,lcsh:RJ1-570 ,Congenital pulmonary airway malformation ,lcsh:Pediatrics ,lcsh:RD1-811 ,respiratory system ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Malignant mesenchymal tumor ,Surgery ,Good prognosis ,business ,Pleuropulmonary blastoma type 1 - 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.
- Published
- 2017
39. Pediatric Acute Lymphoblastic Leukemia
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Motohiro Kato and Motohiro Kato
- Subjects
- Human beings, Children, Lymphoblastic leukemia in children, Infants
- Abstract
This book discusses key aspects of childhood acute lymphoblastic leukemia (ALL), presenting the latest research on the biology and treatment of the disease and related issues. The cure rate for ALL has improved dramatically due to advances such as supportive care, treatment stratification based on relapse risk, and the optimization of treatment regimens. Gathering contributions by eminent scholars Pediatric Acute Lymphoblastic Leukemia is a valuable resource for pediatric hematologists as well as for medical students, interns, residents and fellows. It not only offers comprehensive insights, but also provides a springboard for future research.
- Published
- 2020
40. Association of Multiple Gene Polymorphisms Including Homozygous NUDT15 R139C With Thiopurine Intolerance During the Treatment of Acute Lymphoblastic Leukemia.
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Ko Kudo, Tomohiko Sato, Yuka Takahashi, Kentaro Yuzawa, Akie Kobayashi, Takuya Kamio, Shinya Sasaki, Jun Shimada, Katsuki Otani, Shinichi Tusjimoto, Motohiro Kato, Tsutomu Toki, Kiminori Terui, and and Etsuro Ito
- Published
- 2021
- Full Text
- View/download PDF
41. Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans
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Etsuro Ito, Seiji Kojima, Kenichi Yoshida, Rui Yu, Camille Nadler, Paul S. Monks, Asuka Hira, Nicola K. Wilson, Motohiro Kato, Ashley N. Kamimae-Lanning, Satoru Miyano, Hiromasa Yabe, Tomoo Osumi, Minako Mori, Miharu Yabe, Michael R. G. Hodskinson, Minoru Takata, Hideki Muramatsu, Lucas B. Pontel, Seishi Ogawa, Toshinori Moriguchi, Christopher L. Millington, Yusuke Okamoto, Masayuki Kobayashi, Yuichi Shiraishi, Meng Wang, Ketan J. Patel, Frederic Langevin, Berthold Göttgens, Yusuke Okuno, Sam Watcham, Felix A. Dingler, Rebecca Cordell, Keitaro Matsuo, Nina Oberbeck, Anfeng Mu, Wilson, Nicola [0000-0003-0865-7333], Gottgens, Berthold [0000-0001-6302-5705], and Apollo - University of Cambridge Repository
- Subjects
Male ,DNA Repair ,Somatic cell ,medicine.disease_cause ,Substrate Specificity ,purl.org/becyt/ford/1 [https] ,DNA Adducts ,Mice ,0302 clinical medicine ,Child ,IMMUNODEFICIENCY ,0303 health sciences ,Mutation ,Leukemia ,Aldehyde Dehydrogenase, Mitochondrial ,CANCER ,Cell biology ,Child, Preschool ,Female ,Stem cell ,mutagenesis ,Adolescent ,DNA repair ,DNA damage ,AGEING ,Biology ,HEMATOPOIESIS ,DNA DAMAGE ,Article ,03 medical and health sciences ,medicine ,Animals ,Humans ,cancer ,FORMALDEHYDE ,HEMATOPOIETIC STEM CELLS ,purl.org/becyt/ford/1.6 [https] ,Molecular Biology ,030304 developmental biology ,ALDH2 ,Aldehydes ,MUTAGENESIS ,Mutagenesis ,Alcohol Dehydrogenase ,Infant ,ONCOMETABOLITE ,Cell Biology ,medicine.disease ,oncometabolite ,hematopoiesis ,hematopoietic stem cells ,BONE MARROW FAILURE ,ageing ,formaldehyde ,bone marrow failure ,immunodeficiency ,030217 neurology & neurosurgery - Abstract
Summary Reactive aldehydes arise as by-products of metabolism and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a common substrate of ALDH2 and ADH5 and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone-marrow-derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues., Graphical Abstract, Highlights • Toxic levels of genotoxic formaldehyde are produced endogenously in mammals • Two enzymes, ADH5 and ALDH2, are critical for clearance of endogenous formaldehyde • Their loss in mice and humans causes defective hematopoiesis and increased cancer • Elevated formaldehyde causes DNA damage and mutation signature found in many cancers, Dingler et al. show that formaldehyde is produced endogenously at sufficient levels to induce and overwhelm DNA repair. Two enzymes, ADH5 and ALDH2, are critical in clearance of formaldehyde, whose loss results in a bone marrow failure and leukemia syndrome of purely metabolic origin.
- Published
- 2020
42. HGG-49. A PEDIATRIC THALAMIC HIGH-GRADE GLIOMA WITH H3F3A K27M AND BRAF V600E DOUBLE MUTATIONS
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Hiroshi Fuji, Kimikazu Matsumoto, Yoko Shioda, Koichi Ichimura, Keita Terashima, Takako Yoshioka, Yoshiyuki Tsutsumi, Motohiro Kato, Masahiro Sugawa, Kenichi Usami, Hideki Ogiwara, Yoshiko Nakano, Noriyuki Nakano, Daisuke Tomizawa, Kenichi Sakamoto, Tomoo Osumi, Takao Deguchi, and Chikako Kiyotani
- Subjects
BRAF V600E ,Cancer Research ,Oncology ,business.industry ,Cancer research ,Medicine ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,Neurology (clinical) ,business ,High Grade Glioma ,High-Grade Glioma - Abstract
CASE A 18-month-old boy presented with approximately 2 months history of progressive left hemiparesis and left exotropia. MRI study showed a 3–4 cm T1-iso, T2-high tumor at right thalamus to midbrain with little contrast enhancement. The patient underwent endoscopic biopsy of the tumor, which showed relatively dense proliferation of small cells with round nuclei, mitosis of the tumor cell, but no necrosis. Immunohistochemical showed positive stain of GFAP and Olig2. Ki-67 was 34%. The histopathological diagnosis was compatible with high grade glioma. Chemotherapy with vincristine, cyclophosphamide, cisplatin and etoposide was initiated. Molecular testing of the tumor revealed H3F3A K27M and BRAF V600E double mutations in DNA from frozen tumor tissue. DISCUSSION The concurrent mutation of H3F3A K27M and BRAF V600E in pediatric glioma is very rare, but there are several cases previously reported in literature. Interestingly those cases are heterogenous in age, location, histopathological subtypes and clinical outcome.
- Published
- 2020
43. Nationwide study of pediatric B-cell precursor acute lymphoblastic leukemia with chromosome 8q24/MYC rearrangement in Japan
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Takeshi Taketani, Tomohiko Taki, Hidemi Shimonodan, Naoto Fujita, Rie Kanai, Motohiro Kato, Chihaya Imai, Atsushi Manabe, Hisamichi Tauchi, Yoshiko Hashii, Toshihiko Imamura, Keizo Horibe, Sae Ishimaru, Katsuyoshi Koh, Kimiyoshi Sakaguchi, Keiko Okada, Atsushi Sato, Yasuko Kojima, Arata Watanabe, Nobutaka Kiyokawa, Akiko Saito, and Takao Deguchi
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Burkitt lymphoma/leukemia ,Disease ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immunophenotyping ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Lactate dehydrogenase ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Child ,B cell ,Retrospective Studies ,Gene Rearrangement ,Chemotherapy ,business.industry ,Infant ,Chromosome ,Hematology ,Prognosis ,medicine.disease ,immunophenotype ,Lymphoma ,B-cell precursor acute lymphoblastic leukemia ,Leukemia ,medicine.anatomical_structure ,double-hit lymphoma/leukemia ,chemistry ,Child, Preschool ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Female ,8q24/MYC rearrangement ,business ,Chromosomes, Human, Pair 8 ,Follow-Up Studies ,030215 immunology - Abstract
Background Rearrangements of chromosome 8q24/MYC (8q24/MYC-r), resulting from t(8;14)(q24;q32), t(2;8)(p11;q24), or t(8;22)(q24;q11), are mainly associated with Burkitt lymphoma/leukemia (BL) and rarely observed in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The characteristics of BCP-ALL with 8q24/MYC-r are poorly understood. Procedure A retrospective nationwide study of data from patients with pediatric BCP-ALL with 8q24/MYC-r in Japan was conducted to clarify the clinical and biological characteristics associated with 8q24/MYC-r BCP-ALL. Results Ten patients with BCP-ALL with 8q24/MYC-r, including three with double-hit leukemia (DHL) (two with t(8;14)(q24;q32) and t(14;18)(q32;q21) and one with t(8;14) and t(3;22)(q27;q11)), were identified. Patients with BCP-ALL with 8q24/MYC-r had higher median age and uric acid and lactate dehydrogenase levels, than those without 8q24/MYC-r. All patients were initially treated with ALL-type chemotherapy; however, four, including one with DHL, were switched to BL-type chemotherapy, based on cytogenetic findings. One patient relapsed after standard-risk ALL-type chemotherapy, and two patients with DHL did not attain complete remission with chemotherapy; all three died within 11 months. The other seven patients treated with BL-type or high-risk ALL-type chemotherapy are alive without disease. Conclusions The clinical and laboratory features of BL with IG-MYC rearrangement, displaying a BCP immunophenotype (Wagener et al. and Herbrueggen et al. termed it as pre-BLL), are similar to those of BCP-ALL with 8q24/MYC-r. Low-risk ALL-type chemotherapy may not be appropriate for them, and further studies are required to establish an adequate therapeutic strategy. Further studies of DHL to identify new treatment strategies are also needed.
- Published
- 2020
44. A Case of Gorlin-Goltz Syndrome Without the Characteristic Physical Features That Was Diagnosed After the Development of a Fifth Cancer.
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Daisuke Katayama, Akiko Inoue, Rishu Kayatani, Keisuke Urabe, Ryo Suzuki, Kimitaka Takitani, Masanori Yoshida, Motohiro Kato, and Akira Ashida
- Published
- 2022
- Full Text
- View/download PDF
45. Gemtuzumab Ozogamicin Followed by Unrelated Cord Blood Transplantation With Reduced-intensity Conditioning for a Child With Refractory Acute Promyelocytic Leukemia.
- Author
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Yuji Yamada, Tomoo Osumi, Motohiro Kato, Yoko Shioda, Chikako Kiyotani, Keita Terashima, Akira Hayakawa, Yuka Iijima-Yamashita, Keizo Horibe, Kimikazu Matsumoto, and Daisuke Tomizawa
- Published
- 2022
- Full Text
- View/download PDF
46. Successful Umbilical Cord Blood Transplantation With Reduced-intensity Conditioning for Acute Myeloid Leukemia in a Child With Shwachman-Diamond Syndrome.
- Author
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Satoshi Yoshimura, Takanori Mizuno, Tomoo Osumi, Yoko Shioda, Chikako Kiyotani, Keita Terashima, Takao Deguchi, Hisaya Nakadate, Motohiro Kato, Kimikazu Matsumoto, and Daisuke Tomizawa
- Published
- 2021
- Full Text
- View/download PDF
47. ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype
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Yukihide Momozawa, Ryosuke Kajiwara, Akira Ohara, Akitoshi Kinoshita, Atsushi Manabe, Tsuyoshi Morimoto, Yuya Saito, Ai Yoshimi, Junko Takita, Harumi Kakuda, Kenji Matsumoto, Kentaro Ohki, Katsuyoshi Koh, Hitoshi Ichikawa, Hidemitsu Kurosawa, Koich Matsuda, Kenichiro Hata, Hiromi Sakamoto, Moeko Hino, Keisuke Kato, Junya Fujimura, Yuki Yuza, Motohiro Kato, Yoichi Matsubara, Hiroko Ogata-Kawata, Yasushi Noguchi, Kazuki Terada, Koichi Moriwaki, Nobutaka Kiyokawa, Michiaki Kubo, Kozue Nakamura, Kazuo Sakashita, Teruhiko Yoshida, Tomoo Osumi, Shinsuke Hirabayashi, Kohji Okamura, Akinori Yaguchi, Kazuhiko Nakabayashi, and Takashi Fukushima
- Subjects
0301 basic medicine ,Male ,Adolescent ,Oncogene Proteins, Fusion ,CD33 ,Kaplan-Meier Estimate ,Biology ,ZNF384 ,Translocation, Genetic ,Immunophenotyping ,Fusion gene ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,medicine ,Biomarkers, Tumor ,Cluster Analysis ,Humans ,Child ,Exome ,B cell ,Gene Expression Profiling ,Infant, Newborn ,Computational Biology ,High-Throughput Nucleotide Sequencing ,Infant ,Hematology ,Articles ,Prognosis ,Gene expression profiling ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Child, Preschool ,Immunology ,Cancer research ,Trans-Activators ,Female - 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.
- Published
- 2017
48. Prognostic significance of leukopenia in childhood acute lymphoblastic leukemia
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Yusuke Shiozawa, Junko Takita, Katsuyoshi Koh, Manabu Sotomatsu, Kohmei Ida, Yasuhide Hayashi, and Motohiro Kato
- Subjects
Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Leukopenia ,business.industry ,medicine.medical_treatment ,Hazard ratio ,Cancer ,Articles ,medicine.disease ,chemotherapy ,Gastroenterology ,Oncology ,Internal medicine ,childhood acute lymphoblastic leukemia ,Immunology ,medicine ,Dose escalation ,In patient ,medicine.symptom ,business ,Childhood Acute Lymphoblastic Leukemia ,Childhood all ,white blood cell count - Abstract
Chemotherapy-induced leukopenia has been shown to be associated with the outcomes of several types of cancer, but the association with childhood acute lymphoblastic leukemia (ALL) remains unknown. To elucidate the association of chemotherapy-induced leukopenia with the clinical outcome of childhood ALL, retrospective analysis was performed on 19 child patients with ALL treated according to the ALL-BFM 95 high-risk (HR) protocol. The mean minimum leukocyte count over the first three courses of the consolidation phase was used as the measure of hematological toxicity and ranged between 200 and 1,167/μl. The risk of relapse was significantly higher in patients with a mean minimum leukocyte count above the median of 433/μl (hazard ratio, 6.61; P=0.047). In conclusion, chemotherapy-induced leukopenia was found to correlate with relapse-free survival in childhood HR ALL. Dose escalation based on hematologic toxicity must be prospectively studied.
- Published
- 2014
49. Critical brainstem encephalitis/encephalopathy in a child with COVID-19.
- Author
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Ayumi Kunikata, Kenichiro Hayashi, Akiko Kinumaki, Yusuke Akatsuka, Konomi Shimoda, Motohiro Kato, and Hikoro Matsui
- Published
- 2022
- Full Text
- View/download PDF
50. Isolated Central Nervous System Progression During Systemic Treatment With Brentuximab Vedotin Monotherapy in a Pediatric Patient With Recurrent ALK-negative Anaplastic Large Cell Lymphoma.
- Author
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Yuhwa Kim, Akina Sudo, Ryo Oyama, Dai Keino, Daisuke Tomizawa, Motohiro Kato, Tomoo Osumi, and Tetsuya Mori
- Published
- 2021
- Full Text
- View/download PDF
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