Faculty Profiles - MURAMATSU, Hideki

Papers - MURAMATSU, Hideki

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Neonatal intestinal obstruction in Hoyeraal–Hreidarsson syndrome with novel RTEL1 variants Reviewed

Tobai H., Endo M., Ishimura M., Moriya K., Yano J., Kanamori K., Sato N., Amanuma F., Maruyama H., Muramatsu H., Shibahara J., Narita M., Fumoto S., Peltier D., Ohga S.

Pediatric Blood and Cancer Vol. 70 ( 6 ) 2023.6

Efficacy and safety of bevacizumab, irinotecan, and temozolomide combination for relapsed or refractory pediatric central nervous system embryonal tumor: a single-institution study Reviewed

Shiba Y., Motomura K., Taniguchi R., Kurimoto M., Mizutani K., Ohka F., Aoki K., Ito E., Nishikawa T., Yamaguchi J., Kibe Y., Shimizu H., Maeda S., Nakashima T., Suzuki H., Muramatsu H., Takahashi Y., Saito R.

Journal of Neurosurgery: Pediatrics Vol. 31 ( 6 ) page： 624 - 632 2023.6

Publisher：Journal of Neurosurgery: Pediatrics

OBJECTIVE This study aimed to evaluate the efficacy and safety of combination therapy with bevacizumab (Bev), irinotecan (CPT-11), and temozolomide (TMZ) in children with central nervous system (CNS) embryonal tumor relapse. METHODS The authors retrospectively examined 13 consecutive pediatric patients with relapsed or refractory CNS embryonal tumors who received combination therapy comprising Bev, CPT-11, and TMZ. Specifically, 9 patients had medulloblastoma, 3 had atypical teratoid/rhabdoid tumor (AT/RT), and 1 had CNS embryonal tumor with rhabdoid features. Of the 9 medulloblastoma cases, 2 were categorized in the Sonic hedgehog subgroup and 6 in molecular subgroup 3 for medulloblastoma. RESULTS The complete and partial objective response rates were 66.6% in patients with medulloblastoma and 75.0% in patients with AT/RT or CNS embryonal tumors with rhabdoid features. Furthermore, the 12- and 24-month progression-free survival rates were 69.2% and 51.9% for all patients with recurrent or refractory CNS embryonal tumors, respectively. In contrast, the 12- and 24-month overall survival rates were 67.1% and 58.7%, respectively, for all patients with relapsed or refractory CNS embryonal tumors. The authors observed grade 3 neutropenia, thrombocytopenia, proteinuria, hypertension, diarrhea, and constipation in 23.1%, 7.7%, 23.1%, 7.7%, 7.7%, and 7.7% of patients, respectively. Furthermore, grade 4 neutropenia was observed in 7.1% of patients. Nonhematological adverse effects, such as nausea and constipation, were mild and controlled with standard antiemetics. CONCLUSIONS This study demonstrated favorable survival outcomes in patients with relapsed or refractory pediatric CNS embryonal tumors and thus helped to investigate the efficacy of combination therapy comprising Bev, CPT-11, and TMZ. Moreover, combination chemotherapy had high objective response rates, and all adverse events were tolerable. To date, data supporting the efficacy and safety of this regimen in the relapsed or refractory AT/RT population are limited. These findings suggest the potential efficacy and safety of combination chemotherapy in patients with relapsed or refractory pediatric CNS embryonal tumors.

DOI： 10.3171/2023.1.PEDS22345

Scopus

Droplet Digital PCR Development for Adenovirus Load Monitoring in Children after Hematopoietic Stem Cell Transplantation Reviewed Open Access

Haruta K., Takeuchi S., Yamaguchi M., Horiba K., Suzuki T., Torii Y., Narita A., Muramatsu H., Takahashi Y., Ito Y., Kawada J.i.

Journal of Molecular Diagnostics Vol. 25 ( 6 ) page： 403 - 409 2023.6

Publisher：Journal of Molecular Diagnostics

Human adenovirus (AdV) reactivation after hematopoietic stem cell transplantation (HSCT) is associated with life-threatening clinical manifestations. Although real-tme quantitative PCR (qPCR) has been widely used to measure AdV loads, it has not been standardized for AdV. Droplet digital PCR (ddPCR) is a novel pathogen detection technology that enables the absolute quantification of viral loads. ddPCR would enable a more accurate AdV DNA detection compared with qPCR. In this study, ddPCR was developed for AdV DNA and its performance characteristics compared with those of qPCR. AdV DNAemia incidence during the first 12 weeks after allogenic HSCT was then retrospectively examined by qPCR and ddPCR in 97 HSCT procedures using the preserved 545 DNA samples. ddPCR exhibited better reproducibility and sensitivity, as well as equivalent quantifiability, compared with qPCR. AdV DNA among HSCT patients was detected in 11 (2.0%) and 49 (9.0%) of 545 samples by qPCR and ddPCR, respectively. AdV DNA levels >1000 copies/mL were observed in five cases by qPCR and/or ddPCR. However, two patients developed fulminant hepatitis and died; other patients remained asymptomatic with subsequently undetectable AdV DNA. In conclusion, ddPCR was more sensitive and reproducible in detecting AdV DNA among pediatric HSCT recipients than qPCR. ddPCR offers the potential to provide a more accurate DNAemia detection, determine cutoff values for treatment initiation, and enable antiviral efficacy assessment.

DOI： 10.1016/j.jmoldx.2023.03.004

Open Access

Scopus

Juvenile Hemochromatosis with Non-Transfused Hemolytic Anemia Caused by a de Novo PIEZO1 Gene Mutation Reviewed

Imashuku S., Suemori S.I., Wakamatsu M., Okuno Y., Muramatsu H., Makino S., Miyoshi T., Chonabayashi K., Kanno H.

Journal of Pediatric Hematology/Oncology Vol. 45 ( 4 ) page： E510 - E513 2023.5

Publisher：Journal of Pediatric Hematology/Oncology

Differential diagnosis of juvenile hemochromatosis along with hemolytic anemia is often difficult. We report a 23-year-old woman with macrocytic hemolytic anemia with iron overload. The patient showed high serum ferritin and transferrin saturation and low serum transferrin and ceruloplasmin. We also noticed stomatocytes in her blood smear, which was confirmed by scanning electron microscopy. Target gene sequencing identified a mutation in PIEZO1 (heterozygous c.6008C>A: p.A2003D). This mutation was reported previously in a family with dehydrated hereditary stomatocytosis (DHS1, [OMIM 194380]), but in the current case, it was identified to be a de novo mutation. We underscore DHS1 in the differential diagnosis of iron overload associated with non-Transfused hemolytic anemia in children and young adults.

DOI： 10.1097/MPH.0000000000002639

Scopus

Haematopoietic cell transplantation for children with acute megakaryoblastic leukaemia without Down syndrome Reviewed

Hama A., Taga T., Tomizawa D., Muramatsu H., Hasegawa D., Adachi S., Yoshida N., Noguchi M., Sato M., Okada K., Koh K., Mitsui T., Takahashi Y., Miyamura T., Hashii Y., Kato K., Atsuta Y., Okamoto Y.

British Journal of Haematology Vol. 201 ( 4 ) page： 747 - 756 2023.5

Publisher：British Journal of Haematology

Patients with acute megakaryoblastic leukaemia of Down syndrome (DS-AMKL) have an excellent survival rate; however, patients with non-DS-AMKL experience poor outcomes. Therefore, this study retrospectively analysed 203 children with non-DS-AMKL who underwent their first haematopoietic cell transplantation (HCT) from 1986 to 2015 using a nationwide Japanese HCT registry data to assess HCT outcomes for non-DS-AMKL. The 5-year overall survival (OS) and event-free survival (EFS) rates were 43% and 38% respectively. The 5-year OS rate was significantly higher for patients who underwent HCT in the first complete remission (CR1, 72%) than for those in the second CR (CR2, 23%) and non-CR (16%) (p < 0.001), and for those from a human leukocyte antigen (HLA)-matched (52%) than for those from an HLA-mismatched donor (27%) (p < 0.001). Multivariate analysis for OS revealed that HCT in CR2 and non-CR was a significant risk factor (hazard ratio, 5.86; 95% confidence interval, 3.56–9.53; p < 0.001). The 3-year EFS in patients who received HCT in CR1 using reduced-intensity conditioning (RIC, 35%) was significantly lower than in those using myeloablative conditioning (busulfan-based, 71%; total body irradiation-based, 58%) (p < 0.001). Risk stratification in patients with non-DS-AMKL should be established to determine HCT indication in CR1.

DOI： 10.1111/bjh.18691

Scopus

Germline and somatic RUNX1 variants in a pediatric bone marrow failure cohort Reviewed

Yamamori A., Hamada M., Muramatsu H., Wakamatsu M., Hama A., Narita A., Tsumura Y., Yoshida T., Doi T., Terada K., Higa T., Yamamoto N., Miura H., Shiota M., Watanabe K., Yoshida N., Maemura R., Imaya M., Miwata S., Narita K., Kataoka S., Taniguchi R., Suzuki K., Kawashima N., Nishio N., Iwafuchi H., Ito M., Kojima S., Okuno Y., Takahashi Y.

American Journal of Hematology Vol. 98 ( 5 ) page： E102 - E105 2023.5

愛知県における副腎白質ジストロフィーの拡大新生児マススクリーニングの現状と課題 Reviewed

中田智彦, 伊藤祐史, 村松秀城, 山本啓之, 城所博之, 久保田一生, 山田晋一郎, 勝野雅央, 伊藤哲哉, 下澤伸行, 夏目淳

脳と発達 Vol. 55 ( Suppl. ) page： S314 - S314 2023.5

A nationwide survey of late effects in survivors of juvenile myelomonocytic leukemia in Japan Reviewed

Ozono S., Sakashita K., Yoshida N., Kakuda H., Watanabe K., Maeda M., Ishida Y., Manabe A., Taga T., Muramatsu H.

Pediatric Blood and Cancer Vol. 70 ( 2 ) 2023.2

Publisher：Pediatric Blood and Cancer

We conducted a cross-sectional study using a questionnaire to explore the late effects in survivors of allogenic hematopoietic stem cell transplantation (HSCT) for juvenile myelomonocytic leukemia (JMML). The attending pediatric hematologists/oncologists completed the questionnaires. Of the 30 survivors, approximately 83% showed more than one late effect. The identified late effects included endocrine, dental, skin, ophthalmologic, musculoskeletal, pulmonary, neurocognitive, and cardiovascular dysfunction. The prevalence of short stature, pulmonary, cardiovascular, and nephrological complications was significantly elevated among survivors who were 12 years or more lapsed after HSCT. Therefore, a multidisciplinary follow-up system for survivors of JMML is crucial.

DOI： 10.1002/pbc.30126

Scopus

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

Scopus

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

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

Open Access

Scopus

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

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

Open Access

Scopus

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

Scopus

愛知県におけるTREC/KRECを用いた新生児マススクリーニング検査 Reviewed

若松学, 小島大英, 村松秀城, 奥野友介, 片岡伸介, 中島葉子, 酒井好美, 伊藤哲哉, 高橋義行

日本免疫不全・自己炎症学会雑誌 Vol. 1 ( 2 ) page： 84 - 84 2022.9

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

Scopus

愛知県における重症複合免疫不全症に対するTREC新生児マススクリーニング検査 Reviewed

若松学, 村松秀城, 小島大英, 奥野友介, 片岡伸介, 成田敦, 中島葉子, 柘植郁哉, 酒井好美, 伊藤哲哉, 高橋義行

臨床血液 Vol. 63 ( 8 ) page： 957 - 957 2022.8

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

Web of Science

Scopus

PubMed

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

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

Open Access

Scopus

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

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

Open Access

Scopus

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

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

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Papers - MURAMATSU, Hideki