Publications by authors named "Yasuhiro Okamoto"

101 Publications

[Improvement in platelet count and bleeding symptom during treatment with eltrombopag in a patient with X-linked thrombocytopenia].

Rinsho Ketsueki 2021 ;62(4):257-261

Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University.

Herein, we describe a 13-year-old male adolescent who had chronic thrombocytopenia since infancy. In this case, X-linked thrombocytopenia (XLT) was suspected owing to a family history of chronic thrombocytopenia and small-sized platelets. Moreover, the patient was refractory to immunoglobulin therapy. The Wiskott-Aldrich syndrome protein (WASP) expression analysis revealed a decreased expression. Results showed a missense mutation [c.296A>G (p.Gln99Arg)] in exon 3 of the WASP-interacting protein region. Therefore, a diagnosis of XLT was made. To lift exercise restrictions, we initiated treatment with eltrombopag at a dose of 12.5 µg/day. The platelet count of the patient increased to approximately 50×10/µl after the treatment dose was escalated to 25 µg/day, and bleeding symptoms decreased after the patient resumed exercise. Ultrastructural platelet abnormalities and abnormal platelet aggregation were observed on transmission electron microscopy after the administration of eltrombopag. Therefore, eltrombopag treatment can increase platelet count and reduce bleeding symptoms in patients with XLT.
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http://dx.doi.org/10.11406/rinketsu.62.257DOI Listing
May 2021

Effect of extramedullary disease on allogeneic hematopoietic cell transplantation for pediatric acute myeloid leukemia: a nationwide retrospective study.

Bone Marrow Transplant 2021 Mar 10. Epub 2021 Mar 10.

Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan.

Children with acute myeloid leukemia (AML) commonly develop extramedullary disease (EMD), which comprises central nervous system (CNS) lesions and myeloid sarcoma (MS). In this retrospective analysis, we aimed to determine the effect of EMD on the outcomes of allogeneic hematopoietic cell transplantation (HCT) in 678 pediatric patients with de novo AML (median age, 7 years; range, 0.3-15 years) between 2006 and 2016. We compared the outcomes between patients with (EMD group, n = 158; CNS lesion, n = 47, CNS lesion + MS, n = 9, and MS, n = 102) and without EMD at diagnosis (non-EMD group, n = 520). Survivors were followed for a median of 4.5 years, and the 4-year overall survival (OS) rates were 60.6% and 56.4% in the EMD and non-EMD groups, respectively (P = 0.60). No significant differences in OS were observed with respect to the EMD site, except bone lesions, which were associated with poor OS after HCT in a non-remission status. A multivariate analysis revealed that EMD did not affect the outcomes of HCT. In conclusion, the study findings suggest that EMD should not be considered a poor prognostic factor in HCT for children with AML.
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http://dx.doi.org/10.1038/s41409-021-01250-9DOI Listing
March 2021

Successful Salvage of Very Early Relapse in Pediatric Acute Lymphoblastic Leukemia With Inotuzumab Ozogamicin and HLA-haploidentical Peripheral Blood Stem Cell Transplantation With Posttransplant Cyclophosphamide.

J Pediatr Hematol Oncol 2021 Jan 27. Epub 2021 Jan 27.

Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Kagoshima Prefecture, Japan.

Herein, we describe a 14-year-old female patient with B-cell precursor acute lymphoblastic leukemia who relapsed in early consolidation. Minimal residual disease-negative complete remission was obtained after 1 cycle of inotuzumab ozogamicin therapy. She underwent HLA-haploidentical peripheral blood stem cell transplantation after a myeloablative conditioning regimen. Posttransplant cyclophosphamide, tacrolimus, and mycophenolate mofetil were administered for the prophylaxis of graft-versus-host disease. At 23 months, she was in complete remission. Although the administration of inotuzumab ozogamicin followed by haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide has been limited in children, this strategy may be an effective treatment for pediatric refractory acute lymphoblastic leukemia.
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http://dx.doi.org/10.1097/MPH.0000000000002079DOI Listing
January 2021

Successful laparoscopic extirpation of a vasoactive intestinal polypeptide-secreting neuroblastoma originating from the right adrenal gland: A report of an infantile case.

Asian J Endosc Surg 2021 Jan 3. Epub 2021 Jan 3.

Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan.

We herein report a 10-month-old female infant with a 4-month history of diarrhea with electrolyte abnormalities and growth impairment. A 4-cm right adrenal tumor was detected by computed tomography. No metastasis or accumulation on I -metaiodobenzylguanidine scintigraphy was recognized in the tumor. A vasoactive intestinal peptide-secreting neuroblastic tumor was suspected, and octreotide was started, but the diarrhea persisted. Tumor extirpation was laparoscopically performed. After tumor removal, the symptoms improved immediately, and her growth caught up by 9 months after surgery. A minimally invasive approach for pediatric solid tumor is difficult, especially for neuroblastoma, but may be beneficial for the patient's recovery.
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http://dx.doi.org/10.1111/ases.12916DOI Listing
January 2021

Hematopoietic stem cell transplantation in children and adolescents with nonremission acute lymphoblastic leukemia.

Pediatr Blood Cancer 2020 12 22;67(12):e28732. Epub 2020 Sep 22.

Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.

Background: The appropriateness of allogeneic hematopoietic stem cell transplantation (HSCT) in children and adolescents with leukemia in whom complete remission is not possible remains unclear. This retrospective analysis aimed to investigate the outcomes associated with HSCT, and the risks of HSCT in children and adolescents with nonremission acute lymphoblastic leukemia (ALL).

Procedure: Data from the Japan Society for Hematopoietic Cell Transplantation registry on 325 patients with nonremission ALL (aged <21 years, with blasts in the peripheral blood and/or bone marrow) who had undergone HSCT between January 2001 and December 2015 were evaluated. To assess survival, we developed a scoring system using significant adverse pre-HSCT variables.

Results: Overall, 247 patients died. The median length of follow up among survivors was 1145 days, and the 3-year overall survival was 22% (95% confidence interval [CI]: 18-27%). A low performance score, presence of >25% bone marrow blasts, T-cell phenotype, poor-risk or normal cytogenetics, and history of HSCT were predictors of a poor outcome. Patients scoring 0-1 (n = 109), 2 (n = 91), and 3-7 (n = 125) had a 3-year overall survival of 41% (95% CI: 31-51%), 21% (95% CI: 13-31%), and 7% (95% CI: 3-12%), respectively.

Conclusion: These results support HSCT in certain nonremission patients. Even in patients without complete remission, outcomes differed according to pre-HSCT factors. A scoring system could help determine the appropriateness of HSCT in children and adolescents with nonremission ALL.
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http://dx.doi.org/10.1002/pbc.28732DOI Listing
December 2020

Long-term outcome in patients with Fanconi anemia who received hematopoietic stem cell transplantation: a retrospective nationwide analysis.

Int J Hematol 2021 Jan 19;113(1):134-144. Epub 2020 Sep 19.

Department of Innovative Medical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.

We retrospectively analyzed nationwide records of 163 Fanconi anemia (FA) patients [aplastic anemia (AA), n = 118; myelodysplastic syndrome (MDS), n = 30; acute leukemia, n = 15] who underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 1987 and 2015 in Japan. An alternative donor was used in 119 (73%) patients, and 160 (98%) patients received a non-T-cell-depleted graft. With an 8.7-year median follow-up, 5-year overall survival (OS) was 81%. The 5-year OS was significantly higher in AA patients than in MDS and acute leukemia patients (89%, 71%, and 44%, respectively). In the MDS/leukemia group, factors associated with poor outcome in univariate analysis were older age at HSCT (≥ 18 years), conditioning regimen without anti-thymocyte or lymphocyte globulin, and grade II-IV acute graft-versus-host disease. After 1 year, of 137 survivors, 15 developed subsequent malignancies, of whom 12 were diagnosed with head and neck (HN)/esophageal cancer. An irradiation regimen and older age were associated with the risk of HN/esophageal cancer. Five of seven deaths were attributed to subsequent malignancies more than 5 years after HSCT. On the basis of the risk factors for HSCT in MDS/leukemia patients and subsequent malignancies, a more effective HSCT approach is required.
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http://dx.doi.org/10.1007/s12185-020-02991-xDOI Listing
January 2021

In-Hospital Management Might Reduce Induction Deaths in Pediatric Patients With Acute Lymphoblastic Leukemia: Results From a Japanese Cohort.

J Pediatr Hematol Oncol 2021 03;43(2):39-46

Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima.

Induction deaths (ID) remain a critical issue in the treatment of pediatric patients with acute lymphoblastic leukemia (ALL). The reported rate of ID in this population is 1% or higher. We speculate that this proportion might be lower in Japan because of mandatory hospitalization during induction therapy to manage complications. We retrospectively analyzed the incidence of ID among children with ALL enrolled in 4 Japanese study groups between 1994 and 2013. Among 5620 children, 41 (0.73%) cases of ID were noted. The median age was 6.5 years; 24 children were female, and 7 had T-cell ALL. Infection was the most common cause of ID (n=22), but the incidence (0.39%) was lower than that reported in western countries. Mortality within 48 hours from the onset of infection was low, comprising 25% of infection-related deaths. The incidence of infections caused by Bacillus species was low. Only 1 patient died because of Aspergillus infection. Fatal infections mostly occurred during the third week of induction therapy. Our findings suggest that close monitoring, stringent infection control, and immediate administration of appropriate antibiotics through hospitalization might be important strategies in reducing the rate of infection-related ID in pediatric patients with ALL.
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http://dx.doi.org/10.1097/MPH.0000000000001926DOI Listing
March 2021

Comparison of child and family reports of health-related quality of life in pediatric acute lymphoblastic leukemia patients after induction therapy.

BMC Pediatr 2020 08 19;20(1):390. Epub 2020 Aug 19.

Department of Family Nursing, Division of Health Sciences and Nursing, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Background: This study aims at determining the health-related quality of life (HRQOL) of children with acute lymphoblastic leukemia (ALL) after the induction therapy, assessing the agreement between child self-reports and family proxy-reports HRQOL, and determining the factors related to this agreement, especially child age, family attendance, and children's social relationships beyond the family.

Methods: We analyzed questionnaire data (2012-2017) from the Japanese Pediatric Leukemia/Lymphoma Study Group's clinical study (ALL-B12). Participants were children with B-cell precursor ALL aged 5-18 and their family members, who mostly took care of the child during hospitalization. Participants answered the Pediatric Quality of Life Inventory™ (PedsQL™) Generic Core Scales (PedsQL-G), and Cancer Module (PedsQL-C) to measure pediatric HRQOL. We calculated the differences between child self-reported and family proxy-reported subscale scores along with intraclass correlation coefficients (ICC). We conducted multiple regression analyses according to all participant pairs and age groups (young children, school age, and adolescents), with ICCs for all PedsQL-G subscales (ICC-G) and all PedsQL-C subscales (ICC-C) as the outcome variables.

Results: Five hundred twenty-two pairs of children and their families were analyzed. We observed a moderate level of agreement on most PedsQL subscales between child self-reports and family proxy-reports; however, worry had the weakest agreement for all PedsQL subscales (ICC = .32, 95% confidence interval = .24-.40). The agreement of ICC-C was positively related to family attendance in the hospitalization, only for the young children group (B = .185, p = .003).

Conclusions: We observed some differences between child self-reports and family proxy-reports of HRQOL of children with ALL. Both child self-reports and family proxy-reports captured HRQOL in the induction therapy. We suggest that attending to young children's hospitalization affects the level of agreement between reports on their HRQOL.
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http://dx.doi.org/10.1186/s12887-020-02287-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437003PMC
August 2020

Conditioning regimen for allogeneic bone marrow transplantation in children with acquired bone marrow failure: fludarabine/melphalan vs. fludarabine/cyclophosphamide.

Bone Marrow Transplant 2020 07 23;55(7):1272-1281. Epub 2020 May 23.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Fludarabine/cyclophosphamide-based conditioning regimens are standard in bone marrow transplantation (BMT) for acquired bone marrow failure in children, however, graft failure may occur. Using the data from a nationwide transplantation registry, we compared the outcomes of children aged <16 years with acquired aplastic anemia and refractory cytopenia of childhood who underwent allogeneic BMT with either fludarabine/melphalan (n = 71) or fludarabine/cyclophosphamide (n = 296) between 2000 and 2016. The fludarabine/melphalan regimen provided excellent outcomes, with 3-year overall survival and failure-free survival rates of 98% and 97%, respectively. The 83% 3-year failure-free survival in the fludarabine/cyclophosphamide group was significantly inferior (P = 0.002), whereas the overall survival did not differ between the two groups. Late graft failure was the most common cause of treatment failure in the fludarabine/cyclophosphamide group, which experienced a significantly higher incidence of late graft failure than the fludarabine/melphalan group (11% vs. 3%; P = 0.035). Multivariate analyses showed that the fludarabine/melphalan regimen was associated with a better failure-free survival (hazard ratio [HR] 0.12; P = 0.005) and lower risk of late graft failure (HR 0.16; P = 0.037). Fludarabine/melphalan-based conditioning regimen can be a promising option for children with acquired bone marrow failure receiving BMT.
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http://dx.doi.org/10.1038/s41409-020-0948-8DOI Listing
July 2020

Concurrent Bacteremia Due to Non-vaccine Serotype 24F Pneumococcus in Twins: A Rapid Increase in Serotype 24F-invasive Pneumococcal Disease and its High Invasive Potential.

Pediatr Infect Dis J 2020 01;39(1):85-87

Department of Microbiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Although concurrent bacteremia in siblings is rare, serotype 24F Streptococcus pneumoniae was isolated from the blood of twin 1-year-old girls within a 3-day interval, supporting the high invasive potential of this serotype. As the prevalence of childhood serotype 24F-invasive pneumococcal diseases increases in Europe and the Western Pacific Region, investigation and surveillance of this serotype are necessary.
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http://dx.doi.org/10.1097/INF.0000000000002508DOI Listing
January 2020

Hematopoietic stem cell transplantation for pediatric acute myeloid leukemia patients with KMT2A rearrangement; A nationwide retrospective analysis in Japan.

Leuk Res 2019 12 25;87:106263. Epub 2019 Oct 25.

Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Objective: Pediatric acute myeloid leukemia (AML) with KMT2A rearrangement is detected in 15-20% of all pediatric AML patients and is associated with adverse outcomes even after allogeneic hematopoietic stem cell transplantation (HSCT). To investigate outcomes and prognostic factors, we investigated 90 pediatric AML patients with KMT2A rearrangement after allogeneic HSCT.

Methods: We retrospectively analyzed Japanese registration data for patients who had received allogeneic HSCT between 1988 and 2011. Median age was 3 years (range, 0-15 years), and no gender difference was evident. Median observation period was 119 months.

Results: The 3-year overall survival (OS) rate of KMT2A-rearranged AML was 52.1% (95% confidence interval (CI), 42.4-64%, n = 90), and the 3-year disease-free survival (DFS) rate was 46.7% (95%CI, 36.8-58.2%). The 3-year DFS of KMT2A-rearranged AML was not significantly poorer than that of other AML (P = 0.09), and no significant difference was also seen in 3-year OS rate (P = 0.21). Multivariate analysis showed disease status (complete remission) at HSCT was associated with better outcomes. A significant difference in treatment-related mortality (TRM) was apparent between HSCT from a HLA full-matched related donor and that from a haploidentical donor (P = 0.001).

Discussion: HSCT is a curative option for pediatric AML with KMT2A rearrangement. Pretransplant status was the most significant prognostic indicator for relapse and survival. Enhancing supportive therapy to reduce TRM will further improve treatment outcomes of KMT2A-rearranged pediatric AML.
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http://dx.doi.org/10.1016/j.leukres.2019.106263DOI Listing
December 2019

Nationwide survey of pediatric hypodiploid acute lymphoblastic leukemia in Japan.

Pediatr Int 2019 Nov 21;61(11):1103-1108. Epub 2019 Nov 21.

Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.

Background: Ploidy is a highly significant prognostic factor for pediatric acute lymphoblastic leukemia (ALL). Children with hypodiploid ALL have poor outcomes despite current intensive chemotherapy. Little has been investigated with regard to hypodiploid ALL in Japanese children.

Methods: We retrospectively collected clinical data on hypodiploid ALL cases from the registries of prospective multicenter trials conducted by the four independent clinical study groups in Japan between 1997 and 2012.

Results: A total of 117 ALL patients with hypodiploidy were analyzed in this study. There were 101, eight, and eight patients with 45, 44, and fewer than 44 chromosomes, respectively. The 5 year overall survival rates differed significantly: 86.0%, 87.5%, and 62.5% for patients with 45, 44, and fewer than 44 chromosomes, respectively (P = 0.037). Of the eight patients with 44 chromosomes, seven were alive, including five patients who maintained complete remission without undergoing hematopoietic stem cell transplantation (HSCT). Of the eight patients with fewer than 44 chromosomes, six were good responders to prednisolone and none had induction failure, but the relapse rate was high (5/8). No patients had central nervous system relapse. Four patients underwent HSCT after relapse, but only one survived.

Conclusions: Outcomes of Japanese ALL patients with fewer than 44 chromosomes were poor, as previously reported in other countries. Although the sample size was small, patients with 44 chromosomes had better prognoses than those previously reported. Further studies including international collaboration are needed to improve outcomes for pediatric ALL patients with fewer than 44 chromosomes.
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http://dx.doi.org/10.1111/ped.14006DOI Listing
November 2019

Celecoxib as a Potential Treatment for Intractable Lymphatic Malformation.

Pediatrics 2019 09;144(3)

Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.

Lymphatic malformation (LM) is a congenital disorder resulting from an abnormal development of lymphatic vessels. LM may result in problems of cosmesis and functional impairment, including airway compression. An 11-year-old girl was referred to our department with increasing dysphagia caused by a large left cervical LM with a long history of treatment. Because of the LM location, surgical resection was not an option, and various therapies, including use of picibanil, had proven ineffective. Celecoxib treatment (100 mg/day) was initiated for local pain management. Softening of the lesion was observed 2 weeks after treatment initiation, and the dose was increased to 200 mg/day with additional shrinking of the LM over the next 2 weeks. With parental consent, celecoxib was continued, with a 65% reduction in volume achieved at 6 months. The patient discontinued treatment at 12 months, and the LM volume increased. Control over the LM was achieved with resumption of celecoxib treatment. After 2 years of treatment, the LM persists, but the size of the malformation is significantly smaller. No adverse effects of celecoxib treatment were observed. The anti-cyclooxygenase-2 effect of celecoxib prevented lymphatic vessel growth through an inhibition of cyclooxygenase-2 activity in the conversion of prostaglandin to prostaglandin E2. In conclusion, celecoxib may be a promising therapeutic agent for LM management.
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http://dx.doi.org/10.1542/peds.2019-0319DOI Listing
September 2019

Slowly progressive acute lymphoblastic leukemia after stem cell transplantation.

Pediatr Int 2019 Aug 27;61(8):831-832. Epub 2019 Aug 27.

Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

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http://dx.doi.org/10.1111/ped.13932DOI Listing
August 2019

Brentuximab Vedotin and High-dose Methotrexate Administrated Alternately for Refractory Anaplastic Large-cell Lymphoma With Central Nervous System Disease.

J Pediatr Hematol Oncol 2020 08;42(6):e456-e458

Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.

Pediatric anaplastic large-cell lymphoma (ALCL), which is characterized by strong expression of CD30, is usually responsive to multidrug chemotherapy. Brentuximab vedotin (BV) which is an anti-CD30 antibody-drug conjugate is a promising drug with effects on relapsing or refractory ALCL. However, its effects may not be sufficient for the central nervous system disease. The authors herein reported an 11-year-old boy with ALCL that progressed as central nervous system disease receiving intensive induction chemotherapy has achieved and maintained remission by BV and high-dose methotrexate administrated alternately. Alternate therapy with high-dose methotrexate may complement these shortcomings of BV to provide safe treatment without worsening adverse events.
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http://dx.doi.org/10.1097/MPH.0000000000001550DOI Listing
August 2020

Liver abscess due to Sterigmatomyces halophilus in a boy with acute lymphoblastic leukemia.

J Infect Chemother 2019 Dec 10;25(12):1047-1049. Epub 2019 Jun 10.

Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

We report the first case of liver abscess due to Sterigmatomyces halophilus. Because this pathogen grows poorly in culture medium without added salts, it was identified by sequencing analysis targeting the rRNA gene internal transcribed spacer (ITS) region. This method could be useful for pathogens that cannot be cultured using standard methods.
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http://dx.doi.org/10.1016/j.jiac.2019.05.021DOI Listing
December 2019

[Acute myeloid leukemia evolving from KIT D816-mutated systemic mastocytosis relapsing two months after completion of chemotherapy].

Rinsho Ketsueki 2019 ;60(5):378-381

Division of Pediatrics, Faculty of Medicine, University of Miyazaki.

Here, we report the case of a 9-year-old girl with acute myeloid leukemia (AML) developed from systemic mastocytosis (SM). She experienced bladder and rectal disturbance due to an extramedullary nodule in the paraspinal region of the sacrum. Cytogenetic and genetic analyses of leukemic cells revealed the KIT D816Y mutation besides t (8;21) (q22:q22) /RUNX1-RUNX1T1. Despite receiving proton beam therapy after conventional chemotherapy, the patient relapsed after 2 months. As SM-AML with the KIT D816 mutation in adults exhibits a poor prognosis, hematopoietic stem cell transplantation is recommended. Owing to a few reports of SM-AML in children, the standard therapy for pediatric cases has not been established to date. Based on our experience and the related literature, the prognosis of childhood SM-AML could be as poor as in adults. Hence, further investigation, including mutational analyses of the KIT gene, is warranted to establish a risk-oriented strategy for managing childhood SM-AML.
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http://dx.doi.org/10.11406/rinketsu.60.378DOI Listing
August 2019

Correction to: Factors predicting the recurrence of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children after treatment using the HLH-2004 protocol.

Int J Hematol 2019 May;109(5):629

Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan.

The correct name of the first author should be ''Ryu Yanagisawa'', and not ''Ryu Yanagaisawa'' as given in the original publication of the article.
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http://dx.doi.org/10.1007/s12185-019-02641-xDOI Listing
May 2019

Influence of GST polymorphisms on busulfan pharmacokinetics in Japanese children.

Pediatr Int 2019 Jun;61(6):558-565

Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.

Background: Fatal adverse effects or relapse can occur with excessive or insufficient busulfan exposure in hematopoietic stem cell transplantation. Given that busulfan is mainly metabolized by glutathione S-transferase (GST), we investigated the influence of GST polymorphisms on busulfan pharmacokinetics in Japanese pediatric patients.

Methods: Blood samples were taken from patients receiving high-dose i.v. busulfan as the first dose. Plasma busulfan concentration was measured using high-performance liquid chromatography. The area under the plasma busulfan concentration-time curve (AUC) was calculated. The genotype of GSTA1 was determined on polymerase chain reaction (PCR)-restriction fragment length polymorphism. Multiplex PCR was used to detect the presence or absence of GSTM1 and GSTT1 in the genomic DNA samples.

Results: Twenty patients were consecutively enrolled. Phenotype prediction was defined as follows: poor metabolizer (n = 4), one or more GSTA1*B haplotype or GSTM1/GSTT1 double-null genotypes; and extensive metabolizer (n = 16), other genotypes. GSTA1, M1, and T1 independently had no significant differences in AUC , clearance or elimination rate constant. For the infant with unexpectedly high AUC (2,591 μmol/L min), the GSTA1, M1, and T1 polymorphisms were wild type. On further analysis, the poor metabolizer group had lower clearance and higher AUC except for the aforementioned patient, compared with the extensive metabolizer group (1,531 vs 1,010 μmol/L min; P < 0.01).

Conclusions: GST polymorphisms may have affected busulfan pharmacokinetics, but these effects were obscured by other factors, such as underlying disease, systemic conditions, treatment history, and race.
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http://dx.doi.org/10.1111/ped.13859DOI Listing
June 2019

Factors predicting the recurrence of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children after treatment using the HLH-2004 protocol.

Int J Hematol 2019 May 20;109(5):612-617. Epub 2019 Feb 20.

Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan.

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) is highly prevalent in Japan. To date, no standard treatment for EBV-HLH has been established owing to the diversity in treatment response and the difficulty in assessing prognostic factors. The present prospective study recruited 27 children with EBV-HLH who were also part of the HLH-2004 study. EBV load in the peripheral blood was monitored at diagnosis and 2, 4, and 8 weeks after treatment initiation. Additionally, T-cell receptor (TCR) clonality and other laboratory data were evaluated. TCR clonality was positive in 14 patients at diagnosis. Seven of 27 patients experienced recurrences after treatment. No correlation was noted among any clinical data at diagnosis of patients with and without recurrence. However, the recurrence rate was significantly higher in patients aged < 2 years and/or those with a high plasma EBV load of > 10 copies/mL 2 weeks after treatment than that in patients without these factors. These findings suggest that a younger age or a high EBV load in plasma at the early phase of treatment is a factor predicting a recurrence and helps guide the intensity of subsequent treatment phases for children with EBV-HLH.
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http://dx.doi.org/10.1007/s12185-019-02612-2DOI Listing
May 2019

Hematopoietic stem-cell transplantation in children with refractory acute myeloid leukemia.

Bone Marrow Transplant 2019 09 4;54(9):1489-1498. Epub 2019 Feb 4.

Department of Pediatrics, Kyoto City Hospital, 1-2 Mibuhigashitakadacho, Nakagyo Ward, Kyoto, 604-8845, Japan.

Allogeneic hematopoietic stem cell transplantation (HSCT) can be used to treat children with refractory acute myeloid leukemia (AML). This retrospective analysis aimed to describe the outcomes and risk factors in such children. Data were collected through the nation-wide registry program in Japan. A total of 417 AML (median age: 13 years) patients 20 years or younger at HSCT, between January 2001 and December 2015, were included. A total of 314 patients died, and the median follow-up duration of the survivors was 1052 days. The most frequent cause of death was leukemia progression (58%). The 3-year overall survival (OS) rate was 23% (95% confidence interval [CI]: 19-28%). Chronic GVHD was associated with improved 3-year OS (47%, 95% CI, 36-57%, hazard ratio: 0.603, p = 0.001). Low performance status, presence of more than 25% of marrow blasts, presence of blasts in the blood at transplantation, FAB (other than M1 or M2), male donors, and number of transplantations ≥ 2 were adverse pre-HSCT variables. Patients with 0, 1-2, 3-4, 5, and 6-7 pre-HSCT variables had 3-year OS rates of 52%, 32%, 19%, 8, and 0%, respectively. Our findings may help experts decide if HSCT should be performed in such cases.
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http://dx.doi.org/10.1038/s41409-019-0461-0DOI Listing
September 2019

Outcomes in children with hemophagocytic lymphohistiocytosis treated using HLH-2004 protocol in Japan.

Int J Hematol 2019 Feb 7;109(2):206-213. Epub 2018 Dec 7.

Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan.

Recent advances in intensive chemo- and immunotherapy have contributed to the outcome of hemophagocytic lymphohistiocytosis (HLH); however, the prognosis of HLH in children differs by HLH subtype. In Japan, secondary HLH, particularly Epstein-Barr virus-associated HLH (EBV-HLH), is the most common HLH subtype. The prognosis of HLH has improved in recent years. We here conducted a prospective study of 73 patients who were treated with HLH-2004 protocol in Japan. EBV-HLH, familial HLH (FHL), and HLH of unknown etiology were seen in 41, 9, and 23 patients, respectively. Patients with resistant or relapsed disease after HLH-2004 treatment and those with FHL received hematopoietic stem cell transplantation (HSCT). The induction rate after initial therapy was 58.9%, and the 3-year overall survival (OS) rate of all patients was 73.9% and differed significantly among those with EBV-HLH, FHL, and HLH of unknown etiology. Of the 17 patients who received HSCT, the 3-year OS rates of those with and without complete resolution before HSCT were 83.3% and 54.5%, respectively. Outcomes in children with HLH who were treated with the same protocol differed among HLH subtypes. Appropriate strategy for each subtype should be established in future studies.
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http://dx.doi.org/10.1007/s12185-018-02572-zDOI Listing
February 2019

Importance of Acute Lymphoblastic Leukemia-type Therapy for Bilineal Acute Leukemia.

J Pediatr Hematol Oncol 2019 08;41(6):504-506

Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

We examined 3 pediatric patients with bilineal acute leukemia. Patient 1 with B-cell acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) with B-ALL dominance responded well to prednisolone and ALL-type induction therapy. Patients 2 and 3 with T-ALL and AML with AML dominance responded poorly to prednisolone. Patient 2 was resistant to AML-type therapy; patient 3 was resistant to ALL-type induction therapy until day 15. However, all 3 patients eventually achieved complete remission after ALL-type induction therapy. Thus, ALL-type induction therapy should be initiated for bilineal acute leukemia even with AML-dominant, poor prednisolone response, or poor early response features.
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http://dx.doi.org/10.1097/MPH.0000000000001309DOI Listing
August 2019

Risk Factors and the Prevention of Weight Gain During Induction Chemotherapy in Children With Acute Lymphoblastic.

J Pediatr Hematol Oncol 2019 01;41(1):79-80

Department of Pediatrics, Kagoshima University, Kagoshima, Japan.

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http://dx.doi.org/10.1097/MPH.0000000000001296DOI Listing
January 2019

Giant radiation-induced cavernous haemangioma before reduced-intensity bone marrow transplantation for acute lymphoblastic leukaemia.

Bone Marrow Transplant 2019 02 23;54(2):312-315. Epub 2018 Jul 23.

Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

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http://dx.doi.org/10.1038/s41409-018-0272-8DOI Listing
February 2019

Oral Propranolol in a Child With Infantile Hemangioma of the Urethra.

Urology 2018 Dec 14;122:165-168. Epub 2018 Jun 14.

Department of Urology, Department of Urology, Graduate School of Medical and Dental, Kagoshima University, Kagoshima, Japan.

Infantile hemangiomas (IH) are the most common in the head and neck region. They can occur anywhere in the skin, however, urethral hemangiomas are very rare. We describe a case report of a 3-year-old boy with extensive lesions of IH in the anterior urethra. Urethral IH were disappeared during 1 year of oral administration of propranolol though it brought on urinary retention. This is the first report about oral propranolol treatment in a child with urethral IH. Oral administration of propranolol may be effective for urethral IH and beneficial especially for lesions requiring extensive surgical resection and reconstruction.
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http://dx.doi.org/10.1016/j.urology.2018.06.002DOI Listing
December 2018

Phase II/III study in children and adolescents with newly diagnosed B-cell precursor acute lymphoblastic leukemia: protocol for a nationwide multicenter trial in Japan.

Jpn J Clin Oncol 2018 Jul;48(7):684-691

Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.

B-cell precursor acute lymphoblastic leukemia is the most common pediatric malignancy, but its treatment needs to be modified to cause low acute toxicity and few late complications with a high cure rate. In this trial, we will stratify patients with B-cell precursor acute lymphoblastic leukemia into standard, intermediate and high risk groups according to prognostic factors. In addition, we will establish an evaluation system for minimal residual disease that will enable us to stratify patients based on minimal residual disease in subsequent clinical trials. We will clarify the impact of dexamethasone/vincristine pulse therapy during maintenance therapy in the standard risk group, and intensive l-asparaginase therapy in the intermediate risk group. In the high risk group, usefulness of vincristine intensification will be assessed. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000009339 [http://www.umin.ac.jp/ctr/].
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http://dx.doi.org/10.1093/jjco/hyy071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022563PMC
July 2018

Risk Factors and the Prevention of Weight Gain During Induction Chemotherapy in Children With Acute Lymphoblastic Leukemia.

J Pediatr Hematol Oncol 2018 08;40(6):e334-e337

Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Weight gain is often observed in children with acute lymphoblastic leukemia (ALL) who undergo chemotherapy including steroids. An increase in body mass index (BMI)-standard deviation score (SDS) during induction therapy is reported as a risk factor for obesity after treatment. However, risk factors of an increase in BMI-SDS during induction therapy are not known. Ninety-six patients with ALL who were treated at our hospital between 1996 January and September 2013 were analyzed retrospectively. Daily body weight measurement was initiated in July 2005 in an attempt to control weight. Fifty-four patients were boys and 42 were girls. The median age at onset was 5.1 years (0.5-16.6 y), and 7.3% of patients were overweight/obese at onset. BMI-SDS increased +0.1% (-3.3% to +3.2%) during induction therapy. BMI-SDS increased by 1 and 2 or more SDs in 20% and 3% of patients, respectively. In multivariate analysis, non-high-risk treatment and earlier treatment start date (before daily body weight measurement) were independent risk factors. Ten percent of patients were overweight/obese at 3 years after completion therapy, and high BMI-SDS after induction therapy was a risk factor. Daily body weight measurement might prevent excess weight gain during induction therapy, resulting in patients maintaining a healthy weight after ALL treatment.
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http://dx.doi.org/10.1097/MPH.0000000000001098DOI Listing
August 2018

Epstein-Barr Virus (EBV)-induced B-cell Lymphoproliferative Disorder Mimicking the Recurrence of EBV-associated Hemophagocytic Lymphohistiocytosis.

J Pediatr Hematol Oncol 2019 01;41(1):e44-e46

Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City.

We describe the case of a 23-month-old male infant with Epstein-Barr virus (EBV)-associated lymphoproliferative disorder, which mimicked the recurrence of EBV-associated hemophagocytic lymphohistiocytosis. Chemotherapy with dexamethasone, etoposide, and cyclosporine resolved fever, hepatosplenomegaly, and pancytopenia. However, on day 81 of illness, the patient developed similar symptoms. Plasma EBV-DNA levels markedly increased again, but no T-cell clonality was observed. B cells were identified to be infected with EBV. He was successfully treated with rituximab, dexamethasone and etoposide. When recurrence of EBV-associated hemophagocytic lymphohistiocytosis is suspected, performing tests to identify the infected cells will enable accurate understanding of the clinical condition, resulting in proper treatments.
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http://dx.doi.org/10.1097/MPH.0000000000001075DOI Listing
January 2019

Thiamylal Plus Pentazocine Shows Similar Efficacy as Ketamine Plus Midazolam for Painful Procedures in Children With Leukemia.

J Pediatr Hematol Oncol 2018 05;40(4):e263-e265

Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

This retrospective study compared the use of thiamylal plus pentazocine (TP) to ketamine plus midazolam (KM) in children with leukemia who were undergoing bone marrow aspiration and/or intrathecal chemotherapy. A total of 268 procedures in 35 children with leukemia were retrospectively analyzed for efficacy and adverse events. All procedures were successfully completed without severe adverse events. TP induced significantly faster sedation. The incidents of desaturation were significantly greater in the TP group, but were transient and recovered by oxygen supplementation alone. Therefore, TP can be a useful combination with a similar efficacy as KM for painful procedures in children.
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http://dx.doi.org/10.1097/MPH.0000000000001053DOI Listing
May 2018