Faculty Profiles - MURAMATSU, Hideki

Papers - MURAMATSU, Hideki

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Japanese siblings with cartilage-hair hypoplasia exhibiting different severity Reviewed

Kumagai N., Funato Y., Wakamatsu M., Muramatsu H., Mizuno H.

Pediatrics International Vol. 65 ( 1 ) 2023.1

Late gastroenterological complications in children after allogeneic hematopoietic stem cell transplantation: A retrospective cohort study and a case series of children treated with Kampo medicines Reviewed

Nozomu Kawashima, Shinsuke Kataoka, Motoharu Hamada, Eri Nishikawa, Rieko Taniguchi, Atsushi Narita, Hideki Muramatsu, Nobuhiro Nishio, Yoshiyuki Takahashi

Traditional and Kampo Medicine 2023

Publishing type：Research paper (scientific journal)

Aim: This study aimed to describe children developing late gastrointestinal (GI) complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT), focusing on Kampo medicine. Methods: At the Nagoya University Hospital Department of Pediatrics, 179 consecutive patients underwent allo-HSCT over five years, of whom 167 achieved engraftment and survived at least 100 days post transplant and therefore were included in the study. Results: Thirteen patients (7.8%) developed late GI symptoms. Among these, three had upper GI symptoms, three had lower GI symptoms, while seven had upper/lower GI symptoms. Total parenteral nutrition was administered in 10 (77%) patients for a median of 81 days (range: 20–303). Four (31%) had histologically proven graft-versus-host-disease (GVHD), two (15%) had adverse drug reactions, and one (8%) had a viral infection. All three patients with lower GI symptoms responded to Kampo formulas' warming interior [TM1]. Two patients with upper GI symptoms had epigastric rigidity and responded to Aurantii Fructus Immaturus-based formulas. One patient developed severe cachexia, which was successfully reversed with Kampo medicines. There were no adverse effects due to Kampo medicines. Conclusions: Late GI complications may be a burden on children after allo-HSCT. Kampo medicines may provide a safe and promising therapy to resolve GI symptoms not otherwise specified.

DOI： 10.1002/tkm2.1392

Whole-exome analysis of 177 pediatric patients with undiagnosed diseases Reviewed

Narita K., Muramatsu H., Narumi S., Nakamura Y., Okuno Y., Suzuki K., Hamada M., Yamaguchi N., Suzuki A., Nishio Y., Shiraki A., Yamamori A., Tsumura Y., Sawamura F., Kawaguchi M., Wakamatsu M., Kataoka S., Kato K., Asada H., Kubota T., Muramatsu Y., Kidokoro H., Natsume J., Mizuno S., Nakata T., Inagaki H., Ishihara N., Yonekawa T., Okumura A., Ogi T., Kojima S., Kaname T., Hasegawa T., Saitoh S., Takahashi Y.

Scientific Reports Vol. 12 ( 1 ) 2022.12

Publisher：Scientific Reports

Recently, whole-exome sequencing (WES) has been used for genetic diagnoses of patients who remain otherwise undiagnosed. WES was performed in 177 Japanese patients with undiagnosed conditions who were referred to the Tokai regional branch of the Initiative on Rare and Undiagnosed Diseases (IRUD) (TOKAI-IRUD). This study included only patients who had not previously received genome-wide testing. Review meetings with specialists in various medical fields were held to evaluate the genetic diagnosis in each case, which was based on the guidelines of the American College of Medical Genetics and Genomics. WES identified diagnostic single-nucleotide variants in 66 patients and copy number variants (CNVs) in 11 patients. Additionally, a patient was diagnosed with Angelman syndrome with a complex clinical phenotype upon detection of a paternally derived uniparental disomy (UPD) [upd(15)pat] wherein the patient carried a homozygous DUOX2 p.E520D variant in the UPD region. Functional analysis confirmed that this DUOX2 variant was a loss-of-function missense substitution and the primary cause of congenital hypothyroidism. A significantly higher proportion of genetic diagnoses was achieved compared to previous reports (44%, 78/177 vs. 24–35%, respectively), probably due to detailed discussions and the higher rate of CNV detection.

DOI： 10.1038/s41598-022-14161-6

Clinical parameter-based prediction of DNA methylation classification generates a prediction model of prognosis in patients with juvenile myelomonocytic leukemia Reviewed

Imaizumi T., Meyer J., Wakamatsu M., Kitazawa H., Murakami N., Okuno Y., Yoshida T., Sajiki D., Hama A., Kojima S., Takahashi Y., Loh M., Stieglitz E., Muramatsu H.

Scientific Reports Vol. 12 ( 1 ) 2022.12

Publisher：Scientific Reports

Juvenile myelomonocytic leukemia (JMML) is a rare heterogeneous hematological malignancy of early childhood characterized by causative RAS pathway mutations. Classifying patients with JMML using global DNA methylation profiles is useful for risk stratification. We implemented machine learning algorithms (decision tree, support vector machine, and naïve Bayes) to produce a DNA methylation-based classification according to recent international consensus definitions using a well-characterized pooled cohort of patients with JMML (n = 128). DNA methylation was originally categorized into three subgroups: high methylation (HM), intermediate methylation (IM), and low methylation (LM), which is a trichotomized classification. We also dichotomized the subgroups as HM/IM and LM. The decision tree model showed high concordances with 450k-based methylation [82.3% (106/128) for the dichotomized and 83.6% (107/128) for the trichotomized subgroups, respectively]. With an independent cohort (n = 72), we confirmed that these models using both the dichotomized and trichotomized classifications were highly predictive of survival. Our study demonstrates that machine learning algorithms can generate clinical parameter-based models that predict the survival outcomes of patients with JMML and high accuracy. These models enabled us to rapidly and effectively identify candidates for augmented treatment following diagnosis.

DOI： 10.1038/s41598-022-18733-4

TREC/KREC Newborn Screening followed by Next-Generation Sequencing for Severe Combined Immunodeficiency in Japan Reviewed

Wakamatsu M., Kojima D., Muramatsu H., Okuno Y., Kataoka S., Nakamura F., Sakai Y., Tsuge I., Ito T., Ueda K., Saito A., Morihana E., Ito Y., Ohashi N., Tanaka M., Tanaka T., Kojima S., Nakajima Y., Ito T., Takahashi Y.

Journal of Clinical Immunology Vol. 42 ( 8 ) page： 1696 - 1707 2022.11

Publisher：Journal of Clinical Immunology

Purpose: The aim of this study is to evaluate the usefulness of T cell receptor excision circle (TREC) and/or kappa-deleting recombination excision circle (KREC) measurements integrated with diagnostic next-generation sequencing (NGS) analysis using a severe combined immunodeficiency (SCID) newborn screening (NBS) program. Methods: TREC and/or KREC values were measured in 137,484 newborns between April 2017 and December 2021 using EnLite TREC (n = 80,791) or TREC/KREC kits (n = 56,693). For newborns with positive screening results, diagnostic NGS analysis was performed with a 349-gene panel to detect genetic mutations associated with primary immunodeficiencies (PIDs). Results: A total of 145 newborns (0.11%) had abnormal TREC and/or KREC values, and a genetic diagnosis was established in 2 patients with SCID (1 in 68,742 newborns) (IL2RG-SCID and reticular dysgenesis) and 10 with non-SCID PIDs with T and/or B cell deficiencies (1 in 13,748 newborns) using NGS analysis. Furthermore, TREC values of 2849 newborns were measured and confirmed the significant correlation between the results of both TREC and TREC/KREC kits (P < 0.001) and naïve T cell counts. Conclusions: We performed the first large-scale TREC and TREC/KREC NBS programs in Japan. Our NBS programs followed by the diagnostic NGS analysis for newborns with abnormal TREC and/or KREC values are useful for the early identification and rapid molecular evaluation of not only SCID but also different non-SCID PIDs.

DOI： 10.1007/s10875-022-01335-0

Risk factors for unplanned removal of central venous catheters in hospitalized children with hematological and oncological disorders Reviewed

Miyagishima M., Hamada M., Hirayama Y., Muramatsu H., Tainaka T., Shirota C., Hinoki A., Imaizumi T., Nakatochi M., Kamei M., Nishikawa E., Kawashima N., Narita A., Nishio N., Kojima S., Takahashi Y.

International Journal of Hematology Vol. 116 ( 2 ) page： 288 - 294 2022.8

Publisher：International Journal of Hematology

Central venous catheters (CVCs) are essential devices in the treatment of pediatric patients with hematological and oncological disorders; however, the most suitable type of CVC for these patients remains unclear. We retrospectively compared risk factors for unplanned removal of two commonly used CVCs, peripherally inserted central catheters (PICCs) and tunneled CVCs, to propose which is the better device. We followed 89 patients fitted with a tunneled CVC (total 21,395 catheter-days) and 84 fitted with a PICC (total 9177 catheter-days) between January 1, 2013 and December 31, 2015, until catheter removal. Patients with a PICC had a significantly higher 3-month cumulative incidence of catheter occlusion (5.2% vs. 0%, p = 4.08 × 10−3) and total unplanned removals (29.0% vs. 6.9%, p = 0.0316) than those with tunneled CVCs. However, the cumulative incidence of central line-associated bloodstream infection did not differ significantly by CVC type. Multivariable analysis identified younger age (< 2 years) [sub-distribution hazard ratio (SHR) 2.29; 95% confidence interval (CI) 1.27–4.14] and PICC (SHR 2.73; 95% CI 1.48–5.02) as independent risk factors for unplanned removal. Thus, our results suggest that tunneled CVCs are preferable in pediatric patients with hematological and oncological disorders requiring long-term, intensive treatment.

DOI： 10.1007/s12185-022-03346-4

A patient with very early onset FH-deficient renal cell carcinoma diagnosed at age seven Reviewed

Taniguchi R., Muramatsu H., Okuno Y., Yoshida T., Wakamatsu M., Hamada M., Shirota C., Sumida W., Hinoki A., Tainaka T., Gotoh Y., Tsuzuki T., Tanaka Y., Kojima S., Uchida H., Takahashi Y.

Familial Cancer Vol. 21 ( 3 ) page： 337 - 341 2022.7

Language：Japanese Publisher：Familial Cancer

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by heterozygous germline variants in the fumarate hydratase (FH) gene and is associated with increased susceptibility to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). HLRCC-associated RCC usually occurs in the middle age, with the median age being 40–44 years. This report describes a seven-year-old (84-month-old) male who developed a large right kidney tumor with multiple cystic lesions that contained enhanced solid components. There was no evidence of distant metastasis. The male patient underwent right nephrectomy and has been recovering well without metastasis or recurrence. Pathological examination revealed that tumor cells with relatively prominent nucleoli and surrounded by halos, were located in a limited area. Immunohistochemical staining was negative for FH. Whole-exome sequencing identified his germline variant in the FH gene and its loss of heterozygosity in the tumor. At nine years (114 months) of age, the male patient showed no recurrence of the tumor. This was the youngest-onset case of HLRCC-associated RCC to date. This report may affect the starting age for future RCC-surveillance programs for patients with HLRCC.

DOI： 10.1007/s10689-021-00268-8

Difficulties in diagnosing Malassezia furfur bloodstream infection and possibility of spontaneous resolution in a patient undergoing chemotherapy for neuroblastoma: A case report Reviewed

Tetsuka N., Muramatsu H., Iguchi M., Oka K., Morioka H., Takahashi Y., Yagi T.

Journal of Infection and Chemotherapy Vol. 28 ( 7 ) page： 987 - 990 2022.7

Publisher：Journal of Infection and Chemotherapy

Malassezia furfur is a lipophilic, yeast-like fungus that forms part of the normal human skin microflora and is associated with a wide range of infections, such as pityriasis versicolor, folliculitis, and systemic infections in immunocompromised patients. Although matrix-assisted laser desorption/ionization time-of-flight mass spectrometry has enabled rapid identification of Malassezia species, it is still a challenge to diagnose systemic infections because Malassezia fungemia can often be missed by automated blood culture systems. We report a case in which M. furfur in blood was detected by the presence of yeast-like fungi in blood smears. Yeast-like organisms were observed in the blood smears of a 3-year-old boy, taken over 2 weeks without any symptoms. He had undergone several courses of chemotherapy for neuroblastoma via an indwelling central venous catheter (CVC) that was placed in his right anterior chest for 11 months. Although the blood cultures obtained from an automated blood culture system were negative, M. furfur growth was detected in the subcultured blood taken from the CVC. The CVC was removed, and the scheduled chemotherapy was postponed. No systemic M. furfur bloodstream infection occurred; the infection resolved spontaneously without any specific treatment; only prophylactic fluconazole was administered. M. furfur fungemia may not be diagnosable by an automated blood culture system. Further, M. furfur may not cause infections in humans even when administered intravenously. This report may lead to the discovery of factors related to human infectivity of this disease in the future.

DOI： 10.1016/j.jiac.2022.02.026

Prognostic Factors for Outcomes of Allogeneic HSCT for Children and Adolescents/Young Adults With CML in the TKI Era Reviewed

Shimada H., Tanizawa A., Kondo T., Nagamura-Inoue T., Yasui M., Tojo A., Muramatsu H., Eto T., Doki N., Tanaka M., Sato M., Noguchi M., Uchida N., Takahashi Y., Sakata N., Ichinohe T., Hashii Y., Kato K., Atsuta Y., Ohashi K.

Transplantation and Cellular Therapy Vol. 28 ( 7 ) page： 376 - 389 2022.7

Publisher：Transplantation and Cellular Therapy

The breakthrough effects of tyrosine kinase inhibitors (TKIs) have lessened indications for allogeneic hematopoietic stem cell transplantation (HSCT) in chronic myeloid leukemia (CML). However, HSCT is still attractive for children and adolescents/young adults (AYAs) requiring lifelong TKI therapy. Nevertheless, little has been reported on the outcomes of large clinical studies of HSCT targeting these age groups. This study aimed to identify prognostic factors for the outcomes of HSCT, including reduced-intensity conditioning (RIC)-HSCT, for children and AYAs with CML in the TKI era. We performed a registry analysis for 200 patients with CML aged <30 years who underwent pretransplant TKI therapy from the observational nationwide database established by the Japanese Society for Transplantation and Cellular Therapy. The patients received bone marrow (BM), peripheral blood (PB), or cord blood (CB) from either related or unrelated donors. The indication for HSCT for individual patients was determined by the institution according to European LeukemiaNet recommendations and other guidelines. The 5-year overall survival (OS) rates for patients with chronic phase (CP) (n = 124), accelerated phase (AP) (n = 23), and blastic phase (BP) (n = 53) at diagnosis were 82.8%, 71.1%, and 73.3%, respectively, with no significant difference (P =.3293). The strongest predictor of engraftment was transplant source, with CB (hazard ratio [HR], 0.33) and PB (HR, 2.00) (compared with BM) being independent unfavorable and favorable predictors, respectively. Transplant source was also an independent predictor of chronic GVHD, with PB (HR, 1.81) and CB (HR, 0.39) (compared with BM) being unfavorable and favorable predictors, respectively. The strongest predictor of OS rate for patients with CP at diagnosis was disease phase at HSCT, with second or greater CP, AP, or BP (HR, 2.81) (compared with first CP [CP1]) being an unfavorable predictor. In addition, patients with CP at diagnosis who had major and complete molecular responses at HSCT had excellent outcomes, with 5-year OS rates of 100% and 94.4%, respectively. The 5-year OS rate was compared between RIC (n = 31) and myeloablative conditioning (MAC) (n = 58) in patients with CP1, both of which were 89.3%, with no significant difference (P = .9440). On univariate analysis for the RIC cohort with CP at diagnosis, the age at HSCT (HR, 1.27) (increase per year) and the time from diagnosis to HSCT (HR, 1.83) (increase per year) were significant predictors for OS. Our study demonstrates that RIC may be an appropriate alternative to MAC for children and AYAs with CP1. As for the transplant source, we recommend first selecting BM because of a higher engraftment rate compared to CB and a lower incidence of chronic GVHD compared to PB. Although HSCT in the status of a major molecular response is desirable, it is not advisable to continue TKI pointlessly long because age at HSCT and timing of HSCT are prognostic factors that determine survival. The decision to perform RIC-HSCT instead of continuing TKI should be carefully made, considering the possibility of transplant-related complications.

DOI： 10.1016/j.jtct.2022.04.011

Combination chemotherapy consisting of irinotecan, etoposide, and carboplatin for refractory or relapsed neuroblastoma Reviewed

Imaya M., Muramatsu H., Narita A., Yamamori A., Wakamatsu M., Yoshida T., Miwata S., Narita K., Ichikawa D., Hamada M., Nishikawa E., Kawashima N., Nishio N., Kojima S., Takahashi Y.

Cancer Medicine Vol. 11 ( 9 ) page： 1956 - 1964 2022.5

Language：Japanese Publisher：Cancer Medicine

Background: Patients with primary refractory and relapsed neuroblastoma have a poor prognosis since safe and effective chemotherapies for these patients are currently limited. The development of new chemotherapy regimens for these patients is imperative to improve survival outcomes. Methods: We retrospectively analyzed 40 patients with refractory (n = 36) or relapsed (n = 4) neuroblastoma who received irinotecan, etoposide, and carboplatin (IREC) as a second-line treatment. We evaluated their therapeutic response and the toxicity of IREC. We also assessed the impact of UGT1A1 gene polymorphisms, which are involved in irinotecan metabolism, on outcomes and toxicity. Results: A total of 112 cycles of IREC were administered to 40 patients with a median of 2 cycles per patient (range, 1–9). Six (15%) patients (UGT1A1 wild-type [n = 2] and heterozygous [n = 4]) showed objective responses, including partial response (n = 1), tumor shrinkage (n = 4), and improved findings on their MIBG scan (n = 1). Grade 4 neutropenia, grade 4 leukopenia, and grades 3–4 gastrointestinal toxicity were observed in 110 (98%), 88 (79%), and 3 (3%) cycles, respectively. There was no IREC-related mortality. Patients with UGT1A1 polymorphisms showed a higher frequency of grade 4 leukopenia, but these patients did not have increased treatment-related mortality or non-hematologic toxicity. Conclusions: IREC showed an objective response rate of 15% including 1 case with partial response. IREC was well tolerated regardless of UGT1A1 genotype. This study suggests that IREC is a promising second-line chemotherapy for refractory or relapsed neuroblastoma.

DOI： 10.1002/cam4.4529

Minor PNH clones do not distinguish inherited bone marrow failure syndromes from immune-mediated aplastic anemia Reviewed

Narita A., Miwata S., Imaya M., Tsumura Y., Yamamori A., Wakamatsu M., Hamada M., Taniguchi R., Okuno Y., Muramatsu H., Takahashi Y.

Blood Advances Vol. 6 ( 8 ) page： 2517 - 2519 2022.4

Genetic Study of Fanconi Anemia in Infancy Revealed FANCI Mutations and Defective ALDH2 Variant: A Case Report Reviewed

Urata T., Imamura T., Osone S., Muramatsu H., Takahashi Y., Hosoi H.

Journal of Pediatric Hematology/Oncology Vol. 44 ( 2 ) page： E438 - E441 2022.3

Language：Japanese Publisher：Journal of Pediatric Hematology/Oncology

Fanconi anemia (FA) is a rare genetic disorder that manifests as congenital abnormalities and bone marrow failure (BMF). Most patients with FA present with BMF within the first decade of life; however, neonate and early infancy BMF is rare. Recent studies have shown that a defective aldehyde dehydrogenase 2 (ALDH2) variant accelerates BMF development in patients with FA. Herein, we described an infant case of FA with compound heterozygous FANCI mutation and the defective ALDH2 variant. Our case developed BMF early probably because of ALDH2 deficiency, while the mild malformation might be because of the locus of FANCI mutation.

DOI： 10.1097/MPH.0000000000002254

Nosocomial infection with rotavirus vaccine strain in paediatric patients with immunodeficiency Reviewed

Miura H., Taniguchi K., Narita K., Kawamura Y., Kozawa K., Muramatsu H., Takahashi Y., Ihira M., Yoshikawa T.

Journal of Hospital Infection Vol. 121 page： 9 - 13 2022.3

Publisher：Journal of Hospital Infection

In infants with immunodeficiency, rotavirus (RV) vaccines can be continuously excreted in stool. We analysed nosocomial infection with RV vaccine strain in immunodeficient paediatric patients. RV1 RNAs were detected in stool and serum samples from case A, who was vaccinated with RV1, and case B, who was not. PAGE analysis of serial stool samples of case A revealed several rearrangements of the RV genome. In case B, the only band pattern detected was the same as a rearrangement detected in case A at the same time. In summary, RV vaccination of infants with immunodeficiency poses a risk of nosocomial infections.

DOI： 10.1016/j.jhin.2021.12.009

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

Tanita K., Kawamura Y., Miura H., Mitsuiki N., Tomoda T., Inoue K., Iguchi A., Yamada M., Yoshida T., Muramatsu H., Tada N., Matsui T., Kato M., Eguchi K., Ishimura M., Ohga S., Imai K., Morio T., Yoshikawa T., Kanegane H.

Frontiers in Immunology Vol. 13 2022.2

Publisher：Frontiers in Immunology

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.

DOI： 10.3389/fimmu.2022.786375

A retrospective analysis of azacitidine treatment for juvenile myelomonocytic leukemia Reviewed

Honda Y., Muramatsu H., Nanjo Y., Hirabayashi S., Meguro T., Yoshida N., Kakuda H., Ozono S., Wakamatsu M., Moritake H., Yasui M., Sano H., Manabe A., Sakashita K.

International Journal of Hematology Vol. 115 ( 2 ) page： 263 - 268 2022.2

Language：Japanese Publisher：International Journal of Hematology

Juvenile myelomonocytic leukemia (JMML) is a pediatric hematological malignancy with a poor prognosis. Although several case series have been published describing hematological and molecular responses to azacitidine (AZA) treatment in patients with JMML, the efficacy and safety profile of AZA is not well investigated, especially in Asian children and children undergoing hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed 5 patients who received a total of 12 cycles (median 2 cycles) of AZA treatment in Japan. All five patients were boys and their ages at the time of treatment were 21, 23, 24, 26, and 46 months, respectively. All five patients tolerated AZA treatment, including four patients who received AZA after HSCT. Therapeutic toxicity with AZA was mostly limited to hematological toxicity. The only serious non-hematological adverse event was hyperbilirubinemia (grades III–IV) observed in a patient who received AZA after a second HSCT. Two out of five patients treated with AZA achieved a partial response (PR), while three patients treated for post-transplant relapse did not have an objective response. Future prospective studies should be conducted to develop combination therapies with AZA and other molecular targeted drugs for high-risk patients.

DOI： 10.1007/s12185-021-03248-x

Prospective validation of the provisional entity of refractory cytopenia of childhood, proposed by the World Health Organization Reviewed

Hama A., Hasegawa D., Manabe A., Nozawa K., Narita A., Muramatsu H., Kosaka Y., Kobayashi M., Koh K., Takahashi Y., Watanabe K., Ohara A., Ito M., Kojima S.

British Journal of Haematology Vol. 196 ( 4 ) page： 1031 - 1039 2022.2

Language：Japanese Publisher：British Journal of Haematology

In 2008, the World Health Organization proposed a new entity of childhood myelodysplastic syndrome (MDS), which was referred to as refractory cytopenia of childhood (RCC). However, whether this morphological classification reflects clinical outcomes remains unclear. We performed a prospective evaluation of bone marrow morphology in 252 children with acquired bone marrow failure between 2009 and 2013. Of 252 patients, 63 were diagnosed with aplastic anaemia (AA), 131 with RCC without multilineage dysplasia (RCC-w/o-MLD) and 58 with RCC with MLD (RCC-MLD). One patient with AA, three with RCC-w/o-MLD and nine with RCC-MLD presented with chromosomal abnormalities at diagnosis (P = 0·001). The response rates to immunosuppressive therapy (IST) at 6 months and the cumulative incidence of clonal evolution at 5 years did not significantly differ among the three groups. A multivariate analysis revealed that the morphological classification of RCC-MLD was a significant risk factor for secondary graft failure after haematopoietic cell transplantation (HCT) (P = 0·003). In view of these findings, RCC could be divided into two categories, RCC-w/o-MLD and RCC-MLD, because children with this condition exhibited a distinct morphology, frequent chromosomal abnormalities at diagnosis and a high frequency of secondary graft failure after HCT.

DOI： 10.1111/bjh.17921

Azacitidine as a bridge to transplantation in juvenile myelomonocytic leukemia Reviewed

Takebayashi A., Yamamoto M., Igarashi K., Muramatsu H., Kawasaki Y.

Pediatrics International Vol. 64 ( 1 ) 2022.1

Clinical Impact of Melphalan Pharmacokinetics on Transplantation Outcomes in Children Undergoing Hematopoietic Stem Cell Transplantation Reviewed

Maemura R., Wakamatsu M., Matsumoto K., Sakaguchi H., Yoshida N., Hama A., Yoshida T., Miwata S., Kitazawa H., Narita K., Kataoka S., Ichikawa D., Hamada M., Taniguchi R., Suzuki K., Kawashima N., Nishikawa E., Narita A., Okuno Y., Nishio N., Kato K., Kojima S., Morita K., Muramatsu H., Takahashi Y.

Cell Transplantation Vol. 31 2022.1

Publisher：Cell Transplantation

Melphalan is widely used for hematopoietic stem cell transplantation (HSCT) conditioning. However, the relationship between its pharmacokinetic (PK) and transplantation outcomes in children has not been thoroughly investigated. We prospectively analyzed the relationship between melphalan area under the curve (AUC) and transplantation outcome and examined the development of a predictive model for melphalan clearance in children. This study included 43 children aged 0 to 19 years who underwent HSCT following a melphalan-based conditioning regimen from 2017 to 2021. In univariable analysis, high-melphalan AUC resulted in a significantly lower cumulative incidence of acute graft-versus-host disease and a higher cumulative incidence of thrombotic microangiopathy, although no significant difference was observed in survival. Regression analysis of a randomly selected derivation cohort (n = 21) revealed the following covariate PK model: predicted melphalan clearance (mL/min) = 6.47 × 24-h urinary creatinine excretion rate (CER, g/day) × 24-h creatinine clearance rate (CCR, mL/min) + 92.8. In the validation cohort (n = 22), the measured melphalan clearance values were significantly correlated with those calculated based on the prediction equation (R2 = 0.663). These results indicate that melphalan exposure may be optimized by adjusting the melphalan dose according to CER and CCR.

DOI： 10.1177/09636897221143364

Dorsal myelopathy after nelarabine and intrathecal methotrexate therapy Reviewed

Sawamura F., Natsume J., Nakata T., Muramatsu H., Takahashi Y.

Pediatrics International Vol. 64 ( 1 ) 2022.1

Microsatellite instability-high is rare events in refractory pediatric solid tumors Reviewed

Yoshida T., Muramatsu H., Wakamatsu M., Taniguchi R., Ichikawa D., Nakaguro M., Natsume A., Takahashi Y.

Pediatric Hematology and Oncology Vol. 39 ( 5 ) page： 468 - 474 2022

Language：Japanese Publisher：Pediatric Hematology and Oncology

Microsatellite instability (MSI)-high status is associated with good responsiveness to immune checkpoint inhibitors. Although MSI-high status has been actively investigated in pediatric brain tumors, studies of other pediatric solid tumors are lacking. Among 334 consecutive pediatric patients with solid tumors, we retrospectively analyzed formalin-fixed paraffin-embedded tumor tissues of 36 of 74 patients (49%) who died of disease. We assessed the MSI status in these tissues using five multiplexed markers. The results revealed that none of the patients had an MSI-high status. These results indicate that MSI-high status is a rare event in pediatric patients with refractory/relapsed solid tumors. Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1998266.

DOI： 10.1080/08880018.2021.1998266

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