研究者詳細 - 村松　秀城

論文 - 村松　秀城

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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

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.

DOI： 10.18999/nagjms.81.2.227

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

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.

DOI： 10.1016/j.jiac.2019.01.003

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

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.

DOI： 10.1111/petr.13378

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

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.

DOI： 10.1016/j.exphem.2019.03.001

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

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.

DOI： 10.1038/s41564-018-0334-0

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

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.

DOI： 10.1038/s41564-019-0387-8

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

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.

DOI： 10.1016/j.ymgmr.2018.11.001

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

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.

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 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

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.

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 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

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.

DOI： 10.1016/j.jaci.2018.04.032

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

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.

DOI： 10.7883/yoken.JJID.2018.480

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

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.

DOI： 10.3324/haematol.2018.207241

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

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.

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 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

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.

DOI： 10.1002/pbc.27368

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

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.

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 132 巻 2018年11月

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

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.

DOI： 10.1097/MPH.0000000000001061

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

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

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

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.

DOI： 10.1007/s12185-018-2482-7

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

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.

DOI： 10.1016/j.ebiom.2018.07.008

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