Faculty Profiles - TAKAHASHI, Yoshiyuki

Comparison of Clinical Characteristics of Human Metapneumovirus and Respiratory Syncytial Virus Infections in Hospitalized Young Children. Reviewed Open Access

Akinobu Taniguchi, Jun-Ichi Kawada, Kiyotaka Go, Naozumi Fujishiro, Yosuke Hosokawa, Yuki Maki, Yuichiro Sugiyama, Michio Suzuki, Takeshi Tsuji, Shin Hoshino, Hideki Muramatsu, Hiroyuki Kidokoro, Fumie Kinoshita, Akihiro Hirakawa, Yoshiyuki Takahashi, Yoshiaki Sato, Jun Natsume

Japanese journal of infectious diseases Vol. 72 ( 4 ) page： 237 - 242 2019.7

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

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

Relationship between plasma rabbit anti-thymocyte globulin level and response to immunosuppressive therapy in patients with severe aplastic anemia: Results of a multicenter, prospective, randomized study

Effects of HLA mismatch on cytomegalovirus reactivation in cord blood transplantation Open Access

Yokoyama, H; Kanda, J; Kato, S; Kondo, E; Maeda, Y; Saji, H; Takahashi, S; Onizuka, M; Onishi, Y; Ozawa, Y; Kanamori, H; Ishikawa, J; Ohno, Y; Ichinohe, T; Takanashi, M; Kato, K; Atsuta, Y; Kanda, Y; Ikegame, K; Utsunomiya, A; Kawase, T; Kim, SW; Kuwatsuka, Y; Kobayashi, T; Takatsuka, Y; Takahashi, Y; Tanaka, J; Tamaki, H; Tsuji, M; Nishida, T; Masuko, M; Matsuno, R; Murata, M; Morishima, S; Morishima, Y; Yokoyama, H; Wake, A; Watanabe, N; Ashida, T; Hoshino, T; Yabe, T; Sakamoto, K; Fuji, S; Miyamura, K; Arima, N; Kondo, E; Yoshimitsu, M; Kawamura, K; Kawata, T; Kishimoto, K; Tatara, R; Hagino, T; Fujiwara, SI; Shimomura, Y; Sakaguchi, H; Hirabayashi, S; Ishii, H; Onda, Y; Kato, I; Kawajiri, A; Shindo, T; Tokunaga, M; Nonami, A; Muranushi, H; Yoshinaga, N; Kawashima, N; Shiratori, S; Tada, Y; Tanoue, SU; Hirayama, M; Fukunaga, K; Ohbiki, M

BONE MARROW TRANSPLANTATION Vol. 54 ( 7 ) page： 1004 - 1012 2019.7

Narita, A; Muramatsu, H; Xu, YY; Nishikawa, E; Kawashima, N; Okuno, Y; Nishio, N; Hama, A; Yamazaki, H; Nakao, S; Kojima, S; Takahashi, Y

BONE MARROW TRANSPLANTATION Vol. 54 page： 29 - 29 2019.7

Narita Atsushi, Muramatsu Hideki, Xu Yinyan, Nishikawa Eri, Kawashima Nozomu, Okuno Yusuke, Nishio Nobuhiro, Hama Asahito, Yamazaki Hirohito, Nakao Shinji, Kojima Seiji, Takahashi Yoshiyuki

BONE MARROW TRANSPLANTATION Vol. 54 page： 29-29 2019.7

MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome. Reviewed International journal

Kohji Kato, Fuyuki Miya, Nanako Hamada, Yutaka Negishi, Yoko Narumi-Kishimoto, Hiroshi Ozawa, Hidenori Ito, Ikumi Hori, Ayako Hattori, Nobuhiko Okamoto, Mitsuhiro Kato, Tatsuhiko Tsunoda, Yonehiro Kanemura, Kenjiro Kosaki, Yoshiyuki Takahashi, Koh-Ichi Nagata, Shinji Saitoh

Journal of medical genetics Vol. 56 ( 6 ) page： 388 - 395 2019.6

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

BACKGROUND: In this study, we aimed to identify the gene abnormality responsible for pathogenicity in an individual with an undiagnosed neurodevelopmental disorder with megalencephaly, ventriculomegaly, hypoplastic corpus callosum, intellectual disability, polydactyly and neuroblastoma. We then explored the underlying molecular mechanism. METHODS: Trio-based, whole-exome sequencing was performed to identify disease-causing gene mutation. Biochemical and cell biological analyses were carried out to elucidate the pathophysiological significance of the identified gene mutation. RESULTS: We identified a heterozygous missense mutation (c.173C>T; p.Thr58Met) in the MYCN gene, at the Thr58 phosphorylation site essential for ubiquitination and subsequent MYCN degradation. The mutant MYCN (MYCN-T58M) was non-phosphorylatable at Thr58 and subsequently accumulated in cells and appeared to induce CCND1 and CCND2 expression in neuronal progenitor and stem cells in vitro. Overexpression of Mycn mimicking the p.Thr58Met mutation also promoted neuronal cell proliferation, and affected neuronal cell migration during corticogenesis in mouse embryos. CONCLUSIONS: We identified a de novo c.173C>T mutation in MYCN which leads to stabilisation and accumulation of the MYCN protein, leading to prolonged CCND1 and CCND2 expression. This may promote neurogenesis in the developing cerebral cortex, leading to megalencephaly. While loss-of-function mutations in MYCN are known to cause Feingold syndrome, this is the first report of a germline gain-of-function mutation in MYCN identified in a patient with a novel megalencephaly syndrome similar to, but distinct from, CCND2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. The data obtained here provide new insight into the critical role of MYCN in brain development, as well as the consequences of MYCN defects.

DOI： 10.1136/jmedgenet-2018-105487

愛知県におけるチャイルド・デス・レビュー調査から検証へ

沼口敦, 夏目淳, 齋藤伸治, 吉川哲史, 奥村彰久, 高橋義行

日本小児救急医学会雑誌 Vol. 18 ( 2 ) page： 262 - 262 2019.6

厳しい予後の告知を受け、子ども自身が終末期の意思決定を行った高校生の一例

佐々木美和, 滝良梨子, 梶山早苗, 野田弘実, 谷口理恵子, 上田一仁, 村松秀城, 高橋義行

Palliative Care Research Vol. 14 ( Suppl. ) page： S346 - S346 2019.6

Comparison of high-dose and low-dose corticosteroid therapy for refractory Mycoplasma pneumoniae pneumonia in children. Reviewed International journal Open Access

Toshihiko Okumura, Jun-Ichi Kawada, Masaharu Tanaka, Kotaro Narita, Tomonori Ishiguro, Yuji Hirayama, Sho Narahara, Genki Tsuji, Yuichiro Sugiyama, Michio Suzuki, Takeshi Tsuji, Shin Hoshino, Masahiro Nakatochi, Hideki Muramatsu, Hiroyuki Kidokoro, Yoshiyuki Takahashi, Yoshiaki Sato

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy Vol. 25 ( 5 ) page： 346 - 350 2019.5

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

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

High rates of ovarian function preservation after hematopoietic cell transplantation with melphalan-based reduced intensity conditioning for pediatric acute leukemia: an analysis from the Japan Association of Childhood Leukemia Study (JACLS). Reviewed

Hisanori Fujino, Hiroyuki Ishida, Akihiro Iguchi, Masaei Onuma, Koji Kato, Mariko Shimizu, Masahiro Yasui, Hiroyuki Fujisaki, Kazuko Hamamoto, Kana Washio, Hirotoshi Sakaguchi, Emiko Miyashita, Yuko Osugi, Etsuko Nakagami-Yamaguchi, Akira Hayakawa, Atsushi Sato, Yoshiyuki Takahashi, Keizo Horibe

International journal of hematology Vol. 109 ( 5 ) page： 578 - 583 2019.5

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

Women are at high risk of hypergonadotropic hypogonadism after hematopoietic cell transplantation (HCT). Hypogonadism is universal after irradiation or busulfan. We hypothesized that reduced intensity conditioning (RIC) might protect ovarian function after HCT. We retrospectively reviewed data from patients with acute leukemia treated according to the Japan Association of Childhood Leukemia Study and nationwide multicenter study protocol. We selected 11 female patients with acute leukemia who received first HCT with RIC, had survived for three or more years after HCT, and were aged ≥ 12 years at the last follow-up visit. Median age at diagnosis, HCT, and last visit were 8, 10, and 17 years. Six patients received HLA-matched bone marrow (BM), two HLA-mismatched BM, and three cord blood. Melphalan was used as conditioning regimen in all patients. At the last visit, six of seven post-pubertal patients at transplantation recovered menstruation, and four of four patients who underwent transplantation at the pre-pubertal began menstruation. Height z scores showed no significant reduction between pre-transplant and post-transplant. No patients received growth hormone treatment. Only one recipient displayed subclinical hypothyroidism. Melphalan-based RIC may be an encouraging option for patients with acute leukemia to avoid ovarian and endocrine dysfunction after HCT.

DOI： 10.1007/s12185-019-02627-9

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

Takashi Maeda, Yoshiaki Sato, Akihiro Hirakawa, Masahiro Nakatochi, Fumie Kinoshita, Takeshi Suzuki, Shintaro Ichimura, Ryoichi Ito, Ryuji Kudo, Michio Suzuki, Shin Hoshino, Yuichiro Sugiyama, Hideki Muramatsu, Hiroyuki Kidokoro, Jun-Ichi Kawada, Yoshiyuki Takahashi

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

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

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

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

Koshi Akahane, Atsushi Watanabe, Yoshiyuki Furuichi, Shinpei Somazu, Hiroko Oshiro, Kumiko Goi, Kazuo Sakashita, Hideki Muramatsu, Asahito Hama, Yoshiyuki Takahashi, Kenichi Koike, Seiji Kojima, Kanji Sugita, Takeshi Inukai

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

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

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

難治性マイコプラズマ肺炎に対するステロイド療法の検討

奥村俊彦, 川田潤一, 田中雅大, 成田幸太郎, 石黒智紀, 平山祐司, 楢原翔, 辻元基, 松村秀城, 城所博之, 佐藤義朗, 高橋義行, 杉山裕一朗, 鈴木道雄, 辻健史, 星野伸

日本小児科学会雑誌 Vol. 123 ( 5 ) page： 912 - 913 2019.5

左頸部の軟属腫様皮疹から診断した多臓器型Langerhans cell histiocytosis(LCH)の1例

太田早紀, 桃原真理子, 河野通浩, 秋山真志, 北澤宏展, 高橋義行

日本皮膚科学会雑誌 Vol. 129 ( 6 ) page： 1360 - 1360 2019.5

小児血液・腫瘍医からみた血液・がん疾患に関連する皮膚病変

川島希, 高橋義行

日本皮膚科学会雑誌 Vol. 129 ( 5 ) page： 1069 - 1069 2019.5

非ウイルスベクター法を用いたキメラ抗原受容体遺伝子導入T細胞(CAR-T細胞)療法の現状と展望

高橋義行

日本医学会総会会誌 Vol. 30回 page： LS - 1 2019.4

可能な限り鎮静を減らすために 4歳児が鎮静なく放射線治療ができた関わり

村嶋一歩, 佐々木美和, 野田弘実, 高橋義行

日本小児血液・がん学会雑誌 Vol. 56 ( 1 ) page： 74 - 74 2019.4

友達の死を他の患児へ伝え、グリーフケアにつなげる取り組み

牧田夏美, 佐々木美和, 萩原沙織, 和田拓哉, 森本綾, 西川英里, 高橋義行, 柴田有理, 河野智子

日本小児血液・がん学会雑誌 Vol. 56 ( 1 ) page： 74 - 75 2019.4

Discontinuation of L-asparaginase and poor response to prednisolone are associated with poor outcome of ETV6-RUNX1-positive pediatric B-cell precursor acute lymphoblastic leukemia. Reviewed

Usami I, Imamura T, Takahashi Y, Suenobu SI, Hasegawa D, Hashii Y, Deguchi T, Hori T, Shimada A, Kato K, Ito E, Moriya-Saito A, Kawasaki H, Hori H, Yumura-Yagi K, Hara J, Sato A, Horibe K, Japan, Association of Childhood Leukemia Study Group (JACLS

International journal of hematology Vol. 109 ( 4 ) page： 477 - 482 2019.4

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

ETV6-RUNX1-positive B precursor acute lymphoblastic leukemia (B-ALL) is a common subtype of pediatric B-ALL that has shown excellent outcomes in contemporary clinical trials for pediatric B-ALL. Examinations of the possibility of reducing therapeutic intensity may thus be explored. This prospective study examined outcomes in 205 pediatric patients with ETV6-RUNX1-positive B-ALL uniformly treated following the Japan Association of Childhood Leukemia Study Group (JACLS) ALL-02 protocol. The JACLS ALL-02 protocol does not employ minimal residual disease detected by polymerase chain reaction (PCR-MRD)-based risk stratification; however, 4-year event-free survival (EFS) and overall survival (OS) were 94.4 ± 1.6 and 97.5 ± 1.1%, respectively. In particular, 92 of 205 (44.9%) patients were successfully treated with a less intensive regimen involving only two cycles of high dose methotrexate and one course of re-induction therapy comprising vincristine, L-asparaginase (L-asp), pirarubicin, and prednisolone. Multivariate analysis revealed that discontinuation of L-asp and poor response to prednisolone was, respectively, associated with poor EFS (HR 6.3; 95% CI 1.3-27.0) and OS (HR 17.5; 95% CI 2.3-130), suggesting that the majority of ETV6-RUNX1-positive B-ALL cases may be cured by a less-intensive chemotherapy regimen if the risk stratification system including PCR-MRD monitoring and insufficient use of L-asp is avoided.

DOI： 10.1007/s12185-019-02599-w