記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cisplatin is commonly used to treat solid tumors; however, its use can be complicated by drug-induced hearing loss (ie, ototoxicity). The presence of certain genetic variants has been associated with the development/occurrence of cisplatin-induced ototoxicity, suggesting that genetic factors may be able to predict patients who are more likely to develop ototoxicity. The authors aimed to review genetic associations with cisplatin-induced ototoxicity and discuss their clinical relevance. METHODS: An updated systematic review was conducted on behalf of the Canadian Pharmacogenomics Network for Drug Safety, based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement. Pharmacogenomic studies that reported associations between genetic variation and cisplatin-induced ototoxicity were included. The evidence on genetic associations was summarized and evaluated, and knowledge gaps that can be used to inform future pharmacogenomic studies identified. RESULTS: Overall, 40 evaluated reports, considering 47 independent patient populations, captured associations involving 24 genes. Considering GRADE criteria, genetic variants in 2 genes were strongly (ie, odds ratios ≥3) and consistently (ie, replication in ≥3 independent populations) predictive of cisplatin-induced ototoxicity. Specifically, an ACYP2 variant has been associated with ototoxicity in both children and adults, whereas TPMT variants are relevant in children. Encouraging evidence for associations involving several other genes also exists; however, further research is necessary to determine potential clinical relevance. CONCLUSIONS: Genetic variation in ACYP2 and TPMT may be helpful in predicting patients at the highest risk of developing cisplatin-induced ototoxicity. Further research (including replication studies considering diverse pediatric and adult patient populations) is required to determine whether genetic variation in additional genes may help further identify patients most at risk.

DOI： 10.1097/FTD.0000000000001113

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Autoimmune lymphoproliferative syndrome (ALPS) is a disease of lymphocyte homeostasis caused by FAS-mediated apoptotic pathway dysfunction and is characterized by non-malignant lymphoproliferation with an increased number of TCRαβ+CD4-CD8- double-negative T cells (αβDNTs). Conversely, RAS-associated leukoproliferative disease (RALD), which is caused by gain-of-functional somatic variants in KRAS or NRAS, is considered a group of diseases with a similar course. Herein, we present a 7-year-old Japanese female of RALD harboring NRAS variant that aggressively progressed to juvenile myelomonocytic leukemia (JMML) with increased αβDNTs. She eventually underwent hematopoietic cell transplantation due to acute respiratory distress which was caused by pulmonary infiltration of JMML blasts. In general, αβDNTs have been remarkably increased in ALPS; however, FAS pathway gene abnormalities were not observed in this case. This case with RALD had repeated shock/pre-shock episodes as the condition progressed. This shock was thought to be caused by the presence of a high number of αβDNTs. The αβDNTs observed in this case revealed high CCR4, CCR6, and CD45RO expressions, which were similar to Th17. These increased Th17-like αβDNTs have triggered the inflammation, resulting in the pathogenesis of shock, because Th17 secretes pro-inflammatory cytokines such as interleukin (IL)-17A and granulocyte-macrophage colony-stimulating factor. The presence of IL-17A-secreting αβDNTs has been reported in systemic lupus erythematosus (SLE) and Sjögren's syndrome. The present case is complicated with SLE, suggesting the involvement of Th17-like αβDNTs in the disease pathogenesis. Examining the characteristics of αβDNTs in RALD, JMML, and ALPS may reveal the pathologies in these cases.

DOI： 10.1007/s10875-023-01566-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae.

DOI： 10.1007/s12185-022-03505-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Fatal cardiac complications can occur from the early to late phases after hematopoietic cell transplantation (HCT). Herein, the Japanese transplant registry database was used to retrospectively analyze health records of 33,791 allogeneic HCT recipients to elucidate the pathogenesis and risk factors involved. Overall, 527 patients died of cardiac complications at a median of 130 (range 0-3,924) days after HCT. The cumulative incidence of fatal cardiac complications was 1.2% (95% confidence interval (CI): 1.0-1.3) and 1.6% (95% CI: 1.5-1.8) at 1 and 5 years after HCT, respectively. Fatal cardiovascular events were significantly associated with an HCT comorbidity index (HCT-CI) score of ≥1 specific to the three cardiovascular items, lower performance status, conditioning regimen cyclophosphamide dose of >120 mg/kg, and female sex. Cardiovascular death risk within 60 days after HCT was associated with the type of conditioning regimen, presence of bacterial or fungal infections at HCT, and number of blood transfusions. Contrastingly, late cardiovascular death beyond 1 year after HCT was associated with female sex and older age. Lower performance status and positive cardiovascular disease-related HCT-CI were risk factors for cardiac complications in all phases after HCT. Systematic follow-up may be necessary according to the patients' risk factors and conditions. This article is protected by copyright. All rights reserved.

DOI： 10.1002/hon.3101

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hypertrophic pachymeningitis (HP) is a rare inflammatory disorder characterized by local or diffuse thickening of the cranial and spinal dura mater. HP occurs owing to idiopathic or secondary causes, including autoimmune disease, infection, and trauma. HP has mainly been reported in adults, with few reported cases in children. We encountered an 11-year-old boy with idiopathic HP who presented with chronic inflammation and daily occipital headache. Gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) helped us to diagnose him with HP. He was successfully treated with corticosteroids and azathioprine with no recurrence. We also conducted a literature review of childhood-onset HP and found only 16 cases including our patient. Seven patients had idiopathic HP and the remaining nine had secondary HP, including two with rheumatic disease. The most common clinical symptoms were headache (68.8%) and cranial nerve-related symptoms (68.8%). Inflammatory laboratory markers were elevated in 60% of patients with available data. Fifteen cases were diagnosed using Gd-enhanced MRI. The main initial treatment was steroids and/or immunosuppressants, to which 87.5% of patients responded. However, two patients with HP associated with trauma and neuroblastoma (12.5%) died, and seven patients (43.8%) had left cranial nerve-related sequelae. As the prognosis for childhood HP is poor, early diagnosis and treatment are essential. Children with headache, cranial nerve symptoms, and elevated inflammatory marker levels should be suspected of having HP and Gd-enhanced MRI should be considered.

DOI： 10.1093/mrcr/rxac026

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

MECOM encodes the transcriptional regulators, EVI1 and MDS1-EVI1, from two distinct transcription start sites. EVI1 plays important roles in hematopoiesis and stem cell self-renewal. Recently, our group and others revealed that individuals with MECOM variants present diverse hematological and skeletal defects, including radioulnar synostosis (RUS). In the present study, we analyzed two families suspected with MECOM-associated syndrome. In family 1, a MECOM splicing variant (c.2285+1G>A) was identified in an individual with bone marrow failure (TRS4) without RUS and her mother, who had mild leukocytopenia, thrombocytopenia, and bilateral RUS. A copy neutral loss of heterozygosity decreasing the variant allele frequency was observed in the bone marrow of TRS4 and the peripheral blood leukocytes of her mother. However, TRS4 remained transfusion-dependent. In family 2, a MECOM variant (c.2208-4A>G), which was predicted to cause a cryptic acceptor site that results in a 3-base insertion (an insertion of Ser) in the mRNA, was identified in the proband, with bone marrow failure; this variant was also observed in her brother and father, both of whom have skeletal malformations, but no cytopenia. RT-PCR using leukocytes revealed a transcript with a 3-bp insertion in the proband, her brother, and the father, suggesting that the transcript variant with a 3-bp insertion is independent of blood phenotype. Collectively, these results suggest the presence of intrafamilial clinical heterogeneity in both families with MECOM splicing variants. Somatic genetic event may complicate the understanding of clinical variability among family members.

DOI： 10.1182/bloodadvances.2020003812

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Hematopoietic cell transplantation (HCT) is a curative therapy for most patients with inborn errors of immunity (IEI). We conducted a nationwide study on HCT for patients with IEI other than severe combined immunodeficiency (non-SCID) in Japan. METHODS: Data from the Japanese national database (Transplant Registry Unified Management Program, TRUMP) for 566 patients with non-SCID IEI, who underwent their first HCT between 1985 and 2016, were retrospectively analyzed. RESULTS: The 10-year overall survival (OS) and event-free survival (EFS) were 74% and 64%, respectively. The 10-year OS for HCT from unrelated bone marrow (URBM), accounting for 39% of HCTs, was comparable to that for HCT from matched sibling donor (MSD), 79% and 81%, respectively. HCT from unrelated cord blood (URCB), accounting for 28% of HCTs, was also common, with a 10-year OS of 69% but less robust engraftment. The intensity of conditioning was not associated with OS or neutrophil recovery; however, myeloablative conditioning was more frequently associated with infection-related death. Patients who received myeloablative irradiation showed poor OS. Multivariate analyses revealed that HCT in 1985-1995 (hazard ratio [HR], 2.0; P = 0.03), URCB (HR, 2.0; P = 0.01), and related donor other than MSD (ORD) (HR, 2.9; P < 0.001) were associated with poor OS, and URCB (HR, 3.6; P < 0.001) and ORD (HR, 2.7; P = 0.02) showed a higher incidence of retransplantation. CONCLUSIONS: We present the 1985-2016 status of HCT for non-SCID IEI in Japan with sufficient statistical power, highlighting the potential of URBM as an alternative donor and the feasibility of reduced intensity conditioning.

DOI： 10.1007/s10875-021-01199-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pineal parenchymal tumor of intermediate differentiation (PPTID) is a WHO grade II and III tumor arising from pineal parenchymal cells. PPTID is a rare tumor accounting for less than 1% of all primary central nervous system neoplasms. Therefore, reports describing the clinical characteristics and biological features of PPTID are lacking. Moreover, the therapeutic strategy remains controversial. The current study aimed to evaluate treatment results and problems of contemporary therapeutic modalities of PPTID based on its features compared with other pineal parenchymal tumors. A comprehensive systematic literature review of 69 articles was performed, including articles on PPTID (389 patients) and similar tumors. Patient demographics, disease presentation, imaging characteristics, biological features, and current therapeutic options and their results were reviewed. We found that histopathological findings based on current WHO classification are well associated with survival; however, identifying and treating aggressive PPTID cases with uncommon features could be problematic. A molecular and genetic approach may help improve diagnostic accuracy. Therapeutic strategy, especially for grade III and aforementioned uncommon and aggressive tumors, remains controversial. A combination therapy involving maximum tumor resection, chemotherapy, and radiotherapy could be the first line of treatment. However, although challenging, a large prospective study would be required to identify ways to improve the clinical results of PPTID treatment.

DOI： 10.1007/s10143-021-01674-3

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記述言語：日本語   出版者・発行元：日本小児臨床薬理学会  

造血幹細胞移植の前治療薬として再承認されたthiotepaは、一部が汗から排泄されるため、皮膚障害を発症することが知られている。認知機能低下があり、おむつの着用が必要であった髄芽腫の8歳男児に、thiotepaを含む大量化学療法を施行した。1日1回のシャワー浴を行い、おむつを頻回に交換し、保清に努めたが、患児はthiotepa投与後に、体表面積の10%以上を占める色素沈着(CTCAE version 5.0 grade 2)、陰嚢、肛門部に角層剥離(grade 2)、そして、日常生活が制限される皮膚疼痛(grade 3)を認めた。おむつ着用部のみに角層剥離が点在していたことから、thiotepaによる皮膚障害と診断した。おむつを着用している患者では、過剰な湿潤環境から汗が蓄積しやすく、thiotepaによる皮膚障害のリスクが増加すると考えられた。thiotepa投与期間中は頻回のシャワー浴を行い、汗の蓄積を減らす対策が必要と考えられた。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This article summarizes the background, content and outcomes of a special meeting that was convened among oncologists and scientists to discuss the role of pharmacogenetic (PGx) testing in pediatric clinical oncology practice. This meeting provided an opportunity for what the lead author (AM Issa) refers to as the 'voice of the clinician' dynamic to be amplified in order to better understand how personalized or precision medicine applications such as PGx testing are adopted and incorporated into clinical settings and what we can learn from the experiences of current and ongoing implementation PGx approaches to further the implementation of precision medicine applications in real-world environments. Group dynamics and clinical experience with PGx testing and return of results shaped the discussion.

DOI： 10.2217/pme-2020-0120

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Anthracyclines are widely used as part of chemotherapeutic regimens in paediatric oncology patients. The most serious adverse drug reaction caused by anthracycline use is cardiotoxicity, a serious condition that can lead to cardiac dysfunction and subsequent heart failure. Both clinical and genetic factors contribute to a patient's risk of experiencing anthracycline-induced cardiotoxicity. In particular, genetic variants in RARG, UGT1A6 and SLC28A3 have been consistently shown to influence an individual's risk of experiencing this reaction. By combining clinical and genetic risks, decision-making can be improved to optimize treatment and prevent potentially serious adverse drug reactions. As part of a precision medicine initiative, we used pharmacogenetic testing, focused on RARG, UGT1A6 and SLC28A3 variants, to help predict an individual's risk of experiencing anthracycline-induced cardiotoxicity. Pharmacogenetic results are currently being used in clinical decision-making to inform treatment regimen choice, anthracycline dosing and decisions to initiate cardioprotective agents. In this case series, we demonstrate examples of the impact of genetic testing and discuss its potential to allow patients to be increasingly involved in their own treatment decisions.

DOI： 10.1111/bcpt.13593

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担当区分：筆頭著者  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The clinical implementation of pharmacogenetic biomarkers continues to grow as new genetic variants associated with drug outcomes are discovered and validated. The number of drug labels that contain pharmacogenetic information also continues to expand. Published, peer-reviewed clinical practice guidelines have also been developed to support the implementation of pharmacogenetic tests. Incorporating pharmacogenetic information into health care benefits patients as well as clinicians by improving drug safety and reducing empiricism in drug selection. Barriers to the implementation of pharmacogenetic testing remain. This review explores current pharmacogenetic implementation initiatives with a focus on the challenges of pharmacogenetic implementation and potential opportunities to overcome these challenges. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 7, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI： 10.1146/annurev-pharmtox-030920-025745

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記述言語：英語  

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive type of extranodal non-Hodgkin lymphoma that carries an unsatisfactory prognosis. Treating refractory PCNSL is challenging because of resistance to conventional cytotoxic and intrathecal chemotherapies. Therefore, novel therapeutic approaches are needed. Here, we report a 12-year-old boy with CD20-positive PCNSL, which was refractory to combination chemotherapy and intravenous rituximab. However, the patient achieved complete remission after repeated intraventricular rituximab administration. The results of this case indicate that intraventricular rituximab is an effective option to treat refractory PCNSL in children.

DOI： 10.1097/MPH.0000000000001291

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DOI： 10.1016/j.bbmt.2019.07.025

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DOI： 10.1111/tid.13061

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記述言語：英語  

DOI： 10.1111/bjh.15657

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Kawasaki disease is an acute systemic vasculitis in children. Antiplatelet medicines are commonly used for Kawasaki disease to attenuate vasculitis and prevent thromboembolism; however, the mechanisms have not been elucidated. The objective of this study is to assess the effectiveness of antiplatelet medications for Kawasaki disease. We used Medline, Embase, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi (Ichushi) from January 1947 to August 2018. Studies describing the platelet functions of antiplatelet drugs for Kawasaki disease were included. Twenty studies met the inclusion criteria. There were no randomized controlled trials. Seven studies compared platelet aggregation ability before and after treatment. Eight studies compared platelet aggregation with that in Kawasaki disease patients without treatment. Four studies compared aggregation among different types of antiplatelet drugs or at different doses. Antiplatelet medications administered in the studies included aspirin, flurbiprofen, dipyridamole, and choline salicylate. Methods for the measurement of platelet aggregation ability varied among studies. The groups with antiplatelet treatment tended to have a decreased platelet aggregation function. The statistical analyses were impossible due to insufficient quantitative data and heterogeneity among the studies.Conclusion: The present systematic review revealed that there was insufficient evidence for the effectiveness of antiplatelet therapy for Kawasaki disease. What is Known: • Antiplatelet therapy is widely used for Kawasaki disease to mitigate cardiac complications. • The mechanisms of antiplatelet therapy for Kawasaki disease are not clarified. What is New: • This systematic review showed that the groups with antiplatelet treatment tended to have a decreased platelet aggregation function. • There is insufficient evidence for the effectiveness of antiplatelet therapy for Kawasaki disease.

DOI： 10.1007/s00431-019-03368-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Adverse drug reactions (ADRs) are a major problem in modern medicine, representing up to the fourth-highest cause of mortality. Pharmacogenomic tests are 1 of the most promising methods to tackle the challenge of ADRs. The objective of this study was to analyze the clinical and demographic information of the pan-Canadian active surveillance network, Canadian Pharmacogenomics Network for Drug Safety (CPNDS). Information entered into the database by trained active surveillors between May 15, 2005 and May 9, 2017 was collected and analyzed. Specific data included for analysis were number of ADR reports, reports of drug use without ADRs, date of onset of ADR, suspected drugs, concomitant drugs, and fatal ADR cases. The CPNDS database consisted of 93,974 reports of medication use, including 10,475 reports of ADRs, of which 72.6% occurred in pediatric patients (≤21 years old). Self-reported ancestries were predominantly Europe (38.2%), Canada (9.6%), and East Asia (4.9%). The 5 most frequent ADRs were cutaneous ADRs, peripheral neuropathy, cardiotoxicity, central nervous system toxicity, and ototoxicity. The 5 drugs most commonly suspected to cause ADRs were methotrexate, vincristine, doxorubicin, cisplatin, and L-asparaginase. The CPNDS database is a valuable resource to identify clinical and genomic predictors of ADRs. The database also highlights our candidate ADRs for pharmacogenomic discovery research to identify additional ADR biomarkers. Additionally, the database provides information that can be used for developing strategies to prevent ADRs and raises awareness of ADRs among Canadian healthcare professionals.

DOI： 10.1002/jcph.1336

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記述言語：英語  

In the revised World Health Organization classification 2016, anaplastic pleomorphic xanthoastrocytoma (PXA) has been newly defined as a variant of the PXA entity. Furthermore, some anaplastic PXA were reported to have extremely poor prognosis which showed a type of pediatric glioblastoma (GBM) molecular profile. Recent integrated molecular classification for primary central nervous system tumors proposed some differences between histological and molecular features. Herein, in a genome-wide molecular analysis, we show an extreme aggressive anaplastic PXA that resulted in a pediatric GBM molecular profile. A full implementation of the molecular approach is the key to predict prognosis and decide the treatment strategy for anaplastic PXA.

DOI： 10.1111/cas.13903

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Risk assessment of the use of quetiapine during breastfeeding is challenging owing to a paucity of data. METHODS: A pharmacokinetic study was conducted in lactating women who were taking quetiapine. The primary endpoint was to determine quetiapine concentration profiles in milk and estimated infant exposure levels. Multiple milk and a single blood quetiapine concentrations were determined using a highly sensitive liquid chromatography with tandem mass spectroscopy method. RESULTS: Nine subjects receiving fast-release quetiapine (mean dose, 41 mg/d) were analyzed at steady state. The mean milk/plasma drug concentration ratio at 2-hour postdose was 0.47 (SD, 0.50; range, 0.13-1.67). The mean milk concentration of each patient was 5.7 ng/mL (SD, 4.5; range, 1.4-13.9 ng/mL). The mean infant quetiapine dose via milk per body weight relative to weight-adjusted maternal dose was 0.16 % (SD, 0.08; range, 0.04%-0.35%). CONCLUSIONS: Infant exposure levels to quetiapine via milk are predicted to be very small.

DOI： 10.1097/JCP.0000000000000905

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DOI： 10.1002/ccr3.1249

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ependymomas are primary neuroepithelial malignancies that mainly occur during childhood, and arise from ependymal cells along the ventricular systems of the CNS. Recently, it was elucidated that two-thirds of supratentorial (ST) ependymomas harbor oncogenic fusions of RELA, whose protein product is the principal effector of canonical NF-κB signaling. RELA fusion proteins activate signaling for tumor proliferation and malignant progression, resulting in poorer prognoses in these patients compared to those in patients with other ST ependymomas. In this study, we encountered a case of C11orf-RelA fusion-positive ST anaplastic ependymoma that was diagnosed in first tumor resection surgery of multi-staged gross total resection with molecular evidence. In ependymomas, regardless of tumor location or pathological grade, subtotal resection is associated with higher rates of mortality compared with GTR. Molecular analysis based on the application of recent molecular knowledge for ST ependymomas performs a role in appropriate and individualized treatment strategies.

DOI： 10.1007/s10014-017-0297-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background: Thrombomodulin alfa (TM-alpha) is a new class of anticoagulant drug for patients with disseminated intravascular coagulation (DIC). This study aimed to determine the pharmacokinetics of TM-alpha and determine the optimal dose in pediatric patients with hematological malignancy and DIC.
Procedure: Pediatric patients with hematological malignancy and DIC were administered TM-alpha at a dose of 0.06 mg/kg (380 U/kg) over 30 min every 24 hr. Blood samples were taken at steady state before the start, immediately after the end, and 24 hr after the start of the sixth administration. Population pharmacokinetic analysis was performed using sparse samples with the nonlinear mixed-effect modeling programNONMEM (R), version 7.3.
Results: The actual and predicted plasma concentrations of TM-alpha based on the final population pharmacokinetic model showed a good linear correlation. Clearance and volume of distribution of TM-alpha were affected by body weight. The clearance of TM-alpha in pediatric patients with hematological malignancy and DIC was higher than that in adults as previously reported. Six of eight patients did not achieve the target trough concentration at steady state. Furthermore, the pharmacokinetic simulation based on the estimated pharmacokinetic parameters from the final model demonstrated that TM-alpha administered at a dose of 0.06 mg/kg every 24 hr also failed to achieve the target trough concentration at steady state in the majority of pediatric patients.
Conclusions: Our study shows that further dose adjustment of TM-alpha is necessary considering the higher clearance per body weight in pediatric patients with hematological malignancy and DIC.

DOI： 10.1002/pbc.26234

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記述言語：日本語   出版者・発行元：横浜市立大学医学会  

症例は3歳男児、上気道症状を伴う先行感染があり、その後に黒色尿・貧血・黄疸を認めた。Hb3.6g/dL、LDH 2866IU/L、I-Bil 3.9mg/dL、直接Coombs試験は補体のみ陽性であり自己免疫性溶血性貧血が疑われ当院紹介受診、入院となった。寒冷凝集素症(CAD)、発作性寒冷血色素尿症(PCH)の鑑別目的で初診時および第4病日にDonath-Landsteiner試験(DL試験)を施行したが、溶血が強く判定不能であった。プレドニゾロンを1mg/kg/dayで開始し、症状は軽快した。第8病日にDL試験を再度施行し結果は陽性であり、PCHと診断した。プレドニゾロンを速やかに漸減し、第10病日に退院した。以降は外来にて防寒指導を行い、症状再燃なく終診となった。急性期は溶血所見が強く、DL試験の判定が困難になることがあり、時期を変えて数回実施することが必要であることが示唆された。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J01499&link_issn=&doc_id=20170404530005&doc_link_id=http%3A%2F%2Fid.nii.ac.jp%2F1246%2F00001089%2F&url=http%3A%2F%2Fid.nii.ac.jp%2F1246%2F00001089%2F&type=%89%A1%95l%8Es%97%A7%91%E5%8Aw%81F%89%A1%95l%8Es%97%A7%91%E5%8Aw%8Aw%8Fp%8B%40%8A%D6%83%8A%83%7C%83W%83g%83%8A&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F80205_3.gif

記述言語：日本語   出版者・発行元：横浜市立大学医学会  

23歳、男性。4歳時にB前駆細胞性急性リンパ性白血病を発症。3度再発をし、7歳、9歳、11歳時に合計3回の同種造血細胞移植を施行し、白血病は寛解を維持していた。3度目の移植9年後から拘束性肺障害と繰り返す気胸、継続する咳嗽を認めていた。11年後に胸痛を自覚し、その4ヵ月後に肺腺癌stage IVの診断となった。化学療法を施行したが、抵抗性であり、24歳時に死亡した。二次がんのうち肺癌の頻度は低く、小児がんの悪性の二次がんのうち1.4%と報告されている。移植後、慢性の呼吸器合併症があったため、肺癌の初発症状がわかりにくく、診断に難渋した。症例の蓄積と、有効なフォローアップ方法の確立が望まれる。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Acute megakaryoblastic leukemia (AMKL) in children without Down syndrome (DS) has an extremely poor outcome with 3-year survival of less than 40%, whereas AMKL in children with DS has an excellent survival rate. Recently, a novel recurrent translocation involving CBFA2T3 and GLIS2 was identified in about 30% of children with non-DS AMKL, and the fusion gene was reported as a strong poor prognostic factor in pediatric AMKL. We report the difficult clinical courses of pediatric patients with AMKL harboring the CBFA2T3-GLIS2 fusion gene.

DOI： 10.4274/tjh.2016.0008

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4274/tjh.2016.0008

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Methotrexate (MTX) can lead to neurotoxicity and asymptomatic leukoencephalopathy. However, the mechanism of MTX-related leukoencephalopathy is obscure. MTX and its metabolites inhibit 5-aminoimidazole-4-carboxamide ribonucleotide formiltransferase (ATIC) and promote adenosine release. Recently, it has been reported that adenosine and its receptor are related to certain central nervous system diseases. We investigated whether adenosine pathway gene polymorphisms and clinical factors were related to MTX-related leukoencephalopathy in pediatric patients affected by hematological malignancies.<br />
Fifty-six Japanese childhood acute lymphoblastic leukemia or lymphoma patients were investigated. Patients were evaluated by magnetic resonance imaging of the brain before maintenance therapy or stem cell transplantation. Gene polymorphisms within the adenosine pathway (ATIC, adenosine A2A receptor [ADORA2A]) and the MTX pathway (methylenetetrahydrofolate reductase [MTHFR] and ABCB1) were genotyped using TaqMan assays. Clinical data were collected by accessing the medical records. MTX-related leukoencephalopathy was evaluated by a pediatric neurologist.<br />
Twenty-one (37%) of 56 patients developed

DOI： 10.1002/pbc.26090

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/pbc.26090

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/bcj.2016.52

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：日本小児科学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2016398909

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent reports described the NUP98-NSD1 fusion as an adverse prognostic marker for acute myeloid leukaemia (AML) and PRDM16 (also known as MEL1) as the representative overexpressed gene in patients harbouring NUP98-NSD1 fusion. PRDM16 gene expression levels were measured via real-time polymerase chain reaction in 369 paediatric patients with de novo AML, of whom 84 (23%) exhibited PRDM16 overexpression (PRDM16/ABL1 ratio ≥0·010). The frequencies of patients with high or low PRDM16 expression differed widely with respect to each genetic alteration, as follows: t(8;21), 4% vs. 96%, P < 0·001; inv(16), 0% vs. 100%, P < 0·001; KMT2A (also termed MLL)- partial tandem duplication, 100% vs. 0%, P < 0·001; NUP98-NSD1, 100% vs. 0%, P < 0·001. The overall survival (OS) and event-free survival (EFS) among PRDM16-overexpressing patients were significantly worse than in patients with low PRDM16 expression (3-year OS: 51% vs. 81%, P < 0·001, 3-year EFS: 32% vs. 64%, P < 0·001) irrespective of other cytogenetic alterations except for NPM1. PRDM16 gene expression was particularly useful for stratifying FLT3-internal tandem duplication-positive AML patients (3-year OS: high = 30% vs. low = 70%, P < 0·001). PRDM16 overexpression was highly recurrent in de novo paediatric AML patients with high/intermediate-risk cytogenetic profiles and was independently associated with an adverse outcome.

DOI： 10.1111/bjh.13869

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DOI： 10.1002/cpt.158

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AIMS
Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk.
METHODS Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX.
RESULTS Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model.
CONCLUSIONS A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX). (C) 2014 The British Pharmacological Society

DOI： 10.1111/bcp.12409

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ PUBLISHING GROUP  

Background Oral antibiotics use in infants in developing countries is challenging because liquid formulations are often unavailable. However, dissolving solid formulation of drugs in water poses a risk of gastrointestinal infection. Although mother's milk may be a potential vehicle, no evidence exists to indicate that antibiotics dissolved in human milk are bioequivalent to those dissolved in water. Therefore, we compared pharmacokinetic parameters of an orally administered antibiotic, amoxicillin, dissolved in human milk, to those of water-dissolved amoxicillin.
Methods A pharmacokinetic study was conducted in 16 healthy adult volunteers in a randomised crossover design. Marketed amoxicillin powder for suspension was dissolved in either human milk or water at a final concentration of 50 mg/mL, and 10 mL was given orally in a fasting state. Timed blood samples were obtained and plasma amoxicillin was quantified using liquid chromatography-mass spectrometry.
Findings Results showed that pharmacokinetic parameters, including area-under-the-curve, Cmax and half-life of the water-based and milk-based amoxicillin administration were not significantly different. 90% CIs of the ratios of these parameters in concomitant breast milk administration to those of water were within 89% and 116%, suggesting they are bioequivalent (defined as a range between 80% and 125%).
Interpretation We conclude that oral administration of amoxicillin dissolved in human milk at 50 mg/mL results in pharmacokinetics profiles comparable to amoxicillin dissolved in water. Pharmaceutical interactions between amoxicillin and breast milk are unlikely, suggesting no need to modify dosing schedules.

DOI： 10.1136/archdischild-2013-305151

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

High-dose methotrexate therapy (HD-MTX) has been well established for the treatment of childhood acute lymphoblastic leukemia (ALL). The aims of this study were to investigate whether clinical and pharmacogenetic factors influence plasma MTX concentration and renal dysfunction in patients treated with HD-MTX. In a total of 127 courses of HD-MTX in 51 patients with childhood ALL, influence of clinical and pharmacogenetic factors on plasma MTX concentration and HD-MTX-related renal dysfunction was evaluated. Clinical factors included age, gender, duration of HD-MTX continuous-infusion and duration of pre-hydration before HD-MTX. Pharmacogenetic factors included 5 gene polymorphisms within the MTX pathway genes, namely, SLC19A1, MTHFR, ABCC2 and ABCG2. Short duration of pre-hydration before HD-MTX is the most important risk factor for prolonged high MTX concentration (p &lt; 0.001, OR 6.40, 95 % CI 2.39-17.16) and renal dysfunction (p = 0.013, OR 3.15, 95 % CI 1.27-7.80). The T allele at MTHFR C677T was the risk factor for prolonged high MTX concentration (p = 0.009, OR 5.54, 95 % CI 1.54-19.85), but not for renal dysfunction. We found the influence of MTHFR C677T polymorphism o

DOI： 10.1007/s12185-013-1464-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

High-dose methotrexate therapy (HD-MTX) has been well established for the treatment of childhood acute lymphoblastic leukemia (ALL). The aims of this study were to investigate whether clinical and pharmacogenetic factors influence plasma MTX concentration and renal dysfunction in patients treated with HD-MTX. In a total of 127 courses of HD-MTX in 51 patients with childhood ALL, influence of clinical and pharmacogenetic factors on plasma MTX concentration and HD-MTX-related renal dysfunction was evaluated. Clinical factors included age, gender, duration of HD-MTX continuous-infusion and duration of pre-hydration before HD-MTX. Pharmacogenetic factors included 5 gene polymorphisms within the MTX pathway genes, namely, SLC19A1, MTHFR, ABCC2 and ABCG2. Short duration of pre-hydration before HD-MTX is the most important risk factor for prolonged high MTX concentration (p &lt; 0.001, OR 6.40, 95 % CI 2.39-17.16) and renal dysfunction (p = 0.013, OR 3.15, 95 % CI 1.27-7.80). The T allele at MTHFR C677T was the risk factor for prolonged high MTX concentration (p = 0.009, OR 5.54, 95 % CI 1.54-19.85), but not for renal dysfunction. We found the influence of MTHFR C677T polymorphism on prolonged high MTX concentration. We reconfirmed the importance of adequate pre-hydration before HD-MTX to prevent prolonged high MTX concentration and MTX-related renal dysfunction.

DOI： 10.1007/s12185-013-1464-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The purpose of the study is to establish a simple and relatively inexpensive flow cytometric chemosensitivity assay (FCCA) for leukemia to distinguish leukemic blasts from normal leukocytes in clinical samples.<br />
We first examined whether the FCCA with the mitochondrial membrane depolarization sensor, 5, 50, 6, 60-tetrachloro-1, 10, 3, 30 tetraethyl benzimidazolo carbocyanine iodide (JC-1), could detect drug-induced apoptosis as the conventional FCCA by annexin V/7-AAD detection did and whether it was applicable in the clinical samples. Second, we compared the results of the FCCA for prednisolone (PSL) with clinical PSL response in 18 acute lymphoblastic leukemia (ALL) patients to evaluate the reliability of the JC-1 FCCA. Finally, we performed the JC-1 FCCA for bortezomib (Bor) in 25 ALL or 11 acute myeloid leukemia (AML) samples as the example of the clinical application of the FCCA.<br />
In ALL cells, the results of the JC-1 FCCA for nine anticancer drugs were well correlated with those of the conventional FCCA using anti-annexin V antibody (P &lt; 0.001). In the clinical samples from 18 children with ALL, the results of the JC-1 FCCA for PSL were significantly correlated with the clinica

DOI： 10.1007/s00280-013-2303-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00280-013-2303-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

We describe a 17-month-old female presented with an acute overdose of olanzapine, an atypical antipsychotic. She displayed prolonged extrapyramidal symptoms as compared with that in previous reports and prolactin levels above the upper limits of normal ranges. This is the first report to measure serum prolactin levels in an olanzapine-overdosed toddler and the second to calculate olanzapine's elimination half-life.

DOI： 10.1097/FTD.0b013e3182953ed8

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DOI： 10.1097/FTD.0b013e3182843206

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記述言語：英語   出版者・発行元：WILEY PERIODICALS, INC  

DOI： 10.1002/pbc.23122

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記述言語：英語   出版者・発行元：INFORMA HEALTHCARE  

DOI： 10.3109/10428194.2010.537002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Background:
One severe side effect of calcineurin inhibitors (CNIs: such as cyclosporine [CsA] and tacrolimus [FK506]) is neurotoxicity. CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp), encoded by ABCB1 gene. In the present study, we hypothesized that genetic variability in CYP3A5 and ABCB1 genes may be associated with CNI-related neurotoxicity.
Methods:
The effects of the polymorphisms, such as CYP3A5 A6986G, ABCB1 C1236T, G2677T/A, and C3435T, associated with CNI-related neurotoxicity were evaluated in 63 patients with hematopoietic stem cell transplantation.
Results:
Of the 63 cases, 15 cases developed CNI-related neurotoxicity. In the CsA patient group (n = 30), age (p = 0.008), hypertension (p = 0.017), renal dysfunction (p &lt; 0.001), ABCB1 C1236T (p &lt; 0.001), and G2677T/A (p = 0.014) were associated with neurotoxicities. The CC genotype at ABCB1 C1236T was associated with it, but not significantly so (p = 0.07), adjusted for age, hypertension, and renal dysfunction. In the FK506 patient group (n = 33), CYP3A5 A6986G (p &lt; 0.001), and ABCB1 C1236T (p = 0.002) were associated with neurotoxicity. At least one A allele at CYP3A5 A6986G (expressor genotype) was strongly associated with it according to logistic regression analysis (p = 0.01; OR, 8.5; 95% CI, 1.4-51.4).
Conclusion:
The polymorphisms in CYP3A5 and ABCB1 genes were associated with CNI-related neurotoxicity. This outcome is probably because of CYP3A5 or P-gp functions or metabolites of CNIs.

DOI： 10.1111/j.1399-0012.2009.01181.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

One severe side effect of calcineurin inhibitors (CNIs: such as cyclosporine [CsA] and tacrolimus [FK506]) is neurotoxicity. CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp), encoded by ABCB1 gene. In the present study, we hypothesized that genetic variability in CYP3A5 and ABCB1 genes may be associated with CNI-related neurotoxicity.<br />
The effects of the polymorphisms, such as CYP3A5 A6986G, ABCB1 C1236T, G2677T/A, and C3435T, associated with CNI-related neurotoxicity were evaluated in 63 patients with hematopoietic stem cell transplantation.<br />
  Of the 63 cases, 15 cases developed CNI-related neurotoxicity. In the CsA patient group (n = 30), age (p = 0.008), hypertension (p = 0.017), renal dysfunction (p &lt; 0.001), ABCB1 C1236T (p &lt; 0.001), and G2677T/A (p = 0.014) were associated with neurotoxicities. The CC genotype at ABCB1 C1236T was associated with it, but not significantly so (p = 0.07), adjusted for age, hypertension, and renal dysfunction. In the FK506 patient group (n = 33), CYP3A5 A6986G (p &lt; 0.001), and ABCB1 C1236T (p = 0.002) were associated with neurotoxicity. At least one A allele at CYP3A5 A6986G (expressor genotype) was strongly associated with it according

DOI： 10.1111/j.1399-0012.2009.01181.x

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記述言語：日本語  

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記述言語：英語  

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記述言語：日本語   出版者・発行元：がんの子供を守る会  

4例の小児卵巣悪性胚細胞腫瘍に対し,carboplatin,etoposide,bleomycinによるJEB療法を施行した.初発時の年齢は9歳から14歳,腫瘍の病理組織診断はyolk sac tumorが2例,dysgermiminomaがl例,mixed germ cell tumorが1例であった.初発時から45～61か月現在,全例が無病生存中である.卵巣悪性胚細胞腫瘍に対して行われてきたBEP(bleomycin,etoposide,cisplatin)療法に比しJEB療法は肺毒性や聴器毒性,腎毒性が少なく,安全に施行し得た.晩期障害の点においてJEB療法は小児に有用な治療法であると考えられた.

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その他リンク： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=263299

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Sensitivity to 10 anticancer drugs was evaluated in 6 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cell lines. Authenticity of newly established cell lines was confirmed by genomic fingerprinting. The line YCUB-5R established at relapse was more resistant to 4-hydroperoxy-cyclophosphamide, cytarabine, L-asparaginase, topotecan, fludarabine, and etoposide than YCUB-5 from the same patient at diagnosis. Of the drugs tested, etoposide and SN-38 (irinotecan) showed highest efficacy in the panel, with 50% growth inhibition at 0.22-1.8 mu g/ml and 0.57-3.6 ng/ml, respectively. This cell line panel offers an in vitro model for the development of new therapies for childhood BCP-ALL. (c) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2008.12.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

Rituximab, a chimeric murine/human monoclonal anti-CD20 antibody, was licensed for the treatment of B-cell lymphoma and has also shown efficacy against autoimmune diseases such as immune thrombocytopenic purpura (ITP). It is relatively safe; however, about 1-20% of patients were reported to have developed rituximab-induced serum sickness, which is more common among patients with autoimmune conditions than among those with hematologic malignancies. Here we describe a pediatric patient with steroid-dependent chronic ITP who presented with arthralgia and fever ten days after the second infusion of rituximab (on day 10), and presented with malaise and maculopapular rash on day 21. Oral prednisolone was started and his symptoms resolved. He had an elevated level of human anti-chimeric antibody (HACA) on day 27; thereafter, the HACA level slowly decreased. To our knowledge, among pediatric patients who received rituximab for chronic ITP, this is the sixth documented case of serum sickness and the only one who manifested an elevated level of HACA. Rituximab is a beneficial treatment option against chronic ITP; however, the risk of serum sickness should be considered. Steroid, usually used for the treatment of serum sickness, may prevent the development of severe serum sickness when administered during and after rituximab treatment.

DOI： 10.1007/s12185-009-0269-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

We report three cases of hemophagocytic lymphohistiocytosis (HLH) in infants within the first 6 weeks of life. Diagnosis of HLH was made early after symptoms started. All three cases were Successfully treated with dexamethasone and none relapsed, indicating that not all cases of HLH in very young infants are familial. Pediatr Blood Cancer 2009;52:137-139. (C) 2008 Wiley-Liss, Inc.

DOI： 10.1002/pbc.21758

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

A 13-month-old female underwent unrelated cord blood transplantation (CBT) for juvenile myelomonocytic leukemia (JMML). In spite of progression of the disease after a conditioning regimen with high-dose chemotherapy, a complete remission was induced in concordance with development of acute GVHD after reduction of the immunosupressant. She has been in complete remission for 1 year after transplantation. This case illustrates that CBT can provide a potent graft versus leukemia (GVL) effect against JMML.

DOI： 10.1002/pbc.21200

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記述言語：日本語   出版者・発行元：横浜市立大学医学会  

(症例1)68歳男性.2002年12月に発症したmantle cell lymphoma,clinical stage III A.CHOP療法,rituximab-CHOP療法により完全寛解となった.治療中に直腸癌が認められたため手術を施行した.その後頚部再発をきたし,化学療法,放射線局所照射を行ったが寛解には到らず,2004年4月に,膀帯血移植を施行した.Day19に生着,day28に完全キメラを確認した.Day44に頚部再発を認め,FK506中止し,腫瘍は縮小となったが再び増大し,化学療法を施行中である.(症例2)62歳男性.2002年7月に発症した.myelodysplastic syndrome (MDS) refractory anemia with excess of blasts(RAEB).Acute myeloblastic leukemia(AML)への進展を認めたため2004年5月に膀帯血移植を施行した.Day31に生着,day28に完全キメラを確認した.現在完全寛解を維持している.(症例3)60歳女性.2004年6月に発症したMDS(RAEB in transformation).早々にAMLへ移行したため,PS1で2004年8月に臍帯血移植を施行した.Day78に生着,day28に完全キメラを確認した.Day61に皮膚stage3・grade IIのacute graft versus host diseaseが出現したが,predonisolone 0.5mg/kg開始し速やかに消退した.現在完全寛解を維持している.最近施行されるようになってきた高齢者に対する造血幹細胞移植は,患者の高齢化に伴い健常な同胞ドナー候補を探すことが困難であり,また病勢によっては骨髄バンクからドナー候補を探す時間的な余裕がないことなどが問題となっている.一方,膀帯血移植は当初は小児領域で施行されていたが,最近では主に成人に対して施行されるようになっている.今回60歳以上の高齢者の造血器悪性腫瘍3例に対して臍帯血移植を施行し,その経過,合併症について検討した.高齢者の造血器悪性腫瘍に対して移植を考慮する場合に同胞に適するドナーがいない場合,非血縁骨髄移植のみならず,今後は臍帯血移植も選択肢の一つとして考慮し得るということが示された.Allogenic stem cell transplantation is now done not only for younger but also for elderly patients. It is very difficult for elderly patients to find healthy, suitable related donors, and in many cases there is not enough time to find unrelated bone marrow donors due to disease status. Cord blood transplantation was originally done for pediatric patients, but is now done for more adult patients than pediatric patients. We performed cord blood transplantation for 3 patients over 60 years old with hematological malignancies. We report their clinical courses and complications. If there are no suitable related donors for elderly patients, it is possible to choose not only unrelated bone marrow transplantation, but also cord blood transplantation.

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その他リンク： http://id.nii.ac.jp/1246/00000864/

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