Language：English   Publisher：Pediatric Blood and Cancer  

Hypomethylating agent treatment for myeloid leukemia associated with Down syndrome (ML-DS) has been scarcely reported. Herein, we collected information on azacitidine treatment for ML-DS in Japan. Forty-eight cycles of azacitidine treatment were performed for 12 patients, including 11 relapsed or refractory (R/R) patients. In 40 cycles, azacitidine was used as monotherapy. No azacitidine-related death was observed. One cycle concurrently administered with methotrexate-based intrathecal therapy was discontinued due to toxicities. Only 4 of the 19 cycles given in non-remission achieved complete or partial remission. In conclusion, although most toxicities were acceptable, azacitidine monotherapy might be insufficient for R/R ML-DS cases.

DOI： 10.1002/pbc.31244

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Authorship：Lead author   Language：English   Publisher：Clinical and Experimental Immunology  

The clinical spectrum of Down syndrome (DS) ranges from congenital malformations to premature aging and early-onset senescence. Excessive immunoreactivity and oxidative stress are thought to accelerate the pace of aging in DS patients; however, the immunological profile remains elusive. We investigated whether peripheral blood monocyte-derived dendritic cells (MoDCs) in DS patients respond to lipopolysaccharide (LPS) distinctly from non-DS control MoDCs. Eighteen DS patients (age 2–47 years, 12 males) and 22 controls (age 4–40 years, 15 males) were enrolled. CD14-positive monocytes were immunopurified and cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor and IL-4, yielding MoDCs in vitro. After the LPS-stimulation for 48 hours from days 7 to 9, culture supernatant cytokines were measured by multiplex cytokine bead assays, and bulk-prepared RNA from the cells was used for transcriptomic analyses. MoDCs from DS patients produced cytokines/chemokines (IL-6, IL-8, TNF-α, MCP-1, and IP-10) at significantly higher levels than those from controls in response to LPS. RNA sequencing revealed that DS-derived MoDCs differentially expressed 137 genes (74 upregulated and 63 downregulated) compared with controls. A gene enrichment analysis identified 5 genes associated with Toll-like receptor signaling (KEGG: hsa04620, P = 0.00731) and oxidative phosphorylation (hsa00190, P = 0.0173) pathways. MoDCs obtained from DS patients showed higher cytokine or chemokine responses to LPS than did control MoDCs. Gene expression profiles suggest that hyperactive Toll-like receptor and mitochondrial oxidative phosphorylation pathways configure the immunoreactive signature of MoDCs in DS patients.

DOI： 10.1093/cei/uxae048

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Language：English   Publisher：Blood Advances  

Children with Down syndrome (DS) are at a significantly higher risk of developing acute myeloid leukemia, also termed myeloid leukemia associated with DS (ML-DS). In contrast to the highly favorable prognosis of primary ML-DS, the limited data that are available for children who relapse or who have refractory ML-DS (r/r ML-DS) suggest a dismal prognosis. There are few clinical trials and no standardized treatment approach for this population. We conducted a retrospective analysis of international study groups and pediatric oncology centers and identified 62 patients who received treatment with curative intent for r/r ML-DS between year 2000 to 2021. Median time from diagnosis to relapse was 6.8 (range, 1.1-45.5) months. Three-year event-free survival (EFS) and overall survival (OS) were 20.9 ± 5.3% and 22.1 ± 5.4%, respectively. Survival was associated with receipt of hematopoietic stem cell transplantation (HSCT) (hazard ratio [HR], 0.28), duration of first complete remission (CR1) (HR, 0.31 for > 12 months) and attainment of remission after relapse (HR, 4.03). Patients who achieved complete remission (CR) before HSCT, had an improved OS and EFS of 56.0 ± 11.8% and 50.5 ± 11.9%, respectively compared to those who underwent HSCT without CR (3-year OS and EFS of 10.0 ± 9.5%). Treatment failure after HSCT was predominantly

DOI： 10.1182/bloodadvances.2022009381

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Authorship：Lead author   Language：English   Publisher：Communications Biology  

Protection of telomeres 1a (POT1a) is a telomere binding protein. A decrease of POT1a is related to myeloid-skewed haematopoiesis with ageing, suggesting that protection of telomeres is essential to sustain multi-potency. Since mesenchymal stem cells (MSCs) are a constituent of the hematopoietic niche in bone marrow, their dysfunction is associated with haematopoietic failure. However, the importance of telomere protection in MSCs has yet to be elucidated. Here, we show that genetic deletion of POT1a in MSCs leads to intracellular accumulation of fatty acids and excessive ROS and DNA damage, resulting in impaired osteogenic-differentiation. Furthermore, MSC-specific POT1a deficient mice exhibited skeletal retardation due to reduction of IL-7 producing bone lining osteoblasts. Single-cell gene expression profiling of bone marrow from POT1a deficient mice revealed that B-lymphopoiesis was selectively impaired. These results demonstrate that bone marrow microenvironments composed of POT1a deficient MSCs fail to support B-lymphopoiesis, which may underpin age-related myeloid-bias in haematopoiesis.

DOI： 10.1038/s42003-023-05374-0

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Language：English   Publisher：Blood  

Occupational exposure to medical agents and ionizing radiation has been suggested as a possible risk factor for childhood cancer. However, the relationship between such exposure and pediatric malignant neoplasms has not yet been comprehensively studied. This cohort study aimed to investigate the association between parental occupational exposure to hazardous medical agents or ionizing radiation and the risk of childhood cancer in offspring. Data from a large birth cohort in Japan, which included 104 062 fetuses, were analyzed. The primary outcome was the development of leukemia or brain tumors diagnosed by community physicians during the first 3 years after birth. Exposure factors were medical agents, including anticancer agents, ionizing radiation, and anesthetics, handled by mothers during pregnancy or by fathers for 3 months before conception. The incidence of leukemia, but not of brain tumors, was higher in mothers exposed to anticancer drugs. Multivariable regression analysis showed that maternal exposure to anticancer drugs was associated with an increased risk of leukemia in offspring older than 1 year (adjusted relative risk, 7.99 [95% confidence interval, 1.98-32.3]). Detailed information obtained from medical certificates of patients with identified leukemia revealed no infant leukemia but acute lymphoblastic leukemias in the exposed group. Our findings suggest that maternal occupational exposure to anticancer drugs may be a potential risk factor for acute lymphoblastic leukemia in offspring older than 1 year. Effective prevention methods may be necessary to prevent maternal exposure to anticancer drugs and to reduce the risk of childhood malignant neoplasms.

DOI： 10.1182/blood.2023021008

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Language：Japanese  

Country：Japan  

Event date： 2016.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：九州大学   Country：Japan  

当院で未分化肉腫と診断された4例のうち2例にBCOR-CCNB3が検出された。症例1は7歳女児。6か月時に腰仙部に腫瘤が出現、生検で悪性神経鞘腫が疑われるも確定診断に至らず、未分化肉腫として腫瘍切除術、放射線療法を行うも再発を繰り返し当院紹介。腫瘍亜全摘術、化学療法、放射線療法を行ったが脳転移をきたし永眠した。症例2は12歳女児。左大腿部痛が出現し、CTで骨盤底に腫瘍を認め、生検で未分化肉腫と診断した。化学療法、放射線療法後に自家末梢血幹細胞移植併用超大量化学療法を施行した。腫瘤は残存しているが、治療終了後3年経過し再増大はない。
未分化肉腫は、「あらゆる解析系を用いてもその分化方向が不明であり、既知のいずれの分類にも該当しないもの」と定義され、2013年版の新WHO分類で再編された。近年、軟部肉腫においてBCOR-CCNB3やCIC-DUX4など新たな融合遺伝子が発見され注目されている。BCOR-CCNB3陽性未分化肉腫のまとまった報告は少なく、その臨床像は不明な点も多いが、予後不良な経過を辿る症例もある一方で、集学的治療により治癒率が向上するとの報告もある。当院で経験したBCOR-CCNB3陽性の未分化肉腫の2例のうち、1例は強力な化学療法と放射線治療により腫瘍残存のまま寛解生存しており、積極的かつ強力な集学的治療が奏効する可能性が示唆された。

Event date： 2015.11 - 2016.6

Language：Japanese  

Venue：山梨県甲府   Country：Japan  

【はじめに】ベバシズマブは血管内皮細胞増殖因子（VEGF）に対する抗モノクローナル抗体で、腫瘍への新生血管の抑制作用により腫瘍の成長を阻害し、また血管平滑筋に作用して膜透過性を改善することにより浮腫を改善させる機序も報告されている。当科の脳幹部腫瘍小児例に対しベバシズマブを使用し、症状の著明改善を認めた3例について報告する。
【症例】症例1は13歳男児。頸部痛を主訴に近医を受診、生検にて延髄膠芽腫（脊髄播種あり）と診断した。テモゾロミド＋放射線療法を施行するも麻痺症状等の進行を認めたため、ベバシズマブ投与

Language：English   Publisher：Oxford University Press  

Type：Competition, symposium, etc. 

韓国からの医学生実習受け入れ、指導