記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hematopoietic stem cell transplantation (HSCT) is only indicated for acute lymphoblastic leukemia (ALL) patients for whom other treatments are unlikely to be curative. However, outcomes of patients not in complete remission (CR) at HSCT remain very poor. To improve the outcomes of patients receiving HSCT, it is important to obtain detailed clinical information about patients with ALL receiving HSCT in CR and not in CR. Patients enrolled in the Japan Association of Childhood Leukemia Study ALL-02 who underwent HSCT and were not in CR (non-CR patients, n = 55) were examined. The 1-year overall survival (OS) rate of non-CR patients was 27.3%. Compared with CR patients, non-CR patients experienced very early and early relapse significantly more frequently and had poorer prognostic factors. Most interestingly, high hyperdiploid (HHD) patients showed an excellent 1-year OS of 80%. In addition, long-term survival among surviving HHD patients was longer than 5 years. All eight patients who survived after undergoing HSCT while not in CR were younger than 10 years at initial diagnosis and were negative for central nervous system involvement. While limited, these results suggest that a subset of patients may benefit from HSCT while not in CR.

DOI： 10.1007/s12185-023-03626-7

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担当区分：筆頭著者,　責任著者   記述言語：英語  

The analysis of 165 children and adolescents/young adults with de novo blastic phase chronic myeloid leukemia showed disease status at hematopoietic stem cell transplantation was a strong prognostic factor and clearly separated the patient outcomes.

DOI： 10.1002/ajh.26959

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記述言語：英語  

Among patients with transient abnormal myelopoiesis (TAM) associated with Down syndrome, approximately 20% die within 6 months from multiorgan failure, especially liver fibrosis. We experienced three children with TAM who had low white blood cell counts but increased bilirubin levels. Here, we discuss the detailed clinical courses of these patients, including the pathological findings of liver biopsies. Our cases, together with previous literature, suggest that liver biopsy can be performed safely and provides useful information, especially regarding disease activities, and that low-dose cytarabine is a reasonable option to prevent early death in TAM patients with liver dysfunction.

DOI： 10.18926/AMO/65153

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Asparaginase is an essential drug for acute lymphoblastic leukaemia (ALL) treatment, but has several side effects, and its discontinuation often compromises patient outcomes. In the prospective Japan Association of Childhood Leukaemia Study ALL-02 protocol, two major changes were made: (1) additional chemotherapies to compensate for the reduction of treatment intensity when asparaginase was discontinued and (2) more intensive concomitant corticosteroid administration, relative to our previous ALL-97 protocol. In ALL-02 study, 1192 patients were included and L-asparaginase was discontinued for 88 (7.4%). Discontinuation due to allergy was markedly decreased relative to the ALL-97 protocol (2.3% vs 15.4%). Event-free survival (EFS) among patients with T-ALL was compromised when L-asparaginase was discontinued, as well as among patients with high-risk B-cell ALL, especially when discontinued before maintenance therapy. Moreover, multivariate analysis identified discontinuation of L-asparaginase as an independent poor prognostic factor for EFS. In the current study, additional chemotherapies failed to fully compensate for L-asparaginase discontinuation, illustrating the difficulty of replacing asparaginase with other classes of drugs, although this study was not designed to evaluate the effect of these modifications. Concomitant intensive corticosteroid treatment may help to reduce allergy to asparaginase. These results will assist in further optimization of asparaginase use.

DOI： 10.1111/bjh.18745

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記述言語：英語  

DOI： 10.1002/pbc.30108

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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: Varicella-zoster virus (VZV) reactivation is a serious complication of hematopoietic stem cell transplantation (HSCT). Although low-dose acyclovir can prevent VZV reactivation after HSCT in adults, the efficacy of a dose of acyclovir lower than the recommended dose, such as 60-80 mg/kg/day in children, is unclear. In this study, we aimed to evaluate the incidence of VZV reactivation after HSCT during and after low-dose acyclovir administration for preventing VZV reactivation in children. METHODS: This single-center retrospective study included children aged ≤15 years who received oral acyclovir (at 15 mg/kg/day) to prevent VZV reactivation after HSCT. We examined the cumulative incidence of VZV reactivation after HSCT, during and after prophylactic acyclovir administration. RESULTS: Fifty-three eligible patients were included in this study, of whom 37 underwent allogeneic HSCT. The median duration of prophylactic acyclovir therapy was 264 days (range: 69-1140 days). VZV reactivation occurred in 13 patients (24.5%, 95% confidence interval [CI]: 14.9-37.6). The cumulative incidence of VZV reactivation 1 and 2 years after HSCT was 6.26% (95% CI: 1.60-15.5) and 20.9% (95% CI: 10.3-34.0), respectively. While only one patient developed VZV reactivation during the administration of prophylactic acyclovir, the cumulative incidence of VZV reactivation increased to 24.2% (95% CI: 12.5-38.0) 1 year after the cessation of acyclovir. CONCLUSION: Low-dose acyclovir (15 mg/kg/day) could be effective for preventing VZV reactivation after HSCT in children because VZV reactivation seldom occurs during the administration of 15 mg/kg/day acyclovir.

DOI： 10.1002/pbc.29979

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/pbc.29979

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Acute lymphoblastic leukemia (ALL) is the most common cancer during childhood, and some high-risk patients with ALL require hematopoietic stem cell transplantation (HSCT). Mainly due to small patient numbers, studies focusing specifically on children and adolescents with T-cell ALL (T-ALL) are limited. Using a nationwide registry, we retrospectively analyzed data from patients under 20 years old who underwent their first HSCT for T-ALL between 2000 and 2018. As a result, total 484 patients were included, and their median follow-up period was 6.9 years after HSCT for survivors. While patients receiving HSCT at first complete remission (CR) showed relatively good 5-year leukemia free survival (5yLFS, 73.5%), once relapse occurred, their prognosis was much worse (44.4%) even if they attained second remission again (p < 0.001). Among patients receiving HSCT at CR1, grade II-IV acute graft versus host disease was associated with worse overall and LFS than grade 0-I (5yLFS 69.5% vs. 82.1%, p = 0.026) mainly due to high non-relapse mortality. Among those patients, patients receiving related bone marrow transplantation, unrelated bone marrow transplantation, or unrelated cord blood transplantation showed similar survival (5yLFS, 73.2%, 76.3%, and 77.0%, respectively). For patients undergoing cord blood transplantation at CR1, total-body irradiation-based myeloablative conditioning was associated with better 5yLFS than other conditioning regimens (85.4% vs. 62.2%, p = 0.044), as it reduced the risk of relapse. These results indicate that relapsed patients have much less chance of cure, and that identifying patients who require HSCT for cure and offering them HSCT with optimal settings during CR1 are crucial for children and adolescents with T-ALL.

DOI： 10.1002/hon.2980

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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  

6-Mercaptopurine (6-MP) is widely used for the treatment of paediatric leukaemia and lymphoma. Recently, germline variants in the NUDT15 gene have been identified as one of the major genetic causes for 6-MP-associated adverse effects such as myelosuppression. Patients with hypomorphic NUDT15 variants accumulate excessive levels of DNA-incorporated thioguanine in white blood cells, resulting in severe myelosuppression. Although preclinical studies suggest that these variants may influence the protein stability of NUDT15, this has not been directly characterised in patients. In this study, we report the development of a series of novel monoclonal antibodies against NUDT15, using which we quantitatively assessed NUDT15 protein levels in 37 patients with acute lymphoblastic leukaemia treated with 6-MP, using sandwich enzyme-linked immunosorbent assay (ELISA). The NUDT15 genotype was highly correlated with its protein levels (p < 0.0001), with homozygous and compound heterozygous patients showing exceedingly low NUDT15 expression. There was a positive correlation between NUDT15 protein level and 6-MP tolerance (r = 0.631, p < 0.0001). In conclusion, our results point to low NUDT15 protein abundance as the biochemical basis for NUDT15-mediated 6-MP intolerance, thus providing a phenotypic readout of inherited NUDT15 deficiency.

DOI： 10.1111/bjh.18375

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bjh.18375

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered to be indicated for children and adolescents with high-risk or relapsed T-cell acute lymphoblastic leukemia (T-ALL); however, the outcomes are unsatisfactory. Killer cell immunoglobulin-like receptors (KIRs) are the main receptors on natural killer (NK) cells that play an important role in the graft-versus-leukemia effect after allo-HSCT. In allo-HSCT, when the recipient lacks a donor KIR-ligand (KIR-ligand mismatch in the graft-versus-host [GVH] direction), donor NK cells will be activated against recipient cells. KIR-ligand mismatch in the GVH direction improves outcomes after unrelated cord blood transplantation (UCBT) with acute myeloid leukemia, but the effect in T-ALL is unclear. We evaluated the impact of KIR-ligand mismatch in the GVH direction on the transplantation outcomes of children and adolescents with T-ALL who received UCBT. We conducted a retrospective study using a nationwide registry of the Japanese Society for Transplantation and Cellular Therapy. Patients diagnosed with T-ALL, aged 0 to 19 years, and who underwent first UCBT between 1999 and 2017 were included. A total of 91 patients were included in this study. In all, 23 (25.3%) percent of patients had KIR-ligand mismatch in the GVH direction. The 5-year leukemia-free survival (LFS) and overall survival (OS) rates after UCBT were 65.8% and 69.6%, respectively. In a multivariate analysis, KIR-ligand mismatch in the GVH direction was associated with a significant reduction in the relapse rate (hazard ratio [HR], 0.19; P = .002), resulting in better LFS (HR, 0.18; P =.010) and OS (HR, 0.26; P = .048) without increasing non-relapse mortality (NRM; HR, 1.90; P = .264). The cumulative incidence of GVH disease (GVHD) did not differ between patients with and without KIR-ligand mismatch (grade II-IV acute GVHD, 39.1% versus 36.8%, P = .648, grade III-IV acute GVHD, 13.0% versus 11.8%, P =.857, and chronic GVHD, 26.1% versus 22.9%, P =.736, respectively). Furthermore, acute and chronic GVHD were not associated with good patient outcomes. Notably, no relapse was observed in patients who received KIR-ligand mismatched UCBT in complete remission. KIR-ligand mismatch in the GVH direction improved LFS and decreased relapse rates without increasing NRM in children and adolescents with T-ALL who received UCBT, which was not mediated by GVHD.

DOI： 10.1016/j.jtct.2022.05.037

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担当区分：筆頭著者   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 Science and Business Media LLC  

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. As overall cure rates of childhood ALL have improved, reduction of overall treatment intensity while still ensuring excellent outcomes is imperative for low-risk patients. We report the outcomes of patients treated following the standard-risk protocol from the prospective Japan Association of Childhood Leukemia Study (JACLS) ALL-02 study, which was conducted between 2002 and 2008 for patients with newly diagnosed ALL aged 1-18 years. Of 1138 patients with B-cell precursor ALL, 388 (34.1%) were allocated to this protocol. Excellent outcomes were achieved despite the overall treatment intensity being lower than that of most contemporary protocols: 4 years event-free survival (EFS) was 92.3% and 4 years overall survival 98.2%. Patients with high hyperdiploidy (HHD) involving triple trisomy (trisomy of chromosomes 4, 10, and 17) or ETV6-RUNX1 had even better outcomes (4 years EFS 97.6% and 100%, respectively). Unique characteristics of this protocol include a selection of low-risk patients with a low initial WBC count and good early treatment response and reduction of cumulative doses of chemotherapeutic agents while maintaining dose density. In Japan, we are currently investigating the feasibility of this protocol while incorporating minimal residual disease into the patient stratification strategy.

DOI： 10.1007/s12185-022-03315-x

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その他リンク： https://link.springer.com/article/10.1007/s12185-022-03315-x/fulltext.html

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  

In this study, we performed a retrospective analysis of a cohort of Japanese paediatric patients with B-cell precursor (BCP)-acute lymphoblastic leukaemia (ALL) treated with a Berlin-Frankfurt-Münster (BFM)95-based protocol, to clarify the incidence, clinical characteristics, and risk factors of osteonecrosis (ON) in comparison to the ALL-02 protocol. We identified a high frequency of ON with the BFM95-based protocol compared to the ALL-02 protocol. The incidence of symptomatic ON with the BFM95-based protocol is comparable to previous studies in Western countries. We believe that the type of treatment regimen has more impact on the incidence of symptomatic ON in paediatric ALL than ethnicity.

DOI： 10.1111/bjh.17988

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bjh.17988

担当区分：筆頭著者   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 Science and Business Media LLC  

Approximately 90% of pediatric acute lymphoblastic leukemia (ALL) cases are curable with intensified chemotherapy, but very high-risk patients may require hematopoietic stem cell transplantation (HSCT). A suitable indication for HSCT in the first complete remission (CR1) should be defined to protect patients from long-term complications. We report the outcomes of HSCT in CR1 from the Japan Association of Childhood Leukemia Study (JACLS) ALL-02 study and reassess indications for HSCT. Of 1114 patients, 71 (6.4%) received HSCT in CR1. Indications included high-risk cytogenetic abnormalities and non-CR on day 33. Patients with B-cell precursor (BCP) ALL and a prednisolone poor response (PPR) received HSCT when leukocyte antigen-matched siblings were available. The 4-year overall survival (OS) of transplanted patients was 78.8% (confidence interval 67.3-86.6). Multivariate analysis revealed that cord blood transplantation was associated with poor OS. For BCP-ALL patients with PPR who achieved CR1 after induction therapy, HSCT in CR1 showed excellent outcomes (4-year OS 90.9%) but demonstrated no survival advantage as the outcome with chemotherapy was also excellent (4-year OS 97.0%). This study suggests that in BCP-ALL patients PPR is not an indication for HSCT in CR1. Precise evaluation of treatment responses would increase sophistication of indications for HSCT in CR1.

DOI： 10.1007/s12185-021-03110-0

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その他リンク： http://link.springer.com/article/10.1007/s12185-021-03110-0/fulltext.html

掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

<h4>Background</h4>Tacrolimus is converted from intravenous to oral formulation for the prophylaxis of graft-versus-host disease when patients can tolerate oral intake and graft-versus-host disease is under control. Oral tacrolimus formulation presents poor bioavailability with intraindividual and interindividual variations; however, some factors affecting its blood concentration among pediatric hematopoietic stem cell transplantation (HCT) recipients are still unclear. This study aimed to identify the clinical factors affecting tacrolimus blood concentrations after switching its formulation.<h4>Methods</h4>Changes in the blood concentration/dose ratio (C/D) of tacrolimus in pediatric HCT recipients were analyzed after the switching of tacrolimus from intravenous to oral formulation. Clinical records of 57 pediatric patients who underwent allogenic HCT from January 2006 to April 2019 in our institute were retrospectively reviewed. The C/D of tacrolimus before discontinuation of intravenous infusion (C/Div) was compared with the tacrolimus trough level within 10 days after the initiation of oral administration (C/Dpo). Multiple linear regression analysis was performed to identify factors affecting (C/Dpo)/(C/Div).<h4>Results</h4>The constant coefficient of (C/Dpo)/(C/Div) was 0.1692 [95% confidence interval (CI), 0.137-0.2011]. The concomitant use of voriconazole or itraconazole and female sex were significant variables with a beta coefficient of 0.0974 (95% CI, 0.062-0.133) and -0.0373 (95% CI, -0.072 to -0.002), respectively.<h4>Conclusions</h4>After switching of tacrolimus formulation, pediatric HCT recipients might need oral tacrolimus dose that is 5-6 and 3.5-4.5 times the intravenous dose to maintain tacrolimus blood concentrations and area under the concentration-time curve, respectively. With the concomitant use of voriconazole or itraconazole, an oral tacrolimus dose of 4-5 times the intravenous dose seemed appropriate to maintain blood tacrolimus concentration.

DOI： 10.1097/ftd.0000000000000793

DOI： 10.1097/FTD.0000000000000793

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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  

Monosomy 7 (-7) occurs in various types of paediatric myeloid disorders and has a poor prognosis. Recent studies have demonstrated that patients with germline gain-of-function SAMD9/9L variants and loss-of-function GATA2 variants are prone to developing myelodysplastic syndrome (MDS) associated with -7. However, the prevalence of the genetic variants among paediatric haematologic disorders with -7 is unknown. The present study screened germline variants of GATA2 and SAMD9/9L in 25 patients with various types of paediatric haematological disorders associated with -7. The diagnoses of the 25 patients included MDS (n = 10), acute myeloid leukaemia (AML) and myeloid sarcomas (n = 9), juvenile myelomonocytic leukaemia (n = 3) and other disorders (n = 3). Seven patients with a germline pathogenic GATA2 variant were found. For SAMD9/9L screening, next-generation sequencing was used to detect low-abundance variants and found four novel germline variants. Functional analysis revealed that three out of the four variants showed growth-restricting capacity in vitro and thus, were judged to be pathogenic. Cases with GATA2 mutation tended to be older, compared to those with SAMD9/9L mutations. In conclusion, GATA2 and SAMD9/9L were sequenced in 25 patients with paediatric haematologic disorders associated with -7, and 40% of them were found to have some pathogenic germline variants in the three genes.

DOI： 10.1111/bjh.17006

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bjh.17006

記述言語：英語  

Polymorphisms in methotrexate transporter pathways have been associated with methotrexate toxicities and clearance. Recent genome-wide association studies have revealed that the SLCO1B1 T521C variant is associated with methotrexate elimination. We present a case of a pediatric patient with acute lymphoblastic leukemia who suffered from persistently high plasma methotrexate concentrations and acute kidney injuries after the admin-istration of a medium dose of methotrexate. Subsequent genetic analysis showed that he was a carrier of dys-functional genetic variants associated with methotrexate clearance. This case highlights that polymorphisms of methotrexate transporter pathways can adversely affect methotrexate elimination in a clinically significant manner.

DOI： 10.18926/AMO/61215

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記述言語：日本語   出版者・発行元：(一社)日本小児血液・がん学会  

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Spandidos Publications  

Acute myeloid leukemia (AML) accounts for ~20% of pediatric leukemia cases. The prognosis of pediatric AML has been improved in recent decades, but it trails that of most other types of pediatric cancer, with mortality rates of 30-40%. Consequently, newer more targeted drugs are required for incorporation into treatment plans. These newer drugs selectively target AML cells with specific gene alterations. However, there are significant differences in genetic alterations between adult and pediatric patients with AML. In the present study, inexpensive and rapid next-generation sequencing (NGS) of >150 cancer-related genes was performed for matched diagnostic, remission and relapse (if any) samples from 27 pediatric patients with AML. In this analysis, seven genes were recurrently mutated. KRAS was mutated in seven patients, NRAS was mutated in three patients, and KIT, GATA1, WT1, PTPN11, JAK3 and FLT3 were each mutated in two patients. Among patients with relapsed AML, six harbored KRAS mutations at diagnosis; however, four of these patients lost these mutations at relapse. Additionally, two genetic alterations (FLT3-ITD and TP53 alterations) were detected among patients who eventually relapsed, and these mutations are reported to be adverse prognostic factors for adult patients with AML. This panel-based, targeted sequencing approach may be useful in determining the genetic background of pediatric AML and improving the prediction of treatment response and detection of potentially targetable gene alterations. RAS pathway mutations were highly unstable at relapse; therefore, these mutations should be chosen as a target with caution. Incorporating this panel-based NGS approach into the clinical setting may allow for a patient-oriented strategy of precision treatment for childhood AML.

DOI： 10.3892/br.2020.1353

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担当区分：筆頭著者   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: Philadelphia-negative (Ph-negative) myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are exceptionally rare during childhood. Thus, clinical features of pediatric Ph-negative MPNs remain largely unknown. This study was therefore performed to address this. Methods: We performed a retrospective study to collect clinical information of children diagnosed with Ph-negative MPNs from 2000 to 2016 using questionnaires in qualified institutions in Japan. The results obtained from the questionnaire survey were then combined with those from the national registry data. Results: Among 50 children identified, five had PV, 44 had ET, and one had PMF. Median age at diagnosis was 14.0, 9.0, and 0 years, respectively. Male to female ratio was 4:1, 21:23, and 1:0, respectively. Detection rates of the JAK2 V617F variant were 0/5 in PV and 9/39 in ET. Frequencies of complications, such as thrombosis and subsequent leukemia, were lower than complication frequencies in adults. We identified two children who developed subsequent leukemia, which has not been reported previously, and one of them died. Conclusion: This is the first nationally representative survey of pediatric Ph-negative MPNs. Given its rarity, an international collaboration with comprehensive genetic analyses might be needed to fully elucidate the clinical and genetic features.

DOI： 10.1002/jha2.39

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jha2.39

担当区分：筆頭著者,　責任著者   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  

DOI： 10.1002/jha2.24

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jha2.24

掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/pbc.28323

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/pbc.28323

担当区分：筆頭著者,　責任著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/ped.13977

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ped.13977

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.11406/rinketsu.60.99

J-GLOBAL

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/ped.13754

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients with multi-system (MS)-type langerhans cell histiocytosis (LCH) show poor outcomes, especially congenital MS LCH cases were shown in high mortality rate. We experienced a congenital case of MS LCH with high risk organs, who needed intensive respiratory support after birth. Even though intensive chemotherapy was discontinued, this patient's lung LCH lesions gradually became reduced and his respiratory condition recovered; therefore, we restarted and completed maintenance chemotherapy. The patient maintained complete remission for more than 4 years after the end of chemotherapy. Our case suggests that congenital MS LCH even with severe organ involvement can be treated successfully with chemotherapy.

DOI： 10.18926/AMO/56459

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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.27459

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although the cure rate of ALL has greatly improved, a considerable number of patients suffer from relapse of leukemia. Therefore, ALL remains the leading cause of death from cancer during childhood. To improve the cure rate of these patients, precisely detecting patients with high risk of relapse and incorporating new targeted therapies are urgently needed. This study investigated inexpensive, rapid, next-generation sequencing of more than 150 cancer-related genes for matched diagnostic, remission, and relapse samples of 17 patients (3 months to 15 years old) with relapsed ALL. In this analysis, we identified 16 single-nucleotide variants (SNVs) and insertion/deletion variants and 19 copy number variants (CNVs) at diagnosis and 28 SNVs and insertion/deletion variants and 22 CNVs at relapse. With these genetic alterations, we could detect several B cell precursor ALL patients with high-risk gene alterations who were not stratified into the highest-risk group (5/8, 62.5%). We also detected potentially actionable genetic variants in about half of the patients (8/17, 47.1%). Among them, we found that one patient harbored germline TP53 mutation as a secondary finding. This inexpensive, rapid method can be immediately applied as clinical sequencing and could lead to better management of these patients and potential improvement in the survival rate in childhood ALL.

DOI： 10.1007/s00277-018-3554-8

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その他リンク： http://link.springer.com/content/pdf/10.1007/s00277-018-3554-8.pdf

掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/ped.13615

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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  

INTRODUCTION: Recent clinical outcomes of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) vastly improved owing to tyrosine kinase inhibitor (TKI). However, the genetic status would be different in each case with ABL1 gene mutation or copy number variants (CNVs) such as IKZF1 deletion. In particular, the TKI resistant clone with ABL1 kinase mutation remains problematic. The comprehensive assessment of genetic status including mutation, insertion and deletion (indel) and CNVs is necessary. METHODS: We evaluated a next-generation sequencing (NGS)-based customized HaloPlex target enrichment system panel to simultaneously detect coding mutations, indel and CNVs. We analysed approximately 160 known genes associated with hematological disorders in 5 pediatric Ph+ALL patients. RESULTS: Mono-allelic IKZF1 deletions were found in 4 patients at diagnosis. Furthermore, the mono-allelic deletions were found in exons of RB1, EBF1, PAX5 and ETV6 genes. Bi-allelic deletions were detected in CDKN2A and CDKN2B genes in 1 patient. ABL1 mutation was also detected in 1 patient at relapse. These results were almost comparable with the results of the multiplex ligation-dependent probe amplification (MLPA) method or Sanger sequence. CONCLUSION: Next-generation sequencing-based custom HaloPlex target enrichment system panel allows us to detect the coding mutations, indel, and CNVs in pediatric Ph+ALL simultaneously, and its results seem comparable with those of other methods.

DOI： 10.1111/ijlh.12805

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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：American Society of Clinical Oncology (ASCO)  

Purpose

Osteonecrosis (ON) is a serious complication of the treatment of childhood acute lymphoblastic leukemia (ALL); however, data relating to ON in Asian pediatric patients with ALL are scarce. Therefore, we performed a retrospective analysis of cohorts of Japanese patients with ALL to clarify the incidence, clinical characteristics, and risk factors of ON.

Patients and Methods

The incidence and characteristics of ON were determined in patients with ALL (n = 1,662) enrolled in two studies from the Japan Association of Childhood Leukemia Study (JACLS) group (n = 635 and n = 1,027 patients treated with the ALL-97 and ALL-02 protocols, respectively).

Results

In total, 24 of 1,662 patients suffered from ON, of which 12 of 635 and 12 of 1,027 patients were treated with the ALL-97 and the ALL-02 protocol, respectively. Of the 24 patients, 23 were older than 10 years. In multivariate analysis, age (≥ 10 years) was the sole significant risk factor for ON ( P &lt; .001). Separate evaluation of patients ≥ 10 years of age indicated a 5-year cumulative incidence of ON of 7.2% (95% CI, 4.0% to 12.6%) and 5.9% (95% CI, 3.3% to 10.4%) in the ALL-97 and the ALL-02 protocol, respectively, which was lower than reported previously, despite an administration of dexamethasone (DEX) similar to that in comparable studies; however, concomitant administration of DEX and l-asparaginase was reduced in the JACLS protocols.

Conclusion

We identified a low frequency of ON in the JACLS ALL-97 and ALL-02 studies. Although the sole risk factor for ON was age (≥ 10 years), even among high-risk patients, ON incidence was significantly lower than that reported in previous studies. These results suggest that, not only the total amount of DEX, but also how DEX and l-asparaginase are administered, which affects the clearance of DEX, may be associated with ON incidence in patients with ALL.

DOI： 10.1200/jco.2017.75.5066

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掲載種別：研究論文（学術雑誌）  

DOI： 10.11406/rinketsu.59.389

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記述言語：日本語   出版者・発行元：(一社)日本小児血液・がん学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

BACKGROUND:Pediatric papillary thyroid carcinoma frequently presents with lymph node involvement and distant metastases. Sorafenib, an oral multikinase inhibitor, has been used to treat radioactive iodine (RAI) therapy-refractory thyroid carcinoma in adults; however, pediatric experience is limited. Medical procedures and hospitalization for children with autism spectrum disorder may be challenging. CASE PRESENTATION:An 11-year-old boy with autism spectrum disorder and moderate intellectual impairment presented with dyspnea on exertion with thyroid carcinoma and diffuses lung metastases. Total thyroidectomy and adjuvant RAI therapy is the standard treatment; however, the latter therapy was impractical because of his respiratory status and challenging behaviors. He was therefore started on sorafenib 200 mg/day (150 mg/m2/day) and this dosage was increased to 400 mg/day (300 mg/m2/day). The adverse effects were mild and tolerable. After administration of medication, his dyspnea improved and surgery was performed. We attempted to administer RAI therapy after surgery; however, we abandoned it because he had difficulty taking care of himself according to isolation room rules. Thyrotropin suppression therapy was therefore started and sorafenib treatment (400 mg/day) resumed. Follow-up imaging showed regression of pulmonary metastases. The metastases have remained stable for over 24 months on continuous sorafenib treatment without serious adverse events. CONCLUSION:We inevitably used sorafenib as an alternative to standard therapy because of the patient's specific circumstances. Individualized strategies for pediatric cancer patients with autism spectrum disorder are needed.

DOI： 10.1186/s12885-017-3782-7

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記述言語：日本語   出版者・発行元：(一社)日本小児血液・がん学会  

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

Patients with Down syndrome (DS) have a markedly higher incidence of childhood leukemia, but a lower incidence of most solid tumors, compared with age-matched euploid individuals. Trisomy 21 might be protective against tumorigenesis because of several tumor suppressive mechanisms. Desmoid-type fibromatosis (DF) is a rare monoclonal, fibroblastic proliferation characterized by a variable clinical course. In recent reports, almost all cases of DF involved genomic alterations associated with activation of the Wnt/β-catenin pathway. Here, we report the case of a boy with DS who developed DF without activation of the Wnt/β-catenin pathway. To the best of our knowledge, this is the first case of DS involving DF.

DOI： 10.1111/ped.13241

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ped.13241

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

Childhood anaplastic large cell lymphoma (ALCL) accounts for approx. 10–30 of cases of non-Hodgkin lymphoma, and the ALCL99 study reported 60–75 disease-free survival; however, a relatively high relapse rate was observed (25–30 ). We report 2 patients with Stage III ALCL who relapsed 6–18 months after the end of ALCL99 chemotherapy. A retrospective molecular analysis identified the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) fusion gene in the first diagnostic bone marrow samples taken from both patients. However, antibodies against the ALK protein appeared to be relatively low in the serum of both patients (×100 and ×750). An increase in chemotherapy intensity may be beneficial if Stage III ALCL patients are shown to be NPM-ALK chimera-positive in the first diagnostic bone marrow sample.

DOI： 10.18926/AMO/54815

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その他リンク： http://search.jamas.or.jp/link/ui/2017326192

記述言語：英語   出版者・発行元：(一社)日本小児血液・がん学会  

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記述言語：英語   出版者・発行元：(一社)日本小児血液・がん学会  

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/pbc.26100

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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：Nature Publishing Group  

DOI： 10.1038/jhg.2016.8

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その他リンク： http://www.nature.com/articles/jhg20168

記述言語：英語   出版者・発行元：(一社)日本小児血液・がん学会  

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記述言語：英語   出版者・発行元：(一社)日本小児血液・がん学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

2013年1月〜2015年12月に90日以上の小児科病棟長期入院を開始し、子どものこころ診療部が介入した血液・腫瘍性疾患29例(男児16例、女児13例、年齢中央値6歳1ヵ月)を、介入のきっかけにより4群に分類し発達支援を振り返った。介入のきっかけは骨髄移植前の発達評価10例(34.5%)、発達相談7例(24.1%)、治療困難5例(17.2%)、家族の疲弊7例(24.1%)であった。発達相談・治療困難・家族の疲弊の19例中9例に発達障害を認め、児の発達特性に配慮した療育的関わり、家族への支持的面接や疾病教育、多職種間の連携を行った。転帰は終了16例、継続7例、中断1例、転科1例、転院4例であり悪化は認めなかった。

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記述言語：日本語   出版者・発行元：(一社)日本小児救急医学会  

生後3ヵ月未満の発熱患者では重症細菌感染症(SBI)のリスクが高い。初診時におけるSBIの予測因子の探索を目的に後ろ向き研究を行った。2004年1月から2013年12月に受診した生後3ヵ月未満の乳児のうち、血液培養を採取され十分な臨床情報を有する303例を対象とした。52例(17.2%)がSBIと診断され、尿路感染症が43例(82.7%)、菌血症のみが7例(13.5%)、菌血症と細菌性髄膜炎の併発が2例(3.8%)であった。多変量解析ではsick contactなし、来院時体温>38℃、WBC>10,000/μLがSBIと有意に関連しており、調整オッズ比[95%CI]はそれぞれ2.7[1.4-5.3]、2.2[1.1-4.7]、2.1[1.0-4.2]であった。3つの因子が全てあるとSBIの頻度は45.5%であったが、全てないと2.3%であり、臨床的に有用であると考えられた。(著者抄録)

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC HEMATOLOGY  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY  

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記述言語：日本語   出版者・発行元：(一社)日本小児血液・がん学会  

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記述言語：日本語   出版者・発行元：科学評論社  

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その他リンク： https://search.jamas.or.jp/link/ui/2015058078

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会議種別：ポスター発表  

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会議種別：ポスター発表  

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