Faculty Profiles - TAKAHASHI, Yoshiyuki

Microsatellite instability-high is rare events in refractory pediatric solid tumors. International journal Open Access

Taro Yoshida, Hideki Muramatsu, Manabu Wakamatsu, Rieko Taniguchi, Daisuke Ichikawa, Masato Nakaguro, Atsushi Natsume, Yoshiyuki Takahashi

Pediatric hematology and oncology Vol. 39 ( 5 ) page： 468 - 474 2022.8

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

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

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

Hisashi Ishida, Motohiro Kato, Yuta Kawahara, Sae Ishimaru, Yuho Najima, Shinichi Kako, Maho Sato, Mitsuteru Hiwatari, Maiko Noguchi, Keisuke Kato, Katsuyoshi Koh, Keiko Okada, Fuminori Iwasaki, Ryoji Kobayashi, Shunji Igarashi, Shoji Saito, Yoshiyuki Takahashi, Atsushi Sato, Junji Tanaka, Yoshiko Hashii, Yoshiko Atsuta, Hirotoshi Sakaguchi, Toshihiko Imamura

Hematological oncology Vol. 40 ( 3 ) page： 457 - 468 2022.8

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

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

DOI： 10.1002/hon.2980

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

Moe Miyagishima, Motoharu Hamada, Yuji Hirayama, Hideki Muramatsu, Takahisa Tainaka, Chiyoe Shirota, Akinari Hinoki, Takahiro Imaizumi, Masahiro Nakatochi, Michi Kamei, Eri Nishikawa, Nozomu Kawashima, Atsushi Narita, Nobuhiro Nishio, Seiji Kojima, Yoshiyuki Takahashi

International journal of hematology Vol. 116 ( 2 ) page： 288 - 294 2022.8

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

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

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

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. International journal

Rieko Taniguchi, Hideki Muramatsu, Yusuke Okuno, Taro Yoshida, Manabu Wakamatsu, Motoharu Hamada, Chiyoe Shirota, Wataru Sumida, Akinari Hinoki, Takahisa Tainaka, Yoshimitsu Gotoh, Toyonori Tsuzuki, Yukichi Tanaka, Seiji Kojima, Hiroo Uchida, Yoshiyuki Takahashi

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

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

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. International journal Open Access

Nobuyuki Tetsuka, Hideki Muramatsu, Mitsutaka Iguchi, Keisuke Oka, Hiroshi Morioka, Yoshiyuki Takahashi, Tetsuya Yagi

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy Vol. 28 ( 7 ) page： 987 - 990 2022.7

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

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. International journal Open Access

Hiroyuki Shimada, Akihiko Tanizawa, Takeshi Kondo, Tokiko Nagamura-Inoue, Masahiro Yasui, Arinobu Tojo, Hideki Muramatsu, Tetsuya Eto, Noriko Doki, Masatsugu Tanaka, Maho Sato, Maiko Noguchi, Naoyuki Uchida, Yoshiyuki Takahashi, Naoki Sakata, Tatsuo Ichinohe, Yoshiko Hashii, Koji Kato, Yoshiko Atsuta, Kazuteru Ohashi

Transplantation and cellular therapy Vol. 28 ( 7 ) page： 376 - 389 2022.7

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

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

Registry data analysis of hematopoietic stem cell transplantation on systemic chronic active Epstein-Barr virus infection patients in Japan

[Recommendations (Proposal) for promoting research for overcoming neurological diseases 2020].

Mochizuki H, Aoki M, Ikenaka K, Inoue H, Iwatsubo T, Ugawa Y, Okazawa H, Ono K, Onodera O, Kitagawa K, Saito Y, Shimohata T, Takahashi R, Toda T, Nakahara J, Matsumoto R, Mizusawa H, Mitsui J, Murayama S, Katsuno M, Future Vision Committee of Japanese Society of Neurology, Aoki Y, Ishiura H, Izumi Y, Koike H, Shimada H, Takahashi Y, Tokuda T, Nakajima H, Hatano T, Misawa S, Watanabe H

Rinsho shinkeigaku = Clinical neurology Vol. 62 ( 6 ) page： 443 - 457 2022.6

[Recommendations (Proposal) for promoting research for overcoming neurological diseases 2020].

Rinsho shinkeigaku = Clinical neurology Vol. 62 ( 6 ) page： 429 - 442 2022.6

Yamamoto, M; Sato, M; Onishi, Y; Sasahara, Y; Sano, H; Masuko, M; Nakamae, H; Matsuoka, KI; Ara, T; Washio, K; Onizuka, M; Watanabe, K; Takahashi, Y; Hirakawa, T; Nishio, M; Sakashita, C; Kobayashi, T; Sawada, A; Ichinohe, T; Fukuda, T; Hashii, Y; Atsuta, Y; Arai, A

AMERICAN JOURNAL OF HEMATOLOGY Vol. 97 ( 6 ) page： 780 - 790 2022.6

METABOLOMICS OF URINARY METABOLITES IN CHILDHOOD RHABDOMYOSARCOMA TO DISCOVER NOVEL BIOMARKERS

Nakano, S; Uchida, H; Amano, H; Narita, A; Abe, M; Ishigaki, T; Sakairi, M; Shirota, C; Sumida, W; Makita, S; Takimoto, A; Okamoto, M; Yasui, A; Takada, S; Nakagawa, Y; Terui, Y; Sunagawa, M; Takahashi, Y; Osawa, T; Hinoki, A

PEDIATRIC BLOOD & CANCER Vol. 69 2022.6

TREC測定による新生児マススクリーニングを通じて診断されたX連鎖重症複合免疫不全症の1例

山下大紀, 村松秀城, 佐治木大知, 津村悠介, 前村遼, 今屋雅之, 山森彩子, 若松学, 片岡伸介, 濱田太立, 谷口理恵子, 川島希, 西川英里, 成田敦, 奥野友介, 西尾信博, 小島大英, 中島葉子, 柘植郁哉, 中村富美子, 酒井好美, 伊藤哲哉, 高橋義行

日本小児科学会雑誌 Vol. 126 ( 6 ) page： 970 - 970 2022.6

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

Masayuki Imaya, Hideki Muramatsu, Atsushi Narita, Ayako Yamamori, Manabu Wakamatsu, Taro Yoshida, Shunsuke Miwata, Kotaro Narita, Daisuke Ichikawa, Motoharu Hamada, Eri Nishikawa, Nozomu Kawashima, Nobuhiro Nishio, Seiji Kojima, Yoshiyuki Takahashi

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

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

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

Predictive factors of acute respiratory events during initial induction chemotherapy in patients with advanced neuroblastoma Open Access

Matsui, M; Makimoto, A; Nishio, N; Takahashi, Y; Urashima, M; Yuza, Y

CANCER REPORTS Vol. 5 ( 5 ) page： e1499 2022.5

脊髄圧迫によるoncologic emergencyを呈した大腰筋内の後腹膜腫瘍

片岡伸介, 佐治木大知, 津村悠介, 前村遼, 今屋雅之, 山森彩子, 若松学, 谷口理恵子, 濱田太立, 西川英里, 川島希, 成田敦, 村松秀城, 西尾信博, 高橋義行, 内田広夫, 中川洋一, 田井中貴久, 安井昭洋, 中黒匡人, 下山芳江

日本小児血液・がん学会雑誌 Vol. 59 ( 1 ) page： 72 - 72 2022.5

Minor PNH clones do not distinguish inherited bone marrow failure syndromes from immune-mediated aplastic anemia. International journal Open Access

Atsushi Narita, Shunsuke Miwata, Masayuki Imaya, Yusuke Tsumura, Ayako Yamamori, Manabu Wakamatsu, Motoharu Hamada, Rieko Taniguchi, Yusuke Okuno, Hideki Muramatsu, Yoshiyuki Takahashi

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

Death review of children receiving medical care at home. International journal Open Access

Jun Natsume, Atsushi Numaguchi, Atsuko Ohno, Mihoko Mizuno, Yoshiyuki Takahashi, Akihisa Okumura, Tetsushi Yoshikawa, Shinji Saitoh, Kiyokuni Miura, Masaharu Noda

Pediatric research Vol. 91 ( 5 ) page： 1286 - 1289 2022.4

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

BACKGROUND: Children receiving home medical care need special attention to prevent unexpected death. The aim of this study was to clarify the factors contributing to death in children receiving home medical care from the child death review database. METHODS: Children receiving home medical care were enrolled from the child death review database from 2014 to 2016 in Aichi prefecture, Japan, with a population of one million children. Types of medical care and factors contributing to death were examined. RESULTS: Of the 631 children who died, 40 children (6%) were receiving home medical care (21: tracheostomy; 19: ventilator; 26: suctioning of naso-oral secretions; 19: oxygen inhalation; 32: tube feeding; 6: urethral catheterization; and 1: peritoneal dialysis). The death rate was 50 times that in the general population of children. Ten children had contributory factors that seemed to be preventable. In four children, the families could not replace the tracheostomy tubes during an accident. In three, oxygen saturation or ventilator alarms were not set appropriately. In two, an oxygen cylinder became empty. One child fell down from a seat in a car. CONCLUSIONS: Improvement of devices and correct guidance to caregivers may reduce the death rate in children receiving home medical care. IMPACT: Children receiving home medical care, such as tracheostomy care, mechanical ventilation, or tube feeding, need special attention to prevent unexpected death. In this population-based child death review, 6% of children received home medical care, and it was estimated that 1 of 100 children receiving home medical care died per year. One-quarter of the deaths could be preventable by caregiver education or development of devices.

DOI： 10.1038/s41390-021-01606-3

Hematopoietic Cell Transplantation for Inborn Errors of Immunity Other than Severe Combined Immunodeficiency in Japan: Retrospective Analysis for 1985-2016. International journal Open Access

Satoshi Miyamoto, Katsutsugu Umeda, Mio Kurata, Masakatsu Yanagimachi, Akihiro Iguchi, Yoji Sasahara, Keiko Okada, Takashi Koike, Reo Tanoshima, Masataka Ishimura, Masafumi Yamada, Maho Sato, Yoshiyuki Takahashi, Michiko Kajiwara, Hiroshi Kawaguchi, Masami Inoue, Yoshiko Hashii, Hiromasa Yabe, Koji Kato, Yoshiko Atsuta, Kohsuke Imai, Tomohiro Morio

Journal of clinical immunology Vol. 42 ( 3 ) page： 529 - 545 2022.4

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

PURPOSE: Hematopoietic cell transplantation (HCT) is a curative therapy for most patients with inborn errors of immunity (IEI). We conducted a nationwide study on HCT for patients with IEI other than severe combined immunodeficiency (non-SCID) in Japan. METHODS: Data from the Japanese national database (Transplant Registry Unified Management Program, TRUMP) for 566 patients with non-SCID IEI, who underwent their first HCT between 1985 and 2016, were retrospectively analyzed. RESULTS: The 10-year overall survival (OS) and event-free survival (EFS) were 74% and 64%, respectively. The 10-year OS for HCT from unrelated bone marrow (URBM), accounting for 39% of HCTs, was comparable to that for HCT from matched sibling donor (MSD), 79% and 81%, respectively. HCT from unrelated cord blood (URCB), accounting for 28% of HCTs, was also common, with a 10-year OS of 69% but less robust engraftment. The intensity of conditioning was not associated with OS or neutrophil recovery; however, myeloablative conditioning was more frequently associated with infection-related death. Patients who received myeloablative irradiation showed poor OS. Multivariate analyses revealed that HCT in 1985-1995 (hazard ratio [HR], 2.0; P = 0.03), URCB (HR, 2.0; P = 0.01), and related donor other than MSD (ORD) (HR, 2.9; P < 0.001) were associated with poor OS, and URCB (HR, 3.6; P < 0.001) and ORD (HR, 2.7; P = 0.02) showed a higher incidence of retransplantation. CONCLUSIONS: We present the 1985-2016 status of HCT for non-SCID IEI in Japan with sufficient statistical power, highlighting the potential of URBM as an alternative donor and the feasibility of reduced intensity conditioning.

DOI： 10.1007/s10875-021-01199-w