附属病院 とちぎ子ども医療センター

嶋田 明

シマダ アキラ  (Akira Shimada)

基本情報

所属
自治医科大学 附属病院 とちぎ子ども医療センター小児科 教授
学位
医学博士(鳥取大学)

J-GLOBAL ID
201001053900160599
researchmap会員ID
6000021501

学歴

 4

受賞

 1

論文

 170
  • Genki Yamato, Yusuke Tsumura, Hideki Muramatsu, Akira Shimada, Takahiro Imaizumi, Hiroyuki Tsukagoshi, Taeko Kaburagi, Norio Shiba, Yoshiyuki Yamada, Takao Deguchi, Tomoko Kawai, Kiminori Terui, Etsuro Ito, Kenichiro Watanabe, Yasuhide Hayashi
    Blood advances 2024年5月1日  
    Transient abnormal myelopoiesis (TAM) occurs in 10% of neonates with Down syndrome (DS). Although most patients show spontaneous resolution of TAM, early death occurs in approximately 20% of cases. Therefore, new biomarkers are needed to predict early death and determine therapeutic interventions. This study aimed to determine the association between clinical characteristics and cytokine levels in patients with TAM. A total of 128 patients with DS with TAM enrolled in the TAM-10 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group were included in this study. Five cytokine levels [interleukin (IL)-1b, IL-1 receptor agonist, IL-6, IL-8, and IL-13] were significantly higher in patients with early death than in those with non-early death. Cumulative incidence rates (CIR) of early death were significantly associated with high levels of the five cytokines. Based on unsupervised consensus clustering, patients were classified into three cytokine groups: hot-1 (n = 37), hot-2 (n = 42), and cold (n = 49). The CIR of early death was significantly different between the cytokine groups [hot-1/2 (n = 79); cold (n = 49); CIR (95% confidence interval [CI]) = 16.5% (7.9%-24.2%); 2.0% (0.0%-5.9%), P = 0.013]. Furthermore, cytokine groups (hot-1/2 vs. cold) were independent poor prognostic factors in the multivariable analysis for early death [hazard ratio (95% CI) = 19.25 (2.056-180.3), P = 0.010]. These results provide valuable information that cytokine level measurement was useful in predicting early death in patients with TAM and might help to determine the need for therapeutic interventions.
  • Mika Dofuku, Daisuke Tamura, Marina Mizobe, Koyuru Kurane, Yuriko Hayashi, Hirokazu Kimura, Akira Shimada
    Pediatrics international : official journal of the Japan Pediatric Society 66(1) e15717 2024年  
  • Takahiro Aoki, Norio Shiba, Shinichi Tsujimoto, Genki Yamato, Yusuke Hara, Shota Kato, Kenichi Yoshida, Seishi Ogawa, Yasuhide Hayashi, Shotaro Iwamoto, Tomohiko Taki, Akira Shimada, Yuka Iijima-Yamashita, Keizo Horibe, Akio Tawa, Takashi Taga, Souichi Adachi, Daisuke Tomizawa
    Pediatric blood & cancer e30803 2023年12月6日  
    CD25 is an aberrant marker expressed on the leukemic stem cell (LSC) surface and an immunotherapy target in acute myeloid leukemia (AML). However, the clinical prevalence and significance of CD25 expression in pediatric AML are unknown. High IL2RA/CD25 expression in pediatric AML showed a stem cell-like phenotype, and elevated CD25 expression was associated with lower overall survival (p < .001) and event-free survival (p < .001) in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. This finding was reproduced in AML without a core-binding factor in the Children's Oncology Group study cohort. High CD25 expression has prognostic significance in pediatric AML.
  • Yusuke Hara, Norio Shiba, Kenichi Yoshida, Genki Yamato, Taeko Kaburagi, Yuichi Shiraishi, Kentaro Ohki, Yusuke Shiozawa, Machiko Kawamura, Hirohide Kawasaki, Manabu Sotomatsu, Takumi Takizawa, Hidemasa Matsuo, Akira Shimada, Nobutaka Kiyokawa, Daisuke Tomizawa, Takashi Taga, Etsuro Ito, Keizo Horibe, Satoru Miyano, Souichi Adachi, Tomohiko Taki, Seishi Ogawa, Yasuhide Hayashi
    Genes, chromosomes & cancer 62(7) 412-422 2023年7月  
    Pediatric acute myeloid leukemia (AML) is a poor prognostic subtype of pediatric leukemia. However, the detailed characteristics of many genetic abnormalities are yet to be established in this disease. Although TP53 and RB1 are established as representative tumor suppressor genes in various cancers, alterations of these two genes, especially RB1, have not been characterized in pediatric AML. We performed next-generation sequencing in 328 pediatric AML patients from the Japanese AML-05 trial to ascertain TP53 and RB1 alterations, and their prognostic implications. We identified seven patients with TP53 alterations (2.1%) and six patients with RB1 alterations (1.8%). These alterations were found in only patients without RUNX1::RUNX1T1, CBFB::MYH11, or KMT2A rearrangements. TP53 and RB1 were frequently co-deleted with their neighboring genes PRPF8 and ELF1, respectively. Patients with TP53 alterations had significantly lower 5-year overall survival (OS; 14.3% vs. 71.4%, p < 0.001) and lower 5-year event-free survival (EFS; 0% vs. 56.3%, p < 0.001); similarly, patients with RB1 had significantly lower 5-year OS (0% vs. 71.8%, p < 0.001) and lower 5-year EFS (0% vs. 56.0%, p < 0.001) when compared to patients without these alterations. In gene expression analyses, oxidative phosphorylation, glycolysis, and protein secretion were upregulated in patients with TP53 and/or RB1 alterations. Additionally, Kaplan-Meier analysis revealed that high expressions of SLC2A5, KCNAB2, and CD300LF were related to poor OS of non-core-binding factor AML patients (p < 0.001, p = 0.001, and p = 0.021, respectively). This study will contribute to the development of risk-stratified therapy and precision medicine in pediatric AML.
  • Genki Yamato, Tomoko Kawai, Norio Shiba, Junji Ikeda, Yusuke Hara, Kentaro Ohki, Shin-Ichi Tsujimoto, Taeko Kaburagi, Kenichi Yoshida, Yuichi Shiraishi, Satoru Miyano, Nobutaka Kiyokawa, Daisuke Tomizawa, Akira Shimada, Manabu Sotomatsu, Hirokazu Arakawa, Souichi Adachi, Takashi Taga, Keizo Horibe, Seishi Ogawa, Kenichiro Hata, Yasuhide Hayashi
    Blood advances 6(11) 3207-3219 2022年6月14日  
    We investigated genome-wide DNA methylation patterns in 64 pediatric patients with acute myeloid leukemia (AML). Based on unsupervised clustering with the 567 most variably methylated cytosine guanine dinucleotide (CpG) sites, patients were categorized into 4 clusters associated with genetic alterations. Clusters 1 and 3 were characterized by the presence of known favorable prognostic factors, such as RUNX1-RUNX1T1 fusion and KMT2A rearrangement with low MECOM expression, and biallelic CEBPA mutations (all 8 patients), respectively. Clusters 2 and 4 comprised patients exhibiting molecular features associated with adverse outcomes, namely internal tandem duplication of FLT3 (FLT3-ITD), partial tandem duplication of KMT2A, and high PRDM16 expression. Depending on the methylation values of the 1243 CpG sites that were significantly different between FLT3-ITD+ and FLT3-ITD- AML, patients were categorized into 3 clusters: A, B, and C. The STAT5-binding motif was most frequently found close to the 1243 CpG sites. All 8 patients with FLT3-ITD in cluster A harbored high PRDM16 expression and experienced adverse events, whereas only 1 of 7 patients with FLT3-ITD in the other clusters experienced adverse events. PRDM16 expression levels were also related to DNA methylation patterns, which were drastically changed at the cutoff value of PRDM16/ABL1 = 0.10. The assay for transposase-accessible chromatin sequencing of AMLs supported enhanced chromatin accessibility around genomic regions, such as HOXB cluster genes, SCHIP1, and PRDM16, which were associated with DNA methylation changes in AMLs with FLT3-ITD and high PRDM16 expression. Our results suggest that DNA methylation levels at specific CpG sites are useful to support genetic alterations and gene expression patterns of patients with pediatric AML.

MISC

 94

共同研究・競争的資金等の研究課題

 6