Faculty Profiles - TAKAHASHI, Yoshiyuki

Association between graft source and response to live-attenuated vaccination in pediatric hematopoietic stem cell transplantation recipients: a single-center retrospective study. Reviewed International journal Open Access

Takako Suzuki, Jun-Ichi Kawada, Eri Nishikawa, Yuka Torii, Kazuhiro Horiba, Suguru Takeuchi, Toshihiko Okumura, Hideki Muramatsu, Yoshiyuki Takahashi, Yoshinori Ito

Bone marrow transplantation Vol. 55 ( 9 ) page： 1872 - 1874 2020.9

Establishment of a Novel Fetal Growth Restriction Model and Development of a Stem-Cell Therapy Using Umbilical Cord-Derived Mesenchymal Stromal Cells. International journal Open Access

Yuma Kitase, Yoshiaki Sato, Sakiko Arai, Atsuto Onoda, Kazuto Ueda, Shoji Go, Haruka Mimatsu, Mahboba Jabary, Toshihiko Suzuki, Miharu Ito, Akiko Saito, Akihiro Hirakawa, Takeo Mukai, Tokiko Nagamura-Inoue, Yoshiyuki Takahashi, Masahiro Tsuji, Masahiro Hayakawa

Frontiers in cellular neuroscience Vol. 14 page： 212 - 212 2020.7

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

Fetal growth restriction (FGR) is a major complication of prenatal ischemic/hypoxic exposure and affects 5%-10% of pregnancies. It causes various disorders, including neurodevelopmental disabilities due to chronic hypoxia, circulatory failure, and malnutrition via the placenta, and there is no established treatment. Therefore, the development of treatments is an urgent task. We aimed to develop a new FGR rat model with a gradual restrictive load of uterus/placental blood flow and to evaluate the treatment effect of the administration of umbilical cord-derived mesenchymal stromal cells (UC-MSCs). To create the FGR rat model, we used ameroid constrictors that had titanium on the outer wall and were composed of C-shaped casein with a notch and center hole inside that gradually narrowed upon absorbing water. The ameroid constrictors were attached to bilateral ovarian/uterine arteries on the 17th day of pregnancy to induce chronic mild ischemia, which led to FGR with over 20% bodyweight reduction. After the intravenous administration of 1 × 105 UC-MSCs, we confirmed a significant improvement in the UC-MSC group in a negative geotaxis test at 1 week after birth and a rotarod treadmill test at 5 months old. In the immunobiological evaluation, the total number of neurons counted via the stereological counting method was significantly higher in the UC-MSC group than in the vehicle-treated group. These results indicate that the UC-MSCs exerted a treatment effect for neurological impairment in the FGR rats.

DOI： 10.3389/fncel.2020.00212

Lower limb pain following allogeneic hematopoietic stem cell transplantation in Japanese children. Reviewed

Kenichi Mishima, Hiroshi Kitoh, Masaki Matsushita, Tadashi Nagata, Yasunari Kamiya, Yoshiyuki Takahashi, Naoki Ishiguro

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association Vol. 25 ( 4 ) page： 682 - 687 2020.7

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

BACKGROUND: Patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) can experience musculoskeletal pains in their lower limbs in the early and late post-transplantation period. This study investigated demographics and clinical characteristics of the lower limb pain (LLP) among Japanese survivors of pediatric allo-HSCT. METHODS: A total of 143 consecutive Japanese patients who had undergone allo-HSCT less than 18 years of age in a single institute between 2005 and 2015 were reviewed. Patients referred for in-house orthopedic evaluation of their sustained LLPs that impaired ambulation were defined as LLP group. Illness/transplantation-related parameters were compared between LLP group and non-LLP group. RESULTS: Ninety children with a mean age of 8.5 years at transplantation were enrolled. Their median follow-up period following transplantation was 6.3 years (range, 2.1-12.5). There were four patients in LLP group, whose etiologies were AVN of the femoral head and insufficiency fracture (ISF) of the tibia or the medial cuneiform bone. Cumulative dose of steroids that administered from six months before transplantation to six months after discharge from hospitalization for transplantation was significantly higher in LLP group than non-LLP group. Additionally, the two groups differed significantly in terms of hospitalization period after transplantation. LLP caused by AVN of the femoral head manifested between six months and two years, whereas that caused by ISF within the first six months after transplantation. CONCLUSIONS: The incidence of sustained LLP that impairs ambulation following contemporary allo-HSCT is not common in Japanese pediatric survivors. The risk of developing musculoskeletal LLP may increase with a higher steroid dosage in the peri-transplant period. LLP caused by AVN of the femoral head is likely to manifest later than that caused by ISF.

DOI： 10.1016/j.jos.2019.07.007

Conditioning regimen for allogeneic bone marrow transplantation in children with acquired bone marrow failure: fludarabine/melphalan vs. fludarabine/cyclophosphamide. Reviewed International journal

Nao Yoshida, Yoshiyuki Takahashi, Hiromasa Yabe, Ryoji Kobayashi, Kenichiro Watanabe, Kazuko Kudo, Miharu Yabe, Takako Miyamura, Katsuyoshi Koh, Hiroshi Kawaguchi, Hiroaki Goto, Naoto Fujita, Keiko Okada, Yasuhiro Okamoto, Koji Kato, Masami Inoue, Ritsuro Suzuki, Yoshiko Atsuta, Seiji Kojima

Bone marrow transplantation Vol. 55 ( 7 ) page： 1272 - 1281 2020.7

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

Fludarabine/cyclophosphamide-based conditioning regimens are standard in bone marrow transplantation (BMT) for acquired bone marrow failure in children, however, graft failure may occur. Using the data from a nationwide transplantation registry, we compared the outcomes of children aged <16 years with acquired aplastic anemia and refractory cytopenia of childhood who underwent allogeneic BMT with either fludarabine/melphalan (n = 71) or fludarabine/cyclophosphamide (n = 296) between 2000 and 2016. The fludarabine/melphalan regimen provided excellent outcomes, with 3-year overall survival and failure-free survival rates of 98% and 97%, respectively. The 83% 3-year failure-free survival in the fludarabine/cyclophosphamide group was significantly inferior (P = 0.002), whereas the overall survival did not differ between the two groups. Late graft failure was the most common cause of treatment failure in the fludarabine/cyclophosphamide group, which experienced a significantly higher incidence of late graft failure than the fludarabine/melphalan group (11% vs. 3%; P = 0.035). Multivariate analyses showed that the fludarabine/melphalan regimen was associated with a better failure-free survival (hazard ratio [HR] 0.12; P = 0.005) and lower risk of late graft failure (HR 0.16; P = 0.037). Fludarabine/melphalan-based conditioning regimen can be a promising option for children with acquired bone marrow failure receiving BMT.

DOI： 10.1038/s41409-020-0948-8

Targeting MEF2D-fusion Oncogenic Transcriptional Circuitries in B-cell Precursor Acute Lymphoblastic Leukemia Open Access

Tsuzuki, S; Yasuda, T; Kojima, S; Kawazu, M; Akahane, K; Inukai, T; Imaizumi, M; Morishita, T; Miyamura, K; Ueno, T; Karnan, S; Ota, A; Hyodo, T; Konishi, H; Sanada, M; Nagai, H; Horibe, K; Tomita, A; Suzuki, K; Muramatsu, H; Takahashi, Y; Miyazaki, Y; Matsumura, I; Kiyoi, H; Hosokawa, Y; Mano, H; Hayakawa, F

BLOOD CANCER DISCOVERY Vol. 1 ( 1 ) page： 82 - 95 2020.7

Targeting MEF2D-fusion Oncogenic Transcriptional Circuitries in B-cell Precursor Acute Lymphoblastic Leukemia Reviewed

Shinobu Tsuzuki, Takahiko Yasuda, Shinya Kojima, Masahito Kawazu, Koshi Akahane, Takeshi Inukai, Masue Imaizumi, Takanobu Morishita, Koichi Miyamura, Toshihide Ueno, Sivasundaram Karnan, Akinobu Ota, Toshinori Hyodo, Hiroyuki Konishi, Masashi Sanada, Hirokazu Nagai, Keizo Horibe, Akihiro Tomita, Kyogo Suzuki, Hideki Muramatsu, Yoshiyuki Takahashi, Yasushi Miyazaki, Itaru Matsumura, Hitoshi Kiyoi, Yoshitaka Hosokawa, Hiroyuki Mano, Fumihiko Hayakawa

Blood Cancer Discovery Vol. 1 ( 1 ) page： 82 - 95 2020.7

【骨髄不全症の病態と検査】骨髄不全症と遺伝子異常血球テロメア長測定の臨床的意義

成田敦, 高橋義行

臨床検査 Vol. 64 ( 7 ) page： 761 - 765 2020.7

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(株)医学書院

＜文献概要＞Point ●再生不良性貧血(AA)を含む骨髄不全症患者ではテロメア長の短縮がみられる.造血ストレスに伴う二次性の変化が原因と考えられている.●骨髄不全症患者の一部にはテロメラーゼ複合体遺伝子群の変異を有する患者がいる.診断補助としてテロメア長の測定が有用である.●特徴的な身体症状がみられない不全型の先天性角化不全症(DC)においてはテロメア長の測定や遺伝子診断が必須である.

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01541&link_issn=&doc_id=20200714070008&doc_link_id=10.11477%2Fmf.1542202408&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1542202408&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Safe diagnostic management of malignant mediastinal tumors in the presence of respiratory distress: a 10-year experience. Reviewed International journal Open Access

Tomoko Tanaka, Hizuru Amano, Yujiro Tanaka, Yoshiyuki Takahashi, Tatsuro Tajiri, Takahisa Tainaka, Chiyoe Shirota, Wataru Sumida, Kazuki Yokota, Satoshi Makita, Yukiko Tani, Akinari Hinoki, Hiroo Uchida

BMC pediatrics Vol. 20 ( 1 ) page： 292 - 292 2020.6

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

BACKGROUND: The fundamental treatment for patients with pediatric malignant mediastinal tumors is chemotherapy. Therefore, accurate diagnosis is essential for selecting the appropriate chemotherapeutic regimen. However, malignant mediastinal tumors occasionally cause respiratory distress, and biopsies under general anesthesia are dangerous for such patients as invasive mechanical ventilation can aggravate airway obstruction caused by mass effect. In this study, we reviewed our 10-year diagnostic experience to evaluate the efficacy of our practices and confirm a safe diagnostic protocol for future patients. METHODS: We retrospectively reviewed medical records of children with malignant mediastinal tumors diagnosed at Nagoya University Hospital from 2007 to 2018 who demonstrated respiratory distress. Respiratory distress included dyspnea, massive pleural effusion, wheezing, and hypoxemia owing to tumors. Data on sex, age at onset, primary symptoms, location of tumor, management strategy (especially the method of diagnosis and definitive diagnosis), clinical course, prognosis during the acute phase (within 3 months from the onset of respiratory symptoms), and long-term outcome were collected. RESULTS: Twelve pediatric patients met the review criteria. There were seven anterior mediastinal tumors and five posterior mediastinal tumors. All anterior mediastinal tumors were diagnosed via bone marrow smear, thoracentesis, or core needle biopsy while maintaining spontaneous breathing. Regarding posterior tumors, two patients were diagnosed via a core needle biopsy and lymph node excisional biopsy under spontaneous breathing. Two cases were initially diagnosed solely using tumor markers. One patient with severe tracheal compression underwent tumor resection with extracorporeal membrane oxygenation stand-by. No patient died of diagnostic procedure-related complications. CONCLUSIONS: In 11 of the 12 cases reviewed, safe and accurate tumor diagnosis was accomplished without general anesthesia. A diagnostic strategy without general anesthesia considering the tumor location proved to be useful.

DOI： 10.1186/s12887-020-02183-w

Impact of graft-versus-host disease on the clinical outcome of allogeneic hematopoietic stem cell transplantation for non-malignant diseases. Reviewed

Katsutsugu Umeda, Kohsuke Imai, Masakatsu Yanagimachi, Hiromasa Yabe, Masao Kobayashi, Yoshiyuki Takahashi, Michiko Kajiwara, Nao Yoshida, Yuko Cho, Masami Inoue, Yoshiko Hashii, Yoshiko Atsuta, Tomohiro Morio

International journal of hematology Vol. 111 ( 6 ) page： 869 - 876 2020.6

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

The impact of acute and chronic graft-versus-host disease (GVHD) on clinical outcomes was retrospectively analyzed in 960 patients with non-malignant diseases (NMD) who underwent a first allogeneic hematopoietic stem cell transplantation (HSCT). Grade III-IV acute GVHD (but not grade I-II) was significantly associated with a lower rate of overall survival (OS), and higher non-relapse mortality (NRM) than that seen in patients without acute GVHD. Extensive (but not limited) GVHD was significantly associated with a lower OS rate and higher NRM than that seen in patients without chronic GVHD. Any grade of acute (but not chronic) GVHD was significantly associated with a lower incidence of relapse and a lower proportion of patients requiring a second HSCT or donor lymphocyte infusion for graft failure or mixed chimerism, but its impact on OS was almost negligible. Acute GVHD was significantly associated with lower OS rates in all disease groups, whereas chronic GVHD was significantly associated with lower OS rates in the primary immunodeficiency and histiocytosis groups. In conclusion, acute and chronic GVHD, even if mild, was associated with reduced OS in patients receiving HSCT for NMD and effective strategies should, therefore, be implemented to minimize GVHD.

DOI： 10.1007/s12185-020-02839-4

A familial case of alveolar capillary dysplasia with misalignment of the pulmonary veins: the clinicopathological features and unusual glomeruloid endothelial proliferation. Reviewed International journal Open Access

Akiko Kitano, Masato Nakaguro, Seiichi Tomotaki, Shintaro Hanaoka, Masahiko Kawai, Akiko Saito, Masahiro Hayakawa, Yoshiyuki Takahashi, Hidenori Kawasaki, Takahiro Yamada, Masahiko Ikeda, Tetsuo Onda, Kazutoshi Cho, Hironori Haga, Atsuko Nakazawa, Sachiko Minamiguchi

Diagnostic pathology Vol. 15 ( 1 ) page： 48 - 48 2020.5

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

BACKGROUND: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare disorder of pulmonary vascular abnormality with persistent pulmonary hypertension of the newborn. The symptom usually presents within hours after birth, leading to an early demise. Heterozygous de novo point mutations and genomic deletions of the FOXF1 (forkhead box F1) gene or its upstream enhancer have been identified in most patients with ACD/MPV. Most cases of ACD/MPV are sporadic; however, familial cases are also reported in 10% of patients. CASE PRESENTATION: We herein report a case of familial ACD/MPV that showed unusual glomeruloid proliferation of endothelial cells. In this family, three of the four siblings died within two to 3 days after birth because of persistent pulmonary hypertension and respiratory failure. Only the second child remains alive and healthy. An autopsy was performed for the third and fourth children, resulting in a diagnosis of ACD/MPV based on the characteristic features, including misalignment of smaller pulmonary veins and lymphangiectasis. In both of these children, glomeruloid endothelial proliferation of vessels was noted in the interlobular septa. The vessels were immunohistochemically positive for D2-40, CD31, Factor VIII, and ERG, suggestive of differentiation for both lymphatic and blood vessels. CONCLUSIONS: Unusual glomeruloid endothelial proliferation was observed in a familial ACD/MPV case. This histologic feature has not been described previously in ACD/MPV or any other pulmonary disease. Although the histogenesis of this histologic feature is unclear, this finding may suggest that ACD/MPV is a compound vascular and lymphovascular system disorder that exhibits various histologic features.

DOI： 10.1186/s13000-020-00972-6

Clinical Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation in Children with Juvenile Myelomonocytic Leukemia: A Report from the Japan Society for Hematopoietic Cell Transplantation. Reviewed International journal Open Access

Nao Yoshida, Hirotoshi Sakaguchi, Miharu Yabe, Daiichiro Hasegawa, Asahito Hama, Daisuke Hasegawa, Motohiro Kato, Maiko Noguchi, Kiminori Terui, Yoshiyuki Takahashi, Yuko Cho, Maho Sato, Katsuyoshi Koh, Harumi Kakuda, Hiroyuki Shimada, Yoshiko Hashii, Atsushi Sato, Koji Kato, Yoshiko Atsuta, Kenichiro Watanabe

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Vol. 26 ( 5 ) page： 902 - 910 2020.5

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

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for juvenile myelomonocytic leukemia (JMML), but few large studies of HSCT for JMML exist. Using data from the Japan Society for Hematopoietic Cell Transplantation registry, we analyzed the outcomes of 129 children with JMML who underwent HSCT between 2000 and 2011. The 5-year overall survival (OS) rate and cumulative incidence of relapse were 64% and 34%, respectively. A regimen of busulfan/fludarabine/melphalan was the most commonly used (59 patients) and provided the best outcomes; the 5-year OS rate reached 73%, and the cumulative incidences of relapse and transplantation-related mortality were 26% and 9%, respectively. In contrast, the use of the irradiation-based myeloablative regimen was the most significant risk factor for OS (hazard ratio [HR], 2.92; P = .004) in the multivariate model. In addition, chronic graft-versus-host disease (GVHD) was strongly associated with lower relapse (HR, 0.37; P = .029) and favorable survival (HR, 0.22; P = .006). The current study has shown that a significant proportion of children with JMML can be cured with HSCT, especially those receiving the busulfan/fludarabine/melphalan regimen. Based on the lower relapse and better survival observed in patients with chronic GVHD, additional treatment strategies that focus on enhancing graft-versus-leukemia effects may further improve survival.

DOI： 10.1016/j.bbmt.2019.11.029

Autologous Stem Cell Transplantation for Children With Renal Tumors, and Adults With Wilms Tumor: Retrospective Analysis of the Japanese Transplant Registry Unified Management Program. Reviewed International journal

Ryoji Kobayashi, Masami Inoue, Yoshiyuki Takahashi, Atsushi Kikuta, Atsushi Ogawa, Yuhki Koga, Katsuyoshi Koh, Yoshiko Hashii, Junichi Hara, Koji Kato, Ken Tabuchi, Kimikazu Matsumoto

Journal of pediatric hematology/oncology Vol. 42 ( 4 ) page： 251 - 255 2020.5

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

BACKGROUND: Almost all pediatric patients with renal tumors are diagnosed with nephroblastoma (Wilms tumor), clear cell sarcoma, or malignant rhabdoid tumor. The choice of treatment is important for relapsed and refractory patients with nephroblastoma. Furthermore, clear cell sarcoma of the kidney (CCSK) and malignant rhabdoid tumor of the kidney (MRTK) have a poor prognosis compared with nephroblastoma. Thus, stem cell transplantation (SCT) is sometimes selected to treat these tumors. PATIENTS AND METHODS: The authors targeted a total of 84 patients with nephroblastoma, CCSK, and MRTK who underwent a first autologous SCT between 1992 and 2014, and were registered in the Japanese Transplant Registry Unified Management Program system. The authors retrospectively analyzed the SCT data for survival rate. RESULTS: Five-year overall survival rates for nephroblastoma, CCSK, and MRTK were 72.4%±6.3%, 46.8%±13.8%, and 36.4%±14.5%, respectively. The event-free survival rates at 5 years were 64.9%±6.7%, 35.7%±12.8%, and 27.3%±13.4%, respectively. The relapse rates at 5 years were 25.3%±11.4%, 46.2%±28.4%, and 60.0%±43.1%, respectively. CONCLUSION: Although the survival rate for nephroblastoma was relatively high, those of CCSK and MRTK were poor.

DOI： 10.1097/MPH.0000000000001779