2022/03/25 更新

写真a

ムラマツ ヒデキ
村松 秀城
MURAMATSU, Hideki
所属
医学部附属病院 小児科 講師
大学院担当
大学院医学系研究科
職名
講師

学位 1

  1. 博士(医学) ( 2010年3月   名古屋大学 ) 

研究キーワード 1

  1. 小児血液腫瘍免疫不全

学歴 2

  1. 名古屋大学   医学系研究科   小児科学

    - 2010年3月

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    国名: 日本国

  2. 名古屋大学   医学部

    - 2000年3月

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    国名: 日本国

所属学協会 5

  1. 日本血液学会

  2. 日本造血細胞移植学会

  3. 小児血液がん学会

  4. 日本小児科学会

  5. アメリカ血液学会

 

論文 201

  1. A retrospective analysis of azacitidine treatment for juvenile myelomonocytic leukemia 査読有り

    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   115 巻 ( 2 ) 頁: 263 - 268   2022年2月

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    記述言語:日本語   出版者・発行元: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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  2. Prospective validation of the provisional entity of refractory cytopenia of childhood, proposed by the World Health Organization 査読有り

    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   196 巻 ( 4 ) 頁: 1031 - 1039   2022年2月

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    記述言語:日本語   出版者・発行元:British Journal of Haematology  

    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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  3. Azacitidine as a bridge to transplantation in juvenile myelomonocytic leukemia 査読有り

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

    Pediatrics international : official journal of the Japan Pediatric Society   64 巻 ( 1 )   2022年1月

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    記述言語:日本語   出版者・発行元:Pediatrics international : official journal of the Japan Pediatric Society  

    DOI: 10.1111/ped.14929

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  4. Combination chemotherapy consisting of irinotecan, etoposide, and carboplatin for refractory or relapsed neuroblastoma 査読有り

    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     2022年

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    記述言語:日本語   出版者・発行元:Cancer Medicine  

    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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  5. Simple and robust methylation test for risk stratification of patients with juvenile myelomonocytic leukemia 査読有り

    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   5 巻 ( 24 ) 頁: 5507 - 5518   2021年12月

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    記述言語:日本語   出版者・発行元:Blood Advances  

    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.

    DOI: 10.1182/bloodadvances.2021005080

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  6. A neonate diagnosed with Noonan syndrome with myeloproliferative change 査読有り

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

    Pediatrics International   63 巻 ( 12 ) 頁: 1521 - 1523   2021年12月

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    記述言語:日本語   出版者・発行元:Pediatrics International  

    DOI: 10.1111/ped.14634

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  7. Integrated diagnosis based on transcriptome analysis in suspected pediatric sarcomas 査読有り

    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   6 巻 ( 1 ) 頁: 49   2021年12月

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    記述言語:日本語   出版者・発行元:npj Genomic Medicine  

    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.

    DOI: 10.1038/s41525-021-00210-y

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  8. Acquisition of a rare NUP98–BPTF fusion gene associated with recurrence of acute myeloid leukemia 査読有り

    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   68 巻 ( 10 ) 頁: e29201   2021年10月

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    記述言語:日本語   出版者・発行元:Pediatric Blood and Cancer  

    DOI: 10.1002/pbc.29201

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  9. Clinical diagnostic value of telomere length measurement in inherited bone marrow failure syndromes 査読有り

    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   106 巻 ( 9 ) 頁: 2511 - 2515   2021年9月

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    記述言語:日本語   出版者・発行元:Haematologica  

    DOI: 10.3324/haematol.2021.278334

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  10. 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 査読有り

    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   27 巻 ( 9 ) 頁: 786.e1 - 786.e8   2021年9月

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    記述言語:日本語   出版者・発行元:Transplantation and Cellular Therapy  

    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.

    DOI: 10.1016/j.jtct.2021.05.017

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  11. Autoantibodies against the plakin family proteins as a novel marker for chronic graft-versus-host disease of the lung 査読有り

    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   56 巻 ( 9 ) 頁: 2291 - 2294   2021年9月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    DOI: 10.1038/s41409-021-01335-5

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  12. Relationship between plasma rabbit anti-thymocyte globulin concentration and immunosuppressive therapy response in patients with severe aplastic anemia 査読有り

    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   107 巻 ( 2 ) 頁: 255 - 264   2021年8月

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    記述言語:日本語   出版者・発行元:European Journal of Haematology  

    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.

    DOI: 10.1111/ejh.13644

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  13. Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor 査読有り

    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   148 巻 ( 2 ) 頁: 639 - 644   2021年8月

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    記述言語:日本語   出版者・発行元:Journal of Allergy and Clinical Immunology  

    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.

    DOI: 10.1016/j.jaci.2021.03.010

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  14. 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) 査読有り

    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   56 巻 ( 5 ) 頁: 1218 - 1219   2021年5月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    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.

    DOI: 10.1038/s41409-020-01076-x

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  15. Predictive factors for the development of leukemia in patients with transient abnormal myelopoiesis and Down syndrome 査読有り

    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   35 巻 ( 5 ) 頁: 1480 - 1484   2021年5月

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    記述言語:日本語   出版者・発行元:Leukemia  

    DOI: 10.1038/s41375-021-01171-y

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  16. Reduced-intensity conditioning is effective for hematopoietic stem cell transplantation in young pediatric patients with Diamond–Blackfan anemia 査読有り

    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   56 巻 ( 5 ) 頁: 1013 - 1020   2021年5月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    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.

    DOI: 10.1038/s41409-020-01056-1

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  17. The eldest case of MICPCH with CASK mutation exhibiting gross motor regression 査読有り

    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   43 巻 ( 3 ) 頁: 459 - 463   2021年3月

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    記述言語:日本語   出版者・発行元:Brain and Development  

    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.

    DOI: 10.1016/j.braindev.2020.11.007

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  18. International consensus definition of DNA methylation subgroups in juvenile myelomonocytic leukemia 査読有り

    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   27 巻 ( 1 ) 頁: 158 - 168   2021年1月

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    記述言語:日本語   出版者・発行元:Clinical Cancer Research  

    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.

    DOI: 10.1158/1078-0432.CCR-20-3184

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  19. Detection of subclonal SETBP1 and JAK3 mutations in juvenile myelomonocytic leukemia using droplet digital PCR 査読有り

    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   35 巻 ( 1 ) 頁: 259 - 263   2021年1月

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    記述言語:日本語   出版者・発行元:Leukemia  

    DOI: 10.1038/s41375-020-0817-x

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  20. Genetic study of fanconi anemia in infancy revealed FANCI mutations and defective ALDH2 variant: A case report 査読有り

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

    Journal of Pediatric Hematology/Oncology     2021年

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    記述言語:日本語   出版者・発行元:Journal of Pediatric Hematology/Oncology  

    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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  21. A patient with very early onset FH-deficient renal cell carcinoma diagnosed at age seven 査読有り

    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     2021年

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    記述言語:日本語   出版者・発行元:Familial Cancer  

    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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  22. Usefulness of functional splicing analysis to confirm precise disease pathogenesis in Diamond-Blackfan anemia caused by intronic variants in RPS19 査読有り

    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   38 巻 ( 6 ) 頁: 515 - 527   2021年

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    記述言語:日本語   出版者・発行元:Pediatric Hematology and Oncology  

    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.

    DOI: 10.1080/08880018.2021.1887984

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  23. Microsatellite instability-high is rare events in refractory pediatric solid tumors 査読有り

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

    Pediatric Hematology and Oncology     2021年

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    記述言語:日本語   出版者・発行元:Pediatric Hematology and Oncology  

    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.

    DOI: 10.1080/08880018.2021.1998266

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  24. Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans 査読有り

    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   80 巻 ( 6 ) 頁: 996 - 1012.e9   2020年12月

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    記述言語:日本語   出版者・発行元:Molecular Cell  

    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.

    DOI: 10.1016/j.molcel.2020.10.012

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  25. Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome 査読有り

    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   6 巻 ( 51 )   2020年12月

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    記述言語:日本語   出版者・発行元:Science Advances  

    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.

    DOI: 10.1126/SCIADV.ABD7197

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  26. Myelodysplastic syndromes in a pediatric patient with Cri du Chat syndrome with a ring chromosome 5 査読有り

    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   112 巻 ( 5 ) 頁: 728 - 733   2020年11月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    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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  27. Risk factors for secondary poor graft function after bone marrow transplantation in children with acquired aplastic anemia 査読有り

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

    Pediatric Transplantation   24 巻 ( 7 ) 頁: e13828   2020年11月

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    記述言語:日本語   出版者・発行元:Pediatric Transplantation  

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

    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   54 巻 ( 5 ) 頁: 994 - 1012   2020年10月

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    記述言語:日本語   出版者・発行元:Cellular Physiology and Biochemistry  

    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.

    DOI: 10.33594/000000283

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  29. Change of White Matter Integrity in Children With Hematopoietic Stem Cell Transplantation 査読有り

    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   111 巻   頁: 78 - 84   2020年10月

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    記述言語:日本語   出版者・発行元:Pediatric Neurology  

    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.

    DOI: 10.1016/j.pediatrneurol.2020.06.008

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

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

    Bone Marrow Transplantation   55 巻 ( 9 ) 頁: 1872 - 1874   2020年9月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    DOI: 10.1038/s41409-020-0867-8

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  31. Hematopoietic Cell Transplantation for Chronic Granulomatous Disease in Japan 査読有り

    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   11 巻   頁: 1617   2020年7月

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    記述言語:日本語   出版者・発行元:Frontiers in Immunology  

    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.

    DOI: 10.3389/fimmu.2020.01617

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

    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   1 巻 ( 1 ) 頁: 82 - 95   2020年7月

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    記述言語:英語  

    DOI: 10.1158/2643-3230.BCD-19-0080

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  33. Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex 査読有り

    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   57 巻 ( 4 ) 頁: 245 - 253   2020年4月

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    記述言語:日本語   出版者・発行元:Journal of Medical Genetics  

    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.

    DOI: 10.1136/jmedgenet-2019-106213

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  34. Novel compound heterozygous MCOLN1 mutations identified in a Japanese girl with severe developmental delay and thin corpus callosum 査読有り

    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   42 巻 ( 3 ) 頁: 298 - 301   2020年3月

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    記述言語:日本語   出版者・発行元:Brain and Development  

    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.

    DOI: 10.1016/j.braindev.2019.12.003

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  35. Novel biallelic FA2H mutations in a Japanese boy with fatty acid hydroxylase-associated neurodegeneration 査読有り

    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   42 巻 ( 2 ) 頁: 217 - 221   2020年2月

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    記述言語:日本語   出版者・発行元:Brain and Development  

    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.

    DOI: 10.1016/j.braindev.2019.11.006

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  36. Targetable driver mutations in multicentric reticulohistiocytosis 査読有り

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

    Haematologica   105 巻 ( 2 ) 頁: E61 - E64   2020年1月

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    記述言語:日本語   出版者・発行元:Haematologica  

    DOI: 10.3324/haematol.2019.218735

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

    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   105 巻 ( 4 ) 頁: 1166 - 1167   2020年

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    記述言語:日本語   出版者・発行元:Haematologica  

    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).

    DOI: 10.3324/haematol.2019.245720

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  38. Conditioning regimen for allogeneic bone marrow transplantation in children with acquired bone marrow failure: fludarabine/melphalan vs. fludarabine/cyclophosphamide 査読有り

    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     2020年

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    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.

    DOI: 10.1038/s41409-020-0948-8

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  39. A novel CUL4B splice site variant in a young male exhibiting less pronounced features 査読有り

    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   6 巻 ( 1 ) 頁: 43   2019年12月

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    記述言語:日本語   出版者・発行元:Human Genome Variation  

    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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  40. Study of pathophysiology and molecular characterization of congenital anemia in India using targeted next-generation sequencing approach 査読有り

    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   110 巻 ( 5 ) 頁: 618 - 626   2019年11月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    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.

    DOI: 10.1007/s12185-019-02716-9

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  41. Essential role of PTPN11 mutation in enhanced haematopoietic differentiation potential of induced pluripotent stem cells of juvenile myelomonocytic leukaemia 査読有り

    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   187 巻 ( 2 ) 頁: 163 - 173   2019年10月

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    記述言語:日本語   出版者・発行元:British Journal of Haematology  

    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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  42. Prospective randomized trial comparing two doses of rabbit anti-thymocyte globulin in patients with severe aplastic anaemia 査読有り

    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   187 巻 ( 2 ) 頁: 227 - 237   2019年10月

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    記述言語:日本語   出版者・発行元:British Journal of Haematology  

    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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  43. Risk factors for absence of catch-up growth in small for gestational age very low-birthweight infants 査読有り

    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   61 巻 ( 9 ) 頁: 889 - 894   2019年9月

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    記述言語:日本語   出版者・発行元:Pediatrics International  

    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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  44. Whole abdominopelvic intensity-modulated radiation therapy for peritoneal disseminated rhabdomyosarcoma with three-year follow-up: A case report 査読有り

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

    Radiation Oncology   14 巻 ( 1 ) 頁: 127   2019年7月

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    記述言語:日本語   出版者・発行元:Radiation Oncology  

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

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

    Journal of Human Genetics   64 巻 ( 7 ) 頁: 665 - 671   2019年7月

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    記述言語:日本語   出版者・発行元:Journal of Human Genetics  

    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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  46. 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) 査読有り

    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   14 巻 ( 6 ) 頁: e0218205   2019年6月

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    記述言語:日本語   出版者・発行元:PLoS ONE  

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

    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   81 巻 ( 2 ) 頁: 227 - 232   2019年5月

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    記述言語:日本語   出版者・発行元:Nagoya journal of medical science  

    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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  48. Comparison of high-dose and low-dose corticosteroid therapy for refractory Mycoplasma pneumoniae pneumonia in children 査読有り

    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   25 巻 ( 5 ) 頁: 346 - 350   2019年5月

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    記述言語:日本語   出版者・発行元:Journal of Infection and Chemotherapy  

    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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  49. KLF1 mutation E325K induces cell cycle arrest in erythroid cells differentiated from congenital dyserythropoietic anemia patient-specific induced pluripotent stem cells 査読有り

    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   73 巻   頁: 25 - 37.e8   2019年5月

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    記述言語:日本語   出版者・発行元:Experimental Hematology  

    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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  50. 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 査読有り

    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   23 巻 ( 3 ) 頁: e13378   2019年5月

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    記述言語:日本語   出版者・発行元:Pediatric Transplantation  

    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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  51. Defective Epstein–Barr virus in chronic active infection and haematological malignancy 査読有り

    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   4 巻 ( 3 ) 頁: 404 - 413   2019年3月

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    記述言語:日本語   出版者・発行元:Nature Microbiology  

    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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  52. 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) 査読有り

    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   4 巻 ( 3 ) 頁: 544   2019年3月

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    記述言語:日本語   出版者・発行元:Nature Microbiology  

    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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  53. Allogeneic stem cell transplantation with reduced intensity conditioning for patients with adrenoleukodystrophy 査読有り

    Kato K., Maemura R., Wakamatsu M., Yamamori A., Hamada M., Kataoka S., Narita A., Miwata S., Sekiya Y., Kawashima N., Suzuki K., Narita K., Doisaki S., Muramatsu H., Sakaguchi H., Matsumoto K., Koike Y., Onodera O., Kaga M., Shimozawa N., Yoshida N.

    Molecular Genetics and Metabolism Reports   18 巻   頁: 1 - 6   2019年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Molecular Genetics and Metabolism Reports  

    Objective: The prognosis of adrenoleukodystrophy (ALD)with neurological involvement is generally dismal; however, allogeneic stem cell transplantation (SCT) is recognized as effective to stabilize or improve the clinical symptoms of ALD. Herein, we report the clinical outcomes of patients with ALD who consecutively underwent allogeneic stem cell transplantation with reduced intensity conditioning at our institution. Patients: Sixteen patients with ALD, who were symptomatic (n = 14) or presymptomatic (n = 2), received SCT from 2010 to 2016. The stem cell source was cord blood (n = 14), or bone marrow from a human leukocyte antigen identical sibling (n = 2). The conditioning regimen prior to transplantation was reduced intensity and consisted of fludarabine (125 mg/m2), melphalan (140 mg/m2) and low dose total body irradiation (TBI) of 4Gy (n = 15) or 3Gy (n = 1). Results: Primary engraftment was obtained in 11 patients, and 4 of the 5 patients who lost the primary graft received a second cord blood transplantation and were engrafted. Five years overall and event-free survival were 90.9% and 61.1% respectively, with a median of 45 months (range 16–91). Loes score stabilized or improved by 18 months after transplantation except for patients with internal capsule involvement. Conclusion: Allogeneic SCT with reduced intensity conditioning for patients with ALD was safely performed without major transplant-related complications even in symptomatic patients and neurological symptoms were stabilized after SCT in patients without internal capsule involvement.

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  54. Associations of complementation group, ALDH2 genotype, and clonal abnormalities with hematological outcome in Japanese patients with Fanconi anemia 査読有り

    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   98 巻 ( 2 ) 頁: 271 - 280   2019年2月

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    記述言語:日本語   出版者・発行元:Annals of Hematology  

    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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  55. Comparison of conditioning regimens for autologous stem cell transplantation in children with acute myeloid leukemia: A nationwide retrospective study in Japan 査読有り

    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   66 巻 ( 1 ) 頁: e27459   2019年1月

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    記述言語:日本語   出版者・発行元:Pediatric Blood and Cancer  

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

    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   143 巻 ( 1 ) 頁: 266 - 275   2019年1月

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    記述言語:日本語   出版者・発行元:Journal of Allergy and Clinical Immunology  

    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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  57. Comparison of clinical characteristics of human metapneumovirus and respiratory syncytial virus infections in hospitalized young children 査読有り

    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   72 巻 ( 4 ) 頁: 237 - 242   2019年

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    記述言語:日本語   出版者・発行元:Japanese Journal of Infectious Diseases  

    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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  58. Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients 査読有り

    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   104 巻 ( 10 ) 頁: 1962 - 1973   2019年

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    記述言語:日本語   出版者・発行元:Haematologica  

    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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  59. Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia 査読有り

    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   8 巻 ( 1 ) 頁: 6956   2018年12月

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    記述言語:日本語   出版者・発行元:Scientific Reports  

    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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  60. 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 査読有り

    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   65 巻 ( 12 ) 頁: e27368   2018年12月

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    記述言語:日本語   出版者・発行元:Pediatric Blood and Cancer  

    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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  61. Ureteral dilatation detected in magnetic resonance imaging predicts vesicoureteral reflux in children with urinary tract infection 査読有り

    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   13 巻 ( 12 ) 頁: e0209595   2018年12月

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    記述言語:日本語   出版者・発行元:PLoS ONE  

    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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  62. 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   132 巻   2018年11月

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    記述言語:日本語  

    DOI: 10.1182/blood-2018-99-113801

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  63. Sudden intracranial hemorrhage in a patient with atypical chronic myeloid leukemia in chronic phase 査読有り

    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   40 巻 ( 8 ) 頁: e553 - e556   2018年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Pediatric Hematology/Oncology  

    A 16-year-old boy was incidentally found to have hyperleukocytosis during a school physical examination. He was diagnosed with atypical chronic myeloid leukemia in chronic phase. Although treatment with hydoxyurea was started, his white blood cell count increased and he eventually developed lethal intracranial hemorrhage. Although very rare, intracranial hemorrhage should be considered as a possible complication in patients with atypical chronic myeloid leukemia, even in chronic phase, if they have hyperleukocytosis and thrombocytopenia.

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  64. A patient with a GNAO1 mutation with decreased spontaneous movements, hypotonia, and dystonic features 査読有り

    Okumura A., Maruyama K., Shibata M., Kurahashi H., Ishii A., Numoto S., Hirose S., Kawai T., Iso M., Kataoka S., Okuno Y., Muramatsu H., Kojima S.

    Brain and Development   40 巻 ( 10 ) 頁: 926 - 930   2018年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Brain and Development  

    We report on a 4-year-old girl with a de novo GNAO1 mutation who had neurological findings, including decreased spontaneous movements, hypotonia, and dystonic features. She was referred to our hospital because of delayed psychomotor development. She showed hypotonia and decreased spontaneous movements. Voluntary movements of the limbs were more frequent in the lower extremities than in the upper extremities. Occasional dyskinetic features, such as awkward hand/foot posturing and grimacing, were seen during the voluntary movements. Serum metabolic screening, head magnetic resonance imaging, and electroencephalography were unremarkable. Whole-exome sequencing revealed a de novo mutation in the patient's GNAO1 gene, c.709 G > A (p.E237K). We calculated the free-energy change using the FoldX Suite to evaluate the impact of the E237K mutation. The FoldX calculations showed an increased free-energy change in the active state of the GNAO1 protein, indicating that the E237K mutation destabilizes the active state complexes. No seizures, chorea, tremor, or myoclonia, which are frequently reported in patients with GNAO1 mutations, were observed as of the last follow up. Our patient will improve the understanding of early neurological features in patients with GNAO1 mutations.

    DOI: 10.1016/j.braindev.2018.06.005

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  65. Whole-exome analysis to detect congenital hemolytic anemia mimicking congenital dyserythropoietic anemia 査読有り

    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   108 巻 ( 3 ) 頁: 306 - 311   2018年9月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    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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  66. Integration Mapping of piggyBac-Mediated CD19 Chimeric Antigen Receptor T Cells Analyzed by Novel Tagmentation-Assisted PCR 査読有り

    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   34 巻   頁: 18 - 26   2018年8月

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    記述言語:日本語   出版者・発行元:EBioMedicine  

    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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  67. 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 査読有り

    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   32 巻 ( 5 ) 頁: 348 - 362   2018年6月

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    記述言語:日本語   出版者・発行元:Annals of Nuclear Medicine  

    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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  68. An infant with generalized pustular psoriasis and geographic tongue had a heterozygous IL36RN mutation and IgG2 deficiency 査読有り

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

    Journal of Dermatological Science   90 巻 ( 2 ) 頁: 216 - 218   2018年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Dermatological Science  

    DOI: 10.1016/j.jdermsci.2018.01.017

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  69. Integrated molecular profiling of juvenile myelomonocytic leukemia 査読有り

    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   131 巻 ( 14 ) 頁: 1576 - 1586   2018年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood  

    Juvenile myelomonocytic leukemia (JMML), a rare and aggressive myelodysplastic/ myeloproliferative neoplasm that occurs in infants and during early childhood, is characterized by excessive myelomonocytic cell proliferation. More than 80% of patients harbor germ line and somatic mutations in RAS pathway genes (eg, PTPN11, NF1, NRAS, KRAS, and CBL), and previous studies have identified several biomarkers associated with poor prognosis. However, the molecular pathogenesis of 10% to 20% of patients and the relationships among these biomarkers have not been well defined. To address these issues, we performed an integrated molecular analysis of samples from 150 JMML patients. RNA-sequencing identified ALK/ROS1 tyrosine kinase fusions (DCTN1-ALK, RANBP2-ALK, and TBL1XR1-ROS1) in 3 of 16 patients (18%) who lacked canonical RAS pathway mutations. Crizotinib, an ALK/ROS1 inhibitor, markedly suppressed ALK/ROS1 fusion–positive JMML cell proliferation in vitro. Therefore, we administered crizotinib to a chemotherapy-resistant patient with the RANBP2-ALK fusion who subsequently achieved complete molecular remission. In addition, crizotinib also suppressed proliferation of JMML cells with canonical RAS pathway mutations. Genome-wide methylation analysis identified a hypermethylation profile resembling that of acute myeloid leukemia (AML), which correlated significantly with genetic markers with poor outcomes such as PTPN11/NF1 gene mutations, 2 or more genetic mutations, an AML-type expression profile, and LIN28B expression. In summary, we identified recurrent activated ALK/ROS1 fusions in JMML patients without canonical RAS pathway gene mutations and revealed the relationships among biomarkers for JMML. Crizotinib is a promising candidate drug for the treatment of JMML, particularly in patients with ALK/ROS1 fusions.

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  70. Danaparoid reduces transplant-related mortality in stem cell transplantation for children 査読有り

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

    Pediatric Transplantation   22 巻 ( 2 )   2018年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pediatric Transplantation  

    In SCT, death from transplant-related complications is the major obstacle hindering improvement of transplant outcomes, and proper supportive care is essential to reduce TRM. The transplant outcomes of 210 pediatric patients with malignant and non-malignant disorders who consecutively underwent SCT in our institution from 2000 to 2013 were analyzed. The transplant years were divided into three periods: A (2000-2004), B (2005-2008), and C (2009-2013), and an improvement in 5-year OS and a decrease in 5-year TRM were observed over these time periods; that is, OS was 61.5%, 60.3%, and 79.5% (P =.062), and TRM was 19.9%, 7.9%, and 0.0% (P <.001) in periods A, B, and C, respectively. On multivariate analysis, the prognostic factor for TRM for all patients was administration of danaparoid (HR = 0.109, 95% CI = 0.033-0.363, P <.001), and for patients with hematological malignancies in allogeneic SCT, the prognostic factors were danaparoid (HR = 0.046, 95% CI = 0.006-0.326, P =.002) and advanced disease at SCT (HR = 4.802, 95% CI = 1.734-13.30, P =.003). A reduction in TRM after SCT was observed over the time periods, and supportive care with danaparoid was found to be significantly effective in reducing TRM in SCT for children.

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  71. Biallelic mutations in SZT2 cause a discernible clinical entity with epilepsy, developmental delay, macrocephaly and a dysmorphic corpus callosum 査読有り

    Nakamura Y., Togawa Y., Okuno Y., Muramatsu H., Nakabayashi K., Kuroki Y., Ieda D., Hori I., Negishi Y., Togawa T., Hattori A., Kojima S., Saitoh S.

    Brain and Development   40 巻 ( 2 ) 頁: 134 - 139   2018年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Brain and Development  

    Mutations in SZT2 were first reported in 2013 as a cause of early-onset epileptic encephalopathy. Because only five reports have been published to date, the clinical features associated with SZT2 remain unclear. We herein report an additional patient with biallelic mutations in SZT2. The proband, a four-year-old girl, showed developmental delay and seizures from two years of age. Her seizures were not intractable and readily controlled by valproate. She showed mildly dysmorphic facies with macrocephaly, high forehead, and hypertelorism, and also had pectus carinatum. An EEG showed epileptic discharges which rarely occurred. A brain MRI revealed a short and thick corpus callosum. Whole-exome sequencing detected compound heterozygous biallelic mutations (c.8596dup (p.Tyr2866Leufs∗42) and c.2930-17_2930-3delinsCTCGTG) in SZT2, both of which were novel and predicted to be truncating. This case suggested a broad phenotypic spectrum arises from SZT2 mutations, forming a continuum from epileptic encephalopathy and severe developmental delay to mild intellectual disability without epilepsy. The characteristic thick and short corpus callosum observed in 7/8 cases with epilepsy, including the proband, but not in three non-syndromic cases, appears to be specific, and thus useful for indicating the possibility of SZT2 mutations. This feature has the potential to make loss of SZT2 a clinically discernible disorder despite a wide clinical spectrum.

    DOI: 10.1016/j.braindev.2017.08.003

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  72. Treatment with silver nitrate versus topical steroid treatment for umbilical granuloma: A non-inferiority randomized control trial 査読有り

    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   13 巻 ( 2 ) 頁: e0192688   2018年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLoS ONE  

    Objective The aim of this prospective multicenter randomized controlled trial was to compare the efficacy of silver nitrate cauterization against that of topical steroid ointment in the treatment of neonatal umbilical granuloma. Methods An open-label, non-inferiority randomized controlled trial was conducted from January 2013 to January 2016. The primary endpoint for the silver nitrate cauterization and topical steroid ointment groups was the healing rate after 2 weeks of treatment, applying a non-inferiority margin of 10%. The healing rate was evaluated until completion of 3 weeks of treatment. Results Participants comprised 207 neonates with newly diagnosed umbilical granuloma, randomized to receive silver nitrate cauterization (n = 104) or topical steroid ointment (n = 103). Healing rates after 2 weeks of treatment were 87.5% (91/104) in the silver nitrate cauterization and 82% (82/100) in the topical steroid ointment group group. The difference between groups was -5.5% (95% confidence interval, -19.1%, 8.4%), indicating that the non-inferiority criterion was not met. After 3 weeks of treatment, the healing rate with topical steroid ointment treatment was almost identical to that of silver nitrate cauterization (94/104 [90.4%] vs. 91/100 [91.0%]; 0.6% [-13.2 to 14.3]). No major complications occurred in either group. Conclusions This study did not establish non-inferiority of topical steroid ointment treatment relative to silver nitrate cauterization, presumably due to lower healing rates than expected leading to an underpowered trial. However, considering that silver nitrate cauterization carries a distinct risk of chemical burns and that the overall efficacy of topical steroid ointment treatment is similar to that of silver nitrate cauterization, topical steroid ointment might be considered as a good alternative in the treatment of neonatal umbilical granuloma due to its safety and simplicity. To clarify non-inferiority, a larger study is needed.

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  73. Genetic heterogeneity of uncharacterized childhood autoimmune diseases with lymphoproliferation 査読有り

    Takagi M., Hoshino A., Yoshida K., Ueno H., Imai K., Piao J., Kanegane H., Yamashita M., Okano T., Muramatsu H., Okuno Y., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Ogawa S., Hayashi Y., Kojima S., Morio T.

    Pediatric Blood and Cancer   65 巻 ( 2 )   2018年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pediatric Blood and Cancer  

    Autoimmune diseases in children are rare and can be difficult to diagnose. Single causative genes have been identified for some pediatric autoimmune diseases. Such orphan diseases may not be diagnosed properly due to the variability of patients' phenotypes. Guidelines for the diagnostic process need to be developed. Fifteen patients with uncharacterized childhood autoimmune diseases with lymphoproliferation that had negative testing for autoimmune lymphoproliferative syndrome were subjected to whole-exome sequencing to identify genes associated with these conditions. Five causative genes, CTLA4, STAT3, TNFAIP3, IKZF1, and PSTPIP1, were identified. These genes should be considered as candidates for uncharacterized childhood autoimmune diseases with lymphoproliferation.

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  74. Comprehensive genetic analysis of donor cell derived leukemia with KMT2A rearrangement 査読有り

    Taniguchi R., Muramatsu H., Okuno Y., Suzuki K., Obu S., Nakatochi M., Shimamura T., Takahashi Y., Horikoshi Y., Watanabe K., Kojima S.

    Pediatric Blood and Cancer   65 巻 ( 2 )   2018年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pediatric Blood and Cancer  

    Background: Donor cell leukemia (DCL) occurs after allogeneic hematopoietic stem cell transplantation. Several mechanisms, including occult leukemic/preleukemic subclones in the donor graft and germline predisposition to leukemia, are proposed to be associated with DCL's molecular pathogenesis. We report a comprehensive genetic analysis of a patient with KMT2A-rearranged DCL after allogeneic bone marrow transplantation for refractory cytopenia of childhood. Procedure: We performed a whole-exome sequencing of the recipient's peripheral blood before transplant and the donor's peripheral blood and the recipient's bone marrow at the time of DCL diagnosis. RNA sequencing was also performed to detect fusion genes in DCL blasts. Results: There were no germline mutations that were associated with a predisposition to leukemia in the recipient and donor. Furthermore, there were no detectable somatic alterations except KMT2A-MLLT10 and other related gene fusions in DCL. KMT2A-MLLT10 was not detectable in the donor's bone marrow. Conclusion: We propose a novel pattern of the molecular pathogenesis of DCL solely involving a genetic mutation acquired after transplant with no identifiable genetic factor related to the donor and recipient.

    DOI: 10.1002/pbc.26823

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  75. Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders 査読有り

    Slack J., Albert M.H., Balashov D., Belohradsky B.H., Bertaina A., Bleesing J., Booth C., Buechner J., Buckley R.H., Ouachée-Chardin M., Deripapa E., Drabko K., Eapen M., Feuchtinger T., Finocchi A., Gaspar H.B., Ghosh S., Gillio A., Gonzalez-Granado L.I., Grunebaum E., Güngör T., Heilmann C., Helminen M., Higuchi K., Imai K., Kalwak K., Kanazawa N., Karasu G., Kucuk Z.Y., Laberko A., Lange A., Mahlaoui N., Meisel R., Moshous D., Muramatsu H., Parikh S., Pasic S., Schmid I., Schuetz C., Schulz A., Schultz K.R., Shaw P.J., Slatter M.A., Sykora K.W., Tamura S., Taskinen M., Wawer A., Wolska-Kuśnierz B., Cowan M.J., Fischer A., Gennery A.R.

    Journal of Allergy and Clinical Immunology   141 巻 ( 1 ) 頁: 322 - 328.e10   2018年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Allergy and Clinical Immunology  

    Background Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos–XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). Methods Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. Results Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P =.006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P =.45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. Conclusion RIC HCT resolves DNA repair disorder–associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.

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  76. Unrelated cord blood transplantation in aplastic anemia: Is anti-thymocyte globulin indispensable for conditioning? 査読有り

    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   52 巻 ( 12 ) 頁: 1659 - 1661   2017年12月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    DOI: 10.1038/bmt.2017.169

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  77. Development of clinical paroxysmal nocturnal haemoglobinuria in children with aplastic anaemia 査読有り

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

    British Journal of Haematology   178 巻 ( 6 ) 頁: 954 - 958   2017年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:British Journal of Haematology  

    The clinical significance of paroxysmal nocturnal haemoglobinuria (PNH) in children with aplastic anaemia (AA) remains unclear. We retrospectively studied 57 children with 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% confidence interval, 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. These patients with PNH clones at AA diagnosis should undergo periodic monitoring for potential clinical PNH development.

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  78. Flow cytometric analysis as an additional predictive tool of treatment response in children with chronic-phase chronic myeloid leukemia treated with imatinib 査読有り

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

    Pediatric Blood and Cancer   64 巻 ( 9 )   2017年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pediatric Blood and Cancer  

    Bone marrow samples of newly diagnosed children with chronic-phase chronic myeloid leukemia (CML) were obtained at diagnosis and after imatinib initiation and stained with anti-human CD34, CD38, CD123, CD45RA, cMpl, and lineage antibodies. Flow cytometric analysis revealed that granulocyte macrophage progenitor predominance in CML progenitors at diagnosis and elevated cMpl expression in bone marrow progenitors at 3 months may predict poor outcome in children with chronic-phase CML treated with imatinib. We recommend flow cytometric analysis of bone marrow in the early phase of treatment, as it is a convenient tool that may predict treatment response and guide CML management.

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  79. A case of GATA2-related myelodysplastic syndrome with unbalanced translocation der(1;7)(q10;p10) 査読有り

    Kurata T., Shigemura T., Muramatsu H., Okuno Y., Nakazawa Y.

    Pediatric Blood and Cancer   64 巻 ( 8 )   2017年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pediatric Blood and Cancer  

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  80. Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes 査読有り

    Muramatsu H., Okuno Y., Yoshida K., Shiraishi Y., Doisaki S., Narita A., Sakaguchi H., Kawashima N., Wang X., Xu Y., Chiba K., Tanaka H., Hama A., Sanada M., Takahashi Y., Kanno H., Yamaguchi H., Ohga S., Manabe A., Harigae H., Kunishima S., Ishii E., Kobayashi M., Koike K., Watanabe K., Ito E., Takata M., Yabe M., Ogawa S., Miyano S., Kojima S.

    Genetics in Medicine   19 巻 ( 7 ) 頁: 796 - 802   2017年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Genetics in Medicine  

    Purpose:Precise genetic diagnosis of inherited bone marrow failure syndromes (IBMFS), a heterogeneous group of genetic disorders, is challenging but essential for precise clinical decision making.Methods:We analyzed 121 IBMFS patients using a targeted sequencing covering 184 associated genes and 250 IBMFS patients using whole-exome sequencing (WES).Results:We achieved successful genetic diagnoses for 53 of 121 patients (44%) using targeted sequencing and for 68 of 250 patients (27%) using WES. In the majority of cases (targeted sequencing: 45/53, 85%; WES: 63/68, 93%), the detected variants were concordant with, and therefore supported, the clinical diagnoses. However, in the remaining 13 cases (8 patients by target sequencing and 5 patients by WES), the clinical diagnoses were incompatible with the detected variants.Conclusion:Our approach utilizing targeted sequencing and WES achieved satisfactory diagnostic rates and supported the efficacy of massive parallel sequencing as a diagnostic tool for IBMFS.Genet Med advance online publication 19 January 2017.

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  81. Recurrent MYB rearrangement in blastic plasmacytoid dendritic cell neoplasm 査読有り

    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   31 巻 ( 7 ) 頁: 1629 - 1633   2017年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Leukemia  

    DOI: 10.1038/leu.2017.101

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  82. Common Variable Immunodeficiency Caused by FANC Mutations 査読有り

    Sekinaka Y., Mitsuiki N., Imai K., Yabe M., Yabe H., Mitsui-Sekinaka K., Honma K., Takagi M., Arai A., Yoshida K., Okuno Y., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Muramatsu H., Kojima S., Hira A., Takata M., Ohara O., Ogawa S., Morio T., Nonoyama S.

    Journal of Clinical Immunology   37 巻 ( 5 ) 頁: 434 - 444   2017年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Immunology  

    Common variable immunodeficiency (CVID) is the most common adult-onset primary antibody deficiency disease due to various causative genes. Several genes, which are known to be the cause of different diseases, have recently been reported as the cause of CVID in patients by performing whole exome sequencing (WES) analysis. Here, we found FANC gene mutations as a cause of adult-onset CVID in two patients. B cells were absent and CD4+ T cells were skewed toward CD45RO+ memory T cells. T-cell receptor excision circles (TRECs) and signal joint kappa-deleting recombination excision circles (sjKRECs) were undetectable in both patients. Both patients had no anemia, neutropenia, or thrombocytopenia. Using WES, we identified compound heterozygous mutations of FANCE in one patient and homozygous mutation of FANCA in another patient. The impaired function of FANC protein complex was confirmed by a monoubiquitination assay and by chromosome fragility test. We then performed several immunological evaluations including quantitative lymphocyte analysis and TRECs/sjKRECs analysis for 32 individuals with Fanconi anemia (FA). In total, 22 FA patients (68.8%) were found to have immunological abnormalities, suggesting that such immunological findings may be common in FA patients. These data indicate that FANC mutations are involved in impaired lymphogenesis probably by the accumulation of DNA replication stress, leading to CVID. It is important to diagnose FA because it drastically changes clinical management. We propose that FANC mutations can cause isolated immunodeficiency in addition to bone marrow failure and malignancy.

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  83. Efficacy of neutrophil non-muscle myosin heavy chain-IIA immunofluorescence analysis in determining the pathogenicity of MYH9 variants 査読有り

    Kunishima S., Yusuke O., Muramatsu H., Kojima D., Nagai N., Takahashi Y., Kojima S.

    Annals of Hematology   96 巻 ( 6 ) 頁: 1065 - 1066   2017年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Annals of Hematology  

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  84. Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome 査読有り

    Takagi M., Ogata S., Ueno H., Yoshida K., Yeh T., Hoshino A., Piao J., Yamashita M., Nanya M., Okano T., Kajiwara M., Kanegane H., Muramatsu H., Okuno Y., Shiraishi Y., Chiba K., Tanaka H., Bando Y., Kato M., Hayashi Y., Miyano S., Imai K., Ogawa S., Kojima S., Morio T.

    Journal of Allergy and Clinical Immunology   139 巻 ( 6 ) 頁: 1914 - 1922   2017年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Allergy and Clinical Immunology  

    Background Autoimmune diseases in children are rare and can be difficult to diagnose. Autoimmune lymphoproliferative syndrome (ALPS) is a well-characterized pediatric autoimmune disease caused by mutations in genes associated with the FAS-dependent apoptosis pathway. In addition, various genetic alterations are associated with the ALPS-like phenotype. Objective The aim of the present study was to elucidate the genetic cause of the ALPS-like phenotype. Methods Candidate genes associated with the ALPS-like phenotype were screened by using whole-exome sequencing. The functional effect of the identified mutations was examined by analyzing the activity of related signaling pathways. Results A de novo heterozygous frameshift mutation of TNF-α–induced protein 3 (TNFAIP3, A20), a negative regulator of the nuclear factor κB pathway, was identified in one of the patients exhibiting the ALPS-like phenotype. Increased activity of the nuclear factor κB pathway was associated with haploinsufficiency of TNFAIP3 (A20). Conclusion Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.

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  85. Reticular dysgenesis: International survey on clinical presentation, transplantation, and outcome 査読有り

    Hoenig M., Lagresle-Peyrou C., Pannicke U., Notarangelo L.D., Porta F., Gennery A.R., Slatter M., Cowan M.J., Stepensky P., Al-Mousa H., Al-Zahrani D., Pai S.Y., Al Herz W., Gaspar H.B., Veys P., Oshima K., Imai K., Yabe H., Noroski L.M., Wulffraat N.M., Sykora K.W., Soler-Palacin P., Muramatsu H., Al Hilali M., Moshous D., Debatin K.M., Schuetz C., Jacobsen E.M., Schulz A.S., Schwarz K., Fischer A., Friedrich W., Cavazzana M.

    Blood   129 巻 ( 21 ) 頁: 2928 - 2938   2017年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood  

    Reticular dysgenesis (RD) is a rare congenital disorder defined clinically by the combination of severe combined immunodeficiency (SCID), agranulocytosis, and sensorineural deafness. Mutations in the gene encoding adenylate kinase 2 were identified to cause the disorder. Hematopoietic stem cell transplantation (HSCT) is the only option to cure this otherwise fatal disease.Retrospective data on clinical presentation, genetics, and outcome of HSCT were collected from centers in Europe, Asia, and North America for a total of 32 patients born between 1982 and 2011.Age at presentationwas <4 weeks in 30 of 32 patients (94%). Grafts originated frommismatched family donors in 17 patients (55%), frommatched family donors in 6 patients (19%), and from unrelated marrow or umbilical cord blood donors in 8 patients (26%). Thirteen patients received secondary or tertiary transplants. After transplantation, 21 of 31 patients were reported alive at a mean follow-up of 7.9 years (range: 0.6-23.6 years). All patients who died beyond 6 months after HSCT had persistent or recurrent agranulocytosis due to failure of donor myeloid engraftment. In the absence of conditioning, HSCT was ineffective to overcome agranulocytosis, and inclusion of myeloablativecomponents in theconditioningregimenswasrequiredtoachievestable lymphomyeloidengraftment. Incomparisonwith other SCID entities, considerable differences were noted regarding age at presentation, onset, and type of infectious complications, as well as the requirement of conditioning prior toHSCT.Although long-termsurvival is possible in the presence ofmixed chimerism, highlevel donor myeloid engraftment should be targeted to avoid posttransplant neutropenia.

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  86. Germline IKAROS mutation associated with primary immunodeficiency that progressed to T-cell acute lymphoblastic leukemia 査読有り

    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   31 巻 ( 5 ) 頁: 1221 - 1223   2017年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Leukemia  

    DOI: 10.1038/leu.2017.25

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  87. Long-term outcomes of 95 children with moderate aplastic anemia treated with horse antithymocyte globulin and cyclosporine 査読有り

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

    Pediatric Blood and Cancer   64 巻 ( 5 )   2017年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pediatric Blood and Cancer  

    Background: Currently, the standard management of moderate aplastic anemia (MAA) has not been well described, although the superiority of the combination of antithymocyte globulin (ATG) and cyclosporine (CyA) over CyA alone has been demonstrated in terms of hematological responses and failure-free survival (FFS). Procedure: We adopted this therapeutic strategy and treated 95 children with MAA who were enrolled in two consecutive prospective studies between October 1992 and August 2009. Results: For these patients, the 6-month response rate was 54.7% (complete response, 13.7%; partial response, 41.1%). There were no statistically significant differences in the overall response rates between the transfusion-dependent (48.8%, n = 41) and transfusion-independent groups (59.3%, n = 54; P = 0.4). Treatment failure was defined as the requirement of salvage treatment, and was observed in 52 patients. The 10-year FFS was 44.0% (95% confidence interval [CI], 32.9%–54.6%). Of the 22 patients who underwent a second immunosuppressive therapy (IST), 12 responded. Forty patients underwent hematopoietic stem cell transplantation as second- or third-line therapy and three died of complications. Consequently, the 10-year overall survival rate was 96.0% (95% CI, 88.0%–98.7%) with a median follow-up period of 103 months (range, 29–221 months). Conclusions: Although current guidelines recommend only observation for patients with transfusion-independent MAA, the results of our study justify early intervention with ATG and CyA in those patients. A prospective randomized trial is warranted to clarify the risks and benefits of early intervention with IST and observation alone until progression to severe AA in patients with MAA.

    DOI: 10.1002/pbc.26305

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  88. Diagnostic challenge of Diamond–Blackfan anemia in mothers and children by whole-exome sequencing 査読有り

    Ichimura T., Yoshida K., Okuno Y., Yujiri T., Nagai K., Nishi M., Shiraishi Y., Ueno H., Toki T., Chiba K., Tanaka H., Muramatsu H., Hara T., Kanno H., Kojima S., Miyano S., Ito E., Ogawa S., Ohga S.

    International Journal of Hematology   105 巻 ( 4 ) 頁: 515 - 520   2017年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    Diamond–Blackfan anemia (DBA) is a pure red cell aplasia that arises from defective ribosomal proteins (RPs). Patients with this rare ribosomopathy present with neonatal anemia and occasional dysmorphism. Clinical heterogeneity and clusters of causative RP genes hamper the diagnosis and perinatal management. We report three mother-and-child pairs of anemia who were finally diagnosed by whole-exome sequencing. Each pair showed distinct disease severity and response to anemia treatment. Only one mother had the diagnostic dysmorphism, including short stature, webbed neck, and thenar hypoplasia. This mother had a frame-shift mutation of RPL11 (exon 3, c.58_59del). Her infant showed transient neonatal anemia, but had no mutations of RP genes. The other mother–child pairs had a missense mutation of RPS19 (exon 4, c.185G>A), and a splicing error of RPS7 (exon 3, c.76-1G>T), respectively. Other than the reported mutations, there were no variants in genes significantly associated with anemia. Our results suggested that whole-exome sequencing (WES) is effective for achieving a prompt and correct diagnosis of human ribosomopathy.

    DOI: 10.1007/s12185-016-2151-7

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  89. Exome sequencing identified RPS15A as a novel causative gene for Diamond-Blackfan anemia 査読有り

    Ikeda F., Yoshida K., Toki T., Uechi T., Ishida S., Nakajima Y., Sasahara Y., Okuno Y., Kanezaki R., Terui K., Kamio T., Kobayashi A., Fujita T., Sato-Otsubo A., Shiraishi Y., Tanaka H., Chiba K., Muramatsu H., Kanno H., Ohga S., Ohara A., Kojima S., Kenmochi N., Miyano S., Ogawa S., Ito E.

    Haematologica   102 巻 ( 3 ) 頁: e93 - e96   2017年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Haematologica  

    DOI: 10.3324/haematol.2016.153932

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  90. Recurrent cellulitis caused by Helicobacter cinaedi in a patient with X-linked agammaglobulinaemia 査読有り

    Sugimoto M., Takeichi T., Muramatsu H., Kojima D., Osada Y., Kono M., Kojima S., Akiyama M.

    Acta Dermato-Venereologica   97 巻 ( 2 ) 頁: 277 - 278   2017年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Acta Dermato-Venereologica  

    DOI: 10.2340/00015555-2501

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  91. Clinical utility of next-generation sequencing-based minimal residual disease in paediatric B-cell acute lymphoblastic leukaemia 査読有り

    Sekiya Y., Xu Y., Muramatsu H., Okuno Y., Narita A., Suzuki K., Wang X., Kawashima N., Sakaguchi H., Yoshida N., Hama A., Takahashi Y., Kato K., Kojima S.

    British Journal of Haematology   176 巻 ( 2 ) 頁: 248 - 257   2017年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:British Journal of Haematology  

    We assessed the clinical utility of next-generation sequencing (NGS)-based monitoring of minimal residual disease (MRD) in a uniformly treated cohort of 79 patients with paediatric B-cell acute lymphoblastic leukaemia. Bone marrow samples were collected at the time of diagnosis, days 33 and 80, pre- (4–5 months) and post- (24 months) maintenance therapy time points, and at relapse. We identified leukaemia-specific CDR3 sequences in 72 of 79 patients (91%) and detected MRD in 59 of 232 samples. Although MRD was detected in 28 of 55 samples (51%) on day 33, the frequencies of MRD detection decreased to 25% (16/65) at day 80, 19% (11/58) at 4–5 months and 7·4% (4/54) at 24 months. In a univariate analysis, positive MRD results on day 80 [relative risk (RR) 95% confidence interval (CI) = 7·438 (2·561–21·6), P < 0·001], at 4–5 months [RR (95% CI) = 10·24 (3·374–31·06), P < 0·001], and at 24 months [RR (95% CI) = 19·26 (4·974–74·59), P < 0·001] exhibited statistically significant associations with inferior leukaemia-free survival; this was confirmed using a Cox proportional hazard model. Our study suggests the promising potential of NGS-MRD for patients with B-cell ALL.

    DOI: 10.1111/bjh.14420

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  92. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome–like immunodeficiency 査読有り

    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   138 巻 ( 6 ) 頁: 1672 - 1680.e10   2016年12月

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    記述言語:日本語   出版者・発行元:Journal of Allergy and Clinical Immunology  

    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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  93. Allogeneic hematopoietic stem cell transplantation for dyskeratosis congenita 査読有り

    Elmahadi S., Muramatsu H., Kojima S.

    Current Opinion in Hematology   23 巻 ( 6 ) 頁: 501 - 507   2016年11月

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    記述言語:日本語   出版者・発行元:Current Opinion in Hematology  

    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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  94. Successful T-cell reconstitution after unrelated cord blood transplantation in a patient with complete DiGeorge syndrome 査読有り

    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   138 巻 ( 5 ) 頁: 1471 - 1473.e4   2016年11月

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    記述言語:日本語   出版者・発行元:Journal of Allergy and Clinical Immunology  

    DOI: 10.1016/j.jaci.2016.04.048

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  95. The phenotype and clinical course of Japanese Fanconi Anaemia infants is influenced by patient, but not maternal ALDH2 genotype 査読有り

    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   175 巻 ( 3 ) 頁: 457 - 461   2016年11月

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    記述言語:日本語   出版者・発行元:British Journal of Haematology  

    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.

    DOI: 10.1111/bjh.14243

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  96. MEF2D-BCL9 fusion gene is associated with high-risk acute B-cell precursor lymphoblastic leukemia in adolescents 査読有り

    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   34 巻 ( 28 ) 頁: 3451 - 3459   2016年10月

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    記述言語:日本語   出版者・発行元:Journal of Clinical Oncology  

    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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  97. JAK2, MPL, and CALR mutations in children with essential thrombocythemia 査読有り

    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   104 巻 ( 2 ) 頁: 266 - 267   2016年8月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    DOI: 10.1007/s12185-016-2022-2

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  98. Application of extensively targeted next-generation sequencing for the diagnosis of primary immunodeficiencies 査読有り

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

    Journal of Allergy and Clinical Immunology   138 巻 ( 1 ) 頁: 303 - 305.e3   2016年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Allergy and Clinical Immunology  

    DOI: 10.1016/j.jaci.2016.01.012

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  99. PIEZO1 gene mutation in a Japanese family with hereditary high phosphatidylcholine hemolytic anemia and hemochromatosis-induced diabetes mellitus 査読有り

    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   104 巻 ( 1 ) 頁: 125 - 129   2016年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    Hereditary xerocytosis (HX) or dehydrated hereditary stomatocytosis (DHS) [OMIM 194380], in which PIEZO1 gene mutation has recently been identified, is difficult to diagnose. We report here the discovery of a PIEZO1 gene mutation in a Japanese family (father, daughter, and son) who were previously diagnosed with hereditary high phosphatidylcholine hemolytic anemia (HPCHA). All of the affected family members had non-spherocytic hemolytic anemia associated with severe hemochromatosis-related diabetes mellitus. Although the causative correlation between HPCHA and PIEZO1-gene mutated HX/DHS remains to be clarified, our findings raise an important question as to whether any of the HPCHA cases previously diagnosed in Japan may have in fact been the form of hemolytic anemia known as HX/DHS with PIEZO1 gene mutation.

    DOI: 10.1007/s12185-016-1970-x

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  100. Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia 査読有り

    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   14 巻 ( 7 ) 頁: 1462 - 1469   2016年7月

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    記述言語:日本語   出版者・発行元:Journal of Thrombosis and Haemostasis  

    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.

    DOI: 10.1111/jth.13350

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  101. Immunosuppressive therapy for patients with Down syndrome and idiopathic aplastic anemia 査読有り

    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   104 巻 ( 1 ) 頁: 130 - 133   2016年7月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    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.

    DOI: 10.1007/s12185-016-1997-z

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  102. Genetic predisposition to pediatric myeloid malignancies 査読有り

    Muramatsu H.

    [Rinsho ketsueki] The Japanese journal of clinical hematology   57 巻 ( 6 ) 頁: 730 - 735   2016年6月

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    記述言語:日本語   出版者・発行元:[Rinsho ketsueki] The Japanese journal of clinical hematology  

    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.

    DOI: 10.11406/rinketsu.57.730

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

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

    Pediatric Blood and Cancer   63 巻 ( 4 ) 頁: 659 - 664   2016年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pediatric Blood and Cancer  

    Background: Immunosuppressive therapy (IST) is commonly used for patients with acquired severe aplastic anemia (SAA). Because the clinical response rate and therapeutic outcome for individual patients to IST varies, an in vitro test that identifies potential responders would be desirable. Methods: We evaluated the relationship between thrombopoietin (TPO) levels at the time of diagnosis and the response to IST at 6 months in 85 children (median age, 9.0 years; range, 1.0-15.5 years) with acquired SAA using enzyme-linked immunosorbent assay. Thirty-one age-matched healthy individuals were used as controls. All patients received antithymocyte globulin and cyclosporine. Results: Overall, 39 patients (45.9%) responded to IST at 6 months. TPO plasma levels were significantly higher in nonresponders than in responders (1,555.8 vs. 1,284.7 pg/ml, respectively; P = 0.031). Multivariate analysis identified the TPO levels of >1,796.7 pg/ml (TPO-high group, 20 patients; odds ratio (OR), 8.285; 95% confidence interval (CI), 2.114-32.904; P = 0.002) as independent poor predictors of IST response at 6 months. Moreover, the TPO-high group was associated with lower 5-year failure-free survival rates (30% vs. 68%, P = 0.012) compared with the TPO-low group. Conclusion: The measurement of TPO levels at diagnosis is useful for predicting the response to IST in children with SAA and may help in decision making.

    DOI: 10.1002/pbc.25820

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  104. A Cytokine-Based Diagnostic Program in Pediatric Aplastic Anemia and Hypocellular Refractory Cytopenia of Childhood 査読有り

    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 and Cancer   63 巻 ( 4 ) 頁: 652 - 658   2016年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pediatric Blood and Cancer  

    Background: Distinguishing hypocellular refractory cytopenia of childhood (RCC) from aplastic anemia (AA) is challenging. Thus far, no studies have compared the cytokine profiles in patients with AA to those with hypocellular RCC. In the present study, we addressed whether thrombopoietin (TPO) and interleukin 17 (IL-17) plasma levels are useful for differentiating between the two diseases. Methods: We measured the endogenous plasma concentrations of TPO and IL-17 in 29 patients with AA, 34 patients with hypocellular RCC, and 31 healthy controls using sensitive enzyme-linked immunosorbent assays. Results: The TPO and IL-17 plasma levels were significantly lower in patients with hypocellular RCC than in patients with AA (P < 0.001 and P = 0.007, respectively). The multivariate logistic regression analysis identified moderate disease severity, TPO levels of <1,369.8 pg/ml (TPO-low group, n = 32; odds ratio (OR), 13.40; 95% confidence intervals (CI), 3.001-51.254; P < 0.001), and IL-17 levels of <22.2 pg/ml (IL-17-low group, n = 33; OR, 4.11; 95% CI, 1.033-19.404; P = 0.031) as independent factors discriminating hypocellular RCC from AA. Importantly, 25 (78.1%) of 32 patients in the TPO-low group and 25 (75.8%) of 33 patients in the IL-17-low group were diagnosed as having hypocellular RCC. Moreover, 22 (71%) of 31 patients in the TPO-high group and 21 (70%) of 30 patients in the IL-17-high group were diagnosed as having AA. Conclusions: TPO and IL-17 levels are useful for differentiating hypocellular RCC from AA. Prospective studies are required to confirm our findings.

    DOI: 10.1002/pbc.25799

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  105. Leukostasis in Children and Adolescents with Chronic Myeloid Leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group 査読有り

    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 and Cancer   63 巻 ( 3 ) 頁: 406 - 411   2016年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pediatric Blood and Cancer  

    Background: The details of leukostasis in children and adolescents with chronic myeloid leukemia (CML) are unknown. This study determined the characteristics of leukostasis in children and adolescents with CML. Procedure: A total of 256 cases from a retrospective study of patients with CML conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group from 1996 to 2011 were analyzed, and of these, 238 cases were evaluated in this study. Results: Leukostasis was diagnosed in 23 patients (9.7%). The median leukocyte count and spleen size below the left costal margin in cases with leukostasis were significantly higher and larger when compared to those in cases without leukostasis (458.5 × 109/l vs. 151.8 × 109/l (P < 0.01), and 13 vs. 5 cm (P < 0.01), respectively). Leukostasis occurred with ocular symptoms in 14 cases, priapism in four cases, and dyspnea, syncope, headache, knee pain, difficulty hearing, and aseptic necrosis of the femoral head in one case each. One case had two leukostasis symptoms simultaneously. Three cases were diagnosed before imatinib became available. Five cases received special treatment, and in the remaining 15 cases, all of these symptoms resolved after treatment with imatinib. Conclusions: This retrospective study represents the largest series of children and adolescents in which leukostasis of CML has been reported. Our data provide useful insight into the characteristics of leukostasis in recent cases of children and adolescents with CML.

    DOI: 10.1002/pbc.25803

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  106. Correlation of rabbit antithymocyte globulin serum levels and clinical outcomes in children who received hematopoietic stem cell transplantation from an alternative donor 査読有り

    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   20 巻 ( 1 ) 頁: 105 - 113   2016年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pediatric Transplantation  

    We analyzed the correlation between rabbit ATG (rATG) serum levels and clinical outcomes in 37 children who received rATG at a total dose of 10 or 15 mg/kg during HSCT conditioning from an alternative donor. Fourteen patients had advanced malignant diseases, 13 had severe AA, and 10 had inherited disorders. Complete engraftment was achieved in all patients, and no rejection occurred. The cumulative incidence of grades II-IV acute GVHD and extensive chronic GVHD was 27% (95% CI, 12.5-39.6%) and 8.1% (95% CI, 0-23.1%), respectively. Multivariate analysis identified lower rATG levels at week 4 as an independent risk factor in the development of grades II-IV acute GVHD (p = 0.037). Serious infections were not observed in any patient following HSCT. No correlation was found between EBV reactivation and rATG levels at week 2 and week 4 after HSCT. Furthermore, no correlation was found between relapse and rATG levels two and four wk post-transplantation. The probability of five-yr OS among patients was 70.3% (95% CI, 59.8-79.2%). Our results suggest that targeted rATG administration may protect patients from severe acute GVHD without increasing the risk of EBV reactivation or relapse.

    DOI: 10.1111/petr.12620

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

    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   137 巻 ( 2 ) 頁: 619 - 622.e1   2016年2月

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    記述言語:日本語   出版者・発行元:Journal of Allergy and Clinical Immunology  

    DOI: 10.1016/j.jaci.2015.06.028

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  108. Abnormal urinalysis on day 7 in patients with IgA vasculitis (Henoch-Schönlein purpura) 査読有り

    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   78 巻 ( 4 ) 頁: 359 - 367   2016年

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    記述言語:日本語   出版者・発行元:Nagoya Journal of Medical Science  

    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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  109. Aberrant DNA methylation is associated with a poor outcome in Juvenile myelomonocytic leukemia 査読有り

    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 J.P., Kojima S.

    PLoS ONE   10 巻 ( 12 ) 頁: e0145394   2015年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLoS ONE  

    Juvenile myelomonocytic leukemia (JMML), an overlap of myelodysplastic/myeloproliferative neoplasm, is an intractable pediatric myeloid neoplasm. Epigenetic regulation of transcription, particularly by CpG methylation, plays an important role in tumor progression, mainly by repressing tumor-suppressor genes. To clarify the clinical importance of aberrant DNA methylation, we studied the hypermethylation status of 16 target genes in the genomes of 92 patients with JMML by bisulfite conversion and the pryosequencing technique. Among 16 candidate genes, BMP4, CALCA, CDKN2A, and RARB exhibited significant hypermethylation in 72% (67/92) of patients. Based on the number of hypermethylated genes, patients were stratified into three cohorts based on an aberrant methylation score (AMS) of 0, 1-2, or 3-4. In the AMS 0 cohort, the 5-year overall survival (OS) and transplantation-free survival (TFS) were good (69% and 76%, respectively). In the AMS 1-2 cohort, the 5-year OS was comparable to that in the AMS 0 cohort (68%), whereas TFS was poor (6%). In the AMS 3-4 cohort, 5-year OS and TFS were markedly low (8% and 0%, respectively). Epigenetic analysis provides helpful information for clinicians to select treatment strategies for patients with JMML. For patients with AMS 3-4 in whom hematopoietic stem cell transplantation does not improve the prognosis, alternative therapies, including DNA methyltransferase inhibitors and new molecular-targeting agents, should be established as treatment options.

    DOI: 10.1371/journal.pone.0145394

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  110. Serial investigation of PTPN11 mutation in nonhematopoietic tissues in a patient with juvenile myelomonocytic leukemia who was treated with unrelated cord blood transplantation 査読有り

    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   102 巻 ( 6 ) 頁: 719 - 722   2015年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    After allogeneic stem-cell transplantation, nonhematopoietic tissues contain donor-derived cells; however, whether cells from malignant hematological disease can also be found in nonhematopoietic tissues is unclear. This report describes a juvenile myelomonocytic leukemia (JMML) case with a typical PTPN11 mutation (p.E76K) at different allele frequencies in the bone marrow mononuclear cells, buccal smear cells, and fingernails at diagnosis, which was suggestive of PTPN11 somatic mosaicism; however, the PTPN11 mutation in the buccal smear cells and fingernails was lost after unrelated cord blood transplantation. These results suggest that JMML-derived cells may migrate into and reside in nonhematopoietic tissues and furthermore that these cells can be eradicated by cord blood transplantation.

    DOI: 10.1007/s12185-015-1877-y

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  111. Fulminant adenovirus hepatitis after hematopoietic stem cell transplant: Retrospective real-time PCR analysis for adenovirus DNA in two cases 査読有り

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

    Journal of Infection and Chemotherapy   21 巻 ( 12 ) 頁: 857 - 863   2015年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Infection and Chemotherapy  

    Background: Viral infection is one of the major causes of mortality in patients undergoing hematopoietic stem cell transplant (HSCT). Systemic infection of adenovirus (AdV) has emerged as a not uncommon viral infection with significant morbidity and mortality as with cytomegalovirus and Epstein-Barr virus infection. Routine surveillance for these viruses has become a clinical practice and subsequent preemptive therapy improves patients' outcomes; however, the effectiveness of preemptive therapy for AdV has not been fully investigated in patients with a lethal form of AdV infection. Methods: Sequential AdV loads were retrospectively analyzed in children with fulminant AdV hepatitis after HSCT. Results: The AdV DNA became detectable (1 × 104 copies/mL) as early as 2 weeks after HSCT. These levels reached >1 × 108 copies/mL at the onset of fulminant hepatitis. However, we determined that γ-glutamyltransferase levels were elevated to >100 IU/L at least 2 weeks before the diagnosis of hepatitis. Conclusions: Our observation raises the possibility that elevated γ-glutamyltransferase could be a sentinel marker for AdV hepatitis, which prompts elaborated monitoring of AdV load and targeted treatment.

    DOI: 10.1016/j.jiac.2015.08.018

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  112. Comparison of long-term outcomes between children with aplastic anemia and refractory cytopenia of childhood who received immunosuppressive therapy with antithymocyte globulin and cyclosporine 査読有り

    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   100 巻 ( 11 ) 頁: 1426 - 1433   2015年10月

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    記述言語:日本語   出版者・発行元:Haematologica  

    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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  113. GATA2 and secondary mutations in familial myelodysplastic syndromes and pediatric myeloid malignancies 査読有り

    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   100 巻 ( 10 ) 頁: e398 - e401   2015年10月

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    記述言語:日本語   出版者・発行元:Haematologica  

    DOI: 10.3324/haematol.2015.127092

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  114. Second allogeneic hematopoietic stem cell transplantation in children with severe aplastic anemia 査読有り

    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   50 巻 ( 10 ) 頁: 1312 - 1315   2015年10月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    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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  115. Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism 査読有り

    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   35 巻 ( 7 ) 頁: 610 - 614   2015年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Immunology  

    Primary immunodeficiency disease (PID) is caused by mutations of more than two hundred immunity-related genes. In addition to the heterogeneity of the diseases, the atypical presentation of each disease caused by hypomorphic mutations or somatic mosaicism makes genetic diagnosis challenging. Next-generation sequencing tests all genes simultaneously and has proven its innovative efficacy in genomics. We describe a male PID patient without any family history of immunodeficiency. This patient suffered from recurrent infections from 1 year of age. Laboratory analysis showed hypogammaglobulinemia. T, B, and NK cells were present, but the T cell proliferative response decreased. Whole-exome sequencing analysis identified an IL2RG p.P58T missense mutation. CD8+ and CD56+ cells showed revertant somatic mosaicism to the wild-type allele. A late-onset and atypical presentation of the X-linked severe combined immunodeficiency (X-SCID) phenotype might be associated with revertant somatic mosaicism in T and NK cells. This patient is the seventh reported case of X-SCID with revertant somatic mosaicism. His classical clinical management did not result in a molecular diagnosis because of the atypical presentation. The coverage that is provided by whole-exome sequencing of most PID genes effectively excluded differential diagnoses other than X-SCID. As next-generation sequencing becomes available in clinical practice, it will enhance our knowledge of PID and rescue currently undiagnosed patients.

    DOI: 10.1007/s10875-015-0202-0

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  116. Clinical and genetic features of dyskeratosis congenita, cryptic dyskeratosis congenita, and Hoyeraal-Hreidarsson syndrome in Japan 査読有り

    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   102 巻 ( 5 ) 頁: 544 - 552   2015年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    Dyskeratosis congenita (DKC) is an inherited bone marrow failure (BMF) syndrome typified by reticulated skin pigmentation, nail dystrophy, and mucosal leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is considered to be a severe form of DKC. Unconventional forms of DKC, which develop slowly in adulthood but without the physical anomalies characteristic of DKC (cryptic DKC), have been reported. Clinical and genetic features of DKC have been investigated in Caucasian, Black, and Hispanic populations, but not in Asian populations. The present study aimed to determine the clinical and genetic features of DKC, HHS, and cryptic DKC among Japanese patients. We analyzed 16 patients diagnosed with DKC, three patients with HHS, and 15 patients with cryptic DKC. We found that platelet count was significantly more depressed than neutrophil count or hemoglobin value in DKC patients, and identified DKC patients with large deletions in the telomerase reverse transcriptase and cryptic DKC patients with RTEL1 mutations on both alleles. This led to some patients previously considered to have unclassifiable BMF being diagnosed with cDKC through identification of new gene mutations. It thus seems important from a clinical viewpoint to re-examine the clinical characteristics, frequency of genetic mutations, and treatment efficacy in DKC, HHS, and cDKC.

    DOI: 10.1007/s12185-015-1861-6

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  117. Somatic Mosaicism for a NRAS Mutation Associates with Disparate Clinical Features in RAS-associated Leukoproliferative Disease: a Report of Two Cases 査読有り

    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   35 巻 ( 5 ) 頁: 454 - 458   2015年7月

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    記述言語:日本語   出版者・発行元:Journal of Clinical Immunology  

    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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  118. 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 査読有り

    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   35 巻 ( 3 ) 頁: 244 - 248   2015年3月

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    記述言語:日本語   出版者・発行元:Journal of Clinical Immunology  

    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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  119. Germline mutation of CBL is associated with moyamoya disease in a child with juvenile myelomonocytic leukemia and Noonan syndrome-like disorder 査読有り

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

    Pediatric Blood and Cancer   62 巻 ( 3 ) 頁: 542 - 544   2015年3月

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    記述言語:日本語   出版者・発行元:Pediatric Blood and Cancer  

    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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  120. Aldehyde dehydrogenase-2 polymorphism contributes to the progression of bone marrow failure in children with idiopathic aplastic anaemia 査読有り

    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   168 巻 ( 3 ) 頁: 460 - 463   2015年2月

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    記述言語:日本語   出版者・発行元:British Journal of Haematology  

    DOI: 10.1111/bjh.13122

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  121. Choreito Formula for BK Virus-associated Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation 査読有り

    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   21 巻 ( 2 ) 頁: 319 - 325   2015年2月

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    記述言語:日本語   出版者・発行元:Biology of Blood and Marrow Transplantation  

    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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  122. Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia 査読有り

    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   100 巻 ( 12 ) 頁: 1546 - 1552   2015年

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    記述言語:日本語   出版者・発行元:Haematologica  

    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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  123. First-line treatment for severe aplastic anemia in children: Bone marrow transplantation from a matched family donor versus immunosuppressive therapy 査読有り

    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   99 巻 ( 12 ) 頁: 1784 - 1791   2014年12月

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    記述言語:日本語   出版者・発行元:Haematologica  

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

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

    International Journal of Hematology   100 巻 ( 5 ) 頁: 502 - 506   2014年11月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    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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  125. Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia 査読有り

    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   99 巻 ( 8 ) 頁: 1312 - 1316   2014年8月

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    記述言語:日本語   出版者・発行元:Haematologica  

    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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  126. Bloodstream Infection after Stem Cell Transplantation in Children with Idiopathic Aplastic Anemia 査読有り

    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   20 巻 ( 8 ) 頁: 1145 - 1149   2014年8月

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    記述言語:日本語   出版者・発行元:Biology of Blood and Marrow Transplantation  

    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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  127. Whole-exome sequence analysis of ataxia telangiectasia-like phenotype 査読有り

    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   340 巻 ( 1-2 ) 頁: 86 - 90   2014年5月

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    記述言語:日本語   出版者・発行元:Journal of the Neurological Sciences  

    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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  128. Immunosuppressive therapy with horse anti-thymocyte globulin and cyclosporine as treatment for fulminant aplastic anemia in children 査読有り

    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   93 巻 ( 5 ) 頁: 747 - 752   2014年5月

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    記述言語:日本語   出版者・発行元:Annals of Hematology  

    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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  129. Reduced intensity conditioning in allogeneic stem cell transplantation for AML with Down syndrome 査読有り

    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   61 巻 ( 5 ) 頁: 925 - 927   2014年5月

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    記述言語:日本語   出版者・発行元:Pediatric Blood and Cancer  

    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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  130. A novel WTX mutation in a female patient with osteopathia striata with cranial sclerosis and hepatoblastoma 査読有り

    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   164 巻 ( 4 ) 頁: 998 - 1002   2014年4月

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    記述言語:日本語   出版者・発行元:American Journal of Medical Genetics, Part A  

    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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  131. Long-term outcome after immunosuppressive therapy with horse or rabbit antithymocyte globulin and cyclosporine for severe aplastic anemia in children 査読有り

    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   99 巻 ( 4 ) 頁: 664 - 671   2014年4月

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    記述言語:日本語   出版者・発行元:Haematologica  

    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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  132. Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis 査読有り

    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   95 巻 ( 4 ) 頁: 667 - 676   2014年4月

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    記述言語:日本語   出版者・発行元:Journal of Leukocyte Biology  

    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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  133. RUNX1 mutation associated with clonal evolution in relapsed pediatric acute myeloid leukemia with t(16;21)(p11;q22) 査読有り

    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   99 巻 ( 2 ) 頁: 169 - 174   2014年2月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

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

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

    Journal of Pediatric Hematology/Oncology   36 巻 ( 1 )   2014年1月

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    記述言語:日本語   出版者・発行元:Journal of Pediatric Hematology/Oncology  

    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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  135. Erratum: The landscape of somatic mutations in Down syndrome-related myeloid disorders (Nature Genetics (2013) 45 (1293-1299)) 査読有り

    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   45 巻 ( 12 )   2013年12月

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    記述言語:日本語   出版者・発行元:Nature Genetics  

    DOI: 10.1038/ng1213-1516

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  136. The landscape of somatic mutations in Down syndrome-related myeloid disorders 査読有り

    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   45 巻 ( 11 ) 頁: 1293 - 1301   2013年11月

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    記述言語:日本語   出版者・発行元:Nature Genetics  

    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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  137. Paroxysmal cold hemoglobinuria caused by an IgM-class Donath-Landsteiner antibody 査読有り

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

    Pediatrics International   55 巻 ( 5 ) 頁: 664 - 666   2013年10月

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    記述言語:日本語   出版者・発行元:Pediatrics International  

    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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  138. B-cell function after unrelated umbilical cord blood transplantation using a minimal-intensity conditioning regimen in patients with X-SCID 査読有り

    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   98 巻 ( 3 ) 頁: 355 - 360   2013年9月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    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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  139. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia 査読有り

    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   45 巻 ( 8 ) 頁: 937 - 941   2013年8月

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    記述言語:日本語   出版者・発行元:Nature Genetics  

    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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  140. Somatic SETBP1 mutations in myeloid malignancies 査読有り

    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   45 巻 ( 8 ) 頁: 942 - 946   2013年8月

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    記述言語:日本語   出版者・発行元:Nature Genetics  

    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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  141. Correlation of cyp2c19 phenotype with voriconazole plasma concentration in children 査読有り

    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   35 巻 ( 5 )   2013年7月

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    記述言語:日本語   出版者・発行元:Journal of Pediatric Hematology/Oncology  

    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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  142. 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 査読有り

    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   172 巻 ( 6 ) 頁: 833 - 837   2013年6月

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    記述言語:日本語   出版者・発行元:European Journal of Pediatrics  

    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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  143. Congenital dyserythropoietic anemia type 1 with a novel mutation in the CDAN1 gene previously diagnosed as congenital hemolytic anemia 査読有り

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

    International Journal of Hematology   97 巻 ( 5 ) 頁: 650 - 653   2013年5月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

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

    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   48 巻 ( 5 ) 頁: 737 - 739   2013年5月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    DOI: 10.1038/bmt.2012.206

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  145. Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia 査読有り

    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   60 巻 ( 5 ) 頁: 836 - 841   2013年5月

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    記述言語:日本語   出版者・発行元:Pediatric Blood and Cancer  

    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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  146. ACTN1 mutations cause congenital macrothrombocytopenia 査読有り

    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   92 巻 ( 3 ) 頁: 431 - 438   2013年3月

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    記述言語:日本語   出版者・発行元:American Journal of Human Genetics  

    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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  147. Rabbit antithymocyte globulin and cyclosporine as first-line therapy for children with acquired aplastic anemia 査読有り

    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   121 巻 ( 5 ) 頁: 862 - 863   2013年1月

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    記述言語:日本語   出版者・発行元:Blood  

    DOI: 10.1182/blood-2012-11-465633

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  148. Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia 査読有り

    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   98 巻 ( 1 ) 頁: 107 - 113   2013年1月

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    記述言語:日本語   出版者・発行元:Haematologica  

    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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  149. Progressive hearing loss following acquired cytomegalovirus infection in an immunocompromised child 査読有り

    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   34 巻 ( 1 ) 頁: 89 - 92   2013年1月

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    記述言語:日本語   出版者・発行元:American Journal of Otolaryngology - Head and Neck Medicine and Surgery  

    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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  150. Mutational analysis of RNA splicing machinery components in 206 children with myeloid malignancies 査読有り

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

    Leukemia Research   36 巻 ( 12 )   2012年12月

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    記述言語:日本語   出版者・発行元:Leukemia Research  

    DOI: 10.1016/j.leukres.2012.06.002

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  151. Mutations profile of polycythemia vera and essential thrombocythemia among Japanese children 査読有り

    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   59 巻 ( 3 ) 頁: 530 - 535   2012年9月

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    記述言語:日本語   出版者・発行元:Pediatric Blood and Cancer  

    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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  152. Somatic mosaicism for oncogenic NRAS mutations in juvenile myelomonocytic leukemia 査読有り

    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   120 巻 ( 7 ) 頁: 1485 - 1488   2012年8月

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    記述言語:日本語   出版者・発行元:Blood  

    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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  153. Casitas B-cell lymphoma mutation in childhood T-cell acute lymphoblastic leukemia 査読有り

    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   36 巻 ( 8 ) 頁: 1009 - 1015   2012年8月

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    記述言語:日本語   出版者・発行元:Leukemia Research  

    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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  154. Mutation in the THPO gene is not associated with aplastic anaemia in Japanese children 査読有り

    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   158 巻 ( 4 ) 頁: 553 - 555   2012年8月

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    記述言語:日本語   出版者・発行元:British Journal of Haematology  

    DOI: 10.1111/j.1365-2141.2012.09185.x

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  155. CBL mutation-related patterns of phosphorylation and sensitivity to tyrosine kinase inhibitors 査読有り

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

    Leukemia   26 巻 ( 7 ) 頁: 1547 - 1554   2012年7月

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    記述言語:日本語   出版者・発行元:Leukemia  

    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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  156. De novo childhood myelodysplastic/myeloproliferative disease with unique molecular characteristics 査読有り

    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   158 巻 ( 1 ) 頁: 129 - 137   2012年7月

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    記述言語:日本語   出版者・発行元:British Journal of Haematology  

    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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  157. Loss of heterozygosity in 7q myeloid disorders: Clinical associations and genomic pathogenesis 査読有り

    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   119 巻 ( 25 ) 頁: 6109 - 6117   2012年6月

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    記述言語:日本語   出版者・発行元:Blood  

    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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  158. Excellent outcome of allogeneic bone marrow transplantation for Fanconi anemia using fludarabine-based reduced-intensity conditioning regimen 査読有り

    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   95 巻 ( 6 ) 頁: 675 - 679   2012年6月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    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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  159. Central nervous system lesions due to juvenile myelomonocytic leukemia progressed in a boy undergoing first line chemotherapy 査読有り

    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   95 巻 ( 5 ) 頁: 581 - 584   2012年5月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    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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  160. Incidence, clinical features, and risk factors of idiopathic pneumonia syndrome following hematopoietic stem cell transplantation in children 査読有り

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

    Pediatric Blood and Cancer   58 巻 ( 5 ) 頁: 780 - 784   2012年5月

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    記述言語:日本語   出版者・発行元:Pediatric Blood and Cancer  

    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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  161. Autoimmune-like hepatitis following unrelated BMT successfully treated with rituximab 査読有り

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

    Bone Marrow Transplantation   47 巻 ( 4 ) 頁: 600 - 602   2012年4月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    DOI: 10.1038/bmt.2011.124

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  162. Chronic myelomonocytic leukemia and atypical chronic myeloid leukemia: Novel pathogenetic lesions 査読有り

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

    Seminars in Oncology   39 巻 ( 1 ) 頁: 67 - 73   2012年2月

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    記述言語:日本語   出版者・発行元:Seminars in Oncology  

    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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  163. Molecular lesions in childhood and adult acute megakaryoblastic leukaemia 査読有り

    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   156 巻 ( 3 ) 頁: 316 - 325   2012年2月

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    記述言語:日本語   出版者・発行元:British Journal of Haematology  

    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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  164. Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia 査読有り

    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   159 巻 ( 4 ) 頁: 676 - 681   2011年10月

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    記述言語:日本語   出版者・発行元:Journal of Pediatrics  

    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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  165. Aberrant phosphorylation of STAT5 by granulocyte-macrophage colony-stimulating factor in infant cytomegalovirus infection mimicking juvenile myelomonocytic leukemia 査読有り

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

    Leukemia Research   35 巻 ( 9 ) 頁: 1261 - 1264   2011年9月

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    記述言語:日本語   出版者・発行元:Leukemia Research  

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

    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   15 巻 ( 6 ) 頁: 642 - 649   2011年9月

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    記述言語:日本語   出版者・発行元:Pediatric Transplantation  

    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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  167. [Bone marrow findings of childhood aplastic anemia: analyses of 140 cases by central reviewers]. 査読有り

    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   52 巻 ( 8 ) 頁: 653 - 658   2011年8月

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    記述言語:日本語   出版者・発行元:[Rinshō ketsueki] The Japanese journal of clinical hematology  

    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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  168. CD20-negative Epstein-Barr virus-associated post-transplant lymphoproliferative disease refractory to rituximab in a patient with severe aplastic anemia 査読有り

    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   93 巻 ( 6 ) 頁: 779 - 781   2011年6月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    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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  169. Relapse of aplastic anemia in children after immunosuppressive therapy: A report from the Japan childhood aplastic anemia study group 査読有り

    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   96 巻 ( 6 ) 頁: 814 - 819   2011年6月

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    記述言語:日本語   出版者・発行元:Haematologica  

    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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  170. Prognostic Factors for Outcomes of Pediatric Patients with Refractory or Relapsed Acute Leukemia Undergoing Allogeneic Progenitor Cell Transplantation 査読有り

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

    Biology of Blood and Marrow Transplantation   17 巻 ( 4 ) 頁: 516 - 523   2011年4月

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    記述言語:日本語   出版者・発行元:Biology of Blood and Marrow Transplantation  

    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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  171. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation 査読有り

    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   117 巻 ( 10 ) 頁: 2887 - 2890   2011年3月

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    記述言語:日本語   出版者・発行元:Blood  

    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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  172. Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita 査読有り

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

    Pediatric Transplantation   15 巻 ( 2 ) 頁: 161 - 166   2011年3月

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    記述言語:日本語   出版者・発行元:Pediatric Transplantation  

    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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  173. Analysis of mutations and recombination activity in RAG-deficient patients 査読有り

    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   138 巻 ( 2 ) 頁: 172 - 177   2011年2月

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    記述言語:日本語   出版者・発行元:Clinical Immunology  

    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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  174. Excellent outcomes of children with CML treated with imatinib mesylate compared to that in pre-imatinib era 査読有り

    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   93 巻 ( 2 ) 頁: 186 - 191   2011年2月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    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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  175. Danaparoid as the prophylaxis for hepatic veno-occlusive disease after allogeneic hematopoietic stem cell transplantation in childhood hematological malignancy 査読有り

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

    Pediatric Blood and Cancer   55 巻 ( 6 ) 頁: 1118 - 1125   2010年12月

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    記述言語:日本語   出版者・発行元:Pediatric Blood and Cancer  

    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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  176. Comparison of matched-sibling donor BMT and unrelated donor BMT in children and adolescent with acquired severe aplastic anemia 査読有り

    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   45 巻 ( 10 ) 頁: 1508 - 1513   2010年10月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    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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  177. Relationship between tacrolimus blood concentrations and clinical outcome during the first 4 weeks after SCT in children 査読有り

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

    Bone Marrow Transplantation   45 巻 ( 7 ) 頁: 1161 - 1166   2010年7月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    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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  178. Spectrum of molecular defects in juvenile myelomonocytic leukaemia includes ASXL1 mutations: Short report 査読有り

    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   150 巻 ( 1 ) 頁: 83 - 87   2010年7月

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    記述言語:日本語   出版者・発行元:British Journal of Haematology  

    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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  179. Relapse of leukemia with loss of mismatched HLA resulting from uniparental disomy after haploidentical hematopoietic stem cell transplantation 査読有り

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

    Blood   115 巻 ( 15 ) 頁: 3158 - 3161   2010年4月

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    記述言語:日本語   出版者・発行元:Blood  

    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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  180. Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia 査読有り

    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   115 巻 ( 10 ) 頁: 1969 - 1975   2010年3月

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    記述言語:日本語   出版者・発行元:Blood  

    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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  181. Outcome of 125 Children with Chronic Myelogenous Leukemia Who Received Transplants from Unrelated Donors: The Japan Marrow Donor Program 査読有り

    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   16 巻 ( 2 ) 頁: 231 - 238   2010年2月

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    記述言語:日本語   出版者・発行元:Biology of Blood and Marrow Transplantation  

    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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  182. Mutations of E3 ubiquitin ligase Cbl family members constitute a novel common pathogenic lesion in myeloid malignancies 査読有り

    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   27 巻 ( 36 ) 頁: 6109 - 6116   2009年12月

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    記述言語:日本語   出版者・発行元:Journal of Clinical Oncology  

    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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  183. Downregulation of GATA-2 and overexpression of adipogenic gene-PPARγ in mesenchymal stem cells from patients with aplastic anemia 査読有り

    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   37 巻 ( 12 ) 頁: 1393 - 1399   2009年12月

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    記述言語:日本語   出版者・発行元:Experimental Hematology  

    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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  184. 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 査読有り

    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   15 巻 ( 12 ) 頁: 1603 - 1608   2009年12月

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    記述言語:日本語   出版者・発行元:Biology of Blood and Marrow Transplantation  

    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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  185. Engraftment syndrome following allogeneic hematopoietic stem cell transplantation in children 査読有り

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

    Pediatric Transplantation   13 巻 ( 7 ) 頁: 831 - 837   2009年11月

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    記述言語:日本語   出版者・発行元:Pediatric Transplantation  

    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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  186. Successful treatment with rituximab of refractory idiopathic thrombocytopenic purpura in a patient with Kabuki syndrome 査読有り

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

    International Journal of Hematology   90 巻 ( 2 ) 頁: 174 - 176   2009年9月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    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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  187. Concurrent langerhans cell histiocytosis and nephroblastoma 査読有り

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

    Pediatric Blood and Cancer   52 巻 ( 5 ) 頁: 662 - 664   2009年5月

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    記述言語:日本語   出版者・発行元:Pediatric Blood and Cancer  

    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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  188. Natural history of transfusion-independent non-severe aplastic anemia in children 査読有り

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

    International Journal of Hematology   89 巻 ( 4 ) 頁: 409 - 413   2009年5月

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    記述言語:日本語   出版者・発行元:International Journal of Hematology  

    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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  189. Plasmacytoid dendritic cell leukemia in children 査読有り

    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   31 巻 ( 5 ) 頁: 339 - 343   2009年5月

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    記述言語:日本語   出版者・発行元:Journal of Pediatric Hematology/Oncology  

    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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  190. Late-onset non-infectious pulmonary complications following allogeneic hematopoietic stem cell transplantation in children 査読有り

    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   44 巻 ( 5 ) 頁: 303 - 308   2009年4月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    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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  191. Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia 査読有り

    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   65 巻 ( 3 ) 頁: 334 - 340   2009年3月

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    記述言語:日本語   出版者・発行元:Pediatric Research  

    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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  192. Primary infection of human herpesvirus-6 in an infant who received cord blood SCT 査読有り

    Muramatsu H., Watanabe N., Matsumoto K., Ito M., Yoshikawa T., Kato K., Kojima S.

    Bone Marrow Transplantation   43 巻 ( 1 ) 頁: 83 - 84   2009年

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    DOI: 10.1038/bmt.2008.268

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  193. Congenital erythroid and myeloid hypoplasia terminating myelodysplastic syndrome 査読有り

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

    Journal of Pediatric Hematology/Oncology   30 巻 ( 9 ) 頁: 692 - 695   2008年9月

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    記述言語:日本語   出版者・発行元: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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  194. Risk factors for early death in neonates with Down syndrome and transient leukaemia 査読有り

    Muramatsu H., Kato K., Watanabe N., Matsumoto K., Nakamura T., Horikoshi Y., Mimaya J., Suzuki C., Hayakawa M., Kojima S.

    British Journal of Haematology   142 巻 ( 4 ) 頁: 610 - 615   2008年8月

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    記述言語:日本語   出版者・発行元: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

  195. Acute megakaryoblastic leukaemia (AMKL) in children: A comparison of AMKL with and without Down syndrome 査読有り

    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   140 巻 ( 5 ) 頁: 552 - 561   2008年3月

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    記述言語:日本語   出版者・発行元: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

    Scopus

  196. Anemia in children 査読有り

    Muramatsu H., Kojima S.

    Nippon rinsho. Japanese journal of clinical medicine   66 巻 ( 3 ) 頁: 544 - 547   2008年3月

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    記述言語:日本語   出版者・発行元: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

  197. Wiskott-Aldrich syndrome is an important differential diagnosis in male infants with juvenile myelomonocytic leukemialike features 査読有り

    Watanabe N., Yoshimi A., Kamachi Y., Kawabe T., Muramatsu H., Matsumoto K., Manabe A., Kojima S., Kato K.

    Journal of Pediatric Hematology/Oncology   29 巻 ( 12 ) 頁: 836 - 838   2007年12月

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    記述言語:日本語   出版者・発行元: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

  198. Spatially and temporally regulated expression of N-acetylglucosamine-6-O-sulfotransferase during mouse embryogenesis 査読有り

    Fan Q.W., Uchimura K., Yuzawa Y., Matsuo S., Mitsuoka C., Kannagi R., Muramatsu H., Kadomatsu K., Muramatsu T.

    Glycobiology   9 巻 ( 9 ) 頁: 947 - 955   1999年9月

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    記述言語:日本語   出版者・発行元: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

  199. 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 査読有り

    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   124 巻 ( 3 ) 頁: 670 - 678   1998年9月

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    記述言語:日本語   出版者・発行元: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

    Scopus

  200. Molecular cloning and characterization of an N-acetylglucosamine-6-O- sulfotransferase 査読有り

    Uchimura K., Muramatsu H., Kadomatsu K., Fan Q.W., Kurosawa N., Mitsuoka C., Kannagi R., Habuchi O., Muramatsu T.

    Journal of Biological Chemistry   273 巻 ( 35 ) 頁: 22577 - 22583   1998年8月

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    記述言語:日本語   出版者・発行元: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

    Scopus

  201. Mouse chondroitin 6-sulfotransferase: Molecular cloning, characterization and chromosomal mapping 査読有り

    Uchimura K., Kadomatsu K., Fan Q.W., Muramatsu H., Kurosawa N., Kaname T., Yamamura K.I., Fukuta M., Habuchi O., Muramatsu T.

    Glycobiology   8 巻 ( 5 ) 頁: 489 - 496   1998年5月

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    記述言語:日本語   出版者・発行元: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

    Scopus

▼全件表示

科研費 4

  1. 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

    研究課題/研究課題番号:21K07771  2021年4月 - 2024年3月

    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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    担当区分:研究代表者 

    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    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。

  2. 骨髄不全症候群における胚細胞変異および体細胞変異の解明に基づく新規治療開発

    研究課題/研究課題番号:19H01053  2019年4月 - 2024年3月

    科学研究費助成事業  基盤研究(A)

    牧島 秀樹, 村松 秀城, 前田 高宏, 宮崎 泰司

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    担当区分:研究分担者 

    骨髄不全症は、骨髄幹細胞の低形成に起因し、輸血や造血幹細胞移植を必要とする難治性疾患である。われわれは、後天性の遺伝子異常のみならず(Yoshizato et al. N Engl J Med. 2015)、先天性の胚細胞変異が、予想以上に高頻度に高齢発症の骨髄異形成症候群において陽性であることを明らかにした(Polprasert et al. Cancer Cell. 2015)。そこで、骨髄不全症においても常識をくつがえす胚細胞異常が認められる可能性を考え、関連する体細胞変異を来す原因を明らかにし、骨髄不全症の生涯発症リスクの推定、および予測モデルの構築を可能とし、予防の可能性を提案する。
    本研究は、骨髄不全症をはじめとする血液疾患に関して、ゲノム異常を背景とした多様性をともなう点に注目し、同時に相互に共通した面をもつ疾患群である面も考慮し、臨床の現場に有用な情報を提供することを目的に、病態の背景にあるゲノム異常を解明するために計画された。治療標的となる新規異常を発見するために、本年度において、骨髄不全症を中心に関連する血液疾患あるいはその他の腫瘍性病変がヒトの一生にわたって認められることに注目し、小児例から成人例までを広く研究対象とし、胚細胞変異と体細胞変異を同時に詳細に解析した。これらの疾患群を幅広く検討し、新規胚細胞遺伝子変異および、それを背景にした体細胞変異の獲得パターンの解析を通じて、これまで詳細が不明であった発症リスク上昇のメカニズムを解明し、臨床的に有用なバイオマーカーおよび治療ターゲットを同定した。当初の計画通り、体細胞・胚細胞の由来を問わず、全ての変異について、血液疾患を持たない健常者と比較し、さらには基礎的・臨床的検討を加えることにより、①新規原因遺伝子における胚細胞変異および、それに合併する体細胞変異を発見し、②変異シグニチャーのパターンから変異原性に関わる環境要因・生活習慣を解明すると同時に、③遺伝子変異から疾患リスクを高めるバイオマーカーを抽出し、関連するメカニズムの解明を試みた。その結果、まず、成人発症の骨髄不全症において新規DDX41胚細胞変異を発見し報告した(Polprasertら)。さらには、被爆後の骨髄不全症に関連するATMのゲノム異常について新たな知見を報告した(Taguchiら)。続いて骨髄貪食症候群と関連する血液疾患において世界に先駆けて新規のHAVCR2胚細胞変異を、小児と成人の両者において検出し報告した(Polprasertら)。以上の成果により疾患リスクに関連する因子の同定が可能となった。
    当初、本研究計画時点では、骨髄不全症をはじめとする血液疾患に関して、その発症年齢が一生にわたることに注目し、胚細胞変異と体細胞変異を同時に解析することにより、予後を予測するバイオマーカーを抽出し新たな治療ターゲットを発見することを目的としていたが、骨髄不全症に関連した血液疾患や、他の固形がんなどを共同研究により解析することにより、これまで予測もできなかった、未知のゲノム異常を発見するに至った。
    具体的には、これまで欧米や日本において報告されていたDDX41胚細胞変異に関して、国際共同研究により、東南アジアから初めて症例を報告した(Polprasertら)。さらには、被爆後の骨髄不全症に関連する11番染色体上のATM異常についてを報告し(Taguchiら)、続いて骨髄貪食症候群と関連するT細胞リンパ腫において新規のHAVCR2胚細胞変異を、小児と成人の両者において報告した(Polprasertら)。この成果は、すでに多くの研究において引用されており、近く診断基準に取り入れられると評価されている。また、数千例の骨髄不全症の解析から、疾患のフェノタイプに関連したゲノム異常を明らかにして報告し(Nagataら)、そこから発展し治療関連骨髄腫瘍の原因ゲノム異常を、正常骨髄に検出するというこれまで予想もされなかった所見も得られ報告した(Katagiriら)。これらのゲノム解析の手法を固形がんにも応用した結果、全く新しいパスウェイの関与が、生活習慣に関連したがんの進展および正常組織のリモデリングにおいてゲノム異常と関連して認められることが解明され報告した(Kakiuchiら)。以上の成果により、さまざまな疾患において発症リスクに関連する因子の同定が可能となった。
    これまで明らかとなった、骨髄不全症をはじめとする血液疾患において認められた、胚細胞変異と体細胞変異を踏まえ、本年度も引き続き、疾患発症に関与する新たなゲノム異常の検出、治療効果や予後を予測するバイオマーカーの抽出および新たな治療ターゲットの発見を試みる。骨髄不全症に関連した血液疾患において培った手法を、他の固形がんなどにも応用し、さらに多数の検体を用い、国際共同研究を継続することにより、これまで発見が困難であるために治療法が開発されていない疾患において、予想だにできなかった、未知の病因・病態を明らかにする。
    具体的には、これまで欧米や日本において報告されていた胚細胞変異については、より多くの症例の検討、あるいは関連疾患の検討を行う。すでに欧米およびアジア諸国との共同研究が開始されており、さらなる成果が期待される。また、放射線、喫煙、飲酒、自己免疫反応など、疾患リスクを高める背景と関連するゲノム異常の検出が本年までに可能であったことを応用し、診断基準に取り入れられることが期待される因子を、極めて多数の検体を解析することで発見することを試みる。さらには、疾患のフェノタイプに関連した異常についても引き続き検討し、昨年度の成果を踏まえ、さまざまな疾患において胚細胞変異および体細胞変異の解析を行う。
    当初の計画以上の成果が得られており、研究を遂行する上での問題点はない。

  3. 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

    研究課題/研究課題番号:18K07816  2018年4月 - 2021年3月

    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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    担当区分:研究代表者 

    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    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。

  4. 小児再生不良性貧血の免疫抑制療法反応性を予測するバイオマーカーの開発

    研究課題/研究課題番号:15K09647  2015年4月 - 2018年3月

    科学研究費助成事業  基盤研究(C)

    村松 秀城, 奥野 友介, 小島 勢二, 奥野 友介

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    担当区分:研究代表者 

    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    小児再生不良性貧血患者113例の解析を行い、PNH血球陰性・テロメア長短縮が独立した免疫抑制療法反応の予後不良因子であることを同定した。(Haematologica 2015)。また、トロンボポイエチン(TPO)値が高値の症例では有意に反応不良であった(Pediatr Blood Cancer. 2016)。さらに先天性造血不全に関連した184遺伝子のターゲットシーケンスを開発し(Genetics in Medicine 2017)、特発性再生不良性貧血患者 181例を対象に実施したところ、26例で関連する遺伝子変異が同定され、先天性造血不全遺伝子のスクリーニングの有用性が示された。