Publications by authors named "Motohiro Kato"

240 Publications

[Overview].

Authors:
Motohiro Kato

Rinsho Ketsueki 2022 ;63(7):790

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http://dx.doi.org/10.11406/rinketsu.63.790DOI Listing
August 2022

Low NUDT15 expression levels due to biallelic NUDT15 variants and 6-mercaptopurine intolerance.

Br J Haematol 2022 Jul 29. Epub 2022 Jul 29.

Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

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.
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http://dx.doi.org/10.1111/bjh.18375DOI Listing
July 2022

A phase III clinical trial evaluating efficacy and safety of minimal residual disease-based risk stratification for children with acute myeloid leukemia, incorporating a randomized study of gemtuzumab ozogamicin in combination with post-induction chemotherapy for non-low-risk patients (JPLSG-AML-20).

Jpn J Clin Oncol 2022 Jul 9. Epub 2022 Jul 9.

Human Health Science, Kyoto University, Kyoto, Japan.

The purpose of this study is to establish a treatment with appropriate intensity for children (<16 years old at diagnosis) with de novo acute myeloid leukemia (excluding acute promyelocytic leukemia and myeloid leukemia associated with Down syndrome) according to a risk stratification based on recurrent leukemic cytogenetic abnormalities and flow-cytometric minimal residual disease at end of initial induction chemotherapy and to validate the safety and efficacy of gemtuzumab ozogamicin (GO)-combined post-induction chemotherapy for the non-low-risk (non-LR) patients. The primary endpoint of this phase III study is three-year disease-free survival rate, which will be compared between the GO and non-GO arms of the non-LR (intermediate-risk and high-risk [HR]) patients. All HR patients will be allocated to allogeneic hematopoietic stem cell transplantation in first remission. This trial has been registered at the Japan Registry of Clinical Trials (jRCTs041210015).
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http://dx.doi.org/10.1093/jjco/hyac105DOI Listing
July 2022

Outcomes of salvage haploidentical transplantation using posttransplant cyclophosphamide for graft failure following allogeneic hematopoietic stem cell transplantation.

Int J Hematol 2022 Jun 29. Epub 2022 Jun 29.

Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan.

Haploidentical donors have emerged as an alternative donor source for salvage stem cell transplantation (SCT) after graft failure; however, data regarding salvage haploidentical SCT using posttransplant cyclophosphamide (PTCy) are limited. Using nationwide data (2011-2019), we retrospectively investigated transplant outcomes after salvage haploidentical SCT using PTCy for graft failure (n = 33, median age 34 years). The total dose of PTCy was 75-100 mg/kg (standard dose) in 26 patients (78.8%) and 40-50 mg/kg (lower dose) in 5 patients (15.2%). The neutrophil engraftment rate at 30 days was 81.8%. One-year overall survival (OS) and non-relapse mortality (NRM) rates were 47.4% and 46.0%, respectively. The standard-dose group exhibited better OS (61.1% vs. 0.0% at 1 year, P = 0.022) and NRM (35.1% vs. 80.0% at 1 year, P = 0.052) than the lower-dose group. Moreover, the standard-dose group was less prone to both grades II-IV (11.5% vs. 40.0%) and III-IV (0.0% vs. 40.0%) acute graft-versus-host disease (GVHD). Use of cyclophosphamide in previous SCT and conditioning did not affect OS or NRM. In conclusion, haploidentical salvage SCT using PTCy offers promising survival outcomes. Prospective studies are required to validate the efficacy of salvage haploidentical SCT using PTCy.
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http://dx.doi.org/10.1007/s12185-022-03405-wDOI Listing
June 2022

Serum polyethylene glycol-specific IgE and IgG in patients with hypersensitivity to COVID-19 mRNA vaccines.

Allergol Int 2022 Jun 6. Epub 2022 Jun 6.

Division of Rheumatology and Allergology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan.

Background: The mechanism of allergic reactions to COVID-19 mRNA vaccines has not been clarified. Polyethylene glycol (PEG) is a potential antigen in the components of vaccines. However, there is little evidence that allergy after COVID-19 mRNA vaccination is related to PEG. Furthermore, the role of polysorbate (PS) as an antigen has also not been clarified. The objective of this study was to investigate whether PEG and PS allergies are reasonable causes of allergic symptoms after vaccination by detecting PEG-specific and PS-specific antibodies.

Methods: Fourteen patients who developed immediate allergic reactions to BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccines and nineteen healthy controls who did not present allergic symptoms were recruited. Serum PEG-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) and PS-specific IgE and IgG were measured by enzyme-linked immunosorbent assay. Skin tests using PEG-2000 and PS-80 were applied to five patients and three controls.

Results: Serum levels of PEG-specific IgE and IgG in patients with immediate allergic reactions to the COVID-19 mRNA vaccine were higher than those in the control group. Serum levels of PS-specific IgE in patients with allergy to the vaccine were higher than those in patients of the control group. Intradermal tests using PEG verified the results for PEG-specific IgE and IgG.

Conclusions: The results suggest that PEG is one of the antigens in the allergy to COVID-19 mRNA vaccines. Cross-reactivity between PEG and PS might be crucial for allergy to the vaccines. PEG-specific IgE and IgG may be useful in diagnosing allergy to COVID-19 mRNA vaccines.
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http://dx.doi.org/10.1016/j.alit.2022.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167845PMC
June 2022

Identification of RCC1-LCK as a novel fusion gene in pediatric erythroid sarcoma.

Pediatr Blood Cancer 2022 09 30;69(9):e29848. Epub 2022 Jun 30.

Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Erythroid sarcoma is a very rare subtype of myeloid sarcoma with undetermined biological features. Here, we present an infant with a multifocal erythroid sarcoma, diagnosed because the tumor cells were positive for glycophorin A. After acute myeloid leukemia-oriented chemotherapy and surgical resection followed by cord blood transplantation, he has successfully maintained complete remission without any late effects. Total transcriptome analysis of the tumor identified a novel fusion gene, RCC1-LCK, and high LCK expression levels, suggesting that LCK overexpression was involved in leukemogenesis in this case.
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http://dx.doi.org/10.1002/pbc.29848DOI Listing
September 2022

Impact of KIR-ligand mismatch on pediatric T-cell acute lymphoblastic leukemia in unrelated cord blood transplantation.

Transplant Cell Ther 2022 Jun 1. Epub 2022 Jun 1.

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

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.
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http://dx.doi.org/10.1016/j.jtct.2022.05.037DOI Listing
June 2022

Quantitative assessment of copy number alterations by liquid biopsy for neuroblastoma.

Genes Chromosomes Cancer 2022 Jun 2. Epub 2022 Jun 2.

Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.

Liquid biopsy, a method of detecting genomic alterations using blood specimens, has recently attracted attention as a noninvasive alternative to surgical tissue biopsy. We attempted quantitative analysis to detect amplification of MYCN (MYCNamp) and loss of heterozygosity at 11q (11qLOH), which are clinical requisites as prognostic factors of neuroblastoma (NB). In this study, cell-free DNA (cfDNA) was extracted from plasma samples from 24 NB patients at diagnosis. Copy numbers of MYCN and NAGK genes were quantitatively analyzed by droplet digital PCR (ddPCR). 11qLOH was also assessed by detecting allelic imbalances of heterozygous single nucleotide polymorphisms in the 11q region. The results obtained were compared to those of specimens from tumor tissues. The correlation coefficient of MYCN copy number of cfDNA and tumor DNA was 0.88 (p < 0.00001). 11qLOH was also accurately detected from cfDNA, except for one case with localized NB. Given the high accuracy of liquid biopsy, to investigate components of cfDNA, the proportion of tumor-derived DNA was estimated by examining the variant allele frequency of tumor-specific mutations in cfDNA. The proportion of tumor-derived DNA in cfDNA was 42.5% (range, 16.9%-55.9%), suggesting sufficient sensitivity of liquid biopsy for NB. In conclusion, MYCN copy number and 11qLOH could be quantitatively analyzed in plasma cfDNA by ddPCR assay. These results suggest that plasma cfDNA can be substituted for tumor DNA and can also be applied for comprehensive genomic profiling analysis.
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http://dx.doi.org/10.1002/gcc.23073DOI Listing
June 2022

RUNX1 Inhibition Using Lipid Nanoparticle-Mediated Silencing RNA Delivery as an Effective Treatment for Acute Leukemias.

Exp Hematol 2022 May 26. Epub 2022 May 26.

Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan. Electronic address:

Transcription factor RUNX1 plays key roles in the establishment and maintenance of the hematopoietic system. Although RUNX1 has been considered a beneficial tumor suppressor, several recent reports have described the tumor-promoting role of RUNX1 in a variety of hematopoietic neoplasms. In this study, we assessed the effect of RUNX1 depletion in multiple human leukemia cell lines using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system, and confirmed that RUNX1 is in fact required for sustaining their leukemic proliferation. To achieve efficient RUNX1 inhibition in leukemia cells, we then examined the effect of lipid nanoparticle (LNP)-mediated delivery of RUNX1-targeting small interfering (si)RNA using two tumor-tropic LNPs. The LNPs containing RUNX1-targeting siRNA were efficiently incorporated into myeloid and T-cell leukemia cell lines and patient-derived primary human acute myeloid leukemia (AML) cells, downregulated RUNX1 expression, induced cell cycle arrest and apoptosis, and exhibited the growth-inhibitory effect in them. In contrast, the LNPs were not efficiently incorporated into normal cord blood CD34 cells, indicating their minimum cytotoxicity. Thus, our study highlights RUNX1 as a potential therapeutic target to inhibit leukemogenesis, and provides the LNP-based siRNA delivery as a promising approach to deplete RUNX1 specifically in leukemia cells.
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http://dx.doi.org/10.1016/j.exphem.2022.05.001DOI Listing
May 2022

Novel TENM3-ALK fusion is an alternate mechanism for ALK activation in neuroblastoma.

Oncogene 2022 05 11;41(20):2789-2797. Epub 2022 Apr 11.

Department of Pediatrics, Kyoto University, Yoshidakonoecho, Sakyo-ku, Kyoto, Japan.

The identification of molecular events underlying the pathogenesis of neuroblastoma can likely result in improved clinical outcomes for this disease. In this study, a translocation within chromosome 2p and 4q was found to bring about the formation of an in-frame fusion gene that was composed of portions of the teneurin transmembrane protein 3 (TENM3, also known as ODZ3) gene and the anaplastic lymphoma kinase (ALK) gene in tumor cells from patients with neuroblastoma. Expression of the full length TENM3-ALK cDNA in NIH-3T3 cells led to the formation of a fusion protein that: (1) possesses constitutive tyrosine kinase activity, (2) induces strong activation of the downstream targets of extracellular signal-regulated kinase (ERK), protein kinase B (a.k.a. AKT), and signal transducer and activator of transcription 3 (STAT3), (3) provokes oncogenic transformation in NOD.Cg-PrkdcIl2rg/ShiJic mice, and (4) possesses sensitivity to ALK inhibitors in vitro and in vivo. Our findings demonstrated that patients with neuroblastoma may express a transforming fusion kinase, which is a promising candidate for a therapeutic target and a diagnostic molecular marker for neuroblastoma. The in-frame 5' partner gene that fuses with ALK has not been reported previously in neuroblastoma. Our data provide novel biological insights into the mechanism of ALK activation due to translocation, with implications for neuroblastoma tumorigenesis, and could be useful as a vital marker for the accurate diagnosis of this type of neuroblastoma.
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http://dx.doi.org/10.1038/s41388-022-02301-1DOI Listing
May 2022

Ponatinib in pediatric patients with Philadelphia chromosome-positive leukemia: a retrospective survey of the Japan Children's Cancer Group.

Int J Hematol 2022 Jul 29;116(1):131-138. Epub 2022 Mar 29.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

Ponatinib is effective in adults with Philadelphia chromosome-positive (Ph+) leukemia, resistant or intolerant to second-generation tyrosine kinase inhibitors, but there are limited data on its use in children. The clinical courses of nine pediatric patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL) and four with chronic myeloid leukemia (CML) who received ponatinib therapy were retrospectively reviewed. The median age at the start of ponatinib therapy was 12 years (range 8-16 years). Nine patients were male and four were female. Six patients received ponatinib alone, three received ponatinib with prednisolone, one received ponatinib with rituximab intrathecal therapy, and one received ponatinib with conventional chemotherapy. Two patients received ponatinib both alone and in combination with chemotherapy. The median dose and duration of ponatinib were 16.9 mg/m (7-34.3) and 1.1 months (0.2-22.7), respectively. Six patients with Ph+ ALL and two with CML responded to ponatinib. One of the eight patients who received ponatinib alone had grade 4 increased lipase levels. Grade 3 non-hematologic toxicities included elevated alanine aminotransferase levels (25%), elevated aspartate aminotransferase levels (25%), elevated gamma-glutamyl transferase levels (12.5%), hypertension (12.5%), and polymorphic erythema (12.5%). Ponatinib may be safe and effective in pediatric patients with Ph+ leukemia.
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http://dx.doi.org/10.1007/s12185-022-03329-5DOI Listing
July 2022

Delay in diagnosis of blood disorders due to corticosteroid administration.

Pediatr Int 2022 Jan;64(1):e14997

Children's Cancer Center, National Center for Child Health and Development, Setagaya-ku, Japan.

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http://dx.doi.org/10.1111/ped.14997DOI Listing
January 2022

Case Report: Rotavirus Vaccination and Severe Combined Immunodeficiency in Japan.

Front Immunol 2022 23;13:786375. Epub 2022 Feb 23.

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Severe combined immunodeficiency (SCID) is an inborn error of immunity that occurs in approximately 1 in 50,000 births, mainly due to impaired lymphocyte differentiation. Without curative treatment, such as hematopoietic cell transplantation (HCT) or gene therapy, severe infection in the first year of life could make this condition fatal. The results of HCT are poor when patients have active infections, thus requiring early diagnosis before onset of infection. In five cases of SCID diagnosed in Japan, the oral rotavirus vaccine had been administered before diagnosis. In this study, we demonstrated that the rotavirus from their stools was a vaccine-derived strain. In some cases, severe gastroenteritis triggered the diagnosis of SCID. However, newborn screening for SCID is available before the first rotavirus vaccination using assays for the detection of T-cell receptor excision circles (TRECs). Therefore, to improve the prognosis of patients with SCID in Japan, we should establish a screening system of TRECs for newborns throughout Japan.
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http://dx.doi.org/10.3389/fimmu.2022.786375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905240PMC
May 2022

A Case of Gorlin-Goltz Syndrome Without the Characteristic Physical Features That Was Diagnosed After the Development of a Fifth Cancer.

J Pediatr Hematol Oncol 2022 05 1;44(4):e869-e871. Epub 2022 Mar 1.

Department of Pediatrics, Osaka Medical and Pharmaceutical University, Osaka.

We present a case of Gorlin-Goltz syndrome (GGS) in a patient who developed medulloblastoma, osteosarcoma, myelodysplastic syndrome, basal cell carcinoma, and odontogenic keratocyst by the age of 19 years. He had no known family history and no characteristic physical features of GGS. A frameshift mutation in the PTCH1 gene was found in the oral mucosa as a low-frequency mosaicism, basal cell carcinoma, and normal skin by whole exome sequencing of cancer susceptibility genes. Setting a therapeutic strategy with regard to second cancer development is important for pediatric cancer patients who have a background of cancer predisposition. Advances in comprehensive multigenetic analysis are anticipated to aid in developing such a strategy.
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http://dx.doi.org/10.1097/MPH.0000000000002436DOI Listing
May 2022

Prognostic factors of children and adolescents with T-cell acute lymphoblastic leukemia after allogeneic transplantation.

Hematol Oncol 2022 Aug 3;40(3):457-468. Epub 2022 Mar 3.

Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.

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.
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http://dx.doi.org/10.1002/hon.2980DOI Listing
August 2022

Gemtuzumab Ozogamicin Followed by Unrelated Cord Blood Transplantation With Reduced-intensity Conditioning for a Child With Refractory Acute Promyelocytic Leukemia.

J Pediatr Hematol Oncol 2022 05 28;44(4):178-180. Epub 2022 Jan 28.

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

There is no established treatment for patients with acute promyelocytic leukemia (APL) refractory to targeted therapies with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). We report here a case of an 8-month-old girl with APL who failed standard ATRA-combined chemotherapy. Although molecular remission was achieved after introducing ATRA/ATO combination therapy, molecular relapse occurred during the ATO consolidation courses. Subsequent molecular remission was rapidly achieved after administering 2 doses of gemtuzumab ozogamicin. She was successfully treated with unrelated cord blood transplantation using reduced-intensity conditioning. Gemtuzumab ozogamicin might be a preferable choice for patients with APL refractory to standard therapy.
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http://dx.doi.org/10.1097/MPH.0000000000002404DOI Listing
May 2022

Case Report: Treatment of Extremely Preterm Infants With Birthweight Below 300 g: Case Series.

Front Pediatr 2021 6;9:758683. Epub 2021 Dec 6.

Department of Pediatrics, The University of Tokyo Hospital, Tokyo, Japan.

Reports on the birth of infants weighing <300 g are quite rare and little is known about the best practices in treating such micropreemies. Therefore, we report here on three cases of low birthweight infants weighing <300 g, of whom two infants survived. The birthweights and gestational ages were ranging 279-293 g and 22 + 6/7 - 23 + 6/7 weeks, respectively. All the infants had severe fetal growth restriction and prematurity. The infant in case 1 died of hepatic rupture, perhaps due to birth trauma, which emphasized the need for less invasive obstetric procedures including delivery. The infant in case 2 managed to survive through severe prematurity secondary to hydrops fetalis. However, complications followed soon as tracheal granulation tissue was formed with neurodevelopmental impairment. The infant in case 3 was born recently and her clinical course was less remarkable without severe complications, despite having the least gestational age and birthweight among the three patients. The improved care protocols for extremely low birthweight infants over these years through experiential learning including that with cases 1 and 2 may have ensured the better outcome of case 3. Accumulating evidence and recording the experience of such cases with continuous constructive discussion can contribute to better outcomes and appropriate parental counseling for extremely small babies in the future.
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http://dx.doi.org/10.3389/fped.2021.758683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8685408PMC
December 2021

Nonconditioned ADA-SCID gene therapy reveals ADA requirement in the hematopoietic system and clonal dominance of vector-marked clones.

Mol Ther Methods Clin Dev 2021 Dec 16;23:424-433. Epub 2021 Oct 16.

Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.

Two patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (ADA-SCID) received stem cell-based gene therapy (SCGT) using GCsapM-ADA retroviral vectors without preconditioning in 2003 and 2004. The first patient (Pt1) was treated at 4.7 years old, and the second patient (Pt2), who had previously received T cell gene therapy (TCGT), was treated at 13 years old. More than 10 years after SCGT, T cells showed a higher vector copy number (VCN) than other lineages. Moreover, the VCN increased with differentiation toward memory T and B cells. The distribution of vector-marked cells reflected variable levels of ADA requirements in hematopoietic subpopulations. Although neither patient developed leukemia, clonal expansion of SCGT-derived clones was observed in both patients. The use of retroviral vectors yielded clonal dominance of vector-marked clones, irrespective of the lack of leukemic changes. Vector integration sites common to all hematopoietic lineages suggested the engraftment of gene-marked progenitors in Pt1, who showed severe osteoblast (OB) insufficiency compared to Pt2, which might cause a reduction in the stem/progenitor cells in the bone marrow (BM). The impaired BM microenvironment due to metabolic abnormalities may create space for the engraftment of vector-marked cells in ADA-SCID, despite the lack of preconditioning.
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http://dx.doi.org/10.1016/j.omtm.2021.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566957PMC
December 2021

Establishment of multiplex RT-PCR to detect fusion genes for the diagnosis of Ewing sarcoma.

Diagn Pathol 2021 Nov 8;16(1):102. Epub 2021 Nov 8.

Department of Pathology, National Center for Child Health and Development, Tokyo, 157-8535, Japan.

Background: Detection of the tumor-specific EWSR1/FUS-ETS fusion gene is essential to diagnose Ewing sarcoma. Reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization are commonly used to detect the fusion gene, and assays using next-generation sequencing have recently been reported. However, at least 28 fusion transcript variants have been reported, making rapid and accurate detection difficult.

Methods: We constructed two sets of multiplex PCR assays and evaluated their utility using cell lines and clinical samples.

Results: EWSR1/FUS-ETS was detected in five of six tumors by the first set, and in all six tumors by the second set. The fusion gene detected only by the latter was EWSR1-ERG, which completely lacked exon 7 of EWSR1. The fusion had a short N-terminal region of EWSR1 and showed pathologically atypical features.

Conclusions: We developed multiplex RT-PCR assays to detect EWSR1-ETS and FUS-ETS simultaneously. These assays will aid the rapid and accurate diagnosis of Ewing sarcoma. In addition, variants of EWSR1/FUS-ETS with a short N-terminal region that may have been previously missed can be easily detected.
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http://dx.doi.org/10.1186/s13000-021-01164-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573982PMC
November 2021

Vedolizumab therapy for pediatric steroid-refractory gastrointestinal acute graft-versus-host disease.

Int J Hematol 2022 Apr 1;115(4):590-594. Epub 2021 Nov 1.

Department of Pediatrics, Tokyo Medical and Dental University Hospital, Tokyo, Japan.

Vedolizumab, an immunosuppressive drug that acts locally on the gastrointestinal tract, is mainly used for the treatment of inflammatory bowel disease, and has been reported to be effective against gastrointestinal acute graft-versus-host disease (GI-aGVHD) in adults. However, there is insufficient evidence for pediatric GI-aGVHD. We used vedolizumab to treat three cases of GI-aGVHD in patients aged 1.5-4.4 years. It was significantly effective in two patients and did not cause serious side effects in any patient. Vedolizumab might be effective and safe for pediatric GI-aGVHD refractory to other treatments, but this must be confirmed in future studies.
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http://dx.doi.org/10.1007/s12185-021-03245-0DOI Listing
April 2022

Genomic analysis of two rare cases of pediatric Ph-positive T-ALL.

Pediatr Blood Cancer 2022 03 31;69(3):e29427. Epub 2021 Oct 31.

Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.

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http://dx.doi.org/10.1002/pbc.29427DOI Listing
March 2022

NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia.

Blood Adv 2021 12;5(23):5420-5428

Department of Hematology/Oncology, Chiba Children's Hospital, Chiba, Japan.

The effect of genetic variation on second malignant neoplasms (SMNs) remains unclear. First, we identified the pathogenic germline variants in cancer-predisposing genes among 15 children with SMNs after childhood leukemia/lymphoma using whole-exome sequencing. Because the prevalence was low, we focused on the association between SMNs and NUDT15 in primary acute lymphoblastic leukemia (ALL) cases. NUDT15 is one of the 6-mercaptopurine (6-MP) metabolic genes, and its variants are common in East Asian individuals. The prevalence of NUDT15 hypomorphic variants was higher in patients with SMNs (n = 14; 42.9%) than in the general population in the gnomAD database (19.7%; P = .042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMNs was significantly higher among those with (3.0%; 95% confidence interval [CI], 0.6% to 9.4%) than among those without NUDT15 variants (0.3%; 95% CI, 0.0% to 1.5%; P = .045). The 6-MP dose administered to patients with ALL with a NUDT15 variant was higher than that given to those without SMNs (P = .045). The 6-MP-related mutational signature was observed in SMN specimens after 6-MP exposure. In cells exposed to 6-MP, a higher level of 6-MP induced DNA damage in NUDT15-knockdown induced pluripotent stem cells. Our study indicates that NUDT15 variants may confer a risk of SMNs after treatment with 6-MP in patients with ALL.
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http://dx.doi.org/10.1182/bloodadvances.2021005507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9153020PMC
December 2021

Genetic features of B-cell lymphoblastic lymphoma with TCF3-PBX1.

Cancer Rep (Hoboken) 2021 Sep 23:e1559. Epub 2021 Sep 23.

Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.

Background: Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are categorized as the same entity under precursor lymphoid neoplasms in the World Health Organization classification. However, compared to B-cell ALL, the molecular genetic makeup of B-cell LBL remains to be understood, mainly due to its rarity. We performed whole exome sequencing (WES) on seven patients with TCF3-PBX1-positive B-cell LBL.

Methods: WES was performed using DNA extracted from tumor specimens and paired blood samples at remission for six patients, and tumor-only analysis was performed for one patient whose remission sample was not available. For one patient, a relapsed sample was also analyzed.

Results: KMT2D variants and 6q LOH were found as recurrent alterations. Somatic variants of KMT2D were identified in three of the seven patients. Of note, the two patients with heterozygous nonsense variant of KMT2D were at stage III, without bone marrow infiltration. 6q LOH was also identified in two others, out of the seven patients. The common 6q deleted region of the two patients ranged from 6q12 to 6q16.3. Both patients had bone marrow infiltration. Analysis of recurrent case also revealed that the relapsed clone might be derived from a minor clone of the bone marrow at diagnosis.

Conclusion: In this study, through WES for seven patients with TCF3-PBX1-positive B-LBL, we identified KMT2D mutations and 6q LOH as recurrent alterations. In order to elucidate the relationship between these recurrent alterations and disease specificity or outcomes, further studies comparing with TCF3-PBX1-positive B-ALL are required.
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http://dx.doi.org/10.1002/cnr2.1559DOI Listing
September 2021

Prognostic value of the revised International Prognostic Scoring System five-group cytogenetic abnormality classification for the outcome prediction of hematopoietic stem cell transplantation in pediatric myelodysplastic syndrome.

Bone Marrow Transplant 2021 12 10;56(12):3016-3023. Epub 2021 Sep 10.

Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Aichi, Japan.

Cytogenetic abnormalities are a major risk factor for relapse after hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS). We aimed to evaluate the value of the five-group cytogenetic classification according to the revised International Prognostic Scoring System (R-IPSS) for predicting the outcome after HSCT in pediatric patients with MDS. We retrospectively analyzed the Japanese registration data of 242 pediatric patients with MDS. According to the R-IPSS classification, 112 (45.5%) patients had good, 55 (22.7%) had intermediate, 64 (26.4%) had poor, and 11 (4.6%) had very poor cytogenetics. The 5-year overall survival (5yOS) was 72%, 69%, 59%, and 30% in the good, intermediate, poor, and very poor cytogenetic subgroups (p = 0.026), respectively. The very good, good, and intermediate subgroups were grouped into a "standard" subgroup and reclassified into three subgroups (standard, poor, and very poor). Patients with very poor risk had worse 5yOS (hazard ratio 2.17, 95% confidence interval (CI) 1.02-4.61; p = 0.04) and a much higher 5yCIR (hazard ratio 2.52, 95% CI 1.05-6.04; p = 0.04) than those of patients in the standard group in the multivariate analysis, indicating that very poor risk cytogenetic characteristics independently predicted worse outcome after HSCT in pediatric patients with MDS.
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http://dx.doi.org/10.1038/s41409-021-01446-zDOI Listing
December 2021

[Future perspective of allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia].

Authors:
Motohiro Kato

Rinsho Ketsueki 2021 ;62(8):1275-1280

Department of Pediatrics, the University of Tokyo.

Allogeneic hematopoietic cell transplantation (allo-HCT) plays an important role as the most potent therapeutic option for refractory acute lymphoblastic leukemia (ALL). However, advances of supporting therapy have enabled more intensive chemotherapy, and severe late complication of allo-HCT has been recognized, thus, indication of allo-HCT is now limited to carefully selected population with highest risk for relapse, based on assessment by minimal residual disease status. Furthermore, especially for B-cell precursor ALL, we should re-establish a role of allo-HCT in the entire of therapeutic strategy, including novel options, such as small molecular agents and immunotherapy. We are now required to maximize safety and efficacy of allo-HCT for selected high-risk ALL.
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http://dx.doi.org/10.11406/rinketsu.62.1275DOI Listing
September 2021

Genetic features of precursor B-cell phenotype Burkitt leukemia with IGH-MYC rearrangement.

Cancer Rep (Hoboken) 2022 Jul 2;5(7):e1545. Epub 2021 Sep 2.

Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo, Japan.

Background: An atypical form of Burkitt leukemia/lymphoma (BL), BL with a phenotype of precursor B-cells (preBLL), is listed in the WHO Classification. Recent reports suggested that preBLL and classical BL could be distinguished by the differences in IG-MYC translocation architecture and an additional mutated genes profile. The characteristics of classical BL are IG-MYC by aberrant somatic hypermutation or class switch recombination, and BL-specific gene mutations such as MYC, ID3, and CCND3. Meanwhile, preBLL is characterized by IG-MYC due to aberrant VDJ recombination and mutations in NRAS and KRAS. However, it is not clear whether all preBLL cases can be differentiated. This report investigated the molecular characteristics of an infant preBLL case, with a more advanced stage of maturity than typical preBLL.

Case: The patient showed BL-like morphology with IGH-MYC rearrangement. In the immunophenotyping, CD20 and surface immunoglobulin were negative, whereas other markers were consistent with BL. To evaluate the genetic contribution, we performed whole-exome sequencing. The breakpoint analysis revealed the IG-MYC occurred due to an aberrant VDJ recombination. Meanwhile, additional somatic mutations were detected in FBXO11, one of the mutant genes specific to BL. In the analysis of the specimen in complete remission, mutation in KRAS, frequently mutated in preBLL, was detected with low frequency, suggesting somatic mosaicism.

Conclusion: The present case showed the characteristics of both typical preBLL and classical BL. Because preBLL includes atypical cases such as the present case, further studies are required to elucidate preBLL features.
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http://dx.doi.org/10.1002/cnr2.1545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327653PMC
July 2022

Hematopoietic Cell Transplantation for Severe Combined Immunodeficiency Patients: a Japanese Retrospective Study.

J Clin Immunol 2021 11 27;41(8):1865-1877. Epub 2021 Aug 27.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.

Purpose: Hematopoietic cell transplantation (HCT) is a curative therapy for patients with severe combined immunodeficiency (SCID). Here, we conducted a nationwide study to assess the outcome of SCID patients after HCT in Japan.

Methods: A cohort of 181 SCID patients undergoing their first allogeneic HCT in 1974-2016 was studied by using the Japanese national database (Transplant Registry Unified Management Program, TRUMP).

Results: The 10-year overall survival (OS) of the patients who received HCT in 2006-2016 was 67%. Umbilical cord blood (UCB) transplantation was performed in 81 patients (45%). The outcomes of HCT from HLA-matched UCB (n = 21) and matched sibling donors (n = 22) were comparable, including 10-year OS (91% vs. 91%), neutrophil recovery (cumulative incidence at 30 days, 89% vs. 100%), and platelet recovery (cumulative incidence at 60 days, 89% vs. 100%). Multivariate analysis of the patients who received HCT in 2006-2016 demonstrated that the following factors were associated with poor OS: bacterial or fungal infection at HCT (hazard ratio (HR): 3.8, P = 0.006), cytomegalovirus infection prior to HCT (HR: 9.4, P = 0.03), ≥ 4 months of age at HCT (HR: 25.5, P = 0.009), and mismatched UCB (HR: 19.8, P = 0.01).

Conclusion: We showed the potential of HLA-matched UCB as a donor source with higher priority for SCID patients. We also demonstrated that early age at HCT without active infection is critical for a better prognosis, highlighting the importance of newborn screening for SCID.
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http://dx.doi.org/10.1007/s10875-021-01112-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390179PMC
November 2021

A case of primary CNS embryonal rhabdomyosarcoma with PAX3-NCOA2 fusion and systematic meta-review.

J Neurooncol 2021 Sep 16;154(2):247-256. Epub 2021 Aug 16.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

Purpose: Primary central nervous system (CNS) rhabdomyosarcoma is a rare mesenchymal tumor predominantly seen in children and associated with a poor outcome. We report a case of primary CNS rhabdomyosarcoma with PAX3-NCOA2 fusion and present a systematic meta-review of primary CNS rhabdomyosarcoma to characterize this rare tumor.

Methods: We present the case of a 6-year-old boy with primary CNS rhabdomyosarcoma in the posterior fossa. In a systematic meta-review, we compare the demographic data of primary CNS rhabdomyosarcoma with data of rhabdomyosarcoma at all sites from the SEER database and analyze clinical factors associated with survival outcome.

Results: Our patient underwent gross total resection and received vincristine, actinomycin-D, cyclophosphamide with early introduction of concurrent focal radiation and remained alive with no evidence of disease for 2 years after the end of therapy. Histopathological review revealed embryonal-type rhabdomyosarcoma, and whole-transcriptome analysis revealed PAX3 (EX6)-NCOA2 (EX12) fusion. In all, 77 cases of primary CNS rhabdomyosarcoma were identified through the meta-review. The demographic data of primary CNS rhabdomyosarcoma were similar to data of rhabdomyosarcoma at all sites. Overall and event-free survival outcomes were available for 64 and 56 patients, respectively, with a 3-year OS of 29.0% and a 3-year EFS of 25.7%. The group that received trimodal treatment exhibited better survival outcomes, with a 3-year OS of 57.4% and a 3-year EFS of 46.3%.

Conclusions: Primary CNS rhabdomyosarcoma shares common histological, molecular, and demographic features with non-CNS rhabdomyosarcoma. A trimodal treatment approach with early introduction of radiation therapy may result in favorable survival outcomes.
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http://dx.doi.org/10.1007/s11060-021-03823-6DOI Listing
September 2021
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