Language：Japanese   Publisher：(公社)日本小児科学会  

researchmap

Language：Japanese   Publisher：(一社)日本てんかん学会  

researchmap

Language：Japanese   Publisher：愛媛医学会  

愛媛県では,2021年10月にライソゾーム病(ポンペ病,ファブリー病,ゴーシェ病,ムコ多糖症I・II型),脊髄性筋萎縮症(SMA),重症複合免疫不全症(SCID)の7疾患を対象に拡大新生児スクリーニングを開始した.開始時より,愛媛県内全ての分娩取扱施設から検体が提出され,検査実施率(同意率)も82.6%と高率でのスタートとなった.開始1年半で検査数が1万件を超え,2024年1月までの検査実施率(同意率)の平均値は84.6%と高水準で推移している.要精密検査判定となったのは24件(0.2%)であった.まだ診断確定に至った症例はない.拡大新生児スクリーニングは有料検査ではあるが,保護者の関心度は高く,遺伝性難病の早期発見,早期治療に繋げるために,非常に有用である.しかし,要精密判定の中に,偽陽性の頻度も比較的高いことを実感しており,要精査と判定された家族への遺伝カウンセリングなどサポート体制を充実させることが急務である.愛媛県に続き,四国3県でも検査体制が整い,2023年6月より四国全域で拡大新生児スクリーニングが受検可能となった.全国の実施施設とも情報を共有し,精度管理と陽性者への対応などの課題について連携して取り組んでいき,拡大新生児スクリーニングの有用性を示すことで,全国一律の公費助成化を要望していくことが重要と考えている.(著者抄録)

researchmap

Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ijdrr.2024.104534

researchmap

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

DOI： 10.11412/jspho.61.80

researchmap

Language：Japanese   Publisher：(株)日本臨床社  

researchmap

Language：Japanese   Publisher：(株)東京医学社  

researchmap

Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00648&link_issn=&doc_id=20240205070014&doc_link_id=10.24479%2Fpm.0000001464&url=https%3A%2F%2Fdoi.org%2F10.24479%2Fpm.0000001464&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(一社)日本小児腎臓病学会  

researchmap

Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J02626&link_issn=&doc_id=20240305290001&doc_link_id=10.3165%2Fjjpn.cr.23-006&url=https%3A%2F%2Fdoi.org%2F10.3165%2Fjjpn.cr.23-006&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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

AMeD syndrome is characterized by aplastic anemia, mental retardation, short stature, and microcephaly and is caused by digenic mutations in the aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 5 (ADH5) genes. We have successfully performed hematopoietic stem cell transplantation in two patients with AMeD syndrome and isochromosome 1q. AMeD syndrome with myelodysplastic syndrome or acute myeloblastic leukemia generally has a poor prognosis; however, early diagnosis may improve treatment response. Although the gain of 1q has been considered as a form of early clonal evolution in Fanconi anemia, it may be an equally important finding observed in AMeD syndrome.

DOI： 10.1016/j.lrr.2024.100476

PubMed

researchmap

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

Introduction: With the aim of optimizing the balance of maintaining a safe oxygen saturation and reducing the risk of retinopathy of prematurity in human neonates with fetal growth restriction (FGR), the present study investigated the distinct effects of oxygen supplementation on the retinal neovasculature using a murine premature neonatal oxygen-induced retinopathy (OIR) model with or without fetal growth restriction. Methods: For comparison with normal birth-weight neonates, maternal low-protein diet-induced FGR neonates were subjected to fluctuating oxygen levels to generate oxygen-induced retinopathy. The retinal neovasculature was histologically evaluated, and comprehensive transcriptome analysis was conducted. Results: Compared to OIR neonates with normal birth weight, significant amelioration of the neovasculature, as indicated by decreases in the number of branch junctions, vascular distribution, maximal vascular radius and microaneurysm-like tufts, was observed in OIR mice with FGR. The results of retinal RNA-sequencing revealed downregulation of angiogenic factors that trigger pathological retinal neovascularization, such as the mitogen-activated protein kinase pathway and corresponding upstream signaling pathways in OIR mice with FGR. Conclusion: Our findings demonstrated that FGR neonates have a higher capacity for retinal oxygen stress, and the risk of OIR development is attenuated compared to that in mature neonates with normal birth weight.

DOI： 10.3389/fcell.2024.1288212

PubMed

researchmap

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

Allergic contact dermatitis (ACD) and atopic dermatitis develop through delayed-type hypersensitivity reactions mediated by T cells. The development of immunomodulatory drugs, such as Jak inhibitors, would be useful for the long-term management of these diseases owing to their profile of favorable adverse effects. However, the efficacy of Jak inhibitors for ACD treatment has not been fully determined under a variety of settings. Therefore, we evaluated the effects of ruxolitinib, a Jak inhibitor for Jak1 and Jak2, using a mouse ACD model. As a result, the lower numbers of immune cells, including CD4+ T cells, CD8+ T cells, neutrophils, and possibly macrophages, as well as milder pathophysiological aspects have been observed in the inflamed skin of ACD with the administration of ruxolitinib. In addition, the treatment of differentiating T cells with ruxolitinib downregulated the level of IL-2-mediated glycolysis in vitro. Furthermore, symptoms of ACD did not develop in T-cell-specific Pgam1-deficient mice whose T cells had no glycolytic capacity. Taken together, our data suggest that the downregulation of glycolysis in T cells by ruxolitinib could be an important factor in the suppression of ACD development in mice.

DOI： 10.1016/j.jid.2023.03.1667

PubMed

researchmap

Language：Japanese   Publisher：愛媛医学会  

目的:学校救急体制の整備により,学校管理下での心臓突然死は減少傾向にある.しかし,心停止は依然として一定の頻度で発生しており,その半分は経過観察されていない予測が困難な例であった.学校内のどこからでもAEDを往復2分以内で取りに行ける環境が望ましいと提言されているが,実際にはその条件は満たされていないことも多い.設置場所や設置台数については学校間差が大きいため,現状把握と学校救急体制の改善を目指し調査・検討を行った.方法:2019年7月と8月に愛媛県八幡浜市のすべての小中学校(17校)を訪問しAEDの設置台数,設置場所を確認した.また,学校内に事故現場を想定し,それぞれの場所から最も近いAED設置場所までの往復時間を実際に走って測定した.過去の心停止発生場所の頻度を元にAED有効設置の指数Relative Effective Installation Index(REI Index)を作成し,有効的にAEDを設置するための方法について比較検討を行った.結果:すべての小中学校で1台のAEDが設置されていたが,2台以上設置されている学校はなかった.小学校に関してはプールの授業のためAEDを携行した場合に,2分以上かかる場所ができてしまいAEDの増設が必要であった.中学校に関しては敷地が広く,1台のみでは2分以内でAEDを取りにいくことができない場所が多かった.REI Indexを用いて,事故発生頻度の高い運動場,プールに重点を置いた設置戦略を検討することが可能であった.結論:小学校は現状の1台に加え,移動用の1台増設が必要であった.中学校は敷地が広く2台以上のAEDが必要であった.設置場所の有効性の比較検討に関してREI Indexは有用であると思われる.(著者抄録)

researchmap

Language：Japanese   Publisher：(一社)日本遺伝性腫瘍学会  

遺伝性乳癌卵巣癌症候群(hereditary breast and overian cancer syndrome;HBOC)の患者において乳頭温存乳房全切除術(nipple-sparing mastectomy;NSM)は標準的に実施されている.今回われわれは,NSM後の乳頭乳輪部に乳癌を生じたHBOCの1例を経験したため報告する.症例は49歳,女性.33歳時に左乳癌にてNSM+腋窩郭清を行い,切除断端は陰性であった.43歳時に右乳癌にて手術を施行した.49歳時に左乳頭直下に腫瘤を自覚され受診した.摘出生検にて左乳癌と診断した後,左乳頭乳輪を含めた全切除術を施行した.術後に遺伝学的検査を施行し,BRCA2にc.9076C>T(p.Gln3026*)の病的バリアントを認めた.HBOC患者における治療的NSMの報告は少ないが,これまでに乳頭乳輪部の再発の報告はない.また,いずれの報告も観察期間が2～5年と短く,HBOCでは本症例のように術後長期間を経た後に乳癌を発症する可能性があり,長期的な症例の蓄積が必要と考えられる.(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J07424&link_issn=&doc_id=20230712360008&doc_link_id=%2Fcg3tumor%2F2023%2F002301%2F009%2F0038-0043%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcg3tumor%2F2023%2F002301%2F009%2F0038-0043%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：愛媛県小児科医会  

ファロー四徴症(Tetralogy of Fallot:TOF)は、乳児期以降におけるチアノーゼ性先天性心疾患の中で最も頻度の高い疾患である。一般的には6～9ヵ月以降に心内修復術を行うが、それ以前に重度のチアノーゼや頻回な無酸素発作を繰り返す症例では、段階的治療戦略として体肺動脈シャント手術が必要となり、本邦ではBlalock-Taussig shunt(BT shunt)術が標準的に行われている。BT shunt術には手術リスクや合併症があり、それに代わる治療方法も試みられている。経皮的バルーン肺動脈弁形成術(Percutaneous balloon pulmonary valvuloplasty:PTPV)は、肺動脈弁狭窄が右室流出路狭窄の主体である症例において有効であり、短絡術に代わりうると期待される治療法のひとつである。症例は生後1か月のTOFの男児で、高度のチアノーゼが認められ、肺動脈は低形成(PA index=97mm2/m2)であったが漏斗部狭窄は目立たず、肺動脈弁狭窄が主体であった。この症例に対して、日齢40にPTPVを施行し、経皮的動脈血酸素飽和度が70%台から90%と改善し、PA indexも97mm2/m2から244mm2/m2と十分な成長がみられ、BT shunt術を介さず心内修復術が行われ、良好な結果を得た。TOFに対するPTPVは、段階的手術である体肺動脈シャント手術を回避しうる有用なカテーテル治療法であり、症例に応じて最善の治療法として提供することが重要である。(著者抄録)

researchmap

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

DOI： 10.14309/ajg.0000000000001982

PubMed

researchmap

Language：English  

BACKGROUND: In this study, we report the case of a 14-month-old female patient transferred from another hospital to our hospital with a 9-day history of fever and worsening dyspnea. Case Report. The patient tested positive for influenza type B virus 7 days before being transferred to our hospital but was never treated. The physical examination performed at presentation revealed redness and swelling of the skin at the site of the peripheral venous catheter insertion performed at the previous hospital. Her electrocardiogram revealed ST segment elevations in leads II, III, aVF, and V2-V6. An emergent transthoracic echocardiogram revealed pericardial effusion. As ventricular dysfunction due to pericardial effusion was not present, pericardiocentesis was not performed. Furthermore, blood culture revealed methicillin-resistant Staphylococcus aureus (MRSA). Thus, a diagnosis of acute pericarditis complicated with sepsis and peripheral venous catheter-related bloodstream infection (PVC-BSI) due to MRSA was made. Frequent bedside ultrasound examinations were performed to evaluate the outcomes of the treatment. After administering vancomycin, aspirin, and colchicine, the patient's general condition stabilized. CONCLUSIONS: In children, it is crucial to identify the causative organism and provide appropriate targeted therapy to prevent worsening of the condition and mortality due to acute pericarditis. Moreover, it is important to carefully monitor the clinical course for the progression of acute pericarditis to cardiac tamponade and evaluate the treatment outcomes.

DOI： 10.1155/2023/4374552

PubMed

researchmap

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

In addition to genetic factors, environmental factors play a role in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). This study used Lister hooded rats (LHRs) as ADHD model animals to evaluate the effects of environmental factors. Male LHR pups were kept in four rearing conditions from postnatal day 23 (4 rats in a standard cage; 12 rats in a large flat cage; and 4 or 12 rats in an enriched environment [EE]) until 9 weeks of age. EE rearing but not rearing in a large flat cage decreased the activity of LHRs in the open field test that was conducted for 7 consecutive days. In the drop test, most rats reared in an EE remained on a disk at a height, whereas most rats reared in a standard cage fell off. RNA sequencing revealed that the immediate-early gene expression in the medial prefrontal cortex of LHRs reared in an EE was reduced. cFos-expressing neurons were reduced in number in LHRs reared in an EE. These results suggest that growing in an EE improves ADHD-like behaviors and that said improvement is due to the suppression of neuronal activity in the mPFC.

DOI： 10.3390/cells11223649

PubMed

researchmap

Language：English   Publisher：WILEY  

Web of Science

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. Al-though there was no cure for SMA, newly developed therapeutic drugs (nusinersen, onasemnogene abeparvovec, and risdiplam) have been proven effective for the improvement of motor function and prevention of respiratory insufficiency of infants with SMA. Nusinersen was introduced in Japan in 2017 and onasemnogene abeparvovec in 2020. We hypothesized that the introduction of these drugs might influence the incidence of SMA (more precisely, increase the diagnosis rate of SMA) in Japan. To test this hypothesis, we conducted a second epidemiological study of infantile SMA using questionnaires in Shikoku, Japan between October 2021 and February 2022. The incidence of infantile SMA during the period 2016-2020 was 7.08 (95% confidence interval [CI] 2.45-11.71) per 100,000 live births. According to our previous epidemiological study, the incidence of infantile SMA during 2011-2015 was 2.70 (95% CI 0.05-5.35) per 100,000 live births. The increased incidence of infantile SMA suggests that the widespread news in Japan regarding the introduction of therapeutic agents, nusinersen and onasemnogene abeparvovec, raised clinicians' awareness about SMA, leading to increased and earlier diagnosis of SMA in Shikoku.

DOI： 10.3390/ijns8040052

PubMed

researchmap

Language：English  

Stevens-Johnson syndrome (SJS) with respiratory distress can lead to fatal outcomes. However, there are a few reports of drug-induced lung injury with diffuse alveolar damage caused by acetaminophen, the most severe type. Here, we describe a fatal case of acetaminophen-induced SJS in a child with irreversible lung lesions.

DOI： 10.1002/ccr3.6294

PubMed

researchmap

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

KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.

DOI： 10.1038/s41467-022-32266-4

PubMed

researchmap

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

BACKGROUND: Lack of correlation between subjective and objective measurements of daytime sleepiness is common. Here, the frequency of discrepancy between subjective and objective sleepiness, as well as possible predictors, were examined for an adolescent cohort. METHODS: This study included pediatric patients (aged 10-18 years, n = 211) with various sleep disorder symptoms were evaluated between August 2011 and February 2021. Subjective and objective sleepiness were assessed based on eleven or more scores of the Japanese version of Epworth Sleepiness Scale and a mean sleep latency of 8.0 min or less on the Multiple Sleep Latency Test, respectively. Patients were then classified as both subjectively and objectively sleepy, objectively sleepy, subjectively sleepy, and non-sleepy. Discrepancy-related factors were identified with multivariable logistic regression analysis. RESULTS: The frequency of discrepancy between subjective and objective sleepiness was 46.4%, with 35.5% (75/211) of the patients exhibiting subjective sleepiness without objective sleepiness and 10.9% (23/211) of the patients exhibiting objective sleepiness without subjective sleepiness. Co-existence of neurodevelopmental disorders was associated more often with subjective sleepiness compared to non-sleepiness (odds ratio (OR), 4.12; 95% confidence interval (CI), 1.30 to 12.99) or concordant sleepiness (OR, 7.54; 95% CI, 2.43 to 23.38). CONCLUSIONS: Nearly half of the patients exhibited discrepancy between subjective and objective sleepiness, and it more often involved subjective sleepiness. Furthermore, age, bedtime, and neurodevelopmental disorders were identified as significant factors related to subjective sleepiness without objective sleepiness.

DOI： 10.1016/j.sleep.2022.04.025

PubMed

researchmap

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

researchmap

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

The MLL-10 trial (UMIN000004801) modified a Children's Oncology Group (COG) AALL0631 therapy for infants with KMT2A-rearranged acute lymphoblastic leukemia (ALL). In 2016, one registered case developed secondary immunodeficiency during maintenance therapy and eventually died due to cytomegalovirus infection. Around the same time, fatal secondary immunodeficiencies were reported in five infants with ALL in North America who had received COG-based chemotherapy between 1996 and 2015. Given these cases, we decided to conduct a retrospective study on the postchemotherapy immune status of infants with ALL. A questionnaire collected data on posttreatment immune function, frequency of infections, and supportive care for the 34 infants in the MLL-10 trial. Patients receiving allogeneic hematopoietic stem cell transplantation in first remission were excluded. Responses to the survey were obtained in 28 cases (85%). Most patients were immunocompetent after the completion of chemotherapy (median follow-up duration from the day of chemotherapy completion was 431 days), except for the aforementioned case. There were seven patients with nonsevere viral infection, all of whom recovered. In conclusion, severe chemotherapy-induced immunodeficiency in infants with ALL appears to be rare, but prospective data collection of immune function is necessary to clarify this finding.

DOI： 10.1002/pbc.29772

PubMed

researchmap

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

DOI： 10.1055/a-1858-4826

PubMed

researchmap

Language：English  

In extracardiac Fontan, an epicardial pacemaker implantation has many limitations, especially given that it is highly invasive and a high-risk procedure due to repeat thoracotomy. Herein we illustrate a case with the possibility of transvenous pacing in extracardiac Fontan being less invasive and lower risk transvenous dual-chamber pacemaker implantation by electrophysiological assessment. <Learning objective: Transvenous pacemaker implantation via left superior vena cava may be a viable alternative to epicardial pacing with a minimally invasive procedure in patients with extracardiac Fontan.>.

DOI： 10.1016/j.jccase.2022.01.010

PubMed

researchmap

Language：Japanese   Publisher：愛媛医学会  

がんの発症や進展に関与する「がん関連遺伝子」を標的としたがんゲノム医療は、がん治療の大きな流れになろうとしている。本邦でも包括的がんゲノム遺伝子パネル(comprehensive cancer genomic profiling;comprehensive CGP)検査が、保険診療下で開始され2年余りが経過した。愛媛大学病院でも100例程度の症例を経験し、現在初期の総括が望まれる時期にある。本稿では、保険診療外で行われたCGP検査も含め、我々の経験を踏まえ今後の方向性を議論する。(著者抄録)

researchmap

Language：Japanese   Publisher：愛媛県小児科医会  

胃癌一次予防の一環として、愛媛県西条市では、2017年度より中学2年生を対象としたヘリコバクター・ピロリ検診が開始された。方法は、希望者に一次検診(尿中ピロリ抗体検査)を無料で行い、陽性者に二次検診(尿素呼気試験)を実施し、両者とも陽性をピロリ感染者と判定し、希望者に除菌療法を行う形で行われた。初年度の受診者は386名(受診率37.7%)、一次検診陽性者は18名(陽性率:4.7%)で、そのうち10名が当院を受診した。二次検診で4名が陽性(40.0%)でピロリ感染者と判定した。4名とも消化器症状の既往はなかったが、1名に頭痛を認めた。4名のうち2名は胃癌の家族歴が濃厚であった。4名全員に上部消化管内視鏡検査を施行し、典型的な萎縮性胃炎の所見を認め、1名では胃潰瘍瘢痕を伴った。プロトンポンプ阻害薬(PPI)+アモキシシリン(AMPC)+クラリスロマイシン(CAM)による一次除菌療法を行い、2名は除菌成功、2名は不成功でPPI+AMPC+メトロニダゾール(MNZ)による二次除菌療法を施行し、除菌に成功した。治療に伴う重篤な副作用は認めなかった。今回開始された検診事業は、無症状や家族歴のない症例におけるピロリ菌感染の早期発見・早期除菌という意味では有用と考えられたが、受診率の低さ、一次検診の偽陽性率の高さ、小児適応のない薬剤を用いる倫理的問題など課題もあり、今後検討を重ねたい。(著者抄録)

researchmap

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

Correctly diagnosing a rare childhood cancer such as sarcoma can be critical to assigning the correct treatment regimen. With a finite number of pathologists worldwide specializing in pediatric/young adult sarcoma histopathology, access to expert differential diagnosis early in case assessment is limited for many global regions. The lack of highly-trained sarcoma pathologists is especially pronounced in low to middle-income countries, where pathology expertise may be limited despite a similar rate of sarcoma incidence. To address this issue in part, we developed a deep learning convolutional neural network (CNN)-based differential diagnosis system to act as a pre-pathologist screening tool that quantifies diagnosis likelihood amongst trained soft-tissue sarcoma subtypes based on whole histopathology tissue slides. The CNN model is trained on a cohort of 424 centrally-reviewed histopathology tissue slides of alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma and clear-cell sarcoma tumors, all initially diagnosed at the originating institution and subsequently validated by central review. This CNN model was able to accurately classify the withheld testing cohort with resulting receiver operating characteristic (ROC) area under curve (AUC) values above 0.889 for all tested sarcoma subtypes. We subsequently used the CNN model to classify an externally-sourced cohort of human alveolar and embryonal rhabdomyosarcoma samples and a cohort of 318 histopathology tissue sections from genetically engineered mouse models of rhabdomyosarcoma. Finally, we investigated the overall robustness of the trained CNN model with respect to histopathological variations such as anaplasia, and classification outcomes on histopathology slides from untrained disease models. Overall positive results from our validation studies coupled with the limited worldwide availability of sarcoma pathology expertise suggests the potential of machine learning to assist local pathologists in quickly narrowing the differential diagnosis of sarcoma subtype in children, adolescents, and young adults.

DOI： 10.1038/s41379-022-01075-x

PubMed

researchmap

Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：市立宇和島病院生活協同組合  

目的 小児患者への医療提供体制において、救急搬送は重要項目の一つである。日本では出生率ならびにこどもの割合は年々低下している。そのため、小児医療提供体制の維持が重要である。より良い医療体制の構築の一助となるよう、我々は日本の地域である宇和島市にて小児救急搬送患者の実態調査を行った。方法 愛媛県宇和島市は他の大都市と地理的に離れており、人口調査に向いている。市立宇和島病院はほとんどの小児救急搬送患者を受け入れている。市立宇和島病院ならびに宇和島消防署より情報の提供をいただき、2011年から2016年の小児救急搬送患者について、搬送時の年齢や時間帯や理由について、検討を行った。結果 小児救急搬送患者の年間発生率は、小児人口1,000人あたり2011年が18.4、2016年が16.4であった。日中(8-20時)の搬送が、夜間(20-8時)の搬送より多い傾向にあった。最も多い搬送理由は、けいれん性疾患であった(熱性けいれん46.1%、てんかん9.8%)。搬送患者の33%が入院加療を必要とした。考察 日本の地方における本調査では、小児救急搬送患者の発生率は都市部より低い傾向であり、当地域での医療システムが効果的である可能性が示唆された。今回の人口調査が小児医療体制を改善するための基礎データーの一つとなれば幸いである。(著者抄録)

researchmap

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

DOI： 10.1111/ped.15116

PubMed

researchmap

Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：The Japan Epilepsy Society  

DOI： 10.3805/eands.14.71

researchmap

Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：The Japan Epilepsy Society  

DOI： 10.3805/eands.14.51

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本遺伝性腫瘍学会  

今回われわれは,乳癌発症を契機に遺伝カウンセリングを実施し,母親のリンチ症候群を診断し得た1例を経験した.症例は48歳,女性.左乳房腫瘤を主訴に愛媛大学医学部附属病院乳腺センターを受診し,精査の結果,左乳癌の診断で手術の方針となった.手術目的に入院した際に認定遺伝カウンセラーによる詳細な家族歴聴取を行ったところ,初診時の問診では得られなかった母方家系の複数の大腸癌の家族歴が判明した.リンチ症候群を疑い,患者の母親に対して,遺伝カウンセリングの後に遺伝学的検査を行い,MSH2の病的バリアントを認めたためリンチ症候群の診断に至った.患者にはMSH2の病的バリアントを認めなかった.詳細な家族歴聴取を行うことで,家系内の遺伝性疾患の診断につながることが示唆された.(著者抄録)

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. Pediatric patients in Japan are diagnosed with IgAN at an early stage of the disease through annual urinary examinations. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) have various roles, including proinflammatory effects, and modulation of several kidney diseases; however, no reports have described their roles in pediatric IgAN. In this study, we performed pathological and immunohistochemical analyses of samples from 14 pediatric IgAN patients. Additionally, gene expression arrays of glomeruli by laser-captured microdissection were performed in hemi-nephrectomized high serum IgA (HIGA) mice, a model of IgA nephropathy, to determine the role of Fn14. Glomeruli with intense Fn14 deposition were observed in 80% of mild IgAN cases; however, most severe cases showed glomeruli with little or no Fn14 deposition. Fn14 deposition was not observed in obvious mesangial proliferation or the crescent region of glomeruli, but was detected strongly in the glomerular tuft, with an intact appearance. In HIGA mice, Fn14 deposition was observed mildly beginning at 11 weeks of age, and stronger Fn14 deposition was detected at 14 weeks of age. Expression array analysis indicated that Fn14 expression was higher in HIGA mice at 6 weeks of age, increased slightly at 11 weeks, and then decreased at 26 weeks when compared with controls at equivalent ages. These findings suggest that Fn14 signaling affects early lesions but not advanced lesions in patients with IgAN. Further study of the TWEAK/Fn14 pathway will contribute to our understanding of the progression of IgAN.

DOI： 10.1371/journal.pone.0258090

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本小児血液・がん学会  

researchmap

Language：English  

DOI： 10.1093/ehjcr/ytab347

PubMed

researchmap

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (conference, symposium, etc.)  

Leukemias diagnosed in <1-year-old infants generally have an aggressive clinical nature and unique biological characteristics. Acute lymphoblastic leukemia (ALL) in infants is still intractable and difficult to treat as compared with other pediatric ALLs, for which considerable progress in treatment outcomes has been recently achieved. Infant leukemia cells frequently carry chromosome translocations involving the 11q23 locus, resulting in the rearrangement and fusion of the KMT2A (MLL) gene. Among several KMT2A fusion genes, KMT2A-AFF1 (MLL-AF4) fusion is characteristically observed in neonatal and infant ALL, representing a hallmark of poor prognosis. The cytogenetic/molecular abnormalities t (1;22)(p13.3;q13.1)/RBM15-MKL1 and t (8;16)(p11.2;p13.3)/KAT6A-CREBBP (MOZ-CBP) are also well-known in acute myeloblastic leukemia in this population. Although many neonatal leukemias occurring within the first 28 days of birth are refractory, spontaneous remissions are occasionally observed, especially in the case of t (8;16). Therefore, international collaborative studies are necessary to improve understanding and facilitate the development of better treatment for this rare disease. Thus, this study summarizes the recently reported clinical, cytogenetic, and molecular biology aspects of neonatal and infant leukemias.

DOI： 10.11406/rinketsu.62.1308

PubMed

researchmap

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (conference, symposium, etc.)  

J-GLOBAL

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

The management of systemic artery aneurysms secondary to Kawasaki disease (KD) in adults remains a therapeutic challenge. KD guidelines recommend the use of anticoagulation therapy with warfarin in addition to antiplatelet therapy when a giant coronary aneurysm or a history of thrombosis is documented. However, long-term use of warfarin presents several concerns. This case reports acute thrombotic occlusion due to the giant arterial aneurysm in an adult KD. A surgical resection of the aneurysm was performed because of recurrent thrombotic events, despite anticoagulant therapy with warfarin. Pathological examinations revealed a layered thrombus with inflammation in the aneurysm and Factor Xa expression mainly in newly formed thrombus. This study provides an insight into the anticoagulation therapy for cardiovascular sequelae after KD. <Learning objective: This study, along with pathological evidence, illustrates that Factor Xa might contribute to thrombotic events after Kawasaki disease.>.

DOI： 10.1016/j.jccase.2020.11.005

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

PURPOSE: Patients with a Fontan circulation tend to develop liver fibrosis, liver cirrhosis and even hepatocellular carcinoma. A noninvasive ultrasound technique for liver fibrosis and cardiac function assessment in Fontan-associated liver disease (FALD) is needed to evaluate disease progression in real time. This study aimed to evaluate whether hepatic vein (HV) waveform analysis and elastography could be alternative markers to cardiac index (CI) in patients with FALD and assess factors influencing elastography measurements in FALD cases. METHODS: All patients underwent cardiac catheterization, B-mode ultrasound and ultrasound elastography measurement. Moreover, we measured serum markers related to fibrosis and examined HV blood flow using duplex Doppler ultrasonography. RESULTS: Forty-three patients (median age, 17 years; interquartile range, 12-25 years; 29 men, 6 with liver biopsy) were enrolled. The real-time tissue elastography (RTE) value was significantly higher in patients who underwent surgery > 7 years prior, suggesting that this value probably reflects the liver fibrosis due to FALD from the early fibrosis stage. The ultrasound elastography did not significantly correlate with hemodynamic parameters. The area under the receiver operating curve for the diagnosis of CI < 2.2 L/min/m2 using HV waveform was superior to the results from elastography and calculated fibrosis indices. CONCLUSION: HV waveform can be used as a noninvasive measurable surrogate marker for CI. The RTE value increased overtime after the operation and would reflect liver fibrosis. The combination of RTE and HV waveform type could be useful noninvasive tools to evaluate clinical conditions in FALD patients in real time.

DOI： 10.1007/s10396-020-01078-8

PubMed

researchmap

Other Link： https://link.springer.com/article/10.1007/s10396-020-01078-8/fulltext.html

Language：Japanese   Publisher：愛媛県小児科医会  

デング熱は蚊が媒介するデングウイルスによる感染症であり、主に熱帯・亜熱帯地域での流行が確認されている。しかしながら、近年、日本では年間200例以上の感染例の報告がされてきており、日本での大規模な流行にも注意が必要である。症例は10歳女児。インドネシアから帰国後、発熱が出現した。血液検査で白血球減少・血小板減少を認めた。デングウイルスNS1抗原検査、RT-PCR検査(Reverse transcription polymerase chain reaction)を行いデングウイルス1型によるデング熱と診断した。輸液管理を行い、デング出血熱への移行なく回復した。感染巣不明の発熱と白血球減少・血小板減少を認めた場合、デング熱も鑑別に挙げる必要があり、渡航歴聴取と渡航地での流行疾患の把握が診断の一助となった。デング熱に対する特異的治療はないが、重症化を疑う場合には血漿漏出によるhypovolemic shockと大量出血の合併に注意が必要であり、Hct値を指標とした輸液・輸血管理を行う。(著者抄録)

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

BACKGROUND: Acute lymphoblastic leukaemia with mixed lineage leukaemia gene rearrangement (MLL-ALL) frequently affects infants and is associated with a poor prognosis. Primary refractory and relapsed disease due to resistance to glucocorticoids (GCs) remains a substantial hurdle to improving clinical outcomes. In this study, we aimed to overcome GC resistance of MLL-ALL. METHODS: Using leukaemia patient specimens, we performed bioinformatic analyses to identify target genes/pathways. To test inhibition of target pathways in vivo, we created pre-clinical therapeutic mouse patient-derived xenograft (PDX)-models by transplanting human MLL-ALL leukaemia initiating cells (LIC) into immune-deficient NSG mice. Finally, we conducted B-cell lymphoma-2 (BCL-2) homology domain 3 (BH3) profiling to identify BH3 peptides responsible for treatment resistance in MLL-leukaemia. FINDINGS: Src family kinases (SFKs) and Fms-like tyrosine kinase 3 (FLT3) signaling pathway were over-represented in MLL-ALL cells. PDX-models of infant MLL- ALL recapitulated GC-resistance in vivo but RK-20449, an inhibitor of SFKs and FLT3 eliminated human MLL-ALL cells in vivo, overcoming GC-resistance. Further, we identified BCL-2 dependence as a mechanism of treatment resistance in MLL-ALL through BH3 profiling. Furthermore, MLL-ALL cells resistant to RK-20449 treatment were dependent on the anti-apoptotic BCL-2 protein for their survival. Combined inhibition of SFKs/FLT3 by RK-20449 and of BCL-2 by ABT-199 led to substantial elimination of MLL-ALL cells in vitro and in vivo. Triple treatment combining GCs, RK-20449 and ABT-199 resulted in complete elimination of MLL-ALL cells in vivo. INTERPRETATION: SFKs/FLT3 signaling pathways are promising targets for treatment of treatment-resistant MLL-ALL. Combined inhibition of these kinase pathways and anti-apoptotic BCL-2 successfully eliminated highly resistant MLL-ALL and demonstrated a new treatment strategy for treatment-resistant poor-outcome MLL-ALL. FUNDING: This study was supported by RIKEN (RIKEN President's Discretionary Grant) for FI, Japan Agency for Medical Research and Development (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and by NIH CA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report.

DOI： 10.1016/j.ebiom.2021.103235

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

BACKGROUND: Metaplastic carcinoma of the breast consists of both invasive ductal carcinoma and metaplastic carcinoma. This rare subtype of cancer has a poor prognosis. The development of metaplastic breast cancer and relationship with BRCA1 are not well known. Here, we report a rare case of germline BRCA1 mutation-positive breast cancer with chondroid metaplasia. CASE PRESENTATION: A 39-year-old Japanese woman with a family history of breast cancer in her mother and ovarian cancer in her maternal grandmother consulted at our hospital with a left breast mass. Needle biopsy for the mass was performed, leading to a diagnosis of invasive breast cancer with chondroid metaplasia. We performed left mastectomy + sentinel lymph node biopsy + tissue expander insertion and replaced with a silicone implant later. Pathological examination revealed that the patient had triple-negative breast cancer. Four courses of doxorubicin+ cyclophosphamide therapy were performed as adjuvant therapy after surgery. We performed genetic counseling and genetic testing, and the results suggested the germline BRCA1 mutation 307 T> A (L63*). She has currently lived without a relapse for 2 years post-surgery. CONCLUSIONS: There have been only 6 cases of metaplastic breast carcinoma with germline BRCA1 mutations including our case. Patients with BRCA1 mutations may develop basal-like subtypes or M type of triple-negative breast cancer besides metaplastic breast cancers.

DOI： 10.1186/s13053-020-00162-x

PubMed

researchmap

Other Link： http://link.springer.com/article/10.1186/s13053-020-00162-x/fulltext.html

Language：Japanese  

J-GLOBAL

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01232&link_issn=&doc_id=20210113300009&doc_link_id=10.11251%2Fojjscn.53.49&url=https%3A%2F%2Fdoi.org%2F10.11251%2Fojjscn.53.49&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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

Background. Staphylococcus lugdunensis is one of the clinically important coagulase-negative staphylococci. The purpose of this study was to elucidate the microbiological features of S. lugdunensis in hospitalized children. Methods. From January 2012 to December 2019, all isolates were retrospectively screened for S. lugdunensis. Results. Twenty-five children were eligible for study. Nineteen and six children were classified into a critical care unit group (Group A) and a general medical ward group (Group B), respectively. The prevalence of methicillin-resistant S. lugdunensis was significantly higher in Group A than in Group B (68.4% vs 0%; P < .01). Eleven children (44%) had S. lugdunensis infections, while the remaining children were colonized. Six of the 11 infected children (55%) had healthcare-associated infections. Moreover, 3 isolates exhibited the methicillin resistance. Conclusions. The bacteriological characteristics of S. lugdunensis differ depending on patient background. Selection of antibiotic treatment should in part rely on patient background data.

DOI： 10.1177/2333794X211044796

PubMed

researchmap

Language：English  

The most common organisms isolated from pediatric catheter-related bloodstream infections (CRBSIs) are Gram-positive cocci, such as coagulase-negative staphylococci and Staphylococcus aureus. There are few formal reports of Brevibacterium casei infection and even fewer reports of CRBSI due to this Gram-positive rod. Here we report the first case of CRBSI due to B. casei in an 8-year-old girl with acute myeloid leukemia in Japan. The isolate exhibited decreased susceptibility to ß-lactam antibiotics. Antimicrobial therapy with meropenem and vancomycin, in addition to the removal of central venous catheter line, consequently led to a significant clinical improvement of the patient's symptoms. A literature review found available clinical courses in 16 cases (4 pediatric cases including our case) of B. casei infection. Our case and those in literature suggested that B. casei infection often occurs in patients with indwelling central venous catheters; the literature review further suggested that removal of central venous catheters is required in most cases. Special attention should be paid to the detection of opportunistic infections due to Brevibacterium spp. in immunocompromized children who are using a central venous catheter.

DOI： 10.1155/2021/6691569

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Mary Ann Liebert Inc  

C promoter binding factor 1 (CBF1) (alias RBPJ) is a critical transcription factor involved in Notch signaling. The activation of Notch signaling through CBF1 maintains the angiostatic state of endothelial cells suppressing angiogenesis, that is, the formation of new blood vessels. Vascular endothelial growth factor (VEGF) induces angiogenesis by promoting the proteasomal degradation of CBF1, in addition to endothelial cell proliferation. To date, angiogenic inhibitors targeting VEGF have been successfully used in clinics for cancer and age-related macular degeneration. Most antiangiogenic drugs, however, only target VEGF or VEGF receptors. In this study, to expand the repertoire of antiangiogenic therapeutics, we developed 15 single-stranded deoxyribonucleic acid (ssDNA) aptamers capable of binding to CBF1 with high affinity (Kd; 10-300 nM). To this end, systematic evolution of ligands by the exponential enrichment (SELEX) method was applied. One of the CBF1-binding ssDNA aptamers, Apt-3, inhibited angiogenesis through the activation of Notch signaling in vitro. We found that Apt-3 directly interacted with the LAG1 domain of CBF1. We suggest that the Apt-3 ssDNA aptamer may contribute to the development of a novel angiogenic inhibitor, which does not target VEGF.

DOI： 10.1089/nat.2020.0875

PubMed

researchmap

Other Link： https://www.liebertpub.com/doi/pdf/10.1089/nat.2020.0875

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Appropriate animal models are necessary to determine the molecular and cellular mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). This study used a battery of behavioral tests to compare Lister hooded rats (LHRs), an old outbred strain frequently used for autistic epilepsy research, with Wistar rats and spontaneously hypertensive rats (SHRs), a commonly used ADHD model. The open field, elevated plus maze, light/dark box, and drop tests demonstrated that LHRs were the most hyperactive animals and displayed the most inattentive- and impulsive-like behaviors, which are characteristics of ADHD. The radial arm maze, social interaction, and Morris water maze tests showed that LHRs did not display deficits characteristic of autism or intellectual disability. Although LHRs did not show different monoamine contents, the mRNA expression levels of various genes linked to ADHD (Cdh13, Drd5, Foxp2, Maoa, Sema6d, Slc9a9, and St3gal3) and tyrosine hydroxylase protein expression levels were lower in the prefrontal cortex of LHRs compared with that of Wistar rats or SHRs. c-Fos, synapsin I, and tau protein expression levels in the prelimbic region of the medial prefrontal cortex were also increased in LHRs compared with Wistar rats. Atomoxetine and guanfacine, commonly used non-stimulant treatments for ADHD, ameliorated ADHD-like behaviors in LHRs. These results suggest that LHRs can serve as a better ADHD model to develop novel pharmacological interventions.

DOI： 10.1016/j.neuint.2020.104857

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>
We report the first case of Waardenburg syndrome type 4C and Kallmann syndrome in the same person. The patient, a Japanese girl, presented with bilateral iris depigmentation, bilateral sensorineural hearing loss, Hirschsprung disease, hypogonadotropic hypogonadism, and anosmia. We identified a novel <italic>SOX10</italic> variant, c.124delC, p.Leu42Cysfs*67.

DOI： 10.1038/s41439-020-00118-6

researchmap

Other Link： http://www.nature.com/articles/s41439-020-00118-6

Language：Japanese   Publisher：(同)クリニコ出版  

AYA世代とは、adolescent and young adult(思春期・若年成人)世代の略称であり、概ね15〜39歳と定義されている。この世代に発生する"がん"の特徴として、小児期とは異なり、成人でみられる"がん"の発症が認められるが、小児期と同様に、白血病や悪性リンパ腫も高頻度に認められる。小児期の白血病の治療成績は著明に改善しているが、AYA世代の白血病の治療成績は未だ満足できるものではない。また高齢者に比較すると生存率は高いが、晩期合併症や二次がんの発症が認められ、治療後のQOL(quality of life)は必ずしも高くないことに注目する必要がある。また、AYA世代のがん患者は年齢依存的な心理・社会的な問題が複雑であり、これらの問題点を一つひとつ解決していくことが重要である。(著者抄録)

researchmap

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

DOI： 10.4103/jcrt.JCRT_449_19

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1161/CIRCIMAGING.120.010740

PubMed

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

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

DOI： 10.1111/ped.14247

PubMed

researchmap

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ped.14247

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

BACKGROUND: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder associated with spinal motor neuron loss and characterized by generalized muscle weakness. Only a few reports exist on SMA epidemiology in Japan. Additionally, nusinersen recently became available as a treatment for this condition. We estimated the prevalence of each type of SMA on Shikoku, Japan's fourth-largest major island. METHODS: We sent a questionnaire to all 131 hospitals in Shikoku that have pediatrics or neurology departments from March to September 2019, asking whether each hospital had SMA patients at that time. If so, we sent a second questionnaire to obtain more detailed information on the clinical data and treatment of each patient. RESULTS: A total of 117 hospitals (89.3%) responded to our first questionnaire, and 21 SMA patients were reported, 16 of whom had homozygous deletion of SMN1. Of the 21, nine had SMA type 1, five were type 2, five were type 3, one was type 4, and one was unidentified. The estimated prevalence for all instances of SMA and 5q-SMA was 0.56 and 0.43 per 100,000 people, respectively. Thirteen patients had received nusinersen therapy. Its outcomes varied from no obvious effects and being unable to sit to being able to sit independently. CONCLUSION: Our data showed the prevalence of SMA types 2 and 3 was relatively low on Shikoku compared with previous reports from other countries, suggesting delayed diagnosis may affect the results. Remaining motor function may be one predicting factor. Greater awareness of SMA among clinicians and patients seems necessary for more accurate epidemiological studies.

DOI： 10.1016/j.braindev.2020.05.004

PubMed

researchmap

Language：Japanese   Publisher：(株)診断と治療社  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

researchmap

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

Brain abscesses, infections within the brain parenchyma, can arise as complications of various conditions including infections, trauma, and surgery. However, brain abscesses due to polymicrobial organisms have rarely been reported in children. We herein report a case of a 9-year-old girl with unresolved congenital cyanotic heart disease (CCHD) presenting with right hemiplegia who was diagnosed with brain abscess caused by Streptococcus intermedius, Parvimonas micra, and Fusobacterium nucleatum after oropharyngeal injury. She was treated with intravenous antimicrobial therapy, drainage under craniotomy, and antiedema therapy with glycerol and goreisan, which led to the improvement of right hemiplegia to baseline; she was discharged following eight weeks of intravenous antimicrobial therapy. The clinical diagnosis of the brain abscess was difficult due to the nonspecific presentation, highlighting the importance of cranial imaging without haste in patients at increased risk for brain abscesses such as those with CCHD, presenting with fever in the absence of localizing symptoms or fever, accompanied with abnormal neurological findings.

DOI： 10.1155/2020/8304302

PubMed

researchmap

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

INTRODUCTION: With improved treatments, patients with Duchenne muscular dystrophy (DMD) can survive far beyond adolescence. However, advanced-stage DMD patients are at risk of developing renal dysfunction. In this study, long-term renal function outcomes and associated risk factors in advanced stage DMD were analyzed. METHODS: Fifty-one patients were classified into three different age groups (<20, 20-29, and ≥30 years of age), and cystatin C (CysC) levels were compared among groups. RESULTS: Median serum CysC levels were 0.74 mg/L, 0.63 mg/L, and 0.76 mg/L in the age groups of <20, 20-29, and ≥30 years, respectively (P = .003). Five of the nine patients in the ≥30 years age group showed elevated serum CysC and decreased cardiac function compared with the other four in the group (P = .014). DISCUSSION: Our results indicate an association between cardiac and renal dysfunction in patients with advanced-stage DMD.

DOI： 10.1002/mus.26757

PubMed

researchmap

Language：Japanese   Publisher：Japan Society of Perinatal and Neonatal Medicine  

<p> Cardiac tumors are rare during childhood. The most common cardiac tumor in infants and in children is rhabdomyoma accounting for up to 64％ of all pediatric cardiac tumors. Cardiac rhabdomyoma is often asymptomatic and spontaneous regression is frequently observed. On the other hand, cardiac dysfunction, outflow obstruction and arrhythmia has been reported, resulting in sudden death in some cases. The principal therapy of cardiac rhabdomyoma is symptomatic treatment, although surgical intervention could be a choice for cases with severe symptoms. Recently mTOR inhibitor such as everolimus became available for cardiac rhabdomyoma and is reported to be effective especially in the treatment during fetal to neonatal periods.</p><p> We report a case diagnosed as cardiac rhabdomyoma by fetal echography at 34-week of gestation. The tumor size was around 3.0cm² showing a left ventricular obstruction. As the risk of sudden death is considered to be high because ventricular premature contraction rapidly increased, treatment with everolimus was introduced from the day of birth. As a result, the tumor size reduced from 3.0cm² to 1.4cm² at 14th day following administration, resulting in disappearance of ventricular premature contraction. Administration of everolimus was ceased at 32-day old. Thereafter, the tumor has increased slightly but no symptoms of obstruction of left ventricular out flow tract have been observed. To provide early and appropriate treatment intervention, careful follow up of cardiac function and arrhythmia from pre-natal period is essential.</p>

DOI： 10.34456/jjspnm.56.1_148

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fped.2019.00529

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：金原出版(株)  

＜文献概要＞白血病は小児で最も多い悪性腫瘍であり,その治療成績は著明に改善し,多くの小児患者で治癒が得られている.治療成績の向上に寄与した要因の一つが染色体・遺伝子異常によるリスク層別化である.白血病の有する染色体異常・遺伝子異常はしばしば病型特異的であり,正確な診断・病型分類のみならず,治療方針の選択や予後を推測するうえで重要な情報でもある.近年の核酸解析技術の進歩により,白血病の有する遺伝子異常に関する情報は飛躍的に増加した.それらの意義づけと治療に有用な情報の選択が今後の課題である.白血病診療においては可能な限り分子遺伝学的な異常の有無を検索し,遺伝子異常に基づくリスク評価と治療法の選択が必須である.

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00639&link_issn=&doc_id=20190618110003&doc_link_id=10.18888%2Fsh.0000000943&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fsh.0000000943&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：English  

DOI： 10.1155/2019/7890673

PubMed

researchmap

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

Cell-free DNA (cfDNA), which are small DNA fragments in blood derived from dead cells including tumor cells, could serve as useful biomarkers and provide valuable genetic information about the tumors. cfDNA is now used for the genetic analysis of several types of cancers, as a surrogate for tumor biopsy, designated as "liquid biopsy." Rhabdomyosarcoma (RMS), the most frequent soft tissue tumor in childhood, can arise in any part of the body, and radiological imaging is the only available method for estimating the tumor burden, because no useful specific biological markers are present in the blood. Because tumor volume is one of the determinants of treatment response and outcome, early detection at diagnosis as well as relapse is essential for improving the treatment outcome. A 15-year-old male patient was diagnosed with alveolar RMS of prostate origin with bone marrow invasion. The PAX3-FOXO1 fusion was identified in the tumor cells in the bone marrow. After the diagnosis, cfDNA was serially collected to detect the PAX3-FOXO1 fusion sequence as a tumor marker. cfDNA could be an appropriate source for detecting the fusion gene; assays using cfDNA have proved to be useful for the early detection of tumor progression/recurrence. Additionally, the fusion gene dosage estimated by quantitative polymerase chain reaction reflected the tumor volume during the course of the treatment. We suggest that for fusion gene-positive RMSs, and other soft tissue tumors, the fusion sequence should be used for monitoring the tumor burden in the body to determine the diagnosis and treatment options for the patients.

DOI： 10.1002/gcc.22734

PubMed

researchmap

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

Background: Nonocclusive mesenteric ischemia (NOMI) defines acute mesenteric ischemia without occlusion of the mesenteric arteries. The most common cause of NOMI is vasoconstriction or vasospasm of a mesenteric artery. NOMI generally affects patients >50 years of age, and few cases have been reported in children. Case Presentation: A 15-year-old boy with severe neurodevelopmental disability developed sudden-onset fever, abdominal distention, and dyspnea. Laboratory and radiological findings indicated acute intestinal obstruction and prerenal failure. He developed transient cardiopulmonary arrest and hypovolemic shock. Emergent laparotomy was performed, which revealed segmentally necrotic intestine from the jejunum to the ascending colon with pulsation of peripheral intestinal arteries, leading to a diagnosis of NOMI. The necrotic intestine was resected, and stomas were created. He was discharged on postoperative day 334 with short bowel syndrome as a complication. Conclusions: NOMI should be considered a differential diagnosis for intestinal symptoms with severe general conditions in both adults and children with underlying disease. Immediate surgical exploration is essential with NOMI to save a patient's life.

DOI： 10.1155/2019/5354074

PubMed

researchmap

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

DOI： 10.1080/08880018.2018.1522402

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本小児血液・がん学会  

MLL遺伝子再構成陽性の乳児急性リンパ性白血病(MLL-r ALL)は予後不良の疾患である。日本では1996年より乳児ALLをMLL遺伝子再構成の有無で層別化し、MLL-r群に対しては化学療法と造血幹細胞移植(HSCT)を併用する治療法を実施した。これまでMLL96、MLL98、MLL03、MLL10研究を経て近くMLL16治療研究が開始される予定であるが、ほとんど生存が得られなかった乳児MLL-r ALLの無イベント生存率は約50%まで改善した。乳児白血病の発症機序については胎生期のMLL再構成が1st hitとなるが、その後に起こる2nd hitについては不明である。我々はMLL-r乳児ALLは、let-7b-MGA2-p16系の破綻により幹細胞の分化が抑制され白血病化が誘導される可能性を明らかにした。このような病態解析により乳児ALLに対して脱メチル化剤などの分子標的薬が有効である可能性がある。一方乳児白血病の発症は1 hitのみで充分だという論文が報告されたが、我々はマウスを用いた実験で乳児白血病発症には何らかの2nd hitが必要であることを明らかにした。今後さらに解析を進めて乳児白血病の発症機序を明らかにし、新たな治療法を開発していく必要がある。(著者抄録)

researchmap

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

J-GLOBAL

researchmap

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

DOI： 10.1080/08880018.2018.1539148

PubMed

researchmap

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

DOI： 10.1080/08880018.2018.1459984

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-Liss Inc.  

22q11.2 deletion syndrome is one of the most common human microdeletion syndromes. The clinical phenotype of 22q11.2 deletion syndrome is variable, ranging from mild to life-threatening symptoms, depending mainly on the extent of the deleted region. Brain malformations described in association with 22q11.2 deletion syndrome include polymicrogyria, cerebellar hypoplasia, megacisterna magna, and agenesis of the corpus callosum (ACC), although these are rare. We report here for the first time a patient who manifested combined D-2- and L-2-hydroxyglutaric aciduria as a result of a hemizygous mutation in SLC25A1 in combination with 22q11.2 deletion. The girl was diagnosed to have ACC shortly after birth and a deletion of 22q11.2 was identified by genetic analysis. Although the patient showed cardiac anomalies, which is one of the typical symptoms of 22q11.2 deletion syndrome, her rather severe phenotype and atypical face prompted us to search for additional pathogenic mutations. Three genes present in the deleted 22q11.2 region, SLC25A1, TUBA8, and SNAP29, which have been reported to be associated with brain malformation, were analyzed for the presence of pathogenic mutations. A frameshift mutation, c.18_24dup (p.Ala9Profs*82), was identified in the first exon of the remaining SLC25A1 allele, resulting in the complete loss of normal SLC25A1 function in the patient's cells. Our results support the notion that the existence of another genetic abnormality involving the retained allele on 22q11.2 should be considered when atypical or rare phenotypes are observed.

DOI： 10.1002/ajmg.a.38578

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Gaucher disease is a lysosomal storage disease caused by deficiency of glucocerebrosidase and accumulation of glucocerebroside. Three major sub-types have been described, type 2 is an acute neurological form that exhibits serious general symptoms and poor prognosis, compared with the other types. This case was a girl diagnosed with type 2 Gaucher disease at 12 months of age who presented with poor weight gain from infancy, stridor, hypertonia, hepatosplenomegaly, trismus and an eye movement disorder. Enzyme replacement therapy (ERT) was administered, but she had frequent myoclonus and developmental regression. She needed artificial ventilation because of respiratory failure. She died at 11 years of age. An autopsy demonstrated infiltrating CD68-positive large cells containing abundant lipids in alveoli, while in the liver, kidney and bone marrow CD68-positive cells were small and round. In the bone marrow, myelodysplastic changes were present without Gaucher cells. The infiltration of Gaucher cells in alveoli was marked, suggesting that ERT was relatively ineffective in pulmonary involvement, particularly intra-alveolar. Additional treatments are necessary to improve the neurological and pulmonary prognosis of type 2 Gaucher disease. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bcmd.2016.11.006

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

We report the case of a 10-year-old female with acute myeloid leukemia (AML) FAB M0 carrying a novel t(11;19)(q23;p13.1) MLL-ELL variant, in which intron 8 of MLL is fused to exon 6 of ELL. Complete remission, judged by morphology and cytogenetic analysis, was achieved after the conventional chemotherapy. Eight months after completion of therapy, the level of WT-1 in peripheral blood and the number of cells with the MLL-ELL fusion transcript resurged. However, the patient remained overtly healthy and the morphology in the bone-marrow smear was innocuous, with no sign of relapse or secondary leukemia. Without any evidence of relapse, the patient has been closely observed without any therapeutic intervention. For approximately 2 years after the completion of therapy, despite clonal proliferation of pre-leukemic cells with an MLL-ELL fusion gene, she has maintained complete remission. In this case, the rare variant form of MLL-ELL fusion that has been identified may be related to diminished leukemogenic capacity, resulting in the persistence of pre-leukemic status; an additional genetic abnormality may thus be necessary for full transformation of pre-leukemic cells.

DOI： 10.1007/s12185-017-2289-y

Web of Science

PubMed

researchmap

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

The outcome for infants with KMT2A (MLL)-rearranged acute lymphoblastic leukemia (MLL-r ALL) is dismal despite intensive therapy, including hematopoietic stem cell transplantation (HSCT). Epigenetic dysregulation is considered a key driver of MLL-r leukemogenesis, which theoretically supports the use of epigenetic modifiers as a treatment option. We report an infant MLL-r ALL case with post-HSCT relapse. After achieving a second remission, which was maintained for 10 months using only the DNA methyltransferase inhibitor, azacitidine, the patient successfully received the second HSCT. This report describes the clinical effectiveness of azacitidine for the treatment of infant MLL-r ALL.

DOI： 10.1002/pbc.26697

Web of Science

PubMed

researchmap

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

J-GLOBAL

researchmap

Language：English   Publishing type：Part of collection (book)   Publisher：Springer Singapore  

Hematopoietic stem cells (HSCs), which are responsible for producing all blood cell types, first appear in the early stage of embryonic development and transit through several different tissues, including the yolk sac, aorta-gonad-mesonephros (AGM) region, placenta, and fetal liver, before colonizing in the bone marrow where they reside throughout the individual's life. HSCs, characterized by the ability to self-renew and generate all types of blood cells, are supported by their specific environment called niches and depend on many developmental signaling pathways, molecules, and cytokines for their generation, maintenance, and expansion. Any disruption in this well-balanced system may cause aberrant HSC production, leading to malignant hematopoiesis. Leukemic stem cells (LSCs), originally identified using xenograft models of acute myeloid leukemia (AML), are a distinct cell population that can initiate leukemia in immunodeficient mice. LSCs are thought to emerge from HSCs or hematopoietic progenitors after obtaining multiple genetic changes that provide aberrant growth advantage and self-renewal ability. The emergence of LSCs is a multi-step event, including genetic diversification and clonal selection, resulting in genetic heterogeneity among leukemic cells. LSCs generally exist in the immature CD34+CD38- leukemic population in most cases of AML and share some features with normal HSCs. However, recent studies have shown that in acute lymphoblastic leukemia (ALL), LSCs exist in B-lineage-committed progenitors expressing CD19. In contrast to that in AML, in which LSCs generate leukemic cells in a hierarchical order with LSCs at the top, leukemia propagation in ALL is better explained by a stochastic model.

DOI： 10.1007/978-981-10-3886-0_1

Scopus

researchmap

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

researchmap

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

Background: Recently, a student died of idiopathic ventricular fibrillation in a school where an automated external defibrillator (AED) had been installed. The tragedy could not be prevented because the only AED in the school was installed in the teachers' office, far from the school ground where the accident took place. This prompted establishment of a multiple AED system in schools. The aim of this study was to analyze the efficacy of the multiple AED system to prevent sudden death in school-aged children.
Methods: Assumed accident sites consisted of the school ground, gymnasium, Judo and Kendo hall, swimming pool, and classrooms on the first and the fourth floor. Multiple AED were installed in the teachers' office, gymnasium, some classrooms, and also provided as a portable AED in a rucksack. The time from the accident site to the teachers' office for single AED, and from the accident site to the nearest AED for multiple AED, was calculated.
Results: The AED retrieval time was significantly shorter in 55 elementary schools and in 29 junior high schools when multiple AED were installed compared with single AED. Except for the classroom on the fourth floor, the number of people who took &gt;120 s to bring the AED to the accident site was lower when multiple AED were installed compared with the single AED.
Conclusion: Multiple AED provided in appropriate sites can reduce the time to reach the casualty and hence prevent sudden death in school-aged children.

DOI： 10.1111/ped.13143

Web of Science

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

Leukemia is derived from hematopoietic stem/progenitor cells that have acquired genetic abnormalities, leading to malignant transformation. The basis of therapy for leukemia is a combination of anti-cancer drugs based on risk stratification. The overall 5-year survival rate in leukemia patients of all ages is still 40%, although it has improved in pediatric patients. Leukemia itself is a heterogeneous disease that includes various entities/subtypes with different pathogenic gene aberrations. Selection of the treatment strategy largely depends on risk stratification, and this in turn is mainly based on specific recurrent chromosome aberrations. However, in acute myeloid leukemia (AML), a significant proportion of patients present with a normal karyotype according to conventional cytogenetic analysis and are classified into an intermediate-risk group, which actually consists of various subtypes with different prognoses. In addition, leukemic cells usually harbor one or more driver mutations among their various genetic aberrations, and these driver mutations could affect prognosis. The discovery of additional mutations in genes such as NPM1, CEBPA and fi73, which are frequent in AML patients with a normal karyotype, have improved the precision of risk stratification in AML. In this regard, array-based gene expression analysis and whole exome/transcriptome sequencing could be useful tools for identifying the whole spectrum of genetic aberrations, or for compiling a complete list of mutated genes within leukemic cells. Genetic profiling information obtained using these newly developed methods could provide more accurate information for molecular subtyping and risk stratification in leukemia.

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(株)日本臨床社  

researchmap

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

Acute lymphoblastic leukaemia (ALL) in infants is an intractable cancer in childhood. Although recent intensive chemotherapy progress has considerably improved ALL treatment outcome, disease cure is often accompanied by undesirable long-term side effects, and efficient, less toxic molecular targeting therapies have been anticipated. In infant ALL cells with KMT2A (MU) fusion, the microRNA let-7b (MIRLET7B) is significantly downregulated by DNA hypermethylation of its promoter region. We show here that the expression of HMGA2, one of the oncogenes repressed by MIRLET7B, is reversely upregulated in infant ALL leukaemic cells, particularly in KMT2A-AFF1 (MLL-AF4) positive ALL. In addition to the suppression of MIRLET7B, KMT2A fusion proteins positively regulate the expression of HMGA2. HMGA2 is one of the negative regulators of CDKN2A gene, which encodes the cyclin-dependent kinase inhibitor p16(INK4A). The HMGA2 inhibitor nctropsin, when combined with demethylating agent 5-azacytidine, upregulated and sustained the expression of CDKN2A, which resulted in growth suppression of KMT2A-AFF1-expressing cell lines. This effect was more apparent compared to treatment with 5-azacytidine alone. These results indicate that the MIRLET7B-HMGA2-CDKN2A axis plays an important role in cell proliferation of leukaemic cells and could be a possible molecular target for the therapy of infant ALL with KMT2A-AEF1.

DOI： 10.1111/bjh.13763

Web of Science

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Hematology  

Leukemic stem cells (LSCs) were originally identified in acute myeloid leukemia (AML) cases by using xenograft models, as a distinct cell population that can initiate leukemia in immunodeficient mice. Since then, many efforts have been made to clarify the identities of LSCs and other cancer stem cells in various cancer types, to both understand their biology and determine the most suitable targets for anti-cancer therapies. LSCs were identified as existing in the immature CD34⁺CD38^- leukemic population in most AML cases, and these cells were found to share some features with normal hematopoietic stem cells. On the other hand, recent studies have shown that in childhood acute lymphoblastic leukemia (ALL), LSCs exist among B-lineage-committed progenitors expressing CD19. In contrast to AML, in which LSCs generate leukemic cells in a hierarchical order with LSCs at the top, leukemia propagation in childhood ALL is better explained by a stochastic model. In B-precursor ALL, LSCs form via acquisition of additional genetic change(s) in CD19⁺ B-lineage progenitor cells with self-renewing capacity. These LSCs possess a growth advantage and the capacity to produce progeny with the same ability as the LSCs. Identification of genetic and cellular targets in leukemic transformation is necessary to develop improved anti-cancer therapies.

DOI： 10.11406/rinketsu.56.1871

PubMed

CiNii Books

researchmap

Other Link： https://jlc.jst.go.jp/DN/JLC/20015935128?from=CiNii

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Juvenile myelomonocytic leukemia (JMML) is a clonal disease arising from abnormal hematopoietic stem cells, although the involvement of lymphoid lineage differs among reported cases. Here, we present a case of JMML with a KRAS G13D mutation. The mutation was detected in various hematopoietic lineages, including T and B lymphocytes and also in lineage(-) CD34(+)CD38(-) hematopoietic stem cells, showing a different percentage of affected cells in each lineage. Single cell-based analysis of hematopoietic cells revealed the loss of wild-type KRAS in a significant proportion of G13D-harboring cells. The percentage of loss of heterozygosity (LOH)/non-LOH cells showed lineage-dependent skewing in hematopoietic cells. The loss of the wild-type KRAS allele may be a common secondary genetic change in KRAS-related JMML and may affect the differentiation behavior of early JMML progenitors.

DOI： 10.1111/ejh.12355

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34(+)CD38(+)CD19(+) and CD34(-)CD19(+) cells initiated leukemia, and in MLL-AF9 patients, CD34(-)CD19(+) cells were LICs. In MLL-ENL patients, either CD34(+) or CD34(-) cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34(+)CD38(-)CD19(-)CD33(-) cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34(+)CD38(-)CD19(-)CD33(-) cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4(+) single positive (SP), CD8(+) SP, and CD4(+)CD8(+) double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34(+)CD38(+) and CD34(-) LICs but not in CD34(+)CD38(-)CD19(-)CD33(-) HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.

DOI： 10.1182/blood-2014-03-563304

Web of Science

PubMed

researchmap

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

Cardiac anomaly is one of the hallmarks of DiGeorge syndrome (DGS), observed in approximately 80% of patients. It often shows a characteristic morphology, termed as conotruncal heart defects. In many cases showing only the conotruncal heart defect, deletion of 22q11.2 region cannot be detected by fluorescence in situ hybridization (FISH), which is used to detect deletion in DGS. We investigated the presence of genomic aberrations in six patients with congenital conotruncal heart defects, who show no deletion at 22q11.2 in an initial screening by FISH. In these patients, no abnormalities were identified in the coding region of the TBX1 gene, one of the key genes responsible for the phenotype of DGS. However, when copy number alteration was analyzed by high-resolution array analysis, a small deletion or duplication in the proximal end of DiGeorge critical region was detected in two patients. The affected region contains the DGCR6 and PRODH genes. DGCR6 has been reported to affect the expression of the TBX1 gene. Our results suggest that altered dosage of gene(s) other than TBX1, possibly DGCR6, may also be responsible for the development of conotruncal heart defects observed in patients with DGS and, in particular, in those with stand-alone conotruncal heart defects.

DOI： 10.1038/hgv.2015.4

PubMed

researchmap

Language：Japanese   Publisher：(有)科学評論社  

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2015058079

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

researchmap

Language：Japanese   Publisher：(株)中外医学社  

1歳未満の乳児期に発症する白血病は,他の小児白血病と比し白血球数の著増,肝脾腫や中枢神経浸潤などの髄外浸潤を高率に合併するなど,特徴的な臨床像を呈する.乳児白血病ではMLL遺伝子再構成が高率にみられ,その有無が予後を規定する.特にMLL遺伝子再構成陽性の乳児急性リンパ性白血病は極めて難治であり,分子標的療法など,新たな治療法の開発が強く望まれる.近年の網羅的な遺伝子プロファイリングは,造血細胞の白血病化と生存に必要な要因を抽出するにあたり有効な方法であり,MLL遺伝子再構成陽性例を含む乳児白血病でもその病態が次第に解明されつつある.遺伝子発現プロファイリングの臨床応用により,白血病の病態の解明,および白血病細胞の性格に基づいた精度の高いリスク評価により,個々の症例に応じた適確な治療法への道が開きつつある.(著者抄録)

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a subtype of acute myeloid leukemia, affecting mainly the elderly. It is thought to be derived from plasmacytoid dendritic cell precursors, which frequently present as cutaneous lesions. We have made a detailed analysis of an infant with BPDCN, who manifested with hemophagocytic lymphohistiocytosis. The peripheral blood leukocytes revealed the t(2;17;8)(p23;q23;p23) translocation and a CLTC-ALK fusion gene, which have never been reported in BPDCN or in any myeloid malignancies thus far. Neonatal blood spots on the patient's Guthrie card were analyzed for the presence of the CLTC-ALK fusion gene, identifying the in utero origin of the leukemic cell. Although the leukemic cells were positive for CD4, CD56, CD123, and CD303, indicating a plasmacytoid dendritic cell phenotype, detailed analysis of the lineage distribution of CLTC-ALK revealed that part of monocytes, neutrophils, and T cells possessed the fusion gene and were involved in the leukemic clone. These results indicated that leukemic cells with CLTC-ALK originated in a multipotent hematopoietic progenitor in utero. This is the first report of the CLTC-ALK fusion gene being associated with a myeloid malignancy, which may give us an important clue to the origin of this rare neoplasm. (c) 2013 Wiley Periodicals, Inc.

DOI： 10.1002/gcc.22119

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本検査血液学会  

症例は14歳女児で、咳嗽、耳鳴、頭痛を主訴に、血液検査にて白血球数および芽球の増加、血小板の減少を認め、当科受診となった。骨髄検査および各種遺伝子検査の結果、AML1-ETO転座とFLT3-ITD変異を伴う複雑な染色体異常を有する急性骨髄性白血病(AML)M2と診断した。AML-05プロトコールに準じた治療を開始したが、1回目の緩解導入療法後には5.5%、2回目の緩解導入療法後も4.0%と末梢血中に芽球が認められ、治療抵抗性を示している。

researchmap

Language：Japanese   Publisher：(一社)日本小児血液・がん学会  

同種造血幹細胞移植後にドナー由来の悪性腫瘍を発症することはまれである。症例は6歳女児。生後30生日で急性リンパ性白血病と診断し、生後4ヵ月時に第一寛解期で非血縁者間臍帯血移植を施行した。ドナーは男児で、human leukocyte antigen(HLA)はDNA型で4/6一致であった。移植後12ヵ月目に骨髄再発したため、第二寛解期に非血縁者間骨髄移植を施行した。ドナーは男性でHLAはDNA型で6/6一致であった。2回目の移植から47ヵ月後に、定期検査で末梢血にアウエル小体を有する芽球を認め、その4ヵ月後に骨髄異形成症候群(MDS)/急性骨髄性白血病(AML)と確定診断した。末梢血の芽球・Tリンパ球のHLA検査で骨髄ドナー由来のMDS/AMLと判明した。MDS/AMLに対して非血縁者間骨髄移植を行い、現時点で寛解を維持している。本症例では、化学療法と移植、および免疫抑制剤の長期使用による骨髄環境の変化がMDS/AML発症の要因になった可能性が考えられた。(著者抄録)

researchmap

Language：Japanese   Publisher：(株)日本臨床社  

researchmap

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

MicroRNAs (miRNAs) regulate cell proliferation and differentiation by controlling the expression of proteins involved in many signaling pathways. Recent studies have shown that dysregulation of miRNA expression is associated with increased tumorigenicity and a poor prognosis in several types of cancers. The miRNA let-7b is one of the severely downregulated miRNAs in mixed-lineage leukemia (MLL)-rearranged acute lymphoblastic leukemia (ALL) patients. In vitro transfection of leukemogenic MLL fusion genes into human embryonic kidney-293 cells suppressed let-7b expression. In leukemic cells with an MLL fusion gene, the regulatory region for let-7b expression was hypermethylated, and its expression was partially recovered after culturing the cells with the demethylating agent 5-azacitidine. These results suggest that loss of let-7b expression may be one of the consequences of oncogenic MLL fusion proteins, and contributes to leukemogenesis possibly through the upregulation of let-7b-regulated target genes with leukemogenic potential in hematopoietic cells. The enforced expression of let-7b in ALL cell lines with an MLL fusion gene inhibited their growth, indicating the possible use of let-7b as a new therapeutic tool for refractory infant ALL with an MLL fusion gene. © 2013 Macmillan Publishers Limited All rights reserved.

DOI： 10.1038/leu.2012.242

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/j.1442-200X.2011.03358.x

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

DOI： 10.11406/rinketsu.52.686

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2011347364

Language：Japanese   Publisher：(株)中外医学社  

エピジェネティックな変化であるDNAメチル化は,同一の遺伝情報(DNA)から組織特異的な発現を獲得するための遺伝子発現制御機構として,組織発生や細胞分化,増殖のコントロールに重要な役割を果たしている.白血病を含む悪性腫瘍では,DNAメチル化異常による癌抑制遺伝子の発現消失は,染色体異常や遺伝子変異と並び,腫瘍の進展に関与する重要な因子である.近年のゲノムワイドな解析により,白血病では癌抑制遺伝子のみではなく,様々な機能を有する数多くの遺伝子が異常なDNAメチル化を介して発現異常をきたしていることが明らかになってきた.メチル化される遺伝子群は,その病型により特徴的なパターンをとる.またメチル化が予後と相関する遺伝子も同定され,予後予測因子としてのDNAメチル化異常も注目されている.DNAメチル化に基づく遺伝子の発現異常は,脱メチル化剤によって解除される可逆的な変化であり,治療標的としての重要性も高い.(著者抄録)

researchmap

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

HDR syndrome is an autosomal dominant disorder characterized by hypoparathyroidism, sensorineural deafness, and renal anomaly caused by mutation of the GATA3 gene located at chromosome 10p15. We report the case of a neonate with HDR syndrome and a novel GATA3 mutation. We performed genetic and functional analysis of GATA3 in this patient and identified a novel heterozygous 1516G &gt; C missense mutation in exon 5, resulting in a cysteine-to-serine substitution at codon 321 (Cys321Ser). Mutated and wild-type GATA3 proteins were expressed at a similar level in vitro, indicating that the mutated GATA3 protein was stable. Luciferase assay revealed that the Cys321Ser-mutated GATA3 lacked transactivation activity due to loss of DNA-binding activity as confirmed by gel shift assay. Moreover, mutated GATA3 exerted a dominant-negative effect over the transactivation activity of wild-type GATA3. These findings indicate that not only haploinsufficiency of GATA3 but also the dominant-negative effect of Cys321Ser-mutated GATA3 might have been responsible for the HDR syndrome phenotype of our patient.

DOI： 10.1007/s00109-010-0702-6

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

The ETS variant gene 6 (ETV6) gene is located at 12p13, and is frequently involved in translocations in various human neoplasms, resulting in the expression of fusion proteins consisting of the amino-terminal part of ETV6 and unrelated transcription factors or protein tyrosine kinases. Leukemia with t(1;12)(q21;p13) was previously described in a 5-year-old boy with acute myeloblastic leukemia (AML-M2) who exhibited a novel ETV6-aryl hydrocarbon receptor nuclear translocator (ARNT) fusion protein. We herein report the case of a 2-year-old boy with T-cell lymphoblastic leukemia (T-ALL) harboring t(1;12)(q21;p13). Fluorescence in situ hybridization (FISH) with a ETV6 dual-color DNA probe revealed that the split signals of the ETV6 gene in 96.7% of bone marrow cells, indicating rearrangement of the ETV6 gene. Therefore, we performed a FISH analysis with bacterial artificial chromosome (BAC) probes containing the ARNT, BCL9, and MLLTI1 genes located at 1q21, and these results indicated that the ARNT gene might be involved in the t(1;12)(q21;p13). Reverse transcriptase-polymerase chain reaction analysis disclosed the existence of a ETV6-ARNT fusion gene. To our knowledge, the current report is novel in its report of the ETV6-ARNT fusion in childhood T-ALL. The ETV6 ARNT fusion is associated not only with AML but also with T-ALL. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.cancergencyto.2010.07.121

Web of Science

PubMed

researchmap

Language：Japanese  

CiNii Books

researchmap

Language：Japanese   Publisher：金原出版(株)  

CiNii Books

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

TEL/ETV6 located at chromosome 12p13 encodes a member of the E26 transformation-specific family of transcription factors. TEL is known to be rearranged in a variety of leukemias and solid tumors resulting in the formation of oncogenic chimeric protein. Tel is essential for maintaining hematopoietic stem cells in the bone marrow. To understand the role of TEL in erythropoiesis, we generated transgenic mice expressing human TEL under the control of Gata1 promoter that is activated during the course of the erythroid-lineage differentiation (GATA1-TEL transgenic mice). Although GATA1-TEL transgenic mice appeared healthy up to 18 months of age, the level of hemoglobin was higher in transgenic mice compared to non-transgenic littermates. In addition, CD71(+)/TER119(+) and c-kit(+)/CD41(+) populations proliferated with a higher frequency in transgenic mice when bone marrow cells were cultured in the presence of erythropoietin and thrombopoietin, respectively. In transgenic mice, enhanced expression of Alas-e and beta-major globin genes was observed in erythroid-committed cells. When embryonic stem cells expressing human TEL under the same Gata1 promoter were differentiated into hematopoietic cells, immature erythroid precursor increased better compared to controls as judged from the numbers of burst-forming unit of erythrocytes. Our findings suggest some roles of TEL in expanding erythroid precursors and accumulating hemoglobin. (Cancer Sci 2009; 100: 689-697)

DOI： 10.1111/j.1349-7006.2009.01097.x

Web of Science

PubMed

researchmap

Language：English   Publisher：SPRINGER TOKYO  

DOI： 10.1007/s12185-009-0267-8

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The treatment outcome for infant acute lymphoblastic leukemia (ALL) with positive MLL gene rearrangements remains poor. We analyzed whether additional chromosomal abnormalities (ACA) other than 11q23 translocation could affect the disease behavior and its prognosis.
Eighteen of seventy-four patients with infant acute lymphoblastic leukemia showed ACA, including three-way translocations in four, other novel translocations in four, and complex structural chromosomal changes in four. Only age less than 6 months and positive central nervous system leukemia were significant prognostic factors by multivariate analysis. However, overall survival rates were worse in patients with ACA compared to those with non-ACA. Genetic alterations induced by additional chromosomal changes may be associated with disease progression and poorer overall survival rates in infants with MLL-rearranged ALL. Crown Copyright (c) 2008 Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2009.03.018

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

NOTCH1 mutations are common in T-lineage acute lymphoblastic leukemia (TALL). Twin studies and retrospective screening of neonatal blood spots provide evidence that fusion genes and other chromosomal abnormalities associated with pediatric leukemias can originate prenatally. Whether this is also the case for NOTCH1 mutations is unknown. Eleven cases of T-ALL were screened for NOTCH1 mutations and 4 (36%) had mutations in either the heterodimerization (HD) or proline glutamic acid/serine/threonine (PEST) domains. Of these 4, 3 could be amplified by mutation-specific polymerase chain reaction primers. In one of these 3, with the highest sensitivity, NOTCH1 mutation was detected in neonatal blood spots. In this patient, the blood spot was negative for SIL-TAL1 fusion, present concomitant with NOTCH1 mutation, in the diagnostic sample. We conclude that NOTCH1 can be an early or initiating event in T-ALL arising prenatally, to be complemented by a postnatal SIL-TAL1 fusion.

DOI： 10.1182/blood-2007-02-074690

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

We evaluated the efficacy of a treatment strategy in which infants with acute lymphoblastic leukemia (ALL) were stratified by their MLL gene status and then assigned to different risk-based therapies. A total of 102 patients were registered on two consecutive multicenter trials, designated MLL96 and MLL98, between 1995 and 2001. Those with a rearranged MLL gene (MLL-R, n = 80) were assigned to receive intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT), while those with germline MLL (MLL-G, n = 22) were treated with chemotherapy alone. The 5-year event-free survival (EFS) rate for all 102 infants was 50.9% (95% confidence interval, 41.0-60.8%). The most prominent late effect was growth impairment, observed in 58.9% of all evaluable patients in the MLL-R group. This plan of risk-based therapy appears to have improved the overall prognosis for infants with ALL, compared with previously reported results. However, over half the events in patients with MLL rearrangement occurred before the instigation of HSCT, and that HSCT-related toxic events comprised 36.3% (8/22) of post-transplantation events, suggesting that further stratification within the MLL-R group and the development of more effective early-phase intensification chemotherapy will be needed before the full potential of this strategy is realized.

DOI： 10.1038/sj.leu.2404903

Web of Science

PubMed

researchmap

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

researchmap

Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/sj.leu.2404397

Web of Science

PubMed

researchmap

Language：English   Publisher：WILEY-LISS  

PILL fusion genes are a predominant feature of acute leukemias in infants and in secondary acute myeloid leukemia (AML) associated with prior chemotherapy with topo-II poisons. The former is considered to possibly arise in utero via transplacental chemical exposure. A striking feature of these leukemias is their malignancy and remarkably brief latencies implying the rapid acquisition of any necessary additional mutations. We have suggested that these coupled features might be explained if MLL fusion gene encoded proteins rendered cells more vulnerable to further DNA damage and mutation in the presence of chronic exposure to the agent(s) that induced the MLL fusion itself. We have tested this idea by exploiting a hormone regulated MLL-ENL (MLLTI) activation system and show that MLL-ENL function in normal murine progenitor cells substantially increases the incidence of chromosomal abnormalities in proliferating cells that survive exposure to etoposide VP-16. This phenotype is associated with an altered pattern of cell cycle arrest and/or apoptosis. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/gcc.20338

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：(株)医薬ジャーナル社  

チロシンキナーゼは細胞の増殖をコントロールする細胞生存に必須のタンパク質である.近年慢性骨髄増殖疾患においてチロシンキナーゼJak2の変異が同定され,チロシンキナーゼがその発症に果たす役割が注目されている.一方,骨髄増殖性疾患ではTEL-PDGFRβのように染色体転座にともなうチロシンキナーゼ異常も認められる.転写因子TEL/ETV6(translocation Ets leukemia/Ets variant gene 6)とPDGFRβ(platelet derived growth factor receptor β)等のチロシンキナーゼとのキメラ蛋白を有する骨髄増殖性疾患は異形成をともなうことが多く,Jak2点突然変異を有する疾患群とは異なるスペクトラムの疾患群を形成する.本稿ではTEL-チロシンキナーゼキメラ蛋白を有する骨髄増殖疾患の特徴について述べる(著者抄録)

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：FERRATA STORTI FOUNDATION  

Background and Objectives. The enzyme NAD(P)H:quinone oxidoreductase (NQO1) detoxifies chemicals with quinone rings including benzene metabolites and flavonoids. Previous studies in Caucasian populations have provided evidence that a loss of function allele at nt 609 (C609T, Pro187Ser) is associated with increased risk of infant acute lymphoblastic leukemia (ALL) with MLL-AF4 fusion genes.
Design and Methods. We genotyped 103 infants (&lt;18 months) with ALL or acute myeloid leukemia (AML) in Japan and 185 controls for the frequency of allelic variation at nt 609 and 465 in NQO1 using standardized polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology.
Results. The C609T polymorphism is very common in Japan but we found no link with altered risk for infant ALL. However, a variant of another allele at nt 465 (C465T, Arg139Trp), also associated with diminished enzyme activity, was strongly associated (OR 6.36; Cl 1.84-21.90; p = 0.002) with infant ALL, especially in t(4;11)(q21;q23), MLL-AF4. No association was found between this allele and risk of infant AML with MLL gene fusions or infant ALL without MLL gene fusions. The same C465T allele has been linked recently, in an Oriental population, to sensitivity to benzene hematotoxicity.
Interpretation and Conclusions. These data endorse the notion that infant ALL with MLL fusion genes have a unique etiology possibly involving transplacental exposure to chemicals.

Web of Science

PubMed

researchmap

Language：English   Publisher：CARDEN JENNINGS PUBL CO LTD  

Chromosome translocations disrupting the MLL gene are associated with various hematologic malignancies but are particularly common in infant and secondary therapy-related acute leukemias. The normal MLL-encoded protein is an essential component of a supercomplex with chromatin-modulating activity conferred by histone acetylase and methyltransferase activities, and the protein plays a key role in the developmental regulation of gene expression, including Hox gene expression. In leukemia, this function is subverted by breakage, recombination, and the formation of chimeric fusion with one of many alternative partners. Such MLL translocations result in the replacement of the C-terminal functional domains of MLL with those of a fusion partner, yielding a newly formed MLL chimeric protein with an altered function that endows hematopoietic progenitors with self-renewing and leukemogenic activity. This potent impact of the MLL chimera can be attributed to one of 2 kinds of activity of the fusion partner: direct transcriptional transactivation or dimerization/oligomerization. Key unresolved issues currently being addressed include the set of target genes for MLL fusions, the stem cell of origin for the leukemias, the role of additional secondary mutations, and the origins or etiology of the MLL gene fusions themselves. Further elaboration of the biology of MLL gene-associated leukemia should lead to novel and specific therapeutic strategies.

DOI： 10.1532/IJH97.05042

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

TEL-TRKC is a fusion gene generated by chromosomal translocation and encodes an activated tyrosine kinase. Uniquely, it is found in both solid tumors and leukemia. However, a single exon difference (in TEL) in TEL-TRKC fusions is associated with the two sets of cancer phenotypes. We expressed the two TEL-TRKC variants in vivo by using the 3' regulatory element of SCL that is selectively active in a subset of mesodermal cell lineages, including endothelial and hematopoietic stem cells and progenitors. The leukemia form of TEL-TRKC (- exon 5 of TEL) enhanced hematopoietic stem cell renewal and initiated leukemia. In contrast, the TEL-TRKC solid tumor variant (+ TEL exon 5) elicited an embryonic lethal phenotype with impairment of both angiogenesis and hematopoiesis indicative of an effect at the level of the hemangioblasts. The ability of TEL-TRKC to repress expression of Flk1, a critical regulator of early endothelial and hematopoietic cells, depended on TEL exon 5. These data indicate that related oncogenic fusion proteins similarly expressed in a hierarchy of early stem cells can have selective, cell type-specific developmental impacts.

DOI： 10.1073/pnas.0405318102

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NEW YORK ACAD SCIENCES  

Stem and progenitor cells present attractive targets for transformation by leukemia-associated fusion genes generated by chromosomal translocation. The mechanism by which these fusion genes corrupt the transcriptional programs of these cellular compartments remains largely unknown. We have sought to gain insight into these issues through expressing TEL-AML1 and TEL-TRKC fusion genes in murine stem cells and recording effects on cell behavior in a transplant setting.

DOI： 10.1196/annals.1349.003

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

The MLL (mixed lineage leukemia) gene forms chimeric fusions with a diverse set of partner genes as a consequence of chromosome translocations in leukemia. In several fusion partners, a transcriptional activation domain appears to be essential for conferring leukemogenic capacity on MILL protein. Other fusion partners, however, lack such domains. Here we show that gephyrin (GPHN), a neuronal receptor assembly protein and rare fusion partner of MLL in leukemia, has the capacity as an MLL-GPHN chimera to transform hematopoietic progenitors, despite lack of transcriptional activity. A small 15-amino acid tubulin-binding domain of GPHN is necessary and sufficient for this activity in vitro and in vivo. This domain also confers oligomerization capacity on MLL protein, suggesting that such activity may contribute critically to leukemogenesis. The transduction of MLL-GPHN into hematopoietic progenitor cells caused myeloid and lymphoid lineage leukemias in mice, suggesting that MLL-GPHN can target multipotent progenitor cells. Our results, and other recent data, provide a mechanism for oncogenic conversion of MILL by fusion partners encoding cytoplasmic proteins. (C) 2004 by The American Society of Hematology.

DOI： 10.1182/blood-2003-11-3817

Web of Science

PubMed

researchmap

Language：English   Publisher：CARDEN JENNINGS PUBL CO LTD  

The MLL gene is a major player in leukemia, particularly in infant leukemia and in secondary, therapy-related acute leukemia. The normal MLL gene plays a key role in developmental regulation of gene expression (including HOX genes), and in leukemia this function is subverted by breakage, recombination, and chimeric fusion with one of 40 or more alternative partner genes. In infant leukemias, the chromosome translocations involving MLL arise during fetal hematopoiesis, possibly in a primitive lymphomyeloid stem cell. In general, these leukemias have a very poor prognosis. The malignancy of these leukemias is all the more dramatic considering their very short preclinical natural history or latency. These data raise fundamental issues of how such divergent MLL chimeric genes transform cells, why they so rapidly evolve to a malignant status, and what alternative or novel therapeutic strategies might be considered. We review here progress in tackling these questions. Int J Hematol. 2003;78:390-401. (C) 2003 The Japanese Society of Hematology.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Most patients with acute myeloid leukemia (AML) enter complete remission (CR) after treatment with chemotherapy, but a large number of them experience relapse with resistant disease. To identify genes that are associated with their prognoses, we analyzed gene expression in 54 pediatric patients with AML using an oligonucleotide microarray that contained 12566 probe sets. A supervised approach using the Student t test selected a prognostic set of 35 genes, some of which are associated with the regulation of cell cycle and apoptosis. Most of these genes had not previously been reported to be associated with prognosis and were not correlated with morphologically classified French-American-British (FAB) subtypes or with karyotypes. These results indicate the existence of prognosis-associated genes that are independent of cell lineage and cytogenetic abnormalities, and they can provide therapeutic direction for individual risk-adapted therapy for pediatric AML patients.

DOI： 10.1182/blood-2003-02-0578

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Infant acute myeloid leukemia (AML) of less than 12 months old is generally characterized by a high incidence of acute monoblastic or myelomonoblastic leukemia with hyperleukocytosis and extramedullary involvement. Most of the leukemic cells have 11q23 translocations, which lead to the MLL gene rearrangements. The MLL gene rearrangements occur at a high frequency in monoblastic subtype, hyperleukocytosis or young age in infant AML. Compared with acute lymphoblastic leukemia, however, it remains unknown whether prenatal origin exists in the pathogenesis of infant AML. Recently, the treatment outcome of infant AML has been clarified by two study groups, which confirmed the effect of intensive chemotherapy including repeated cycles of cytarabine and anthracyclines for infant AML. Presence of the MLL gene rearrangements, gender, age and white blood cell count showed no influence on the outcome of infant AML. The allogeneic hematopoietic stem cell transplantation (HSCT) remains the treatment of choice for infant AML when a matched related donor is available. Monitoring of minimal residual disease by real-time PCR is a useful technique to predict the outcome or efficacy of the treatment in infant AML. Although intensive chemotherapy and/or allogeneic HSCT have cured most AML infants, some still relapse and ultimately die. A need remains for future development by exploiting the unusual biologic properties of leukemic progenitor cells expressing the abnormal MLL gene product.

DOI： 10.1080/1042819031000063363

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING LTD  

We studied the effectiveness of risk-directed therapy for infants younger than 13 months of age with acute lymphoblastic leukaemia (ALL). Fifty-five infants were assigned to different treatment programs (from December 1995 to December 1998) on the basis of their MLL gene status at diagnosis. Forty-two cases (76.3%) had a rearranged MLL gene (MLL (+) ) and were treated with remission induction therapy followed by sequential intensive chemotherapy, including multiple genotoxic agents (MLL9601 protocol). Haematopoietic stem cell transplantation (HSCT) was attempted if suitable donors were available. Thirteen infants (23.7%) were classified as MLL (-) and treated for 2.5 years with intensive chemotherapy for high-risk B-ALL (MLL9602 protocol). Complete remission was induced in 38 of the 42 infants (90.5%) with MLL (+) ALL and in all 13 patients (100%) with MLL (-) disease. In the MLL (+) subgroup, the estimated event-free survival (EFS) rate at 3 years post diagnosis was 34.0% +/- 7.5%, compared with 92.3% +/- 7.4% in the MLL (-) subgroup (overall comparison, P = 0.001 by log-rank analysis). Both age less than 6 months (hazard ratio = 6.87, 95% CI = 0.91-52.3; P = 0.013) and central nervous system (CNS) involvement at diagnosis (hazard ratio = 2.92 95% CI = 1.29-6.63; P = 0.015) were significant independent predictors of an inferior outcome. These findings indicate a strategic advantage in classifying infant ALL as either MLL (+) or MLL (-) early in the clinical course and selecting therapy accordingly. Standard chemotherapy for high-risk B-lineage ALL appeared adequate for MLL (-) cases. Novel therapeutic initiatives are warranted for infants with MLL (+) disease, particularly those with initial CNS leukaemic involvement or age less than 6 months, or both.

DOI： 10.1046/j.1365-2141.2002.03754.x

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：CARDEN JENNINGS PUBL CO LTD  

The correlation between infant leukemia and in utero exposure to topoisomerase II (topo-II) inhibitor has been clarified. We examined the in vitro effect of topo-II inhibitor (etoposide) on cleavage of the MLL. gene in cord and peripheral blood mononuelcar cells (MNCs). Southern blot analysis showed cleavage of the MLL gene in peripheral blood MNCs of infants when the MNC's were exposed to etoposide. MNCs were incubated with etoposide at various concentrations (1 to 50 muM), and a ligation-mediated polymerase chain reaction (LM-PCR) was used to detect double strand breaks (DSBs) of DNA in intron 8 of the MLL breakpoint cluster region. PCR products obtained with LM-PCR were subcloned and sequenced to identify the breakpoint in the MLL gene. The PCR products indicated DSBs of the MLL gene were obtained without any difference in the incidence between 3 different samples (cord and peripheral blood from infants and children). Sequencing analysis showed that the DSBs occurred on the telomeric side of intron 8 and near exon 9. There was no evidence that the cord blood was more susceptible to MLL DNA breakage by topo-II inhibitor than were other cells, Instability of the partner gene during the fetal period could be associated with the pathogenesis of infant leukemia.

DOI： 10.1007/BF02982722

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：特定非営利活動法人 日本小児血液・がん学会  

Many fusion genes have been isolated from genomic breakpoints of chromosome translocations specifically observed in hematopoietic malignancies. Most of the fusion genes involve functionally important key regulatory genes involved in the development of hematopoietic cells, such as transcription factors or protein tyrosine kinases. The loss of functional domain and/or gain of another functional domain from the translocation partner gene often modulate the normal function of a key regulator protein. This abnormally formed fusion protein has the potential to inhibit the differentiation of hematopoietic cells, to promote proliferation, and/or to inhibit apoptotic cell death, finally leading to overt leukemia. The genetic and functional analyses of leukemogenic fusion genes are essential not only to elucidate leukemogenic mechanisms, but also to discover new methods of treatment and ultimately the prevention of leukemia. In this review the current molecular bases of fusion gene formation and current clinical applications are discussed.

DOI： 10.11412/jjph1987.15.427

CiNii Books

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

This study analyzed data on 35 infants with acute myeloid leukemia (AML) who were treated with intensive chemotherapy between 1995 and 1998 in Japan. The incidence of boys, younger age (&lt; 6 months old), and hyperleukocytosis at onset was high in patients with the M4/M5 subtype (n = 23) in the French-American-British classification, compared with the non-M4/M5 subtype (n = 12). Thirteen (56%) and 16 (70%) patients with the M4/M5 subtype also showed 11q23 translocations and MLL gene rearrangements, respectively, whereas only one patient with the non-M4/M5 subtype had this rearrangement. All 35 patients were treated with the ANLL91 protocol consisting of etoposide, high-dose cytarabine, and anthracyclines. Overall survival and the event-free survival (EFS) rates at 3 years of all patients were 76% (95% confidence interval [Cl], 61.3%-90.7%) and 72% (95% Cl, 56.4%-87.9%), respectively. EFS showed no significant difference between 2 subgroups divided by age, gender, presence of the MLL gene rearrangements, and white blood cell count at onset; EFS in patients with the M4/M5 subtype tended to be better than those with the non-M4/M5 subtype. Although all 6 patients who underwent allogeneic stem cell transplantation (SCT) have been in complete remission, no benefit of SCT was confirmed. These findings suggest that the intensive chemotherapy with the ANLL91 protocol might have been responsible for the observed good outcome of infant AML, even without SCT. The presence of the MLL gene rearrangements or the age at onset had no impact on the outcome of infant AML. (C) 2001 by The American Society of Hematology.

DOI： 10.1182/blood.V98.13.3589

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

We report a novel MLL-associated chromosome translocation t(11;14)(q23;q24) in a child who showed signs of acute undifferentiated leukemia 3 years after intensive chemotherapy, that included the topoisomerase-II inhibitor VP 16. Screening of a cDNA library of the patient's leukemic cells showed a novel fusion transcript between MLL and the Gephyrin (GPHN) gene on 14q24. The resulting MLL-GPHN fusion gene encodes MLL AT hook motifs and a DNA methyltransferase homology domain fused to the C-terminal half of Gephyrin, including a presumed tubulin binding site and a domain homologous to the Escherichia coli molybdenum cofactor biosynthesis protein MoeA. Genomic breakpoint analysis showed potential, in vitro topoisomerase-II DNA-binding sites spanning the breakpoints in both MLL and GPHN but no flanking sequences that might mediate homologous recombination. This suggests that MLL-GPHN may have been generated by VP 16/topoisomerase-II-induced DNA double-strand breaks, followed by error-prone DNA repair via non-homologous end joining. Gephyrin was originally identified as a submembraneous scaffold protein that anchors and immobilizes postsynaptic membrane neurotransmitter receptors to underlying cytoskeletal elements. It also is reported to bind to phosphatidylinositol 3,4,5-triphosphate binding proteins involved in actin dynamics and downstream signaling and, interacts with ATM-related family member RAFTI. Gephyrin domains in the chimeric protein therefore could contribute novel signal sequences or might modify MLL activity by oligomerization or intracellular redistribution. (C) 2001 Wiley-Liss, Inc.

DOI： 10.1002/gcc.1185

Web of Science

PubMed

researchmap

Language：English   Publisher：WILEY-LISS  

DOI： 10.1002/mpo.1223

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

We observed a fatal case of Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) with an abnormal karyotype. Increased levels of alpha beta T cells of the patient were investigated using an inverse polymerase chain reaction (PCR) of the T-cell receptor variable region gene, followed by J beta -PCR and single-strand conformation polymorphism (SSCP) to confirm the clonality of specific alpha beta -T cell subsets. A high frequency (&gt; 15%) was recognized in V beta9 at onset, but not in any V beta and V alpha families 2 weeks after chemotherapy. High levels (&gt; 20%) of some J beta genes were detected in all V beta families investigated. and the predominant bias of the J beta2 gene relative to the J beta1 gene (86.1% versus 13.9% at onset, and 77.4% versus 23.5% after chemotherapy) was recognized in pan-alpha beta T cells. When each V beta -J beta fragment was compared among the samples at onset and after chemotherapy by SSCP analysis, several distinct bands were observed that indicate a clonal evolution. Thus, the findings suggest that some of the alpha beta T cell clones could be associated with abnormal karyotypes in EBV-HLH. The present findings provide molecular evidence of the presence of oligoclonal T cells in pan-alpha beta -T cells and clonal evolution during a short clinical course in EBV-HLH with abnormal karyotypes. (C) 2001 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0165-4608(01)00435-6

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

TEL-AML1 fusion resulting from the t(12; 21)(p13;q22) is one of the most common genetic abnormalities in childhood acute lymphoblastic leukemia. Recent findings that site-specific cleavage of the MLL gene can be induced by chemotherapeutic agents such as topoisomerase-ll inhibitors suggest that apoptogenic agents can cause chromosomal translocations in hematopoietic cells, This study demonstrates a possible relationship between exposure to apoptogenic stimuli, TEL breaks, and the formation of TEL-AML1 fusion in immature B lymphocytes, Short-term culture of immature B cell lines in the presence of apoptogenic stimuli such as serum starvation, etoposide, or salicylic acid induced double-strand breaks (DSBs) in intron 5 of the TEL gene and intron 1 of the AML1 gene. TEL-AML1 fusion transcripts were also identified by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in cell lines treated by serum starvation or aminophylline. DSBs within the TEL gene were also associated with fusion to other unknown genes, presumably as a result of chromosomal translocation. We also examined 67 cord blood and 147 normal peripheral blood samples for the existence of inframe TEL-AML1 fusion transcripts. One cord blood sample (1.5%) and 13 normal peripheral blood samples (8.8%) were positive as detected by nested RT-PCR, These data suggest that breakage and fusion of TEL and AML I may be relatively common events and that sublethal apoptotic signals could play a role in initiating leukemogenesis via the promotion of DNA damage. (C) 2001 by The American Society of Hematology

DOI： 10.1182/blood.V97.3.737

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

We analyzed 32 patients with various hematological malignancies including acute myelocytic leukemia and non-Hodgkin lymphoma with a breakpoint at 11q22-q25 of chromosome 11, but who did not have rearrangements of the MLL/ALL-1 gene. The breakpoint in each patient was identified by fluorescence in situ hybridization using 21 cosmid probes and 2 YAC probes. Breakpoints for each "rearrangement" involving translocations such as t(1;11), t(2;11), inv(11), t(11;15), and t(10;11) found in 5 of the 11 patients had breakpoints in a small region from Cc111-430 to Cc111-526 at 11q22-q23.1. Furthermore, breakpoints for chromosome deletions at 11q21-q23 in 10 patients were located in the same region as that of translocations. A commonly deleted region among 8 patients was identified from Cc111-526 to Cc111-555 at 11q23.1. Fluorescence in situ hybridization analysis revealed that breakpoints for additive chromosome [add(11)] aberrations, which had additional material of unknown origin at 11q23 to 11925 in 11 patients, were not located at 11q23 but rather at the more telomeric site of Cc111-503 to VIJ(2)2072 at 11q25. These results indicated that the patients had several restricted breakpoint sites, which means that these chromosomal regions have recurrent oncogenes and tumor suppressor genes for pathogenesis for leukemia and lymphoma. (C) 2001 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0165-4608(00)00316-2

Web of Science

PubMed

researchmap

Language：English  

CiNii Books

researchmap

Language：Japanese   Publisher：(有)科学評論社  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

The X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by an abnormal responses to infection with Epstein-Barr virus (EBV), resulting in fatal infectious mononucleosis, hypogammaglobulinemia, virus-associated hemophagocytic syndrome, and malignant lymphoma. Mutations in the gene coding for a T cell-specific SLAM-associated protein (SAP) have been recently identified in XLP patients. We report on a 1-year-old boy representing fulminant hemophagocytic syndrome. He developed high fever, lymphadenopathy, hepatosplenomegaly with liver dysfunction, and pancytopenia with marrow hemophagocytosis, EBV DNA was abnormally increased in the blood. Polymerase chain reaction failed to amplify SAP mRNA and genomic DNA products from the patient's peripheral blood. A large deletion of the SAP gene was confirmed by fluorescence in situ hybridization (FISH), FISH analysis also disclosed that the patient's mother was a carrier. We conclude that FISH can be useful in the diagnosis of XLP with large deletions of the SAP gene and its carrier state. Am. J, Hematol, 64: 128-132, 2000, (C) 2000 Wiley-Liss. Inc.

DOI： 10.1002/(SICI)1096-8652(200006)64:2<128::AID-AJH11>3.0.CO;2-#

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

BACKGROUND. Loss of imprinting (LOI) of insulin-like growth factor-2 (IGF-2) has been implicated in the pathogenesis of certain human cancers and tumor-predisposing overgrowth disorders, such as Beckwith-Wiedemann syndrome. In a previous study, the authors revealed that certain patients with childhood acute leukemia and neuroblastoma had had rapid somatic growth after birth, suggesting the involvement of growth factor(s) in tumorigenesis. In the current study, the authors examined whether relaxation of IGF-2 imprinting occurred in infant leukemia and childhood neuroblastoma.
METHODS. The genomic DNA of infant leukemia, childhood neuroblastoma, and control individuals was amplified by polymerase chain reaction (PCR). Patients who had heterozygous genotype were selected as informative cases using Apa I polymorphism in exon 9 of the IGF-2 gene. Total RNA was isolated from informative cases, followed by cDNA synthesis. cDNA was amplified by PCR, and direct sequence was performed for determining allele specific transcription.
RESULTS. Twenty of 22 infant leukemia blasts and ail of 16 neuroblastoma cells showed normal monoallelic expression of IGF-2 as well as 23 controls. The height and weight of two acute lymphoblastic leukemia patients with LOI were within normal ranges for Japanese children.
CONCLUSIONS. The current study revealed that the imprinting status of IGF-2 was generally maintained in infant leukemia and confirmed that it was maintained in childhood neuroblastoma. The results suggest that LOI of IGF-2 does not play a major role in the carcinogenesis of these diseases or in rapid physical growth of the patients. Cancer 2000;88:2372-7. (C) 2000 American Cancer Society.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

In recent pediatric collaborative studies of acute myeloid leukemia (AML), patients with Down's syndrome (DS) have better outcome than other patients when they were treated according to their intensive AML protocols. This may be attributed to enhanced sensitivity of DS AML cells to selected chemotherapeutic agents. We evaluated a less intensive chemotherapeutic regimen which was specifically designed for children with AML-DS. Remission induction chemotherapy consisted of daunorubicin (25 mg/m(2)/day for 2 days), cytosine arabinoside (100 mg/m(2)/day for 7 days), and etoposide (150 mg/m(2)/day for 3 days). Patients received one to seven courses of consolidation therapy of the same regimen. Thirty-three patients were enrolled on the study and their clinical, hematologic and immunophenotypic features were analyzed. Of the 33 patients, all were younger than 4 years and diagnosed as having acute megakaryoblastic leukemia or myelodysplastic syndrome. All patients achieved a complete remission and estimated 8 year event-free survival rate was 80 +/- 7%. Three patients relapsed and two died due to cardiac toxicity and one due to septic shock. The results of our study showed that patients with AML-DS constitute a unique biologic subgroup and should be treated according to a less intensive protocol designed for AML-DS.

Web of Science

researchmap

Language：English   Publisher：NATURE PUBLISHING GROUP  

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：(株)医薬ジャーナル社  

researchmap

Language：Japanese   Publisher：(一社)日本血液学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

The ETV6/TEL gene has been reported to fuse to PDGFR beta b MDS1/EVI1, BTL, ACS2, STL, JAK2, ASL, CDX2, TRKC, AML1, and MN1. Among them, PDGFR beta, ASL, JAK2, and TRKC are tyrosine kinases (TK), We identified a novel ETV6 partner gene, ARG (ABL-related gene or ASL2), another TK gene in a cell line established from a patient with acute myelogenous leukemia (AML-MB) with a t(15;17)(q22;q11.2) and a t(1;12)(q25;p13), which has the remarkable feature to differentiate to mature eosinophils in culture with all-trans retinoic acid and cytokines, The ETV6/ARG transcripts consisted of exon 1 to 5 of ETV6 and the 3' portion of ARG starting from exon IB or exon 2, resulting in an open reading frame for a fusion protein consisting of the entire PNT oligomerization domain of ETV6 and all of the functional domains of ARG including the TK domain. This is the same protein structure as identified In the other ETV6 TK fusion proteins. The reciprocal ARG/ETV6 transcript was not expressed, and the normal ETV6 allele was not deleted or rearranged. Although the ABL Is known to be involved in various human malignancies, ARG has not been involved in human malignancies despite its high homology to ASL, Thus, this Is the first report showing involvement of ARG in human leukemia, The ETV6/ARG protein may be involved in the unique differentiation capacity of this cell line. (C) 2000 by The American Society of Hematology.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

The protein p27(Klp1) is one of the cyclin-dependent kinase inhibitors that are known to play important roles in the regulation of cell-circle progression. Low. levels of p27 expression in malignant cells are associated with poor prognosis in patients with breast. lung, colorectal and gastric cancers, To determine the relation of cyclin-dependent kinase inhibitors to histopathological grades of B-cell non-Hodgkin's lymphomas, the expression of p27, cyclin Df and cyclin E in lymph node tissues was investigated in 56 patients with B-cell non-Hodgkin's lymphomas by western blotting and immunohistochemical techniques. High levels of p27 expression were observed in most lymph node tissue samples (93%) obtained from patients with low grade B-cell non-Hodgkin's lymphomas, while expression was low in lymph node tissue taken from all patients with intermediate and high grade B-cell non-Hodgkin's lymphomas. The difference in p27 expression in lymphoma tissues was significant among the different histopathological grades of B-cell non-Hodgkin's lymphomas (P&lt;0.01), The analysis of the survival time of patients showed that the reduction of p27 expression correlated with poor prognosis. Cyclin DI. showed a high level of expression in mantle cell lymphomas and high grade B-cell non-Hodgkin's lymphomas. Cyclin E showed limited expression in Ig of 31 lymphoma tissues, Both cyclin D1 and E protein expression were not significantly different among the grades of B-cell non-Hodgkin's lymphomas. These results demonstrate that the level of p27 expression in lymphoma tissue is an important parameter in the classification of B-cell non-Hodgkin's lymphomas and in the prediction of prognosis.

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Fluorescence in situ hybridization (FISH) is suitable for detecting different types of chromosome aberrations on interphase nuclei even in specimens with no or few chromosome metaphases. However, it is not known why FISH is superior to conventional G-banding analysis. The sensitivity of interphase FISH was compared to that of G-handing analysis in 288 leukemia/lymphoma patients for 10 different types of chromosome aberrations: t(9;22) (M- and m-BCR), t(8;21), 11q23 abnormalities, t(15;17), del(5)/-5, del(13)/-13, +8, -7, and +12. The results revealed that t(15;17) positive cells could not proliferate well in culture, leading to underestimation of abnormality by G-banding, Monosomy 7 in acute myelocytic leukemia (AML) and myelodysplastic syndrome (MDS) as well as trisomy 12 and deletion chromosome 13 in chronic lymphocytic leukemias (CLL) were also severely underestimated by G-banding. On the other hand, no discrepancies were observed in t(8;21), t(9;22), translations involving 11q23, or in trisomy 8. These findings indicate the superiority of interphase FISH over conventional cytogenetics for detecting chromosome abnormalities in small clones, especially for monosomy 7 or (15;17) translocations. (C) Elsevier Science Inc., 1999. All rights reserved.

DOI： 10.1016/S0165-4608(99)00079-5

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：STOCKTON PRESS  

In order to identify a commonly deleted region of 13q14 on chromosome 13, we performed fluorescence in situ hybridization (FISH) on 17 patients with myeloid malignancies and 12 patients with lymphoid leukemia/lymphoma who exhibited either deletion or translocation at 13q14. Three cosmid probes (RB, D13S319 and D13S25) hybridizing to sequences on 13q14 were used. Fourteen of the 17 patients with myeloid malignancies (82.4%) exhibited allelic loss at the RE, D13S319 and D13S25 locus, whereas only three of the 12 patients with lymphoid malignancies (25.0%) exhibited loss within these loci. These three patients had chronic lymphocytic leukemia (CLL). Six, two and one of the remaining nine lymphoid leukemia/lymphoma patients had breakpoints centromeric to the RE gene, telomeric to D13S25 and within the D13S319 locus, respectively. A high frequency of allelic loss was found using these probes in patients with myeloid malignancies, compared to in patients with leukemia in the lymphoid origin, except CLL patients. These results indicate that loss of the RE gene itself or a region between RE and D13S319, which includes commonly deleted loci, may play an important role in myeloid leukemogenesis.

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：日本小児血液学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：CARDEN JENNINGS PUBL CO LTD  

Monosomy 7 in isolated bone marrow mononuclear cells and colony forming cells from patients with aplastic anemia who later developed myelodysplastic syndrome/leukemia with monosomy 7 were examined by fluorescence in situ hybridization. Colonies derived from bone marrow mononuclear cells of the aplastic anemia patients consisted of a mixture of cells of normal karyotype and monosomy 7, ranging from 0 to 97.2%. This result suggests that colony forming cells initially had a normal karyotype but then lost chromosome 7 during growth in the semisolid culture. This finding suggests the genetically unstable condition of chromosome 7 in colony forming cells in aplastic anemia patients This chromosome instability of colony forming cells may lead to malignant transformation. (C) 1999 The Japanese Society of Hematology.

Web of Science

PubMed

researchmap

Language：Japanese  

DOI： 10.11412/jjph1987.13.199

CiNii Books

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Ataxia telangiectasia (AT) carrier-derived :lymphoblastoid cell lines (AT-LCLs/hetero) with suboptimal ATM protein expression were examined for the regulation of radiosensitivity, apoptosis, and mitotic spindle checkpoint in response to DNA-damaging agents. Although AT-LCLs/hetero showed intermediate radiation sensitivity, as determined by clonogenic assay, they were resistant to early-onset apoptosis, as much as AT patient-derived LCLs (AT-LCLs/homo) Furthermore, two of three AT-LCLs/hetero shelved defective mitotic spindle checkpoint control in response to X-ray irradiation, which is, a recently characterized biological feature in AT-LCLs/homo, Our findings indicate that carriers of ATM mutation have biological abnormalities due to haploinsufficiency of ATM protein or dominant-negative effect of mutant ATM protein. Thus, although it is still controversial whether ATM mutation carriers are at higher risk for cancer during adulthood, our findings based on in vitro biological indicators support the notion that at least some of such carriers are at a higher risk for cancer development than those without ATM mutation. Oar findings may help to reevaluate epidemiological studies on cancer susceptibility in AT carriers.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder expressed in infancy and characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies. Our previous hematological analysis indicated similarities between human CAMT and murine c-mpl (thrombopoietin receptor) deficiency. Because the c-mpl gene was considered as one of the candidate genes for this disorder, se analyzed the genomic sequence of the c-mpl gene of a 10-year-old Japanese girl with CAMT. We detected two heterozygous point mutations: a C-to-T transition at the cDNA nucleotide position 556 (Q186X) in exon 4 and a single nucleotide deletion of thymine at position 1,499 (1,499 delT) in exon 10, Both mutations sere predicted to result in a prematurely terminated c-Mpl protein, which, if translated, lacks all intracellular domains essential for signal transduction, Each of the mutations sas segregated from the patient's parents. Accordingly, the patient was a compound heterozygote for two mutations of the c-mpl gene, each derived from one of the parents. The present study suggests that at least a certain type of CAMT is caused qv the c-mpl mutation, which disrupts the function of thrombopoietin receptor.

DOI： 10.1073/pnas.96.6.3132

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Chromosome translocations involving band 12p13 are known to be involved in a variety of hematologic malignancies, some of them resulting in rearrangement of the ETV6/TEL gene. Applying the fluorescence in situ hybridization (FISH) method, we found a cryptic translocation t(12;15)(p13;q25) in an adult acute myeloid leukemia (AML) patient. Hybridization with cosmid probes showed that the ETV6 gene was rearranged in this translocation. A patient-specific cDNA library was screened with ETV6 cDNA, and a novel fusion transcript was identified between the ETV6 and TRKC/NTRK3 gene located on 15q25. TRKC is a receptor tyrosine kinase that is activated by neurotrophin-3 (NT-3). It is known to be expressed broadly in neural tissues but not in hematologic cells, so far. ETV6-TRKC chimeric transcript encoded the pointed (PNT) domain of the ETV6 gene that fused to the protein-tyrosine kinase (PTK) domain of the TRKC gene. Two types of fusion transcript were determined, one that included the entire PTK domain of TRKC and the other in which the 3'-terminal 462 bp of TRKC was truncated within the PTK domain. Western blot analysis showed the expression of both chimeric proteins of 52 and 38 kD in size. Our results suggest that chimeric PTK expressed in the leukemic cells may contribute to cellular transformation by abnormally activating TRK signaling pathways. Moreover, this is the first report on truncated neurotrophin receptors associated in leukemia. (C) 1999 by The American Society of Hematology.

Web of Science

PubMed

researchmap

Language：Japanese  

DOI： 10.11406/rinketsu.39.1163

CiNii Books

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

We examined the regulation of apoptosis, radiosensitivity, and spindle checkpoint in response to DNA-damaging agents in ataxia telangiectasia (AT)-derived lymphoblastoid cell lines (AT-LCLs), which lack AT mutated (ATM) protein expression. In addition to the previous findings that AT-LCLs are defective in regulation of cell cycle at the G(1), S, and G(2)-M checkpoints in response to X-ray irradiation (X-IR) and are highly sensitive to X-IR (J. Biol. Chem., 271: 20486-20493, 1996), we showed for the first time that AT-LCLs were defective in X-IR-associated spindle checkpoint control. The cells were also resistant to early apoptosis as much as LCLs derived from patients with Li-Fraumeni syndrome (LFS-LCLs). Terminal deoxynucleotidyl transferase-mediated nick end labeling assay of LCLs, however, demonstrated a significant increase in apoptotic cells among AT-LCLs cultured over a longer period after X-IR. These findings were in contrast to those of LFS-LCL, which showed very little increase in terminal deoxynucleotidyl transferase-mediated nick end labeling-positive population, even in cells with hyperploidy. Thus, although early apoptosis and cell cycle controls in response to DNA damage are disrupted in broth ATM and p53 mutations, cells from AT patients are much more susceptible to late-onset apoptosis than those of LFS. These differences may depend on the level of accumulation of DNA damage and/or threshold that triggers late-onset cell death in ATM or p53 mutations. Our findings allow a better understanding of the role of ATM in p53-dependent and independent signal transduction pathways in response to DNA damaging agents.

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：(株)ニュー・サイエンス社  

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/1999035551

Language：English   Publishing type：Research paper (scientific journal)   Publisher：STOCKTON PRESS  

The MLL gene located on chromosome 11q23 and its translocation to the AF-4 gene located on chromosome 4q21 play a pivotal role in leukemogenesis in infancy. Studies of identical leukemic twins have provided evidence of the MLL rearrangement as a fetal event during pregnancy. We analyzed the presence and frequency of the MLL/AF-4 rearrangement in normal cord blood. Although no chimeric mRNA of MLL or AF-4 was detected in 65 cord blood samples, in-frame fusion transcripts of exon 11 and exon 4 or 5 of the AF-4 gene were detected in three of the samples by a nested polymerase chain reaction. When primers of exon 11 and exon 5 of the AF-4 gene were used, two forms of fusion transcripts (AF-4 exon 11/4 or exon 11/5) were detected in 20 of the 65 cord blood samples (31%) and also four of six leukemic cell samples with 1(4;11) (67%), whereas such transcripts were not observed in any of 21 peripheral blood samples nor in fetal fibroblasts. These findings suggest that the in-frame fusion of exon 11 and exon 4 or 5 of the AF-4 gene frequently occurs in hematopoietic cells during the intrauterine period, even in a healthy fetus. Although it is unknown whether the proteins of the AF-4 fusion transcripts have some functions, the instability of the AF-4 gene may be associated with the leukemogenesis of infant leukemia.

Web of Science

PubMed

researchmap

Language：English   Publisher：W B SAUNDERS CO  

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Fluorescence in situ hybridization (FISH) analysis was applied to detect t(12;21) using two yeast artificial chromosome probes and cosmid probes covering the TEL(ETV6) and the AML1 gene to clarify the incidence of abnormality of t(12;21) in Japanese childhood acute lymphoblastic leukemia (ALL), We detected seven TEL/AML1 fusion positive patients (9.5%), all of whom were diagnosed as B-lineage ALL, among 74 childhood ALL. On the other hand, no TEL/AML1 fusion positive patients were found among 37 adult ALL. The incidence among Japanese seemed to be lower than that among other nations, Of the seven patients with the TEL/AML1 fusion, five exhibited normal karyotype, one was t(8;12)(q11;p13), i(21q) and the remaining one exhibited a near-triploid karyotype in conventional G-banding, The FISH method clearly demonstrated that all patients with the TEL/AML1 fusion had subpopulations of leukemic cells with deletion of the normal TEL allele, which is significant for understanding the progression of leukemia with t(12;21).

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

The t(1;19)(q23;p13) translocation involving the E2A gene on chromosome 19p13.3 is a nonrandom translocation that is often seen in childhood pre-B-cell acute lymphoblastic leukemia (ALL). However, recent studies have demonstrated the presence of immunophenotypic and molecular heterogeneity among patients with the cytogenetically identical chromosome translocation. Here we report a novel pre-B ALL cell line, TS-2, with t(1;19) translocation not involving the E2A gene. The breakpoint of t(1;19) in TS-2 was demonstrated to be at 19p13.3, a region indistinguishable from the locus of the E2A gene, by cytogenetic study and fluorescence in situ hybridization. However, rearrangement of the E2A gene was not detected in TS-2 by Southern blot analysis. Moreover, the expressions of PBX1 or E2A/PBX1 fusion genes were not detected by an extensive study with Northern blot analysis and reverse transcription-polymerase chain reaction. These findings suggest that TS-2 may have a genetic abnormality involving uncharacterized gene(s) at 19p13.3 distinct from the E2A gene and, therefore, may be useful for investigating the heterogeneity of molecular pathogenesis in leukemias with t(1;19)(q23;p13) translocation. (C) Elsevier Science Inc., 1998.

DOI： 10.1016/S0165-4608(97)00260-4

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：(株)中外医学社  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：STOCKTON PRESS  

p16 and p15 genes are putative tumor suppressor genes located on chromosome 9p21. In acute leukemias, alterations of p16 and p15 genes have been reported to occur exclusively in lymphoid lineage. We analyzed alterations of p16 and p15 genes in 46 acute leukemias with MLL gene rearrangements by Southern blot analysis, and investigated the association with clinical characteristics. We identified homozygous deletion of p16 and p15 genes in five (19%) of 27 acute lymphoblastic leukemias (ALLs) and in two (11%) of 19 acute myeloid leukemias (AMLs). Patients with homozygous deletion of p16 and p15 genes showed higher average leukocyte counts (343 x 10(9)/l vs 271 x 10(9)/l) and lower estimated 2-year survival rates than those with normal p16 and p15 genes (14.3 vs 30.7%), although the differences were not statistically significant. In addition, we investigated mutation of p16 gene by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) in 31 patients, but no mutation was found in the patients tested. Our results suggest that alterations of p16 and p15 genes are involved in a subset of acute leukemias with MLL gene rearrangement not only of lymphoid but also of myeloid phenotype. Homozygous deletion of p16 and p15 genes may be a possible adverse prognostic factor, although further analysis would be needed to confirm it.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Lymphoblastoid cell lines (LCLs) with heterozygous p53 mutations at residues 286A, 133R, 282W, 132E, and 213ter were established from fire independent Li-Fraumeni syndrome families, When cell cycle regulation in response to gamma-irradiation was studied, these LCLs showed an abnormal G(1) checkpoint associated with defective inhibition of cyclin E/cyclin-dependent kinase 2 activity in all cases except for 282W LCL, which showed a normal G(1) checkpoint. On the other hand, the control of S-phase-G(2) as determined by cyclin A/cyclin-dependent kinase 2 activity was defective in all these LCLs. The mitotic checkpoint was also defective in the two LCLs analyzed as either competent or incompetent for G(1) arrest. When radiation-induced apoptosis, which requires wild-type p53 function under optimal conditions, was studied, all of these LCLs showed significant failure compared to normal LCLs. These findings indicate that although p53-dependent transactivation and G(1)-S-phase cell cycle control are variably dysregulated, the induction of apoptosis and control of the cell cycle at S-phase-G(2) and the mitotic checkpoint in response to DNA-damaging agents are consistently dysregulated in heterozygous mutant LCLs. This suggests that these dysfunctions underlie, at least in part, the susceptibility of Li-Fraumeni syndrome families to cancer. Furthermore, the approach presented is a potentially useful method for studying individual carriers of different germ-line p53 mutations and different biological features.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Thirty-eight sex-mismatched bone marrow transplantation patients with various hematological diseases were followed-up using fluorescence in situ hybridization. Probes specific for various translocations, the X chromosome (DXZ1) and the whole Y chromosome (WCP Y), were used to assess successful engraftment and residual host cells. The combination of translocation and WCP Y probes enabled the identification of host and donor cells in addition to the identification of malignant vs. normal cells in the transplant recipient. Fifteen patients were sequentially followed up. The results obtained using the combination of translocation plus WCP Y probes were more reliable than those with DXZ1 plus WCP Y probes, or the translocation probe alone, especially when the percentage of residual leukemic cells detected by the translocation probe alone was around the cut-off level.

Web of Science

PubMed

researchmap

Language：English   Publisher：HARWOOD ACAD PUBL GMBH  

Acute leukemia with t(4;12)(q11-13;p12-13) is rare but has unique characteristics. The incidence of t(4;12) in acute leukemias was about 0.6% in our laboratory. Twelve patients with acute leukemia with t(4;12) have been reported until now. They included eight acute myeloid (AML: MO 2, M1 3, M2 1, M4 1, and M7 1), three acute lymphoblastic (ALL: L1) and one acute unclassified leukemia (AUL). There were some differences between adults and children with t(4;12). The eight adult patients included seven with AML and one with AUL, two of whom had a history of exposure to mutagenic agents and/or genotoxic therapy. Three patients had the CD7(+)HLA-DR(+)CD13(+)CD34(+)c-kit(+) phenotype, suggesting that the leukemic cells were of stem cell origin. Four children expressed the B lymphoid phenotype (HLA-DR(+)CD10(+)CD19(+)) although one had myeloperoxidase positivity. It was difficult for adult patients to achieve complete remission with the usual therapy regimen, whereas children with t(4;12) seemed to be easier to treat. Rearrangement of the TEL gene located on the short arm of chromosome 12 (12p13), was investigated in two adult patients. FISH analysis using the YAC probe that covers the TEL gene region, revealed split signals in these patients, suggesting a break inside or near the TEL gene. The t(4;12) abnormality is associated with unique characteristics of acute leukemia namely stem cell or secondary AML in adults, and B lymphoid leukemia in children.

DOI： 10.3109/10428199709042495

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：STOCKTON PRESS  

We performed fluorescence in situ hybridization (FISH) upon 9;22 and 15;17 translocation-positive bone marrow cells to monitor the clinical course of 46 patients with chronic myelocytic leukemia (CML) and nine with acute promyelocytic leukemia (AML M3) who received chemotherapy and/or bone marrow transplantation (BMT). M-BCR-ABL and PML-RAR alpha probes were used to detect translocations of t(9;22) and t(15;17), respectively. Signals from CML patients treated with interferon (17 patients) or BMT (29 patients) were 0.5-15% positive for the 9;22 translocation. Among nine M3 patients who received extensive chemotherapy or BMT, 1-5% were positive for the 15;17 translocation. A highly sensitive FISH procedure using both translocation probes and a whole chromosome Y probe was established and applied to eight sex-mismatched BMT patients (seven CML and one AML M3), in which 0.1-0.6% of signals positive for the specific translocations were detected. These results suggested that interphase FISH is powerful enough to identify minor cell populations of 9;22 or 15;17 translocations after therapy, as well as to detect specific chromosome abnormalities at diagnosis.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO  

Seven secondary leukemia patients were treated for solid tumors or malignant lymphoma with anticancer drugs or radiation. We studied bone marrow samples from these patients by fluorescence in situ hybridization (FISH). Of the seven patients, three had increased signals for the ABL oncogene (9q34) on interphase nuclei and at metaphase. One of the three patients also had four signals for the CD3 (MLL) region (11q23). Whole painting probes revealed that these chromosomal regions were translocated onto structurally abnormal chromosomes, resulting in partial tri-, tetra- or penta-somy of these regions. We called this type of translocation ''segmental jumping translocation (SJT).'' SJT of the ABL oncogene was not detected in samples from 15 patients with de novo acute myelocytic leukemia (AML), 12 with myelodysplastic syndrome (MDS), or 20 with chronic myelocytic leukemia (CML) at the chronic phase. Furthermore, monosomy 7 was also found in the patients with the gene amplification. These results indicate that SJT of ABL and/or CD3 (MLL) genes is associated with the leukemogenesis of secondary leukemia. The SJT may be one mechanism of gene amplification. (C) 1997 by The American Society of Hematology.

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：ライフサイエンス出版(株)  

researchmap

Language：Japanese   Publisher：長崎医学会  

被曝後45年を経過して発症した被爆者白血病を疫学的及び細胞遺伝学的に検討した結果,被爆者にとって被曝による白血病発症の危険性は今も残存していることが明らかとなった

researchmap

Language：Japanese   Publisher：(株)南江堂  

researchmap

Language：Japanese  

CiNii Books

researchmap

Language：Japanese   Publisher：(株)東京医学社  

researchmap

Language：Japanese  

CiNii Books

researchmap

Language：Japanese   Publisher：日本臨床検査医学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

A novel human leukaemia cell line (Kasumi-4) was established from the peripheral blood of a 6-year-old girl suffering from chronic myelogenous leukaemia (CML) in blast crisis. The Kasumi-4 cells had the following characteristic features: undifferentiated blasts which were positive for CD34, CD33 and CD13 surface markers, but negative for myeloperoxidase platelet peroxidase, CD36, CD41 and CD42; chromosome abnormalities of t(9;22;11) (q34;q11;q13), inv(3)(q21q26); and elevated expression of EVI1 gene which is located at chromosome band 3q26. Megakaryocytic maturation was not observed in the liquid culture following the addition of TPA, IL-3, IL-6 or GM-CSF. b2-a2 type of BCR-ABL chimaeric messenger RNA was detected by RT-PCR analysis. This is the first leukaemia cell line with a three-way translocation containing the Ph chromosome and the second cell line with an inv(3)(q21q26). This cell line appears to be useful for studying the mechanisms of leukaemogenesis involving these chromosomal abnormalities and related oncogenes.

DOI： 10.1046/j.1365-2141.1996.4821023.x

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：広島医学会  

1)78名の500m以内近距離被爆者から2例目の急性白血病患者を認めた.近距離被爆者における急性白血病発生率は非被爆者に比べ12.8倍高値であると推定された. 2)本例について経時的な末梢血の観察及び染色体検査,トランスフォーミング遺伝子の解析を行った.これらの結果から近距離被爆者における白血病発生機構を考察した

researchmap

Language：Japanese   Publisher：広島医学会  

遺伝子異常をFISH法を用いて非被曝白血病と比べた.比較に用いた異常は7番染色体のモノソミー,9番染色体の9q34領域のABL遺伝子と11番染色体の11q23領域のMLL遺伝子である.モノソミー7は二次性白血病では75.0%,被爆者白血病では34.8%であった.ABL遺伝子はSegmental jumping translocationという方法で複数の他染色体へ転座し,遺伝子増幅していた.この異常は二次性白血病8名中3名と高率にみられ,被爆者白血病7名中1名にみられたが,非被曝白血病12名中にはなかった.11q23領域の異常では二次性白血病や被爆者白血病に重複や欠失が多く,非被曝白血病に転座が多い

researchmap

Language：Japanese   Publisher：(株)文光堂  

メチルマロン酸血症は分枝鎖アミノ酸由来の有機酸代謝障害をきたす先天性代謝疾患である.予後不良とされるメチルマロニルCoAムターゼ完全欠損型で,生後2年8ヵ月間生存した女児の1解剖例を経験した.生後3日目にアシドーシス発作をきたしメチルマロン酸血症と診断され,カルニチンの投与等の治療を受け良好に経過していたが,死亡3日前,急激にアシドーシス発作が出現し,腎不全及び心不全状態で死亡した.剖検所見では組織学的及び超微形態学的に,肝細胞,心筋細胞,腎尿細管上皮及び骨格筋に脂質沈着を認めた.生化学的分析では総脂質量,ことに中性脂肪(triglyceride)の増加をみた.この脂質沈着には,慢性的なカルニチン不足状態が関与していることが示唆された

CiNii Books

researchmap

Language：Japanese   Publisher：広島大学医学出版会  

30症例の11番染色体長腕23領域(11q23)転座を有する造血器腫瘍症例について解析を行った.12症例の小児白血病例では全例MLL遺伝子再構成を認めた.成人白血病及び悪性リンパ腫例ではMLL遺伝子再構成は各々54%,40%であり又複雑な染色体異常を示すなど,小児例と成人例で11q23異常の型や臨床像の異なることが明らかとなった.更に,小児急性白血病の1例に新たな11q23転座t(11;14)(q23;q24)を見出し,その転座切断点のクローニング及び解析を行った所,切断点のごく近傍の11番側及び14番側染色体上にheptamer様V-D-J recombinase認識配列及びトポイソメラーゼIIコンセンサス様配列を認めた.t(11;14)(q23;q24)の発症にはrecombinase及びトポイソメラーゼII阻害剤の使用が関わっている可能性が示唆された

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：STOCKTON PRESS  

Web of Science

PubMed

researchmap

Language：Japanese  

CiNii Books

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

Serial cytogenetic analysis revealed karyotypically unrelated clones in four patients with acute myeloblastic leukaemia (AML) in remission. At diagnosis, three patients had t(8;21)(q22;q22) and one had an inv(16)(p13q22). After 18-22 months in remission, different clones emerged in each patient with myelodysplastic features of the bone marrow cells. The emergence of clones with abnormalities of chromosome 7 in remission seems to be an unfavourable factor for prognosis.

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：(株)東京医学社  

researchmap

Language：Japanese   Publisher：長崎医学会  

researchmap

Language：Japanese   Publisher：(有)科学評論社  

researchmap

Language：Japanese   Publisher：(株)医学書院  

researchmap

researchmap

Event date： 2024.6

Language：Japanese  

researchmap

Event date： 2024.6

Language：Japanese  

researchmap

Event date： 2024.6

Language：Japanese  

researchmap

Event date： 2024.6

Language：Japanese  

researchmap

Event date： 2024.6

Language：Japanese  

researchmap

Event date： 2024.5

Language：Japanese  

researchmap

Event date： 2024.5

Language：Japanese  

researchmap

Event date： 2024.5

Language：Japanese  

researchmap

Event date： 2024.4

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2024.4

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2024.4

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2024.4

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2024.4

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2023.10

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2023.10

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2023.10

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2023.10

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

researchmap

Event date： 2023.10

Language：Japanese  

researchmap

Event date： 2023.9

Language：Japanese  

researchmap

Event date： 2023.9

Language：Japanese  

researchmap

Event date： 2023.9

Language：Japanese  

researchmap

Event date： 2023.6

Language：Japanese  

researchmap

Event date： 2023.5

Language：Japanese  

researchmap

Event date： 2023.5

Language：Japanese  

researchmap

Event date： 2023.5

Language：Japanese  

researchmap

Event date： 2023.5

Language：Japanese  

researchmap

Event date： 2023.4

Language：Japanese  

researchmap

Event date： 2023.2

Language：Japanese  

researchmap

Event date： 2023.2

Language：Japanese  

researchmap

Event date： 2023.2

Language：Japanese  

researchmap

Event date： 2023.2

Language：Japanese  

researchmap

Event date： 2023.2

Language：Japanese  

researchmap

Event date： 2022.12

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

researchmap

Event date： 2022.11

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2022.11

Presentation type：Oral presentation (general)  

researchmap

Event date： 2022.11

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2022.11

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2022.11

researchmap

Event date： 2022.11

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2022.11

researchmap

Event date： 2022.10

researchmap

Event date： 2022.10

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2022.10

researchmap

Event date： 2022.10

Language：English  

researchmap

Event date： 2022.10

Language：English  

researchmap

Event date： 2022.10

Language：Japanese  

researchmap

Event date： 2022.10

Language：English  

researchmap

Event date： 2022.9

researchmap

Event date： 2022.8

Language：Japanese  

researchmap

Event date： 2022.8

Language：Japanese  

researchmap

Event date： 2022.7

Language：Japanese  

researchmap

Event date： 2022.7

Language：Japanese  

researchmap

Event date： 2022.7

Language：Japanese  

researchmap

Event date： 2022.7

Language：Japanese  

researchmap

Event date： 2022.7

Language：Japanese  

researchmap

Event date： 2022.7

Presentation type：Oral presentation (general)  

researchmap

Event date： 2022.6

researchmap

Event date： 2022.6

Language：Japanese  

researchmap

Event date： 2022.5

Language：Japanese  

researchmap

Event date： 2022.5

Language：Japanese  

researchmap

Event date： 2022.5

Language：Japanese  

researchmap

Event date： 2022.5

Language：Japanese  

researchmap

Event date： 2022.4

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2022.4

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2022.3

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2022.1

Presentation type：Poster presentation  

researchmap

Event date： 2022.1

Language：Japanese   Presentation type：Oral presentation (invited, special)  

researchmap

Event date： 2022.1

Presentation type：Oral presentation (general)  

researchmap

Event date： 2022.1

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2022.1

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2022.1

Presentation type：Poster presentation  

researchmap

Event date： 2021.12

Language：Japanese   Presentation type：Oral presentation (invited, special)  

researchmap

Event date： 2021.11

Language：Japanese  

researchmap

Event date： 2021.11

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2021.11

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2021.11

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2021.11

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2021.11

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2021.9

Language：Japanese   Presentation type：Oral presentation (invited, special)  

researchmap

Event date： 2021.9

Language：Japanese  

researchmap

Event date： 2021.7

Language：Japanese   Presentation type：Oral presentation (general)  

File： 第32回小児神経学会中国・四国地方会.pdf

researchmap

Event date： 2021.7

Language：Japanese  

researchmap

Event date： 2021.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：京都（ハイブリッド開催）  

researchmap

Event date： 2021.4

Language：Japanese   Presentation type：Poster presentation  

Venue：京都（ハイブリッド開催）  

researchmap

Event date： 2021.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：京都（ハイブリッド開催）   Country：Japan  

researchmap

Event date： 2021.4

Language：Japanese   Presentation type：Poster presentation  

Venue：京都（ハイブリッド開催）  

researchmap

Event date： 2021.3

Language：Japanese  

researchmap

Event date： 2020.11

Language：Japanese   Presentation type：Oral presentation (invited, special)  

researchmap

Event date： 2020.11

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2020.11

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2020.11 - 2020.12

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2020.11

Language：Japanese  

researchmap

Event date： 2020.11

Language：Japanese  

researchmap

Event date： 2020.11

Language：Japanese  

researchmap

Event date： 2020.11

Language：Japanese  

researchmap

Event date： 2020.10

Language：English   Presentation type：Symposium, workshop panel (nominated)  

researchmap

Event date： 2020.10

Language：English   Presentation type：Poster presentation  

researchmap

Event date： 2020.9

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2020.8

Language：Japanese  

researchmap

Event date： 2020.8

Language：Japanese  

researchmap

Event date： 2020.8

Language：Japanese  

researchmap

Event date： 2020.8

Language：Japanese  

researchmap

Event date： 2020.4

Language：Japanese  

researchmap

Event date： 2020.2

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

researchmap

Event date： 2020.1

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2020.1

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2020.1

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2019.10

Language：Japanese  

researchmap

Event date： 2019.10

Language：Japanese  

researchmap

Event date： 2016.11

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2016.10

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

researchmap

Event date： 2016.10

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2015.10

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2007.11

Language：English  

researchmap

Event date： 1997.11

Language：English  

researchmap

Event date： 1997.11

Language：English  

researchmap

Language：Japanese  

researchmap

Language：Japanese   Presentation type：Poster presentation  

researchmap

Language：Japanese  

researchmap

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

researchmap

Language：Japanese  

researchmap

Language：Japanese   Presentation type：Poster presentation  

researchmap

Language：Japanese  

researchmap

Language：Japanese  

researchmap

Language：Japanese   Presentation type：Poster presentation  

researchmap

Language：Japanese  

researchmap

Language：Japanese   Presentation type：Poster presentation  

researchmap

Language：Japanese   Presentation type：Poster presentation  

researchmap

Language：Japanese  

researchmap

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Language：Japanese  

researchmap

Language：Japanese   Presentation type：Oral presentation (invited, special)  

researchmap