Faculty Profiles - MURAMATSU, Hideki

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

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

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

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

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

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

Language：Japanese Publisher：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.

DOI： 10.1007/s00277-018-3517-0

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

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

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

Language：Japanese Publisher：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.

DOI： 10.1002/pbc.27459

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

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

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

Language：Japanese Publisher：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.

DOI： 10.1016/j.jaci.2018.04.032

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

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

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

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

Language：Japanese Publisher：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.

DOI： 10.7883/yoken.JJID.2018.480

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

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

Language：Japanese Publisher：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.

DOI： 10.3324/haematol.2018.207241

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

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

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

Language：Japanese Publisher：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.

DOI： 10.1038/s41598-018-25260-8

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

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

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

Language：Japanese Publisher：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.

DOI： 10.1002/pbc.27368

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

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

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

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

Language：Japanese Publisher：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.

DOI： 10.1371/journal.pone.0209595

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

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

BLOOD Vol. 132 2018.11

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

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

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

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

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

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

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

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

Language：Japanese Publisher：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.

DOI： 10.1007/s12185-018-2482-7