Faculty Profiles - MURAMATSU, Hideki

Papers - MURAMATSU, Hideki

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

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

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

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

Nature Genetics Vol. 45 ( 12 ) 2013.12

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

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

Somatic SETBP1 mutations in myeloid malignancies Reviewed

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

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

Language：Japanese Publisher：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

Correlation of cyp2c19 phenotype with voriconazole plasma concentration in children Reviewed

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

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

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

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

Language：Japanese Publisher：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

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

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

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

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

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

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

Language：Japanese Publisher：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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