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田村 彰広大学院医学研究科 医科学専攻准教授
研究活動情報
■ 論文- Recently, heterozygous loss-of-function NFKB1 variants were identified as the primary cause of common variable immunodeficiency (CVID) in the European population. However, pathogenic NFKB1 variants have never been reported in the Japanese population. We present a 29-year-old Japanese woman with CVID. A novel variant, c.136 C > T, p.(Gln46*), was identified in NFKB1. Her mother and daughter carried the same variant, demonstrating the first Japanese pedigree with an NFKB1 pathogenic variant.2024年03月, Human genome variation, 11(1) (1), 15 - 15, 英語, 国際誌研究論文（学術雑誌）
- More than half of patients with high-risk neuroblastoma (HR-NB) experience relapse/regrowth due to the activation of chemoresistant minimal residual disease (MRD). MRD in patients with HR-NB can be evaluated by quantitating neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow (BM) and peripheral blood (PB) samples. Although several sets of NB-mRNAs have been shown to possess a prognostic value for MRD in BM samples (BM-MRD), MRD in PB samples (PB-MRD) is considered to be low and difficult to evaluate. The present report describes an HR-NB case presenting higher PB-MRD than BM-MRD before 1st and 2nd relapse/regrowth. A 3-year-old female presented with an abdominal mass, was diagnosed with HR-NB, and treated according to the nationwide standard protocol for HR-NB. Following systemic induction and consolidation therapy with local therapy, the patient achieved complete remission but experienced a 1st relapse/regrowth 6 months after maintenance therapy. The patient partially responded to salvage chemotherapy and anti-GD2 immunotherapy but had a 2nd relapse/regrowth 14 months after the 1st relapse/regrowth. Consecutive PB-MRD and BM-MRD monitoring revealed that PB-MRD was lower than BM-MRD at diagnosis (100 times) and 1st and 2nd relapse/regrowth (1,000 and 3 times) but became higher than BM-MRD before 1st and 2nd relapse/regrowth. The present case highlights that PB-MRD can become higher than BM-MRD before relapse/regrowth of patients with HR-NB.2023年09月, Oncology letters, 26(3) (3), 369 - 369, 英語, 国際誌
- (公社)日本小児科学会, 2023年04月, 日本小児科学会雑誌, 127(4) (4), 625 - 625, 日本語汎血球減少と斜指を契機に診断したMECOM関連症候群の女児
- (公社)日本小児科学会, 2023年04月, 日本小児科学会雑誌, 127(4) (4), 632 - 632, 日本語血性鼻汁をきっかけに診断したLCHの男児
- (公社)日本小児科学会, 2023年04月, 日本小児科学会雑誌, 127(4) (4), 625 - 626, 日本語一過性の細胞免疫不全所見を認めた超早期発症型炎症性腸疾患の1例
- 兵庫県小児科医会, 2023年, 兵庫県小児科医会報, (79) (79), 13 - 17, 日本語
- Infantile fibrosarcoma (IFS) commonly harbors ETS variant transcription factor 6 (ETV6)-neurotrophic receptor tyrosine kinase 3 (NTRK3) fusion. However, the recent accessibility to clinical next-generation sequencing (NGS) has revealed ETV6-NTRK3 negative spindle cell sarcomas resembling IFS morphologically, involving NTRK1/2, MET, RET and BRAF. The present report describes a pediatric case of spindle cell sarcoma with KIAA1549-BRAF resembling IFS morphologically. A 20-month-old female patient was referred to Kobe Children's Hospital (Kobe, Japan) for the treatment of intrathoracic spindle cell sarcoma. Pathologically, the intrathoracic tumor cells were composed of spindle cells with focal hemagiopericytomatous pattern. In immunohistochemistry analysis, the intrathoracic tumor cells focally expressed desmin and WT-1 and were negative for pan-tropomyosin receptor kinase (TRK), S-100 and CD34. Fluorescence in situ hybridization analysis for ETV6 and capicua transcriptional repressor revealed negative split signals. Although the patient was initially diagnosed with IFS morphologically, KIAA1549-BRAF fusion transcript was detected by comprehensive genomic profiling with NGS using intrathoracic tumor tissues and confirmed by reverse transcription-PCR. Chemotherapy induced a reduction in the tumor size. At present, the patient is alive with the disease and has been receiving therapy for 8 months since the initiation of chemotherapy. Review of BRAF-altered spindle cell sarcomas resembling IFS morphologically revealed the inconsistency in immunohistochemical expression patterns and the diversity of BRAF fusion genes and mutations. Therefore, the elucidation of genomic profiling by NGS may assist in making an appropriate diagnosis and selecting novel alternative therapies in ETV6-NTRK3-negative spindle cell sarcomas resembling IFS morphologically.2022年12月, Oncology letters, 24(6) (6), 452 - 452, 英語, 国際誌
- (一社)日本小児感染症学会, 2022年11月, 日本小児感染症学会総会・学術集会プログラム・抄録集, 54回, 252 - 252, 日本語EBV-HLHに対する最適な治療を求めて
- (一社)日本小児感染症学会, 2022年11月, 日本小児感染症学会総会・学術集会プログラム・抄録集, 54回, 252 - 252, 日本語EBV-HLHに対する最適な治療を求めて
- Rotavirus (RV) is the leading cause of acute gastroenteritis (AGE), particularly in infants. In 2006, the high efficacy of oral RV vaccines (RVVs, RotarixTM and RotaTeqTM) was demonstrated. Voluntary RVV started in Japan in 2011, and in October 2020 were launched as universal oral RVVs in Japan. However, the impact of changes from voluntary to universal RVVs has not been studied in a primary emergency medical center in Japan. We investigated changes in the number of pediatric patients with AGE after introducing universal RVVs in our center. A clinical database of consecutive patients aged <16 who presented to Kobe Children's Primary Emergency Medical Center between 1 April 2016 and 30 June 2022 was reviewed. After implementing universal RVVs, fewer children presented with RV-associated AGE (the reduction of proportion of the patients in 2022 was -61.7% (all ages), -57.9% (<1 years), -67.8% (1-<3 years), and -61.4% (3-<5 years) compared to 2019). A similar decrease in those of age who were not covered by the universal RVV was observed. There was a significant decline in the number of patients with AGE during the RV season who presented to the emergency department after implementing universal RVVs.2022年10月, Vaccines, 10(11) (11), 英語, 国際誌研究論文（学術雑誌）
- More than half of high-risk neuroblastoma (NB) patients have experienced relapse due to the activation of chemoresistant minimal residual disease (MRD) even though they are treated by high-dose chemotherapy with autologous peripheral blood stem cell (PBSC) transplantation. Although MRD in high-risk NB patients can be evaluated by quantitative PCR with several sets of neuroblastoma-associated mRNAs (NB-mRNAs), the prognostic significance of MRD in PBSC grafts (PBSC-MRD) is unclear. In the present study, we collected 20 PBSC grafts from 20 high-risk NB patients and evaluated PBSC-MRD detected by droplet digital PCR (ddPCR) with 7NB-mRNAs (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNA). PBSC-MRD in 11 relapsed patients was significantly higher than that in 9 non-relapsed patients. Patients with a higher PBSC-MRD had a lower 3-year event-free survival (P = 0.0148). The present study suggests that PBSC-MRD detected by ddPCR with 7NB-mRNAs has a prognostic impact on high-risk NB patients.2022年10月, Heliyon, 8(10) (10), e10978, 英語, 国際誌研究論文（学術雑誌）
- Although clinical trials have reported an improvement in the prognosis of hemophagocytic lymphohistiocytosis (HLH), current treatment outcomes are unsatisfactory, especially in severe cases. Most clinical trial patients with severe disease discontinue participation due to complications associated with HLH or treatment-related toxicity. A retrospective survey of patients who discontinued participation in the JPLSG HLH-2004 clinical trial was conducted to review the detailed course of these cases to optimize HLH treatment and supportive care. Findings in these patients were compared with those of 45 patients who completed the protocol treatment. The 3 year overall survival rate of patients who completed treatment was 86.7%, versus 50.7% for those who did not complete treatment. Incidence of serious adverse events, such as infections, coagulopathy, and posterior reversible encephalopathy syndrome, during the initial 8 weeks of treatment was much higher in patients who did not complete treatment than in patients who completed treatment. To improve overall outcomes of patients with HLH, it is important to not only optimize HLH-directed therapy but also provide appropriate supportive care.2022年09月, International journal of hematology, 116(3) (3), 434 - 441, 英語, 国内誌研究論文（学術雑誌）
- 2022年07月, Haematologica, 107(7) (7), 1719 - 1725, 英語, 国際誌研究論文（学術雑誌）
- Few reports have examined whether prophylactic allogeneic hematopoietic cell transplantation (HCT) for X-linked lymphoproliferative syndrome type 1 (XLP1) improves the prognosis. We compared the prognosis of symptomatic probands and affected siblings in the same family. Twenty-two cases (10 probands and 12 affected siblings) in Japan, the United Kingdom, and the United States were analyzed. The overall survival (OS) rate at 5 years after diagnosis was 70.0% in probands and 91.7% in affected siblings (p = 0.0789). The prognosis of patients who developed symptoms of XLP1 before HCT and those who did not was also compared. The 5-year probability of OS from the time of diagnosis in asymptomatic patients (100%) was significantly better than that in symptomatic patients (66.7%). These results suggested that early HCT as soon as the diagnosis is made improves the prognosis in asymptomatic XLP1 patients.2022年04月, Clinical immunology (Orlando, Fla.), 237, 108993 - 108993, 英語, 国際誌研究論文（学術雑誌）
- (一社)兵庫県医師会, 2022年03月, 兵庫県医師会医学雑誌, 64(2) (2), 35 - 35, 日本語小児悪性脳腫瘍の発症・進行メカニズムに関連した単球・マクロファージ系血細胞の多様性に関する基礎的研究
- (公社)日本小児科学会, 2022年02月, 日本小児科学会雑誌, 126(2) (2), 230 - 230, 英語診断時単球絶対数とリンパ球絶対数の乗算低値は神経芽腫の予後不良に相関する(Low multiplication value of monocyte and lymphocyte count may be associated with poor prognosis in neuroblastoma)
- BACKGROUND: An unprovoked seizure is a seizure or a cluster of seizures occurring within 24 h in a patient older than 1 month of age without precipitating factors. Recent studies have reported that extrinsic factors, such as meteorological conditions and air pollutants, may be important in seizure occurrence. Thus, this study aimed to examine the association between the number of visits to the emergency department (ED) by children for nighttime unprovoked seizures and exposure to multi-faceted factors, such as meteorological conditions and air pollution. METHODS: We conducted a clinical observational analysis and reviewed consecutive patients younger than 16 years of age who visited the primary ED center in Kobe City, Japan, during nighttime (7:30 p.m.-7:00 a.m.) between January 1, 2011 and December 31, 2015. We investigated the effects of meteorological factors and air pollutants on the number of patients with unprovoked seizures using multivariate analysis of Poisson regression estimates. RESULTS: In total, 151,119 children visited the ED, out of which 97 patients presented with unprovoked seizures. The mean age of the patients was 4.7 years (range, 1 month to 15.3 years), and 54.6% of them were boys. The total number of patients with unprovoked seizures showed no significant changes with the seasons; however, there were dominant peaks during the fall and fewer visits during the summer. The multivariate analysis of Poisson regression estimates revealed a significant positive relationship between the number of patients presenting with unprovoked seizures and precipitation (+1 patient/87 mm; p = 0.03) and methane (+1 patient/0.14 ppm; p = 0.03) levels and a negative relationship between the number of patients presenting with unprovoked seizures and nitrogen dioxide level (-1 patient/0.02 ppm; p = 0.04). CONCLUSIONS: The present study is the first to evaluate the association between the number of children who presented to the ED with nighttime unprovoked seizures and environmental factors after controlling for confounding factors.2021年12月, Epilepsy & behavior : E&B, 125, 108434 - 108434, 英語, 国際誌研究論文（学術雑誌）
- 2021年11月, PEDIATRIC BLOOD & CANCER, 68, 英語A Retrospective Survey of the Discontinuation Cases of JPSLG HLH-2004 Clinical Trial
- The clinical characteristics, cause, and risk factors of sarcopenia are unclear in children. The aim of this study was to describe the course of and identify the factors related to muscle mass change during chemotherapy in children with neuroblastoma. A total of 24 consecutive patients aged below 18 years with newly diagnosed high-risk neuroblastoma between 2010 and 2018 in our hospital were enrolled in a case-series study. The psoas muscle index (PMI) was calculated as a parameter of muscle mass based on computer tomography (CT) images of the psoas muscle. PMIs were evaluated at 4 time points (TPs): TP1, at the diagnosis of neuroblastoma; TP2, after the first cycle of chemotherapy; TP3, after the third cycle of chemotherapy; and TP4, at the end of the induction chemotherapy. PMI recovery was defined as an increase in PMI between TP2 and TP4. The mean PMI decreased by 15% between TP1 and TP2 (TP1 7.09 ± 0.99 vs. TP2 6.01 ± 0.98, P < 0.001) and by 10% between TP1 and TP4 (TP1 7.09 vs. TP4 6.35, P = 0.004). PMI recovery between TP1 and TP2 was observed in 7 (29%) patients. The median age of patients with PMI recovery was significantly lower (2 vs. 4 years, P = 0.028), and the proportion of boys was significantly higher in patients with PMI recovery (100% vs. 41%, P = 0.017).Conclusion: This study demonstrated that prominent PMI reduction occurs during the early time of chemotherapy, and a younger age and male sex may be predictive factors for PMI recovery. What is Known: • Sarcopenia is a common disorder in elderly people. • Several causes and risk factors have been reported in adults. • Children with previous hematological malignancies have decreased physical activity. What is New: • Prominent muscle mass loss was observed early in children with high-risk neuroblastoma during chemotherapy. • Age and sex were found to be potentially associated with muscle mass recovery.2021年11月, European journal of pediatrics, 180(11) (11), 3265 - 3271, 英語, 国際誌研究論文（学術雑誌）
- Neuroblastoma (NB) is the most common extracranial solid tumor in children and originates from sympathoadrenal or Schwann cell precursors derived from neural crest. These neural crest derivatives also constitute the hematopoietic and mesenchymal stem cells in bone marrow (BM) that is the most frequent site of NB metastasis and relapse. In NB patients, NB cells have been pathologically detected in BM and peripheral blood (PB), and minimal residual disease (MRD) in BM and PB (BM-MRD and PB-MRD) can be monitored by quantitating several sets of NB-associated mRNAs (NB-mRNAs). Although previous studies have shown varying degrees of correlation between BM-MRD and PB-MRD, the underlying factors and/or mechanisms remains unknown. In the present study, we determined the levels of BM-MRD and PB-MRD by quantitating seven NB-mRNAs in 133 pairs of concurrently collected BM and PB samples from 19 high-risk NB patients with clinical disease evaluation, and examined their correlation in overall and subgroups of sample pairs. The levels of BM-MRD and PB-MRD were moderately (r = 0.418, p < 0.001) correlated with each other in overall sample pairs. The correlation became strong (r = 0.725, p < 0.001), weak (r = 0.284, p = 0.008), and insignificant (p = 0.194) in progression, stable, and remission subgroups of sample pairs, respectively. It also became stronger in subgroups of sample pairs with poor treatment responses and poor prognostic factors. Present study suggests that MRD in high-risk NB shows a dynamic and disease burden-dependent correlation between BM and PB.2021年08月, Translational oncology, 14(8) (8), 101019 - 101019, 英語, 国際誌研究論文（学術雑誌）
- Vanillylmandelic acid (VMA), homovanillic acid (HVA), neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) are classical tumor markers and are used as standard clinical evaluations for patients with neuroblastoma (NB). Minimal residual disease (MRD) can be monitored by quantifying several sets of NB-associated mRNAs in the bone marrow (BM) and peripheral blood (PB) of patients with NB. Although MRD in BM and PB has been revealed to be a strong prognostic factor that is independent of standard clinical evaluations, its interrelation with tumor markers remains uncharacterized. The present study determined the levels of tumor markers (VMA, HVA, NSE and LDH) and MRD (BM-MRD and PB-MRD) in 133 pairs of concurrently collected BM, PB and urine samples from 19 patients with high-risk NB. The patients were evaluated during the entire course of treatment, which included 10 diagnoses, 32 treatments, 36 post-treatment, 9 relapses and 46 post-relapse sample pairs. The level of BM-MRD and PB-MRD was determined by quantifying 7 NB-mRNAs (collapsin response mediator protein 1, dopamine beta-hydroxylase, dopa decarboxylase, growth-associated protein 43, ISL LIM homeobox 1, pairedlike homeobox 2b and tyrosine hydroxylase) using droplet digital PCR. In overall sample pairs, tumor markers (VMA, HVA, NSE and LDH) demonstrated weak but significant correlations (P<0.011) with BM-MRD and PB-MRD. In subgroups according to each patient evaluation, the degree of correlation between tumor markers and MRD became stronger in patients with adrenal gland tumors, BM metastasis at diagnosis and relapse/regrowth compared with overall sample pairs. In contrast, tumor markers demonstrated variable correlations with MRD in subgroups according to each sample evaluation (BM infiltration at sampling, collection time point and disease status). The results suggested that tumor markers may demonstrate limited correlation with MRD in patients with high-risk NB.2021年07月, Molecular and clinical oncology, 15(1) (1), 137 - 137, 英語, 国際誌研究論文（学術雑誌）
- 2021年07月, Haemophilia : the official journal of the World Federation of Hemophilia, 27(4) (4), e510-e512, 英語, 国際誌
- (公社)日本小児科学会, 2021年02月, 日本小児科学会雑誌, 125(2) (2), 250 - 250, 英語高リスク神経芽腫における微小残存病変(MRD)と腫瘍マーカーの相関に関する臨床的検討(Clinical analysis of the correlation between minimal residual disease and tumor markers in high-risk neuroblastoma)
- Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant tumors of the central nervous system that predominantly occur in infants, and are characterized by the presence of rhabdoid cells and inactivation of INI1 or (rarely) BRG1. Most AT/RT are identified as primary tumors; however, rare AT/RT or INI1-deficient RTs arising from other primary tumors have been reported. Here, we report 3 cases of hitherto unclassifiable low-grade tumors with loss of INI1 nuclear expression, for which we propose the designation of central nervous system low-grade diffusely infiltrative tumors with INI1 deficiency (CNS LGDIT-INI1), 2 of which progressed to secondary RT. All 3 CNS LGDIT-INI1 exhibited a similar histology: diffusely distributed small tumor cells with round to oval or irregular nuclei and scant cytoplasm were admixed with degenerative neurons and large reactive astrocytes in an edematous, myxoid, or collagenous background. Mitotic figures were absent. Immunohistochemistry revealed that the tumor cells in all 3 CNS LGDIT-INI1 and 2 RT were negative for INI1. Genetically, total or partial homozygous deletions of the INI1 gene were detected in all CNS LGDIT-INI1 and RT excluding 1 CNS LGDIT-INI1 without sufficient DNA quality and quantity. Despite the loss of INI1 expression, these low-grade lesions were clearly distinguishable from AT/RT by their low proliferative activity, diffusely infiltrative growth pattern, and lack of rhabdoid cells and polyphenotypic immunoreactivity. In conclusion, CNS LGDIT-INI1 may represent a rare group of tumors that are clinically indolent but have a high propensity to progress to RT.2020年11月, The American journal of surgical pathology, 44(11) (11), 1459 - 1468, 英語, 国際誌研究論文（学術雑誌）
- American Society of Hematology, 2020年07月, Blood Advances, 32(2) (2), 43 - 3356, 英語研究論文（学術雑誌）
- The transcription factor CCAAT enhancer-binding protein β (C/EBPβ) is required for stress-induced granulopoiesis at the level of hematopoietic stem/progenitor cells (HSPCs); however, its role and mechanisms of action in HSPCs are unknown. In this study, we assessed the regulation and functions of C/EBPβ in HSPCs, especially under stress conditions. After 5-fluorouracil treatment or bone marrow transplantation, Cebpb-/- HSPCs exhibited impaired cell-cycle activation and myeloid differentiation at the early and late phases of regeneration, respectively, whereas at steady state, Cebpb deficiency did not affect HSPCs. C/EBPβ was upregulated in response to hematopoietic stress, especially in CD150high long term-hematopoietic stem cells (LT-HSCs). Intracellular flow cytometric analysis that detected distinct domains of C/EBPβ revealed that, among the 3 isoforms of C/EBPβ, liver-enriched inhibitory protein (LIP) was upregulated in LT-HSCs prior to liver-enriched activating protein (LAP)/LAP* during regeneration. Early upregulation of LIP promoted cell-cycle entry of LT-HSCs by positively regulating Myc and expanded the HSPCs pool. Subsequent myeloid differentiation of amplified HSPCs was mediated by LAP/LAP*, which were upregulated at a later phase of regeneration. Collectively, our findings show that stress-induced sequential upregulation of C/EBPβ isoforms is critical for fine-tuning the proliferation and differentiation of regenerating HSPCs.2020年07月, Blood advances, 4(14) (14), 3343 - 3356, 英語, 国際誌研究論文（学術雑誌）
- This prospective observational study analyzed the pharmacokinetics of busulfan in Japanese children and evaluated the predicting accuracy of previous pediatric PPK models of busulfan. This study enrolled five patients (aged 2-12 years, BW 14-48 kg) receiving a busulfan-based conditioning regimen for hematopoietic stem cell transplantation at our hospital between January 2017 and December 2018. All patients received a 2-hour intravenous busulfan infusion four times daily for a total of 16 doses. After the infusions, 51 plasma samples were collected with the plasma busulfan concentration measured by liquid chromatography-tandem mass spectrometry. PPK model fitting was analyzed using the (%MPE) and the (%MAPE). Limited sampling strategies for estimating busulfan AUC were also evaluated. High interpatient variability was observed in the PK parameters. The most suitable PPK model that reflected our data was McCune's two-compartment model (%MPE -8.7, %MAPE 19.3). A combination sampling method using the busulfan concentration at 2 and 6 hours after the start of the first busulfan dose was found to be able to estimate AUC4 day . These results provide useful information on busulfan therapeutic drug monitoring in the Japanese pediatric population.2020年06月, Pediatric transplantation, 24(4) (4), e13696, 英語, 国際誌研究論文（学術雑誌）
- Monitoring of several sets of neuroblastoma-associated mRNAs (NB-mRNAs) by real-time quantitative PCR (qPCR) can be used to evaluate minimal residual disease in NB patients. Droplet digital PCR (ddPCR) is an adaption of qPCR that potentially provides simpler and more reproducible detection of low levels of mRNAs. However, whether minimal residual disease in NB patients can be monitored by ddPCR using a set of NB-mRNAs is not yet tested. In this study, 208 bone marrow (BM) and 67 peripheral blood samples were retrospectively collected from 20 high-risk NB patients with clinical disease evaluation at two Japanese centers between 2011 and 2018, and level of each NB-mRNA (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs) was determined by ddPCR. Level of 7NB-mRNAs (defined as the combined signature of each NB-mRNA) was higher in BM than peripheral blood, but correlated significantly with each other. In accordance with disease burden, it varied with disease status (remission, stable, or progression) and collection time point (diagnosis, treatment, post-treatment, or relapse). In 73 post-treatment BM samples, it was significantly higher in 17 relapsed/regrown samples than in 56 nonrelapsed/nonregrown samples. Furthermore, ddPCR had a better prognostic value than qPCR in detecting 7NB-mRNAs in the same 73 post-treatment BM samples. This study suggests that ddPCR detection of 7NB-mRNAs is significantly associated with tumor relapse/regrowth in high-risk NB patients.2020年02月, The Journal of molecular diagnostics : JMD, 22(2) (2), 236 - 246, 英語, 国際誌研究論文（学術雑誌）
- Despite the growing evidences that immune dysfunction contributes to tumor progression, the prognostic value in patients with neuroblastoma regarding circulating immune blood cell counts has not been well characterized. To answer this, we conducted a retrospective study to evaluate the prognostic value of the circulating immune cell counts at diagnosis in a cohort of 55 patients with neuroblastoma. Based on a novel index by multiplying the absolute monocyte count (AMC)/μl and absolute lymphocyte count (ALC)/μl, we sub-grouped patients with AMC × ALC ≥ 1 × 106 (/μl)2 as high group and patients with AMC × ALC < 1 × 106 (/μl)2 as low group. In the entire cohort, the 4-year progression-free survival (PFS), and overall survival (OS) for high group (n = 38) vs low group (n = 17) was 81.7% (95%CI; 63.6-91.3%) and 90.7% (95%CI; 73.8-96.9%) vs 31.7% (11.6-54.1%) and 56.5% (29.7-76.4%; p < 0.001 for PFS and p = 0.015 for OS), respectively, suggesting that a low AMC × ALC is associated with poor prognosis. In the subgroup analysis for high-risk patients, the 4-year PFS and OS for high group (n = 17) vs low group (n = 13) was 59.8% (31.2-79.7%) and 79.8% (49.4-93.0%) vs 8.5% (0.5-31.7%) and 42.0% (15.4-66.8%; p < 0.001 for PFS and p = 0.089 for OS), respectively. Our data demonstrate that AMC × ALC at diagnosis is a cost-effective and easily measurable biomarker for predicting prognosis in neuroblastoma.2020年, Frontiers in oncology, 10, 572413 - 572413, 英語, 国際誌研究論文（学術雑誌）
- 2019年12月, PEDIATRIC BLOOD & CANCER, 66, S27 - S27, 英語Central Nervous System Complications During Hospital Treatment in Children with ALL[査読有り]
- 2019年12月, PEDIATRIC BLOOD & CANCER, 66, S28 - S28, 英語Nelarabine Neurotoxicity in Pediatric Patient With T-cell Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma[査読有り]
- 2019年12月, PEDIATRIC BLOOD & CANCER, 66, S57 - S58, 英語Central Venous Catheter-Related Complications in Children With Down Syndrome and Acute Leukemia[査読有り]
- 2019年12月, PEDIATRIC BLOOD & CANCER, 66, S73 - S74, 英語VitB12 Deficiency Anemia in an Infant Born to Ileum-resected Mother[査読有り]
- 2019年12月, PEDIATRIC BLOOD & CANCER, 66, S78 - S79, 英語Time Course of Neurological Disability After Re-RT for Diffuse Intrinsic Pontine Glioma[査読有り]
- 2019年12月, PEDIATRIC BLOOD & CANCER, 66, S40 - S41, 英語Airway Management by Tracheostomy in ChildrenWith Hematological and Oncological Diseases[査読有り]
- 2019年12月, PEDIATRIC BLOOD & CANCER, 66, S78 - S78, 英語Endocrine Complications in Children With Optic Pathway Glioma[査読有り]
- 2019年12月, PEDIATRIC BLOOD & CANCER, 66, S51 - S51, 英語Congenital Mesenchymoma of the Thyroid Gland[査読有り]
- 2019年12月, Bone marrow transplantation, 54(12) (12), 1926 - 1929, 英語, 国際誌
- We report two malignant sacrococcygeal tumors in infants that were associated with pathogenic DICER1 variation. These tumors were composed of primitive neuroepithelium, embryonal rhabdomyosarcoma, and cartilage and initially diagnosed as immature teratomas. One child developed intracranial metastasis and died. The second child underwent surgery and chemotherapy and achieved complete remission. This child subsequently developed five additional DICER1-associated neoplasms by age nine. Genetic analysis revealed that both tumors harbored biallelic pathogenic DICER1 variation. We believe these cases represent another novel subtype of DICER1-associated tumor. This new entity, which we propose to call DICER1-associated presacral malignant teratoid neoplasm, may be difficult initially to distinguish from immature teratoma, but recognizing it as an entity can prompt appropriate classification as an aggressive malignancy and facilitate appropriate genetic counseling, DICER1 germline variant testing, screening, and education.2019年12月, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 32(12) (12), 1744 - 1750, 英語, 国際誌研究論文（学術雑誌）
- 2019年10月, Pediatrics and neonatology, 60(5) (5), 579 - 580, 英語, 国際誌研究論文（学術雑誌）
- The dismal prognosis of patients with disseminated Ewing sarcoma necessitates the development of novel treatment strategies. Pazopanib is an oral multi-targeted tyrosine kinase inhibitor that is active against advanced soft tissue sarcoma. However, the clinical activity and feasibility of pazopanib for treating Ewing sarcoma remain poorly understood. Moreover, clinical information on the use of tandem high-dose chemotherapy for Ewing sarcoma is limited. A 14-year-old boy with Ewing sarcoma was transferred to our hospital for treatment. Magnetic resonance imaging, computed tomography scans, and bone scintigraphy revealed multiple lesions in the pubis, ilium, ischium, femur, rib, cranial bone, thoracic vertebrae, sacrum, obturator muscle, adductor magnus muscle, testicular cord, and lungs. Bone scintigraphy after intensive chemotherapies confirmed that multiple abnormal accumulations were still present in the cranial bone and pubis. Subsequently, the patient received tandem high-dose chemotherapy including topotecan, and radiotherapy. Abnormal accumulations have disappeared in bone scintigraphy. Subsequently, pazopanib maintenance therapy was initiated. Despite the presence of innumerable lesions at diagnosis, the patient has been in near-complete remission for the past 1 year with pazopanib administration. This confirms that adding pazopanib maintenance therapy after tandem high-dose chemotherapy is a therapeutic option for cases with disseminated Ewing sarcoma.2019年07月, International cancer conference journal, 8(3) (3), 95 - 100, 英語, 国際誌
- (地独)大阪府立病院機構大阪母子医療センター, 2019年03月, 大阪母子医療センター雑誌, 34(2) (2), 145 - 146, 日本語Low grade diffuse neuroepithelial tumor with INI1 deficiencyの1例
- Neuroblastoma is a common extracranial solid tumor of neural crest (NC) origin that accounts for up to 15% of all pediatric cancer deaths. The disease arises from a transient population of NC cells that undergo an epithelial-mesenchymal transition (EMT) and generate diverse cell-types and tissues. Patients with neuroblastoma are characterized by their extreme heterogeneity ranging from spontaneous regression to malignant progression. More than half of newly diagnosed patients present highly metastatic tumors and are stratified into a high-risk group with dismal outcome. As many as 20% of high-risk patients have residual disease that is refractory or progressive during induction chemotherapy. Although a majority of high-risk patients achieve remission, larger part of those patients has minimal residual disease (MRD) that causes relapse even after additional consolidation therapy. MRD is composed of drug-resistant tumor cells and dynamically presented as cancer stem cells (CSCs) in residual tumors, circulating tumor cells (CTCs) in peripheral blood (PB), and disseminated tumor cells (DTCs) in bone marrow (BM) and other metastatic sites. EMT appears to be a key mechanism for cancer cells to acquire MRD phenotypes and malignant aggressiveness. Due to the restricted availability of residual tumors, PB and BM have been used to isolate and analyze CTCs and DTCs to evaluate MRD in cancer patients. In addition, recent technical advances make it possible to use circulating tumor DNA (ctDNA) shed from tumor cells into PB for MRD evaluation. Because MRD can be detected by tumor-specific antigens, genetic or epigenetic changes, and mRNAs, numerous assays using different methods and samples have been reported to detect MRD in cancer patients. In contrast to the tumor-specific gene-rearrangement-positive acute lymphoblastic leukemia (ALL) and the oncogenic fusion-gene-positive chronic myelogenous leukemia (CML) and several solid tumors, the clinical significance of MRD remains to be established in neuroblastoma. Given the extreme heterogeneity of neuroblastoma, dynamics of MRD in neuroblastoma patients will hold a key to the clinical validation. In this review, we summarize the biology and detection methods of cancer MRD in general and evaluate the available assays and clinical significance of neuroblastoma MRD to clarify its dynamics in neuroblastoma patients.2019年, Frontiers in oncology, 9, 455 - 455, 英語, 国際誌研究論文（学術雑誌）
- 2018年11月, PEDIATRIC BLOOD & CANCER, 65, S39 - S40, 英語Clinical Characteristics of Neuroblastoma with Central Nervous System Metastases at First Relapse[査読有り]
- 2018年11月, PEDIATRIC BLOOD & CANCER, 65, S77 - S77, 英語Re-Considering Old Strategies as Palliative Treatment for DIPG (Diffuse Intrinsic Pontine Glioma)[査読有り]
- 2018年11月, PEDIATRIC BLOOD & CANCER, 65, S99 - S99, 英語Successful Induction Therapy with Prednisolone and Maintenance Therapy with Cyclosporine for Subcutaneous Panniculitis-Like T-Cell Lymphoma: A Case Report[査読有り]
- 2018年11月, PEDIATRIC BLOOD & CANCER, 65, S103 - S104, 英語Secondary Thyroid Carcinoma After Irradiation for Hematopoietic Stem Cell Transplantation in Childhood[査読有り]
- 2018年11月, PEDIATRIC BLOOD & CANCER, 65, S60 - S60, 英語Clinical Characteristics and Risk Factors of Hypertension in the Early Phase After Allogeneic Stem Cell Transplantation[査読有り]
- 2018年11月, PEDIATRIC BLOOD & CANCER, 65, S102 - S102, 英語Dermal Mucormycosis with Blood Stream Infection During High-Dose Chemotherapy (HDC) with BCOR-ITD Positive Undifferentiated Sarcoma: A Case Report[査読有り]
- 2018年11月, BLOOD, 132, 英語[査読有り]
- 2018年11月, PEDIATRIC BLOOD & CANCER, 65, S50 - S51, 英語Mediastinal Yolk Sac Tumor in a Patient with Concurrent 8p23.1 Duplication and 8p23.2-pter Deletion[査読有り]
- Disseminated fusariosis is a fatal infection in immunocompromised hosts. However, the optimal antifungal treatment for disseminated fusariosis has not yet been established. We report a case of disseminated fusariosis after chemotherapy for acute lymphoblastic leukemia, presenting with multiple skin, lung and kidney lesions and cerebrospinal fluid invasion. The combination therapy of liposomal amphotericin B and caspofungin resolved disseminated fusariosis successfully.2018年10月, The Pediatric infectious disease journal, 37(10) (10), e251-e253, 英語, 国際誌研究論文（学術雑誌）
- The dismal prognosis of pediatric acute myeloid leukemia (AML) relapsing after hematopoietic stem cell transplantation (HSCT) requires exploration of novel strategies to prevent relapse. Azacitidine (AZA) maintenance therapy could potentially reduce the recurrence rate post HSCT. Here, we presents the cases of three children with high-risk AML post HSCT who were treated with low-dose AZA maintenance therapy, demonstrating the feasibility of this therapy. Currently, all three are in complete remission for 13-41 months despite their high-risk characteristics. Our encouraging data warrant larger prospective studies to assess the efficacy and safety of low-dose AZA maintenance therapy post HSCT for pediatric patients with high-risk AML.2018年10月, Pediatric blood & cancer, 65(10) (10), e27284, 英語, 国際誌研究論文（学術雑誌）
- We report a case of a neonate with Noonan syndrome presenting with concurrent hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia, which resulted in premature death. Cases with Noonan syndrome diagnosed during the neonatal period might not necessarily show mild clinical course, and premature death is a possible outcome to be considered.2018年07月, Clinical case reports, 6(7) (7), 1202 - 1207, 英語, 国際誌
- ETV6-ABL1 fusion is a rare but recurrent oncogenic lesion found in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), without an established chromosomal abnormality, and is associated with poor outcome. In ETV6-ABL1-positive cases, an in-frame fusion produced by a complex rearrangement results in constitutive chimeric tyrosine kinase activity. Monosomy 7 is also a rare and unfavorable chromosomal abnormality in childhood BCP-ALL. Here, we report a 14-year-old female BCP-ALL patient with ETV6-ABL1 fusion combined with monosomy 7. She was admitted to our hospital because of persistent fever. Bone marrow nuclear cell count on admission was 855,000/µL with 90.0% blastic cells of lymphoid morphology. Blasts were positive for CD10, CD19, CD20, CD34, cyCD79a, cyTdT, HLA-DR, and CD66c, had a karyotype of 45, XX, - 7 [18/20] and a split signal for ABL1 FISH probe (92.7%), and were sensitive to tyrosine kinase inhibitors, imatinib and dasatinib, in vitro. ETV6-ABL1 fusion transcript was identified by whole transcriptome sequencing and confirmed by RT-PCR. She was treated with the high-risk protocol based on ALL-BFM 95, achieved complete remission (CR) after induction chemotherapy, and maintained CR for 4 months. To our knowledge, this is the first report of ETV6-ABL1 fusion combined with monosomy 7 in childhood BCP-ALL.2018年05月, International journal of hematology, 107(5) (5), 604 - 609, 英語, 国内誌研究論文（学術雑誌）
- Background: X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immune deficiency, which is caused by SH2D1A gene mutations. XLP1 is commonly associated with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphoma. The only curative treatment for XLP1 is allogeneic hematopoietic cell transplantation. However, published data detailing the clinical course of, and indications for, allogeneic hematopoietic cell transplantation in asymptomatic patients with XLP1 is lacking. Although relevant family history could be useful in identifying patients with XLP1 before disease onset, no guidelines have been established on the management of asymptomatic patients with XLP1. Therefore, clinicians and families face dilemmas in balancing between the risk of waiting for the disease onset, and the risk of transplant-related mortality associated with allogeneic hematopoietic cell transplantation, which is often performed at a very young age. We first describe the detailed clinical course of an asymptomatic patient with XLP1 who successfully underwent allogeneic hematopoietic cell transplantation. Case presentation: A boy was born at 39 weeks of gestation, weighing 3016 g at birth. He appeared fine, but he underwent genetic testing because his maternal cousin had XLP1. He was found to have a novel c.207_208insC (p.Pro70ProfsX4) mutation in exon 3 of SH2D1A, which was also found in his cousin. There was no HLA-identical donor in his family. Immunoglobulin was administered monthly to prevent EBV infection while searching for an alternative donor. He underwent allogeneic bone marrow transplantation (BMT) from an allele HLA 8/8 fully matched, unrelated donor with a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, melphalan, and low-dose total body irradiation (TBI) at 20 months of age. The patient has been doing well for 2 years post transplantation and maintaining complete donor chimerism without any evidence of chronic graft versus host disease. Conclusions: We describe a case of an asymptomatic patient with XLP1, who successfully underwent unrelated BMT with RIC regimen consisting of fludarabine, melphalan, and 3 Gy TBI. That was well tolerated and successfully generated complete chimerism in every subpopulation. This case delineates the option of allogeneic hematopoietic cell transplantation even in asymptomatic patients with XLP1.2018年, Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology, 14, 82 - 82, 英語, 国際誌
- 2017年12月, BLOOD, 130, 英語Molecular Diagnosis of Hemophilia B Leyden in Japanese Brothers Reveals Spontaneous Amelioration in Early Childhood with c.-35 G > A Onecut Binding Site Mutation[査読有り]
- 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.2017年12月, International journal of hematology, 106(6) (6), 847 - 851, 英語, 国内誌研究論文（学術雑誌）
- 2017年11月, PEDIATRIC BLOOD & CANCER, 64, S39 - S40, 英語Treatment Results and Prognostic Factors of Retinoblastoma: A Single Institution Experience[査読有り]
- 2017年11月, PEDIATRIC BLOOD & CANCER, 64, S107 - S107, 英語Pathological Fracture in Children with Nonosteogenic Malignant Tumor[査読有り]
- 2017年11月, PEDIATRIC BLOOD & CANCER, 64, S115 - S115, 英語Epidemiology of Factor VIII Inhibitor Development in Patients with Severe Hemophilia A Treated in our Institution[査読有り]
- Congenital pure erythroid leukemia is exceedingly rare and poses a diagnostic challenge. We report an atypical case of congenital pure erythroid leukemia that did not express typical erythroid markers. The patient presented with a high white blood cell count with blastic cells at birth. Although flow cytometric analyses of peripheral blood and bone marrow showed a large CD45-negative cell population, we did not identify any evidence of monoclonality. While the circulating blasts decreased with only supportive care, hepatomegaly with multiple nodules was accompanied by liver failure, disseminated intravascular coagulation, and development of hemophagocytic lymphohistiocytosis. Pathological examination of the liver biopsy specimen revealed a small round cell tumor that was negative for nearly all hematopoietic cell markers, including classical erythroid cell markers, and positive for CD43, CD71, and E-cadherin, an early erythroid marker epithelial calcium-dependent adhesion protein, suggesting that these tumor cells originated from an immature erythroblast. We found high β-catenin and c-Myc protein expression, which were not previously described in pure erythroid leukemia. Cytosine arabinoside temporarily alleviated clinical symptoms; however, the patient died of progressive disease at 8 months of age. This case indicates that E-cadherin is useful for diagnosing pure erythroid leukemia, even in immature cases.2017年11月, International journal of hematology, 106(5) (5), 711 - 717, 英語, 国内誌研究論文（学術雑誌）
- The transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) is highly expressed in monocytes/macrophages. However, its roles in monopoiesis are largely unknown. Here, we investigated the roles of C/EBPβ in monopoiesis. Further subdivision of monocytes revealed that Cebpb messenger RNA was highly upregulated in Ly6C- monocytes in bone marrow. Accordingly, the number of Ly6C- monocytes was significantly reduced in Cebpb-/- mice. Bone marrow chimera experiments and Mx1-Cre-mediated deletion of Cebpb revealed a cell-intrinsic and monocyte-specific requirement for C/EBPβ in monopoiesis. In Cebpb-/- mice, turnover of Ly6C- monocytes was highly accelerated and apoptosis of Ly6C- monocytes was increased. Expression of Csf1r, which encodes a receptor for macrophage colony-stimulating factor, was significantly reduced in Ly6C- monocytes of Cebpb-/- mice. C/EBPβ bound to positive regulatory elements of Csf1r and promoted its transcription. Collectively, these results indicate that C/EBPβ is a critical factor for Ly6C- monocyte survival, at least in part through upregulation of Csf1r.2017年10月, Blood, 130(16) (16), 1809 - 1818, 英語, 国際誌研究論文（学術雑誌）
- 2017年06月, NEURO-ONCOLOGY, 19, 22 - 22, 英語IMMATURE TERATOMA WITH DICER1 MUTATIONS: A CASE REPORT[査読有り]
- A 10-year-old girl was referred to our hospital with left preauricular adenopathy and gingival swelling. She was diagnosed with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) based on being positive for expressions of CD10, CD19, TdT and HLA-DR. She showed no CD20 expression at the time of diagnosis. Based on the initial diagnosis of BCP-ALL, induction chemotherapy for BCP-ALL was initiated. However, the blasts did not disappear from her peripheral blood. Bone marrow examination on day 33 identified 81.3% residual blasts with positive expressions of CD19, 20 and HLA-DR and negative CD10 and TdT expressions; these cells were morphologically and phenotypically different from those at the initial diagnosis. Based on cytogenetic studies, the final diagnosis was double-hit lymphoma/leukemia (DHL) with IgH-BCL2 and Igλ-MYC. Although dose intensive chemotherapy, including rituximab, led to complete remission, bone marrow and central nervous system relapse occurred. At relapse, blasts expressed CD10, CD19 and HLA-DR, but not CD20, findings the same as those at the onset. The patient died of the disease 44 days after cord blood transplantation with non-remission status. DHL in childhood is extremely rare and its prognosis is poor. The establishment of an effective treatment for DHL is highly anticipated.2017年, [Rinsho ketsueki] The Japanese journal of clinical hematology, 58(2) (2), 143 - 149, 日本語, 国内誌研究論文（学術雑誌）
- 2016年12月, BLOOD, 128(22) (22), 英語[査読有り]
- The CCAAT/enhancer-binding protein β (C/EBPβ) transcription factor is required for granulopoiesis under stress conditions. However, little is known about its roles in steady state hematopoiesis. Here, we analyzed the peripheral blood and bone marrow of Cebpb(-/-) mice at steady state by flow cytometry and unexpectedly found that the number of peripheral blood monocytes was severely reduced, while the number of bone marrow monocytes was maintained. The ability of Cebpb(-/-) bone marrow cells to give rise to macrophages/monocytes in vitro was comparable to that of wild-type bone marrow cells. Apoptosis of monocytes was enhanced in the peripheral blood, but not in the bone marrow of Cebpb(-/-) mice. These results indicate that C/EBPβ is required for the survival of monocytes in peripheral blood.2015年08月, Biochemical and biophysical research communications, 464(2) (2), 654 - 8, 英語, 国際誌研究論文（学術雑誌）
- Steady-state hematopoiesis responds to extracellular stimuli to meet changing demands and also to pathologically altered intracellular signaling. Granulocyte production increases following infection or in response to cytokine stimulation, and activation of the CCAAT/enhancer-binding protein β (C/EBPβ) transcription factor is required for such stress-induced granulopoiesis, whereas C/EBPα plays a critical role in maintaining steady-state granulopoiesis. Different roles of these C/EBP transcription factors in different modes of hematopoiesis are evolutionally conserved from zebrafish to humans. In addition to reactions against infections, C/EBPβ is responsible for cancer-driven myelopoiesis, which promotes cancer progression, at least in part, by abrogating the immune response in the cancer microenvironment. The BCR-ABL fusion protein activates emergency-specific pathway of granulopoiesis by upregulating C/EBPβ. This in turn causes chronic phase chronic myeloid leukemia, which is characterized by myeloid expansion. The C/EBPβ transcription factor also plays a role in other hematological malignancies of both myeloid and lymphoid lineage origin. Thus, elucidation of the upstream and downstream networks surrounding C/EBPβ will lead to the development of novel therapeutic strategies for diseases mediated by non-steady-state hematopoiesis.2015年07月, Cancer science, 106(7) (7), 797 - 802, 英語, 国際誌研究論文（学術雑誌）
- 日本癌学会, 2014年09月, 日本癌学会総会記事, 73回, P - 2243, 英語BCR-ABL発現白血病細胞に対するC/EBPβを介したIFNαの作用(Effects of IFNα on BCR-ABL-expressing leukemic cells through upregulation of C/EBPβ)
- Parathyroid hormone (PTH) stimulates hematopoiesis in mouse models. The involvement of osteoblasts in this process has been well investigated; however, the effects of PTH on human hematopoiesis and bone marrow mesenchymal stromal cells (BM-MSCs) are unclear. Here, we show that BM-MSCs contribute to the hematopoiesis-stimulating effects of PTH via upregulation of cadherin-11 (CDH11). When culture-expanded human BM-MSCs were stimulated with PTH, their ability to expand cocultured CD34(+) hematopoietic progenitor cells (HPCs) was enhanced. Furthermore, when PTH-treated BM-MSCs were subcutaneously implanted into NOD/SCID mice, the induction of hematopoietic cells was enhanced. Culture-expanded human BM-MSCs expressed CDH11, and the level of CDH11 expression increased following PTH stimulation. Depletion of CDH11 expression in BM-MSCs using small interfering RNA abolished the enhancement of HPC expansion by PTH-treated BM-MSCs. In lethally irradiated mice that underwent BM transplantation, CDH11 expression in BM-MSCs was higher and survival was better in PTH-treated mice than in control mice. The number of hematopoietic cells in BM and the number of red blood cells in peripheral blood were higher in PTH-treated mice than in control mice. Our results demonstrate that PTH stimulates hematopoiesis through promoting the upregulation of CDH11 expression in BM-MSCs, at least in part. PTH treatment may be an effective strategy to enhance the ability of BM-MSCs to support hematopoiesis.2014年08月, Stem cells (Dayton, Ohio), 32(8) (8), 2245 - 55, 英語, 国際誌研究論文（学術雑誌）
- The transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) regulates the differentiation of a variety of cell types. Here, the role of C/EBPβ expressed by bone marrow mesenchymal stromal cells (BMMSCs) in B-cell lymphopoiesis was examined. The size of the precursor B-cell population in bone marrow was reduced in C/EBPβ-knockout (KO) mice. When bone marrow cells from C/EBPβ-KO mice were transplanted into lethally irradiated wild-type (WT) mice, which provide a normal bone marrow microenvironment, the size of the precursor B-cell population was restored to a level equivalent to that generated by WT bone marrow cells. In coculture experiments, BMMSCs from C/EBPβ-KO mice did not support the differentiation of WT c-Kit(+) Sca-1(+) Lineage(-) hematopoietic stem cells (KSL cells) into precursor B cells, whereas BMMSCs from WT mice did. The impaired differentiation of KSL cells correlated with the reduced production of CXCL12/stromal cell-derived factor-1 by the cocultured C/EBPβ-deficient BMMSCs. The ability of C/EBPβ-deficient BMMSCs to undergo osteogenic and adipogenic differentiation was also defective. The survival of leukemic precursor B cells was poorer when they were cocultured with C/EBPβ-deficient BMMSCs than when they were cocultured with WT BMMSCs. These results indicate that C/EBPβ expressed by BMMSCs plays a crucial role in early B-cell lymphopoiesis.2014年03月, Stem cells (Dayton, Ohio), 32(3) (3), 730 - 40, 英語, 国際誌研究論文（学術雑誌）
- Granulopoiesis is tightly regulated to meet host demands during both "steady-state" and "emergency" situations, such as infections. The transcription factor CCAAT/enhancer binding protein β (C/EBPβ) plays critical roles in emergency granulopoiesis, but the precise developmental stages in which C/EBPβ is required are unknown. In this study, a novel flow cytometric method was developed that successfully dissected mouse bone marrow cells undergoing granulopoiesis into five distinct subpopulations (#1-5) according to their levels of c-Kit and Ly-6G expression. After the induction of candidemia, rapid mobilization of mature granulocytes and an increase in early granulocyte precursors accompanied by cell cycle acceleration was followed by a gradual increase in granulocytes originating from the immature populations. Upon infection, C/EBPβ was upregulated at the protein level in all the granulopoietic subpopulations. The rapid increase in immature subpopulations #1 and #2 observed in C/EBPβ knockout mice at 1 d postinfection was attenuated. Candidemia-induced cell cycle acceleration and proliferation of hematopoietic stem/progenitors were also impaired. Taken together, these data suggest that C/EBPβ is involved in the efficient amplification of early granulocyte precursors during candidemia-induced emergency granulopoiesis.2012年11月, Journal of immunology (Baltimore, Md. : 1950), 189(9) (9), 4546 - 55, 英語, 国際誌研究論文（学術雑誌）
- OBJECTIVES: To determine the efficacy of methylprednisolone pulse therapy for children with Mycoplasma pneumoniae pneumonia (MP) that is refractory to antibiotic treatment. METHODS: Refractory patients were defined as cases showing clinical and radiological deterioration despite appropriate antibiotic therapy for 7 days or more. We identified 6 such children (male/female: 3/3) aged 3-9 years who were treated between 1998 and 2006. During the same period, 190 children with MP were admitted to our institution. RESULTS: Common laboratory findings of the patients included cytopenia, elevated serum lactate dehydrogenase and ferritin levels, and elevated urine beta(2)-microglobulin levels, suggesting complication of hypercytokinemic condition. We initiated intravenous methylprednisolone at a dose of 30 mg/kg on 10.2+/-2.8 clinical days and administered it once daily for 3 consecutive days. Fever subsided 4-14 h after initiation of steroid pulse therapy in all patients. This dramatic effect was accompanied by rapid improvement of radiological abnormalities including infiltrates and pleural effusion, followed by improvement of laboratory abnormalities. There were no adverse events of steroid therapy. CONCLUSIONS: This is the first case-series study showing an effect of 3-day methylprednisolone pulse therapy on refractory MP in children. This therapy is apparently an efficacious and well-tolerated treatment for refractory MP.2008年09月, The Journal of infection, 57(3) (3), 223 - 8, 英語, 国際誌研究論文（学術雑誌）
- [ATIC-ALK-positive anaplastic large cell lymphoma: a case report and review of the literature].We report a 10-year-old girl with ATIC-anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL). She presented with inguinal, axillary, and paraaortic lymph node swellings that showed spontaneous regression over a 3-month period, followed by recurrence after an interval of 8 months. Radiological and clinical findings indicated Ann Arbor stage IIIA. Pathological findings showed that staining of ALK was restricted to the cytoplasm of ALCL cells. ATIC-ALK chimeric transcripts were detected by reverse transcriptase polymerase chain reaction. The patient was assigned to the standard risk group proposed by the international multicenter study for pediatric ALCL, ALCL99. The patient responded well to the treatment and remained in complete remission for more than 26 months. To date, 7 genes have been identified as a fusion partner of ALK, with the highest frequency in nucleophosmin (NPM). Little is known about the clinical implications of subtypes of ALCL harboring each of the 7 fusion genes, especially those of variant fusion genes other than NPM-ALK. In this paper, we review 9 patients with ATIC-ALK-positive ALCL in the literature in addition to discussing our patient. In eight of these 10 cases, disease occurred within the first three decades. Five of 6 cases that were followed continuously remained in complete remission.2008年05月, [Rinsho ketsueki] The Japanese journal of clinical hematology, 49(5) (5), 325 - 30, 日本語, 国内誌研究論文（学術雑誌）
- (公社)日本小児科学会, 2024年04月, 日本小児科学会雑誌, 128(4) (4), 624 - 624, 日本語潰瘍性大腸炎の発症時に免疫性血小板減少症を合併した1例
- 2019年12月, PEDIATRIC BLOOD & CANCER, 66, S81 - S82, 英語Level of Seven Neuroblastoma-Associated mRNAs Analyzed by ddPCR is Correlated Between Bone Marrow and Peripheral Blood in High-risk Neuroblastoma研究発表ペーパー・要旨（国際会議）
- (一社)日本小児血液・がん学会, 2019年09月, 日本小児血液・がん学会雑誌, 56(2) (2), 256 - 257, 日本語血友病未治療例(PUPs)に対する半減期延長凝固因子製剤(EHL)の使用経験
- (一社)日本小児血液・がん学会, 2019年09月, 日本小児血液・がん学会雑誌, 56(2) (2), 258 - 258, 日本語集学的治療を行った転移性ユーイング肉腫(ESFT)の2例
- (一社)日本血栓止血学会, 2019年05月, 日本血栓止血学会誌, 30(2) (2), 450 - 450, 日本語治療歴のない血友病患者(PUPs)に対する半減期延長凝固因子製剤(EHL)の使用経験
- (一社)日本病理学会, 2019年04月, 日本病理学会会誌, 108(1) (1), 413 - 413, 日本語当院のEwing肉腫及びEwing-like肉腫にPD-1/PD-L1の免疫染色を用いた検討
- (一社)兵庫県医師会, 2019年03月, 兵庫県医師会医学雑誌, 61(2) (2), 33 - 33, 日本語HLA不一致同種造血幹細胞移植の安全性確立に関する研究
- (公社)日本小児科学会, 2019年03月, 日本小児科学会雑誌, 123(3) (3), 621 - 621, 日本語兵庫県がん・生殖医療ネットワークを通じた小児がん患者における卵巣凍結保存の取り組み
- (公社)日本小児科学会, 2019年02月, 日本小児科学会雑誌, 123(2) (2), 266 - 266, 日本語Atraumatic needle使用による腰椎穿刺後合併症の出現頻度
- (公社)日本小児科学会, 2019年02月, 日本小児科学会雑誌, 123(2) (2), 317 - 317, 日本語高リスク神経芽腫患者における化学療法中の筋肉量減少
- 2018年11月, PEDIATRIC BLOOD & CANCER, 65, S38 - S39, 英語Quantitation of Minimal Residual Disease by Droplet Digital PCR in High-Risk Neuroblastoma Patients研究発表ペーパー・要旨（国際会議）
- 2018年11月, PEDIATRIC BLOOD & CANCER, 65, S71 - S71, 英語Immunohistochemical Analysis for Predicting Prognosis in Hepatoblastoma研究発表ペーパー・要旨（国際会議）
- (一社)日本小児血液・がん学会, 2018年10月, 日本小児血液・がん学会雑誌, 55(4) (4), 325 - 325, 日本語早期に遺伝子診断が得られ治療介入できた先天性葉酸吸収不全の一例
- (一社)日本小児血液・がん学会, 2018年10月, 日本小児血液・がん学会雑誌, 55(4) (4), 312 - 312, 日本語AYA世代ALLの寛解導入療法中に発症した脳静脈血栓症
- 2018年10月, CANCER RESEARCH, 78(19) (19), 英語研究発表ペーパー・要旨（国際会議）
- (一社)日本血液学会-東京事務局, 2018年09月, 臨床血液, 59(9) (9), 1685 - 1685, 英語ELANE遺伝子変異を有する重症感染症を合併しない好中球減少症の1例(Long-term severe infection free survival with neutropenia due to ELANE mutation without G-CSF)
- (一社)日本血液学会-東京事務局, 2018年09月, 臨床血液, 59(9) (9), 1698 - 1698, 英語経時的なRT-qPCRにより、急性GVHD出現後に初めてMRDの消失を確認したNUP98-NSD1陽性AML例(Monitoring RT-qPCR revealed the elimination of MRD after the onset of aGVHD in the NUP98-NSD1(+) AML)
- (一社)日本小児血液・がん学会, 2018年06月, 日本小児血液・がん学会雑誌, 55(1) (1), 41 - 42, 日本語Indolentな経過を示したnon-Hodgkin lymphomaの2例
- (一社)日本小児血液・がん学会, 2018年06月, 日本小児血液・がん学会雑誌, 55(1) (1), 44 - 44, 日本語早期の一次定期補充療法導入後、一過性にインヒビターが出現し頭蓋内出血を発症した重症血友病A乳児例
- (一社)日本小児血液・がん学会, 2018年06月, 日本小児血液・がん学会雑誌, 55(1) (1), 61 - 61, 日本語兵庫県がん・生殖医療ネットワークにおける小児がん患者に対する卵巣組織凍結保存の試み
- (公社)日本小児科学会, 2018年04月, 日本小児科学会雑誌, 122(4) (4), 815 - 815, 日本語小児がん患者に対する粒子線治療の試み
- (公社)日本小児科学会, 2018年02月, 日本小児科学会雑誌, 122(2) (2), 230 - 230, 日本語小児がん患者における聴力障害発症頻度とリスク因子についての後方視的検討
- (公社)日本小児科学会, 2018年02月, 日本小児科学会雑誌, 122(2) (2), 231 - 231, 日本語再発神経芽腫の臨床的検討
- (公社)日本小児科学会, 2018年02月, 日本小児科学会雑誌, 122(2) (2), 232 - 232, 日本語小児急性白血病に対する化学療法の好中球減少期における予防的抗菌薬投与
- (地独)大阪府立病院機構大阪母子医療センター, 2017年03月, 大阪府立母子保健総合医療センター雑誌, 32(1-2) (1-2), 36 - 37, 日本語新生児Small round cell tumor pure erythroid leakemiaが疑われた1例
- (公社)日本小児科学会, 2017年02月, 日本小児科学会雑誌, 121(2) (2), 461 - 461, 日本語急性リンパ性白血病に対する強化療法中にcytomegalovirus網膜炎を来した一乳児例
- 2016年12月, The American Society of Hematology 58th Annual Meeting and Exposition, 128(22) (22), 英語C/EBPβ is a critical regulator of CML stem cell differentiation and exhaustion induced by interferon-α研究発表ペーパー・要旨（国際会議）
- 2016年12月, American Society of Hematology, 58th Annual Meeting and Exposition, 128(22) (22), 英語C/EBPβ Is Required for Survival of Ly6C- Monocytes after Committment to Monocyte Lineage through Upregulation of Csf1r研究発表ペーパー・要旨（国際会議）
- (一社)日本小児血液・がん学会, 2016年11月, 日本小児血液・がん学会雑誌, 53(4) (4), 267 - 267, 英語Cisplatin複数回投与を受けた小児患者における化学療法に伴う嘔吐の予防(Prevention of chemotherapy-induced vomiting in children receiving multiple-day cisplatin chemotherapy)
- (一社)日本小児血液・がん学会, 2016年11月, 日本小児血液・がん学会雑誌, 53(4) (4), 275 - 275, 英語小児における同種造血幹細胞移植後の眼合併症(Ocular complications after allogeneic hematopoietic stem cell transplantation in children)
- (一社)日本小児血液・がん学会, 2016年11月, 日本小児血液・がん学会雑誌, 53(4) (4), 302 - 302, 英語小児中枢神経外胚細胞性腫瘍79症例の臨床的検討(Clinical analysis of 79 children with Extracranial germ cell tumor)
- (一社)日本小児血液・がん学会, 2016年11月, 日本小児血液・がん学会雑誌, 53(4) (4), 325 - 325, 日本語神経芽腫群腫瘍のリスク分類と組織分類の検討
- (一社)日本小児血液・がん学会, 2016年11月, 日本小児血液・がん学会雑誌, 53(4) (4), 329 - 329, 英語網膜芽細胞腫に対するvincristine、etoposide、carboplatin併用療法(VEC療法)治療関連毒性の検討(Treatment-related toxicities in patients with retinoblastoma receiving vincristine, etoposide and carboplatin combination therapy)
- (一社)日本小児血液・がん学会, 2016年11月, 日本小児血液・がん学会雑誌, 53(4) (4), 354 - 354, 英語化学療法中に発症した播種性Fusarium症に対してliposomal amphotericin Bとcaspofungin併用療法が奏功したALL(Successful combination therapy with liposomal amphotericin B and caspofungin for disseminated fusarinosis)
- (一社)日本小児血液・がん学会, 2016年11月, 日本小児血液・がん学会雑誌, 53(4) (4), 356 - 356, 英語乳児純赤芽球型急性赤白血病(Infantile pure erythroid leukemia)
- (一社)日本小児血液・がん学会, 2016年11月, 日本小児血液・がん学会雑誌, 53(4) (4), 262 - 262, 英語小児難治固形腫瘍に対するTMC大量化学療法(Topotecan/melphalan/cyclophosphamide)の有効性(The efficacy of high-dose topotecan, melphalan, and cyclophosphamide for children with advanced solid tumors: A single-institution experience)
- 2015年12月, American Society of Hematology, 57th Annual Meeting, 126(23) (23), 英語Csf1r Is a Downstream Target of C/EBPβ in Ly6C¯ Monocytes.研究発表ペーパー・要旨（国際会議）
- 2015年12月, BLOOD, 126(23) (23), 英語Bortezomib Attenuates Adhesion of B Cell Precursor Acute Lymphoblastic Lleukemia Cells to Bone Marrow Mesenchymal Stromal/Stem Cells Via Regulating SPARC Expression研究発表ペーパー・要旨（国際会議）
- 2015年12月, American Society of Hematology, 57th Annual Meeting, 126(23) (23), 英語C/EBPβ Isoforms Distinctively and Collaboratively Regulate the Behavior of Hematopoietic Stem and Progenitor Cells in Regenerative Conditions.研究発表ペーパー・要旨（国際会議）
- 2015年12月, BLOOD, 126(23) (23), 英語Vitamin K2 Supports Hematopoiesis through Acting on Bone Marrow Mesenchymal Stromal/Stem Cells研究発表ペーパー・要旨（国際会議）
- 日本癌学会, 2015年10月, 第74回日本癌学会学術総会（名古屋）, 74回, P - 3228, 英語ボルテゾミブは前駆B細胞性白血病細胞の骨髄間葉系幹細胞への接着を減弱させる研究発表ペーパー・要旨（全国大会，その他学術会議）
- 2015年09月, International Society for Experimental Hematology, 44th Annual Scientific Meeting, 43(9) (9), S104 - S104, 英語IFNα promotes differentiation of BCR-ABL+ leukemic cells through upregulating C/EBPβ.研究発表ペーパー・要旨（国際会議）
- 2014年12月, The 56th ASH Annual Meeting (San Francisco, CA), 124(21) (21), 英語Essential Roles of C/EBPβ in Survival of Ly6C– monocytes.研究発表ペーパー・要旨（国際会議）
- 2014年12月, BLOOD, 124(21) (21), 英語Effects of Irradiation on the Functional Characteristics of Human Bone Marrow Mesenchymal Stromal/Stem Cells研究発表ペーパー・要旨（国際会議）
- 2012年11月, BLOOD, 120(21) (21), 英語Mesenchymal Stem Cells Skewed Their Phenotype Toward the Osteogenic Lineage Support the Hematopoietic Cell Differentiation研究発表ペーパー・要旨（国際会議）
- 2012年11月, BLOOD, 120(21) (21), 英語Expression of C/EBP beta in Bone Marrow Mesenchymal Stem Cells Is Mandatory for Early-Stage B Cell Lymphopoiesis研究発表ペーパー・要旨（国際会議）
- 2012年11月, 54th Annual Meeting and Exposition、American Society of Hematology (Atlanta, USA), 120(21) (21), 英語C/EBP-Mediated Expansion of Hematopoietic Stem/Progenitors Precedes ‘Emergency’ Granulopoiesis Induced by Candidemia研究発表ペーパー・要旨（国際会議）
- (公社)日本小児科学会, 2009年03月, 日本小児科学会雑誌, 113(3) (3), 607 - 607, 日本語前頭葉を主として障害する乳幼児急性脳症(AIEF)の1例
- 日本学術振興会, 科学研究費助成事業, 若手研究, 国立研究開発法人理化学研究所, 2020年04月01日 - 2023年03月31日C/EBPβ依存的非古典的単球の小児がん進行への関与メカニズムの解明高リスク神経芽腫は、集学的治療後も半数以上が再発する難治疾患で、病態解明や効果的な治療開発が進んでいない。近年、抗GD2抗体による免疫療法の有効性が報告されているが、効果は限定的であることが問題となっている。申請者らは、臨床情報の大規模な解析により、初診時における末梢血単球数と長期予後に強い相関があることを発見した。この発見は、診断時の単球の状態を評価することによって個別化医療が可能であることを示唆する。 これまで慣習的に用いられているCD14とCD16を用いた単球解析法で細胞ソーティングした後、１細胞RNA-seq解析を行ったところ、従来単球と定義されていた細胞集団にはNK細胞や樹状細胞、好酸球、好塩基球等が多数混在し、非常に雑多な細胞集団であることが明らかになった。従来のCD14とCD16表面マーカーを用いた単球解析では、その純度や抽出可能な情報等において不十分であることを明らかとなった。 さらに、申請者らの独自解析の結果、抗GD2抗体のFc部分を認識するFCGR3Aは、NK細胞と比較して単球で高発現していることに加え、単球の中でも発現が不均一であることを発見した。さらに近年、CD47/SIRPαやMHC class I/LILRB family、CD24/Siglec-10など、マクロファージによるDon’t eat me signalを標的とした、がん免疫療法の有効性が報告され、注目されているが、SIRPαやLILRB family、Siglec-10などのDon’t eat me signalについても、単球の中での発現が不均一であることを発見した。そこで申請者らは、従来のCD14/CD16の分類ではなく、機能に基づいた新規分類によって、単球は更に詳細に細分化され、病態毎に疾患特異的単球が存在すると仮定した。