Updated on 2024/04/03

写真a

 
MURAMATSU, Hideki
 
Organization
Nagoya University Hospital Pediatrics Lecturer
Graduate School
Graduate School of Medicine
Title
Lecturer

Degree 1

  1. 博士(医学) ( 2010.3   名古屋大学 ) 

Research Interests 3

  1. 小児血液腫瘍免疫不全

  2. Juvenile myelomonocytic leukemia

  3. Transient abnormal myelopoiesis

Research History 2

  1. Nagoya University Hospital   Department of Pediatrics   Lecturer

    2018.5

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    Country:Japan

  2. Nagoya University Hospital   Department of Pediatrics   Assistant Professor

    2010.7 - 2018.4

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    Country:Japan

Education 4

  1. Nagoya University   Graduate School, Division of Medical Sciences

    - 2010.3

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    Country: Japan

  2. Department of Pediatrics, Nagoya University Graduate School of Medicine

    2006.4 - 2010.3

  3. Nagoya University   Faculty of Medicine

    - 2000.3

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    Country: Japan

  4. Nagoya University

    1994.4 - 2000.3

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    Country: Japan

Professional Memberships 7

  1. 小児血液がん学会

  2. 日本人類遺伝学会

  3. 日本免疫不全・自己炎症学会

  4. 日本小児科学会

  5. 日本血液学会

  6. 日本造血・免疫細胞療法学会

  7. American Society of Hematology

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Committee Memberships 4

  1.   日本造血・免疫細胞療法学会 評議員  

       

  2.   日本血液学会 評議員  

       

  3.   日本小児血液がん学会 評議員  

       

  4.   日本免疫不全・自己炎症学会 理事  

       

 

Papers 242

  1. Nanopore sequencing in distinguishing between wild-type and vaccine strains of Varicella-Zoster virus. Reviewed

    Fukuda Y, Suzuki T, Iwata KI, Haruta K, Yamaguchi M, Torii Y, Narita A, Muramatsu H, Takahashi Y, Kawada JI

    Vaccine     2024.3

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    Language:English  

    DOI: 10.1016/j.vaccine.2024.03.046

    PubMed

  2. Novel mutation in KIF23 causing congenital dyserythropoietic anemia type III in patients who underwent allogeneic hematopoietic stem cell transplantation. Reviewed

    Fujikawa T, Uemura S, Hasegawa D, Morisada N, Nakamura S, Kozaki A, Saito A, Kishimoto K, Ishida T, Mori T, Yakushijin K, Katayama Y, Yamashita D, Wakamatsu M, Hamada M, Muramatsu H, Takahashi Y, Kosaka Y

    Pediatric blood & cancer     page: e30736   2024.3

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    Language:English  

    DOI: 10.1002/pbc.30736

    PubMed

  3. Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms. Reviewed

    Sato T, Yoshida K, Toki T, Kanezaki R, Terui K, Saiki R, Ojima M, Ochi Y, Mizuno S, Yoshihara M, Uechi T, Kenmochi N, Tanaka S, Matsubayashi J, Kisai K, Kudo K, Yuzawa K, Takahashi Y, Tanaka T, Yamamoto Y, Kobayashi A, Kamio T, Sasaki S, Shiraishi Y, Chiba K, Tanaka H, Muramatsu H, Hama A, Hasegawa D, Sato A, Koh K, Karakawa S, Kobayashi M, Hara J, Taneyama Y, Imai C, Hasegawa D, Fujita N, Yoshitomi M, Iwamoto S, Yamato G, Saida S, Kiyokawa N, Deguchi T, Ito M, Matsuo H, Adachi S Prof, Hayashi Y, Taga T, Moriya Saito A, Horibe K, Watanabe K, Tomizawa D, Miyano S, Takahashi S, Ogawa S, Ito E

    Blood     2024.3

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    Language:English  

    DOI: 10.1182/blood.2023022247

    PubMed

  4. Pharmacokinetics, safety, and efficacy of 20% subcutaneous immunoglobulin (Ig20Gly) administered weekly or every 2 weeks in Japanese patients with primary immunodeficiency diseases: a phase 3, open-label study Reviewed

    Hirokazu Kanegane, Akifumi Endo, Satoshi Okada, Hidenori Ohnishi, Masataka Ishimura, Ryuta Nishikomori, Kohsuke Imai, Shigeaki Nonoyama, Hideki Muramatsu, Taizo Wada, Atsushi Kuga, Ko Sakamoto, Sharon Russo-Schwarzbaum, Liang-Hui Chu, Barbara McCoy, Zhaoyang Li, Leman Yel

    Immunotherapy Advances     2024.3

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    Publishing type:Research paper (scientific journal)  

    DOI: 10.1093/immadv/ltae001

  5. Scoring system for diagnosis and pretreatment risk assessment of neuroblastoma using urinary biomarker combinations. Reviewed

    Amano H, Uchida H, Harada K, Narita A, Fumino S, Yamada Y, Kumano S, Abe M, Ishigaki T, Sakairi M, Shirota C, Tainaka T, Sumida W, Yokota K, Makita S, Karakawa S, Mitani Y, Matsumoto S, Tomioka Y, Muramatsu H, Nishio N, Osawa T, Taguri M, Koh K, Tajiri T, Kato M, Matsumoto K, Takahashi Y, Hinoki A

    Cancer science     2024.2

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    Language:English  

    DOI: 10.1111/cas.16116

    PubMed

  6. A retrospective analysis of gene fusions and treatment outcomes in pediatric acute megakaryoblastic leukemia without Down syndrome. Reviewed

    Suzuki K, Hama A, Okuno Y, Xu Y, Narita A, Yoshida N, Muramatsu H, Nishio N, Kato K, Kojima S, Yoo KH, Takahashi Y

    Haematologica     2024.2

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    Language:English  

    DOI: 10.3324/haematol.2023.283760

    PubMed

  7. Myeloproliferative disorder in a patient with RIT1-associated Noonan syndrome: Case report and literature review. Reviewed

    Suzuki K, Wakamatsu M, Ito Y, Ishikawa M, Shimotakahara A, Futagawa H, Yamamoto Y, Nagamine H, Saito O, Muramatsu H, Yuza Y

    Pediatric blood & cancer   Vol. 71 ( 2 ) page: e30780   2024.2

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    Language:English  

    DOI: 10.1002/pbc.30780

    PubMed

  8. Allogeneic Hematopoietic Cell Transplantation for Juvenile Myelomonocytic Leukemia with a Busulfan, Fludarabine, and Melphalan Regimen: JPLSG JMML-11. Reviewed

    Sakashita K, Yoshida N, Muramatsu H, Ohtsuka Y, Watanabe K, Yabe M, Kakuda H, Honda Y, Watanabe T, Haba M, Ohmori S, Matsuda K, Yuza Y, Saito A, Horibe K, Adachi S, Manabe A

    Transplantation and cellular therapy   Vol. 30 ( 1 ) page: 105.e1 - 105.e10   2024.1

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    Language:English  

    DOI: 10.1016/j.jtct.2023.10.002

    PubMed

  9. Noonan Syndrome-related Myeloproliferative Disorder Occurring in the Neonatal Period: Case Report and Literature Review. Reviewed International journal

    Yuki Hoshino, Kunihiko Moriya, Kanako Mitsui-Sekinaka, Yu Hashimoto, Satoshi Nakayama, Daichi Sajiki, Hideki Muramatsu, Hidetoshi Hagiwara, Shuichi Suzuki, Yujin Sekinaka, Hajime Wakamatsu, Hiroyuki Kawaguchi, Kohsuke Imai

    Journal of pediatric hematology/oncology     2023.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    Noonan syndrome-related myeloproliferative disorder (NS/MPD) and juvenile myelomonocytic leukemia (JMML) are rare MPDs that occur in young children. We herein report a case of NS/MPD with neonatal onset. The patient had a characteristic appearance and high monocyte count in the peripheral blood and bone marrow. Genetic testing showed the E139D mutation in PTPN11; however, the patient did not meet all the diagnostic criteria for JMML, and we thus diagnosed him with NS/MPD. Eight other cases of NS/MPD with neonatal onset are also summarized. The initial presentation varied, and the prognosis was considered poor compared with previous reports of NS/MPD.

    DOI: 10.1097/MPH.0000000000002803

    PubMed

  10. A Japanese retrospective study of non-tuberculous mycobacterial infection in children, adolescents, and young adult patients with hematologic-oncologic diseases. Reviewed International journal

    Yusuke Tsumura, Hideki Muramatsu, Nobuyuki Tetsuka, Takahiro Imaizumi, Kikue Sato, Kento Inoue, Yoshitomo Motomura, Yuko Cho, Daiki Yamashita, Daichi Sajiki, Ryo Maemura, Ayako Yamamori, Masayuki Imaya, Manabu Wakamatsu, Kotaro Narita, Shinsuke Kataoka, Motoharu Hamada, Rieko Taniguchi, Eri Nishikawa, Atsushi Narita, Nobuhiro Nishio, Seiji Kojima, Yoshihiko Hoshino, Yoshiyuki Takahashi

    Haematologica     2023.10

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    Language:English   Publishing type:Research paper (scientific journal)  

    Non-tuberculous mycobacterial infection (NTM) is rare in healthy children, with lymphadenitis being the most common presentation. Immunocompromised populations are known to be at high risk, but the clinical picture of NTM infection in pediatric hematology/oncology patients is unclear. In this nationwide retrospective analysis of patients under the age of 40 treated in Japanese pediatric hematology/oncology departments who developed NTM infection between January 2010 and December 2020, 36 patients (21 patients with hematopoietic stem cell transplantation (HSCT) and 15 nontransplant patients) were identified. Post-transplant patients were infected with NTM at 24 sites, including the lungs (n = 12), skin and soft tissues (n = 6), bloodstream (n = 4), and others (n = 2). Nine of twelve patients with pulmonary NTM infection had a history of pulmonary graft-versus-host disease (GVHD), and rapid-growing mycobacteria (RGM) were isolated from five of them. In nontransplant patients, the primary diseases were acute lymphoblastic leukemia (ALL; n = 5), inborn errors of immunity (IEI; n = 6), and others (n = 4). All cases of ALL had bloodstream infections with RGM, whereas all cases of IEI were infected with slow-growing mycobacteria (SGM). In summary, three typical clinical scenarios for pediatric hematology/oncology patients have been established: RGM-induced pulmonary disease in patients with pulmonary GVHD, RGM bloodstream infection in patients with ALL, and SGM infection in patients with IEI. Our findings suggest that NTM must be regarded as a pathogen for infections in these high-risk patients, especially those with pulmonary GVHD, who may require active screening for NTM.

    DOI: 10.3324/haematol.2023.283636

    PubMed

  11. Severe β-thalassemia (Hb Zunyi) mimicking congenital dyserythropoietic anemia. Reviewed International journal

    Jun Nagahama, Takuro Nishikawa, Tatsuro Nakamura, Shunsuke Nakagawa, Yuichi Kodama, Hideyuki Terazono, Manabu Wakamatsu, Hideki Muramatsu, Yasuhiro Yamashiro, Hitoshi Kanno, Yasuhiro Okamoto

    Pediatric blood & cancer   Vol. 70 ( 12 ) page: e30706   2023.10

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    DOI: 10.1002/pbc.30706

    PubMed

  12. Successful treatment of DOCK8 deficiency by allogeneic hematopoietic cell transplantation from alternative donors Reviewed

    Kono A., Wakamatsu M., Umezawa Y., Muramatsu H., Fujiwara H., Tomomasa D., Inoue K., Hattori K., Mitsui T., Takada H., Minegishi Y., Takahashi Y., Yamamoto M., Mori T., Kanegane H.

    International Journal of Hematology   Vol. 118 ( 4 ) page: 519 - 525   2023.10

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    Publisher:International Journal of Hematology  

    Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare autosomal recessive inborn error of immunity (IEI) characterized by eczematous dermatitis, elevated serum IgE, and recurrent infections, comprising a seemingly hyper-IgE syndrome (HIES). DOCK8 deficiency is only curable with allogeneic hematopoietic cell transplantation (HCT), but the outcome of HCT from alternative donors is not fully understood. Here, we describe the cases of two Japanese patients with DOCK8 deficiency who were successfully treated by allogeneic HCT from alternative donors. Patient 1 underwent cord blood transplantation at the age of 16 years, and Patient 2 underwent haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide at the age of 22 years. Each patient received a fludarabine-based conditioning regimen. Their clinical manifestations, including refractory molluscum contagiosum, promptly improved post-HCT. They achieved successful engraftment and immune reconstitution without serious complications. Alternative donor sources such as cord blood and haploidentical donors can be options for allogeneic HCT for DOCK8 deficiency.

    DOI: 10.1007/s12185-023-03613-y

    Scopus

  13. Pediatric erythroblastic transformation of JAK2-mutated prefibrotic primary myelofibrosis with concurrent PHF6 mutations Reviewed

    Oshiro T., Hamada S., Kiyuna S., Sakiyama H., Hyakuna N., Tamaki T., Muramatsu H., Nakanishi K.

    Pediatric Blood and Cancer   Vol. 70 ( 10 )   2023.10

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    Publisher:Pediatric Blood and Cancer  

    DOI: 10.1002/pbc.30508

    Scopus

  14. Updated guidelines for chronic active Epstein–Barr virus disease Reviewed

    Jun-ichi Kawada, Yoshinori Ito, Koichi Ohshima, Masaki Yamada, Shinsuke Kataoka, Hideki Muramatsu, Akihisa Sawada, Taizo Wada, Ken-Ichi Imadome, Ayako Arai, Keiji Iwatsuki, Shouichi Ohga, Hiroshi Kimura

    International Journal of Hematology     2023.9

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    Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abstract

    Chronic active Epstein–Barr virus disease (CAEBV), formerly named chronic active Epstein–Barr virus infection, is characterized by systemic inflammation and clonal proliferation of Epstein–Barr virus (EBV)-infected T or NK cells. As CAEBV is a potentially life-threatening illness, appropriate diagnosis and therapeutic interventions are necessary for favorable clinical outcomes. Substantial evidence regarding the pathogenesis and treatment of CAEBV has been accumulated since previous guidelines for the diagnosis of CAEBV were proposed. To reflect this evidence, we updated the guidelines for the diagnosis and treatment of CAEBV to improve clinical management of the disease. The details of the updated guidelines are presented in this report. Diagnosis of CAEBV now requires confirmation of a high copy number of EBV genome and EBV-infected T or NK cells. An EBV DNA load ≥ 10,000 IU/mL in whole blood is proposed as the diagnostic cutoff value for CAEBV in this updated guideline. A standard treatment approach for CAEBV has not been established, and hematopoietic stem cell transplantation (HSCT) is considered the only curative treatment. Chemotherapy can be administered to control disease activity before HSCT.

    DOI: 10.1007/s12185-023-03660-5

    Scopus

    Other Link: https://link.springer.com/article/10.1007/s12185-023-03660-5/fulltext.html

  15. Vedolizumab for children with intestinal graft-versus-host disease: a case report and literature review Reviewed

    Fukuta T., Muramatsu H., Yamashita D., Sajiki D., Maemura R., Tsumura Y., Yamamori A., Imaya M., Wakamatsu M., Nishikawa E., Narita K., Kataoka S., Taniguchi R., Narita A., Nishio N., Takahashi Y.

    International Journal of Hematology   Vol. 118 ( 3 ) page: 411 - 417   2023.9

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    Publisher:International Journal of Hematology  

    Acute graft-versus-host disease (aGVHD) is a challenging complication of allogeneic hematopoietic stem cell transplantation, and alternative therapies for patients showing inadequate response to steroids are limited. Vedolizumab, an anti-α4β7 integrin antibody widely used for treating inflammatory bowel diseases, has recently been studied in adult patients with steroid-refractory intestinal aGVHD. However, few studies have examined its safety and effectiveness in pediatric patients with intestinal aGVHD. We report the case of a male patient with intestinal late-onset aGVHD treated with vedolizumab. He underwent allogeneic cord blood transplantation for warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome and developed intestinal late-onset aGVHD 31 months after transplantation. The patient was refractory to steroids; however, vedolizumab was initiated 43 months after transplantation (at the age of 7 years) and the symptoms of intestinal aGVHD were alleviated. Additionally, favorable endoscopic findings were observed, such as reduction of erosion and regenerative epithelial growth. We also evaluated the efficacy of vedolizumab in 10 patients with intestinal aGVHD (9 from the literature review and the present case). Six patients (60%) showed an objective response to vedolizumab. No serious adverse events were observed in any patients. Vedolizumab is a potential treatment option for steroid-refractory intestinal aGVHD in pediatric patients.

    DOI: 10.1007/s12185-023-03590-2

    Scopus

  16. Two Cases of Juvenile Myelomonocytic Leukemia and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease Reviewed

    Yamamoto H., Natsume J., Kaneko K., Takahashi T., Wakamatsu M., Ogawa C., Kumai S., Suzui R., Sawamura F., Shiraki A., Nakata T., Kidokoro H., Muramatsu H., Takahashi Y.

    Pediatric Neurology   Vol. 144   page: 1 - 4   2023.7

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    Publisher:Pediatric Neurology  

    Background: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an autoimmune demyelinating disorder that often manifests after infections or vaccinations. We report two patients who developed MOGAD out of eight patients with juvenile myelomonocytic leukemia (JMML) that has never been reported. Methods: We investigated two patients with JMML who developed MOGAD among 127 patients with leukemia from 2012 to 2021. Results: Patient 1 was treated for JMML and developed fever and impaired consciousness at two years and one month of age. Magnetic resonance imaging revealed high-intensity lesions in the left frontal and left occipital white matter. The serum anti-MOG antibody test was positive, while the test was negative in the stored serum 45 days before the onset of encephalopathy. He had relapse of MOGAD after steroid therapy and plasmapheresis. Patient 2, who was treated for JMML, became apathetic and mute at three years and seven months of age. Magnetic resonance imaging revealed left frontoparietal subcortical high-intensity lesions. Anti-MOG antibody at the onset of encephalopathy was positive, while it was negative in stored serum 57 days before and 47 days after the onset. Conclusion: We treated two patients who developed MOGAD out of eight patients with JMML and none with MOGAD out of 119 patients with acute lymphocytic leukemia, acute myelocytic leukemia, or chronic myelocytic leukemia. The activated autoimmune process via the RAS pathway abnormality may have led to the formation of the anti-MOG antibody and the onset of MOGAD. MOGAD can occur in children with JMML, and abnormalities of the RAS pathway possibly contribute to its onset.

    DOI: 10.1016/j.pediatrneurol.2023.03.002

    Scopus

  17. Human leukocyte antigen 7/8-matched unrelated bone marrow transplantation using anti-thymocyte globulin in children Reviewed

    Hamada M., Muramatsu H., Torii Y., Suzuki K., Narita A., Yoshida T., Imaya M., Yamamori A., Wakamatsu M., Miwata S., Narita K., Kataoka S., Kawashima N., Taniguchi R., Nishikawa E., Nishio N., Ito Y., Kojima S., Takahashi Y.

    International Journal of Hematology   Vol. 118 ( 1 ) page: 125 - 130   2023.7

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    Publisher:International Journal of Hematology  

    Human leukocyte antigen (HLA) mismatched unrelated donor transplantation is associated with an increased risk of graft-versus-host disease, graft failure, and infection, which increases post-transplant morbidity and mortality. In this single-center retrospective study, outcomes were evaluated in 30 consecutive children who underwent bone marrow transplantation (BMT) from HLA 1 allele-mismatched (HLA 7/8-matched) unrelated donors with rabbit anti-thymocyte globulin (rATG) as graft-versus-host disease (GVHD) prophylaxis. The 3-year overall survival (OS), event-free survival (EFS), and GVHD-relapse-free survival rates were 91.7% (95% CI 70.5%–91.9%), 88.3% (95% CI 67.5%–96.1%), and 73.9% (95% CI 52.4%–86.8%), respectively. Grade II–IV and III–IV acute GVHD occurred in 10 (33%) and 2 (7.0%) patients, respectively. The 3-year cumulative incidence of chronic GVHD was 7.8%. No fatal viral infections occurred. The study results show the feasibility of HLA 7/8-matched unrelated BMT with ATG to achieve favorable outcomes and acceptable GVHD, especially for patients who lack a fully matched donor.

    DOI: 10.1007/s12185-023-03571-5

    Scopus

  18. Successful living-donor liver transplantation for sustained liver failure even after resolution of infiltrative massive hepatic invasion of stage 4S neuroblastoma: a case report. Reviewed International journal

    Kanta Jobara, Ayako Yamamori, Masato Shizuku, Nobuhiko Kurata, Yasuhiro Fujimoto, Hideki Muramatsu, Yoshiyuki Takahashi, Yasuhiro Ogura

    Surgical case reports   Vol. 9 ( 1 ) page: 100 - 100   2023.6

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    Language:English   Publishing type:Research paper (scientific journal)  

    BACKGROUND: Neuroblastoma is the most common extracranial solid tumor in childhood. Stage 4S neuroblastoma is a unique subset of neuroblastoma characterized by a favorable course and potentially low malignancy with a high rate of spontaneous tumor regression. However, recent reports have shown that there is a subgroup of patients with stage 4S neuroblastoma characterized by MYCN amplification, chromosomal aberrations, age of < 2 months at diagnosis, and significantly poorer outcomes. CASE PRESENTATION: A 1-month-old male infant with a huge abdominal tumor was transferred to our hospital and diagnosed with stage 4S neuroblastoma. The patient showed respiratory distress due to abdominal compartment syndrome secondary to massive hepatic invasion, and he required a silo operation and mechanical ventilation. After chemotherapy using carboplatin and etoposide, the infiltrative massive hepatic invasion was resolved and the abdominal compartment syndrome gradually improved; however, liver dysfunction as evidenced by hyperbilirubinemia, coagulopathy, and hyperammonemia continued. At the age of 3 months, living-donor liver transplantation was performed for treatment of sustained liver failure using a reduced lateral segment graft from the patient's father. Post-transplant liver function recovered immediately. Examination of the explanted liver demonstrated that the majority of liver tissue had been replaced by fibroblastic cells after massive hepatocyte dropout. There were only small areas of residual neuroblastoma cells in the liver specimen. The patient was discharged from the hospital 5 months after transplantation with home intermittent respiratory support. At the time of this writing (23 months after liver transplantation), he was in good condition with no signs of recurrence of neuroblastoma. CONCLUSIONS: We have herein presented a case of successful pediatric living-donor liver transplantation for sustained liver failure even after resolution of infiltrative massive hepatic invasion of stage 4S neuroblastoma. Our case clearly shows that liver transplantation can be added as an appropriate extended treatment option for liver failure after resolution of stage 4S neuroblastoma.

    DOI: 10.1186/s40792-023-01681-0

    PubMed

  19. Neonatal intestinal obstruction in Hoyeraal–Hreidarsson syndrome with novel RTEL1 variants Reviewed

    Tobai H., Endo M., Ishimura M., Moriya K., Yano J., Kanamori K., Sato N., Amanuma F., Maruyama H., Muramatsu H., Shibahara J., Narita M., Fumoto S., Peltier D., Ohga S.

    Pediatric Blood and Cancer   Vol. 70 ( 6 )   2023.6

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    Publisher:Pediatric Blood and Cancer  

    DOI: 10.1002/pbc.30250

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  20. Efficacy and safety of bevacizumab, irinotecan, and temozolomide combination for relapsed or refractory pediatric central nervous system embryonal tumor: a single-institution study Reviewed

    Shiba Y., Motomura K., Taniguchi R., Kurimoto M., Mizutani K., Ohka F., Aoki K., Ito E., Nishikawa T., Yamaguchi J., Kibe Y., Shimizu H., Maeda S., Nakashima T., Suzuki H., Muramatsu H., Takahashi Y., Saito R.

    Journal of Neurosurgery: Pediatrics   Vol. 31 ( 6 ) page: 624 - 632   2023.6

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    Publisher:Journal of Neurosurgery: Pediatrics  

    OBJECTIVE This study aimed to evaluate the efficacy and safety of combination therapy with bevacizumab (Bev), irinotecan (CPT-11), and temozolomide (TMZ) in children with central nervous system (CNS) embryonal tumor relapse. METHODS The authors retrospectively examined 13 consecutive pediatric patients with relapsed or refractory CNS embryonal tumors who received combination therapy comprising Bev, CPT-11, and TMZ. Specifically, 9 patients had medulloblastoma, 3 had atypical teratoid/rhabdoid tumor (AT/RT), and 1 had CNS embryonal tumor with rhabdoid features. Of the 9 medulloblastoma cases, 2 were categorized in the Sonic hedgehog subgroup and 6 in molecular subgroup 3 for medulloblastoma. RESULTS The complete and partial objective response rates were 66.6% in patients with medulloblastoma and 75.0% in patients with AT/RT or CNS embryonal tumors with rhabdoid features. Furthermore, the 12- and 24-month progression-free survival rates were 69.2% and 51.9% for all patients with recurrent or refractory CNS embryonal tumors, respectively. In contrast, the 12- and 24-month overall survival rates were 67.1% and 58.7%, respectively, for all patients with relapsed or refractory CNS embryonal tumors. The authors observed grade 3 neutropenia, thrombocytopenia, proteinuria, hypertension, diarrhea, and constipation in 23.1%, 7.7%, 23.1%, 7.7%, 7.7%, and 7.7% of patients, respectively. Furthermore, grade 4 neutropenia was observed in 7.1% of patients. Nonhematological adverse effects, such as nausea and constipation, were mild and controlled with standard antiemetics. CONCLUSIONS This study demonstrated favorable survival outcomes in patients with relapsed or refractory pediatric CNS embryonal tumors and thus helped to investigate the efficacy of combination therapy comprising Bev, CPT-11, and TMZ. Moreover, combination chemotherapy had high objective response rates, and all adverse events were tolerable. To date, data supporting the efficacy and safety of this regimen in the relapsed or refractory AT/RT population are limited. These findings suggest the potential efficacy and safety of combination chemotherapy in patients with relapsed or refractory pediatric CNS embryonal tumors.

    DOI: 10.3171/2023.1.PEDS22345

    Scopus

  21. Droplet Digital PCR Development for Adenovirus Load Monitoring in Children after Hematopoietic Stem Cell Transplantation Reviewed

    Haruta K., Takeuchi S., Yamaguchi M., Horiba K., Suzuki T., Torii Y., Narita A., Muramatsu H., Takahashi Y., Ito Y., Kawada J.i.

    Journal of Molecular Diagnostics   Vol. 25 ( 6 ) page: 403 - 409   2023.6

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    Publisher:Journal of Molecular Diagnostics  

    Human adenovirus (AdV) reactivation after hematopoietic stem cell transplantation (HSCT) is associated with life-threatening clinical manifestations. Although real-tme quantitative PCR (qPCR) has been widely used to measure AdV loads, it has not been standardized for AdV. Droplet digital PCR (ddPCR) is a novel pathogen detection technology that enables the absolute quantification of viral loads. ddPCR would enable a more accurate AdV DNA detection compared with qPCR. In this study, ddPCR was developed for AdV DNA and its performance characteristics compared with those of qPCR. AdV DNAemia incidence during the first 12 weeks after allogenic HSCT was then retrospectively examined by qPCR and ddPCR in 97 HSCT procedures using the preserved 545 DNA samples. ddPCR exhibited better reproducibility and sensitivity, as well as equivalent quantifiability, compared with qPCR. AdV DNA among HSCT patients was detected in 11 (2.0%) and 49 (9.0%) of 545 samples by qPCR and ddPCR, respectively. AdV DNA levels >1000 copies/mL were observed in five cases by qPCR and/or ddPCR. However, two patients developed fulminant hepatitis and died; other patients remained asymptomatic with subsequently undetectable AdV DNA. In conclusion, ddPCR was more sensitive and reproducible in detecting AdV DNA among pediatric HSCT recipients than qPCR. ddPCR offers the potential to provide a more accurate DNAemia detection, determine cutoff values for treatment initiation, and enable antiviral efficacy assessment.

    DOI: 10.1016/j.jmoldx.2023.03.004

    Scopus

  22. Juvenile Hemochromatosis with Non-Transfused Hemolytic Anemia Caused by a de Novo PIEZO1 Gene Mutation Reviewed

    Imashuku S., Suemori S.I., Wakamatsu M., Okuno Y., Muramatsu H., Makino S., Miyoshi T., Chonabayashi K., Kanno H.

    Journal of Pediatric Hematology/Oncology   Vol. 45 ( 4 ) page: E510 - E513   2023.5

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    Publisher:Journal of Pediatric Hematology/Oncology  

    Differential diagnosis of juvenile hemochromatosis along with hemolytic anemia is often difficult. We report a 23-year-old woman with macrocytic hemolytic anemia with iron overload. The patient showed high serum ferritin and transferrin saturation and low serum transferrin and ceruloplasmin. We also noticed stomatocytes in her blood smear, which was confirmed by scanning electron microscopy. Target gene sequencing identified a mutation in PIEZO1 (heterozygous c.6008C>A: p.A2003D). This mutation was reported previously in a family with dehydrated hereditary stomatocytosis (DHS1, [OMIM 194380]), but in the current case, it was identified to be a de novo mutation. We underscore DHS1 in the differential diagnosis of iron overload associated with non-Transfused hemolytic anemia in children and young adults.

    DOI: 10.1097/MPH.0000000000002639

    Scopus

  23. Haematopoietic cell transplantation for children with acute megakaryoblastic leukaemia without Down syndrome Reviewed

    Hama A., Taga T., Tomizawa D., Muramatsu H., Hasegawa D., Adachi S., Yoshida N., Noguchi M., Sato M., Okada K., Koh K., Mitsui T., Takahashi Y., Miyamura T., Hashii Y., Kato K., Atsuta Y., Okamoto Y.

    British Journal of Haematology   Vol. 201 ( 4 ) page: 747 - 756   2023.5

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    Publisher:British Journal of Haematology  

    Patients with acute megakaryoblastic leukaemia of Down syndrome (DS-AMKL) have an excellent survival rate; however, patients with non-DS-AMKL experience poor outcomes. Therefore, this study retrospectively analysed 203 children with non-DS-AMKL who underwent their first haematopoietic cell transplantation (HCT) from 1986 to 2015 using a nationwide Japanese HCT registry data to assess HCT outcomes for non-DS-AMKL. The 5-year overall survival (OS) and event-free survival (EFS) rates were 43% and 38% respectively. The 5-year OS rate was significantly higher for patients who underwent HCT in the first complete remission (CR1, 72%) than for those in the second CR (CR2, 23%) and non-CR (16%) (p < 0.001), and for those from a human leukocyte antigen (HLA)-matched (52%) than for those from an HLA-mismatched donor (27%) (p < 0.001). Multivariate analysis for OS revealed that HCT in CR2 and non-CR was a significant risk factor (hazard ratio, 5.86; 95% confidence interval, 3.56–9.53; p < 0.001). The 3-year EFS in patients who received HCT in CR1 using reduced-intensity conditioning (RIC, 35%) was significantly lower than in those using myeloablative conditioning (busulfan-based, 71%; total body irradiation-based, 58%) (p < 0.001). Risk stratification in patients with non-DS-AMKL should be established to determine HCT indication in CR1.

    DOI: 10.1111/bjh.18691

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  24. Germline and somatic RUNX1 variants in a pediatric bone marrow failure cohort Reviewed

    Yamamori A., Hamada M., Muramatsu H., Wakamatsu M., Hama A., Narita A., Tsumura Y., Yoshida T., Doi T., Terada K., Higa T., Yamamoto N., Miura H., Shiota M., Watanabe K., Yoshida N., Maemura R., Imaya M., Miwata S., Narita K., Kataoka S., Taniguchi R., Suzuki K., Kawashima N., Nishio N., Iwafuchi H., Ito M., Kojima S., Okuno Y., Takahashi Y.

    American Journal of Hematology   Vol. 98 ( 5 ) page: E102 - E105   2023.5

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    Publisher:American Journal of Hematology  

    DOI: 10.1002/ajh.26874

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  25. 愛知県における副腎白質ジストロフィーの拡大新生児マススクリーニングの現状と課題 Reviewed

    中田 智彦, 伊藤 祐史, 村松 秀城, 山本 啓之, 城所 博之, 久保田 一生, 山田 晋一郎, 勝野 雅央, 伊藤 哲哉, 下澤 伸行, 夏目 淳

    脳と発達   Vol. 55 ( Suppl. ) page: S314 - S314   2023.5

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  26. A nationwide survey of late effects in survivors of juvenile myelomonocytic leukemia in Japan Reviewed

    Ozono S., Sakashita K., Yoshida N., Kakuda H., Watanabe K., Maeda M., Ishida Y., Manabe A., Taga T., Muramatsu H.

    Pediatric Blood and Cancer   Vol. 70 ( 2 )   2023.2

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    We conducted a cross-sectional study using a questionnaire to explore the late effects in survivors of allogenic hematopoietic stem cell transplantation (HSCT) for juvenile myelomonocytic leukemia (JMML). The attending pediatric hematologists/oncologists completed the questionnaires. Of the 30 survivors, approximately 83% showed more than one late effect. The identified late effects included endocrine, dental, skin, ophthalmologic, musculoskeletal, pulmonary, neurocognitive, and cardiovascular dysfunction. The prevalence of short stature, pulmonary, cardiovascular, and nephrological complications was significantly elevated among survivors who were 12 years or more lapsed after HSCT. Therefore, a multidisciplinary follow-up system for survivors of JMML is crucial.

    DOI: 10.1002/pbc.30126

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  27. Japanese siblings with cartilage-hair hypoplasia exhibiting different severity Reviewed

    Kumagai N., Funato Y., Wakamatsu M., Muramatsu H., Mizuno H.

    Pediatrics International   Vol. 65 ( 1 )   2023.1

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    Publisher:Pediatrics International  

    DOI: 10.1111/ped.15557

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  28. Late gastroenterological complications in children after allogeneic hematopoietic stem cell transplantation: A retrospective cohort study and a case series of children treated with Kampo medicines Reviewed

    Nozomu Kawashima, Shinsuke Kataoka, Motoharu Hamada, Eri Nishikawa, Rieko Taniguchi, Atsushi Narita, Hideki Muramatsu, Nobuhiro Nishio, Yoshiyuki Takahashi

    Traditional and Kampo Medicine     2023

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    Publishing type:Research paper (scientific journal)  

    Aim: This study aimed to describe children developing late gastrointestinal (GI) complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT), focusing on Kampo medicine. Methods: At the Nagoya University Hospital Department of Pediatrics, 179 consecutive patients underwent allo-HSCT over five years, of whom 167 achieved engraftment and survived at least 100 days post transplant and therefore were included in the study. Results: Thirteen patients (7.8%) developed late GI symptoms. Among these, three had upper GI symptoms, three had lower GI symptoms, while seven had upper/lower GI symptoms. Total parenteral nutrition was administered in 10 (77%) patients for a median of 81 days (range: 20–303). Four (31%) had histologically proven graft-versus-host-disease (GVHD), two (15%) had adverse drug reactions, and one (8%) had a viral infection. All three patients with lower GI symptoms responded to Kampo formulas' warming interior [TM1]. Two patients with upper GI symptoms had epigastric rigidity and responded to Aurantii Fructus Immaturus-based formulas. One patient developed severe cachexia, which was successfully reversed with Kampo medicines. There were no adverse effects due to Kampo medicines. Conclusions: Late GI complications may be a burden on children after allo-HSCT. Kampo medicines may provide a safe and promising therapy to resolve GI symptoms not otherwise specified.

    DOI: 10.1002/tkm2.1392

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  29. Whole-exome analysis of 177 pediatric patients with undiagnosed diseases Reviewed

    Narita K., Muramatsu H., Narumi S., Nakamura Y., Okuno Y., Suzuki K., Hamada M., Yamaguchi N., Suzuki A., Nishio Y., Shiraki A., Yamamori A., Tsumura Y., Sawamura F., Kawaguchi M., Wakamatsu M., Kataoka S., Kato K., Asada H., Kubota T., Muramatsu Y., Kidokoro H., Natsume J., Mizuno S., Nakata T., Inagaki H., Ishihara N., Yonekawa T., Okumura A., Ogi T., Kojima S., Kaname T., Hasegawa T., Saitoh S., Takahashi Y.

    Scientific Reports   Vol. 12 ( 1 )   2022.12

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    Recently, whole-exome sequencing (WES) has been used for genetic diagnoses of patients who remain otherwise undiagnosed. WES was performed in 177 Japanese patients with undiagnosed conditions who were referred to the Tokai regional branch of the Initiative on Rare and Undiagnosed Diseases (IRUD) (TOKAI-IRUD). This study included only patients who had not previously received genome-wide testing. Review meetings with specialists in various medical fields were held to evaluate the genetic diagnosis in each case, which was based on the guidelines of the American College of Medical Genetics and Genomics. WES identified diagnostic single-nucleotide variants in 66 patients and copy number variants (CNVs) in 11 patients. Additionally, a patient was diagnosed with Angelman syndrome with a complex clinical phenotype upon detection of a paternally derived uniparental disomy (UPD) [upd(15)pat] wherein the patient carried a homozygous DUOX2 p.E520D variant in the UPD region. Functional analysis confirmed that this DUOX2 variant was a loss-of-function missense substitution and the primary cause of congenital hypothyroidism. A significantly higher proportion of genetic diagnoses was achieved compared to previous reports (44%, 78/177 vs. 24–35%, respectively), probably due to detailed discussions and the higher rate of CNV detection.

    DOI: 10.1038/s41598-022-14161-6

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  30. Clinical parameter-based prediction of DNA methylation classification generates a prediction model of prognosis in patients with juvenile myelomonocytic leukemia Reviewed

    Imaizumi T., Meyer J., Wakamatsu M., Kitazawa H., Murakami N., Okuno Y., Yoshida T., Sajiki D., Hama A., Kojima S., Takahashi Y., Loh M., Stieglitz E., Muramatsu H.

    Scientific Reports   Vol. 12 ( 1 )   2022.12

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    Juvenile myelomonocytic leukemia (JMML) is a rare heterogeneous hematological malignancy of early childhood characterized by causative RAS pathway mutations. Classifying patients with JMML using global DNA methylation profiles is useful for risk stratification. We implemented machine learning algorithms (decision tree, support vector machine, and naïve Bayes) to produce a DNA methylation-based classification according to recent international consensus definitions using a well-characterized pooled cohort of patients with JMML (n = 128). DNA methylation was originally categorized into three subgroups: high methylation (HM), intermediate methylation (IM), and low methylation (LM), which is a trichotomized classification. We also dichotomized the subgroups as HM/IM and LM. The decision tree model showed high concordances with 450k-based methylation [82.3% (106/128) for the dichotomized and 83.6% (107/128) for the trichotomized subgroups, respectively]. With an independent cohort (n = 72), we confirmed that these models using both the dichotomized and trichotomized classifications were highly predictive of survival. Our study demonstrates that machine learning algorithms can generate clinical parameter-based models that predict the survival outcomes of patients with JMML and high accuracy. These models enabled us to rapidly and effectively identify candidates for augmented treatment following diagnosis.

    DOI: 10.1038/s41598-022-18733-4

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  31. TREC/KREC Newborn Screening followed by Next-Generation Sequencing for Severe Combined Immunodeficiency in Japan Reviewed

    Wakamatsu M., Kojima D., Muramatsu H., Okuno Y., Kataoka S., Nakamura F., Sakai Y., Tsuge I., Ito T., Ueda K., Saito A., Morihana E., Ito Y., Ohashi N., Tanaka M., Tanaka T., Kojima S., Nakajima Y., Ito T., Takahashi Y.

    Journal of Clinical Immunology   Vol. 42 ( 8 ) page: 1696 - 1707   2022.11

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    Purpose: The aim of this study is to evaluate the usefulness of T cell receptor excision circle (TREC) and/or kappa-deleting recombination excision circle (KREC) measurements integrated with diagnostic next-generation sequencing (NGS) analysis using a severe combined immunodeficiency (SCID) newborn screening (NBS) program. Methods: TREC and/or KREC values were measured in 137,484 newborns between April 2017 and December 2021 using EnLite TREC (n = 80,791) or TREC/KREC kits (n = 56,693). For newborns with positive screening results, diagnostic NGS analysis was performed with a 349-gene panel to detect genetic mutations associated with primary immunodeficiencies (PIDs). Results: A total of 145 newborns (0.11%) had abnormal TREC and/or KREC values, and a genetic diagnosis was established in 2 patients with SCID (1 in 68,742 newborns) (IL2RG-SCID and reticular dysgenesis) and 10 with non-SCID PIDs with T and/or B cell deficiencies (1 in 13,748 newborns) using NGS analysis. Furthermore, TREC values of 2849 newborns were measured and confirmed the significant correlation between the results of both TREC and TREC/KREC kits (P < 0.001) and naïve T cell counts. Conclusions: We performed the first large-scale TREC and TREC/KREC NBS programs in Japan. Our NBS programs followed by the diagnostic NGS analysis for newborns with abnormal TREC and/or KREC values are useful for the early identification and rapid molecular evaluation of not only SCID but also different non-SCID PIDs.

    DOI: 10.1007/s10875-022-01335-0

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  32. Risk factors for unplanned removal of central venous catheters in hospitalized children with hematological and oncological disorders Reviewed

    Miyagishima M., Hamada M., Hirayama Y., Muramatsu H., Tainaka T., Shirota C., Hinoki A., Imaizumi T., Nakatochi M., Kamei M., Nishikawa E., Kawashima N., Narita A., Nishio N., Kojima S., Takahashi Y.

    International Journal of Hematology   Vol. 116 ( 2 ) page: 288 - 294   2022.8

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    Central venous catheters (CVCs) are essential devices in the treatment of pediatric patients with hematological and oncological disorders; however, the most suitable type of CVC for these patients remains unclear. We retrospectively compared risk factors for unplanned removal of two commonly used CVCs, peripherally inserted central catheters (PICCs) and tunneled CVCs, to propose which is the better device. We followed 89 patients fitted with a tunneled CVC (total 21,395 catheter-days) and 84 fitted with a PICC (total 9177 catheter-days) between January 1, 2013 and December 31, 2015, until catheter removal. Patients with a PICC had a significantly higher 3-month cumulative incidence of catheter occlusion (5.2% vs. 0%, p = 4.08 × 10−3) and total unplanned removals (29.0% vs. 6.9%, p = 0.0316) than those with tunneled CVCs. However, the cumulative incidence of central line-associated bloodstream infection did not differ significantly by CVC type. Multivariable analysis identified younger age (< 2 years) [sub-distribution hazard ratio (SHR) 2.29; 95% confidence interval (CI) 1.27–4.14] and PICC (SHR 2.73; 95% CI 1.48–5.02) as independent risk factors for unplanned removal. Thus, our results suggest that tunneled CVCs are preferable in pediatric patients with hematological and oncological disorders requiring long-term, intensive treatment.

    DOI: 10.1007/s12185-022-03346-4

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  33. A patient with very early onset FH-deficient renal cell carcinoma diagnosed at age seven Reviewed

    Taniguchi R., Muramatsu H., Okuno Y., Yoshida T., Wakamatsu M., Hamada M., Shirota C., Sumida W., Hinoki A., Tainaka T., Gotoh Y., Tsuzuki T., Tanaka Y., Kojima S., Uchida H., Takahashi Y.

    Familial Cancer   Vol. 21 ( 3 ) page: 337 - 341   2022.7

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    Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by heterozygous germline variants in the fumarate hydratase (FH) gene and is associated with increased susceptibility to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). HLRCC-associated RCC usually occurs in the middle age, with the median age being 40–44 years. This report describes a seven-year-old (84-month-old) male who developed a large right kidney tumor with multiple cystic lesions that contained enhanced solid components. There was no evidence of distant metastasis. The male patient underwent right nephrectomy and has been recovering well without metastasis or recurrence. Pathological examination revealed that tumor cells with relatively prominent nucleoli and surrounded by halos, were located in a limited area. Immunohistochemical staining was negative for FH. Whole-exome sequencing identified his germline variant in the FH gene and its loss of heterozygosity in the tumor. At nine years (114 months) of age, the male patient showed no recurrence of the tumor. This was the youngest-onset case of HLRCC-associated RCC to date. This report may affect the starting age for future RCC-surveillance programs for patients with HLRCC.

    DOI: 10.1007/s10689-021-00268-8

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  34. Difficulties in diagnosing Malassezia furfur bloodstream infection and possibility of spontaneous resolution in a patient undergoing chemotherapy for neuroblastoma: A case report Reviewed

    Tetsuka N., Muramatsu H., Iguchi M., Oka K., Morioka H., Takahashi Y., Yagi T.

    Journal of Infection and Chemotherapy   Vol. 28 ( 7 ) page: 987 - 990   2022.7

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    Malassezia furfur is a lipophilic, yeast-like fungus that forms part of the normal human skin microflora and is associated with a wide range of infections, such as pityriasis versicolor, folliculitis, and systemic infections in immunocompromised patients. Although matrix-assisted laser desorption/ionization time-of-flight mass spectrometry has enabled rapid identification of Malassezia species, it is still a challenge to diagnose systemic infections because Malassezia fungemia can often be missed by automated blood culture systems. We report a case in which M. furfur in blood was detected by the presence of yeast-like fungi in blood smears. Yeast-like organisms were observed in the blood smears of a 3-year-old boy, taken over 2 weeks without any symptoms. He had undergone several courses of chemotherapy for neuroblastoma via an indwelling central venous catheter (CVC) that was placed in his right anterior chest for 11 months. Although the blood cultures obtained from an automated blood culture system were negative, M. furfur growth was detected in the subcultured blood taken from the CVC. The CVC was removed, and the scheduled chemotherapy was postponed. No systemic M. furfur bloodstream infection occurred; the infection resolved spontaneously without any specific treatment; only prophylactic fluconazole was administered. M. furfur fungemia may not be diagnosable by an automated blood culture system. Further, M. furfur may not cause infections in humans even when administered intravenously. This report may lead to the discovery of factors related to human infectivity of this disease in the future.

    DOI: 10.1016/j.jiac.2022.02.026

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  35. Prognostic Factors for Outcomes of Allogeneic HSCT for Children and Adolescents/Young Adults With CML in the TKI Era Reviewed

    Shimada H., Tanizawa A., Kondo T., Nagamura-Inoue T., Yasui M., Tojo A., Muramatsu H., Eto T., Doki N., Tanaka M., Sato M., Noguchi M., Uchida N., Takahashi Y., Sakata N., Ichinohe T., Hashii Y., Kato K., Atsuta Y., Ohashi K.

    Transplantation and Cellular Therapy   Vol. 28 ( 7 ) page: 376 - 389   2022.7

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    The breakthrough effects of tyrosine kinase inhibitors (TKIs) have lessened indications for allogeneic hematopoietic stem cell transplantation (HSCT) in chronic myeloid leukemia (CML). However, HSCT is still attractive for children and adolescents/young adults (AYAs) requiring lifelong TKI therapy. Nevertheless, little has been reported on the outcomes of large clinical studies of HSCT targeting these age groups. This study aimed to identify prognostic factors for the outcomes of HSCT, including reduced-intensity conditioning (RIC)-HSCT, for children and AYAs with CML in the TKI era. We performed a registry analysis for 200 patients with CML aged <30 years who underwent pretransplant TKI therapy from the observational nationwide database established by the Japanese Society for Transplantation and Cellular Therapy. The patients received bone marrow (BM), peripheral blood (PB), or cord blood (CB) from either related or unrelated donors. The indication for HSCT for individual patients was determined by the institution according to European LeukemiaNet recommendations and other guidelines. The 5-year overall survival (OS) rates for patients with chronic phase (CP) (n = 124), accelerated phase (AP) (n = 23), and blastic phase (BP) (n = 53) at diagnosis were 82.8%, 71.1%, and 73.3%, respectively, with no significant difference (P =.3293). The strongest predictor of engraftment was transplant source, with CB (hazard ratio [HR], 0.33) and PB (HR, 2.00) (compared with BM) being independent unfavorable and favorable predictors, respectively. Transplant source was also an independent predictor of chronic GVHD, with PB (HR, 1.81) and CB (HR, 0.39) (compared with BM) being unfavorable and favorable predictors, respectively. The strongest predictor of OS rate for patients with CP at diagnosis was disease phase at HSCT, with second or greater CP, AP, or BP (HR, 2.81) (compared with first CP [CP1]) being an unfavorable predictor. In addition, patients with CP at diagnosis who had major and complete molecular responses at HSCT had excellent outcomes, with 5-year OS rates of 100% and 94.4%, respectively. The 5-year OS rate was compared between RIC (n = 31) and myeloablative conditioning (MAC) (n = 58) in patients with CP1, both of which were 89.3%, with no significant difference (P = .9440). On univariate analysis for the RIC cohort with CP at diagnosis, the age at HSCT (HR, 1.27) (increase per year) and the time from diagnosis to HSCT (HR, 1.83) (increase per year) were significant predictors for OS. Our study demonstrates that RIC may be an appropriate alternative to MAC for children and AYAs with CP1. As for the transplant source, we recommend first selecting BM because of a higher engraftment rate compared to CB and a lower incidence of chronic GVHD compared to PB. Although HSCT in the status of a major molecular response is desirable, it is not advisable to continue TKI pointlessly long because age at HSCT and timing of HSCT are prognostic factors that determine survival. The decision to perform RIC-HSCT instead of continuing TKI should be carefully made, considering the possibility of transplant-related complications.

    DOI: 10.1016/j.jtct.2022.04.011

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  36. Combination chemotherapy consisting of irinotecan, etoposide, and carboplatin for refractory or relapsed neuroblastoma Reviewed

    Imaya M., Muramatsu H., Narita A., Yamamori A., Wakamatsu M., Yoshida T., Miwata S., Narita K., Ichikawa D., Hamada M., Nishikawa E., Kawashima N., Nishio N., Kojima S., Takahashi Y.

    Cancer Medicine   Vol. 11 ( 9 ) page: 1956 - 1964   2022.5

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    Background: Patients with primary refractory and relapsed neuroblastoma have a poor prognosis since safe and effective chemotherapies for these patients are currently limited. The development of new chemotherapy regimens for these patients is imperative to improve survival outcomes. Methods: We retrospectively analyzed 40 patients with refractory (n = 36) or relapsed (n = 4) neuroblastoma who received irinotecan, etoposide, and carboplatin (IREC) as a second-line treatment. We evaluated their therapeutic response and the toxicity of IREC. We also assessed the impact of UGT1A1 gene polymorphisms, which are involved in irinotecan metabolism, on outcomes and toxicity. Results: A total of 112 cycles of IREC were administered to 40 patients with a median of 2 cycles per patient (range, 1–9). Six (15%) patients (UGT1A1 wild-type [n = 2] and heterozygous [n = 4]) showed objective responses, including partial response (n = 1), tumor shrinkage (n = 4), and improved findings on their MIBG scan (n = 1). Grade 4 neutropenia, grade 4 leukopenia, and grades 3–4 gastrointestinal toxicity were observed in 110 (98%), 88 (79%), and 3 (3%) cycles, respectively. There was no IREC-related mortality. Patients with UGT1A1 polymorphisms showed a higher frequency of grade 4 leukopenia, but these patients did not have increased treatment-related mortality or non-hematologic toxicity. Conclusions: IREC showed an objective response rate of 15% including 1 case with partial response. IREC was well tolerated regardless of UGT1A1 genotype. This study suggests that IREC is a promising second-line chemotherapy for refractory or relapsed neuroblastoma.

    DOI: 10.1002/cam4.4529

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  37. Minor PNH clones do not distinguish inherited bone marrow failure syndromes from immune-mediated aplastic anemia Reviewed

    Narita A., Miwata S., Imaya M., Tsumura Y., Yamamori A., Wakamatsu M., Hamada M., Taniguchi R., Okuno Y., Muramatsu H., Takahashi Y.

    Blood Advances   Vol. 6 ( 8 ) page: 2517 - 2519   2022.4

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    DOI: 10.1182/bloodadvances.2021006044

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  38. Genetic Study of Fanconi Anemia in Infancy Revealed FANCI Mutations and Defective ALDH2 Variant: A Case Report Reviewed

    Urata T., Imamura T., Osone S., Muramatsu H., Takahashi Y., Hosoi H.

    Journal of Pediatric Hematology/Oncology   Vol. 44 ( 2 ) page: E438 - E441   2022.3

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    Fanconi anemia (FA) is a rare genetic disorder that manifests as congenital abnormalities and bone marrow failure (BMF). Most patients with FA present with BMF within the first decade of life; however, neonate and early infancy BMF is rare. Recent studies have shown that a defective aldehyde dehydrogenase 2 (ALDH2) variant accelerates BMF development in patients with FA. Herein, we described an infant case of FA with compound heterozygous FANCI mutation and the defective ALDH2 variant. Our case developed BMF early probably because of ALDH2 deficiency, while the mild malformation might be because of the locus of FANCI mutation.

    DOI: 10.1097/MPH.0000000000002254

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  39. Nosocomial infection with rotavirus vaccine strain in paediatric patients with immunodeficiency Reviewed

    Miura H., Taniguchi K., Narita K., Kawamura Y., Kozawa K., Muramatsu H., Takahashi Y., Ihira M., Yoshikawa T.

    Journal of Hospital Infection   Vol. 121   page: 9 - 13   2022.3

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    In infants with immunodeficiency, rotavirus (RV) vaccines can be continuously excreted in stool. We analysed nosocomial infection with RV vaccine strain in immunodeficient paediatric patients. RV1 RNAs were detected in stool and serum samples from case A, who was vaccinated with RV1, and case B, who was not. PAGE analysis of serial stool samples of case A revealed several rearrangements of the RV genome. In case B, the only band pattern detected was the same as a rearrangement detected in case A at the same time. In summary, RV vaccination of infants with immunodeficiency poses a risk of nosocomial infections.

    DOI: 10.1016/j.jhin.2021.12.009

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  40. Case Report: Rotavirus Vaccination and Severe Combined Immunodeficiency in Japan Reviewed

    Tanita K., Kawamura Y., Miura H., Mitsuiki N., Tomoda T., Inoue K., Iguchi A., Yamada M., Yoshida T., Muramatsu H., Tada N., Matsui T., Kato M., Eguchi K., Ishimura M., Ohga S., Imai K., Morio T., Yoshikawa T., Kanegane H.

    Frontiers in Immunology   Vol. 13   2022.2

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    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.

    DOI: 10.3389/fimmu.2022.786375

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  41. A retrospective analysis of azacitidine treatment for juvenile myelomonocytic leukemia Reviewed

    Honda Y., Muramatsu H., Nanjo Y., Hirabayashi S., Meguro T., Yoshida N., Kakuda H., Ozono S., Wakamatsu M., Moritake H., Yasui M., Sano H., Manabe A., Sakashita K.

    International Journal of Hematology   Vol. 115 ( 2 ) page: 263 - 268   2022.2

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    Language:Japanese   Publisher:International Journal of Hematology  

    Juvenile myelomonocytic leukemia (JMML) is a pediatric hematological malignancy with a poor prognosis. Although several case series have been published describing hematological and molecular responses to azacitidine (AZA) treatment in patients with JMML, the efficacy and safety profile of AZA is not well investigated, especially in Asian children and children undergoing hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed 5 patients who received a total of 12 cycles (median 2 cycles) of AZA treatment in Japan. All five patients were boys and their ages at the time of treatment were 21, 23, 24, 26, and 46 months, respectively. All five patients tolerated AZA treatment, including four patients who received AZA after HSCT. Therapeutic toxicity with AZA was mostly limited to hematological toxicity. The only serious non-hematological adverse event was hyperbilirubinemia (grades III–IV) observed in a patient who received AZA after a second HSCT. Two out of five patients treated with AZA achieved a partial response (PR), while three patients treated for post-transplant relapse did not have an objective response. Future prospective studies should be conducted to develop combination therapies with AZA and other molecular targeted drugs for high-risk patients.

    DOI: 10.1007/s12185-021-03248-x

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  42. Prospective validation of the provisional entity of refractory cytopenia of childhood, proposed by the World Health Organization Reviewed

    Hama A., Hasegawa D., Manabe A., Nozawa K., Narita A., Muramatsu H., Kosaka Y., Kobayashi M., Koh K., Takahashi Y., Watanabe K., Ohara A., Ito M., Kojima S.

    British Journal of Haematology   Vol. 196 ( 4 ) page: 1031 - 1039   2022.2

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    In 2008, the World Health Organization proposed a new entity of childhood myelodysplastic syndrome (MDS), which was referred to as refractory cytopenia of childhood (RCC). However, whether this morphological classification reflects clinical outcomes remains unclear. We performed a prospective evaluation of bone marrow morphology in 252 children with acquired bone marrow failure between 2009 and 2013. Of 252 patients, 63 were diagnosed with aplastic anaemia (AA), 131 with RCC without multilineage dysplasia (RCC-w/o-MLD) and 58 with RCC with MLD (RCC-MLD). One patient with AA, three with RCC-w/o-MLD and nine with RCC-MLD presented with chromosomal abnormalities at diagnosis (P = 0·001). The response rates to immunosuppressive therapy (IST) at 6 months and the cumulative incidence of clonal evolution at 5 years did not significantly differ among the three groups. A multivariate analysis revealed that the morphological classification of RCC-MLD was a significant risk factor for secondary graft failure after haematopoietic cell transplantation (HCT) (P = 0·003). In view of these findings, RCC could be divided into two categories, RCC-w/o-MLD and RCC-MLD, because children with this condition exhibited a distinct morphology, frequent chromosomal abnormalities at diagnosis and a high frequency of secondary graft failure after HCT.

    DOI: 10.1111/bjh.17921

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  43. Azacitidine as a bridge to transplantation in juvenile myelomonocytic leukemia Reviewed

    Takebayashi A., Yamamoto M., Igarashi K., Muramatsu H., Kawasaki Y.

    Pediatrics International   Vol. 64 ( 1 )   2022.1

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    Language:Japanese   Publisher:Pediatrics International  

    DOI: 10.1111/ped.14929

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  44. Clinical Impact of Melphalan Pharmacokinetics on Transplantation Outcomes in Children Undergoing Hematopoietic Stem Cell Transplantation Reviewed

    Maemura R., Wakamatsu M., Matsumoto K., Sakaguchi H., Yoshida N., Hama A., Yoshida T., Miwata S., Kitazawa H., Narita K., Kataoka S., Ichikawa D., Hamada M., Taniguchi R., Suzuki K., Kawashima N., Nishikawa E., Narita A., Okuno Y., Nishio N., Kato K., Kojima S., Morita K., Muramatsu H., Takahashi Y.

    Cell Transplantation   Vol. 31   2022.1

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    Melphalan is widely used for hematopoietic stem cell transplantation (HSCT) conditioning. However, the relationship between its pharmacokinetic (PK) and transplantation outcomes in children has not been thoroughly investigated. We prospectively analyzed the relationship between melphalan area under the curve (AUC) and transplantation outcome and examined the development of a predictive model for melphalan clearance in children. This study included 43 children aged 0 to 19 years who underwent HSCT following a melphalan-based conditioning regimen from 2017 to 2021. In univariable analysis, high-melphalan AUC resulted in a significantly lower cumulative incidence of acute graft-versus-host disease and a higher cumulative incidence of thrombotic microangiopathy, although no significant difference was observed in survival. Regression analysis of a randomly selected derivation cohort (n = 21) revealed the following covariate PK model: predicted melphalan clearance (mL/min) = 6.47 × 24-h urinary creatinine excretion rate (CER, g/day) × 24-h creatinine clearance rate (CCR, mL/min) + 92.8. In the validation cohort (n = 22), the measured melphalan clearance values were significantly correlated with those calculated based on the prediction equation (R2 = 0.663). These results indicate that melphalan exposure may be optimized by adjusting the melphalan dose according to CER and CCR.

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  45. Dorsal myelopathy after nelarabine and intrathecal methotrexate therapy Reviewed

    Sawamura F., Natsume J., Nakata T., Muramatsu H., Takahashi Y.

    Pediatrics International   Vol. 64 ( 1 )   2022.1

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    DOI: 10.1111/ped.15334

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  46. Microsatellite instability-high is rare events in refractory pediatric solid tumors Reviewed

    Yoshida T., Muramatsu H., Wakamatsu M., Taniguchi R., Ichikawa D., Nakaguro M., Natsume A., Takahashi Y.

    Pediatric Hematology and Oncology   Vol. 39 ( 5 ) page: 468 - 474   2022

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    Microsatellite instability (MSI)-high status is associated with good responsiveness to immune checkpoint inhibitors. Although MSI-high status has been actively investigated in pediatric brain tumors, studies of other pediatric solid tumors are lacking. Among 334 consecutive pediatric patients with solid tumors, we retrospectively analyzed formalin-fixed paraffin-embedded tumor tissues of 36 of 74 patients (49%) who died of disease. We assessed the MSI status in these tissues using five multiplexed markers. The results revealed that none of the patients had an MSI-high status. These results indicate that MSI-high status is a rare event in pediatric patients with refractory/relapsed solid tumors. Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1998266.

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  47. Simple and robust methylation test for risk stratification of patients with juvenile myelomonocytic leukemia Reviewed

    Kitazawa H., Okuno Y., Muramatsu H., Aoki K., Murakami N., Wakamatsu M., Suzuki K., Narita K., Kataoka S., Ichikawa D., Hamada M., Taniguchi R., Kawashima N., Nishikawa E., Narita A., Nishio N., Hama A., Loh M.L., Stieglitz E., Kojima S., Takahashi Y.

    Blood Advances   Vol. 5 ( 24 ) page: 5507 - 5518   2021.12

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    Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm that develops during infancy and early childhood. The array-based international consensus definition of DNA methylation has recently classified patients with JMML into the following 3 groups: high (HM), intermediate (IM), and low methylation (LM). To develop a simple and robust methylation clinical test, 137 patients with JMML were analyzed using the Digital Restriction Enzyme Analysis of Methylation (DREAM), which is a next-generation sequencing–based methylation analysis. Unsupervised consensus clustering of the discovery cohort (n 5 99) using DREAM data identified HM (HM_DREAM; n 5 35) and LM subgroups (LM_DREAM; n 5 64). Of the 98 cases that could be compared with the international consensus classification, 90 HM (n 5 30) and LM (n 5 60) cases had 100% concordance with DREAM clustering results. Of the remaining 8 cases comprising the IM group, 4 were classified as belonging to the HM_DREAM group and 4 to the LM_DREAM group. A machine-learning classifier was successfully constructed using a support vector machine (SVM), which divided the validation cohort (n 5 38) into HM (HM_SVM, n 5 18) and LM (LM_SVM; n 5 20) groups. Patients with the HM_SVM profile had a significantly poorer 5-year overall survival rate than those with the LM_SVM profile. In conclusion, we developed a robust methylation test using DREAM for patients with JMML. This simple and straightforward test can be easily incorporated into diagnosis to generate a methylation classification for patients so they can receive risk-adapted treatment in the context of future clinical trials.

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  48. Integrated diagnosis based on transcriptome analysis in suspected pediatric sarcomas Reviewed

    Ichikawa D., Yamashita K., Okuno Y., Muramatsu H., Murakami N., Suzuki K., Kojima D., Kataoka S., Hamada M., Taniguchi R., Nishikawa E., Kawashima N., Narita A., Nishio N., Hama A., Kasai K., Mizuno S., Shimoyama Y., Nakaguro M., Okita H., Kojima S., Nakazawa A., Takahashi Y.

    npj Genomic Medicine   Vol. 6 ( 1 ) page: 49   2021.12

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    Pediatric solid tumors are a heterogeneous group of neoplasms with over 100 subtypes. Clinical and histopathological diagnosis remains challenging due to the overlapping morphological and immunohistochemical findings and the presence of atypical cases. To evaluate the potential utility of including RNA-sequencing (RNA-seq) in the diagnostic process, we performed RNA-seq in 47 patients with suspected pediatric sarcomas. Histopathologists specialized in pediatric cancer re-evaluated pathological specimens to reach a consensus diagnosis; 42 patients were diagnosed with known subtypes of solid tumors whereas 5 patients were diagnosed with undifferentiated sarcoma. RNA-seq analysis confirmed and refined consensus diagnoses and further identified diagnostic genetic variants in four of the five patients with undifferentiated sarcoma. Genetic lesions were detected in 23 patients, including the novel SMARCA4-THOP1 fusion gene and 22 conventional or recently reported genetic events. Unsupervised clustering analysis of the RNA-seq data identified a distinct cluster defined by the overexpression of rhabdomyosarcoma-associated genes including MYOG and CHRNG. These findings suggest that RNA-seq-based genetic analysis may aid in the diagnosis of suspected pediatric sarcomas, which would be useful for the development of stratified treatment strategies.

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  49. A neonate diagnosed with Noonan syndrome with myeloproliferative change Reviewed

    Nagatomo K., Fukushima H., Kanai Y., Muramatsu H., Takada H.

    Pediatrics International   Vol. 63 ( 12 ) page: 1521 - 1523   2021.12

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  50. Next-Generation Sequencing to Detect Pathogens in Pediatric Febrile Neutropenia: A Single-Center Retrospective Study of 112 Cases Reviewed

    Horiba K., Torii Y., Okumura T., Takeuchi S., Suzuki T., Kawada J.I., Muramatsu H., Takahashi Y., Ogi T., Ito Y.

    Open Forum Infectious Diseases   Vol. 8 ( 11 )   2021.11

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    Background. Febrile neutropenia (FN) is a frequent complication in immunocompromised patients. However, causative microorganisms are detected in only 10% of patients. This study aimed to detect the microorganisms that cause FN using next-generation sequencing (NGS) to identify the genome derived from pathogenic microorganisms in the bloodstream. Here, we implemented a metagenomic approach to comprehensively analyze microorganisms present in clinical samples from patients with FN. Methods. FN is defined as a neutrophil count <500 cells/µL and fever ≥37.5°C. Plasma/serum samples of 112 pediatric patients with FN and 10 patients with neutropenia without fever (NE) were sequenced by NGS and analyzed by a metagenomic pipeline, PATHDET. Results. The putative pathogens were detected by NGS in 5 of 10 FN patients with positive blood culture results, 15 of 87 FN patients (17%) with negative blood culture results, and 3 of 8 NE patients. Several bacteria that were common in the oral, skin, and gut flora were commonly detected in blood samples, suggesting translocation of the human microbiota to the bloodstream in the setting of neutropenia. The cluster analysis of the microbiota in blood samples using NGS demonstrated that the representative bacteria of each cluster were mostly consistent with the pathogens in each patient. Conclusions. NGS technique has great potential for detecting causative pathogens in patients with FN. Cluster analysis, which extracts characteristic microorganisms from a complex microbial population, may be effective to detect pathogens in minute quantities of microbiota, such as those from the bloodstream.

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  51. Acquisition of a rare NUP98–BPTF fusion gene associated with recurrence of acute myeloid leukemia Reviewed

    Kawaguchi K., Azumi S., Itakura Y., Takachi T., Ogura T., Horikoshi Y., Suzuki K., Muramatsu H., Hama A., Takahashi Y., Watanabe K.

    Pediatric Blood and Cancer   Vol. 68 ( 10 ) page: e29201   2021.10

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  52. Clinical diagnostic value of telomere length measurement in inherited bone marrow failure syndromes Reviewed

    Miwata S., Narita A., Okuno Y., Suzuki K., Hamada M., Yoshida T., Imaya M., Yamamori A., Wakamatsu M., Narita K., Kitazawa H., Ichikawa D., Taniguchi R., Kawashima N., Nishikawa E., Nishio N., Kojima S., Muramatsu H., Takahashi Y.

    Haematologica   Vol. 106 ( 9 ) page: 2511 - 2515   2021.9

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  53. Echocardiography Monitoring of Pulmonary Hypertension after Pediatric Hematopoietic Stem Cell Transplantation: Pediatric Pulmonary Arterial Hypertension and Pulmonary Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation Reviewed

    Kawashima N., Fukasawa Y., Nishikawa E., Ohta-Ogo K., Ishibashi-Ueda H., Hamada M., Ichikawa D., Narita A., Okuno Y., Muramatsu H., Nishio N., Kojima S., Kato T., Takahashi Y.

    Transplantation and Cellular Therapy   Vol. 27 ( 9 ) page: 786.e1 - 786.e8   2021.9

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    Pulmonary hypertension (PH) is associated with high morbidity in children undergoing hematopoietic stem cell transplantation (HSCT). However, owing to the lack of sequential echocardiography, the nature of the condition is not fully understood. This study was conducted to investigate whether routine echocardiography performed after HSCT could detect patients with PH at an earlier stage and elucidate the role of intervention using tadalafil. The study population comprised 93 consecutive children age <18 years who underwent a total of 109 HSCTs. All patients underwent routine transthoracic echocardiography during HSCT. Four children (4%) with a median age of 4 years (range, 0.7 to 6 years) were found to have PH, and their median tricuspid regurgitation peak velocity (TRV) was 4.1 m/s (range, 3.5 to 4.2 m/s). PH was diagnosed at a median of 52 days (range, 21 to 118 days) after HSCT. Three of them were diagnosed with neuroblastoma, and 1 was diagnosed with infantile leukemia. One patient developed PH after autologous HSCT, and 3 received killer immunoglobulin-like receptor ligand-mismatched cord blood. Busulfan was used for conditioning in all patients, and the proportion of patients receiving this medication was significantly higher in the PH group compared with the non-PH group (100% versus 30%; P =.011). Three of the 4 patients had a durable response (TRV ≤2.8 m/s) at a median of 46 days (range, 14 to 79 days) after starting treatment with tadalafil. No patient experienced exacerbation of PH, and treatment was completed at median of 96 days (range, 46 to 212 days). Our data suggest that routine echocardiography monitoring after HSCT should be considered in children receiving busulfan, although the precise follow-up timing needs further study. In addition, safe and effective administration of tadalafil must be ensured by close monitoring.

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  54. Autoantibodies against the plakin family proteins as a novel marker for chronic graft-versus-host disease of the lung Reviewed

    Kawashima N., Nishikawa E., Tsuchisaka A., Hashimoto T., Okuno Y., Hamada M., Ichikawa D., Narita A., Muramatsu H., Nishio N., Kojima S., Muro Y., Takahashi Y.

    Bone Marrow Transplantation   Vol. 56 ( 9 ) page: 2291 - 2294   2021.9

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  55. Relationship between plasma rabbit anti-thymocyte globulin concentration and immunosuppressive therapy response in patients with severe aplastic anemia Reviewed

    Narita A., Muramatsu H., Ichikawa D., Hamada M., Nishikawa E., Suzuki K., Kawashima N., Okuno Y., Nishio N., Hama A., Yamazaki H., Nakao S., Kojima S., Takahashi Y.

    European Journal of Haematology   Vol. 107 ( 2 ) page: 255 - 264   2021.8

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    Objectives: Patients with acquired aplastic anemia (AA) without HLA-matched sibling donors or aged >40 years receive immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG). We investigated the relationship between plasma rabbit ATG (r-ATG) concentration and IST response. Methods: From May 2012 to October 2017, 81 patients with severe AA who required initial IST were included. A 1:1 block randomization was employed for 2.5 and 3.5 mg/kg doses of r-ATG. Results: No significant difference in response rates was observed between the 2.5 and 3.5 mg/kg groups (63% vs. 58%, P =.894). Median r-ATG concentrations on days 14 and 28 after IST were 15.2 (0.0-97.7) and 1.8 (0.0-74.9 µg/mL), respectively. According to r-ATG concentration, response rates were significantly higher in the group with higher r-ATG concentration than in those with lower r-ATG concentration (day 14, 88% vs. 52%; P =.006 and day 28, 79% vs. 46%; P =.005). In multivariate analysis, higher r-ATG concentrations at day 28 were independent predictors of favorable response to IST at 6 months (odds ratio, 0.29; 95% confidence interval, 0.09-0.93; P =.037). Conclusions: The present data indicate that higher r-ATG concentration at day 28 resulted in improved IST response.

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  56. Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor Reviewed

    Kataoka S., Kawashima N., Okuno Y., Muramatsu H., Miwata S., Narita K., Hamada M., Murakami N., Taniguchi R., Ichikawa D., Kitazawa H., Suzuki K., Nishikawa E., Narita A., Nishio N., Yamamoto H., Fukasawa Y., Kato T., Yamamoto H., Natsume J., Kojima S., Nishino I., Taketani T., Ohnishi H., Takahashi Y.

    Journal of Allergy and Clinical Immunology   Vol. 148 ( 2 ) page: 639 - 644   2021.8

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    Background: Type I interferonopathies are a recently established subgroup of autoinflammatory diseases caused by mutations in genes associated with proteasome degradation or cytoplasmic RNA- and DNA-sensing pathways. Objective: This study aimed to unveil the molecular pathogenesis of a patient with novel type I interferonopathy, for which no known genetic mutations have been identified. Methods: We performed the whole-exome sequencing of a 1-month-old boy with novel type I interferonopathy. We also investigated proteasome activities using patient-derived B lymphoblastoid cell lines (LCLs) and normal LCLs transduced with the mutant gene. Results: Whole-exome sequencing identified a de novo proteasome 20S subunit beta 9 (PSMB9) p.G156D mutation in the patient who developed fever, a chilblain-like skin rash, myositis, and severe pulmonary hypertension due to the hyperactivation of IFN-α. Patient-derived LCLs revealed reduced proteasome activities, and exogenous transduction of mutant PSMB9 p.G156D into normal LCLs significantly suppressed proteasome activities, and the endogenous PSMB9 protein was lost along with the reduction of other immunoproteasome subunits, PSMB8 and PSMB10 proteins. He responded to the administration of a Janus kinase inhibitor, tofacitinib, and he was successfully withdrawn from venoarterial extracorporeal membranous oxygenation. At age 7 months, he received an unrelated cord blood transplantation. At 2 years posttransplantation, he no longer required tofacitinib and experienced no disease recurrence. Conclusions: We present the case of a patient with a novel type I interferonopathy caused by a de novo PSMB9 p.G156D mutation that suppressed the wild-type PSMB9 protein expression. Janus kinase inhibitor and stem cell transplantation could be curative therapies in patients with severe interferonopathies.

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  57. Correction: Reduced-intensity conditioning is effective for hematopoietic stem cell transplantation in young pediatric patients with Diamond-Blackfan anemia (Bone Marrow Transplantation, (2021), 56, 5, (1013-1020), 10.1038/s41409-020-01056-1) Reviewed

    Koyamaishi S., Kamio T., Kobayashi A., Sato T., Kudo K., Sasaki S., Kanezaki R., Hasegawa D., Muramatsu H., Takahashi Y., Sasahara Y., Hiramatsu H., Kakuda H., Tanaka M., Ishimura M., Nishi M., Ishiguro A., Yabe H., Sarashina T., Yamamoto M., Yuza Y., Hyakuna N., Yoshida K., Kanno H., Ohga S., Ohara A., Kojima S., Miyano S., Ogawa S., Toki T., Terui K., Ito E.

    Bone Marrow Transplantation   Vol. 56 ( 5 ) page: 1218 - 1219   2021.5

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    In the original version of this Article, in Table 1 the Year of HST for cases 3, 4, 15, and 25 was not shown. They now appear in Table 1 in the PDF and HTML versions of the Article.

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  58. Reduced-intensity conditioning is effective for hematopoietic stem cell transplantation in young pediatric patients with Diamond–Blackfan anemia Reviewed

    Koyamaishi S., Kamio T., Kobayashi A., Sato T., Kudo K., Sasaki S., Kanezaki R., Hasegawa D., Muramatsu H., Takahashi Y., Sasahara Y., Hiramatsu H., Kakuda H., Tanaka M., Ishimura M., Nishi M., Ishiguro A., Yabe H., Sarashina T., Yamamoto M., Yuza Y., Hyakuna N., Yoshida K., Kanno H., Ohga S., Ohara A., Kojima S., Miyano S., Ogawa S., Toki T., Terui K., Ito E.

    Bone Marrow Transplantation   Vol. 56 ( 5 ) page: 1013 - 1020   2021.5

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    Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of Diamond–Blackfan anemia (DBA). However, data regarding the optimal conditioning regimen for DBA patients are limited. We retrospectively compared the outcomes of DBA patients who underwent HSCT using either myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens. The patients belonged to a cohort treated at our hospitals between 2000 and 2018. HSCT was performed in 27 of 165 patients (16.4%). The median age at the time of HSCT was 3.6 years. Stem cell sources included bone marrow for 25 patients (HLA-matched sibling donors, n = 5; HLA-mismatched related donors, n = 2; HLA-matched/mismatched unrelated donors, n = 18) or cord blood for 2 patients. MAC or RIC regimens were used in 12 and 15 patients, respectively. Engraftment was successful in all 27 patients who underwent HSCT. Three patients who underwent HSCT using MAC regimens developed sinusoidal obstruction syndrome. The 3-year overall survival (OS) and failure-free survival rates (FFS) post-transplantations were 95.2% and 88.4%, respectively, with no significant differences between MAC and RIC regimens. Our data suggest that HSCTs using RIC regimens are effective and obtain engraftment with excellent OS and FFS for young DBA patients.

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  59. Predictive factors for the development of leukemia in patients with transient abnormal myelopoiesis and Down syndrome Reviewed

    Yamato G., Deguchi T., Terui K., Toki T., Watanabe T., Imaizumi T., Hama A., Iwamoto S., Hasegawa D., Ueda T., Yokosuka T., Tanaka S., Yanagisawa R., Koh K., Saito A.M., Horibe K., Hayashi Y., Adachi S., Mizutani S., Taga T., Ito E., Watanabe K., Muramatsu H.

    Leukemia   Vol. 35 ( 5 ) page: 1480 - 1484   2021.5

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  60. The eldest case of MICPCH with CASK mutation exhibiting gross motor regression Reviewed

    Nishio Y., Kidokoro H., Takeo T., Narita H., Sawamura F., Narita K., Kawano Y., Nakata T., Muramatsu H., Hara S., Kaname T., Natsume J.

    Brain and Development   Vol. 43 ( 3 ) page: 459 - 463   2021.3

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    Background: MICPCH is manifested as microcephaly associated with pontocerebellar hypoplasia and global developmental delay but developmental regression has never been reported. We describe the detailed clinical history of a woman with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) with a CASK mutation who exhibited gross motor regression after adolescence. Case: The patient experienced severe motor and intellectual developmental delay with microcephaly from infancy. The initial diagnosis was Rett syndrome based on her clinical features, including hand stereotypes and the absence of structural abnormality on magnetic resonance imaging (MRI) performed at the age of 5 years. Although gross motor abilities developed slowly and she could walk independently, she never acquired speech or understanding of languages. After adolescence, her motor ability gradually regressed so that she was unable to stand without support and moved with a wheelchair. At the age of 31 years, because of her atypical clinical course for Rett syndrome, whole exome sequencing was performed, which revealed a de novo heterozygous c.2068 + 1G > A mutation in the CASK gene (NM_001126055). Brain MRI revealed mild pontocerebellar hypoplasia compatible with the clinical phenotype of MICPCH. Discussion: This case suggests that MICPCH with a CASK mutation might cause developmental regression after adolescence and might be regarded as a neurodegenerative disorder.

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  61. International consensus definition of DNA methylation subgroups in juvenile myelomonocytic leukemia Reviewed

    Schonung M., Meyer J., Nollke P., Olshen A.B., Hartmann M., Murakami N., Wakamatsu M., Okuno Y., Plass C., Loh M.L., Niemeyer C.M., Muramatsu H., Flotho C., Stieglitz E., Lipka D.B.

    Clinical Cancer Research   Vol. 27 ( 1 ) page: 158 - 168   2021.1

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    Purpose: Known clinical and genetic markers have limitations in predicting disease course and outcome in juvenile myelomonocytic leukemia (JMML). DNA methylation patterns in JMML have correlated with outcome across multiple studies, suggesting it as a biomarker to improve patient stratification. However, standardized approaches to classify JMML on the basis of DNA methylation patterns are lacking. We, therefore, sought to define an international consensus for DNA methylation subgroups in JMML and develop classification methods for clinical implementation. Experimental Design: Published DNA methylation data from 255 patients with JMML were used to develop and internally validate a classifier model. Accuracy across platforms (EPIC-arrays and MethylSeq) was tested using a technical validation cohort (32 patients). The suitability of both methods for single-patient classification was demonstrated using an independent cohort (47 patients). Results: Analysis of pooled, published data established three DNA methylation subgroups as a de facto standard. Unfavorable prognostic parameters (PTPN11 mutation, elevated fetal hemoglobin, and older age) were significantly enriched in the high methylation (HM) subgroup. A classifier was then developed that predicted subgroups with 98% accuracy across different technological platforms. Applying the classifier to an independent validation cohort confirmed an association of HM with secondary mutations, high relapse incidence, and inferior overall survival (OS), while the low methylation subgroup was associated with a favorable disease course. Multivariable analysis established DNA methylation subgroups as the only significant factor predicting OS. Conclusions: This study provides an international consensus definition for DNA methylation subgroups in JMML. We developed and validated methods which will facilitate the design of risk-stratified clinical trials in JMML.

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  62. Detection of subclonal SETBP1 and JAK3 mutations in juvenile myelomonocytic leukemia using droplet digital PCR Reviewed

    Wakamatsu M., Okuno Y., Murakami N., Miwata S., Kitazawa H., Narita K., Kataoka S., Ichikawa D., Hamada M., Taniguchi R., Suzuki K., Kawashima N., Nishikawa E., Narita A., Nishio N., Kojima S., Muramatsu H., Takahashi Y.

    Leukemia   Vol. 35 ( 1 ) page: 259 - 263   2021.1

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  63. Usefulness of functional splicing analysis to confirm precise disease pathogenesis in Diamond-Blackfan anemia caused by intronic variants in RPS19 Reviewed

    Takafuji S., Mori T., Nishimura N., Yamamoto N., Uemura S., Nozu K., Terui K., Toki T., Ito E., Muramatsu H., Takahashi Y., Matsuo M., Yamamura T., Iijima K.

    Pediatric Hematology and Oncology   Vol. 38 ( 6 ) page: 515 - 527   2021

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    Diamond-Blackfan anemia (DBA) is mainly caused by pathogenic variants in ribosomal proteins and 22 responsible genes have been identified to date. The most common causative gene of DBA is RPS19 [NM_001022.4]. Nearly 180 RPS19 variants have been reported, including three deep intronic variants outside the splicing consensus sequence (c.72-92A > G, c.356 + 18G > C, and c.411 + 6G > C). We also identified one case with a c.412-3C > G intronic variant. Without conducting transcript analysis, the pathogenicity of these variants is unknown. However, it is difficult to assess transcripts because of their fragility. In such cases, in vitro functional splicing assays can be used to assess pathogenicity. Here, we report functional splicing analysis results of four RPS19 deep intronic variants identified in our case and in previously reported cases. One splicing consensus variant (c.411 + 1G > A) was also examined as a positive control. Aberrant splicing with a 2-bp insertion between exons 5 and 6 was identified in the patient samples and minigene assay results also identified exon 6 skipping in our case. The exon 6 skipping transcript was confirmed by further evaluation using quantitative RT-PCR. Additionally, minigene assay analysis of three reported deep intronic variants revealed that none of them showed aberrant splicing and that these variants were not considered to be pathogenic. In conclusion, the minigene assay is a useful method for functional splicing analysis of inherited disease.

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  64. Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans Reviewed

    Dingler F.A., Wang M., Mu A., Millington C.L., Oberbeck N., Watcham S., Pontel L.B., Kamimae-Lanning A.N., Langevin F., Nadler C., Cordell R.L., Monks P.S., Yu R., Wilson N.K., Hira A., Yoshida K., Mori M., Okamoto Y., Okuno Y., Muramatsu H., Shiraishi Y., Kobayashi M., Moriguchi T., Osumi T., Kato M., Miyano S., Ito E., Kojima S., Yabe H., Yabe M., Matsuo K., Ogawa S., Göttgens B., Hodskinson M.R.G., Takata M., Patel K.J.

    Molecular Cell   Vol. 80 ( 6 ) page: 996 - 1012.e9   2020.12

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    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.

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  65. Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome Reviewed

    Oka Y., Hamada M., Nakazawa Y., Muramatsu H., Okuno Y., Higasa K., Shimada M., Takeshima H., Hanada K., Hirano T., Kawakita T., Sakaguchi H., Ichimura T., Ozono S., Yuge K., Watanabe Y., Kotani Y., Yamane M., Kasugai Y., Tanaka M., Suganami T., Nakada S., Mitsutake N., Hara Y., Kato K., Mizuno S., Miyake N., Kawai Y., Tokunaga K., Nagasaki M., Kito S., Isoyama K., Onodera M., Kaneko H., Matsumoto N., Matsuda F., Matsuo K., Takahashi Y., Mashimo T., Kojima S., Ogi T.

    Science Advances   Vol. 6 ( 51 )   2020.12

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    Rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase (ADH5FDH), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, Adh5−/−Aldh2E506K/E506K double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.

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  66. Myelodysplastic syndromes in a pediatric patient with Cri du Chat syndrome with a ring chromosome 5 Reviewed

    Nozawa A., Ozeki M., Yasue S., Endo S., Kadowaki T., Ohnishi H., Muramatsu H., Hama A., Takahashi Y., Kojima S., Fukao T.

    International Journal of Hematology   Vol. 112 ( 5 ) page: 728 - 733   2020.11

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    Few hematological complications have previously been reported in association with Cri du Chat syndrome (CdCS). A case of myelodysplastic syndromes (MDS) in a pediatric patient with CdCS is herein presented. A 17-year-old female with CdCS caused by ring chromosome 5 was admitted to the hospital for investigation of a 1-month history of anemia. Based on the morphological findings of bone marrow, the patient was diagnosed with refractory cytopenia with multilineage dysplasia. The risk group was classified as intermediate-1 in the International Prognostic Scoring System (IPSS), and low in the revised IPSS. Assessment by microarray comparative genomic hybridization (CGH) identified the breakpoints of ring chromosome 5 as 46,XX,r(5)(p14.3q35.3). This revealed that the 5q terminal deletion did not include the common deleted region of MDS with del(5q). Treatment with azacitidine was initiated to control disease progression and improve quality of life. At baseline, the patient had a mean transfusion requirement of 3 units/month, which decreased to 2 units/month after six cycles of azacitidine and to 1 unit/month after 10 cycles of azacitidine. Cytopenia observed in the presented case seemed irrelevant to ring chromosome 5 which is the causative cytogenetic abnormality of CdCS, and further analyses may be needed to clarify the pathogenesis.

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  67. Risk factors for secondary poor graft function after bone marrow transplantation in children with acquired aplastic anemia Reviewed

    Hama A., Muramatsu H., Narita A., Nishikawa E., Kawashima N., Nishio N., Kojima S., Takahashi Y.

    Pediatric Transplantation   Vol. 24 ( 7 ) page: e13828   2020.11

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    In patients with acquired AA, PGF is a major cause of cytopenia after hematopoietic stem cell transplantation. An increased incidence of PGF, especially sPGF, has been noted after the introduction of the FLU/CY regimen in children with acquired AA. To clarify the risk factors for sPGF, the clinical data of 49 patients (median age, 11 years; range, 1-19 years) with AA who received allogeneic BMT at Nagoya University Hospital from 1997 to 2016 were analyzed. Out of the 49 patients, 7 developed sPGF, and the 5-year CI was 0.15 (95% CI, 0.04-0.25). Five received the FLU/CY regimen, and the 5-year CI of sPGF was significantly higher in patients who received the regimen (0.36; 95% CI, 0.12-0.62) than in those who were conditioned with the non-FLU/CY regimen (0.06; 95% CI, 0.01-0.17; P =.01). The multivariate analysis confirmed that the FLU/CY regimen (hazard ratio, 6.12; 95% CI, 1.16-32.4; P =.03) was a significant risk factor for sPGF. sPGF improved spontaneously without stem cell boost infusions in 5 patients, ranging from 460 to 3539 days after BMT. The 10-year CI of the spontaneous trilineage recovery was 0.83 (95% CI, 0.00-0.97), and all 7 patients are alive. The FLU/CY regimen was identified as a risk factor for the sPGF development in patients with AA. The establishment of the optimal conditioning regimens for children with AA is warranted.

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  68. MicroRNA-155-5p plays a critical role in transient leukemia of down syndrome by targeting tumor necrosis factor receptor superfamily members Reviewed

    Sas V., Pasca S., Jurj A., Pop L., Muramatsu H., Ono H., Dima D., Teodorescu P., Iluta S., Turcas C., Onaciu A., Munteanu R., Zimta A.A., Blag C., Popa G., von Gamm E.D.A., Arghirescu S., Serban M., Man S., Marian M., Petrushev B., Berce C., Colita A., Zdrenghea M., Kojima S., Gulei D., Takahashi Y., Tomuleasa C.

    Cellular Physiology and Biochemistry   Vol. 54 ( 5 ) page: 994 - 1012   2020.10

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    Background/Aims: Down syndrome associated disorders are caused by a complex genetic context where trisomy 21 is a central component in relation to other changes involving epigenetic regulators and signaling molecules. This unique genetic context is responsible for the predisposition of people with Down syndrome to acute leukemia. Although, the research in this field has discovered some important pathogenic keys, the exact mechanism of this predisposition is not known. Methods: In this study we applied functional enrichment analysis to evaluate the interactions between genes localized on chromosome 21, genes already identify as having a key role in acute leukemia of Down syndrome, miRNAs and signaling pathways implicated in cancer and cell development and found that miR-155 has a high impact in genes present on chromosome 21. Forward, we performed next generation sequencing on DNA samples from a cohort of patients diagnosed with acute leukemia of Down syndrome and in vitro functional assay using a CMK-86 cell line, transfected with either mimic or inhibitor of the microRNA-155-5p. Results: Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome, which can be correlated to microRNA-155-5p aberrant activity, may play an important role in cell signaling and thus be linked to acute myeloid leukemia. Conclusion: Some genes, already shown to be mutated in AML-DS, are potential targets for miR-155. Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome may play an important role in cell signaling and thus be linked to acute myeloid leukemia.

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  69. Change of White Matter Integrity in Children With Hematopoietic Stem Cell Transplantation Reviewed

    Sakaguchi Y., Natsume J., Kidokoro H., Tanaka M., Okai Y., Ito Y., Yamamoto H., Ohno A., Nakata T., Nakane T., Kawai H., Taoka T., Muramatsu H., Naganawa S., Takahashi Y.

    Pediatric Neurology   Vol. 111   page: 78 - 84   2020.10

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    Background: Advances in hematopoietic stem cell transplantation have improved the survival rate of malignant diseases and congenital immunodeficiencies. It has become important to assess long-term complications in survivors. To assess neurological abnormalities in children treated by transplantation, diffusion tensor imaging was performed. Methods: Forty children who underwent head diffusion tensor imaging before and after their first transplantation were enrolled. Patients with brain lesions on conventional MRI were excluded. Fractional anisotropy and mean diffusivity were compared between patients and 28 control subjects using tract-based spatial statistics. The Strengths and Difficulties Questionnaire was administered as a behavioral evaluation after transplantation, and diffusion tensor images of patients with and without behavioral abnormalities were compared. Results: The age of patients and controls was 0 to 19 years and 0 to 16 years, respectively. The date of diffusion tensor imaging was 10 to 57 days before and 40 to 153 days after transplantation. Tract-based spatial statistics showed fractional anisotropy reduction in widespread white matter in patients before and after transplantation. Mean diffusivity was high before transplantation and normalized after transplantation. Analysis comparing before and after hematopoietic stem cell transplantation shows no difference in fractional anisotropy and significantly high mean diffusivity before hematopoietic stem cell transplantation. In patients with behavioral abnormalities, low fractional anisotropy and high mean diffusivity remained after transplantation. Conclusions: Longitudinal diffusion tensor imaging showed white matter abnormalities in children without conventional MRI abnormalities, which were related to behavioral problems after transplantation. Diffusion tensor imaging is useful for behavioral assessment in children undergoing transplantation.

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  70. Association between graft source and response to live-attenuated vaccination in pediatric hematopoietic stem cell transplantation recipients: a single-center retrospective study Reviewed

    Suzuki T., Kawada J.i., Nishikawa E., Torii Y., Horiba K., Takeuchi S., Okumura T., Muramatsu H., Takahashi Y., Ito Y.

    Bone Marrow Transplantation   Vol. 55 ( 9 ) page: 1872 - 1874   2020.9

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  71. Hematopoietic Cell Transplantation for Chronic Granulomatous Disease in Japan Reviewed

    Yanagimachi M., Kato K., Iguchi A., Sasaki K., Kiyotani C., Koh K., Koike T., Sano H., Shigemura T., Muramatsu H., Okada K., Inoue M., Tabuchi K., Nishimura T., Mizukami T., Nunoi H., Imai K., Kobayashi M., Morio T.

    Frontiers in Immunology   Vol. 11   page: 1617   2020.7

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    Hematopoietic cell transplantation (HCT) is established as a curative treatment for severe chronic granulomatous disease (CGD). However, outcomes of HCT for CGD in Japan had not been precisely reported. We evaluated the outcome of HCT for CGD in Japan by means of a nationwide survey. A total of 91 patients (86 males and 5 females) with CGD who received HCT between 1992 and 2013 was investigated. Their median age at HCT was 11 years (0–39). Sixty-four patients had X-linked CGD caused by CYBB gene mutations, 13 had autosomal recessive CGD (7 CYBA and 6 NCF2), and 14 were genetically undetermined. Seventy patients are still alive at a median follow-up of 38.9 (3.7–230) months. Three-year OS and EFS was 73.7 and 67.6%, respectively. Twenty-one patients died mainly from transplant-related mortality. The cumulative incidence of grade II to IV acute GVHD and extensive chronic GVHD was 27.2 and 17.9%, respectively. Risk factors for EFS after HCT for CGD were age >30 years (P < 0.01), non-CYBB gene mutations (P < 0.01) and CBT (P < 0.01). Regarding the reduced intensity conditioning (RIC) regimen, risk factors for EFS included anti-thymocyte globulin (P = 0.048) and not using low-dose irradiation therapy (P < 0.01), in addition to the preceding risk factors. We report outcomes of HCT for CGD in Japan. Future studies are needed to improve such outcomes, especially for patients harboring non-CYBB gene mutations and suffering from adult CGD. A RIC regimen including low-dose irradiation may be a good option to explore further.

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  72. Targeting MEF2D-fusion Oncogenic Transcriptional Circuitries in B-cell Precursor Acute Lymphoblastic Leukemia Reviewed

    Tsuzuki S., Yasuda T., Kojima S., Kawazu M., Akahane K., Inukai T., Imaizumi M., Morishita T., Miyamura K., Ueno T., Karnan S., Ota A., Hyodo T., Konishi H., Sanada M., Nagai H., Horibe K., Tomita A., Suzuki K., Muramatsu H., Takahashi Y., Miyazaki Y., Matsumura I., Kiyoi H., Hosokawa Y., Mano H., Hayakawa F.

    Blood Cancer Discovery   Vol. 1 ( 1 ) page: 82 - 95   2020.7

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    The cellular context that integrates gene expression, signaling, and metabolism dictates the oncogenic behavior and shapes the treatment responses in distinct cancer types. Although chimeric fusion proteins involving transcription factors (TF) are hallmarks of many types of acute lymphoblastic leukemia (ALL), therapeutically targeting the fusion proteins is a challenge. In this work, we characterize the core regulatory circuitry (CRC; interconnected autoregulatory loops of TFs) of B-ALL involving MEF2D-fusions and identify MEF2D-fusion and SREBF1 TFs as crucial CRC components. By gene silencing and pharmacologic perturbation, we reveal that the CRC integrates the pre-B-cell receptor (BCR) and lipid metabolism to maintain itself and govern malignant phenotypes. Small-molecule inhibitors of pre-BCR signaling and lipid biosynthesis disrupt the CRC and silence the MEF2D fusion in cell culture and show therapeutic efficacy in xenografted mice. Therefore, pharmacologic disruption of CRC presents a potential therapeutic strategy to target fusion protein–driven leukemia.

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  73. Conditioning regimen for allogeneic bone marrow transplantation in children with acquired bone marrow failure: fludarabine/melphalan vs. fludarabine/cyclophosphamide Reviewed

    Yoshida N., Takahashi Y., Yabe H., Kobayashi R., Watanabe K., Kudo K., Yabe M., Miyamura T., Koh K., Kawaguchi H., Goto H., Fujita N., Okada K., Okamoto Y., Kato K., Inoue M., Suzuki R., Atsuta Y., Kojima S., Yoshida N., Takahashi Y., Kobayashi R., Watanabe K.i., Kudo K., Kato K., Muramatsu H., Narita A., Wakamatsu M., Kojima S.

    Bone Marrow Transplantation   Vol. 55 ( 7 ) page: 1272 - 1281   2020.7

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    Fludarabine/cyclophosphamide-based conditioning regimens are standard in bone marrow transplantation (BMT) for acquired bone marrow failure in children, however, graft failure may occur. Using the data from a nationwide transplantation registry, we compared the outcomes of children aged <16 years with acquired aplastic anemia and refractory cytopenia of childhood who underwent allogeneic BMT with either fludarabine/melphalan (n = 71) or fludarabine/cyclophosphamide (n = 296) between 2000 and 2016. The fludarabine/melphalan regimen provided excellent outcomes, with 3-year overall survival and failure-free survival rates of 98% and 97%, respectively. The 83% 3-year failure-free survival in the fludarabine/cyclophosphamide group was significantly inferior (P = 0.002), whereas the overall survival did not differ between the two groups. Late graft failure was the most common cause of treatment failure in the fludarabine/cyclophosphamide group, which experienced a significantly higher incidence of late graft failure than the fludarabine/melphalan group (11% vs. 3%; P = 0.035). Multivariate analyses showed that the fludarabine/melphalan regimen was associated with a better failure-free survival (hazard ratio [HR] 0.12; P = 0.005) and lower risk of late graft failure (HR 0.16; P = 0.037). Fludarabine/melphalan-based conditioning regimen can be a promising option for children with acquired bone marrow failure receiving BMT.

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  74. Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex Reviewed

    Kato K., Oka Y., Muramatsu H., Vasilev F.F., Otomo T., Oishi H., Kawano Y., Kidokoro H., Nakazawa Y., Ogi T., Takahashi Y., Saitoh S.

    Journal of Medical Genetics   Vol. 57 ( 4 ) page: 245 - 253   2020.4

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    Background 3C/Ritscher-Schinzel syndrome is characterised by congenital cranio-cerebello-cardiac dysplasia, where CCDC22 and WASHC5 are accepted as the causative genes. In combination with the retromer or retriever complex, these genes play a role in endosomal membrane protein recycling. We aimed to identify the gene abnormality responsible for the pathogenicity in siblings with a 3C/Ritscher-Schinzel-like syndrome, displaying cranio-cerebello-cardiac dysplasia, coloboma, microphthalmia, chondrodysplasia punctata and complicated skeletal malformation. Methods Exome sequencing was performed to identify pathogenic variants. Cellular biological analyses and generation of knockout mice were carried out to elucidate the gene function and pathophysiological significance of the identified variants. Results We identified compound heterozygous pathogenic variants (c.1097dup; p.Cys366Trpfs∗28 and c.2755G>A; p.Ala919Thr) in the VPS35L gene, which encodes a core protein of the retriever complex. The identified missense variant lacked the ability to form the retriever complex, and the frameshift variant induced non-sense-mediated mRNA decay, thereby confirming biallelic loss of function of VPS35L. In addition, VPS35L knockout cells showed decreased autophagic function in nutrient-rich and starvation conditions, as well as following treatment with Torin 1. We also generated Vps35l -/- mice and demonstrated that they were embryonic lethal at an early stage, between E7.5 and E10.5. Conclusions Our results suggest that biallelic loss-of-function variants in VPS35L underlies 3C/Ritscher-Schinzel-like syndrome. Furthermore, VPS35L is necessary for autophagic function and essential for early embryonic development. The data presented here provide a new insight into the critical role of the retriever complex in fetal development.

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  75. Novel compound heterozygous MCOLN1 mutations identified in a Japanese girl with severe developmental delay and thin corpus callosum Reviewed

    Yamaguchi N., Ban K., Suzuki A., Nakamura Y., Kato K., Muramatsu H., Okuno Y., Hattori A., Kaname T., Takahashi Y., Saitoh S.

    Brain and Development   Vol. 42 ( 3 ) page: 298 - 301   2020.3

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    Mucolipidosis type IV (MLIV) is a rare lysosomal storage disorder causing severe psychomotor developmental delay and progressive visual impairment. MLIV is an autosomal recessive disease caused by mutations in MCOLN1, which encodes for mucolipin-1. Here, we report a case of a 4-year-old Japanese girl with severe intellectual disability and motor deficits. Brain magnetic resonance imaging showed signal abnormalities in the white matter and thinning of the corpus callosum. Whole-exome sequencing was performed on the proband and her parents, and novel compound heterozygous mutations at c.936_938del (p.Phe313del) and c.1503dupC (p.Ile502Hisfs*106) in MCOLN1 (NM_020533.2) were identified in the proband. Additional biochemical examinations revealed elevated serum gastrin level and iron deficiency anemia, leading to the diagnosis of MLIV. More reports of such pathogenic mutations are expected to broaden the understanding of the channel function of mucolipin-1 and genotype-phenotype correlations.

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  76. Novel biallelic FA2H mutations in a Japanese boy with fatty acid hydroxylase-associated neurodegeneration Reviewed

    Kawaguchi M., Sassa T., Kidokoro H., Nakata T., Kato K., Muramatsu H., Okuno Y., Yamamoto H., Kaname T., Kihara A., Natsume J.

    Brain and Development   Vol. 42 ( 2 ) page: 217 - 221   2020.2

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    FA2H encodes fatty acid 2-hydroxylase, which plays a significant role in maintaining the neuronal myelin sheath. Previous reports have revealed that a FA2H mutation leads to spastic paraplegia, leukodystrophy, and neurodegeneration with brain iron accumulation, collectively referred to as fatty acid hydroxylase-associated neurodegeneration (FAHN). The disease severity of FAHN varies among individual patients and may be explained by the enzyme activity of FA2H mutant proteins. Here we report a 10-year-old Japanese boy with FAHN having novel heterozygous mutations in FA2H. The patient presented with a spastic gait since the age of 5 years and was unable to walk without a cane by the time he was 8 years old. Brain MRI demonstrated a partial thinning of the corpus callosum, slight reduction of cerebellar volume, and posterior dominant periventricular leukodystrophy. Whole exome sequencing revealed two novel missense mutations in FA2H with compound heterozygous inheritance (NM_024306, p.Val149Leu, and p.His260Gln mutations). The enzyme activities of the p.Val149Leu and p.His260Gln variants were 60%–80% and almost 0%, respectively. Our cell-based enzyme assay demonstrated partial functionality for one of the variants, indicating a milder phenotype. However, considered along with previous reports, there was no definite relationship between the disease severity and residual enzyme activity measured using a similar method. Further research is needed to precisely predict the phenotypic severity of this disorder.

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  77. Targetable driver mutations in multicentric reticulohistiocytosis Reviewed

    Murakami N., Sakai T., Arai E., Muramatsu H., Ichikawa D., Asai S., Shimoyama Y., Ishiguro N., Takahashi Y., Okuno Y., Nishida Y.

    Haematologica   Vol. 105 ( 2 ) page: E61 - E64   2020.1

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  78. Erratum: Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients (Haematologica (2019) (1967) DOI: 10.3324/haematol.2018.207241) Reviewed

    Mori M., Hira A., Yoshida K., Muramatsu H., Okuno Y., Shiraishi Y., Anmae M., Yasuda J., Tadaka S., Kinoshita K., Osumi T., Noguchi Y., Adachi S., Kobayashi R., Kawabata H., Imai K., Morio T., Tamura K., Takaori-Kondo A., Yamamoto M., Miyano S., Kojima S., Ito E., Ogawa S., Matsuo K., Yabe H., Yabe M., Takata M.

    Haematologica   Vol. 105 ( 4 ) page: 1166 - 1167   2020

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    An incorrected version of table 2 appared On October 2019 Issue, page 1967. The corrected version of table 2 is published on the next page. (Table Presented).

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  79. A novel CUL4B splice site variant in a young male exhibiting less pronounced features Reviewed

    Nakamura Y., Okuno Y., Muramatsu H., Kawai T., Satou K., Ieda D., Hori I., Ohashi K., Negishi Y., Hattori A., Takahashi Y., Kojima S., Saitoh S.

    Human Genome Variation   Vol. 6 ( 1 ) page: 43   2019.12

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    Patients with variants in CUL4B exhibit syndromic intellectual disability (MIM #300354). A seven-year-old boy presented with intellectual disability, a history of seizure, characteristic facial features, and short stature. Whole-exome sequencing detected a c.974+3A>G variant in CUL4B, which was subsequently confirmed to disrupt mRNA splicing. The current patient showed less pronounced phenotypic features compared with the previously reported cases. This report, therefore, provides evidence of genotype–phenotype correlations in CUL4B-related disorders.

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  80. Study of pathophysiology and molecular characterization of congenital anemia in India using targeted next-generation sequencing approach Reviewed

    Kedar P.S., Harigae H., Ito E., Muramatsu H., Kojima S., Okuno Y., Fujiwara T., Dongerdiye R., Warang P.P., Madkaikar M.R.

    International Journal of Hematology   Vol. 110 ( 5 ) page: 618 - 626   2019.11

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    Most patients with anemia are diagnosed through clinical phenotype and basic laboratory testing. Nonetheless, in cases of rare congenital anemias, some patients remain undiagnosed despite undergoing an exhaustive workup. Genetic testing is complicated by the large number of genes that are involved in rare anemias, due to similarities in the clinical presentation. We sought to enhance the diagnosis of patients with congenital anemias by using targeted next-generation sequencing. The genetic diagnosis was performed by gene capture followed by next-generation sequencing of 76 genes known to cause anemia syndromes. Genetic diagnosis was achieved in 17 of 21 transfusion-dependent patients and undiagnosed by conventional workup. Four cases were diagnosed with red cell membrane protein defects, four patients were diagnosed with pyruvate kinase deficiency, one case of adenylate kinase deficiency, one case of glucose phosphate isomerase deficiency, one case of hereditary xerocytosis, three cases having combined membrane and enzyme defect, two cases with Diamond–Blackfan anemia (DBA) and 1 with CDA type II with 26 different mutations, of which 21 are novel. Earlier incorporation of this NGS method into the workup of patients with congenital anemia may improve patient care and enable genetic counselling.

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  81. Essential role of PTPN11 mutation in enhanced haematopoietic differentiation potential of induced pluripotent stem cells of juvenile myelomonocytic leukaemia Reviewed

    Shigemura T., Matsuda K., Kurata T., Sakashita K., Okuno Y., Muramatsu H., Yue F., Ebihara Y., Tsuji K., Sasaki K., Nakahata T., Nakazawa Y., Koike K.

    British Journal of Haematology   Vol. 187 ( 2 ) page: 163 - 173   2019.10

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    We established mutated and non-mutated induced pluripotent stem cell (iPSC) clones from a patient with PTPN11 (c.226G>A)-mutated juvenile myelomonocytic leukaemia (JMML). Both types of iPSCs fulfilled the quality criteria. Mutated iPSC colonies generated significantly more CD34+ and CD34+CD45+ cells compared to non-mutated iPSC colonies in a culture coated with irradiated AGM-S3 cells to which four growth factors were added sequentially or simultaneously. The haematopoietic differentiation potential of non-mutated JMML iPSC colonies was similar to or lower than that of iPSC colonies from a healthy individual. The PTPN11 mutation coexisted with the OSBP2 c.389C>T mutation. Zinc-finger nuclease-mediated homologous recombination revealed that correction of PTPN11 mutation in iPSCs with PTPN11 and OSBP2 mutations resulted in reduced CD34+ cell generation to a level similar to that obtained with JMML iPSC colonies with the wild-type of both genes, and interestingly, to that obtained with normal iPSC colonies. Transduction of the PTPN11 mutation into JMML iPSCs with the wild-type of both genes increased CD34+ cell production to a level comparable to that obtained with JMML iPSC colonies harbouring the two genetic mutations. Thus, PTPN11 mutation may be the most essential abnormality to confer an aberrant haematopoietic differentiation potential in this disorder.

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  82. Prospective randomized trial comparing two doses of rabbit anti-thymocyte globulin in patients with severe aplastic anaemia Reviewed

    Narita A., Zhu X., Muramatsu H., Chen X., Guo Y., Yang W., Zhang J., Liu F., Jang J.H., Kook H., Kim H., Usuki K., Yamazaki H., Takahashi Y., Nakao S., Wook Lee J., Kojima S.

    British Journal of Haematology   Vol. 187 ( 2 ) page: 227 - 237   2019.10

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    The treatment of choice for patients with severe aplastic anaemia (SAA) includes immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and ciclosporin A. However, the optimal dose for rabbit ATG has yet to be established. We herein report the first prospective, randomized, multicentre study comparing two doses of rabbit ATG in patients with SAA. Patients with SAA who required initial IST in Japan (n = 89), China (n = 85) and Korea (n = 48) were enrolled between May 2012 and October 2017. A 1:1 block randomization was employed for two doses of rabbit ATG. In total, 222 patients were randomized, with 112 patients receiving 2·5 mg/kg and 110 receiving 3·5 mg/kg of rabbit ATG for 5 days. The primary endpoint was the haematological response at day 180. After 6 months, no significant difference in response rates was observed between the 2·5 and 3·5 mg/kg groups (49% vs. 48%, P = 0·894). Overall survival at 3 years was similar between the two groups [85% (95% confidence interval [CI], 76%−91%) vs. 91% (95% CI, 82%−96%); P = 0·107]. The current study revealed no significant differences in the efficacy and safety between the 2·5 and 3·5 mg/kg doses of rabbit ATG in patients with SAA. Trial registration: UMIN000011134.

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  83. Risk factors for absence of catch-up growth in small for gestational age very low-birthweight infants Reviewed

    Arai S., Sato Y., Muramatsu H., Yamamoto H., Aoki F., Okai Y., Kataoka S., Hanada Y., Hamada M., Morimoto Y., Kojima S., Natsume J., Takahashi Y., Sugiyama Y., Hoshino S., Kawada J., Kidokoro H., Hayakawa M., Hattori T., Kato Y., Yasuda A., Oshiro M., Takemoto K., Nishimura N., Hayashi S., Hyodo R., Ito M., Narahara S., Ieda K., Yamamoto H.

    Pediatrics International   Vol. 61 ( 9 ) page: 889 - 894   2019.9

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    Background: Many small for gestational age (SGA) infants have catch-up growth during the first 2 years of life, but approximately 10% have no catch-up growth, and short stature continues into adulthood. Identification of risk factors for absence of catch-up growth at an early age may be useful for earlier diagnosis and earlier treatment. Methods: This was a retrospective multicenter study. The subjects were SGA infants with very low-birthweight (VLBW), who were followed up until the age of 3 years. The risk factors for absence of catch-up growth were identified on statistical analysis. Results: Of the 217 SGA infants in this study, 181 were in the catch-up group and 36 were in the no catch-up group. The catch-up rate was 83%. On multivariate analysis adjusted for gestational age, birthweight, birth height, and birth head circumference, multipara, Z and ΔZ scores of length at 12 months of corrected age, and the Z score of height at 24 months of corrected age were risk factors for lack of catch-up at 3 years. Conclusions: The length Z and ΔZ scores at 12 months of corrected age may be useful for an earlier diagnosis and earlier initiation of growth hormone treatment in VLBW infants.

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  84. Whole abdominopelvic intensity-modulated radiation therapy for peritoneal disseminated rhabdomyosarcoma with three-year follow-up: A case report Reviewed

    Kawamura M., Okudaira K., Itoh Y., Kamomae T., Nishikawa E., Muramatsu H., Takahashi Y., Yokota K., Naganawa S.

    Radiation Oncology   Vol. 14 ( 1 ) page: 127   2019.7

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    Background: The role of local radiotherapy in the treatment of metastatic rhabdomyosarcoma is important. However, with peritoneal dissemination, the application of local therapy is challenging. Although there are few reports addressing the efficacy of the whole abdominopelvic irradiation to peritoneal disseminated rhabdomyosarcoma patients, no precise curse of treatment nor the follow up result is explained in paper nor in the text. Case presentation: Six years old rhabdomyosarcoma boy with peritoneal dissemination was treated at our facility under COG D9803 protocol (vincristine, dactinomycin, and cyclophosphamide (VAC)). He underwent tumor resection on the 14th week according to the protocol. During surgery, the 2-cm residual tumor was completely resected, but in the pelvis, numerous nodules that were suspected as peritoneal disseminated tumors were observed. We administered 30 Gy/20fr whole abdominopelvic radiotherapy using volumetric modulated arc therapy (VMAT) technique and a 6 Gy sequential boost to pelvis after the surgery and completed the protocol treatment. During the course of treatment, the patient experienced G4 hematological toxicity and received multiple transfusions, particularly after whole abdominopelvic irradiation. He has achieved complete remission and is alive without evidence of recurrence and severe late adverse effect for 3 years. In terms of growth, his height and weight are within the average values for Japanese boys at the same age. Conclusion: By using the VMAT technique, a patient with peritoneal disseminated rhabdomyosarcoma can be treated, and a dose of 30 Gy to the whole abdominopelvis with concurrent chemotherapy may be tolerable.

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  85. Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1 Reviewed

    Yamamoto-Shimojima K., Imaizumi T., Aoki Y., Inoue K., Kaname T., Okuno Y., Muramatsu H., Kato K., Yamamoto T.

    Journal of Human Genetics   Vol. 64 ( 7 ) page: 665 - 671   2019.7

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    Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder caused by abnormalities in the gene PLP1. Most females harboring heterozygous PLP1 abnormalities are basically asymptomatic. However, as a result of abnormal patterns of X-chromosome inactivation, it is possible for some female carriers to be symptomatic. Whole-exome sequencing of a female patient with unknown spastic paraplegia was performed to obtain a molecular diagnosis. As a result, a de novo heterozygous single-nucleotide deletion in PLP1 [NM_000533.5(PLP1_v001):c.783del; p.Thr262Leufs*20] was identified. RNA sequencing was performed in a patient-derived lymphoblastoid cell line, confirming mono-allelic expression of the mutated allele and abnormal inactivation of the wild-type allele. The patient-derived lymphoblastoid cell line was then treated with VX680 or 5azadC, which resulted in restored expression of the wild-type allele. These two agents thus have the potential to reverse inappropriately-skewed inactivation of the X-chromosome.

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  86. Correction: Treatment with silver nitrate versus topical steroid treatment for umbilical granuloma: A non-inferiority randomized control trial (PLoS ONE (2018) 13: 2 (e0192688) DOI: 10.1371/journal.pone.0192688) Reviewed

    Ogawa C., Sato Y., Suzuki C., Mano A., Tashiro A., Niwa T., Hamazaki S., Tanahashi Y., Suzumura M., Hayano S., Hayakawa M., Tsuji T., Hoshino S., Sugiyama Y., Kidokoro H., Kawada J.i., Muramatsu H., Hirakawa A., Ando M., Natsume J., Kojima S.

    PLoS ONE   Vol. 14 ( 6 ) page: e0218205   2019.6

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    In the TSO treatment subsection of the Materials and methods section, the concentration of betamethasone valerate ointment is incorrect. The correct sentence is: Patients were applied with 0.12% betamethasone valerate ointment to the lesion twice a day after washing or bathing by parents.

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  87. Design of a prospective multicenter randomized controlled trial evaluating the effects of gastric lavage on coffee-ground emesis in neonates: study protocol Reviewed

    Maeda T., Sato Y., Hirakawa A., Nakatochi M., Kinoshita F., Suzuki T., Ichimura S., Ito R., Kudo R., Suzuki M., Hoshino S., Sugiyama Y., Muramatsu H., Kidokoro H., Kawada J.I., Takahashi Y.

    Nagoya journal of medical science   Vol. 81 ( 2 ) page: 227 - 232   2019.5

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    Neonates who swallow a considerable amount of maternal blood may exhibit vomiting and suckling disorder during the first few days of the postnatal period. Some clinicians treat these neonates with gastric lavage (GL) to prevent vomiting and the establishment of enteral feeding empirically, but there was no study assessing the effect of GL for neonates with coffee-ground emesis. We designed a multicenter randomized controlled trial to evaluate the efficacy and safety of GL in neonates with coffee-ground emesis. Vigorous neonates with birth weight ranging from 2500 g to 3999 g and gestational age between 37w0d and 41w6d who presented with coffee-ground emesis on more than twice and diagnosed as false melena, were divided into two groups using computerized randomization. We defined feeding intolerance (FI) as (1) ≥2 vomiting episodes in 4h or ≥3 episodes in 24h and/or (2) feeding failure on at least two occasions because of retching or poor sucking. Primary outcome is percentage of infants who present FI within 24 hours from admission. We also assessed the residual volumes, number of vomiting episodes, percentage of weight reduction at postnatal day 4, rates of body weight gain at 1 month of age, and peak serum total bilirubin value before discharge. To our knowledge, this is the first study to evaluate the safety and efficacy of GL for neonates with coffee-ground emesis. This trial is registered at UMIN Clinical Trials Registry as UMIN000026483.

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  88. Comparison of high-dose and low-dose corticosteroid therapy for refractory Mycoplasma pneumoniae pneumonia in children Reviewed

    Okumura T., Kawada J.i., Tanaka M., Narita K., Ishiguro T., Hirayama Y., Narahara S., Tsuji G., Sugiyama Y., Suzuki M., Tsuji T., Hoshino S., Nakatochi M., Muramatsu H., Kidokoro H., Takahashi Y., Sato Y., Miyajima Y., Uno N., Nagai N., Ando S., Sudo Y., Naruse K., Takahashi Y., Suzui R., Nagata Y., Kawabe T., Shibata M., Shibata Y., Morishita M., Kajita M., Ito T., Kido S., Hasegawa S., Ikeda K., Tokumo N., Kato M., Kato K., Fukumi D., Doi S., Omori M., Watanabe N., Takada H.

    Journal of Infection and Chemotherapy   Vol. 25 ( 5 ) page: 346 - 350   2019.5

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    Background: Mycoplasma pneumoniae pneumonia (MPP) is generally a self-limiting disease, but it may become refractory. It is thought that refractory MPP is linked to the excessive immunologic responses of the host. Consequently, the use of adjunctive systemic corticosteroids may have beneficial effects. In this study, we compared the effects of high- and low-dose corticosteroid therapy in a pediatric population with refractory MPP. Methods: We retrospectively collected data from 91 pediatric MPP patients treated with adjunctive systemic corticosteroids between April 2014 and October 2016. The patients were divided into the following two groups: high-dose corticosteroid group (2 mg/kg/day or more of prednisolone equivalents; n = 38) and low-dose corticosteroid group (<2 mg/kg/day; n = 53). Additionally, we compared the number of febrile days post-corticosteroid administration. We used 25 paired patients in a propensity score matching analysis to correct for confounding factors both by age and by days (from onset till corticosteroid therapy initiation). Results: We observed that in the high-dose corticosteroid group defervescence following corticosteroid therapy initiation was achieved significantly earlier and length of hospitalization was significantly shorter (0.8 ± 1.0 vs. 1.5 ± 1.4 days and 8.2 ± 2.4 vs. 10.7 ± 2.7 days, respectively). In the propensity score matching, we observed that significant differences in the length of fever following corticosteroid therapy initiation and hospitalization were still present. Further, neither of the groups developed corticosteroid-related adverse events. Conclusion: Our results suggest that patients with refractory MPP treated with high-dose corticosteroid could achieve defervescence earlier and have a shorter hospitalization.

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  89. KLF1 mutation E325K induces cell cycle arrest in erythroid cells differentiated from congenital dyserythropoietic anemia patient-specific induced pluripotent stem cells Reviewed

    Kohara H., Utsugisawa T., Sakamoto C., Hirose L., Ogawa Y., Ogura H., Sugawara A., Liao J., Aoki T., Iwasaki T., Asai T., Doisaki S., Okuno Y., Muramatsu H., Abe T., Kurita R., Miyamoto S., Sakuma T., Shiba M., Yamamoto T., Ohga S., Yoshida K., Ogawa S., Ito E., Kojima S., Kanno H., Tani K.

    Experimental Hematology   Vol. 73   page: 25 - 37.e8   2019.5

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    Krüppel-like factor 1 (KLF1), a transcription factor controlling definitive erythropoiesis, is involved in sequential control of terminal cell division and enucleation via fine regulation of key cell cycle regulator gene expression in erythroid lineage cells. Type IV congenital dyserythropoietic anemia (CDA)is caused by a monoallelic mutation at the second zinc finger of KLF1 (c.973G>A, p.E325K). We recently diagnosed a female patient with type IV CDA with the identical missense mutation. To understand the mechanism underlying the dyserythropoiesis caused by the mutation, we generated induced pluripotent stem cells (iPSCs)from the CDA patient (CDA-iPSCs). The erythroid cells that differentiated from CDA-iPSCs (CDA-erythroid cells)displayed multinucleated morphology, absence of CD44, and dysregulation of the KLF1 target gene expression. In addition, uptake of bromodeoxyuridine by CDA-erythroid cells was significantly decreased at the CD235a+/CD71+ stage, and microarray analysis revealed that cell cycle regulator genes were dysregulated, with increased expression of negative regulators such as CDKN2C and CDKN2A. Furthermore, inducible expression of the KLF1 E325K, but not the wild-type KLF1, caused a cell cycle arrest at the G1 phase in CDA-erythroid cells. Microarray analysis of CDA-erythroid cells and real-time polymerase chain reaction analysis of the KLF1 E325K inducible expression system also revealed altered expression of several KLF1 target genes including erythrocyte membrane protein band 4.1 (EPB41), EPB42, glutathione disulfide reductase (GSR), glucose phosphate isomerase (GPI), and ATPase phospholipid transporting 8A1 (ATP8A1). Our data indicate that the E325K mutation in KLF1 is associated with disruption of transcriptional control of cell cycle regulators in association with erythroid membrane or enzyme abnormalities, leading to dyserythropoiesis.

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  90. Successful hematopoietic stem cell transplantation from an HLA-mismatched parent for engraftment failure after unrelated cord blood transplantation in patients with juvenile myelomonocytic leukemia: Report of two cases Reviewed

    Akahane K., Watanabe A., Furuichi Y., Somazu S., Oshiro H., Goi K., Sakashita K., Muramatsu H., Hama A., Takahashi Y., Koike K., Kojima S., Sugita K., Inukai T.

    Pediatric Transplantation   Vol. 23 ( 3 ) page: e13378   2019.5

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    JMML is an aggressive hematopoietic malignancy of early childhood, and allogeneic HSCT is the only curative treatment for this disease. Umbilical cord blood is one of donor sources for HSCT in JMML patients who do not have an HLA-compatible relative, but engraftment failure remains a major problem. Here, we report two cases of JMML who were successfully rescued by HSCT from an HLA-mismatched parent after development of primary engraftment failure following unrelated CBT. Both patients had severe splenomegaly and underwent unrelated CBT from an HLA-mismatched donor. Immediately after diagnosis of engraftment failure, both patients underwent HSCT from their parent. For the second HSCT, we used RIC regimens consisting of FLU, CY, and a low dose of rabbit ATG with or without TBI and additionally administered ETP considering their persistent severe splenomegaly. Both patients achieved engraftment without severe treatment-related adverse effects. After engraftment of second HSCT, their splenomegaly was rapidly regressed, and both patients showed no sign of relapse for over 4 years. These observations demonstrate that HSCT from an HLA-mismatched parent could be a feasible salvage treatment for primary engraftment failure in JMML patients.

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  91. Defective Epstein–Barr virus in chronic active infection and haematological malignancy Reviewed

    Okuno Y., Murata T., Sato Y., Muramatsu H., Ito Y., Watanabe T., Okuno T., Murakami N., Yoshida K., Sawada A., Inoue M., Kawa K., Seto M., Ohshima K., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Narita Y., Yoshida M., Goshima F., Kawada J.i., Nishida T., Kiyoi H., Kato S., Nakamura S., Morishima S., Yoshikawa T., Fujiwara S., Shimizu N., Isobe Y., Noguchi M., Kikuta A., Iwatsuki K., Takahashi Y., Kojima S., Ogawa S., Kimura H.

    Nature Microbiology   Vol. 4 ( 3 ) page: 404 - 413   2019.3

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    Epstein–Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer1,2. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification1,2. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms3. Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF14–7, while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.

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  92. Correction to: Defective Epstein–Barr virus in chronic active infection and haematological malignancy (Nature Microbiology, (2019), 4, 3, (404-413), 10.1038/s41564-018-0334-0) Reviewed

    Okuno Y., Murata T., Sato Y., Muramatsu H., Ito Y., Watanabe T., Okuno T., Murakami N., Yoshida K., Sawada A., Inoue M., Kawa K., Seto M., Ohshima K., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Narita Y., Yoshida M., Goshima F., Kawada J.i., Nishida T., Kiyoi H., Kato S., Nakamura S., Morishima S., Yoshikawa T., Fujiwara S., Shimizu N., Isobe Y., Noguchi M., Kikuta A., Iwatsuki K., Takahashi Y., Kojima S., Ogawa S., Kimura H.

    Nature Microbiology   Vol. 4 ( 3 ) page: 544   2019.3

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    In the version of this Letter originally published, in the sentence beginning “The major driver role of DDX3X mutations..”, the citation “Fig. 2a–f” should have been “Fig. 2”. In addition, in the sentence beginning “Another finding of interest was the presence of identical driver mutations..”, the citation “Fig. 3a,b and Fig. 4” should have been “Fig. 3”. This has now been amended in all versions of the Letter.

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  93. Allogeneic stem cell transplantation with reduced intensity conditioning for patients with adrenoleukodystrophy Reviewed

    Kato Koji, Maemura Ryo, Wakamatsu Manabu, Yamamori Ayako, Hamada Motoharu, Kataoka Shinsuke, Narita Atsushi, Miwata Shunsuke, Sekiya Yuko, Kawashima Nozomu, Suzuki Kyogo, Narita Kotaro, Doisaki Sayoko, Muramatsu Hideki, Sakaguchi Hirotoshi, Matsumoto Kimikazu, Koike Yuka, Onodera Osamu, Kaga Makiko, Shimozawa Nobuyuki, Yoshida Nao

    MOLECULAR GENETICS AND METABOLISM REPORTS   Vol. 18   page: 1 - 6   2019.3

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  94. Associations of complementation group, ALDH2 genotype, and clonal abnormalities with hematological outcome in Japanese patients with Fanconi anemia Reviewed

    Yabe M., Koike T., Ohtsubo K., Imai E., Morimoto T., Takakura H., Koh K., Yoshida K., Ogawa S., Ito E., Okuno Y., Muramatsu H., Kojima S., Matsuo K., Mori M., Hira A., Takata M., Yabe H.

    Annals of Hematology   Vol. 98 ( 2 ) page: 271 - 280   2019.2

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    Fanconi anemia (FA) is a genetically and clinically heterogeneous disorder that predisposes patients to bone marrow failure (BMF), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). To study which genetic and phenotypic factors predict clinical outcomes for Japanese FA patients, we examined the FA genes, bone marrow karyotype, and aldehyde dehydrogenase-2 (ALDH2) genotype; variants of which are associated with accelerated progression of BMF in FA. In 88 patients, we found morphologic MDS/AML in 33 patients, including refractory cytopenia in 16, refractory anemia with excess blasts (RAEB) in 7, and AML in 10. The major mutated FA genes observed in this study were FANCA (n = 52) and FANCG (n = 23). The distribution of the ALDH2 variant alleles did not differ significantly between patients with mutations in FANCA and FANCG. However, patients with FANCG mutations had inferior BMF-free survival and received hematopoietic stem cell transplantation (HSCT) at a younger age than those with FANCA mutations. In FANCA, patients with the c.2546delC mutation (n = 24) related to poorer MDS/AML-free survival and a younger age at HSCT than those without this mutation. All patients with RAEB/AML had an abnormal karyotype and poorer prognosis after HSCT; specifically, the presence of a structurally complex karyotype with a monosomy (n = 6) was associated with dismal prognosis. In conclusion, the best practice for a clinician may be to integrate the morphological, cytogenetic, and genetic data to optimize HSCT timing in Japanese FA patients.

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  95. Comparison of conditioning regimens for autologous stem cell transplantation in children with acute myeloid leukemia: A nationwide retrospective study in Japan Reviewed

    Sakaguchi H., Muramatsu H., Hasegawa D., Kudo K., Ishida H., Yoshida N., Koh K., Noguchi M., Shiba N., Tokimasa S., Fukuda T., Goto H., Miyamura T., Nakazawa Y., Hashii Y., Inoue M., Atsuta Y.

    Pediatric Blood and Cancer   Vol. 66 ( 1 ) page: e27459   2019.1

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    Background: Indications for hematopoietic stem cell transplantation (HSCT) have decreased with the improvement in chemotherapy for pediatric acute myeloid leukemia (AML) in the last decade. We conducted reevaluation of autologous HSCT (AHSCT) to compare myeloablative conditioning (MAC) regimens for pediatric AML without the need for consideration of toxicities caused by allogeneic immune reactions. Procedure: This retrospective study analyzed the clinical outcomes of 220 children with AML who underwent consecutive AHSCT between 1989 and 2002 in Japan by the national prospective registry. The transplantation outcomes of various conditioning regimens were compared. Results: The median follow-up period of the survivors was 160 months. The clinical outcomes of busulfan + cyclophosphamide ± etoposide or busulfan + melphalan regimens were significantly superior compared with other busulfan-based and total body irradiation-based regimens (leukemia-free survival [LFS]: 68% vs 42% and 55%, P = 0.001; overall survival [OS]: 74% vs 49% and 61%, P < 0.001). Multivariate analysis showed that busulfan + cyclophosphamide ± etoposide and busulfan + melphalan regimens were independent favorable factors for LFS (hazard ratio: 0.46; P < 0.001) and OS (hazard ratio: 0.40; P < 0.001) compared with the other busulfan-based regimen, and both age 2 years or older and advanced stage at AHSCT were independent poor predictors for LFS and OS, simultaneously. Conclusion: Busulfan + cyclophosphamide ± etoposide and busulfan + melphalan regimens exhibited superior antileukemic effects compared with other BU-based myeloablative regimens.

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  96. Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1 Reviewed

    Okano T., Imai K., Tsujita Y., Mitsuiki N., Yoshida K., Kamae C., Honma K., Mitsui-Sekinaka K., Sekinaka Y., Kato T., Hanabusa K., Endo E., Takashima T., Hiroki H., Yeh T.W., Tanaka K., Nagahori M., Tsuge I., Bando Y., Iwasaki F., Shikama Y., Inoue M., Kimoto T., Moriguchi N., Yuza Y., Kaneko T., Suzuki K., Matsubara T., Maruo Y., Kunitsu T., Waragai T., Sano H., Hashimoto Y., Tasaki K., Suzuki O., Shirakawa T., Kato M., Uchiyama T., Ishimura M., Tauchi T., Yagasaki H., Jou S.T., Yu H.H., Kanegane H., Kracker S., Durandy A., Kojima D., Muramatsu H., Wada T., Inoue Y., Takada H., Kojima S., Ogawa S., Ohara O., Nonoyama S., Morio T.

    Journal of Allergy and Clinical Immunology   Vol. 143 ( 1 ) page: 266 - 275   2019.1

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    Background: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined. Objective: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT. Methods: We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities. Results: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT. Conclusion: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning–HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.

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  97. Comparison of clinical characteristics of human metapneumovirus and respiratory syncytial virus infections in hospitalized young children Reviewed

    Taniguchi A., Kawada J.I., Go K., Fujishiro N., Hosokawa Y., Maki Y., Sugiyama Y., Suzuki M., Tsuji T., Hoshino S., Muramatsu H., Kidokoro H., Kinoshita F., Hirakawa A., Takahashi Y., Sato Y., Natsume J., Yamakawa K., Okumura A., Kato T., Nagai N., Moriyama M., Miyajima Y., Yamamori K., Shibata M., Hasegawa M., Shinohara O., Nishimura N., Aoshima T., Morishita M., Nomura Y., Kuraishi K.

    Japanese Journal of Infectious Diseases   Vol. 72 ( 4 ) page: 237 - 242   2019

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    Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are the leading causes of acute respiratory tract infection in children, and clinical manifestations of these virus infections are considered similar. To investigate the differences in clinical characteristics between HMPV and RSV infections in young children, we prospectively enrolled children < 3 years old who required hospitalization with acute respiratory tract infection due to HMPV or RSV at 10 hospitals in Japan. We enrolled 48 children with HMPV infection and 141 with RSV infection. Patients with HMPV infection were older than those with RSV infection. High-grade fever was more frequently observed in patients with HMPV infection, whereas no significant differences in respiratory symptoms were apparent. Abnormal serum lactate dehydrogenase values and consolidation shadows on chest X-ray were more frequently observed in patients with HMPV infection. During hospitalization, nasal mucus suction was more frequently required in patients with RSV infection. On the other hand, β2-adrenergic agonists, corticosteroids, and leukotriene receptor antagonists were more frequently used in patients with HMPV infection. These findings suggest that HMPV and RSV infections show similar respiratory symptoms, but HMPV infection is more likely to lead to the development of pneumonia, at least among hospitalized young children.

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  98. Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients Reviewed

    Mori M., Hira A., Yoshida K., Muramatsu H., Okuno Y., Shiraishi Y., Anmae M., Yasuda J., Tadaka S., Kinoshita K., Osumi T., Noguchi Y., Adachi S., Kobayashi R., Kawabata H., Imai K., Morio T., Tamura K., Takaori-Kondo A., Yamamoto M., Miyano S., Kojima S., Ito E., Ogawa S., Matsuo K., Yabe H., Yabe M., Takata M.

    Haematologica   Vol. 104 ( 10 ) page: 1962 - 1973   2019

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    Fanconi anemia is a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies. It results from mutations in one of the 22 known FANC genes. The number of Japanese Fanconi anemia patients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FANC genes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. FANCA and FANCG pathogenic variants accounted for the disease in 58% and 25% of Fanconi anemia patients, respectively. We identified one FANCA and two FANCG hot spot mutations, which are found at low percentages (0.04- 0.1%) in the whole-genome reference panel of 3,554 Japanese individuals (Tohoku Medical Megabank). FANCBwas the third most common complementation group and only one FANCC case was identified in our series. Based on the data from the Tohoku Medical Megabank, we estimate that approximately 2.6% of Japanese are carriers of disease-causing FANC gene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemia patients to date and the results will be useful for future clinical management.

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  99. Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia Reviewed

    Nemoto M., Hattori H., Maeda N., Akita N., Muramatsu H., Moritani S., Kawasaki T., Maejima M., Ode H., Hachiya A., Sugiura W., Yokomaku Y., Horibe K., Iwatani Y.

    Scientific Reports   Vol. 8 ( 1 ) page: 6956   2018.12

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    Complete tyrosine kinase 2 (TYK2) deficiency has been previously described in patients with primary immunodeficiency diseases. The patients were infected with various pathogens, including mycobacteria and/or viruses, and one of the patients developed hyper-IgE syndrome. A detailed immunological investigation of these patients revealed impaired responses to type I IFN, IL-10, IL-12 and IL-23, which are associated with increased susceptibility to mycobacterial and/or viral infections. Herein, we report a recessive partial TYK2 deficiency in two siblings who presented with T-cell lymphopenia characterized by low naïve CD4+ T-cell counts and who developed Epstein-Barr virus (EBV)-associated B-cell lymphoma. Targeted exome-sequencing of the siblings' genomes demonstrated that both patients carried novel compound heterozygous mutations (c.209-212delGCTT/c.691C > T, p.Cys70Serfs∗21/p.Arg231Trp) in the TYK2. The TYK2 protein levels were reduced by 35% in the T cells of the patient. Unlike the response under complete TYK2 deficiency, the patient's T cells responded normally to type I IFN, IL-6, IL-10 and IL-12, whereas the cells displayed an impaired response to IL-23. Furthermore, the level of STAT1 was low in the cells of the patient. These studies reveal a new clinical entity of a primary immunodeficiency with T-cell lymphopenia that is associated with compound heterozygous TYK2 mutations in the patients.

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  100. Sequential use of second-generation tyrosine kinase inhibitors following imatinib therapy in pediatric chronic myeloid leukemia: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group Reviewed

    Kurosawa H., Tanizawa A., Muramatsu H., Tono C., Watanabe A., Shima H., Ito M., Yuza Y., Hamamoto K., Hotta N., Okada M., Saito A.M., Manabe A., Mizutani S., Adachi S., Horibe K., Ishii E., Shimada H.

    Pediatric Blood and Cancer   Vol. 65 ( 12 ) page: e27368   2018.12

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    Background: The details of the sequential use of imatinib for first-line treatment followed by second-generation tyrosine kinase inhibitors (2G-TKIs) for pediatric chronic myeloid leukemia (CML) are still unknown. This study analyzed clinical responses and adverse effects of the use of 2G-TKIs following imatinib in pediatric chronic phase (CP)-CML. Procedures: The Japanese Pediatric Leukemia/Lymphoma Study Group conducted a retrospective study of patients with newly diagnosed CML from 1996 to 2011. A total of 152 cases that received imatinib as first-line therapy were analyzed. Results: Excluding 46 cases treated with hematopoietic stem cell transplantation before nilotinib and dasatinib became available, 31 of 106 patients changed to 2G-TKIs. The primary reason for changing from imatinib was poor response, followed by intolerance, with the main reason for the latter being musculoskeletal events. Switches from imatinib to 2G-TKIs with intolerance occurred significantly earlier than switches with poor response. Sixteen and 15 patients were treated with nilotinib and dasatinib, respectively, following imatinib therapy. After switching to 2G-TKIs, the response status improved in 63% of evaluable patients. The adverse effect profiles of nilotinib and dasatinib tended to be different, with hyperbilirubinemia observed in 33% of nilotinib-treated patients, but in none of the cases with dasatinib. Conclusion: This retrospective study represents the first series of children and adolescents in whom sequential use of imatinib followed by 2G-TKIs was reported. These data provide useful insights into the selection of 2G-TKIs as first-line treatment for children and adolescents with CP-CML.

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  101. Ureteral dilatation detected in magnetic resonance imaging predicts vesicoureteral reflux in children with urinary tract infection Reviewed

    Murakami N., Kawada J.i., Watanabe A., Arakawa T., Kano T., Suzuki T., Tanaka R., Kojima D., Kawano Y., Hoshino S., Muramatsu H., Takahashi Y., Sato Y., Koyama M., Natsume J.

    PLoS ONE   Vol. 13 ( 12 ) page: e0209595   2018.12

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    Objective Urinary tract infection (UTI), one of the most common bacterial infections occurring during infancy and early childhood, is frequently associated with vesicoureteral reflux (VUR). Although several guidelines recommend performing ultrasonography as a screening test, its utility is not adequate and appropriate screening tests are strongly desirable. In this study, we evaluate the use of magnetic resonance imaging (MRI) as a screening test for VUR in children with UTI. Methods We prospectively studied 108 patients with suspected UTI between April 2014 and March 2016. UTI was diagnosed on the basis of diffusion-weighted MRI (DW-MRI) and urine culture findings. We measured ureteral dilatation using MRI in 96 patients with UTI and assessed the relationship between ureteral dilatation in MRI and VUR in 46 patients who underwent voiding cystourethrography (VCUG). Results Among 108 patients, 88 and 8 were diagnosed with upper and lower UTI, respectively. Among 46 patients who underwent VCUG, 23 had VUR (14 low grade and 9 high grade). Patients with ureteral dilatation detected on MRI had VUR more frequently than those without ureteral dilatation (any grades VUR, 71% vs. 32%; P = 0.02; high-grade VUR, 38% vs. 2%, P = 0.007). Overall, ureteral dilatation findings on MRI achieved sensitivity 65.2% and specificity 73.9% as a screening test for VUR. In addition, DW-MRI achieved sensitivity 100% and specificity 81.8% in the diagnosis of upper UTI. Conclusion These findings suggested that MRI is a valuable tool for screening of VUR as well as diagnosis of upper UTI.

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  102. The Presence of Defective Epstein-Barr Virus (EBV) Infection in Patients with EBV-Associated Hematological Malignancy

    Okuno Yusuke, Murata Takayuki, Sato Yoshitaka, Muramatsu Hideki, Ito Yoshinori, Watanabe Takahiro, Okuno Tatsuya, Murakami Norihiro, Yoshida Kenichi, Sawada Akihisa, Inoue Masami, Kawa Keisei, Seto Masao, Ohshima Koichi, Shiraishi Yuichi, Chiba Kenichi, Tanaka Hiroko, Miyano Satoru, Narita Yohei, Yoshida Masahiro, Goshima Fumi, Kawada Junichi, Nishida Tetsuya, Kiyoi Hitoshi, Kato Seiichi, Nakamura Shigeo, Morishima Satoko, Fujiwara Shigeyoshi, Shimizu Norio, Isobe Yasushi, Noguchi Masaaki, Kikuta Atsushi, Iwatsuki Keiji, Takahashi Yoshiyuki, Kojima Seiji, Ogawa Seishi, Kimura Hiroshi

    BLOOD   Vol. 132   2018.11

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  103. Sudden Intracranial Hemorrhage in a Patient With Atypical Chronic Myeloid Leukemia in Chronic Phase. Reviewed

    Kouzuki K, Umeda K, Saida S, Kato I, Hiramatsu H, Funaki T, Kanda K, Muramatsu H, Yoshida K, Ogawa S, Adachi S

    Journal of pediatric hematology/oncology   Vol. 40 ( 8 ) page: e553 - e556   2018.11

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  104. A patient with a GNAO1 mutation with decreased spontaneous movements, hypotonia, and dystonic features Reviewed

    Okumura Akihisa, Maruyama Koichi, Shibata Mami, Kurahashi Hirokazu, Ishii Atsushi, Numoto Shingo, Hirose Shinichi, Kawai Tomoko, Iso Manami, Kataoka Shinsuke, Okuno Yusuke, Muramatsu Hideki, Kojima Seiji

    BRAIN & DEVELOPMENT   Vol. 40 ( 10 ) page: 926 - 930   2018.11

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  105. Whole-exome analysis to detect congenital hemolytic anemia mimicking congenital dyserythropoietic anemia Reviewed

    Hamada M., Doisaki S., Okuno Y., Muramatsu H., Hama A., Kawashima N., Narita A., Nishio N., Yoshida K., Kanno H., Manabe A., Taga T., Takahashi Y., Miyano S., Ogawa S., Kojima S.

    International Journal of Hematology   Vol. 108 ( 3 ) page: 306 - 311   2018.9

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    Congenital dyserythropoietic anemia (CDA) is a heterogeneous group of rare congenital disorders characterized by ineffective erythropoiesis and dysplastic changes in erythroblasts. Diagnosis of CDA is based primarily on the morphology of bone marrow erythroblasts; however, genetic tests have recently become more important. Here, we performed genetic analysis of 10 Japanese patients who had been diagnosed with CDA based on laboratory findings and morphological characteristics. We examined 10 CDA patients via central review of bone marrow morphology and genetic analysis for congenital bone marrow failure syndromes. Sanger sequencing for CDAN1, SEC23B, and KLF1 was performed for all patients. We performed whole-exome sequencing in patients without mutation in these genes. Three patients carried pathogenic CDAN1 mutations, whereas no SEC23B mutations were identified in our cohort. WES unexpectedly identified gene mutations known to cause congenital hemolytic anemia in two patients: canonical G6PD p.Val394Leu mutation and SPTA1 p.Arg28His mutation. Comprehensive genetic analysis is warranted for more effective diagnosis of patients with suspected CDA.

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  106. Integration Mapping of piggyBac-Mediated CD19 Chimeric Antigen Receptor T Cells Analyzed by Novel Tagmentation-Assisted PCR Reviewed

    Hamada M., Nishio N., Okuno Y., Suzuki S., Kawashima N., Muramatsu H., Tsubota S., Wilson M.H., Morita D., Kataoka S., Ichikawa D., Murakami N., Taniguchi R., Suzuki K., Kojima D., Sekiya Y., Nishikawa E., Narita A., Hama A., Kojima S., Nakazawa Y., Takahashi Y.

    EBioMedicine   Vol. 34   page: 18 - 26   2018.8

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    Insertional mutagenesis is an important risk with all genetically modified cell therapies, including chimeric antigen receptor (CAR)-T cell therapy used for hematological malignancies. Here we describe a new tagmentation-assisted PCR (tag-PCR) system that can determine the integration sites of transgenes without using restriction enzyme digestion (which can potentially bias the detection) and allows library preparation in fewer steps than with other methods. Using this system, we compared the integration sites of CD19-specific CAR genes in final T cell products generated by retrovirus-based and lentivirus-based gene transfer and by the piggyBac transposon system. The piggyBac system demonstrated lower preference than the retroviral system for integration near transcriptional start sites and CpG islands and higher preference than the lentiviral system for integration into genomic safe harbors. Integration into or near proto-oncogenes was similar in all three systems. Tag-PCR mapping is a useful technique for assessing the risk of insertional mutagenesis.

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  107. Diagnostic performance of <sup>18</sup>F-FDG PET/CT and whole-body diffusion-weighted imaging with background body suppression (DWIBS) in detection of lymph node and bone metastases from pediatric neuroblastoma Reviewed

    Ishiguchi H., Ito S., Kato K., Sakurai Y., Kawai H., Fujita N., Abe S., Narita A., Nishio N., Muramatsu H., Takahashi Y., Naganawa S.

    Annals of Nuclear Medicine   Vol. 32 ( 5 ) page: 348 - 362   2018.6

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    Objective: Recent many studies have shown that whole body “diffusion-weighted imaging with background body signal suppression” (DWIBS) seems a beneficial tool having higher tumor detection sensitivity without ionizing radiation exposure for pediatric tumors. In this study, we evaluated the diagnostic performance of whole body DWIBS and 18F-FDG PET/CT for detecting lymph node and bone metastases in pediatric patients with neuroblastoma. Methods: Subjects in this retrospective study comprised 13 consecutive pediatric patients with neuroblastoma (7 males, 6 females; mean age, 2.9 ± 2.0 years old) who underwent both 18F-FDG PET/CT and whole-body DWIBS. All patients were diagnosed as neuroblastoma on the basis of pathological findings. Eight regions of lymph nodes and 17 segments of skeletons in all patients were evaluated. The images of 123I-MIBG scintigraphy/SPECT-CT, bone scintigraphy/SPECT, and CT were used to confirm the presence of lymph node and bone metastases. Two radiologists trained in nuclear medicine evaluated independently the uptake of lesions in 18F-FDG PET/CT and the signal-intensity of lesions in whole-body DWIBS visually. Interobserver difference was overcome through discussion to reach a consensus. The sensitivities, specificities, and overall accuracies of 18F-FDG PET/CT and whole-body DWIBS were compared using McNemer’s test. Positive predictive values (PPVs) and negative predictive values (NPVs) of both modalities were compared using Fisher’s exact test. Results: The total numbers of lymph node regions and bone segments which were confirmed to have metastasis in the total 13 patients were 19 and 75, respectively. The sensitivity, specificity, overall accuracy, PPV, and NPV of 18F-FDG PET/CT for detecting lymph node metastasis from pediatric neuroblastoma were 100, 98.7, 98.9, 95.0, and 100%, respectively, and those for detecting bone metastasis were 90.7, 73.1, 80.3, 70.1, and 91.9%, respectively. In contrast, the sensitivity, specificity, overall accuracy, PPV, and NPV of whole-body DWIBS for detecting bone metastasis from pediatric neuroblastoma were 94.7, 24.0, 53.0, 46.4 and 86.7%, respectively, whereas those for detecting lymph node metastasis were 94.7, 85.3, 87.2, 62.1, and 98.5%, respectively. The low specificity, overall accuracy, and PPV of whole-body DWIBS for detecting bone metastasis were due to a high incidence of false-positive findings (82/108, 75.9%). The specificity, overall accuracy, and PPV of whole-body DWIBS for detecting lymph node metastasis were also significantly lower than those of 18F-FDG PET/CT for detecting lymph node metastasis, although the difference between these 2 modalities was less than that for detecting bone metastasis. Conclusion: The specificity, overall accuracy, and PPV of whole-body DWIBS are significantly lower than those of 18F-FDG PET/CT because of a high incidence of false-positive findings particularly for detecting bone metastasis, whereas whole-body DWIBS shows a similar level of sensitivities for detecting lymph node and bone metastases to those of 18F-FDG PET/CT. DWIBS should be carefully used for cancer staging in children because of its high incidence of false-positive findings in skeletons.

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  108. An infant with generalized pustular psoriasis and geographic tongue had a heterozygous IL36RN mutation and IgG2 deficiency. Reviewed

    Oi R, Takeichi T, Okuno Y, Kojima D, Sugawara K, Kono M, Muramatsu H, Akiyama M

    Journal of dermatological science   Vol. 90 ( 2 ) page: 216 - 218   2018.5

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  109. Integrated molecular profiling of juvenile myelomonocytic leukemia. Reviewed

    Murakami N, Okuno Y, Yoshida K, Shiraishi Y, Nagae G, Suzuki K, Narita A, Sakaguchi H, Kawashima N, Wang X, Xu Y, Chiba K, Tanaka H, Hama A, Sanada M, Ito M, Hirayama M, Watanabe A, Ueno T, Kojima S, Aburatani H, Mano H, Miyano S, Ogawa S, Takahashi Y, Muramatsu H

    Blood   Vol. 131 ( 14 ) page: 1576 - 1586   2018.4

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  110. Danaparoid reduces transplant-related mortality in stem cell transplantation for children. Reviewed

    Kato K, Sakaguchi H, Muramatsu H, Sekiya Y, Kawashima N, Narita A, Doisaki S, Watanabe N, Yoshida N, Matsumoto K

    Pediatric transplantation   Vol. 22 ( 2 )   2018.3

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  111. Treatment with silver nitrate versus topical steroid treatment for umbilical granuloma: A non-inferiority randomized control trial. Reviewed

    Ogawa C, Sato Y, Suzuki C, Mano A, Tashiro A, Niwa T, Hamazaki S, Tanahashi Y, Suzumura M, Hayano S, Hayakawa M, Tsuji T, Hoshino S, Sugiyama Y, Kidokoro H, Kawada JI, Muramatsu H, Hirakawa A, Ando M, Natsume J, Kojima S

    PloS one   Vol. 13 ( 2 ) page: e0192688   2018.2

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  112. Genetic heterogeneity of uncharacterized childhood autoimmune diseases with lymphoproliferation Reviewed

    Takagi Masatoshi, Hoshino Akihiro, Yoshida Kenichi, Ueno Hiroo, Imai Kohsuke, Piao Jinhua, Kanegane Hirokazu, Yamashita Motoi, Okano Tsubasa, Muramatsu Hideki, Okuno Yusuke, Shiraishi Yuichi, Chiba Kenichi, Tanaka Hiroko, Miyano Satoru, Ogawa Seishi, Hayashi Yasuhide, Kojima Seiji, Morio Tomohiro

    PEDIATRIC BLOOD & CANCER   Vol. 65 ( 2 )   2018.2

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  113. Comprehensive genetic analysis of donor cell derived leukemia with KMT2A rearrangement Reviewed

    Taniguchi Rieko, Muramatsu Hideki, Okuno Yusuke, Suzuki Kyogo, Obu Satoshi, Nakatochi Masahiro, Shimamura Teppei, Takahashi Yoshiyuki, Horikoshi Yasuo, Watanabe Kenichiro, Kojima Seiji

    PEDIATRIC BLOOD & CANCER   Vol. 65 ( 2 )   2018.2

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  114. Biallelic mutations in SZT2 cause a discernible clinical entity with epilepsy, developmental delay, macrocephaly and a dysmorphic corpus callosum Reviewed

    Nakamura Yuji, Togawa Yasuko, Okuno Yusuke, Muramatsu Hideki, Nakabayashi Kazuhiko, Kuroki Yoko, Ieda Daisuke, Hori Ikumi, Negishi Yutaka, Togawa Takao, Hattori Ayako, Kojima Seiji, Saitoh Shinji

    BRAIN & DEVELOPMENT   Vol. 40 ( 2 ) page: 134 - 139   2018.2

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  115. Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders Reviewed

    Slack James, Albert Michael H., Balashov Dmitry, Belohradsky Bernd H., Bertaina Alice, Bleesing Jack, Booth Claire, Buechner Jochen, Buckley Rebecca H., Ouachee-Chardin Marie, Deripapa Elena, Drabko Katarzyna, Eapen Mary, Feuchtinger Tobias, Finocchi Andrea, Gaspar H. Bobby, Ghosh Sujal, Gillio Alfred, Gonzalez-Granado Luis I., Grunebaum Eyal, Gungor Tayfun, Heilmann Carsten, Helminen Merja, Higuchi Kohei, Imai Kohsuke, Kalwak Krzysztof, Kanazawa Nubuo, Karasu Gulsun, Kucuk Zeynep Y., Laberko Alexandra, Lange Andrzej, Mahlaoui Nizar, Meisel Roland, Moshous D., Muramatsu Hideki, Parikh Suhag, Pasic Srdjan, Schmid Irene, Schuetz Catharina, Schulz Ansgar, Schultz Kirk R., Shaw Peter J., Slatter Mary A., Sykora Karl-Walter, Tamura Shinobu, Taskinen Mervi, Wawer Angela, Wolska-Kusnierz Beata, Cowan Morton J., Fischer Alain, Gennery Andrew R.

    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY   Vol. 141 ( 1 ) page: 322 - 328.e10   2018.1

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  116. Unrelated cord blood transplantation in aplastic anemia: Is anti-thymocyte globulin indispensable for conditioning? Reviewed

    Kudo K., Muramatsu H., Narita A., Yoshida N., Kobayashi R., Yabe H., Endo M., Inoue M., Hara J., Kounami S., Inagaki J., Hashii Y., Kato K., Tabuchi K., Kojima S.

    Bone Marrow Transplantation   Vol. 52 ( 12 ) page: 1659 - 1661   2017.12

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  117. Flow cytometric analysis as an additional predictive tool of treatment response in children with chronic-phase chronic myeloid leukemia treated with imatinib Reviewed

    Shima Haruko, Kiyokawa Nobutaka, Miharu Masashi, Tanizawa Akihiko, Kurosawa Hidemitsu, Watanabe Akihiro, Ito Masaki, Tono Chikako, Yuza Yuki, Muramatsu Hideki, Hotta Noriko, Okada Masahiko, Hamamoto Kazuko, Kajiwara Ryosuke, Saito Akiko M., Horibe Keizo, Mizutani Shuki, Adachi Souichi, Ishii Eiichi, Shimada Hiroyuki

    PEDIATRIC BLOOD & CANCER   Vol. 64 ( 9 )   2017.9

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  118. Development of clinical paroxysmal nocturnal haemoglobinuria in children with aplastic anaemia Reviewed

    Narita Atsushi, Muramatsu Hideki, Okuno Yusuke, Sekiya Yuko, Suzuki Kyogo, Hamada Motoharu, Kataoka Shinsuke, Ichikawa Daisuke, Taniguchi Rieko, Murakami Norihiro, Kojima Daiei, Nishikawa Eri, Kawashima Nozomu, Nishio Nobuhiro, Hama Asahito, Takahashi Yoshiyuki, Kojima Seiji

    BRITISH JOURNAL OF HAEMATOLOGY   Vol. 178 ( 6 ) page: 954 - 958   2017.9

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  119. A case of GATA2-related myelodysplastic syndrome with unbalanced translocation der(1;7)(q10;p10) Reviewed

    Kurata Takashi, Shigemura Tomonari, Muramatsu Hideki, Okuno Yusuke, Nakazawa Yozo

    PEDIATRIC BLOOD & CANCER   Vol. 64 ( 8 )   2017.8

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  120. Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes Reviewed

    Muramatsu Hideki, Okuno Yusuke, Yoshida Kenichi, Shiraishi Yuichi, Doisaki Sayoko, Narita Atsushi, Sakaguchi Hirotoshi, Kawashima Nozomu, Wang Xinan, Xu Yinyan, Chiba Kenichi, Tanaka Hiroko, Hama Asahito, Sanada Masashi, Takahashi Yoshiyuki, Kanno Hitoshi, Yamaguchi Hiroki, Ohga Shouichi, Manabe Atsushi, Harigae Hideo, Kunishima Shinji, Ishii Eiichi, Kobayashi Masao, Koike Kenichi, Watanabe Kenichiro, Ito Etsuro, Takata Minoru, Yabe Miharu, Ogawa Seishi, Miyano Satoru, Kojima Seiji

    GENETICS IN MEDICINE   Vol. 19 ( 7 ) page: 796 - 802   2017.7

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  121. Recurrent MYB rearrangement in blastic plasmacytoid dendritic cell neoplasm Reviewed

    Suzuki K., Suzuki Y., Hama A., Muramatsu H., Nakatochi M., Gunji M., Ichikawa D., Hamada M., Taniguchi R., Kataoka S., Murakami N., Kojima D., Sekiya Y., Nishikawa E., Kawashima N., Narita A., Nishio N., Nakazawa Y., Iwafuchi H., Watanabe K-i, Takahashi Y., Ito M., Kojima S., Kato S., Okuno Y.

    LEUKEMIA   Vol. 31 ( 7 ) page: 1629 - 1633   2017.7

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  122. Common Variable Immunodeficiency Caused by FANC Mutations Reviewed

    Sekinaka Yujin, Mitsuiki Noriko, Imai Kohsuke, Yabe Miharu, Yabe Hiromasa, Mitsui-Sekinaka Kanako, Honma Kenichi, Takagi Masatoshi, Arai Ayako, Yoshida Kenichi, Okuno Yusuke, Shiraishi Yuichi, Chiba Kenichi, Tanaka Hiroko, Miyano Satoru, Muramatsu Hideki, Kojima Seiji, Hira Asuka, Takata Minoru, Ohara Osamu, Ogawa Seishi, Morio Tomohiro, Nonoyama Shigeaki

    JOURNAL OF CLINICAL IMMUNOLOGY   Vol. 37 ( 5 ) page: 434 - 444   2017.7

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  123. Efficacy of neutrophil non-muscle myosin heavy chain-IIA immunofluorescence analysis in determining the pathogenicity of MYH9 variants Reviewed

    Kunishima Shinji, Yusuke Okuno, Muramatsu Hideki, Kojima Daiei, Nagai Noriko, Takahashi Yoshiyuki, Kojima Seiji

    ANNALS OF HEMATOLOGY   Vol. 96 ( 6 ) page: 1065 - 1066   2017.6

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  124. Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome Reviewed

    Takagi Masatoshi, Ogata Shohei, Ueno Hiroo, Yoshida Kenichi, Yeh Tzuwen, Hoshino Akihiro, Piao Jinhua, Yamashita Motoy, Nanya Mai, Okano Tsubasa, Kajiwara Michiko, Kanegane Hirokazu, Muramatsu Hideki, Okuno Yusuke, Shiraishi Yuichi, Chiba Kenichi, Tanaka Hiroko, Bando Yuki, Kato Motohiro, Hayashi Yasuhide, Miyano Satoru, Imai Kohsuke, Ogawa Seishi, Kojima Seiji, Morio Tomohiro

    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY   Vol. 139 ( 6 ) page: 1914 - 1922   2017.6

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  125. Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome Reviewed

    Hoenig Manfred, Lagresle-Peyrou Chantal, Pannicke Ulrich, Notarangelo Luigi D., Porta Fulvio, Gennery Andrew R., Slatter Mary, Cowan Morton J., Stepensky Polina, Al-Mousa Hamoud, Al-Zahrani Daifulah, Pai Sung-Yun, Al Herz Waleed, Gaspar Hubert B., Veys Paul, Oshima Koichi, Imai Kohsuke, Yabe Hiromasa, Noroski Lenora M., Wulffraat Nico M., Sykora Karl-Walter, Soler-Palacin Pere, Muramatsu Hideki, Al Hilali Mariam, Moshous Despina, Debatin Klaus-Michael, Schuetz Catharina, Jacobsen Eva-Maria, Schulz Ansgar S., Schwarz Klaus, Fischer Alain, Friedrich Wilhelm, Cavazzana Marina

    BLOOD   Vol. 129 ( 21 ) page: 2928 - 2938   2017.5

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  126. Germline IKAROS mutation associated with primary immunodeficiency that progressed to T-cell acute lymphoblastic leukemia Reviewed

    Yoshida N., Sakaguchi H., Muramatsu H., Okuno Y., Song C., Dovat S., Shimada A., Ozeki M., Ohnishi H., Teramoto T., Fukao T., Kondo N., Takahashi Y., Matsumoto K., Kato K., Kojima S.

    LEUKEMIA   Vol. 31 ( 5 ) page: 1221 - 1223   2017.5

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  127. Long-term outcomes of 95 children with moderate aplastic anemia treated with horse antithymocyte globulin and cyclosporine Reviewed

    Nishikawa Eri, Yagasaki Hiroshi, Hama Asahito, Yabe Hiromasa, Ohara Akira, Kosaka Yoshiyuki, Kudo Kazuko, Kobayashi Ryoji, Ohga Shouichi, Morimoto Akira, Watanabe Ken-ichiro, Yoshida Nao, Muramatsu Hideki, Takahashi Yoshiyuki, Kojima Seiji

    PEDIATRIC BLOOD & CANCER   Vol. 64 ( 5 )   2017.5

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  128. Diagnostic challenge of Diamond-Blackfan anemia in mothers and children by whole-exome sequencing Reviewed

    Ichimura Takuya, Yoshida Kenichi, Okuno Yusuke, Yujiri Toshiaki, Nagai Kozo, Nishi Masanori, Shiraishi Yuichi, Ueno Hiroo, Toki Tsutomu, Chiba Kenichi, Tanaka Hiroko, Muramatsu Hideki, Hara Toshiro, Kanno Hitoshi, Kojima Seiji, Miyano Satoru, Ito Etsuro, Ogawa Seishi, Ohga Shouichi

    INTERNATIONAL JOURNAL OF HEMATOLOGY   Vol. 105 ( 4 ) page: 515 - 520   2017.4

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  129. Exome sequencing identified RPS15A as a novel causative gene for Diamond-Blackfan anemia Reviewed

    Ikeda Fumika, Yoshida Kenichi, Toki Tsutomu, Uechi Tamayo, Ishida Shiori, Nakajima Yukari, Sasahara Yoji, Okuno Yusuke, Kanezaki Rika, Terui Kiminori, Kamio Takuya, Kobayashi Akie, Fujita Takashi, Sato-Otsubo Aiko, Shiraishi Yuichi, Tanaka Hiroko, Chiba Kenichi, Muramatsu Hideki, Kanno Hitoshi, Ohga Shouichi, Ohara Akira, Kojima Seiji, Kenmochi Naoya, Miyano Satoru, Ogawa Seishi, Ito Etsuro

    HAEMATOLOGICA   Vol. 102 ( 3 ) page: e93 - e96   2017.2

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    DOI: 10.3324/haematol.2016.153932

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  130. Recurrent Cellulitis Caused by Helicobacter cinaedi in a Patient with X-linked Agammaglobulinaemia Reviewed

    Sugimoto Masayo, Takeichi Takuya, Muramatsu Hideki, Kojima Daiei, Osada Yukari, Kono Michihiro, Kojima Seiji, Akiyama Masashi

    ACTA DERMATO-VENEREOLOGICA   Vol. 97 ( 2 ) page: 277 - 278   2017.2

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    DOI: 10.2340/00015555-2501

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  131. Clinical utility of next-generation sequencing-based minimal residual disease in paediatric B-cell acute lymphoblastic leukaemia Reviewed

    Sekiya Yuko, Xu Yinyan, Muramatsu Hideki, Okuno Yusuke, Narita Atsushi, Suzuki Kyogo, Wang Xinan, Kawashima Nozomu, Sakaguchi Hirotoshi, Yoshida Nao, Hama Asahito, Takahashi Yoshiyuki, Kato Koji, Kojima Seiji

    BRITISH JOURNAL OF HAEMATOLOGY   Vol. 176 ( 2 ) page: 248 - 257   2017.1

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    DOI: 10.1111/bjh.14420

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  132. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome–like immunodeficiency Reviewed

    Tsujita Y., Mitsui-Sekinaka K., Imai K., Yeh T.W., Mitsuiki N., Asano T., Ohnishi H., Kato Z., Sekinaka Y., Zaha K., Kato T., Okano T., Takashima T., Kobayashi K., Kimura M., Kunitsu T., Maruo Y., Kanegane H., Takagi M., Yoshida K., Okuno Y., Muramatsu H., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Kojima S., Ogawa S., Ohara O., Okada S., Kobayashi M., Morio T., Nonoyama S.

    Journal of Allergy and Clinical Immunology   Vol. 138 ( 6 ) page: 1672 - 1680.e10   2016.12

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    Background Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, PIK3CD and PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6. Objective This study aimed to identify novel genes responsible for APDS. Methods Whole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays. Results We identified heterozygous mutations of phosphatase and tensin homolog (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that PTEN expression was decreased in these patients. Patients with PTEN mutations and those with PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway. Conclusion PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.

    DOI: 10.1016/j.jaci.2016.03.055

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  133. Allogeneic hematopoietic stem cell transplantation for dyskeratosis congenita Reviewed

    Elmahadi S., Muramatsu H., Kojima S.

    Current Opinion in Hematology   Vol. 23 ( 6 ) page: 501 - 507   2016.11

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    Purpose of review Dyskeratosis congenita is an inherited bone marrow failure syndrome caused by defects in telomere maintenance. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure because of dyskeratosis congenita. The present review summarizes the literature with respect to the diagnosis and treatment of patients with dyskeratosis congenita who received HSCT, and discusses the recent progress in the management of dyskeratosis congenita. Recent findings The recent systematic review of the literature showed poor long-term outcome, with 10-year survival estimates of only 23% in 109 patients with dyskeratosis congenita who received HSCT. Multivariate analysis identified age greater than 20 years at HSCT, HSCT before 2000, and alternative donor source to be poor prognostic markers. HSCT for dyskeratosis congenita is characterized by a marked decline in long-term survival because of late deaths from pulmonary complications. However, a prospective study using danazol showed promising results in gain in telomere length and hematologic responses. Summary A recent prospective study may support the recommendation that HSCT is not indicated for patients with dyskeratosis congenita; instead, they should receive androgen, particularly danazol, as a first-line therapy. Another option may be routine use of androgen after HSCT for the prophylaxis of pulmonary fibrosis.

    DOI: 10.1097/MOH.0000000000000290

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  134. Successful T-cell reconstitution after unrelated cord blood transplantation in a patient with complete DiGeorge syndrome Reviewed

    Kojima D., Muramatsu H., Okuno Y., Kataoka S., Murakami N., Tanahashi Y., Suzuki K., Kato T., Sekiya Y., Kawashima N., Narita A., Nishio N., Hama A., Imai K., Nonoyama S., Takahashi Y., Kojima S.

    Journal of Allergy and Clinical Immunology   Vol. 138 ( 5 ) page: 1471 - 1473.e4   2016.11

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    DOI: 10.1016/j.jaci.2016.04.048

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  135. The phenotype and clinical course of Japanese Fanconi Anaemia infants is influenced by patient, but not maternal ALDH2 genotype Reviewed

    Yabe M., Yabe H., Morimoto T., Fukumura A., Ohtsubo K., Koike T., Yoshida K., Ogawa S., Ito E., Okuno Y., Muramatsu H., Kojima S., Matsuo K., Hira A., Takata M.

    British Journal of Haematology   Vol. 175 ( 3 ) page: 457 - 461   2016.11

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    Studies using Fanconi anaemia (FA) mutant mouse models suggested that the combination of a defective FA pathway and aldehyde dehydrogenase-2 (ALDH2) dysfunction could provoke bone marrow failure, leukaemia and developmental defects, and that both maternal and fetal aldehyde detoxification are crucial to protect the developing embryo from DNA damage. We studied the ALDH2 genotypes of 35 Japanese FA patients and their mothers. We found that a normal maternal ALDH2 allele was not essential for fetal development of ALDH2-deficient patients, and none of the post-natal clinical parameters were clearly affected by the maternal ALDH2 genotype in these patients.

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  136. MEF2D-BCL9 fusion gene is associated with high-risk acute B-cell precursor lymphoblastic leukemia in adolescents Reviewed

    Suzuki K., Okuno Y., Kawashima N., Muramatsu H., Okuno T., Wang X., Kataoka S., Sekiya Y., Hamada M., Murakami N., Kojima D., Narita K., Narita A., Sakaguchi H., Sakaguchi K., Yoshida N., Nishio N., Hama A., Takahashi Y., Kudo K., Kato K., Kojima S.

    Journal of Clinical Oncology   Vol. 34 ( 28 ) page: 3451 - 3459   2016.10

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    Purpose: Acute lymphoblastic leukemia (ALL) makes up a significant proportion of all pediatric cancers, and relapsed ALL is a leading cause of cancer-associated deaths in children. Identification of risk factors and druggable molecular targets in ALL can lead to a better stratification of treatments and subsequent improvement in prognosis. Patients and Methods: We enrolled 59 children with relapsed or primary refractory ALL who were treated in our institutions. We primarily performed RNA sequencing (RNA-seq) using patients' leukemic cells to comprehensively detect gene fusions and analyze gene expression profiles. On the basis of results obtained by RNA-seq, we performed genetic validation, functional analysis, and in vitro drug sensitivity testing using patients' samples and an exogenous expression model. Results: We identified a total of 26 gene fusions in 22 patients by RNA-seq. Among these, 19 were non-random gene fusions already described in ALL, and four of the remaining seven involved identical combination of MEF2D and BCL9. All MEF2D-BCL9-positive patients had B-cell precursor immunophenotype and were characterized as being older in age, being resistant to chemotherapy, having very early relapse, and having leukemic blasts that mimic morphologically mature B-cell leukemia with markedly high expression of HDAC9. Exogenous expression of MEF2D-BCL9 in a B-cell precursor ALL cell line promoted cell growth, increased HDAC9 expression, and induced resistance to dexamethasone. Using a primary culture of leukemic blasts from a patient, we identified several molecular targeted drugs that conferred inhibitory effects in vitro. Conclusion: A novel MEF2D-BCL9 fusion we identified characterizes a novel subset of pediatric ALL, predicts poor prognosis, and may be a candidate for novel molecular targeting.

    DOI: 10.1200/JCO.2016.66.5547

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  137. Kampo patterns and radiology in children receiving choreito for hemorrhagic cystitis after hematopoietic stem cell transplantation Reviewed

    Kawashima N., Sekiya Y., Narita A., Kamei M., Muramatsu H., Nishio N., Hama A., Ito Y., Takahashi Y., Kojima S.

    Traditional and Kampo Medicine   Vol. 3 ( 2 ) page: 136 - 144   2016.10

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    Aim: Choreito reduces the disease burden of hemorrhagic cystitis (HC) in children undergoing hematopoietic stem cell transplantation, but the underlying Kampo mechanism has not yet been clarified. To obtain pathophysiological insights, the present study evaluated changes in Kampo patterns and genitourinary imaging during choreito treatment. Methods: Ten consecutive children with late-onset HC after stem cell transplantation were treated with choreito. Kampo patterns and computed tomography (CT) before and after choreito treatment were retrospectively analyzed. Results: Ten children with a median age of 9.7 years (range, 5.4–14 years) were diagnosed with late-onset HC; 9 had BK virus and 1 had adenovirus. The median duration from the beginning of choreito intake to complete resolution was 12 days (range, 4–28 days). All 10 children fulfilled the Kampo pattern of Bladder damp–heat at diagnosis; all had heat and/or hardness in the lower abdomen, and 8 children had a slippery pulse. CT was obtained in 4 of the 10 children at the time of diagnosis, all of which showed bladder wall thickening and perivesical inflammation. After choreito treatment for a median of 26 days (range, 8–40 days), none of the children had any sign of damp–heat, which coincided with the disappearance of perivesical inflammation, as confirmed on CT. Conclusion: Lower abdominal heat/hardness with a slippery pulse may reflect damp–heat accumulation in the lower energizer, causing HC. Improvement in these examinations can be used as a surrogate response marker in choreito treatment for HC, which should be confirmed in future prospective studies.

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  138. JAK2, MPL, and CALR mutations in children with essential thrombocythemia Reviewed

    Sekiya Y., Okuno Y., Muramatsu H., Ismael O., Kawashima N., Narita A., Wang X., Xu Y., Hama A., Fujisaki H., Imamura T., Hasegawa D., Kosaka Y., Sunami S., Ohtsuka Y., Ohga S., Takahashi Y., Kojima S., Shimada A.

    International Journal of Hematology   Vol. 104 ( 2 ) page: 266 - 267   2016.8

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    DOI: 10.1007/s12185-016-2022-2

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  139. Application of extensively targeted next-generation sequencing for the diagnosis of primary immunodeficiencies. Reviewed

    Kojima D, Wang X, Muramatsu H, Okuno Y, Nishio N, Hama A, Tsuge I, Takahashi Y, Kojima S

    The Journal of allergy and clinical immunology   Vol. 138 ( 1 ) page: 303 - 305.e3   2016.7

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    DOI: 10.1016/j.jaci.2016.01.012

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  140. PIEZO1 gene mutation in a Japanese family with hereditary high phosphatidylcholine hemolytic anemia and hemochromatosis-induced diabetes mellitus. Reviewed

    Imashuku S, Muramatsu H, Sugihara T, Okuno Y, Wang X, Yoshida K, Kato A, Kato K, Tatsumi Y, Hattori A, Kita S, Oe K, Sueyoshi A, Usui T, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Ogawa S, Kojima S, Kanno H

    International journal of hematology   Vol. 104 ( 1 ) page: 125 - 129   2016.7

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    DOI: 10.1007/s12185-016-1970-x

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  141. Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia Reviewed

    Kitamura K., Okuno Y., Yoshida K., Sanada M., Shiraishi Y., Muramatsu H., Kobayashi R., Furukawa K., Miyano S., Kojima S., Ogawa S., Kunishima S.

    Journal of Thrombosis and Haemostasis   Vol. 14 ( 7 ) page: 1462 - 1469   2016.7

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    Essentials Two groups recently reported GFI1B as a novel causative gene for congenital macrothrombocytopenia. We performed functional analysis of a novel GFI1B mutation and previous mutations. An immunofluorescence analysis of the platelet CD34 expression can be useful as a screening test. Mutant-transduced megakaryocytes produced enlarged proplatelet tips which were reduced in number. Summary: Background GFI1B is an essential transcription factor for megakaryocyte and erythrocyte development. Two groups have recently identified GFI1B as a novel causative gene for congenital macrothrombocytopenia associated with α-granule deficiency. Methods We performed whole exome sequencing and identified a novel GFI1B p.G272fsX274 mutation in a family with macrothrombocytopenia, and a decreased number of platelet α-granules and abnormally shaped red blood cells. p.G272fsX274 and the previous two mutations all predicted disruption of an essential DNA-binding domain in GFI1B. We therefore performed functional studies to characterize the biochemical and biological effects of these three patient-derived mutations. Results An immunofluorescence analysis revealed decreased thrombospondin-1 and increased CD34 expression in platelets from our patient. Consistent with the previous studies, the three patient-derived mutants were unable to repress the expression of the reporter gene and had a dominant-negative effect over wild-type GFI1B. In addition, the three mutations abolished recognition of a consensus-binding site in gel shift assays. Furthermore, transduction of mouse fetal liver-derived megakaryocytes with the three GFI1B mutants resulted in the production of abnormally large proplatelet tips, which were reduced in number. Conclusions Our study provides further proof of concept that GFI1B is an essential protein for the normal development of the megakaryocyte lineage.

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  142. Immunosuppressive therapy for patients with Down syndrome and idiopathic aplastic anemia Reviewed

    Suzuki K., Muramatsu H., Okuno Y., Narita A., Hama A., Takahashi Y., Yoshida M., Horikoshi Y., Watanabe K.i., Kudo K., Kojima S.

    International Journal of Hematology   Vol. 104 ( 1 ) page: 130 - 133   2016.7

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    Idiopathic aplastic anemia (AA) is a rare hematological complication of Down syndrome (DS). The safety and efficacy of immunosuppressive therapy (IST) in individuals with DS remain unknown. We used a standard regimen of IST, comprising antithymocyte globulin and cyclosporine A, to treat three children with DS and idiopathic acquired AA. Two patients achieved a hematological (complete or partial) response and became transfusion independent at the final follow-up. The third patient failed to respond to IST and underwent bone marrow transplantation from a human leukocyte antigen (HLA)-mismatched unrelated donor. None of the patients experienced severe or unexpected adverse events during IST. Our experience suggests that IST is a safe and reasonable treatment, even in individuals with DS who suffer from AA and lack an HLA-matched sibling donor.

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  143. Genetic predisposition to pediatric myeloid malignancies Reviewed

    Muramatsu H.

    [Rinsho ketsueki] The Japanese journal of clinical hematology   Vol. 57 ( 6 ) page: 730 - 735   2016.6

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    Various genetic disorders are known to be associated with cancer predisposition. For example, children with Down syndrome are predisposed to developing acute myeloid leukemia, and those with RASopathies, such as Noonan syndrome, are predisposed to juvenile myelomonocytic leukemia. To date, more than 250 diseases or syndromes have been reported to be associated with the development of pediatric cancers. Recently, the advent of the massive parallel sequencing technique revealed several germline mutations, including RUNX1, CEBPA, GATA2, SRP72, ETV6, and DDX41, which are associated with familial myeloid malignancies. A significant number of children with myeloid malignancies may harbor pathognomonic germline variants. It is strongly recommended that precise diagnosis, genetic counseling, familial screening, and follow-up programs be provided for patients with such a predisposition to cancer. To identify genetic disorders associated with predispositions to pediatric myeloid malignancies, the development of an efficient screening system with the massive parallel sequencer for germline and somatic mutations, which would also be useful for familial genetic studies and prediction of tumor progression, is needed.

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  144. Markedly High Plasma Thrombopoietin (TPO) Level is a Predictor of Poor Response to Immunosuppressive Therapy in Children With Acquired Severe Aplastic Anemia. Reviewed

    Elmahdi S, Muramatsu H, Narita A, Ismael O, Hama A, Nishio N, Okuno Y, Xu Y, Wang X, Takahashi Y, Kojima S

    Pediatric blood & cancer   Vol. 63 ( 4 ) page: 659 - 664   2016.4

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    DOI: 10.1002/pbc.25820

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  145. A Cytokine-Based Diagnostic Program in Pediatric Aplastic Anemia and Hypocellular Refractory Cytopenia of Childhood. Reviewed

    Elmahdi S, Hama A, Manabe A, Hasegawa D, Muramatsu H, Narita A, Nishio N, Ismael O, Kawashima N, Okuno Y, Xu Y, Wang X, Takahashi Y, Ito M, Kojima S

    Pediatric blood & cancer   Vol. 63 ( 4 ) page: 652 - 658   2016.4

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    DOI: 10.1002/pbc.25799

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  146. Leukostasis in Children and Adolescents with Chronic Myeloid Leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group. Reviewed

    Kurosawa H, Tanizawa A, Tono C, Watanabe A, Shima H, Ito M, Yuza Y, Hotta N, Muramatsu H, Okada M, Kajiwara R, Moriya Saito A, Mizutani S, Adachi S, Horibe K, Ishii E, Shimada H

    Pediatric blood & cancer   Vol. 63 ( 3 ) page: 406 - 411   2016.3

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  147. Correlation of rabbit antithymocyte globulin serum levels and clinical outcomes in children who received hematopoietic stem cell transplantation from an alternative donor. Reviewed

    Elmahdi S, Muramatsu H, Narita A, Torii Y, Ismael O, Kawashima N, Okuno Y, Sekiya Y, Xu Y, Wang X, Hama A, Ito Y, Takahashi Y, Kojima S

    Pediatric transplantation   Vol. 20 ( 1 ) page: 105 - 113   2016.2

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    DOI: 10.1111/petr.12620

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  148. Extrapulmonary tuberculosis mimicking Mendelian susceptibility to mycobacterial disease in a patient with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation Reviewed

    Kataoka S., Muramatsu H., Okuno Y., Hayashi Y., Mizoguchi Y., Tsumura M., Okada S., Kobayashi M., Sano C., Sato H., Oh-Iwa I., Ito M., Kojima D., Hama A., Takahashi Y., Kojima S.

    Journal of Allergy and Clinical Immunology   Vol. 137 ( 2 ) page: 619 - 622.e1   2016.2

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    DOI: 10.1016/j.jaci.2015.06.028

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  149. Abnormal urinalysis on day 7 in patients with IgA vasculitis (Henoch-Schönlein purpura) Reviewed

    Kawashima N., Kawada J.I., Nishikado Y., Kitase Y., Ito S., Muramatsu H., Sato Y., Kato T., Natsume J., Kojima S.

    Nagoya Journal of Medical Science   Vol. 78 ( 4 ) page: 359 - 367   2016

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    Rare progression to renal failure imposes a burden on children with IgA vasculitis (Henoch-Schönlein purpura, HSP). An abnormal urinalysis on day 7 (7d-UA) may be a surrogate marker for persistent nephritis, but this has not been established. We retrospectively analyzed the risk factors for persistent nephritis in a cohort of 138 children. Of 35 children with abnormal 7d-UA, 24 (69%) had an abnormal urinalysis 6 months after the diagnosis of HSP, which was significantly more than 6 of 103 children (6%) with normal 7d-UA (P < 0.0001). The negative predictive values for normal urinalysis and negative proteinuria 6 months after diagnosis were 0.94 (95% confidence interval [CI], 0.90-0.97) and 0.98 (95% CI, 0.95-0.99), respectively. When children with abnormal urinalysis 6 months after diagnosis were compared with those without, the following factors were significantly associated: age at diagnosis, abnormal urinalysis at diagnosis, abnormal 7d-UA, complement C3, steroid treatment, and presence of abdominal pain. However, multivariate analysis revealed that abnormal 7d-UA was the only significant risk factor for abnormal urinalysis 6 months after diagnosis (odds ratio 54.3, 95% CI 15.3-275, P = 1.89 × 10-6). Abnormal 7d-UA may be an independent risk factor for persistent nephritis, but this should be confirmed in a prospective study.

    DOI: 10.18999/nagjms.78.4.359

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  150. Aberrant DNA Methylation Is Associated with a Poor Outcome in Juvenile Myelomonocytic Leukemia. Reviewed

    Sakaguchi H, Muramatsu H, Okuno Y, Makishima H, Xu Y, Furukawa-Hibi Y, Wang X, Narita A, Yoshida K, Shiraishi Y, Doisaki S, Yoshida N, Hama A, Takahashi Y, Yamada K, Miyano S, Ogawa S, Maciejewski JP, Kojima S

    PloS one   Vol. 10 ( 12 ) page: e0145394   2015.12

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  151. Fulminant adenovirus hepatitis after hematopoietic stem cell transplant: Retrospective real-time PCR analysis for adenovirus DNA in two cases. Reviewed

    Kawashima N, Muramatsu H, Okuno Y, Torii Y, Kawada J, Narita A, Nakanishi K, Hama A, Kitamura A, Asai N, Nakamura S, Takahashi Y, Ito Y, Kojima S

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   Vol. 21 ( 12 ) page: 857 - 863   2015.12

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    DOI: 10.1016/j.jiac.2015.08.018

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  152. Serial investigation of PTPN11 mutation in nonhematopoietic tissues in a patient with juvenile myelomonocytic leukemia who was treated with unrelated cord blood transplantation. Reviewed

    Hiramoto R, Imamura T, Muramatsu H, Wang X, Kanayama T, Zuiki M, Yoshida H, Moroto M, Fujiki A, Chiyonobu T, Osone S, Ishida H, Kojima S, Hosoi H

    International journal of hematology   Vol. 102 ( 6 ) page: 719 - 722   2015.12

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    DOI: 10.1007/s12185-015-1877-y

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  153. Comparison of long-term outcomes between children with aplastic anemia and refractory cytopenia of childhood who received immunosuppressive therapy with antithymocyte globulin and cyclosporine Reviewed

    Hama A., Takahashi Y., Muramatsu H., Ito M., Narita A., Kosaka Y., Tsuchida M., Kobayashi R., Ito E., Yabe H., Ohga S., Ohara A., Kojima S.

    Haematologica   Vol. 100 ( 11 ) page: 1426 - 1433   2015.10

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    The 2008 World Health Organization classification proposed a new entity in childhood myelodysplastic syndrome, refractory cytopenia of childhood. However, it is unclear whether this morphological classification reflects clinical outcomes. We retrospectively reviewed bone marrow morphology in 186 children (median age 8 years; range 1-16 years) who were enrolled in the prospective study and received horse antithymocyte globulin and cyclosporine between July 1999 and November 2008. The median follow-up period was 87 months (range 1-146 months). Out of 186 patients, 62 (33%) were classified with aplastic anemia, 94 (49%) with refractory cytopenia of childhood, and 34 (18%) with refractory cytopenia with multilineage dysplasia. Aplastic anemia patients received granulocyte colony-stimulating factor more frequently and for longer durations than other patients (P<0.01). After six months, response rates to immunosuppressive therapy were not significantly different among the 3 groups. Acquisition of chromosomal abnormalities was observed in 5 patients with aplastic anemia, 4 patients with refractory cytopenia of childhood, and 3 patients with refractory cytopenia with multilineage dysplasia. Although the cumulative incidence of total clonal evolution at ten years was not significantly different among the 3 groups, the cumulative incidence of monosomy 7 development was significantly higher in aplastic anemia than in the other groups (P=0.02). Multivariate analysis revealed that only granulocyte colony-stimulating factor administration duration of 40 days or more was a significant risk factor for monosomy 7 development (P=0.02). These findings suggest that even the introduction of a strict morphological distinction from hypoplastic myelodysplastic syndrome cannot eradicate clonal evolution in children with aplastic anemia.

    DOI: 10.3324/haematol.2015.128553

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  154. GATA2 and secondary mutations in familial myelodysplastic syndromes and pediatric myeloid malignancies Reviewed

    Wang X., Muramatsu H., Okuno Y., Sakaguchi H., Yoshida K., Kawashima N., Xu Y., Shiraishi Y., Chiba K., Tanaka H., Saito S., Nakazawa Y., Masunari T., Hirose T., Elmahdi S., Narita A., Doisaki S., Ismael O., Makishima H., Hama A., Miyano S., Takahashi Y., Ogawa S., Kojima S.

    Haematologica   Vol. 100 ( 10 ) page: e398 - e401   2015.10

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    DOI: 10.3324/haematol.2015.127092

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  155. Second allogeneic hematopoietic stem cell transplantation in children with severe aplastic anemia Reviewed

    Kudo K., Muramatsu H., Yoshida N., Kobayashi R., Yabe H., Tabuchi K., Kato K., Koh K., Takahashi Y., Hashii Y., Kawano Y., Inoue M., Cho Y., Sakamaki H., Kawa K., Kato K., Suzuki R., Kojima S.

    Bone Marrow Transplantation   Vol. 50 ( 10 ) page: 1312 - 1315   2015.10

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    The outcome of 55 children with severe aplastic anemia (SAA) who received a second hematopoietic stem cell transplantation (HSCT) was retrospectively analyzed using the registration data of the Japanese Society for Hematopoietic Cell Transplantation. The 5-year overall survival (OS) and failure-free survival (FFS) after the second transplantation were 82.9% (95% confidence interval (CI), 69.7-90.8)) and 81.2% (95% CI, 67.8-89.4), respectively. FFS was significantly better when the interval between the first and second transplantation was >60 days (88.9%; 95% CI, 73.0-95.7) than when it was ≤60 days (61.4%; 95% CI, 33.3-80.5; P=0.026). All 12 patients who were conditioned with regimens containing fludarabine and melphalan were alive with hematopoietic recovery. These findings justify the recommendation of a second HSCT for children with SAA who have experienced graft failure after first HSCT.

    DOI: 10.1038/bmt.2015.153

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  156. Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism. Reviewed

    Okuno Y, Hoshino A, Muramatsu H, Kawashima N, Wang X, Yoshida K, Wada T, Gunji M, Toma T, Kato T, Shiraishi Y, Iwata A, Hori T, Kitoh T, Chiba K, Tanaka H, Sanada M, Takahashi Y, Nonoyama S, Ito M, Miyano S, Ogawa S, Kojima S, Kanegane H

    Journal of clinical immunology   Vol. 35 ( 7 ) page: 610 - 614   2015.9

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    DOI: 10.1007/s10875-015-0202-0

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  157. Clinical and genetic features of dyskeratosis congenita, cryptic dyskeratosis congenita, and Hoyeraal-Hreidarsson syndrome in Japan. Reviewed

    Yamaguchi H, Sakaguchi H, Yoshida K, Yabe M, Yabe H, Okuno Y, Muramatsu H, Takahashi Y, Yui S, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Inokuchi K, Ito E, Ogawa S, Kojima S

    International journal of hematology   Vol. 102 ( 5 ) page: 544 - 552   2015.9

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    DOI: 10.1007/s12185-015-1861-6

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  158. Somatic Mosaicism for a NRAS Mutation Associates with Disparate Clinical Features in RAS-associated Leukoproliferative Disease: a Report of Two Cases Reviewed

    Shiota M., Yang X., Kubokawa M., Morishima T., Tanaka K., Mikami M., Yoshida K., Kikuchi M., Izawa K., Nishikomori R., Okuno Y., Wang X., Sakaguchi H., Muramatsu H., Kojima S., Miyano S., Ogawa S., Takagi M., Hata D., Kanegane H.

    Journal of Clinical Immunology   Vol. 35 ( 5 ) page: 454 - 458   2015.7

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    RAS-associated leukoproliferative disease (RALD) is a newly classified disease; thus its clinical features and management are not fully understood. The cases of two patients with characteristic features of RALD are described herein. Patient 1 was a 5-month-old female with clinical features typical of autoimmune lymphoproliferative syndrome (ALPS) and markedly elevated TCRαβ+CD4−CD8− T cell numbers. Genetic analyses failed to detect an ALPS-related gene mutation; however, whole exome sequencing and other genetic analyses revealed somatic mosaicism for the G13D NRAS mutation. These data were indivative of NRAS-associated RALD with highly elevated αβ-double-negative T cells. Patient 2 was a 12-month-old girl with recurrent fever who clearly met the diagnostic criteria for juvenile myelomonocytic leukemia (JMML). Genetic analyses revealed somatic mosaicism, again for the G13D NRAS mutation, suggesting RALD associated with somatic NRAS mosaicism. Notably, unlike most JMML cases, Patient 2 did not require steroids or hematopoietic stem cell transplantation. Genetic analysis of RAS should be performed in patients fulfilling the diagnostic criteria for ALPS in the absence of ALPS-related gene mutations if the patients have elevated αβ-double-negative-T cells and in JMML patients if autoimmunity is detected. These clinical and experimental data increase our understanding of RALD, ALPS, and JMML.

    DOI: 10.1007/s10875-015-0163-3

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  159. A Female Patient with Incomplete Hemophagocytic Lymphohistiocytosis Caused by a Heterozygous XIAP Mutation Associated with Non-Random X-Chromosome Inactivation Skewed Towards the Wild-Type XIAP Allele Reviewed

    Yang X., Hoshino A., Taga T., Kunitsu T., Ikeda Y., Yasumi T., Yoshida K., Wada T., Miyake K., Kubota T., Okuno Y., Muramatsu H., Adachi Y., Miyano S., Ogawa S., Kojima S., Kanegane H.

    Journal of Clinical Immunology   Vol. 35 ( 3 ) page: 244 - 248   2015.3

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    X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency that often leads to hemophagocytic lymphohistiocytosis (HLH). XLP can be classified as XLP1 or XLP2, caused by mutations in SH2D1A and XIAP, respectively. In women, X-chromosome inactivation (XCI) of most X-linked genes occurs on one of the X chromosomes in each cell. The choice of which X chromosome remains activated is generally random, although genetic differences and selective advantage may cause one of the X chromosomes to be preferentially inactivated. Here we describe three patients with pancytopenia, including one female patient, in a Japanese family with a novel XIAP mutation. All three patients exhibited deficient XIAP protein expression, impaired NOD2/XIAP signaling, and augmented activation-induced cell death. In the female patient, the paternally derived X chromosome was non-randomly and exclusively inactivated in her peripheral blood and hair root cells. In contrast to asymptomatic females, this patient exhibied non-random XCI skewed towards the wild-type XIAP allele. This is the first report of a female patient with incomplete HLH resulting from a heterozygous XIAP mutation in association with non-random XCI.

    DOI: 10.1007/s10875-015-0144-6

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  160. Germline mutation of CBL is associated with moyamoya disease in a child with juvenile myelomonocytic leukemia and Noonan syndrome-like disorder Reviewed

    Hyakuna N., Muramatsu H., Higa T., Chinen Y., Wang X., Kojima S.

    Pediatric Blood and Cancer   Vol. 62 ( 3 ) page: 542 - 544   2015.3

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    Germline mutations in CBL have been identified in patients with Noonan syndrome-like phenotypes, while juvenile myelomonocytic leukemia (JMML) harbors duplication of a germline CBL, resulting in acquired isodisomy. The association between moyamoya disease and Noonan syndrome carrying a PTPN11 mutation has recently been reported. We present a patient with JMML who developed moyamoya disease and neovascular glaucoma. Our patient exhibited a Noonan syndrome-like phenotype. Genetic analysis revealed acquired isodisomy and a germline heterozygous mutation in CBL. This is a rare case of CBL mutation associated with moyamoya disease. Prolonged RAS pathway signaling may cause disruption of cerebrovascular development.

    DOI: 10.1002/pbc.25271

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  161. Aldehyde dehydrogenase-2 polymorphism contributes to the progression of bone marrow failure in children with idiopathic aplastic anaemia Reviewed

    Kawashima N., Narita A., Wang X., Xu Y., Sakaguchi H., Doisaki S., Muramatsu H., Hama A., Nakanishi K., Takahashi Y., Kojima S.

    British Journal of Haematology   Vol. 168 ( 3 ) page: 460 - 463   2015.2

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    DOI: 10.1111/bjh.13122

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  162. Choreito Formula for BK Virus-associated Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation Reviewed

    Kawashima N., Ito Y., Sekiya Y., Narita A., Okuno Y., Muramatsu H., Irie M., Hama A., Takahashi Y., Kojima S.

    Biology of Blood and Marrow Transplantation   Vol. 21 ( 2 ) page: 319 - 325   2015.2

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    Therapy for BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is limited after hematopoietic stem cell transplantation (HSCT). We examined whether choreito, a formula from Japanese traditional Kampo medicine, is effective for treating BKV-HC. Among children who underwent allogeneic HSCT between October 2006 and March 2014, 14 were diagnosed with BKV-HC (median, 36 days; range, 14 to 330 days) after HSCT, and 6 consecutive children received pharmaceutical-grade choreito extract granules. The hematuria grade before treatment was significantly higher in the choreito group than in the nonchoreito group (. P=.018). The duration from therapy to complete resolution was significantly shorter in the choreito group (median, 9 days; range, 4 to 17 days) than in the nonchoreito group (median, 17 days; range, 15 to 66 days; P=.037). In 11 children with macroscopic hematuria, the duration from treatment to resolution of macroscopic hematuria was significantly shorter in the choreito group than in the nonchoreito group (median, 2 days versus 11 days; P=.0043). The BKV load in urine was significantly decreased 1 month after choreito administration. No adverse effects related to choreito administration were observed. Choreito may be a safe and considerably promising therapy for the hemostasis of BKV-HC after HSCT.

    DOI: 10.1016/j.bbmt.2014.10.018

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  163. Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia Reviewed

    Narita A., Muramatsu H., Sekiya Y., Okuno Y., Sakaguchi H., Nishio N., Yoshida N., Wang X., Xu Y., Kawashima N., Doisaki S., Hama A., Takahashi Y., Kudo K., Moritake H., Kobayashi M., Kobayashi R., Ito E., Yabe H., Ohga S., Ohara A., Kojima S.

    Haematologica   Vol. 100 ( 12 ) page: 1546 - 1552   2015

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    Acquired aplastic anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in aplastic anemia. We enrolled 113 aplastic anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of aplastic anemia patients was −0.99 standard deviation (SD) (range −4.01–+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P<0.001). The combined absence of a minor paroxysmal nocturnal hemoglobinuria population and a short telomere length is an efficient predictor of poor immunosuppressive therapy response, which should be considered while deciding treatment options: immunosuppressive therapy or first-line hematopoietic stem cell transplantation.

    DOI: 10.3324/haematol.2015.132530

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  164. First-line treatment for severe aplastic anemia in children: Bone marrow transplantation from a matched family donor versus immunosuppressive therapy Reviewed

    Yoshida N., Kobayashi R., Yabe H., Kosaka Y., Yagasaki H., Watanabe K.I., Kudo K., Morimoto A., Ohga S., Muramatsu H., Takahashi Y., Kato K., Suzuki R., Ohara A., Kojima S.

    Haematologica   Vol. 99 ( 12 ) page: 1784 - 1791   2014.12

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    The current treatment approach for severe aplastic anemia in children is based on studies performed in the 1980s, and updated evidence is required. We retrospectively compared the outcomes of children with acquired severe aplastic anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation from an HLA-matched family donor registered in the Japanese Society for Hematopoietic Cell Transplantation Registry. Between 1992 and 2009, 599 children (younger than 17 years) with severe aplastic anemia received a bone marrow transplant from an HLA-matched family donor (n=213) or immunosuppressive therapy (n=386) as first-line treatment. While the overall survival did not differ between patients treated with immunosuppressive therapy or bone marrow transplantation [88% (95% confidence interval: 86-90) versus 92% (90-94)], failure-free survival was significantly inferior in patients receiving immunosuppressive therapy than in those undergoing bone marrow transplantation [56% (54-59) versus 87% (85-90); P<0.0001]. There was no significant improvement in outcomes over the two time periods (1992-1999 versus 2000-2009). In multivariate analysis, age <10 years was identified as a favorable factor for overall survival (P=0.007), and choice of first-line immunosuppressive therapy was the only unfavorable factor for failure-free survival (P<0.0001). These support the current algorithm for treatment decisions, which recommends bone marrow transplantation when an HLA-matched family donor is available in pediatric severe aplastic anemia.

    DOI: 10.3324/haematol.2014.109355

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  165. Clinical course of juvenile myelomonocytic leukemia in the blast crisis phase treated by acute myeloid leukemia-oriented chemotherapy and allogeneic hematopoietic stem cell transplantation Reviewed

    Ueda S., Sakata N., Muramatsu H., Sakaguchi H., Wang X., Xu Y., Kojima S., Yamaguchi T., Higa T., Takemura T.

    International Journal of Hematology   Vol. 100 ( 5 ) page: 502 - 506   2014.11

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    Juvenile myelomonocytic leukemia (JMML) is a mixed myeloproliferative and myelodysplastic disorder that occurs in early childhood. The clinical course of JMML is highly variable. A third of patients follow a relatively indolent course, although approximately 15 % cases are thought to develop acute myeloid leukemia, referred to as blast crisis. The etiology and clinical characteristics of blast crisis remain unclear. We document the case of a 27-month-old boy who presented with hepatosplenomegaly, skin rash, and lymphadenopathy. An initial diagnosis of acute erythroid leukemia was made according to the French–American–British classification. Following estimation of hypersensitivity to GM-CSF and genetic analysis of PTPN11, he was diagnosed with JMML in the blast crisis phase. Although he had several poor prognostic factors, including monosomy 7 and high HbF percentage, he achieved partial remission after treatment with acute myeloid leukemia-oriented chemotherapy followed by allogeneic hematopoietic stem cell transplantation. He has been in complete remission for over 6 years.

    DOI: 10.1007/s12185-014-1638-3

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  166. Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia Reviewed

    Sakaguchi H., Nishio N., Hama A., Kawashima N., Wang X., Narita A., Doisaki S., Xu Y., Muramatsu H., Yoshida N., Takahashi Y., Kudo K., Moritake H., Nakamura K., Kobayashi R., Ito E., Yabe H., Ohga S., Ohara A., Kojima S.

    Haematologica   Vol. 99 ( 8 ) page: 1312 - 1316   2014.8

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    Predicting the response to immunosuppressive therapy could provide useful information to help the clinician define treatment strategies for patients with aplastic anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with aplastic anemia, using flow fluorescence in situ hybridization. Median age of patients was ten years (range 1.5-16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies using antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at six months was 52% (33 of 64). The probability of 5-year failure-free survival and overall survival were 56% (95% confidence interval (CI): 41-69%) and 97% (95%CI: 87-99%), respectively. Median telomere length in responders was -0.4 standard deviation (SD) (-2.7 to +3.0 SD) and -1.5 SD (-4.0 to +1.6 (SD)) in non-responders (P<0.001). Multivariate analysis showed that telomere length shorter than -1.0 SD (hazard ratio (HR): 22.0; 95%CI: 4.19-115; P<0.001), platelet count at diagnosis less than 25×109/L (HR: 13.9; 95%CI: 2.00-96.1; P=0.008), and interval from diagnosis to immunosuppressive therapy longer than 25 days (HR: 4.81; 95%CI: 1.15-20.1; P=0.031) were the significant variables for poor response to immunosuppressive therapy. Conversely to what has been found in adult patients, measurement of the telomere length of lymphocytes at diagnosis is a promising assay in predicting the response to immunosuppressive therapy in children with aplastic anemia. © 2014 Ferrata Storti Foundation.

    DOI: 10.3324/haematol.2013.091165

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  167. Bloodstream Infection after Stem Cell Transplantation in Children with Idiopathic Aplastic Anemia Reviewed

    Kobayashi R., Yabe H., Kikuchi A., Kudo K., Yoshida N., Watanabe K., Muramatsu H., Takahashi Y., Inoue M., Koh K., Inagaki J., Okamoto Y., Sakamaki H., Kawa K., Kato K., Suzuki R., Kojima S.

    Biology of Blood and Marrow Transplantation   Vol. 20 ( 8 ) page: 1145 - 1149   2014.8

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    Bloodstream infection (BSI) is the most common infectious complication of hematopoietic stem cell transplantation (HSCT) and can cause substantial morbidity and mortality. Identification of risk factors for BSI might be helpful in efforts to reduce transplantation-related death. This study analyzed the incidence of BSI and risk factors for BSI after HSCT in pediatric patients with aplastic anemia (AA). BSI occurred in 39 of the 351 patients with AA (11.1%). Onset of BSI occurred at a median of 8 days after HSCT (range, 0 to 92 days). The 5-year overall survival rate was lower in patients with BSI than in patients without BSI (63.32% ± 7.90% versus 93.35% ± 1.44%; P < .0001). Univariate analysis identified the following variables as associated with BSI: history of immunosuppressive therapy with antithymocyte globulin (ATG), transplantation from an unrelated donor, frequent blood transfusion before transplantation, major or major plus minor ABO type mismatch, graft-versus-host disease prophylaxis with tacrolimus and without cyclosporine, and long interval from diagnosis to transplantation. Among these factors, long interval from diagnosis to transplantation was the sole statistically significant risk factor for BSI on multivariate analysis. In patients who underwent HSCT from a related donor, age ≥14 years at transplantation was risk factor for BSI. In contrast, history of immunosuppressive therapy with ATG, frequent blood transfusion before HSCT, graft failure, and major or major plus minor ABO type mismatch were risk factors for BSI in patients who underwent HSCT from an unrelated donor. Because the overall 5-year survival rate without BSI was >90%, even in patients who were received a transplant from an unrelated donor, control of BSI is very important for successful HSCT in pediatric patients with AA. © 2014 American Society for Blood and Marrow Transplantation.

    DOI: 10.1016/j.bbmt.2014.04.006

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  168. Whole-exome sequence analysis of ataxia telangiectasia-like phenotype Reviewed

    Hasegawa S., Imai K., Yoshida K., Okuno Y., Muramatsu H., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Kojima S., Ogawa S., Morio T., Mizutani S., Takagi M.

    Journal of the Neurological Sciences   Vol. 340 ( 1-2 ) page: 86 - 90   2014.5

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    A number of diseases exhibit neurodegeneration with/without additional symptoms such as immunodeficiency, increased cancer risk, and microcephalus. Ataxia telangiectasia and Nijmegen breakage syndrome, for example, develop as a result of mutations in genes involved in the DNA damage response. However, such diseases can be difficult to diagnose as they are only rarely encountered by physicians. To overcome this challenge, nine patients with symptoms that resemble those of ataxia telangiectasia, including neurodegeneration, hypogammaglobulinemia, telangiectasia, and/or elevated serum α-fetoprotein, were subjected to whole-exome sequencing (WES) to identify the causative mutations. Molecular diagnosis was achieved in two patients: one displayed CD40 ligand (CD40LG) deficiency, while a second showed a homozygous SIL1 mutation, which has been linked to Marinesco-Sjögren syndrome (MSS). Typical features of CD40LG deficiency and MSS are distinct from the symptoms usually seen in ataxia telangiectasia. These dissociations between phenotype and genotype make it difficult to achieve molecular diagnosis of orphan diseases. Whole-exome sequencing analyses will assist in the molecular diagnosis of such cases and allow the identification of genotypes that would not be expected from the phenotype. © 2014 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.jns.2014.02.033

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  169. Immunosuppressive therapy with horse anti-thymocyte globulin and cyclosporine as treatment for fulminant aplastic anemia in children Reviewed

    Yagasaki H., Shichino H., Ohara A., Kobayashi R., Yabe H., Ohga S., Hamamoto K., Ohtsuka Y., Shimada H., Inoue M., Muramatsu H., Takahashi Y., Kojima S.

    Annals of Hematology   Vol. 93 ( 5 ) page: 747 - 752   2014.5

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    Patients with severe aplastic anemia (SAA) and an absolute neutrophil count (ANC) of 0 typically have fatal outcomes. We defined fulminant AA (FAA) as ANC=0 for at least 2 weeks prior to and after immunosuppressive therapy (IST). We analyzed the outcomes of 35 children with FAA among 288 children who enrolled in a prospective study for AA (AA-97 study). AA was classified as FAA (n=35), very SAA (vSAA; n=129), or SAA (n=124). All of the children received the IST with horse anti-thymocyte globulin (ATG) and cyclosporine (CsA). A significantly lower response rate at 6 months was seen in children with FAA when compared to those with vSAA or SAA (40.0, 63.6, and 63.7 %, respectively; p=0.027). Of 20 nonresponder patients in the FAA group, 11 were rescued by alternative donor transplantation, and 5 patients showed a late response after 6 months. Consequently, no significant difference was noted in overall survival when comparing the FAA, vSAA, and SAA groups (88.5, 95.8, and 96.8 %). These findings indicate that IST with ATG and CsA is justified as a first-line treatment for children with FAA who lack a human leukocyte antigen-matched sibling donor. © 2013 Springer-Verlag Berlin Heidelberg.

    DOI: 10.1007/s00277-013-1984-x

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  170. Reduced intensity conditioning in allogeneic stem cell transplantation for AML with Down syndrome Reviewed

    Muramatsu H., Sakaguchi H., Taga T., Tabuchi K., Adachi S., Inoue M., Kitoh T., Suminoe A., Yabe H., Azuma E., Shioda Y., Ogawa A., Kinoshita A., Kigasawa H., Osugi Y., Koike K., Kawa K., Kato K., Atsuta Y., Kudo K.

    Pediatric Blood and Cancer   Vol. 61 ( 5 ) page: 925 - 927   2014.5

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    Allogeneic hematopoietic stem cell transplantation (HSCT) has not been widely used in patients with acute myeloid leukemia (AML) and Down syndrome (DS) due to fear of transplantation-related toxicity. A retrospective analysis of the outcome of allogeneic HSCT was conducted in 15 patients with AML and DS. The five patients transplanted with the reduced intensity conditioning (4 in complete remission (CR) and 1 in non-CR) had a significantly better survival rate than 10 patients transplanted with a conventional conditioning (4 in CR and 6 in non-CR) (3-year EFS (95% confidence interval): 80.0% (20.4-96.9%) vs. 10.0% (0.6%-35.8%), P=0.039). Pediatr Blood Cancer 2014;61:925-927. © 2013 Wiley Periodicals, Inc.

    DOI: 10.1002/pbc.24883

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  171. A novel WTX mutation in a female patient with osteopathia striata with cranial sclerosis and hepatoblastoma Reviewed

    Fujita A., Ochi N., Fujimaki H., Muramatsu H., Takahashi Y., Natsume J., Kojima S., Nakashima M., Tsurusaki Y., Saitsu H., Matsumoto N., Miyake N.

    American Journal of Medical Genetics, Part A   Vol. 164 ( 4 ) page: 998 - 1002   2014.4

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    Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant sclerosing bone dysplasia. Typically affected females show macrocephaly, characteristic facial appearance, cleft palate, mild learning difficulties, hearing loss, sclerosis of the long bones and skull, and longitudinal striations visible on radiographs of the long bones, pelvis and scapulae. Typically affected males usually die at the fetal or early neonatal stage. Because of its variable expressivity, which ranges from asymptomatic to fetal death, clinical diagnosis of OSCS can be difficult. Here, we identify a unique female patient presenting with severe macrocephaly, characteristic facial appearance, developmental delay, and hepatoblastoma. Exome sequencing identified a novel de novo nonsense mutation (c.1045C>T, p.Glu349*) in the WTX gene associated with OSCS. The OSCS diagnosis was confirmed in this patient based on the hallmark appearance of longitudinal striations in long bones when viewed by X-ray. WTX is also known as a tumor suppressor gene, and somatic mutations in that gene have been identified in Wilms tumors. In addition to this patient, although two patients with OSCS have been reported to have colorectal cancer or ovarian cancer, Wilms tumor has never been reported in association with this disorder. Tumor susceptibility in patients with OSCS is discussed. © 2014 Wiley Periodicals, Inc.

    DOI: 10.1002/ajmg.a.36369

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  172. Long-term outcome after immunosuppressive therapy with horse or rabbit antithymocyte globulin and cyclosporine for severe aplastic anemia in children Reviewed

    Jeong D.C., Chung N.G., Cho B., Zou Y., Ruan M., Takahashi Y., Muramatsu H., Ohara A., Kosaka Y., Yang W., Kim H.K., Zhu X., Kojima S.

    Haematologica   Vol. 99 ( 4 ) page: 664 - 671   2014.4

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    Some prospective studies showed that rabbit antithymocyte globulin was inferior to horse antithymocyte globulin as first-line therapy for patients with severe aplastic anemia. We retrospectively analyzed the clinical outcome of 455 children with severe aplastic anemia who received horse antithymocyte globulin (n=297) or rabbit antithymocyte globulin (n=158) combined with cyclosporine as first-line therapy between 1992 and 2010. The response rates were comparable between the horse and rabbit antithymocyte globulin groups at 3 months [46% (136/294) versus 42% (66/153), P=0.55] and 6 months [60% (178/292) versus 55% (87/143), P=1.0]. Using multivariate analysis, differences in antithymocyte globulin preparations were not associated with response rates. However, 2-year and 10- year overall survival rates in the horse antithymocyte globulin group were significantly better than those in the rabbit antithymocyte globulin group (2-year overall survival: 96% versus 87%, 10-year overall survival: 92% versus 84%, P=0.004). On the basis of multivariate analysis, use of rabbit antithymocyte globulin was a significant adverse factor for overall survival (hazard ratio = 3.56, 95% confidence interval, 1.53 - 8.28, P=0.003). Rabbit antithymocyte globulin caused more profound immunosuppression, which might be responsible for the higher incidence of severe infections. Considering that there are no studies showing the superiority of rabbit antithymocyte globulin over horse antithymocyte globulin, horse antithymocyte globulin should be recommended as a firstline therapy. However, our results justify the use of rabbit antithymocyte globulin as first-line therapy if horse antithymocyte globulin is not available. © Ferrata Storti Foundation.

    DOI: 10.3324/haematol.2013.089268

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  173. Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis Reviewed

    Mizoguchi Y., Tsumura M., Okada S., Hirata O., Minegishi S., Imai K., Hyakuna N., Muramatsu H., Kojima S., Ozaki Y., Imai T., Takeda S., Okazaki T., Ito T., Yasunaga S., Takihara Y., Bryant V.L., Kong X.F., Cypowyj S., Boisson-Dupuis S., Puel A., Casanova J.L., Morio T., Kobayashi M.

    Journal of Leukocyte Biology   Vol. 95 ( 4 ) page: 667 - 676   2014.4

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    CMCD is a rare congenital disorder characterized by persistent or recurrent skin, nail, and mucosal membrane infections caused by Candida albicans. Heterozygous GOF STAT1 mutations have been shown to confer AD CMCD as a result of impaired dephosphorylation of STAT1. We aimed to identify and characterize STAT1 mutations in CMCD patients and to develop a simple diagnostic assay of CMCD. Genetic analysis of STAT1 was performed in patients and their relatives. The mutations identified were characterized by immunoblot and reporter assay using transient gene expression experiments. Patients' leukocytes are investigated by flow cytometry and immunoblot. Six GOF mutations were identified, three of which are reported for the first time, that affect the CCD and DBD of STAT1 in two sporadic and four multiplex cases in 10 CMCD patients from Japan. Two of the 10 patients presented with clinical symptoms atypical to CMCD, including other fungal and viral infections, and three patients developed bronchiectasis. Immunoblot analyses of patients' leukocytes showed abnormally high levels of pSTAT1 following IFN-γ stimulation. Based on this finding, we performed a flow cytometry-based functional analysis of STAT1 GOF alleles using IFN-γ stimulation and the tyrosine kinase inhibitor, staurosporine. The higher levels of pSTAT1 observed in primary CD14+ cells from patients compared with control cells persisted and were amplified by the presence of staurosporine. We developed a flow cytometry-based STAT1 functional screening method that would greatly facilitate the diagnosis of CMCD patients with GOF STAT1 mutations. © Society for Leukocyte Biology.

    DOI: 10.1189/jlb.0513250

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  174. RUNX1 mutation associated with clonal evolution in relapsed pediatric acute myeloid leukemia with t(16;21)(p11;q22) Reviewed

    Ismael O., Shimada A., Elmahdi S., Elshazley M., Muramatsu H., Hama A., Takahashi Y., Yamada M., Yamashita Y., Horide K., Kojima S.

    International Journal of Hematology   Vol. 99 ( 2 ) page: 169 - 174   2014.2

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    TLS/FUS-ERG chimeric fusion transcript resulting from translocation changes involving chromosomes 16 and 21 is a rare genetic event associated with acute myeloid leukemia (AML). The distinct t(16;21) AML subtype exhibits unique clinical and morphological features and is associated with poor prognosis and a high relapse rate; however, the underlying mechanism remains to be clarified. Recently, whole-genome sequencing revealed a large set of genetic alterations that may be relevant for the dynamic clonal evolution and relapse pathogenesis of AML. Here, we report three pediatric AML patients with t(16;21) (p11; q22). The TLS/FUS-ERG fusion transcript was detected in all diagnostic and relapsed samples, with the exception of one relapsed sample. We searched for several genetic lesions, such as RUNX1, FLT3, c-KIT, NRAS, KRAS, TP53, CBL, ASXL1, IDH1/2, and DNMT3A, in primary and relapsed AML samples. Interestingly, we found RUNX1 mutation in relapsed sample of one patient in whom cytogenetic analysis showed the emergence of a new additional clone. Otherwise, there were no genetic alterations in FLT3, c-KIT, NRAS, KRAS, TP53, CBL, ASXL1, IDH1/2, or DNMT3A. Our results suggest that precedent genetic alterations may be essential to drive the progression and relapse of t(16;21)-AML patients. © 2013 The Japanese Society of Hematology.

    DOI: 10.1007/s12185-013-1495-5

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  175. Long-term parvovirus B19 infections with genetic drift after cord blood transplantation complicated by persistent CD4<sup>+</sup> lymphocytopenia Reviewed

    Suzuki M., Ito Y., Shimada A., Saito M., Muramatsu H., Hama A., Takahashi Y., Kimura H., Kojima S.

    Journal of Pediatric Hematology/Oncology   Vol. 36 ( 1 )   2014.1

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    A 5-month-old girl was diagnosed with Langerhans cell histiocytosis and received unrelated umbilical cord blood transplantation at the age of 14 months. After cord blood transplantation, CD4 lymphocytopenia from unknown causes was observed, and persistent infections with human parvovirus B19 (B19) occurred. We performed repeated longitudinal genetic analysis for B19, which revealed 6 nucleotide mutations in B19 nonstructural protein regions in the patient. The resulting changes of the nonstructural 1 structure may have altered antigenicity of the virus and could play a role in the pathogenesis of persistent infection under immunocompromised conditions. Copyright © 2013 by Lippincott Williams & Wilkins.

    DOI: 10.1097/MPH.0000000000000008

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  176. Erratum: The landscape of somatic mutations in Down syndrome-related myeloid disorders (Nature Genetics (2013) 45 (1293-1299)) Reviewed

    Yoshida K., Toki T., Okuno Y., Kanezaki R., Shiraishi Y., Sato-Otsubo A., Sanada M., Park M.J., Terui K., Suzuki H., Kon A., Nagata Y., Sato Y., Wang R., Shiba N., Chiba K., Tanaka H., Hama A., Muramatsu H., Hasegawa D., Nakamura K., Kanegane H., Tsukamoto K., Adachi S., Kawakami K., Kato K., Nishimura R., Izraeli S., Hayashi Y., Miyano S., Kojima S., Ito E., Ogawa S.

    Nature Genetics   Vol. 45 ( 12 )   2013.12

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    DOI: 10.1038/ng1213-1516

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  177. The landscape of somatic mutations in Down syndrome-related myeloid disorders Reviewed

    Yoshida K., Toki T., Okuno Y., Kanezaki R., Shiraishi Y., Sato-Otsubo A., Sanada M., Park M.J., Terui K., Suzuki H., Kon A., Nagata Y., Sato Y., Wang R.N., Shiba N., Chiba K., Tanaka H., Hama A., Muramatsu H., Hasegawa D., Nakamura K., Kanegane H., Tsukamoto K., Adachi S., Kawakami K., Kato K., Nishimura R., Izraeli S., Hayashi Y., Miyano S., Kojima S., Ito E., Ogawa S.

    Nature Genetics   Vol. 45 ( 11 ) page: 1293 - 1301   2013.11

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    Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%). © 2013 Nature America, Inc. All rights reserved.

    DOI: 10.1038/ng.2759

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  178. Paroxysmal cold hemoglobinuria caused by an IgM-class Donath-Landsteiner antibody Reviewed

    Hayashi H., Yasutomi M., Hayashi T., Yuasa M., Kawakita A., Hata I., Tanizawa A., Muramatsu H., Kojima S., Ohshima Y.

    Pediatrics International   Vol. 55 ( 5 ) page: 664 - 666   2013.10

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    We report on a 4-year-old boy who developed paroxysmal cold hemoglobinuria (PCH) following the first dose of a seven-valent pneumococcal conjugate vaccine. He was admitted because of dark urine after exposure to cold air. Laboratory tests indicated anemia, increased serum indirect bilirubin and lactate dehydrogenase, and decreased serum haptoglobin. Donath-Landsteiner (D-L) test was positive. The D-L antibody belonged to the IgM class and exhibited anti-P specificity. Symptoms and signs subsided after supportive care without any medication. Although PCH is often associated with viral or bacterial infection and is caused by IgG-class D-L antibodies with anti-P specificity, this case was unique because a D-L antibody of the IgM class with anti-P specificity caused PCH after immunization with a pneumococcal vaccine. © 2013 Japan Pediatric Society.

    DOI: 10.1111/ped.12110

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  179. B-cell function after unrelated umbilical cord blood transplantation using a minimal-intensity conditioning regimen in patients with X-SCID Reviewed

    Kumaki S., Sasahara Y., Kamachi Y., Muramatsu H., Morio T., Goi K., Sugita K., Urabe T., Takada H., Kojima S., Tsuchiya S., Hara T.

    International Journal of Hematology   Vol. 98 ( 3 ) page: 355 - 360   2013.9

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    Patients with X-linked severe combined immunodeficiency (X-SCID) suffer from severe and persistent infections, and usually die early in life unless treated by hematopoietic stem cell transplantation. If a patient has an HLA-identical sibling donor, preparative conditioning is not necessary for T-cell engraftment and B-cell function. However, in the absence of such a donor, long-term reconstitution of full B-cell function is often problematic, leading in many cases to a lifetime requirement for immunoglobulin replacement therapy. Preparative myeloablative conditioning has been shown to improve long-term B-cell function, but may aggravate pre-existing infection and transplant-related toxicity. It is thus important to determine the minimum intensity of conditioning that assures immunoglobulin production. In the present study, we performed reduced-intensity conditioning (RIC), consisting of fludarabine 125 mg/m2 and melphalan 80 mg/m2, prior to unrelated umbilical cord blood transplantation (UCBT) for five patients with X-SCID, none of them had an HLA-identical donor. Four patients survived more than 4 years without sequelae, and none required long-term immunoglobulin replacement therapy. One patient succumbed to sepsis in conjunction with severe GVHD. Our result demonstrates that the RIC regimen described above in combination with UCBT is an effective and less toxic conditioning to correct B-cell function in patients with X-SCID. © 2013 The Japanese Society of Hematology.

    DOI: 10.1007/s12185-013-1408-7

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  180. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia Reviewed

    Sakaguchi H., Okuno Y., Muramatsu H., Yoshida K., Shiraishi Y., Takahashi M., Kon A., Sanada M., Chiba K., Tanaka H., Makishima H., Wang X., Xu Y., Doisaki S., Hama A., Nakanishi K., Takahashi Y., Yoshida N., Maciejewski J.P., Miyano S., Ogawa S., Kojima S.

    Nature Genetics   Vol. 45 ( 8 ) page: 937 - 941   2013.8

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    Juvenile myelomonocytic leukemia (JMML) is an intractable pediatric leukemia with poor prognosis1 whose molecular pathogenesis is poorly understood, except for somatic or germline mutations of RAS pathway genes, including PTPN11, NF1, NRAS, KRAS and CBL, in the majority of cases 2-4. To obtain a complete registry of gene mutations in JMML, whole-exome sequencing was performed for paired tumor-normal DNA from 13 individuals with JMML (cases), which was followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 non-silent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 and JAK3 genes were among common targets for secondary mutations. Mutations in the latter were often subclonal and may be involved in the progression rather than the initiation of leukemia, and these mutations associated with poor clinical outcome. Our findings provide new insights into the pathogenesis and progression of JMML. © 2013 Nature America, Inc. All rights reserved.

    DOI: 10.1038/ng.2698

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  181. Somatic SETBP1 mutations in myeloid malignancies Reviewed

    Makishima H., Yoshida K., Nguyen N., Przychodzen B., Sanada M., Okuno Y., Ng K.P., Gudmundsson K.O., Vishwakarma B.A., Jerez A., Segui I.G., Takahashi M., Shiraishi Y., Nagata Y., Guinta K., Mori H., Sekeres M.A., Chiba K., Tanaka H., Muramatsu H., Sakaguchi H., Paquette R.L., McDevitt M.A., Kojima S., Saunthararajah Y., Miyano S., Shih L.Y., Du Y., Ogawa S., Maciejewski J.P.

    Nature Genetics   Vol. 45 ( 8 ) page: 942 - 946   2013.8

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    Here we report whole-exome sequencing of individuals with various myeloid malignancies and identify recurrent somatic mutations in SETBP1, consistent with a recent report on atypical chronic myeloid leukemia (aCML). Closely positioned somatic SETBP1 mutations encoding changes in Asp868, Ser869, Gly870, Ile871 and Asp880, which match germline mutations in Schinzel-Giedion syndrome (SGS), were detected in 17% of secondary acute myeloid leukemias (sAML) and 15% of chronic myelomonocytic leukemia (CMML) cases. These results from deep sequencing demonstrate a higher mutational detection rate than reported with conventional sequencing methodology. Mutant cases were associated with advanced age and monosomy 7/deletion 7q (-7/del(7q)) constituting poor prognostic factors. Analysis of serially collected samples indicated that SETBP1 mutations were acquired during leukemic evolution. Transduction with mutant Setbp1 led to the immortalization of mouse myeloid progenitors that showed enhanced proliferative capacity compared to cells transduced with wild-type Setbp1. Somatic mutations of SETBP1 seem to cause gain of function, are associated with myeloid leukemic transformation and convey poor prognosis in myelodysplastic syndromes (MDS) and CMML. © 2013 Nature America, Inc. All rights reserved.

    DOI: 10.1038/ng.2696

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  182. Correlation of cyp2c19 phenotype with voriconazole plasma concentration in children Reviewed

    Narita A., Muramatsu H., Sakaguchi H., Doisaki S., Tanaka M., Hama A., Shimada A., Takahashi Y., Yoshida N., Matsumoto K., Kato K., Kudo K., Furukawa-Hibi Y., Yamada K., Kojima S.

    Journal of Pediatric Hematology/Oncology   Vol. 35 ( 5 )   2013.7

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    Voriconazole is a triazole antifungal agent with potent activity against a broad spectrum of pathogens, including Aspergillus and Candida species. In human adults, allelic polymorphisms of CYP2C19 are known to correlate with significant variation in voriconazole plasma concentration. Here, we report an analysis of CYP2C19 phenotype and voriconazole plasma concentrations in children. Methods: This retrospective study included 37 children who had voriconazole plasma concentrations measured from May 2006 to June 2011. All had single-nucleotide polymorphisms that define the 3 major CYP2C19 alleles. Patients were classified as follows: normal metabolizers, intermediate metabolizers, poor metabolizers, or hypermetabolizers. Results: The frequencies of the 3 CYP2C19 genetic polymorphisms were similar to those previously reported for Japanese adults. Trough plasma concentrations of voriconazole were significantly higher in the poor metabolizer and intermediate metabolizer groups compared with the normal metabolizer and hypermetabolizer groups (P=0.004). Two patients with high plasma concentrations experienced voriconazole-related severe adverse events (syndrome of inappropriate antidiuretic hormone secretion and cardiac toxicities). Conclusions: The current study suggests that a significant association exists in children between the voriconazole plasma concentration and the CYP2C19 phenotype. Dose adjustment based on CYP2C19 phenotype may be useful during voriconazole therapy, especially for Japanese children, who as a group have a higher incidence of the poor metabolizer and intermediate metabolizer phenotypes. Copyright © 2013 by Lippincott Williams & Wilkins.

    DOI: 10.1097/MPH.0b013e3182880eaa

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  183. Lack of CD4<sup>+</sup>CD25<sup>+</sup>FOXP3<sup>+</sup> regulatory T cells is associated with resistance to intravenous immunoglobulin therapy in patients with Kawasaki disease Reviewed

    Hirabayashi Y., Takahashi Y., Xu Y., Akane K., Villalobos I.B., Okuno Y., Hasegawa S., Muramatsu H., Hama A., Kato T., Kojima S.

    European Journal of Pediatrics   Vol. 172 ( 6 ) page: 833 - 837   2013.6

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    The aim of this study was to investigate changes in CD4 +CD25+FOXP3+ regulatory T cells (Tregs) throughout the clinical course of Kawasaki disease (KD) and correlations with response to intravenous immunoglobulin (IVIg) therapy. Participants comprised 18 patients who fulfilled the diagnostic criteria for KD and 20 healthy subjects. Expressions of CD25 and FOXP3 among all CD4+ T cells in peripheral blood mononuclear cells were analyzed by flow cytometry before and 7 and 30 days after IVIg therapy. Before treatment, percentages of CD4+CD25 +FOXP3+ Tregs among total CD4+ Tregs were significantly lower among KD patients (4.19 %; range, 0.16-8.11 %) than among healthy subjects (7.32 %; 4.18-13.42 %; P = 0.0001). Both percentages and absolute numbers of CD4+CD25+FOXP3+ Tregs on day 7 after IVIg therapy were significantly increased compared with values before treatment (8.02 % (range, 0.51-12.6 %) vs. 4.19 % (range, 0.16-8.11 %), P = 0.0005; 93.25/ μL (range, 6.67-258.05) vs. 41.85/ μL (range, 0.44-160.62), P < 0.0001, respectively). Moreover, percentages and absolute numbers of CD4+CD25+FOXP3+ Tregs before treatment were significantly lower in the IVIg-resistant group than in the IVIg-sensitive group (0.18 % (range, 0.16-3.34 %) vs. 4.52 % (range, 2.8-8.11 %), P = 0.0022; 0.68/μL (range, 0.44-53.81) vs. 51.66/μL (range, 2.88-160.62), P = 0.0098, respectively). The frequency of CD4 +CD25+FOXP3+ Tregs in four of the five IVIg-resistant patients at diagnosis was more than 3 standard deviations below that in healthy subjects. Two of these four patients displayed coronary abnormalities, and one of these two patients developed coronary aneurysm. Conclusion: Lack of CD4+CD25+FOXP3+ Tregs before treatment may predict resistance to IVIg therapy in patients with KD. © 2013 Springer-Verlag Berlin Heidelberg.

    DOI: 10.1007/s00431-013-1937-3

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  184. Congenital dyserythropoietic anemia type 1 with a novel mutation in the CDAN1 gene previously diagnosed as congenital hemolytic anemia Reviewed

    Fujino H., Doisaki S., Park Y.D., Hama A., Muramatsu H., Kojima S., Sumimoto S.

    International Journal of Hematology   Vol. 97 ( 5 ) page: 650 - 653   2013.5

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    The congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of genetic disorders of red cell production. They are characterized by ineffective erythropoiesis and dyserythropoiesis. Here, we present the clinical description and mutation analysis of a Japanese female with CDA type 1. She has long been diagnosed with unclassified congenital hemolytic anemia from the neonatal period. However, bone marrow morphology and genetic testing of the CDAN1 gene at the age of 12 years confirmed the afore-mentioned diagnosis. Thus, we should be aware of the possibility of CDA if the etiology of congenital anemia or jaundice cannot be clearly elucidated. © 2013 The Japanese Society of Hematology.

    DOI: 10.1007/s12185-013-1338-4

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  185. Recipient seropositivity for adenovirus type 11 (AdV11) is a highly predictive factor for the development of AdV11-induced hemorrhagic cystitis after allogeneic hematopoietic SCT Reviewed

    Nakazawa Y., Saito S., Yanagisawa R., Suzuki T., Ito T., Ishida F., Muramatsu H., Matsumoto K., Kato K., Ishida H., Umeda K., Adachi S., Nakahata T., Koike K.

    Bone Marrow Transplantation   Vol. 48 ( 5 ) page: 737 - 739   2013.5

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    DOI: 10.1038/bmt.2012.206

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  186. Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia Reviewed

    Yoshimi A., Kamachi Y., Imai K., Watanabe N., Nakadate H., Kanazawa T., Ozono S., Kobayashi R., Yoshida M., Kobayashi C., Hama A., Muramatsu H., Sasahara Y., Jakob M., Morio T., Ehl S., Manabe A., Niemeyer C., Kojima S.

    Pediatric Blood and Cancer   Vol. 60 ( 5 ) page: 836 - 841   2013.5

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    Background: Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency caused by defects of the WAS protein (WASP) gene. Patients with WAS typically demonstrate micro-thrombocytopenia. Procedures: The report describes seven male infants with WAS that initially presented with leukocytosis, monocytosis, and myeloid and erythroid precursors in the peripheral blood (PB) and dysplasia in the bone marrow (BM), which was initially indistinguishable from juvenile myelomonocytic leukaemia (JMML). Results: The median age of affected patients was 1 month (range, 1-4 months). Splenomegaly was absent in four of these patients, which was unusual for JMML. A mutation analysis of genes in the RAS-signalling pathway did not support a diagnosis of JMML. Non-haematological features, such as eczema (n=7) and bloody stools (n=6), ultimately led to the diagnosis of WAS at a median age of 4 months (range, 3-8 months), which was confirmed by absent (n=6) or reduced (n=1) WASP expression in lymphocytes by flow cytometry (FCM) and a WASP gene mutation. Interestingly, mean platelet volume (MPV) was normal in three of five patients and six of seven patients demonstrated occasional giant platelets, which was not compatible with WAS. Conclusions: These data suggest that WAS should be considered in male infants presenting with JMML-like features if no molecular markers of JMML can be detected. © 2012 Wiley Periodicals, Inc.

    DOI: 10.1002/pbc.24359

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  187. ACTN1 mutations cause congenital macrothrombocytopenia Reviewed

    Kunishima S., Okuno Y., Yoshida K., Shiraishi Y., Sanada M., Muramatsu H., Chiba K., Tanaka H., Miyazaki K., Sakai M., Ohtake M., Kobayashi R., Iguchi A., Niimi G., Otsu M., Takahashi Y., Miyano S., Saito H., Kojima S., Ogawa S.

    American Journal of Human Genetics   Vol. 92 ( 3 ) page: 431 - 438   2013.3

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    Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole-exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but for which no known responsible mutations have been documented. In 13 Japanese CMTP-affected pedigrees, we identified six (46%) affected by ACTN1 variants cosegregating with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represented the fourth most common cause in Japanese individuals. Individuals with ACTN1 variants presented with moderate macrothrombocytopenia with anisocytosis but were either asymptomatic or had only a modest bleeding tendency. ACTN1 encodes α-actinin-1, a member of the actin-crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that altered α-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1 variants caused a disorganized actin-based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP. © 2013 The American Society of Human Genetics.

    DOI: 10.1016/j.ajhg.2013.01.015

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  188. Rabbit antithymocyte globulin and cyclosporine as first-line therapy for children with acquired aplastic anemia Reviewed

    Takahashi Y., Muramatsu H., Sakata N., Hyakuna N., Hamamoto K., Kobayashi R., Ito E., Yagasaki H., Ohara A., Kikuchi A., Morimoto A., Yabe H., Kudo K., Watanabe K.I., Ohga S., Kojima S.

    Blood   Vol. 121 ( 5 ) page: 862 - 863   2013.1

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    DOI: 10.1182/blood-2012-11-465633

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  189. Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia Reviewed

    Kar S.A., Jankowska A., Makishima H., Visconte V., Jerez A., Sugimoto Y., Muramatsu H., Traina F., Afable M., Guinta K., Tiu R.V., Przychodzen B., Sakaguchi H., Kojima S., Sekeres M.A., List A.F., McDevitt M.A., Maciejewski J.P.

    Haematologica   Vol. 98 ( 1 ) page: 107 - 113   2013.1

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    Chronic myelomonocytic leukemia is a heterogeneous disease with multifactorial molecular pathogenesis. Various recurrent somatic mutations have been detected alone or in combination in chronic myelomonocytic leukemia. Recently, recurrent mutations in spliceosomal genes have been discovered. We investigated the contribution of U2AF1, SRSF2 and SF3B1 mutations in the pathogenesis of chronic myelomonocytic leukemia and closely related diseases. We genotyped a cohort of patients with chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia for somatic mutations in U2AF1, SRSF2, SF3B1 and in the other 12 most frequently affected genes in these conditions. Chromosomal abnormalities were assessed by nucleotide polymorphism array-based karyotyping. The presence of molecular lesions was correlated with clinical endpoints. Mutations in SRSF2, U2AF1 and SF3B1 were found in 32%, 13% and 6% of cases of chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, respectively. Spliceosomal genes were affected in various combinations with other mutations, including TET2, ASXL1, CBL, EZH2, RAS, IDH1/2, DNMT3A, TP53, UTX and RUNX1. Worse overall survival was associated with mutations in U2AF1 (P=0.047) and DNMT3A (P=0.015). RAS mutations had an impact on overall survival in secondary acute myeloid leukemia (P=0.0456). By comparison, our screening of juvenile myelomonocytic leukemia cases showed mutations in ASXL1 (4%), CBL (10%), and RAS (6%) but not in IDH1/2, TET2, EZH2, DNMT3A or the three spliceosomal genes. SRSF2 and U2AF1 along with TET2 (48%) and ASXL1 (38%) are frequently affected by somatic mutations in chronic myelomonocytic leukemia, quite distinctly from the profile seen in juvenile myelomonocytic leukemia. Our data also suggest that spliceosomal mutations are of ancestral origin. © 2013 Ferrata Storti Foundation.

    DOI: 10.3324/haematol.2012.064048

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  190. Progressive hearing loss following acquired cytomegalovirus infection in an immunocompromised child Reviewed

    Kato K., Otake H., Tagaya M., Takahashi Y., Ito Y., Hama A., Muramatsu H., Kojima S., Naganawa S., Nakashima T.

    American Journal of Otolaryngology - Head and Neck Medicine and Surgery   Vol. 34 ( 1 ) page: 89 - 92   2013.1

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    We report a rare case of progressive hearing loss after acquired CMV infection in a child with Langerhans cell histiocytosis (LCH). A 5-month-old female was diagnosed as having LCH. When she was 14 months old, she received an unrelated donor umbilical cord blood transfusion for the treatment of intractable LCH. CMV infection was confirmed after the blood transfusion. Because her own umbilical cord had no CMV, the CMV infection was not congenital. When she was 7 years old, mixed hearing loss was noted with bilateral otitis media with effusion. After that time, the sensorineural hearing loss progressed to bilateral profound hearing loss over 3 years. Three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging with gadolinium contrast enhancement revealed a high intensity area in the inner ear that suggested bilateral labyrinthitis. This case demonstrates the possibility that, under the immunodeficiency, the acquired CMV infection causes progressive sensorineural hearing loss. © 2013 Elsevier Inc.

    DOI: 10.1016/j.amjoto.2012.09.006

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  191. Mutational analysis of RNA splicing machinery components in 206 children with myeloid malignancies Reviewed

    Sakaguchi H., Makishima H., Muramatsu H., Visconte V., Jerez A., Jankowska A.M., Tiu R.V., Maciejewski J.P., Kojima S.

    Leukemia Research   Vol. 36 ( 12 )   2012.12

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    DOI: 10.1016/j.leukres.2012.06.002

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  192. Mutations profile of polycythemia vera and essential thrombocythemia among Japanese children Reviewed

    Ismael O., Shimada A., Hama A., Sakaguchi H., Doisaki S., Muramatsu H., Yoshida N., Ito M., Takahashi Y., Akita N., Sunami S., Ohtsuka Y., Asada Y., Fujisaki H., Kojima S.

    Pediatric Blood and Cancer   Vol. 59 ( 3 ) page: 530 - 535   2012.9

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    Background: Acquired somatic mutations of JAK2 have been reported to play a pivotal role in the pathogenesis of BCR-ABL1-negative myeloproliferative neoplasm (MPN). However, the molecular characteristics of childhood MPN remain to be elucidated. Patient and Methods: We investigated a group of pediatric patients diagnosed either with essential thrombocythemia (ET; N=9) or polycythemia vera (PV; N=4) according to WHO criteria (median age=10 years; range 1.5-15 years) in whom direct sequencing was performed for the existence of genetic alterations in JAK2, MPL, TET2, ASXL1, CBL, IDH1, and IDH2. More sensitive allele specific polymerase chain reaction was used for JAK2 V617F genotyping. Results: We found three patients harbor JAK2 V617F mutation (2/9 ET and 1/4 PV). Bone marrow examination showed small and large megakaryocytes with dysplastic features in JAK2 V617F-positive ET patients compared to those without JAK2 V617F. We identified a previously unrecognized missense mutation at codon 1230 in exon 12 of ASXL1 gene in ET and PV patients (1/9 ET and 1/4 PV). Otherwise, no genetic alterations could be detected in JAK2 exon 12, MPL, TET2, CBL, IDH1, and IDH2 in all ET and PV patients. Conclusion: Although JAK2 mutations in childhood ET and PV are not as frequent as reported in adult patients, JAK2 is the most frequently mutated gene in childhood MPN known so far. Owing to the presence of childhood MPN without any genetic alterations in JAK2, MPL, TET2, ASXL1, CBL, IDH1, and IDH2, new biological markers have to be found. © 2011 Wiley Periodicals, Inc.

    DOI: 10.1002/pbc.23409

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  193. Somatic mosaicism for oncogenic NRAS mutations in juvenile myelomonocytic leukemia Reviewed

    Doisaki S., Muramatsu H., Shimada A., Takahashi Y., Mori-Ezaki M., Sato M., Kawaguchi H., Kinoshita A., Sotomatsu M., Hayashi Y., Furukawa-Hibi Y., Yamada K., Hoshino H., Kiyoi H., Yoshida N., Sakaguchi H., Narita A., Wang X., Ismael O., Xu Y., Nishio N., Tanaka M., Hama A., Koike K., Kojima S.

    Blood   Vol. 120 ( 7 ) page: 1485 - 1488   2012.8

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    Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. Somatic mutations in genes involved in GM-CSF signal transduction, such as NRAS, KRAS, PTPN11, NF1, and CBL, have been identified in more than 70% of children with JMML. In the present study, we report 2 patients with somatic mosaicism for oncogenic NRAS mutations (G12D and G12S) associated with the development of JMML. The mutated allele frequencies quantified by pyrosequencing were various and ranged from 3%-50% in BM and other somatic cells (ie, buccal smear cells, hair bulbs, or nails). Both patients experienced spontaneous improvement of clinical symptoms and leukocytosis due to JMML without hematopoietic stem cell transplantation. These patients are the first reported to have somatic mosaicism for oncogenic NRAS mutations. The clinical course of these patients suggests that NRAS mosaicism may be associated with a mild disease phenotype in JMML. © 2012 by The American Society of Hematology.

    DOI: 10.1182/blood-2012-02-406090

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  194. Casitas B-cell lymphoma mutation in childhood T-cell acute lymphoblastic leukemia Reviewed

    Saito Y., Aoki Y., Muramatsu H., Makishima H., Maciejewski J.P., Imaizumi M., Rikiishi T., Sasahara Y., Kure S., Niihori T., Tsuchiya S., Kojima S., Matsubara Y.

    Leukemia Research   Vol. 36 ( 8 ) page: 1009 - 1015   2012.8

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    Somatic CBL mutations have been reported in a variety of myeloid neoplasms but are rare in acute lymphoblastic leukemia (ALL). We analyzed 77 samples from hematologic malignancies, identifying a somatic mutation in CBL (p.C381R) in one patient with T-ALL that was associated with a uniparental disomy at the CBL locus and a germline heterozygous mutation in one patient with JMML. Two NOTCH1 mutations and homozygous deletions in LEF1 and CDKN2A were identified in T-ALL cells. The activation of the RAS pathway was enhanced, and activation of the NOTCH1 pathway was inhibited in NIH 3T3 cells that expressed p.C381R. This study appears to be the first to identify a CBL mutation in T-ALL. © 2012 Elsevier Ltd.

    DOI: 10.1016/j.leukres.2012.04.018

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  195. Mutation in the THPO gene is not associated with aplastic anaemia in Japanese children Reviewed

    Wang X., Muramatsu H., Sakaguchi H., Xu Y., Narita A., Tsumura Y., Doisaki S., Tanaka M., Ismael O., Shimada A., Hama A., Takahashi Y., Kojima S.

    British Journal of Haematology   Vol. 158 ( 4 ) page: 553 - 555   2012.8

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    Language:Japanese   Publisher:British Journal of Haematology  

    DOI: 10.1111/j.1365-2141.2012.09185.x

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  196. CBL mutation-related patterns of phosphorylation and sensitivity to tyrosine kinase inhibitors Reviewed

    Makishima H., Sugimoto Y., Szpurka H., Clemente M.J., Ng K.P., Muramatsu H., O'Keefe C., Saunthararajah Y., MacIejewski J.P.

    Leukemia   Vol. 26 ( 7 ) page: 1547 - 1554   2012.7

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    Recurrent homozygous CBL-inactivating mutations in myeloid malignancies decrease ubiquitin ligase activity that inactivates SRC family kinases (SFK) and receptor tyrosine kinases (RTK). However, the most important SFK and RTK affected by these mutations, and hence, the most important therapeutic targets, have not been clearly characterized. We compared SFK and RTK pathway activity and inhibitors in acute myeloid leukemia cell lines containing homozygous R420Q mutation (GDM-1), heterozygous deletion (MOLM13) and wild-type (WT) CBL (THP1, U937). As expected with CBL loss, GDM-1 displayed high KIT expression and granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity. Ectopic expression of WT CBL decreased GDM-1 proliferation but not cell lines with WT CBL. GDM-1, but not the other cell lines, was highly sensitive to growth inhibition by dasatinib (dual SFK and RTK inhibitor, LD50 50 nM); there was less or no selective inhibition of GDM-1 growth by sunitinib (RTK inhibitor), imatinib (ABL, KIT inhibitor), or PP2 (SFK inhibitor). Phosphoprotein analysis identified phosphorylation targets uniquely inhibited by dasatinib treatment of GDM-1, including a number of proteins in the KIT and GM-CSF receptor pathways (for example, KIT Tyr721, STAT3 Tyr705). In conclusion, the promiscuous effects of CBL loss on SFK and RTK signaling appear to be best targeted by dual SFK and RTK inhibition. © 2012 Macmillan Publishers Limited.

    DOI: 10.1038/leu.2012.7

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  197. De novo childhood myelodysplastic/myeloproliferative disease with unique molecular characteristics Reviewed

    Ismael O., Shimada A., Hama A., Elshazley M., Muramatsu H., Goto A., Sakaguchi H., Tanaka M., Takahashi Y., Yinyan X., Fukuda M., Miyajima Y., Yamashita Y., Horibe K., Hanada R., Ito M., Kojima S.

    British Journal of Haematology   Vol. 158 ( 1 ) page: 129 - 137   2012.7

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    Myelodysplastic/myeloproliferative uclassifiable (MDS/MPN-U) is a rare myeloid neoplasm characterized by myelodysplasia and myeloproliferation at the time of initial presentation, which is usually a diagnosis of exclusion. The molecular pathogenesis of MDS/MPN-U patients remains to be elucidated. Among five patients diagnosed with MDS/MPN-U, three patients harboured RUNX1 (AML1) mutations; one carried somatic mosaicism of RUNX1 mutation with JAK2V617F mutation and one had dual RUNX1 and FLT3-internal tandem duplication mutations with progression to acute myeloid leukaemia (AML). Germline mutation of TP53 was detected as a sole genetic lesion in one patient. JAK2V617F and somatic mosaicism of KRAS and TET2 mutations co-existed in one patient. Otherwise, no alterations were detected in PTPN11, NRAS, CBL and ASXL1 genes. ETV6-PDGFRB fusion transcript was not detected in all patients. Four patients recieved haematopoietic stem cell transplantation (HSCT); three patients relapsed and one achieved complete remission after three donor lymphocyte infusions. Our findings suggest that the mutational spectrum observed in childhood MDS/MPN-U is quite different from that seen in juvenile myelomonocytic leukaemia and, to some extent, resemble chronic myelomonocytic leukaemia. Moreover, two patients had constitutional alterations of genes frequently found in AML. Further investigations are required to define the roles of these genetic alterations in the pathogenesis of childhood MDS/MPN-U. © 2012 Blackwell Publishing Ltd.

    DOI: 10.1111/j.1365-2141.2012.09140.x

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  198. Loss of heterozygosity in 7q myeloid disorders: Clinical associations and genomic pathogenesis Reviewed

    Jerez A., Sugimoto Y., Makishima H., Verma A., Jankowska A.M., Przychodzen B., Visconte V., Tiu R.V., O'Keefe C.L., Mohamedali A.M., Kulasekararaj A.G., Pellagatti A., McGraw K., Muramatsu H., Moliterno A.R., Sekeres M.A., McDevitt M.A., Kojima S., List A., Boultwood J., Mufti G.J., Maciejewski J.P.

    Blood   Vol. 119 ( 25 ) page: 6109 - 6117   2012.6

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    Loss of heterozygosity affecting chromosome 7q is common in acute myeloid leukemia and myelodysplastic syndromes, pointing toward the essential role of this region in disease phenotype and clonal evolution. The higher resolution offered by recently developed genomic platforms may be used to establish more precise clinical correlations and identify specific target genes. We analyzed a series of patients with myeloid disorders using recent genomic technologies (1458 by single-nucleotide polymorphism arrays [SNP-A], 226 by next-generation sequencing, and 183 by expression microarrays). Using SNP-A, we identified chromosome 7q loss of heterozygosity segments in 161 of 1458 patients (11%); 26% of chronic myelomonocytic leukemia patients harbored 7q uniparental disomy, of which 41% had a homozygous EZH2 mutation. In addition, we describe an SNP-A - isolated deletion 7 hypocellular myelodysplastic syndrome subset, with a high rate of progression. Using direct and parallel sequencing, we found no recurrent mutations in typically large deletion 7q and monosomy 7 patients. In contrast, we detected a markedly decreased expression of genes included in our SNP-A defined minimally deleted regions. Although a 2-hit model is present in most patients with 7q uniparental disomy and a myeloproliferative phenotype, haplodeficient expression of defined regions of 7q may underlie pathogenesis in patients with deletions and predominant dysplastic features. © 2012 by The American Society of Hematology.

    DOI: 10.1182/blood-2011-12-397620

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  199. Excellent outcome of allogeneic bone marrow transplantation for Fanconi anemia using fludarabine-based reduced-intensity conditioning regimen Reviewed

    Shimada A., Takahashi Y., Muramatsu H., Hama A., Ismael O., Narita A., Sakaguchi H., Doisaki S., Nishio N., Tanaka M., Yoshida N., Matsumoto K., Kato K., Watanabe N., Kojima S.

    International Journal of Hematology   Vol. 95 ( 6 ) page: 675 - 679   2012.6

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    Fanconi anemia (FA) is a disorder characterized by developmental anomalies, bone marrow failure and a predisposition to malignancy. It has recently been shown that hematopoietic stem cell transplantation using fludarabine (FLU)-based reduced-intensity conditioning is an efficient and quite safe therapeutic modality. We retrospectively analyzed the outcome of bone marrow transplantation (BMT) in eight patients with FA performed in two institutes between 2001 and 2011. There were seven females and one male with a median age at diagnosis = 4.5 years (range 2-12 years). The constitutional characteristics associated with FA, such as developmental anomalies, short stature and skin pigmentation, were absent in three of the patients. One patient showed myelodysplastic features at the time of BMT. All patients received BMT using FLU, cyclophosphamide (CY) and rabbit antithymocyte globulin (ATG) either from a related donor (n = 4) or an unrelated donor (n = 4). Acute graft-versushost disease (GVHD) of grade I developed in one patient, while chronic GVHD was not observed in any patient. All patients are alive and achieved hematopoietic recovery at a median follow-up of 72 months (range 4-117 months). BMT using FLU/low-dose CY/ATG -based regimens regardless to the donor is a beneficial therapeutic approach for FA patients. © The Japanese Society of Hematology 2012.

    DOI: 10.1007/s12185-012-1079-9

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  200. Central nervous system lesions due to juvenile myelomonocytic leukemia progressed in a boy undergoing first line chemotherapy Reviewed

    Fukushima H., Fukushima T., Hiraki A., Suzuki R., Mahmoud S.S.A., Yoshimi A., Nakao T., Kato K., Kobayashi C., Koike K., Fukasawa M., Morishita Y., Doisaki S., Muramatsu H., Sumazaki R.

    International Journal of Hematology   Vol. 95 ( 5 ) page: 581 - 584   2012.5

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    Juvenile myelomonocytic leukemia is a rare malignancy that occurs in pediatric patients. Previous reports, have described leukemic cells may infiltrate many organs, such as the lungs, skin, liver, spleen, and intestines, but not the central nervous system, although central nervous system infiltration remains a point of concern in every patient with acute leukemia. Here, we present one case of a boy with juvenile myelomonocytic leukemia who developed multiple lesions in the brain while undergoing chemotherapy with 6-mercaptopurine and cytarabine. We diagnosed the central nervous system involvement by magnetic resonance imaging, cerebrospinal fluid cytology, and the patient's clinical course. He was treated with a high dose of cytarabine and intrathecal chemotherapy, then with unrelated cord blood stem cell transplantation. He has been in a first complete remission for more than 18 months after cord blood stem cell transplantation without any neurological sequelae. In conclusion, we encountered a boy with juvenile myelomonocytic leukemia who developed central nervous system lesions under standard chemotherapy. We subsequently switched treatment to central nervous system-oriented chemotherapy, which resulted in a good clinical condition and successful cord blood stem cell transplantation. © The Japanese Society of Hematology 2012.

    DOI: 10.1007/s12185-012-1046-5

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  201. Incidence, clinical features, and risk factors of idiopathic pneumonia syndrome following hematopoietic stem cell transplantation in children Reviewed

    Sakaguchi H., Takahashi Y., Watanabe N., Doisaki S., Muramatsu H., Hama A., Shimada A., Yagasaki H., Kudo K., Kojima S.

    Pediatric Blood and Cancer   Vol. 58 ( 5 ) page: 780 - 784   2012.5

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    Background: Idiopathic pneumonia syndrome (IPS) is a severe complication that can occur after hematopoietic stem cell transplantation (HSCT) and is often associated with a fatal outcome despite intensive supportive care. Procedure: To assess the incidence and risk factors of IPS, we reviewed 251 consecutive patients (median age, 7.0 years) who received HSCT at the Department of Pediatrics, Nagoya University Hospital, between January 1990 and July 2009. Results: Twenty of 251 (cumulative incidence of IPS at 2 years after HSCT, 8.0%; 95% confidence interval (CI), 5.1-12.4%) patients developed IPS. The median duration from HSCT to diagnosis of IPS was 67 days (range, 12-486 days). Patients with IPS had significantly higher 5-year transplant-related mortality compared to patients without IPS (52% (95% CI, 19-77%) vs. 13% (95% CI, 5-25%), P<0.001), and the probability of 5-year overall survival was significantly worse for patients with IPS (42% (95% CI, 25-64%) vs. 68% (95% CI, 59-76%), P=0.01). By multivariate analysis, high risk in underlying disease (HR, 2.5; 95% CI, 1.0-6.7; P=0.05) and a busulfan-containing regimen (HR, 3.5; 95% CI, 1.3-9.9; P<0.01) were identified as the independent risk factors for developing IPS. Conclusion: The prophylactic strategies for IPS in patients with these risk factors were warranted. © 2011 Wiley Periodicals, Inc.

    DOI: 10.1002/pbc.23298

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  202. Autoimmune-like hepatitis following unrelated BMT successfully treated with rituximab Reviewed

    Narita A., Muramatsu H., Takahashi Y., Sakaguchi H., Doisaki S., Nishio N., Hama A., Shimada A., Ito M., Kojima S.

    Bone Marrow Transplantation   Vol. 47 ( 4 ) page: 600 - 602   2012.4

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    DOI: 10.1038/bmt.2011.124

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  203. Chronic myelomonocytic leukemia and atypical chronic myeloid leukemia: Novel pathogenetic lesions Reviewed

    Muramatsu H., Makishima H., MacIejewski J.P.

    Seminars in Oncology   Vol. 39 ( 1 ) page: 67 - 73   2012.2

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    Chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML) are distinct, yet related, entities of myelodysplastic/ myeloproliferative neoplasms (MDS/MPN) characterized by morphologic dysplasia with accumulation of monocytes or neutrophils, respectively. Our understanding of the molecular pathogenesis of CMML and aCML has advanced, mainly due to the application of novel technologies such as array-based karyotyping and next-generation sequencing. In addition to previously known recurrent aberrations, somatic uniparental disomy affecting chromosomes 3, 4, 7, and 11 frequently occurs in CMML. Novel somatic mutations of genes, including those associated with proliferation signaling (CBL, RAS, RUNX1, JAK2 (V617F)) and with modification of epigenetic status (TET2, ASXL1, UTX, EZH2) have been found. Various combinations of mutations suggest a multistep pathogenesis and may account for clinical heterogeneity. Most recently, several spliceosome- associated-gene mutations were reported and SRSF2 mutations are frequently detected in CMML. The prognostic and diagnostic significance of these molecular lesions, in particular their value as biomarkers of response or resistance to specific therapies, while uncertain now is likely to be clarified as large systematic studies come to completion. © 2012 Elsevier Inc. All rights reserved.

    DOI: 10.1053/j.seminoncol.2011.11.004

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  204. Molecular lesions in childhood and adult acute megakaryoblastic leukaemia Reviewed

    Hama A., Muramatsu H., Makishima H., Sugimoto Y., Szpurka H., Jasek M., O'Keefe C., Takahashi Y., Sakaguchi H., Doisaki S., Shimada A., Watanabe N., Kato K., Kiyoi H., Naoe T., Kojima S., Maciejewski J.P.

    British Journal of Haematology   Vol. 156 ( 3 ) page: 316 - 325   2012.2

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    While acute megakaryoblastic leukaemia (AMKL) occurs in children with (DS-AMKL) and without (paediatric non-DS-AMKL) Down syndrome, it can also affect adults without DS (adult non-DS-AMKL). We have analysed these subgroups of patients (11 children with DS-AMKL, 12 children and four adults with non-DS-AMKL) for the presence of molecular lesions, including mutations and chromosomal abnormalities studied by sequencing and single nucleotide polymorphism array-based karyotyping, respectively. In children, AMKL was associated with trisomy 21 (somatic in non-DS-AMKL), while numerical aberrations of chromosome 21 were only rarely associated with adult AMKL. DS-AMKL was also associated with recurrent somatic gains of 1q (4/11 DS-AMKL patients). In contrast to trisomy 21 and gains of 1q, other additional chromosomal lesions were evenly distributed between children and adults with AMKL. A mutational screen found GATA1 mutations in 11/12 DS-AMKL, but mutations were rare in paediatric non-DS-AMKL (1/12) and adult AMKL (0/4). JAK3 (1/11), JAK2 (1/11), and TP53 mutations (1/11) were found only in patients with DS-AMKL. ASXL1, IDH1/2, DNMT3A, RUNX1 and CBL mutations were not found in any of the patient group studied, while NRAS mutation was identified in two patients with paediatric non-DS-AMKL. © 2011 Blackwell Publishing Ltd.

    DOI: 10.1111/j.1365-2141.2011.08948.x

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  205. Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia Reviewed

    Shima H., Tokuyama M., Tanizawa A., Tono C., Hamamoto K., Muramatsu H., Watanabe A., Hotta N., Ito M., Kurosawa H., Kato K., Tsurusawa M., Horibe K., Shimada H.

    Journal of Pediatrics   Vol. 159 ( 4 ) page: 676 - 681   2011.10

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    Objective: To determine the extent of growth impairment resulting from imatinib treatment in children with chronic myeloid leukemia (CML). Study design: Clinical records of 48 chronic-phase CML children administered imatinib as the first-line therapy between 2001 and 2006 were analyzed retrospectively. Cumulative change in height was assessed using the height height-SDS and converted height data from age- and sex-adjusted Japanese norms. Results: A decrease in height-SDS was observed in 72.9% of children, with a median maximum reduction in height-SDS of 0.61 during imatinib treatment. Median follow-up time was 34 months (range, 10-88 months). Growth impairment was seen predominantly in children who started imatinib at a prepubertal age compared with those who started at pubertal age. Growth velocity tended to recuperate in prepubertal children with growth impairment, as they reached pubertal age, suggesting that imatinib had little impact on growth during puberty. Conclusions: Growth impairment was a major adverse effect of long-term imatinib treatment in children with CML. We report the distinct inhibitory effect of imatinib on growth in prepubertal and pubertal children with CML. We should be aware of growth deceleration in children, especially in young children given imatinib before puberty and subjected to prolonged exposure. © 2011 Mosby Inc. All rights reserved.

    DOI: 10.1016/j.jpeds.2011.03.046

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  206. Aberrant phosphorylation of STAT5 by granulocyte-macrophage colony-stimulating factor in infant cytomegalovirus infection mimicking juvenile myelomonocytic leukemia Reviewed

    Nishio N., Takahashi Y., Tanaka M., Xu Y., Yoshida N., Sakaguchi H., Doisaki S., Hama A., Muramatsu H., Shimada A., Kojima S.

    Leukemia Research   Vol. 35 ( 9 ) page: 1261 - 1264   2011.9

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    Juvenile myelomonocytic leukemia (JMML) progenitor cells exhibit in vitro hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Phospho-specific flow cytometry using anti-phosphorylated STAT5 antibody is a new method recently reported to detect GM-CSF hypersensitivity of cells. However, colony assays using methylcellulose medium to measure GM-CSF-hypersensitivity remain as the current gold standard. Interestingly, cytomegalovirus (CMV) infection in infancy often presents with a variety of clinical symptoms that mimic JMML, with CMV giving a positive result by colony assay. We wanted to determine whether aberrant STAT5 activation occurs in CMV infection by using phospho-specific flow cytometry, and to ascertain whether this method is effective at discriminating CMV infection from JMML. Peripheral blood mononuclear cells from patients with JMML and CMV infection displayed an elevated proportion of p-STAT5 cells after low-dose GM-CSF stimulation when compared with cells from normal individuals. However, we found no significant differences in the percentage of p-STAT5 positive cells from patients with CMV infection and JMML at any doses of the GM-CSF doses used. We conclude that patients with CMV infection cannot be discriminated from patients with JMML by this new diagnostic method. © 2011 Elsevier Ltd.

    DOI: 10.1016/j.leukres.2011.04.014

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  207. Total body irradiation and melphalan as a conditioning regimen for children with hematological malignancies undergoing transplantation with stem cells from HLA-identical related donors Reviewed

    Watanabe N., Takahashi Y., Matsumoto K., Horikoshi Y., Hama A., Muramatsu H., Yoshida N., Yagasaki H., Kudo K., Horibe K., Kato K., Kojima S.

    Pediatric Transplantation   Vol. 15 ( 6 ) page: 642 - 649   2011.9

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    Although some studies have reported that TBI and MEL offer an effective conditioning regimen for autologous SCT in acute leukemia, little has been reported regarding outcomes of allogeneic SCT. We retrospectively evaluated outcomes for 50 pediatric patients who underwent allo-SCT conditioned with intravenous MEL (180-210 mg/m 2) and fractionated TBI (12-13.2 Gy) from HLA-identical related donors. Nineteen patients were in CR1, 18 were in CR2, and 13 showed advanced-stage disease (≤yen;CR3). Patients had received allo-SCT from HLA-identical siblings (n = 45) or phenotypically HLA-identical family donors (n = 5). Median duration of follow-up for all disease-free patients was 61 months (range, 8.8-177 months). At the time of analysis, 12 patients had died. Eleven of those died of relapse, and one died of TRM. DFS rates for all patients, patients with AML (n = 12), and patients with lymphoid malignancy (n = 38) were 61.4% and 82.1%, respectively. DFS rates for CR1, CR2, and ≤yen;CR3 cases were 89.2%, 88.1%, and 23.1%, respectively (p < 0.05). MEL/TBI for pediatric patients with hematological malignancies was associated with lower relapse rates and no increase in toxicity, resulting in better survival. © 2011 John Wiley & Sons A/S.

    DOI: 10.1111/j.1399-3046.2011.01544.x

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  208. [Bone marrow findings of childhood aplastic anemia: analyses of 140 cases by central reviewers]. Reviewed

    Hama A., Yoshimi A., Sakaguchi H., Doisaki S., Muramatsu H., Shimada A., Takahashi Y., Nozawa K., Ito M., Tsuchida M., Manabe A., Ohara A., Kojima S.

    [Rinshō ketsueki] The Japanese journal of clinical hematology   Vol. 52 ( 8 ) page: 653 - 658   2011.8

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    The revised WHO classification proposed the term "refractory cytopenia of childhood (RCC)" for children with myelodysplastic syndrome (MDS) with a low blast count. The differential diagnosis between RCC and aplastic anemia (AA) is challenging, especially when bone marrow is hypoplastic and there is no detectable chromosomal abnormality. To reveal the difference between AA and RCC with respect to the clinical and biological features, we retrospectively reviewed the bone marrow smears of 140 patients registered for childhood AA-97 study, which were classified into three groups as follows; the AA group was defined as having no morphologically dysplastic changes; the AA-RCC borderline group was defined as having <10% dysplastic changes in the erythroid lineage only; and the RCC group was defined as having dysplastic changes in more than two cell lineages or >10% in a single cell lineage. The patients were classified into the AA group (n=96, 69%), AA-RCC borderline group (n=20, 14%) and RCC group (n=24, 17%). Most of the patients in the AA group were classified as having very severe disease, whereas most of the patients in the RCC group were classified as non-severe disease. Only 2 patients in the AA group developed acute myeloid leukemia. The response rate to immunosuppressive therapy did not differ among the 3 groups. To demonstrate whether the two diseases are truly different entities, it is necessary to compare molecular backgrounds between the AA and RCC groups.

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  209. CD20-negative Epstein-Barr virus-associated post-transplant lymphoproliferative disease refractory to rituximab in a patient with severe aplastic anemia Reviewed

    Muramatsu H., Takahashi Y., Shimoyama Y., Doisaki S., Nishio N., Ito Y., Hama A., Shimada A., Yagasaki H., Ito M., Kojima S.

    International Journal of Hematology   Vol. 93 ( 6 ) page: 779 - 781   2011.6

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    Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD) is a life-threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT). Monitoring of EBV DNA in high-risk patients with subsequent pre-emptive rituximab treatment is highly effective, and can prevent EBV-associated disease following HSCT. Here, we report a 10-year-old girl with aplastic anemia who developed CD20 negative EBV-PTLD after unrelated bone marrow transplantation that was refractory to rituximab treatment. Similar to other types of lymphoma, the absence of CD20 antigen is likely to be characteristic of rituximab-refractory EBV-PTLD. © 2011 The Japanese Society of Hematology.

    DOI: 10.1007/s12185-011-0870-3

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  210. Relapse of aplastic anemia in children after immunosuppressive therapy: A report from the Japan childhood aplastic anemia study group Reviewed

    Kamio T., Ito E., Ohara A., Kosaka Y., Tsuchida M., Yagasaki H., Mugishima H., Yabe H., Morimoto A., Ohga S., Muramatsu H., Hama A., Kaneko T., Nagasawa M., Kikuta A., Osugi Y., Bessho F., Nakahata T., Tsukimoto I., Kojima S.

    Haematologica   Vol. 96 ( 6 ) page: 814 - 819   2011.6

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    Background Although the therapeutic outcome of acquired aplastic anemia has improved markedly with the introduction of immunosuppressive therapy using antithymocyte globulin and cyclosporine, a significant proportion of patients subsequently relapse and require second-line therapy. However, detailed analyses of relapses in aplastic anemia children are limited. Design and Methods We previously conducted two prospective multicenter trials of immunosuppressive therapy for children with aplastic anemia: AA-92 and AA-97, which began in 1992 and 1997, respectively. In this study, we assessed the relapse rate, risk factors for relapse, and the response to secondline treatment in children with aplastic anemia treated with antithymocyte globulin and cyclosporine. Results From 1992 to 2007, we treated 441 children with aplastic anemia with standard immunosuppressive therapy. Among the 264 patients who responded to immunosuppressive therapy, 42 (15.9%) relapsed. The cumulative incidence of relapse was 11.9% at 10 years. Multivariate analysis revealed that relapse risk was significantly associated with an immunosuppressive therapy regimen using danazol (relative risk, 3.15; P=0.001) and non-severe aplastic anemia (relative risk, 2.51; P=0.02). Seventeen relapsed patients received additional immunosuppressive therapy with antithymocyte globulin and cyclosporine. Eight patients responded within 6 months. Seven of nine non-responders to second immunosuppressive therapy received hematopoietic stem cell transplantation and five are alive. Eleven patients underwent hematopoietic stem cell transplantation directly and seven are alive. Conclusions In the present study, the cumulative incidence of relapse at 10 years was relatively low compared to that in other studies mainly involving adult patients. A multicenter prospective study is warranted to establish optimal therapy for children with aplastic anemia. ©2011 Ferrata Storti Foundation.

    DOI: 10.3324/haematol.2010.035600

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  211. Prognostic Factors for Outcomes of Pediatric Patients with Refractory or Relapsed Acute Leukemia Undergoing Allogeneic Progenitor Cell Transplantation Reviewed

    Watanabe N., Takahashi Y., Matsumoto K., Hama A., Muramatsu H., Doisaki S., Horibe K., Kato K., Kojima S.

    Biology of Blood and Marrow Transplantation   Vol. 17 ( 4 ) page: 516 - 523   2011.4

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    Allogeneic stem cell transplantation (SCT) is the only curative therapy for patients with refractory or relapsed acute leukemia, although the prognosis remains poor. Few reports have described outcomes of SCT in pediatric patients with refractory acute leukemia. To identify prognostic factors for these patients, we retrospectively evaluated SCT outcomes for advanced acute leukemia in 82 pediatric patients from 3 transplant units in Nagoya City between 1990 and 2008. Median age at transplantation was 8 years (range, 0.5-17 years). Transplantation was performed in the first refractory relapse for 53 patients (64.6%), in the second or subsequent relapse for 16 patients (19.5%), and during primary induction failure for 13 patients (15.9%). Only 4 patients (4.9%) underwent transplantation in the untreated first relapse, and 39 patients (47.6%) received unrelated donor progenitor cells. Of the 82 patients, 61 died (77.9%), with a median survival of 7.1 months (95% confidence interval [CI], 4.2-10.0 months). Median disease-free survival (DFS) was 4.7 months (95% CI, 2.6-6.9 months). In multivariate analysis, peripheral blood blasts, cord blood transplantation, and more than 3 courses of previous salvage chemotherapy were predictive of DFS. These results support the notion that allogeneic SCT offers only a small chance of cure for most pediatric patients with refractory or relapsed acute leukemia, and suggest that reduction of the leukemia burden and earlier optimal timing of transplantation are essential for long-term survival even in patients with refractory acute leukemia. © 2011 American Society for Blood and Marrow Transplantation.

    DOI: 10.1016/j.bbmt.2010.07.019

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  212. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation Reviewed

    Takagi M., Shinoda K., Piao J., Mitsuiki N., Takagi M., Matsuda K., Muramatsu H., Doisaki S., Nagasawa M., Morio T., Kasahara Y., Koike K., Kojima S., Takao A., Mizutani S.

    Blood   Vol. 117 ( 10 ) page: 2887 - 2890   2011.3

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    Autoimmune lymphoproliferative syndrome (ALPS) is classically defined as a disease with defective FAS-mediated apoptosis (type I-III). Germline NRAS mutation was recently identified in type IV ALPS. We report 2 cases with ALPS-like disease with somatic KRAS mutation. Both cases were characterized by prominent autoimmune cytopenia and lymphoadenopathy/splenomegaly. These patients did not satisfy the diagnostic criteria for ALPS or juvenile myelomonocytic leukemia and are probably defined as a new disease entity of RAS-associated ALPS-like disease (RALD). © 2011 by The American Society of Hematology.

    DOI: 10.1182/blood-2010-08-301515

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  213. Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita Reviewed

    Nishio N., Takahashi Y., Ohashi H., Doisaki S., Muramatsu H., Hama A., Shimada A., Yagasaki H., Kojima S.

    Pediatric Transplantation   Vol. 15 ( 2 ) page: 161 - 166   2011.3

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    DC is an inherited bone marrow failure syndrome mainly characterized by nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Bone marrow failure is the most common cause of death in patients with DC. Because previous results of HSCT with a myeloablative regimen were disappointing, we used a reduced-intensity conditioning regimen for two patients with classic DC, and one patient with cryptic DC who harbored the TERT mutation. Graft sources included two mismatched-related bone marrow (BM) donors and one unrelated BM donor. Successful engraftment was achieved with few regimen-related toxicities in all patients. They were alive 10, 66, and 72 months after transplantation, respectively. Long-term follow-up is crucial to determine the late effects of our conditioning regimen. © 2010 John Wiley & Sons A/S.

    DOI: 10.1111/j.1399-3046.2010.01431.x

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  214. Analysis of mutations and recombination activity in RAG-deficient patients Reviewed

    Asai E., Wada T., Sakakibara Y., Toga A., Toma T., Shimizu T., Nampoothiri S., Imai K., Nonoyama S., Morio T., Muramatsu H., Kamachi Y., Ohara O., Yachie A.

    Clinical Immunology   Vol. 138 ( 2 ) page: 172 - 177   2011.2

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    Mutations in the recombination activating genes (RAG1 or RAG2) can lead to a variety of immunodeficiencies. Herein, we report 5 cases of RAG deficiency from 5 families: 3 of Omenn syndrome, 1 of severe combined immunodeficiency, and 1 of combined immunodeficiency with oligoclonal TCRγδ+ T cells, autoimmunity and cytomegalovirus infection. The genetic defects were heterogeneous and included 6 novel RAG mutations. All missense mutations except for Met443Ile in RAG2 were located in active core regions of RAG1 or RAG2. V(D)J recombination activity of each mutant was variable, ranging from half of the wild type activity to none, however, a significant decrease in average recombination activity was demonstrated in each patient. The reduced recombination activity of Met443Ile in RAG2 may suggest a crucial role of the non-core region of RAG2 in V(D)J recombination. These findings suggest that functional evaluation together with molecular analysis contributes to our broader understanding of RAG deficiency. © 2010 Elsevier Inc.

    DOI: 10.1016/j.clim.2010.11.005

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  215. Excellent outcomes of children with CML treated with imatinib mesylate compared to that in pre-imatinib era Reviewed

    Muramatsu H., Takahashi Y., Sakaguchi H., Shimada A., Nishio N., Hama A., Doisaki S., Yagasaki H., Matsumoto K., Kato K., Kojima S.

    International Journal of Hematology   Vol. 93 ( 2 ) page: 186 - 191   2011.2

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    Allogeneic hematopoietic stem cell transplantation (HSCT) and tyrosine kinase inhibitor have revolutionized the treatment of patients with chronic myeloid leukemia (CML). In this study, the clinical impact of HSCT and imatinib mesylate (IM) was retrospectively analyzed in 28 children with CML treated in our institutes from 1984 to 2008. Twelve patients were given oral IM. At 36 months after initiation of IM therapy, the complete cytogenetic response rate was 90.9%, and the major molecular response rate was 36.4%. Sixteen children received allogeneic HSCT without administration of IM. The stage of disease at transplantation was: first chronic phase (n = 10), second chronic phase (n = 2), accelerated phase (n = 2), and blastic crisis (n = 2). The progression rate was significantly lower in patients treated with IM than in those treated without IM (0 vs. 28.6%, p = 0.006). In summary, the survival outcomes of pediatric patients with CML were dramatically improved by treatment with IM compared to HSCT. © 2011 The Japanese Society of Hematology.

    DOI: 10.1007/s12185-010-0764-9

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  216. Danaparoid as the prophylaxis for hepatic veno-occlusive disease after allogeneic hematopoietic stem cell transplantation in childhood hematological malignancy Reviewed

    Sakaguchi H., Watanabe N., Muramatsu H., Doisaki S., Yoshida N., Matsumoto K., Kato K.

    Pediatric Blood and Cancer   Vol. 55 ( 6 ) page: 1118 - 1125   2010.12

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    Background: Veno-occlusive disease (VOD) is a regimen-related toxicity that occurs in the early phase of hematopoietic stem cell transplantation (HSCT). Therapeutic modalities for established VOD are limited, and severe VOD characterized by multiple organ failure is associated with a fatal prognosis despite intensive supportive care. Procedure: We analyzed the data of 95 consecutive allogeneic HSCT for childhood hematological malignancies, and assessed the efficacy of our VOD prophylaxis regimen based on danaparoid (n = 48), comparing with historical control regimen based on dalteparin (n = 47). Results: Eight patients (danaparoid cohort in one; dalteparin cohort in seven) developed VOD on day +30 (median onset, day +22; range, day +11 to day +28) after HSCT. The probability of developing VOD for the danaparoid cohort was 2% (95% CI, 0-6%) and that of the dalteparin cohort was 15% (95% CI, 5-26%). In the Cox hazard proportional model, the danaparoid cohort had a significant advantage over the dalteparin cohort for the prophylaxis of VOD (hazard ratio (HR), 0.0; 95% CI, 0.0-0.3; P < 0.01) without increasing hemorrhagic events. Conclusions: Our findings suggest that danaparoid may have promise for the prophylaxis of VOD after allogeneic HSCT and further randomized studies are warranted. © 2010 Wiley-Liss, Inc.

    DOI: 10.1002/pbc.22645

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  217. Comparison of matched-sibling donor BMT and unrelated donor BMT in children and adolescent with acquired severe aplastic anemia Reviewed

    Yagasaki H., Takahashi Y., Hama A., Kudo K., Nishio N., Muramatsu H., Tanaka M., Yoshida N., Matsumoto K., Watanabe N., Kato K., Horibe K., Kojima S.

    Bone Marrow Transplantation   Vol. 45 ( 10 ) page: 1508 - 1513   2010.10

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    From January 1991 to March 2007, 61 children and adolescent with acquired severe aplastic anemia received BMT in our institutions. We retrospectively compared the outcome of 30 cases of matched-sibling donor BMT (MSD-BMT) and 31 cases of unrelated donor BMT (URD-BMT). We observed one graft failure among MSD-BMT recipients and three graft failures among URD-BMT recipients, respectively. No patients in the MSD-BMT group developed grades II-IV acute GVHD compared with 11 of 30 patients (37%) in the URD-BMT group (P<0.001). One of 30 MSD-BMT recipients (3%) developed chronic GVHD compared with 8 of 30 URD-BMT recipients (27%) (P=0.013). The incidence of EBV and CMV reactivation was 11 of 20 URD-BMT recipients and 23 of 30, respectively. One patient in the URD-BMT group died of a motor accident 5.5 years after BMT. Ten-year OS was 100% in MSDBMT recipients and 93.8% (95% CI, 81.9-100%) in URD-BMT recipients, respectively (P=0.252). Ten-year failure-free survival was 96.7% (95% CI, 90.2-100%) in the MSD-BMT group and 84.7% (95% CI, 70.2-99.2%) in the URD-BMT group, respectively (P=0.161). © 2010 Macmillan Publishers Limited All rights reserved.

    DOI: 10.1038/bmt.2009.378

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  218. Relationship between tacrolimus blood concentrations and clinical outcome during the first 4 weeks after SCT in children Reviewed

    Watanabe N., Matsumoto K., Muramatsu H., Horibe K., Matsuyama T., Kojima S., Kato K.

    Bone Marrow Transplantation   Vol. 45 ( 7 ) page: 1161 - 1166   2010.7

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    The relationship between tacrolimus concentration and acute GVHD is not well known, with few published data available for lower target levels. We hypothesized that lower levels of tacrolimus would correlate with higher incidence of acute GVHD and poorer prognosis. Receiver operator characteristic curves (ROC) were used to quantify tacrolimus blood levels as predictors of grade II-IV acute GVHD. A total of 97 pediatric patients with hematological malignancies met the study criteria. On the ROC, a cutoff of 7 ng/ml provided the best balance between sensitivity and specificity (62.8 vs 68.2%, respectively). Cumulative incidence of acute GVHD was 65.9% (range 58.5-73.3%) in patients with mean tacrolimus concentration of 7 ng/ml and 34.8% (range 27.8-41.8%) in patients with mean tacrolimus concentration of 7 ng/ml (P0.002). Incidence of non-relapse mortality (NRM) was higher in patients with tacrolimus of 7 ng/ml (42.9%; range 35.6-50.2%) than in patients with tacrolimus of 7 ng/ml (28.3%; range 17.4-39.2%; P0.008). This translated into better EFS in patients with tacrolimus of 7 ng/ml (48.9%; range 39.8-58.0%) than in patients with tacrolimus of 7 ng/ml (31.8%; range 25.0-38.6%; P0.031). Multivariate analysis showed that tacrolimus concentration was significantly associated with clinical outcomes. Mean whole-blood level of tacrolimus as continuous infusion should be maintained at 7 ng/ml for pediatric patients. © 2010 Macmillan Publishers Limited All rights reserved.

    DOI: 10.1038/bmt.2009.327

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  219. Spectrum of molecular defects in juvenile myelomonocytic leukaemia includes ASXL1 mutations: Short report Reviewed

    Sugimoto Y., Muramatsu H., Makishima H., Prince C., Jankowska A.M., Yoshida N., Xu Y., Nishio N., Hama A., Yagasaki H., Takahashi Y., Kato K., Manabe A., Kojima S., MacIejewski J.P.

    British Journal of Haematology   Vol. 150 ( 1 ) page: 83 - 87   2010.7

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    Summary Mutations in NF1, PTPN11, NRAS, KRAS and CBL have been reported to play a pathogenetic role in juvenile myelomonocytic leukaemia (JMML), a rare myelodyplastic/myeloproliferative neoplasm occurring in children. Recently, mutations in ASXL1 were identified in chronic myelomonocytic leukaemia and other myeloid malignancies. We sequenced exon 12 of ASLX1 in 49 JMML patients, and found 2 novel heterozygous (nonsense and frameshift) mutations, one occurring as a sole lesion, the other was in conjunction with a PTPN11 mutation. ASXL1 cooperates with KDM1A in transcriptional repression and thereby ASXL1 mutations may synergize with or mimic other JMML-related mutations. © 2010 Blackwell Publishing Ltd.

    DOI: 10.1111/j.1365-2141.2010.08196.x

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  220. Relapse of leukemia with loss of mismatched HLA resulting from uniparental disomy after haploidentical hematopoietic stem cell transplantation Reviewed

    Villalobos I.B., Takahashi Y., Akatsuka Y., Muramatsu H., Nishio N., Hama A., Yagasaki H., Saji H., Kato M., Ogawa S., Kojima S.

    Blood   Vol. 115 ( 15 ) page: 3158 - 3161   2010.4

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    We investigated human leukocyte antigen (HLA) expression on leukemic cells derived from patients at diagnosis and relapse after hematopoietic stem cell transplantation (HSCT) using flow cytometry with locus-specific antibodies. Two of 3 patients who relapsed after HLA-haploidentical HSCT demonstrated loss of HLA alleles in leukemic cells at relapse; on the other hand, no loss of HLA alleles was seen in 6 patients who relapsed after HLA-identical HSCT. Single-nucleotide polymorphism array analyses of sorted leukemic cells further revealed the copy number-neutral loss of heterozygosity, namely, acquired uniparental disomy on the short arm of chromosome 6, resulting in the total loss of the mismatched HLA haplotype. These results suggest that the escape from immunosurveillance by the loss of mismatched HLA alleles may be a crucial mechanism of relapse after HLA-haploidentical HSCT. Accordingly, the status of mismatched HLA on relapsed leukemic cells should be checked before donor lymphocyte infusion. © 2010 by The American Society of Hematology.

    DOI: 10.1182/blood-2009-11-254284

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  221. Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia Reviewed

    Muramatsu H., Makishima H., Jankowska A.M., Cazzolli H., O'Keefe C., Yoshida N., Xu Y., Nishio N., Hama A., Yagasaki H., Takahashi Y., Kato K., Manabe A., Kojima S., Maciejewski J.P.

    Blood   Vol. 115 ( 10 ) page: 1969 - 1975   2010.3

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    Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. When we investigated the presence of recurrent molecular lesions in a cohort of 49 children with JMML, neurofibromatosis phenotype (and thereby NF1 mutation) was present in 2 patients (4%), whereas previously described PTPN11, NRAS, and KRAS mutations were found in 53%, 4%, and 2% of cases, respectively. Consequently, a significant proportion of JMML patients without identifiable pathogenesis prompted our search for other molecular defects. When we applied single nucleotide polymorphism arrays to JMML patients, somatic uniparental disomy 11q was detected in 4 of 49 patients; all of these cases harbored RING finger domain c-Cbl mutations. In total, c-Cbl mutations were detected in 5 (10%) of 49 patients. No mutations were identified in Cbl-b and TET2. c-Cbl and RAS pathway mutations were mutually exclusive. Comparison of clinical phenotypesshowedearlier presentation and lower hemoglobin F levels in patients with c-Cbl mutations. Our results indicate that mutations in c-Cbl may represent key molecular lesions in JMML patients without RAS/PTPN11 lesions, suggesting analogous pathogenesis to those observed in chronic myelomonocytic leukemia (CMML) patients. © 2010 by The American Society of Hematology.

    DOI: 10.1182/blood-2009-06-226340

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  222. Outcome of 125 Children with Chronic Myelogenous Leukemia Who Received Transplants from Unrelated Donors: The Japan Marrow Donor Program Reviewed

    Muramatsu H., Kojima S., Yoshimi A., Atsuta Y., Kato K., Nagatoshi Y., Inoue M., Koike K., Kawase T., Ito M., Kurosawa H., Tanizawa A., Tono C., Hamamoto K., Hotta N., Watanabe A., Morishima Y., Kawa K., Shimada H.

    Biology of Blood and Marrow Transplantation   Vol. 16 ( 2 ) page: 231 - 238   2010.2

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    Because of a small number of patients, only a few studies have addressed the outcome of bone marrow transplantation (BMT) in children with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), who receive graft from a volunteer-unrelated donor (VUD), especially after practical application of imatinib mesylate. The outcomes of BMT from a VUD in 125 children with Ph+ CML were retrospectively reviewed. Patients were identified through the Japan Marrow Donor Program as having undergone BMT between 1993 and 2005 and were aged 1-19 years at the time of transplant (median age, 14 years). The probabilities of 5-year overall survival (OS) and leukemia-free survival (LFS) were 59.3% and 55.5%, respectively. Multivariate analysis identified the following unfavorable survival factors: infused total nucleated cell dose < 314 × 106 /kg (relative risk [RR] = 2.43; 95% confidence interval [CI] = 1.33-4.44; P = .004), advanced phase (RR = 2.43; 95% CI = 1.37-4.31; P = .004), and no major cytogenetic response (MCyR) at the time of BMT (RR = 6.55; 95% CI = 1.98-21.6; P = .002). Of the 17 patients treated with imatinib, 15 (88%) achieved MCyR at the time of BMT, and this group had an excellent 5-year OS of 81.9%. Disease phase, infused total nucleated cell dose, and cytogenetic response were independent risk factors for survival of unrelated BMT. These findings provide important information for assessing the indications for and improving outcome in unrelated BMT for the treatment of pediatric CML. © 2010 American Society for Blood and Marrow Transplantation.

    DOI: 10.1016/j.bbmt.2009.09.022

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  223. Mutations of E3 ubiquitin ligase Cbl family members constitute a novel common pathogenic lesion in myeloid malignancies Reviewed

    Makishima H., Cazzolli H., Szpurka H., Dunbar A., Tiu R., Huh J., Muramatsu H., O'Keefe C., Hsi E., Paquette R.L., Kojima S., List A.F., Sekeres M.A., McDevitt M.A., Maciejewski J.P.

    Journal of Clinical Oncology   Vol. 27 ( 36 ) page: 6109 - 6116   2009.12

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    Purpose: Acquired somatic uniparental disomy (UPD) is commonly observed in myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), or secondary acute myelogenous leukemia (sAML) and may point toward genes harboring mutations. Recurrent UPD11q led to identification of homozygous mutations in c-Cbl, an E3 ubiquitin ligase involved in attenuation of proliferative signals transduced by activated receptor tyrosine kinases. We examined the role and frequency of Cbl gene family mutations in MPN and related conditions. Methods: We applied high-density SNP-A karyotyping to identify loss of heterozygosity of 11q in 442 patients with MDS, MDS/MPN, MPN, sAML evolved from these conditions, and primary AML. We sequenced c-Cbl, Cbl-b, and Cbl-c in patients with or without corresponding UPD or deletions and correlated mutational status with clinical features and outcomes. Results: We identified c-Cbl mutations in 5% and 9% of patients with chronic myelomonocytic leukemia (CMML) and sAML, and also in CML blast crisis and juvenile myelomonocytic leukemia (JMML). Most mutations were homozygous and affected c-Cbl; mutations in Cbl-b were also found in patients with similar clinical features. Patients with Cbl family mutations showed poor prognosis, with a median survival of 5 months. Pathomorphologic features included monocytosis, monocytoid blasts, aberrant expression of phosphoSTAT5, and c-kit overexpression. Serial studies showed acquisition of c-Cbl mutations during malignant evolution. Conclusion: Mutations in the Cbl family RING finger domain or linker sequence constitute important pathogenic lesions associated with not only preleukemic CMML, JMML, and other MPN, but also progression to AML, suggesting that impairment of degradation of activated tyrosine kinases constitutes an important cancer mechanism. © 2009 by American Society of Clinical Oncology.

    DOI: 10.1200/JCO.2009.23.7503

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  224. Downregulation of GATA-2 and overexpression of adipogenic gene-PPARγ in mesenchymal stem cells from patients with aplastic anemia Reviewed

    Xu Y., Takahashi Y., Wang Y., Hama A., Nishio N., Muramatsu H., Tanaka M., Yoshida N., Villalobos I.B., Yagasaki H., Kojima S.

    Experimental Hematology   Vol. 37 ( 12 ) page: 1393 - 1399   2009.12

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    Aplastic anemia (AA) is characterized by a reduced number of hematopoietic stem cells and fatty replacement in the bone marrow. Transcriptional factor GATA-2 plays several important roles in both hematopoiesis and adipogenesis. Decreased levels of GATA-2 compromise the proliferation and survival of hematopoietic stem cells. GATA-2 suppresses adipocyte differentiation through direct inhibition of adipogenic factors, including peroxisome proliferator-activated receptor-γ (PPARγ). Previous studies have shown that expression of GATA-2 is decreased in marrow CD34-positive cells in AA. To elucidate the mechanisms of fatty marrow replacement, we evaluated the mRNA expression for GATA-2 and PPARγ in mesenchymal stem cells (MSCs) from patients with AA by quantitative real-time polymerase chain reaction. GATA-2 expression by MSCs from AA patients was significantly lower than in normal subjects. Conversely, expression of PPARγ was significantly higher in AA patients. Western blot analysis demonstrated that protein levels of GATA-2 were lower in AA patients than those in normal subjects. Moreover, incubation with interferon-γ induced downregulation of GATA-2 levels in MSCs from normal subjects. These findings indicate that fatty marrow replacement in AA patients can be explained by downregulation of GATA-2 and overexpression of PPARγ in MSCs. Decreased expression of GATA-2 might be responsible for the pathogenesis and development of the clinical features of the disease. © 2009 ISEH - Society for Hematology and Stem Cells.

    DOI: 10.1016/j.exphem.2009.09.005

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  225. Tacrolimus/Methotrexate versus Cyclosporine/Methotrexate as Graft-versus-Host Disease Prophylaxis in Patients with Severe Aplastic Anemia Who Received Bone Marrow Transplantation from Unrelated Donors: Results of Matched Pair Analysis Reviewed

    Yagasaki H., Kojima S., Yabe H., Kato K., Kigasawa H., Sakamaki H., Tsuchida M., Kato S., Kawase T., Muramatsu H., Morishima Y., Kodera Y.

    Biology of Blood and Marrow Transplantation   Vol. 15 ( 12 ) page: 1603 - 1608   2009.12

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    Tacrolimus (FK) and cyclosporine (CsA) have been shown to be effective in the prophylaxis of graft-versus-host disease (GVHD). However, no comparative studies have yet been conducted to examine the efficacy of FK/methotrexate (MTX) and CsA/MTX in patients with severe aplastic anemia (SAA) given unrelated donor bone marrow transplantation (U-BMT). We used matched-pair analysis to compare FK/MTX with CsA/MTX in patients with SAA who received U-BMT through the Japan Marrow Donor Program. Forty-seven pairs could be matched exactly for recipient age and conditioning regimens. Forty-five patients achieved engraftment in the FK group and 42 patients in the CsA group. The probability of grade II-IV acute GVHD (aGVHD) was 28.9% in the FK group and 32.6% in the CsA group (P = .558). The probability of chronic GVHD (cGVHD) was 13.3% in the FK group and 36.0% in the CsA group (P = .104). The 5-year survival rate was 82.8% in the FK group and 49.5% in the CsA group (P = .012). The study shows the superiority of FK/MTX over CsA/MTX in overall survival because of the lower incidence of transplantation-related deaths. A prospective randomized study comparing FK/MTX and CsA/MTX is warranted. © 2009 American Society for Blood and Marrow Transplantation.

    DOI: 10.1016/j.bbmt.2009.08.012

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  226. Engraftment syndrome following allogeneic hematopoietic stem cell transplantation in children Reviewed

    Nishio N., Yagasaki H., Takahashi Y., Hama A., Muramatsu H., Tanaka M., Yoshida N., Yoshimi A., Kudo K., Ito M., Kojima S.

    Pediatric Transplantation   Vol. 13 ( 7 ) page: 831 - 837   2009.11

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    ES is a complication that occurs immediately before or at the timing of neutrophil engraftment following autologous or allogeneic SCT. It is characterized by fever, skin rash, and non-cardiac pulmonary infiltrates. We evaluated the incidence, risk factors, and outcomes of ES following allogeneic SCT in children. Of 100 pediatric patients, 20 (20%) developed ES occurring at a median of 14 days (range 8-27 days) post-transplant. Patients presented with fever (100%), skin rash (100%), diffuse pulmonary infiltration (25%), and body weight gain (85%). On multivariate analysis, significant risk factors for ES included younger age (<8 yr old) and human leukocyte antigen disparity between donors and recipients. Univariate analysis showed that patients with ES had a higher incidence of developing chronic graft-versus-host disease and ES was not associated with other complications. Event-free survival did not significantly differ between patients with and without ES regardless of the presence of malignant or non-malignant diseases. © 2008 John Wiley & Sons A/S.

    DOI: 10.1111/j.1399-3046.2008.01068.x

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  227. Successful treatment with rituximab of refractory idiopathic thrombocytopenic purpura in a patient with Kabuki syndrome Reviewed

    Torii Y., Yagasaki H., Tanaka H., Mizuno S., Nishio N., Muramatsu H., Hama A., Takahashi Y., Kojima S.

    International Journal of Hematology   Vol. 90 ( 2 ) page: 174 - 176   2009.9

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    Kabuki syndrome (KS) is often associated with autoimmune abnormalities, such as idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, leukoplakia and thyroiditis, as well as congenital anomalies. We herein present a KS patient with refractory ITP who achieved durable and complete remission in response to a total of four once-monthly infusions of rituximab. KS patients are often more susceptible to infection, so splenectomy should be avoided. Therefore, rituximab therapy is an alternative option for KS patients with ITP who fail to respond to first-line therapy. © 2009 The Japanese Society of Hematology.

    DOI: 10.1007/s12185-009-0387-1

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  228. Concurrent langerhans cell histiocytosis and nephroblastoma Reviewed

    Narui R., Yagasaki H., Takahashi Y., Hama A., Nishio N., Muramatsu H., Shimoyama Y., Kojima S.

    Pediatric Blood and Cancer   Vol. 52 ( 5 ) page: 662 - 664   2009.5

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    Both Langerhans cell histiocytosis (LCH) and nephroblastoma are rare in children. We report herein the first case of a patient with both diseases concurrently. A 2-year-old female presented with bone pain and swelling of the right humerus. As a result of the local incision biopsy, she was diagnosed as LCH. A nephroblastoma of the left kidney was discovered during her staging work-up. After complete resection of the nephroblastoma, she received standard chemoradiotherapy for nephroblastoma. She is alive without relapse 14 months after initial presentation. © 2009 Wiley-Liss, Inc..

    DOI: 10.1002/pbc.21927

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  229. Natural history of transfusion-independent non-severe aplastic anemia in children Reviewed

    Nishio N., Yagasaki H., Takahashi Y., Muramatsu H., Hama A., Yoshida N., Kudo K., Kojima S.

    International Journal of Hematology   Vol. 89 ( 4 ) page: 409 - 413   2009.5

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    Although the known clinical courses of non-severe aplastic anemia (NSAA) in children comprise spontaneous resolution, persistent NSAA, or progression to severe aplastic anemia (SAA), only a few published reports have indicated the outcome of transfusion-independent NSAA. We retrospectively evaluated the incidence and time of progression from transfusion-independent to transfusion-dependent NSAA or SAA. We reviewed the records of 70 children with acquired AA who were referred to our hospital between 1986 and 2006, and among them we found 22 patients who had transfusion-independent NSAA at diagnosis and were treated with supportive care alone until progression to transfusion-dependent AA. 22 patients were followed up for a median of 86 months (range, 11-198 months). The Kaplan-Meier estimates for progression-free survival were 62 ± 12 and 22 ± 13% at 60 and 120 months after diagnosis, respectively. None of the patients treated with supportive care alone improved hematologically. In conclusion, because the incidence of disease progression was high in patients with NSAA, a prospective randomized trial of early intervention with IST or observation alone until disease progression to SAA, followed by IST when the patients become transfusion-dependent is warranted. © 2009 The Japanese Society of Hematology.

    DOI: 10.1007/s12185-009-0302-9

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  230. Plasmacytoid dendritic cell leukemia in children Reviewed

    Hama A., Kudo K., Itzel B.V., Muramatsu H., Nishio N., Yoshida N., Takahashi Y., Yagasaki H., Ito M., Kojima S.

    Journal of Pediatric Hematology/Oncology   Vol. 31 ( 5 ) page: 339 - 343   2009.5

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    CD4/CD56 malignancies are rare hematologic neoplasms, which have recently been shown to represent the malignant counterpart of plasmacytoid dendritic cells (pDC). A 5-year-old boy initially presented with multiple subcutaneous lesions on his upper and lower extremities. Skin biopsy results showed large atypical lymphoid cells in the dermis. The blast cells were stained with CD4 and CD56. In the bone marrow aspirate, 20% of the blast cells were found. The patient was diagnosed as acute unclassified leukemia and received chemotherapy designed for the treatment of acute myeloid leukemia. He achieved a complete remission that lasted for 8 months. However, multiple subcutaneous lesions recurred 1 month after the end of the therapy, with increasing blast cells in his blood. Immunophenotypically, the blast cells were positive for CD2, CD4, CD7, and CD56, and negative for CD3, CD13, CD19, CD33, and CD34 antigens. The blast cells were positive for CD123 (interleukin-3 receptor α chain) and blood dendritic cell antigen-2, which are expressed on pDC. The patient was diagnosed as acute leukemia derived from pDC. The CD4, CD56, CD3, CD13, CD19, CD33 profile is highly suggestive of this disease, and the CD123 and blood dendritic cell antigen-2 markers are useful in helping to diagnose pDC leukemia. © 2009 by Lippincott Williams & Wilkins.

    DOI: 10.1097/MPH.0b013e31819b7215

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  231. Late-onset non-infectious pulmonary complications following allogeneic hematopoietic stem cell transplantation in children Reviewed

    Nishio N., Yagasaki H., Takahashi Y., Muramatsu H., Hama A., Tanaka M., Yoshida N., Watanabe N., Kudo K., Yoshimi A., Kojima S.

    Bone Marrow Transplantation   Vol. 44 ( 5 ) page: 303 - 308   2009.4

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    Late-onset non-infectious pulmonary complications (LONIPCs) that arise beyond 3 months after allogeneic hematopoietic SCT include bronchiolitis obliterans (BO), bronchiolitis obliterans with organizing pneumonia (BOOP) and idiopathic pneumonia syndrome (IPS). We retrospectively analyzed the incidence and outcome of LONIPCs among pediatric hematopoietic SCT recipients. We included 97 patients who survived for more than 3 months among the 114 who underwent allogeneic hematopoietic SCT between April 1997 and May 2007. Of the 97 enrolled patients, 10 (10.3%) developed LONIPCs at a median of 187 days after hematopoietic SCT (range, 123-826 days). Of the 10 patients with LONIPCs, eight had BO and two had IPS. Multivariate analysis showed that the onset of LONIPCs was associated with high-risk underlying disease and extensive chronic GVHD (hazard ratio, 5.42 (95% confidence interval, 1.36-21.7) and hazard ratio, 11.7 (95% confidence interval, 2.40-57.1), respectively). Only two patients responded to therapy with steroids and six of the 10 patients died. The 5-year OS rate was significantly lower among patients with, than without LONIPCs (28.0 vs 87.2%, P = 0.000). Considering that we are lacking optimal therapies for LONIPCs, strategies aimed at the prevention of LONIPCs should be attempted.

    DOI: 10.1038/bmt.2009.33

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  232. Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia Reviewed

    Yoshida N., Yagasaki H., Xu Y., Matsuda K., Yoshimi A., Takahashi Y., Hama A., Nishio N., Muramatsu H., Watanabe N., Matsumoto K., Kato K., Ueyama J., Inada H., Goto H., Yabe M., Kudo K., Mimaya J., Kikuchi A., Manabe A., Koike K., Kojima S.

    Pediatric Research   Vol. 65 ( 3 ) page: 334 - 340   2009.3

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    Mutations in RAS, neurofibromatosis type 1 (NF1), and PTPN11, constituents of the granulocyte-macrophage colony-stimulating factor signaling pathway, have been recognized in patients with juvenile myelomonocytic leukemia (JMML). We assessed 71 children with JMML for NRAS, KRAS, and PTPN11 mutations and evaluated their clinical significance. Of the 71 patients, three had been clinically diagnosed with neurofibromatosis type 1, and PTPN11 and NRAS/KRAS mutations were found in 32 (45%) and 13 (18%) patients, respectively. No simultaneous aberrations were found. Compared with patients with RAS mutation or without any aberrations, patients with PTPN11 mutation were significantly older at diagnosis and had higher fetal Hb levels, both of which have been recognized as poor prognostic factors. As was expected, overall survival was lower for patients with the PTPN11 mutation than for those without (25 versus 64%; p = 0.0029). In an analysis of 48 patients who received hematopoietic stem cell transplantation, PTPN11 mutations were also associated with poor prognosis for survival. Mutation in PTPN11 was the only unfavorable factor for relapse after hematopoietic stem cell transplantation (p = 0.001). All patients who died after relapse had PTPN11 mutation. These results suggest that JMML with PTPN11 mutation might be a distinct subgroup with specific clinical characteristics and poor outcome. Copyright © 2009 International Pediatric Research Foundation, Inc.

    DOI: 10.1203/PDR.0b013e3181961d2a

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  233. Primary infection of human herpesvirus-6 in an infant who received cord blood SCT Reviewed

    Muramatsu H., Watanabe N., Matsumoto K., Ito M., Yoshikawa T., Kato K., Kojima S.

    Bone Marrow Transplantation   Vol. 43 ( 1 ) page: 83 - 84   2009

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    Language:Japanese   Publisher:Bone Marrow Transplantation  

    DOI: 10.1038/bmt.2008.268

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  234. Congenital erythroid and myeloid hypoplasia terminating myelodysplastic syndrome Reviewed

    Nishio N., Yagasaki H., Takahashi Y., Muramatsu H., Hama A., Xu Y., Villalobos I.B., Kojima S.

    Journal of Pediatric Hematology/Oncology   Vol. 30 ( 9 ) page: 692 - 695   2008.9

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    Language:Japanese   Publisher:Journal of Pediatric Hematology/Oncology  

    We describe a 4-month-old infant girl with congenital erythroid and myeloid hypoplasia who developed myelodysplastic syndrome. Bone marrow examination showed severe erythroid and myeloid hypoplasia without dysplastic morphology. Flow cytometry detected autoantibodies to myeloid cells, indicating a diagnosis of Diamond-Blackfan anemia with autoimmune neutropenia. The patient was administered prednisolone and rituximab, which brought the neutrophil count and hemoglobin level to within the normal range. However, bicytopenia recurred at the age of 22 months. She was diagnosed with myelodysplastic syndrome because of trilineage dysplasia and the clonal abnormality of 46,XX,dup(1)(q21;q32) in bone marrow. She was transplanted with cord blood from an unrelated human leukocyte antigen-matched donor and has since remained in complete remission for 20 months. © 2008 by Lippincott Williams & Wilkins.

    DOI: 10.1097/MPH.0b013e31816e23a1

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  235. Risk factors for early death in neonates with Down syndrome and transient leukaemia Reviewed

    Muramatsu H., Kato K., Watanabe N., Matsumoto K., Nakamura T., Horikoshi Y., Mimaya J., Suzuki C., Hayakawa M., Kojima S.

    British Journal of Haematology   Vol. 142 ( 4 ) page: 610 - 615   2008.8

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    Language:Japanese   Publisher:British Journal of Haematology  

    Transient leukaemia (TL) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells in the peripheral blood that resolves spontaneously. Some TL patients die at an early age due to organ failure. Seventy DS patients with TL were studied retrospectively to identify clinical and laboratory characteristics associated with early death (<6 months of age). Sixteen of 70 patients (22.9%) died early. The main causes of death were organ failure, particularly hepatic and cardiopulmonary failure. On univariate analysis, early gestational age (EGA), high white blood cell (WBC) count (≥100 × 109/l), percentage of peripheral blasts, elevated aspartate transaminase (AST), elevated direct bilirubin (DB), and low Apgar score were significantly associated with poor survival. On multivariate analysis, EGA, WBC count, and DB were independent predictors of poor outcome. A simple risk stratification system combining EGA and WBC count was devised to predict poor outcome. Term infants (EGA ≥ 37 weeks) whose WBC count was lower than 100 × 109/l had the best outcome [7.7% (3/39) died early], while preterm infants (EGA < 37 weeks) whose WBC count was higher than 100 × 109/l had the worst outcome [54.5% (6/11) died early]. This stratification system may be useful for identifying high-risk patients who need early therapeutic interventions. © 2008 The Authors.

    DOI: 10.1111/j.1365-2141.2008.07231.x

    Scopus

  236. Acute megakaryoblastic leukaemia (AMKL) in children: A comparison of AMKL with and without Down syndrome Reviewed

    Hama A., Yagasaki H., Takahashi Y., Nishio N., Muramatsu H., Yoshida N., Tanaka M., Hidaka H., Watanabe N., Yoshimi A., Matsumoto K., Kudo K., Kato K., Horibe K., Kojima S.

    British Journal of Haematology   Vol. 140 ( 5 ) page: 552 - 561   2008.3

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    Language:Japanese   Publisher:British Journal of Haematology  

    To characterize childhood acute megakaryoblastic leukaemia (AMKL), we reviewed 45 children with AMKL diagnosed between 1986 and 2005 at Nagoya University Hospital and Japanese Red Cross Nagoya First Hospital. Twenty-four patients (53%) had AMKL associated with Down syndrome (DS-AMKL) and 21 (47%) had non-DS-AMKL. The median age of the DS-AMKL patients was 21 months (range, 8-38 months) and that of non-DS-AMKL patients was 15 months (range, 2-185 months). The morphology of blast cells was categorized into three groups according to the stage of megakaryocyte maturation. The blast cells were more immature in DS-AMKL than in non-DS-AMKL in terms of morphology and immunophenotyping. Cytogenetic abnormalities of leukaemic cells were classified into seven categories: normal karyotype including constitutional trisomy 21 in DS-AMKL; numerical abnormalities only; t(1;22)(p13;q13); 3q21q26 abnormalities; t(16;21)(p11;q22); -5/del(5q) and/or -7/del(7q); and other structural changes. The outcome of children with either DS-AMKL or non-DS-AMKL is excellent. The 10-year overall survival estimate was 79% [95% confidence interval (CI): 54-90] for DS-AMKL and 76% (95% CI: 58-91) for non-DS-AMKL (P = 0.81) with a median follow-up of 78 months (range, 20-243 months). Our study shows the diverse heterogeneity of childhood AMKL and the need for subclassification according to cytogenetic and morphological features. © 2008 The Authors.

    DOI: 10.1111/j.1365-2141.2007.06971.x

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  237. Anemia in children Reviewed

    Muramatsu H., Kojima S.

    Nippon rinsho. Japanese journal of clinical medicine   Vol. 66 ( 3 ) page: 544 - 547   2008.3

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    Language:Japanese   Publisher:Nippon rinsho. Japanese journal of clinical medicine  

    Anemia is one of the most common symptoms in children caused by numerous underlying diseases. In majority of patients, these diseases can be correctly diagnosed through physical examination, history taking, and routine laboratory tests. Bone marrow failure syndromes associated with several genetic diseases are rare causes of anemia in childhood. We reviewed the recent progress of molecular mechanisms in bone marrow failure syndromes, such as Shwachman-Diamond syndrome (SDS), Diamond-Blackfan anemia (DBA), and dyskeratosis congenita (DC), which are all predicted to involve defective ribosome synthesis. Delineation of the precise role of each gene product in ribosomal biogenesis and hematopoiesis may have both therapeutic and prognostic significance.

    Scopus

  238. Wiskott-Aldrich syndrome is an important differential diagnosis in male infants with juvenile myelomonocytic leukemialike features Reviewed

    Watanabe N., Yoshimi A., Kamachi Y., Kawabe T., Muramatsu H., Matsumoto K., Manabe A., Kojima S., Kato K.

    Journal of Pediatric Hematology/Oncology   Vol. 29 ( 12 ) page: 836 - 838   2007.12

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    Language:Japanese   Publisher:Journal of Pediatric Hematology/Oncology  

    A newborn presented with thrombocytopenia at birth and subsequently developed leukocytosis, monocytosis, and mild hepatomegaly. The bone marrow was normocellular with dysplasia and spontaneous granulocyte-monocyte colony formation was demonstrated. These findings fulfilled the diagnostic criteria of juvenile myelomonocytic leukemia. Then he developed atopic dermatitislike eczema, which led to the consideration of Wiskott-Aldrich syndrome (WAS). Lack of intracellular WASP expression and WASP gene mutation confirmed the diagnosis of WAS. After stem cell transplantation, he is alive in good condition with normal WASP expression. WAS should be considered as a differential diagnosis in male infants with juvenile myelomonocytic leukemialike features. © 2007 Lippincott Williams & Wilkins, Inc.

    DOI: 10.1097/MPH.0b013e3181580ec5

    Scopus

  239. Spatially and temporally regulated expression of N-acetylglucosamine-6-O-sulfotransferase during mouse embryogenesis Reviewed

    Fan Q.W., Uchimura K., Yuzawa Y., Matsuo S., Mitsuoka C., Kannagi R., Muramatsu H., Kadomatsu K., Muramatsu T.

    Glycobiology   Vol. 9 ( 9 ) page: 947 - 955   1999.9

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    Language:Japanese   Publisher:Glycobiology  

    GlcNAc-6-O-sulfotransferase is involved in formation of 6-sulfo-N-acetyllactosamine-containing structures such as 6-sulfo sialyl Lewis x. We investigated the mode of expression of GlcNAc-6-O-sulfotransferase during postimplantation embryogenesis in the mouse by in situ hybridization. Sulfotransferase mRNA was not detected on embryonic day (E) 6.5, while on E7.5 it was detected in the mesoderm, ectoderm, and ectoplacental cone. On E10.5, the sulfotransferase signals were mainly observed in the nervous tissue. On E12.5 and 13.5, various tissues in the process of differentiation expressed this mRNA. Several epithelial and mesenchymal tissues undergoing epithelial-mesenchymal interactions strongly expressed the mRNA. For example, in the developing tooth strong sulfotransferase mRNA expression was found only in the condensing mesenchyme on E13.5. On E13.5 and 15.5, the sites showing intense expression of the sulfotransferase again became restricted. In the brain, sulfotransferase mRNA was frequently found as discrete signals in narrow regions. These results suggest that 6-sulfo-N-acetyllactosamine structures have important roles in development. On E13.5 and 15.5, G152 (6-sulfo sialyl Lewis x antigen) was expressed in the neocortex, and AG223 (6-sulfo Lewis x antigen) in the thalamus and neocortex where the sulfotransferase signal was detected. However, in other organs, expression of these antigens did not correlate with the sulfotransferase mRNA, implicating complex nature of regulation of expression of the fucosyl 6-sulfo antigens.

    DOI: 10.1093/glycob/9.9.947

    Scopus

  240. Human N-acetylglucosamine-6-O-sulfotransferase involved in the biosynthesis of 6-sulfo sialyl Lewis X: Molecular cloning, chromosomal mapping, and expression in various organs and tumor cells Reviewed

    Uchimura K., Muramatsu H., Kaname T., Ogawa H., Yamakawa T., Fan Q.W., Mitsuoka C., Kannagi R., Habuchi O., Yokoyama I., Yamamura K.I., Ozaki T., Nakagawara A., Kadomatsu K., Muramatsu T.

    Journal of Biochemistry   Vol. 124 ( 3 ) page: 670 - 678   1998.9

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    Language:Japanese   Publisher:Journal of Biochemistry  

    N-Acetylglucosamine-6-O-sulfotransferase catalyzes the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate to position 6 of a non-reducing N-acetylglucosamine (GlcNAc) residue. We have cloned human GlcNAc-6-O-sulfotransferase cDNA, based on the sequence homology to cloned cDNA of mouse GlcNAc-6-O-sulfotransferase. The predicted protein sequence of the human enzyme was highly homologous to that of the mouse enzyme; in the 363 amino acid stretch of the catalytic region, the two proteins were nearly identical except for conservative changes in 3 amino acid residues. The expressed enzyme transferred sulfate to GlcNAcβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4GlcNAc. Co-transfection of the enzyme cDNA and fucosyltransferase VII cDNA into COS-7 cells resulted in cell surface expression of 6-sulfo sialyl Lewis X. Fluorescence in situ hybridization analysis revealed that the GlcNAc-6-O-sulfotransferase gene is located on human chromosome 7q31. mRNA of the human enzyme was strongly expressed in the bone marrow, peripheral blood leukocytes, spleen, brain, spinal cord, ovary, and placenta, and moderate levels of expression were observed in many organs including lymph nodes and thymus. In situ hybridization with the mouse system showed that the transcript was localized in specific regions of the brain, i.e. pyramidal cells in the CA3 subregion of the hippocampus, cerebellar nucleus and Purkinje cells. Among human tumor cells, strong expression of the mRNA was found in MOLT-4 and Jarkat lymphoblastic leukemia cells, Raji lymphoma cells, K-562 chronic myelogeneous leukemia cells, U251 glioma cells, and G361 melanoma cells. Carbohydrate structures synthesized by the sulfotransferase may be involved in various aspects of the differentiation and behavior of blood cells, their progenitor cells, and neurons in the central nervous system.

    DOI: 10.1093/oxfordjournals.jbchem.a022164

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  241. Molecular cloning and characterization of an N-acetylglucosamine-6-O- sulfotransferase Reviewed

    Uchimura K., Muramatsu H., Kadomatsu K., Fan Q.W., Kurosawa N., Mitsuoka C., Kannagi R., Habuchi O., Muramatsu T.

    Journal of Biological Chemistry   Vol. 273 ( 35 ) page: 22577 - 22583   1998.8

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    Language:Japanese   Publisher:Journal of Biological Chemistry  

    We isolated a cDNA clone encoding mouse N-acetyl-glucosamine-6-O- sulfotransferase based on sequence homology to the previously cloned mouse chondroitin 6-sulfotransferase. The cDNA clone contained an open reading frame that predicts a type II transmembrane protein composed of 483 amino acid residues. The expressed enzyme transferred sulfate to the 6 position of nonreducing GlcNAc in GlcNAβ1-31-3Galβ1-4GlcNAc. Galβ1-4GlcNAcβ1-3Galβ1- 4GlcNAc and various glycosaminoglycans did not serve as acceptors. Expression of the cDNA in COS-7 cells resulted in production of a cell-surface antigen, the epitope of which was NeuAcα2-3Galβ1-4(SO4-6)GlcNAc; double transfection with fucosyltransferase IV yielded Galβl-4(Fucal-3)(SO4- 6)Glc-NAc antigen. The sulfotransferase mRNA was strongly expressed in the cerebrum, cerebellum, eye, pancreas, and lung of adult mice. In situ hybridization revealed that the mRNA was localized in high endothelial venules of mesenteric lymph nodes. The sulfotransferase was concluded to be involved in biosynthesis of glycoconjugates bearing the 6-sulfo N- acetyllactosamine structure such as 6-sulfo sialyl Lewis X. The products of the sulfotransferase probably include glycoconjugates with intercellular recognition signals; one candidate of such a glycoconjugate is an L-selectin ligand.

    DOI: 10.1074/jbc.273.35.22577

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  242. Mouse chondroitin 6-sulfotransferase: Molecular cloning, characterization and chromosomal mapping Reviewed

    Uchimura K., Kadomatsu K., Fan Q.W., Muramatsu H., Kurosawa N., Kaname T., Yamamura K.I., Fukuta M., Habuchi O., Muramatsu T.

    Glycobiology   Vol. 8 ( 5 ) page: 489 - 496   1998.5

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    Language:Japanese   Publisher:Glycobiology  

    Chondroitin 6-sulfotransferase (C6ST) catalyzes the transfer or sulfate from 3'-phosphoadenosine 5'-phosphosulfate to position 6 of the N-aceytylgalactosamine residue of chondroitin. Using chick C6ST cDNA as a probe, we cloned the cDNA of mouse C6ST. The mouse enzyme was predicted to be composed of 472 amino acids, and exhibited 71% sequence identity with the chicken enzyme. The mouse and chicken catalytic domains exposed to the luminal side exhibited 81% identity while the homology of the remaining regions was less. Transfection and expression of the mouse cDNA in COS-7 cells yielded C6ST activity. Keratan sulfate sulfotransferase activity which was simultaneously expressed, amounted to 3% of the C6ST activity, this value being significantly lower than that observed in the case of the chicken enzyme. Mouse C6ST mRNA was strongly expressed in the spleen, lung, and eye. In situ hybridization revealed that the transcript was localized in stromal cells in the marginal zone and red pulp of the spleen, and stromal cells in the bone marrow. Fluorescence in situ hybridization analysis revealed the gene is located in mouse chromosome 9.

    DOI: 10.1093/glycob/8.5.489

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MISC 4

  1. 小児血液・腫瘍患者における非結核性抗酸菌感染症についての後方視的全国調査

    津村 悠介, 村松 秀城, 西川 英里, 手塚 宣行, 成田 敦, 井上 健斗, 長 祐子, 本村 良知, 星野 仁彦, 高橋 義行

    臨床血液   Vol. 64 ( 8 ) page: 822 - 822   2023.8

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    Language:Japanese   Publisher:(一社)日本血液学会-東京事務局  

  2. 遺伝性骨髄不全症候群における造血細胞移植の課題 Fanconi貧血と重症型先天性角化不全症

    木下 恵志郎, 江口 克秀, 石村 匡崇, 長谷川 一太, 矢田 裕太郎, 園田 素史, 白石 暁, 村松 秀城, 大賀 正一

    日本小児血液・がん学会雑誌   Vol. 58 ( 4 ) page: 304 - 304   2021.10

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    Language:Japanese   Publisher:(一社)日本小児血液・がん学会  

  3. 1.マススクリーニングで発見され長期無治療経過観察後,腫瘍の進行を認めた神経芽腫の1例(【III】一般演題,第52回東海小児がん研究会,研究会)

    鳥居 ゆか, 高橋 義行, 西尾 信博, 村松 秀城, 谷ヶ崎 博, 小島 勢二, 住田 亙, 田井中 貴久, 小野 靖之, 金子 健一朗, 安藤 久賀, 下山 芳江, 中村 栄男, 宮島 雄二, 伊藤 雅文

    小児がん : 小児悪性腫瘍研究会記録   Vol. 46 ( 1 ) page: 58 - 58   2009

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    Language:Japanese   Publisher:がんの子供を守る会  

    CiNii Books

    Other Link: https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=263089

  4. 1.Opsoclonus-myoclonus-ataxia(OMA)にて発症した神経芽細胞腫の1歳女児例(【I】病理検討,第47回東海小児がん研究会,研究会)

    宮内 愛, 横塚 太郎, 村松 秀城, 祖父江 文子, 夏目 淳, 松本 公一, 加藤 剛二

    小児がん : 小児悪性腫瘍研究会記録   Vol. 42 ( 1 ) page: 112 - 112   2005

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    Language:Japanese   Publisher:がんの子供を守る会  

    CiNii Books

    Other Link: https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=261165

KAKENHI (Grants-in-Aid for Scientific Research) 8

  1. Investigating the pathogenesis of bone marrow failure in children using single-cell gene expression analysis.

    Grant number:22K07819  2022.4 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

  2. ChIP-Seqを用いた若年性骨髄単球性白血病の網羅的ヒストン修飾解析

    Grant number:21K07771  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(C)

    村松 秀城, 奥野 友介

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    Authorship:Principal investigator 

    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    若年性骨髄単球性白血病(juvenile myelomonocytic leukemia; JMML)は、主に5歳未満の小児に発症する予後不良な造血器腫瘍である。本研究では、予備的検討で確立したChIP-Seqの手法を利用し、H3K27ac、H3K36me3、H3K27me3、H3K4me3などの代表的なヒストン修飾に対するChIP-Seqを平行して行うことで、JMMLにおけるヒストン修飾の網羅的プロファイリングを行う。加えて、過去の研究で解析済みの全ゲノムシーケンス・RNAシーケンスなどの網羅的遺伝子情報との統合的な解析により、JMMLの分子学的発症メカニズムの全体像を明らかにする。

  3. Clinical application of germline and somatic mutations in bone marrow failure syndromes.

    Grant number:19H01053  2019.4 - 2024.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (A)

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    Authorship:Coinvestigator(s) 

  4. 次世代シーケンサーを用いた若年性骨髄単球性白血病のメチル化解析法の開発

    Grant number:18K07816  2018.4 - 2021.3

    科学研究費助成事業  基盤研究(C)

    村松 秀城, 奥野 友介

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    Authorship:Principal investigator 

    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    若年性骨髄単球性白血病(JMML)は予後不良な小児骨髄増殖性疾患である。我々はイルミナ社450kメチル化アレイを用いたメチル化プロファイリングを行い、高メチル化群の予後が不良であることを明らかにした(Murakami N, et al. Blood 2018)。
    イルミナ社の450kメチル化アレイは豊富な実績がある安定したDNAメチル化解析プラットフォームである。しかしながら、その解析コストは安価ではなく、実臨床の現場に実装する上では、より低コストかつハイスループットな検査法の開発が求められる。本研究では、450kメチル化アレイ解析を実施済みの臨床検体を用いて、Digital restriction enzyme analysis of methylation (DREAM)法によるメチル化解析を実施した。DREAM法は、同じCCCGGG配列を認識するが、シトシンがメチル化していると切断しない制限酵素(SmaI)およびメチル化していても切断する制限酵素(XmaI)で順番にDNAを処理し、その後イルミナ社の次世代シーケンサーでショートリードシーケンスを行う方法である。
    同法を用いて、101例のJMML患者のメチル化解析を行った。教師なしクラスタリングを施行したところ、2つのサブグループ(高メチル化群・低メチル化群)に分類することが可能であった。450kによる分類と、今回のDREAM法による分類の一致率は、95.0%であった。
    ドイツ、サンフランシスコと協力して、約300例のJMML患者検体の450kメチル化アレイデータの共同解析を行い、解析方法のハーモナイゼーションを完了し、国際共同研究として論文投稿準備中である。また、患者年齢、HbF、RAS経路遺伝子変異など、シンプルな臨床情報によるメチル化分類の予測統計モデルを作成に成功した。あわせて論文投稿準備中である。
    当初の計画どおり、DREAM法による全ゲノムメチル化解析の解析パイプラインを構築し、450kアレイによるJMMLのメチル化分類の結果を高度に再現できることを明らかにすることができた。費用は450kの約1/6と安価であり、特定の製品に依存しない優れた解析方法である。同法を用いてJMML患者を層別化することで、JMML患者の治療方針決定に対して有用な情報を得ることが可能であることを示すことができた。validationコホートとして、日本人JMMLに加えて、サンフランシスコのグループとの共同研究として、アメリカ人JMML患者においても同様に予後予測できることを確認することができた。現在、論文作成作業もほぼ完了しており、間もなく投稿できる見込みである。また、後述する国際共同研究によるメチル化アレイの解析パイプラインのハーモナイゼーションについても計画以上のペースで進行しており、こちらも論文作成作業がほぼ完了し、間もなく投稿できる見込みである。
    2017年9月にローマで行われたEWOG-MDSシンポジウムで、申請者らを含む各国のメチル化アレイの結果に基づくリスク分類のデータが発表され、他国のグループ(ドイツ、サンフランシスコ)もJMML臨床検体を用いた450kメチル化アレイによる解析を進めていることが明らかとなった。アレイデータのデータ処理・クラスタリングの手法は単一ではなく、臨床研究グループごとにリスク分類の定義づけが異なると、お互いの臨床研究の成果を比較検討することが今後、大変困難となることが予想された。申請者は、メチル化解析に基づくリスク分類を実臨床で利用するにあたり、リスク分類のハーモナイゼーションが必要であることを提案し、ハイデルベルク大学のDaniel Lipka博士、カリフォルニア大学サンフランシスコ校のElliot Stieglitz博士と同意が得られた。それぞれのデータの論文発表
    がなされ、3グループ合計で約300例のアレイデータを共有し、共同解析を行い、解析方法のハーモナイゼーションについてほぼ完了した。現在、国際共同研究として複数の論文投稿準備中である。さらに、臨床情報を用いた遺伝子メチル化状態の統計学的予測モデルを作成し、有効性を確認することができた。現在、論文作成中である。

  5. Comprehensive gene analysis of clonal hematopoiesis in childhood aplastic anemia

    Grant number:17K16248  2017.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    Atsushi Narita, TAKAHASHI Yoshiyuki, MURAMATSU Hideki, OKUNO Yusuke, NAKATOCHI Masahiro

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    We retrospectively studied 57 children with Aplastic anemia (AA) between 1992 and 2010. During the follow‐up, five patients developed clinical PNH, in whom somatic PIGA mutations were detected by targeted sequencing. The 10‐year probability of clinical PNH development was 10.2% (95% CI, 3.6%-20.7%). Furthermore, the detection of minor PNH clones by flow cytometry at AA diagnosis was a risk factor for the subsequent development of clinical PNH.
    We performed whole-exome sequencing (WES) of paired bone marrow-germline reference samples in 41 patients. WES detected reccurent gene X mutations as a novel mutational target. Gene X mutation may be associated the pahophisiology of AA.

  6. Development of biomarkers to predict immunosuppressive therapy reactivity of aplastic anemia in children

    Grant number:15K09647  2015.4 - 2018.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Muramatsu Hideki, OKUNO Yusuke

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    Authorship:Principal investigator 

    Grant amount:\4810000 ( Direct Cost: \3700000 、 Indirect Cost:\1110000 )

    We analyzed 113 patients with aplastic anemia (AA) in children and identified that absence of PNH-type blood cells and telomere shortening are independent poor prognostic factors for immunosuppressive therapy (IST) reaction (Haematologica 2015). We also identified that patients with high thrombopoietin (TPO) levels showed significantly lower response rate to IST (Pediatr Blood Cancer. 2016). Furthermore, we developed a target sequencing system of 184 genes associated with congenital hematopoietic failure (Genetics in Medicine 2017), and performed on 181 patients with idiopathic AA. In 26 cases, relevant gene mutations were identified, indicating the usefulness of screening for congenital hematopoietic failure genes in pediatric AA patients.

  7. Genomewide methylation analysis of juvenile myelomonocytic leukemia

    Grant number:22790975  2010 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    MURAMATSU Hideki

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    We analyzed JMML patients' genomic DNA with the methylation array for whole genome methylation analysis, and validated by pyrosequencing technique. As a result, promoters of CDKM2A, H19, CALCA, IGF2, and BMP4 are significantly highly methylated in JMML patients compared to normal control, but methylation status of those genes are not associated with clinical outcome.

  8. Development of a new classification depend on epigenetic information in pediatric acquired bone marrow failure syndrome

    Grant number:22659193  2010 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    KOJIMA Seiji, TAKAHASHI Yoshiyuki, MURAMATSU Hideki

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    The differential diagnosis between aplastic anemia(AA) and hypoplastic myelodysplastic syndrome(MDS), especially, refractory cytopenia of childhood(RCC) is still difficult. Six of 9 RCC specimens showed the TP53 gene mutation in TP53 positive stained cells cut by lazer microdissection system, however, there is no TP53 mutation in AA specimens. Furthermore, 2 of 5 RCC specimens showed the highly methylated status in the promotor region of p16 gene, but not in AA specimens. Higher expression of Evi-1, GATA-2 and AML1/RUNX1 were found than those at AA/MDS phase. We also found AML1/RUNX1 and N-RAS mutations occurred in this process.

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Teaching Experience (On-campus) 5

  1. 医学部 臨床医学系 小児科学講義

    2022

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    小児免疫学

  2. 成育医療“新生児から成人まで関わる子どもの病気”

    2022

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    成育医療の概念/小児がん医療の進歩について

  3. 成育医療“新生児から成人まで関わる子どもの病気”

    2023

  4. 医学部 臨床医学系 小児科学講義

    2023

  5. プレミアムレクチャー

    2021

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    若年性骨髄単球性白血病(JMML)の分子学的メカニズムの解明

 

Media Coverage 1

  1. 娘の難病見つけた微量の血液検査、依然「6人に1人」の現実 Newspaper, magazine

    毎日新聞  2023.1

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    Author:Other