Details of a Researcher - MORITAKE Hiroshi

Targeting cholesterol biosynthesis for AT/RT: comprehensive expression analysis and validation in newly established AT/RT cell line. Reviewed

Matsumoto F, Yokogami K, Yamada A, Moritake H, Watanabe T, Yamashita S, Sato Y, Takeshima H

Human cell 37 ( 2 ) 523 - 530 2024.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Human Cell

Atypical teratoid/rhabdoid (AT/RT) is a rare and highly malignant tumor of the central nervous system (CNS). It is most commonly found in children less than 5 years of age and is associated with inactivation of loss of function of SMARCB1/INI1. An experimental model for AT/RT is necessary to develop new and effective therapies. We established a patient-derived new cell line (MZ611ATRT), which showed loss of BAF-47. MZ611ATRT genetically features somatic heterozygous deletion of SMARCB1 and single nucleotide deletion of the residual allele, exon 5 ([c.541delC]), resulting in a stop codon at codon 954 by frameshift. We assessed the RNA-sequencing data of the other two AT/RT cell lines with forced expression of SMARCB1 available from public databases. We found SMARCB1 overexpression significantly down-regulates the expression of a group of enzymes related to cholesterol biosynthesis. Simvastatin was highly sensitive against MZ611ATRT cells and induced apoptosis (IC50 was 3.098 µM for MZ611ATRT, 41.88uM for U-87 MG, 23.34uM for IOMM-Lee, and 18.12uM for U-251 MG.). Pathways involved in cholesterol biosynthesis may be new targets for adjuvant therapy of AT/RT.

DOI： 10.1007/s13577-023-01022-1

B-cell deficiency identified by newborn screening Reviewed

Matsumoto Takayuki, Nishimura Toyoki, Yamamoto Ayako, Sawada Hirotake, Moritake Hiroshi

JSIAD Journal 3 ( 1 ) 16 - 20 2024.2

Authorship：Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Society for Immunodeficiency and Autoinflammatory Diseases

Newborn screening（NBS）is carried out at public expense for approximately 20 diseases in Japan; however, each prefecture independently conducts additional NBS including several more diseases. Miyazaki Prefecture has optionally included inborn errors of immunity（IEIs）and lysosomal storage diseases since April 2020. We herein report a baby who suffered from B-cell deficiency（BCD）that was identified by NBS conducted in Miyazaki Prefecture. The baby had low levels of kappa-deleting recombination excision circles（KRECs）and was referred to our hospital. Several measurements of CD19-positive B cells in the peripheral blood consistently showed values <2%, leading to the diagnosis of BCD. Periodic immunoglobulin replacement successfully led to a healthy outcome without serious infection developing over a period of more than 17 months. This is the first case of BCD identified by NBS and that underwent prophylactic gamma globulin replacement in Japan. Severe combined immunodeficiency disease and BCD are IEIs known to cause severe sequelae, and patients sometimes die without a correct diagnosis being made; therefore, their early diagnosis and early treatment are extremely important. The inclusion of IEIs in NBS has proven to be cost-effective all over the world. In the future, it is expected that IEIs will be covered by NBS public funds in Japan as well.

DOI： 10.34563/jsiadjournal.3.1_16

Early hematopoietic cell transplantation for familial hemophagocytic lymphohistiocytosis in a regional treatment network in Japan Reviewed

Ishimura M., Eguchi K., Sonoda M., Tanaka T., Shiraishi A., Sakai Y., Yasumi T., Miyamoto T., Voskoboinik I., Hashimoto K., Matsumoto S., Ozono S., Moritake H., Takada H., Ohga S.

International Journal of Hematology 119 ( 5 ) 592 - 602 2024

Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Hematology

Familial hemophagocytic lymphohistiocytosis (FHLH) is a fatal hyperinflammation syndrome arising from the genetic defect of perforin-mediated cytolysis. Curative hematopoietic cell transplantation (HCT) is needed before development of central nervous system (CNS) disease. We studied treatment outcomes of 13 patients (FHLH2 n = 11, FHLH3 n = 2) consecutively diagnosed from 2011 to 2022 by flow cytometric screening for non-myeloablative HCT in a regional treatment network in Kyushu, Japan. One patient with a novel PRF1 variant escaped screening, but all patients with FHLH2 reached diagnosis and 8 of them received HCT until 3 and 9 months of age, respectively. The earliest HCT was conducted 65 days after birth. Three pretransplant deaths occurred in newborns with liver failure at diagnosis. Ten posttransplant patients have remained disease-free, 7 of whom had no neurological involvement. Time from first etoposide infusion to HCT was shorter in patients without CNS disease or bleeding than in patients with those factors (median [range] days: 62 [50–81] vs. 122 [89–209], p = 0.016). Six of 9 unrelated patients had a PRF1 c.1090_1091delCT variant. These results suggest that the critical times to start etoposide and HCT are within 3 months after birth and during etoposide control, respectively. Newborn screening may increase the percentage of disease-free survivors without complications.

DOI： 10.1007/s12185-024-03721-3

Pediatric acute myeloid leukemia Reviewed

MORITAKE Hiroshi

Rinsho Ketsueki 65 ( 9 ) 928 - 936 2024

Authorship：Lead author,　Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Hematology

Acute myeloid leukemia (AML) accounts for approximately 25% of pediatric leukemia cases in Japan, with approximately 150 patients being newly diagnosed with AML annually. Pediatric acute myeloid leukemia is classified into three groups: myeloid leukemia associated with Down syndrome (ML-DS), acute promyelocytic leukemia (APL), and de novo AML. Patients with ML-DS have an event-free survival rate over 80%; however, relapsed patients have dismal outcomes, even if they receive hematopoietic cell transplantation. APL is curable with all-trans retinoic acid and arsenic trioxide. In de novo AML, 10% of patients fail to achieve remission, and approximately 30% of patients who successfully achieve remission subsequently experience AML relapse. This review highlights the therapeutic approach for these three diseases with context from past clinical studies in Japan, and shares promising new therapeutic options for relapsed/refractory de novo AML.

DOI： 10.11406/rinketsu.65.928

Safety and efficacy of ripasudil eye drops in preterm infants with retinopathy of prematurity: phase 1/2, open label, single-arm trial Reviewed

Arima M., Inoue H., Misumi A., Tsukamoto S., Matsushita I., Araki S., Ohta M., Takahashi K., Imazato M., Goto T., Aoki Y., Tagawa K., Hirose M., Fujita Y., Yoshida N., Nakao S., Kondo H., Kusuhara K., Kimura K., Hasegawa S., Ikeda Y., Kodama Y., Moritake H., Ochiai M., Ohga S., Kishimoto J., Todaka K., Ieiri I., Sonoda K.H.

Japanese Journal of Ophthalmology 68 ( 5 ) 490 - 499 2024

Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Ophthalmology

Purpose: To assess the safety and efficacy of ripasudil for retinopathy of prematurity (ROP). Study design: Phase 1/2, multicenter, open-label, single-arm, 12-week clinical trial. Methods: Infants born with gestational age (GA) of ≤ 32 weeks or weight of ≤ 1500 g with zone I or II, ≥ stage 1, ROP in both eyes were enrolled. Ripasudil eye drops were administered to patients in both eyes. Phase 1 was a dose-escalation study (once daily for 1 week, then twice daily for 2 weeks); an additional dosing up to 9 weeks was allowed if no safety issues occurred. In phase 2, ripasudil was administered twice daily for up to 12 weeks. Adverse events were assessed. The proportion of patients with type 1 ROP progression, number of days for type 1 ROP progression, and progression to the most advanced ROP stage were estimated. Results: Twenty-four infants were enrolled (phase 1, n = 3; phase 2, n = 21). Nineteen and four patients experienced systemic and ocular adverse events, respectively. Efficacy endpoints were not different between the ripasudil and historical control groups. However, in the GA ≤ 27 weeks subgroup, fewer patients progressed to type 1 ROP in the ripasudil than in the historical control group (P = 0.09). In the GA ≤ 27 weeks subgroups, the 25th percentile for the number of days for type 1 ROP progression was 22 days in the historical control group and 44 days in the ripasudil group. Conclusion: Ripasudil was safe and inhibited/delayed type 1 ROP progression, especially in infants with short GA.

DOI： 10.1007/s10384-024-01100-3

Cytokine Storm Originating from the Intrapericardial Cavity in a Child With Pericardial Effusion Following COVID-19 Reviewed

Ebihara Shusei, Kodama Yoshihiko, Takamura Kazunari, Harada Masako, Moritake Hiroshi

Journal of Pediatric Cardiology and Cardiac Surgery advpub ( 0 ) 82 - 86 2024

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：特定非営利活動法人日本小児循環器学会

Symptoms of coronavirus infectious disease 2019 (COVID-19) are usually mild in young patients. Some children, however, present with a significant degree of complications which may be associated with an excessive reaction by the immune system. Herein, we report an analysis of cytokine and chemokine in an 11-year-old girl diagnosed with left ventricular dysfunction and cardiac tamponade complicated with COVID-19. She recovered without complications after intravenous immunoglobulin, dexamethasone, remdesivir, and surgical pericardial drainage. Cytokine concentrations had markedly increased in the pericardial fluid specimen; especially for interleukin-6 being disproportionate to its serum concentration. Cytokine storm originating from the pericardial cavity was considered an underlying mechanism of her condition.

DOI： 10.24509/jpccs.23-012

Current status and future perspective of pediatric malignancy in Kyushu and Okinawa regions Reviewed

Moritake Hiroshi

The Japanese Journal of Pediatric Hematology / Oncology 61 ( 5 ) 318 - 323 2024

Authorship：Lead author,　Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Pediatric Hematology / Oncology

A pediatric malignancy is a representative “rare cancer”, with a yearly incidence of only 2,000. Therefore, it is reasonable to consolidate clinical expertise in “centers of excellence” where pediatric patients can be treated appropriately. Acute lymphoblastic leukemia is the most common pediatric malignancy, and there is little disparity in treatment outcomes between facilities because of the remarkable progress in treatment, making it a representative disease for which standardization is important. Thus, while consolidation is generally necessary for pediatric malignancies, standardization is particularly important in certain cases. In the Kyushu and Okinawa regions, cooperation between facilities in each prefecture and Kyushu University Hospital as a core hospital has been established. A facility can become a Japanese pediatric hematology and oncology specialist training facility via two routes: becoming an affiliate of Kyushu University Hospital or becoming an independent parent facility, for which certified instructors in pediatric hematology and oncology and certified surgeons for pediatric malignancies are required. Furthermore, a certain number of new patients with pediatric malignancy annually is necessary. There are only two independent facilities in the Kyushu and Okinawa regions, each able to discuss cases that are difficult to deal with and share information through monthly web conferencing systems. There are no difficulties in daily practice, although the successful training of certified instructors and surgeons is necessary to increase the number of independent facilities for the management of pediatric malignancies.

DOI： 10.11412/jspho.61.318

Novel splice site variant of TMEM38B in osteogenesis imperfecta type XIV Reviewed

Kodama Y., Meiri S., Asada T., Matsuyama M., Makino S., Iwai M., Yamaguchi M., Moritake H.

Human Genome Variation 10 ( 1 ) 25 2023.12

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Human Genome Variation

Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by brittle bones. In this case report, we describe a patient who suffered from OI type XIV with a novel splice site variant in the TMEM38B gene. Further research is needed to better understand the relationship between the phenotype of OI type XIV and this variant.

DOI： 10.1038/s41439-023-00252-x

Outcomes following induction failure in Japanese children with acute lymphoblastic leukemia. Reviewed

Imai C, Sato A, Hiwatari M, Shimomura Y, Hori T, Suenobu S, Imamura T, Hara J, Hasegawa D, Takahashi H, Moriya K, Katayama S, Tomizawa D, Moritake H, Taga T, Horibe K, Koh K, Manabe A, Okamoto Y

International journal of hematology 118 ( 1 ) 99 - 106 2023.4

Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Hematology

The characteristics and prognosis of Japanese children with acute lymphoblastic leukemia (ALL) who fail to achieve complete remission after remission induction chemotherapy (i.e., experience induction failure) are poorly understood. Therefore, we retrospectively analyzed data of patients enrolled in Japanese clinical trials for newly diagnosed ALL between 1996 and 2009. Among 4956 participants, 89 (1.8%) experienced induction failure. With a 6.0-year median follow-up, the 5-year overall survival rate of the entire cohort was 43.0% ± 5.5%. Survival rates did not differ between patients with B-cell precursor ALL (BCP-ALL) and T-cell ALL (T-ALL). In multivariate analysis, day 15 M3 marrow (bone marrow blast count ≥ 25%) was significantly correlated with poorer survival in the whole or BCP-ALL cohorts. In T-ALL, age < 6 years was significantly associated with poor survival. However, due to the small sample size, this correlation must be further investigated. Most T-ALL and BCR-ABL-positive BCP-ALL patients underwent allogeneic stem cell transplantation (allo-SCT). Survival rates did not differ between BCR-ABL-negative BCP-ALL patients who did and did not undergo allo-SCT, possibly due to the inclusion of lower-risk patients in the latter group. In conclusion, the induction failure rate and survival after diagnosis of induction failure in our study were comparable to previously reported figures.

DOI： 10.1007/s12185-023-03600-3

BMPR2 variant may be related to pulmonary hypertension after lung irradiation Reviewed

Harada M., Yamada A., Nagasawa S., Yamashita N., Kinoshita M., Yoshiura K.i., Moritake H.

Pediatrics International 65 ( 1 ) e15652 2023.1

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Pediatrics International

DOI： 10.1111/ped.15652

Pneumocystis pneumonia during everolimus therapy for Kasabach–Merritt phenomenon Reviewed

Otomi K., Yamada A., Kurogi J., Kamimura S., Moritake H.

Pediatrics International 65 ( 1 ) e15593 2023.1

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Pediatrics International

DOI： 10.1111/ped.15593

Steroid-refractory gastrointestinal acute graft-versus-host disease treated with vedolizumab and ruxolitinib in a pediatric patient with therapy-related acute myeloid leukemia Reviewed

NAGASAWA Shun, YAMADA Ai, KINOSHITA Mariko, KAMIMURA Sachiyo, TANAKA Hiroyuki, NISHIKAWA Takuro, OKAMOTO Yasuhiro, MORITAKE Hiroshi

Rinsho Ketsueki 64 ( 1 ) 23 - 29 2023

Authorship：Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Hematology

A 12-year-old girl developed Philadelphia chromosome-positive acute myeloid leukemia due to therapy-related myelodysplastic syndrome with monosomy 7 following neuroblastoma treatment. She underwent allogenic bone marrow transplantation from a human leukocyte antigens-DR1 locus-mismatched unrelated donor. However, on day 49 post transplantation, she presented with diarrhea due to gastrointestinal acute graft-versus-host disease (aGVHD), and treatments with prednisolone, budesonide rectal foam, and human mesenchymal stem cells were ineffective. Therefore, vedolizumab was administered from day 100, which improved the symptoms from gut stage 3 to gut stage 1. Consequently, prednisolone was withdrawn without any serious adverse effects. However, the symptoms worsened to gut stage 3 again; therefore, ruxolitinib was administered to achieve complete remission. Vedolizumab exhibits gut-selective action without systemic immunosuppressive activity. Hence, vedolizumab administration before other systemic immunosuppressive agents may be recommended in patients with steroid-refractory gastrointestinal aGVHD. Thus far, only a few reports have been published regarding the administration of vedolizumab and ruxolitinib for steroid-refractory gastrointestinal aGVHD in children. Further evidence should be obtained from patients treated with vedolizumab and ruxolitinib to confirm their effectiveness for pediatric steroid-refractory gastrointestinal aGVHD.

DOI： 10.11406/rinketsu.64.23

Successful treatment of eltrombopag following immunosuppressive therapy in pediatric aplastic anemia Reviewed

KUBOTA Isamu, NAGASAWA Shun, NAKAGAWA Midori, YAMADA Ai, KINOSHITA Mariko, KAMIMURA Sachiyo, SHIMONODAN Hidemi, MORITAKE Hiroshi

Rinsho Ketsueki 64 ( 8 ) 741 - 745 2023

Authorship：Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Hematology

Immunosuppressive therapy (IST) is the first-line treatment for patients with aplastic anemia (AA) who require blood transfusion when a human leukocyte antigen-matched related donor is unavailable. However, the proportion of patients with AA who are refractory to IST remains high (30%). IST in combination with eltrombopag has been studied in adults, but its efficacy and safety in children have not been established. We present three cases of AA that were initially refractory to IST but improved with additional eltrombopag administration. These patients were successfully managed using this strategy without the use of hematopoietic cell transplantation (HCT). The first patient achieved a complete response within one month after receiving eltrombopag. When the second and third patients were given eltrombopag, they were able to safely reduce the amount of cyclosporin they were given. They avoided blood transfusions, but no measurable response was obtained. The conjunctival icterus was detected and treated using a dose reduction of eltrombopag. Eltrombopag may be effective in children with AA who are refractory to IST, allowing them to avoid blood transfusions and HCT. More cases treated with this strategy are needed to confirm its efficacy and safety for children with AA.

DOI： 10.11406/rinketsu.64.741

Novel Strategy Involving High-Dose Chemotherapy with Stem Cell Rescue Followed by Intrathecal Topotecan Maintenance Therapy without Whole-Brain Irradiation for Atypical Teratoid/Rhabdoid Tumors Reviewed

Yamada A., Kinoshita M., Kamimura S., Jinnouchi T., Azuma M., Yamashita S., Yokogami K., Takeshima H., Moritake H.

Pediatric Hematology and Oncology 40 ( 7 ) 629 - 642 2023

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Pediatric Hematology and Oncology

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare aggressive central nervous system tumor that typically affects children under three years old and has poor survival with a high risk for neurologic deficits. The primary purpose of this study was to successfully treat the disease and delay or avoid whole-brain radiotherapy for children with AT/RT. A retrospective analysis was performed for six children diagnosed with AT/RT and treated with multimodal treatment at a single institute between 2014 and 2020. Furthermore, germline SMARCB1 aberrations and MGMT methylation status of the tumors were analyzed. One patient who did not receive a modified IRS-III regimen replaced with ifosphamide, carboplatin, and etoposide (ICE) in induction chemotherapy was excluded from this analysis. Five patients who received ICE therapy were under three years old. After a surgical approach, they received intensive chemotherapy and high-dose chemotherapy with autologous peripheral blood stem cell transplantation (HDCT/autoPBSCT) followed by intrathecal topotecan maintenance therapy. Three patients underwent single HDCT/autoPBSCT, and the other two received sequential treatment. Two patients with germline SMARCB1 aberrations and metastases died of progressive AT/RT or therapy-related malignancy, while 3 with localized tumors without germline SMARCB1 aberrations remained alive. One survivor received local radiotherapy only, while the other two did not undergo radiotherapy. All three surviving patients were able to avoid whole-brain radiotherapy. Our results suggest that AT/RT patients with localized tumors without germline SMARCB1 aberrations can be rescued with multimodal therapy, including induction therapy containing ICE followed by HDCT/autoPBSCT and intrathecal topotecan maintenance therapy without radiotherapy. Further large-scale studies are necessary to confirm this hypothesis.

DOI： 10.1080/08880018.2023.2220734

High-dose cytarabine induction therapy and flow cytometric measurable residual disease monitoring for children with acute myeloid leukemia Reviewed

Tomizawa D., Matsubayashi J., Iwamoto S., Hiramatsu H., Hasegawa D., Moritake H., Hasegawa D., Terui K., Hama A., Tsujimoto S.i., Kiyokawa N., Miyachi H., Deguchi T., Hashii Y., Iijima-Yamashita Y., Taki T., Noguchi Y., Koike K., Koh K., Yuza Y., Moriya Saito A., Horibe K., Taga T., Tanaka S., Adachi S.

Leukemia 38 ( 1 ) 202 - 206 2023

Language：English Publishing type：Research paper (scientific journal) Publisher：Leukemia

DOI： 10.1038/s41375-023-02075-9

Left atrial appendage aneurysm enlarged in the neonatal period. Reviewed

Yamashita N, Harada M, Moritake H

Cardiology in the young 33 ( 8 ) 1 - 3 2022.12

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Cardiology in the Young

We describe a newborn with a congenital left atrial appendage aneurysm. The aneurysm size did not change prenatally. However, it rapidly enlarged after birth. MRI was useful for assessing the aneurysm extent and exact size, and for diagnosis. Respiratory distress and feeding difficulties appeared, and surgery was performed. These symptoms disappeared post-operatively. The patient is alive without complications or recurrence.

DOI： 10.1017/S1047951122003985

A Metastatic Neuroblastic Tumor in a 28-Month-old Boy: Unusual Spontaneous Regression from Neuroblastoma to Ganglioneuroma? Reviewed

パゾパニブが有効であった多発肺転移を有する難治性Ewing肉腫 Reviewed

2022.10

Authorship：Corresponding author Publishing type：Research paper (scientific journal)

Yamada A., Kinoshita M., Kamimura S., Nakame K., Moritake H.

Journal of Pediatric Hematology/Oncology 44 ( 2 ) E589 - E592 2022.3

Authorship：Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Pediatric Hematology/Oncology

Neuroblastoma with bone metastasis is well known to have an extremely poor prognosis. We experienced the case of a patient with adrenal ganglioneuroblastoma (GNB) with metastases of subcutaneous nodules, a lymph node, and multiple bones. A pathologic examination of tumors from different sites revealed both GNB and ganglioneuroma. A genetic comparison between these tumors identified the same molecular signatures, suggesting the possibility of spontaneous differentiation in the remaining GNB. The patient has been healthy without aggressive chemotherapy, and the patient's pathologic urinary catecholamines normalized. Even if unusual, we have to recognize probable spontaneous differentiation from neuroblastoma to GNB and then to ganglioneuroma, even in sites of bone metastasis.

DOI： 10.1097/MPH.0000000000002226