研究者総覧

嶋田 明 (シマダ アキラ)

  • 小児科 教授
メールアドレス: shimada.akirajichi.ac.jp
Last Updated :2021/11/23

研究者情報

学位

  • 医学博士(鳥取大学)

ホームページURL

J-Global ID

研究キーワード

  • 感染免疫学   血液腫瘍学   小児科   hematology/oncology. immunology/infectious disease   Pediatrics   

研究分野

  • ライフサイエンス / 胎児医学、小児成育学

経歴

  • 2016年  - 岡山大学岡山大学病院 准教授
  • 2016年  - Associate Professor,University Hospital of Medicine and Dentistry,Okayama University

学歴

  •         - 1999年   鳥取大学   医学研究科
  •         - 1999年   鳥取大学   Graduate School, Division of Medicine
  •         - 1992年   鳥取大学   医学部
  •         - 1992年   鳥取大学   Faculty of Medicine

所属学協会

  • 日本臨床腫瘍学会   日本家族性腫瘍学会   日本人類遺伝学会   日本造血細胞移植学会   日本小児血液がん学会   アメリカ癌学会   日本血液学会   米国血液学会   日本小児科学会   American Association of Cancer Research   Japan Pediatric Society   

研究活動情報

論文

  • Takahiro Aoki, Hiroyuki Takahashi, Shiro Tanaka, Norio Shiba, Daiichiro Hasegawa, Shotaro Iwamoto, Kiminori Terui, Hiroshi Moritake, Hideki Nakayama, Akira Shimada, Katsuyoshi Koh, Hiroaki Goto, Yoshiyuki Kosaka, Akiko M Saito, Keizo Horibe, Akitoshi Kinoshita, Akio Tawa, Takashi Taga, Souichi Adachi, Daisuke Tomizawa
    British journal of haematology 193 1 176 - 180 2021年04月 
    The variability in myelosuppression after chemotherapy for acute myeloid leukaemia (AML) can affect its prognosis; however, the underlying mechanism remains controversial. In the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study, we showed that prolonged neutropenia was associated with high overall survival (P = 0·011) and low frequency of relapse (P = 0·042) in patients without granulocyte-colony stimulating factor (G-CSF) who completed the indicated treatment protocol. Our data indicate that predisposition to prolonged neutropenia after chemotherapy is correlated with a better outcome of AML treatment. Our results promote the usage of individualised drug dosing strategies to improve the therapeutic outcome in AML patients.
  • Taeko Kaburagi, Genki Yamato, Norio Shiba, Kenichi Yoshida, Yusuke Hara, Ken Tabuchi, Yuichi Shiraishi, Kentaro Ohki, Manabu Sotomatsu, Hirokazu Arakawa, Hidemasa Matsuo, Akira Shimada, Tomohiko Taki, Nobutaka Kiyokawa, Daisuke Tomizawa, Keizo Horibe, Satoru Miyano, Takashi Taga, Souichi Adachi, Seishi Ogawa, Yasuhide Hayashi
    Haematologica 2021年03月 
    RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) out of 328 patients: NF1 (n = 7, 2.1%), PTPN11 (n = 15, 4.6%), CBL (n = 6, 1.8%), NRAS (n = 44, 13.4%), KRAS (n = 12, 3.7%). Most of these alterations were mutually exclusive and were also mutually exclusive with other aberrations of signal transduction pathways such as FLT3-ITD (p = 0.001) and KIT mutation (p = 0.004). NF1 alterations were frequently detected in patients with complex karyotype (p = 0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (p = 0.007). At least four of seven patients with NF1 alterations had bi-allelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis [OS, p = 0.023; event-free survival (EFS), p = 0.037]. Patients with PTPN11 mutations more frequently received stem cell transplantation (p = 0.035) and showed poor EFS than patients without PTPN11 mutations (p = 0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.
  • Takashi Taga, Shiro Tanaka, Daisuke Hasegawa, Kiminori Terui, Tsutomu Toki, Shotaro Iwamoto, Hidefumi Hiramatsu, Takako Miyamura, Yoshiko Hashii, Hiroshi Moritake, Hideki Nakayama, Hiroyuki Takahashi, Akira Shimada, Tomohiko Taki, Etsuro Ito, Asahito Hama, Masafumi Ito, Katsuyoshi Koh, Daiichiro Hasegawa, Akiko M Saito, Souichi Adachi, Daisuke Tomizawa
    Leukemia 2021年02月 
    Myeloid leukemia of Down syndrome (ML-DS) is associated with good response to chemotherapy, resulting in favorable outcomes. However, no universal prognostic factors have been identified to date. To clarify a subgroup with high risk of relapse, the role of minimal residual disease (MRD) was explored in the AML-D11 trial by the Japanese Pediatric Leukemia/Lymphoma Study Group. MRD was prospectively evaluated at after induction therapy and at the end of all chemotherapy, using flow cytometry (FCM-MRD) and GATA1-targeted deep sequencing (GATA1-MRD). A total of 78 patients were eligible and 76 patients were stratified to the standard risk (SR) group by morphology. In SR patients, FCM-MRD and GATA1-MRD after induction were positive in 5/65 and 7/59 patients, respectively. Three-year event-free survival (EFS) and overall survival (OS) rates were 93.3% and 95.0% in the FCM-MRD-negative population, and 60.0% and 80.0% in the positive population. Three-year EFS and OS rates were both 96.2% in the GATA1-MRD-negative population, and 57.1% and 71.4% in the positive population. Adjusted hazard ratios for associations of FCM-MRD or GATA1-MRD with EFS were 10.98 (p = 0.01) and 27.68 (p < 0.01), respectively. Detection of MRD by either FCM or GATA1 after initial induction therapy represents a significant prognostic factor for predicting ML-DS relapse.
  • Risa Matsumura, Shinji Mochizuki, Natsuki Maruyama, Yusuke Morishita, Hiroshi Kawaguchi, Satoshi Okada, Miyuki Tsumura, Shunsaku Kaji, Junya Shimizu, Akira Shimada, Masao Kobayashi
    International journal of hematology 113 2 302 - 307 2021年02月 
    Human C1q deficiency is frequently associated with systemic lupus erythematosus (SLE), which requires long-term systemic corticosteroid administration. We report the case of a 12-year-old female patient with C1q deficiency presenting with intractable SLE who successfully underwent bone marrow transplantation from a human leukocyte antigen (HLA)-mismatched unrelated donor with an immunosuppressive conditioning regimen based on fludarabine, melphalan, and anti-thymocyte globulin. She developed Grade I graft-versus-host disease, but did not have any transplantation-related morbidity. Complete donor chimerism has been maintained for 2 years after transplantation, leading to the restoration of C1q levels and the resolution of SLE symptoms. Normal C1q mRNA expression was observed in CD14 + cells. Hematopoietic stem cell transplantation from an HLA-mismatched donor is a feasible treatment for patients with C1q deficiency with refractory SLE that is dependent on systemic corticosteroid treatment who do not have an HLA-matched donor.
  • Takayuki Hamabata, Katsutsugu Umeda, Kagehiro Kouzuki, Takayuki Tanaka, Tomoo Daifu, Seishiro Nodomi, Satoshi Saida, Itaru Kato, Shiro Baba, Hidefumi Hiramatsu, Mitsujiro Osawa, Akira Niwa, Megumu K Saito, Yasuhiko Kamikubo, Souichi Adachi, Yoshiko Hashii, Akira Shimada, Hiroyoshi Watanabe, Kenji Osafune, Keisuke Okita, Tatsutoshi Nakahata, Kenichiro Watanabe, Junko Takita, Toshio Heike
    Scientific reports 11 1 2107 - 2107 2021年01月
  • Hiroshi Moritake, Shiro Tanaka, Takako Miyamura, Hideki Nakayama, Norio Shiba, Akira Shimada, Kiminori Terui, Yuki Yuza, Katsuyoshi Koh, Hiroaki Goto, Harumi Kakuda, Akiko Saito, Daisuke Hasegawa, Shotaro Iwamoto, Takashi Taga, Souichi Adachi, Daisuke Tomizawa
    Pediatric blood & cancer 68 1 e28736  2021年01月 
    BACKGROUND: The prognosis of children with acute myeloid leukemia (AML) has improved with the efficacy of hematopoietic cell transplantation (HCT) as a second-line therapy and improvements in supportive care following anthracycline- and cytarabine-based chemotherapy; however, the outcomes of children with relapsed AML still remain unsatisfactory. PROCEDURE: In order to identify prognostic factors and improve their prognosis, we analyzed 111 patients who relapsed after treatment with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol and who were registered in the retrospective JPLSG AML-05R study. RESULTS: The 5-year overall survival rate was 36.1%. The major determinant of survival was duration from the diagnosis to relapse. The mean duration in the nonsurviving group (10.1 ± 4.1 months) was shorter than that in the surviving group (16.3 ± 8.3 months) (P < .01). Moreover, achieving a second complete remission (CR2) prior to HCT was associated with a good prognosis (P < .01). Etoposide, cytarabine, and mitoxantrone (ECM)- or fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG)-based regimens were therefore recommended for reinduction therapy (P < .01). A genetic analysis also revealed the prognostic significance of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication as a poor prognostic marker (P = .04) and core binding factor-AML, t(8;21), and inv(16) as good prognostic markers (P < .01). CONCLUSIONS: Achieving a CR2 prior to HCT is important in order to improve the prognosis of relapsed pediatric AML. Recent molecular targeted therapies, such as FLT3 inhibitors, may contribute to overcome their prognoses. Larger prospective investigations are necessary to establish individualized treatment strategies for patients with relapsed childhood AML.
  • Kiichiro Kanamitsu, Takashi Yorifuji, Hisashi Ishida, Kaori Fujiwara, Kana Washio, Akira Shimada, Hirokazu Tsukahara
    Therapeutic drug monitoring 42 6 803 - 810 2020年12月 
    BACKGROUND: Tacrolimus is converted from intravenous to oral formulation for the prophylaxis of graft-versus-host disease when patients can tolerate oral intake and graft-versus-host disease is under control. Oral tacrolimus formulation presents poor bioavailability with intraindividual and interindividual variations; however, some factors affecting its blood concentration among pediatric hematopoietic stem cell transplantation (HCT) recipients are still unclear. This study aimed to identify the clinical factors affecting tacrolimus blood concentrations after switching its formulation. METHODS: Changes in the blood concentration/dose ratio (C/D) of tacrolimus in pediatric HCT recipients were analyzed after the switching of tacrolimus from intravenous to oral formulation. Clinical records of 57 pediatric patients who underwent allogenic HCT from January 2006 to April 2019 in our institute were retrospectively reviewed. The C/D of tacrolimus before discontinuation of intravenous infusion (C/Div) was compared with the tacrolimus trough level within 10 days after the initiation of oral administration (C/Dpo). Multiple linear regression analysis was performed to identify factors affecting (C/Dpo)/(C/Div). RESULTS: The constant coefficient of (C/Dpo)/(C/Div) was 0.1692 [95% confidence interval (CI), 0.137-0.2011]. The concomitant use of voriconazole or itraconazole and female sex were significant variables with a beta coefficient of 0.0974 (95% CI, 0.062-0.133) and -0.0373 (95% CI, -0.072 to -0.002), respectively. CONCLUSIONS: After switching of tacrolimus formulation, pediatric HCT recipients might need oral tacrolimus dose that is 5-6 and 3.5-4.5 times the intravenous dose to maintain tacrolimus blood concentrations and area under the concentration-time curve, respectively. With the concomitant use of voriconazole or itraconazole, an oral tacrolimus dose of 4-5 times the intravenous dose seemed appropriate to maintain blood tacrolimus concentration.
  • Daiichiro Hasegawa, Akio Tawa, Daisuke Tomizawa, Tomoyuki Watanabe, Akiko Moriya Saito, Kazuko Kudo, Takashi Taga, Shotaro Iwamoto, Akira Shimada, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Hiroyuki Takahashi, Hideki Nakayama, Katsuyoshi Koh, Hiroaki Goto, Yoshiyuki Kosaka, Hayato Miyachi, Keizo Horibe, Tatsutoshi Nakahata, Souichi Adachi
    Pediatric blood & cancer 67 12 e28692  2020年12月 
    We previously reported that risk-stratified therapy and intensive postremission chemotherapy (PRC) contributed to the improved survival of childhood acute myeloid leukemia (AML) in the AML99 study, which led us to consider a reduction in the number of PRC courses with more restrictive indications for stem cell transplantation (SCT) in the successor AML-05 study. We here report the outcome of AML patients without core-binding factor mutation (non-CBF AML) in the AML-05 study. Two-hundred eighty-nine children (age < 18 years old) with non-CBF AML were eligible. Patients with unfavorable cytogenetics and/or poor bone marrow response to the first induction course were candidates for SCT in the AML-05 study. After two courses of induction, a further three courses of PRC were given in AML-05, while four courses were given in the AML99 study. The 3-year event-free survival (EFS) rate in the AML-05 study (46.7%, 95% CI: 40.6-52.6%) was comparable to that of non-CBF AML in the AML99 study (51.5%, 95% CI: 42.7-59.6%) (P = .16). However, the 3-year overall survival (OS) rate in the AML-05 study (62.9%, 95% CI: 56.3-68.8%) was slightly lower than that in the AML99 study (71.6%, 95% CI: 63.2-78.5%) (P = .060), mainly due to decreased remission induction rate and increased nonrelapsed mortality. In conclusion, reductions in the number of PRC courses from four to three, together with repetitive cycles of high-dose cytarabine, were acceptable for non-CBF childhood AML.
  • Yasuhisa Tatebe, Kiichiro Kanamitsu, Hirotaka Kanzaki, Hisashi Ishida, Kaori Fujiwara, Kana Washio, Yoshihisa Kitamura, Toshiaki Sendo, Akira Shimada, Hirokazu Tsukahara
    Acta medica Okayama 74 6 545 - 550 2020年12月 
    Polymorphisms in methotrexate transporter pathways have been associated with methotrexate toxicities and clearance. Recent genome-wide association studies have revealed that the SLCO1B1 T521C variant is associated with methotrexate elimination. We present a case of a pediatric patient with acute lymphoblastic leukemia who suffered from persistently high plasma methotrexate concentrations and acute kidney injuries after the admin-istration of a medium dose of methotrexate. Subsequent genetic analysis showed that he was a carrier of dys-functional genetic variants associated with methotrexate clearance. This case highlights that polymorphisms of methotrexate transporter pathways can adversely affect methotrexate elimination in a clinically significant manner.
  • Hisashi Ishida, Akihiro Iguchi, Michinori Aoe, Ritsuo Nishiuchi, Takehiro Matsubara, Dai Keino, Masashi Sanada, Akira Shimada
    Biomedical reports 13 5 46 - 46 2020年11月 
    Acute myeloid leukemia (AML) accounts for ~20% of pediatric leukemia cases. The prognosis of pediatric AML has been improved in recent decades, but it trails that of most other types of pediatric cancer, with mortality rates of 30-40%. Consequently, newer more targeted drugs are required for incorporation into treatment plans. These newer drugs selectively target AML cells with specific gene alterations. However, there are significant differences in genetic alterations between adult and pediatric patients with AML. In the present study, inexpensive and rapid next-generation sequencing (NGS) of >150 cancer-related genes was performed for matched diagnostic, remission and relapse (if any) samples from 27 pediatric patients with AML. In this analysis, seven genes were recurrently mutated. KRAS was mutated in seven patients, NRAS was mutated in three patients, and KIT, GATA1, WT1, PTPN11, JAK3 and FLT3 were each mutated in two patients. Among patients with relapsed AML, six harbored KRAS mutations at diagnosis; however, four of these patients lost these mutations at relapse. Additionally, two genetic alterations (FLT3-ITD and TP53 alterations) were detected among patients who eventually relapsed, and these mutations are reported to be adverse prognostic factors for adult patients with AML. This panel-based, targeted sequencing approach may be useful in determining the genetic background of pediatric AML and improving the prediction of treatment response and detection of potentially targetable gene alterations. RAS pathway mutations were highly unstable at relapse; therefore, these mutations should be chosen as a target with caution. Incorporating this panel-based NGS approach into the clinical setting may allow for a patient-oriented strategy of precision treatment for childhood AML.
  • Takanori Oyama, Takuo Noda, Kana Washio, Akira Shimada
    Medicine 99 38 e22297  2020年09月 
    RATIONALE: Growing teratoma syndrome is defined as an increase in tumor size during or after systemic chemotherapy for germ cell tumors. These cases involve normal tumor maker levels and histological features of only mature teratoma. We report a rare case of an ovarian immature teratoma in a Japanese child that was diagnosed as growing teratoma syndrome. PATIENT CONCERNS: A 12-year-old girl presented a painful abdominal mass. She underwent left salpingo-oophorectomy for grade 1 immature teratoma in the left ovary. She did not undergo additional chemotherapy or radiotherapy. Four months later, she presented with grade 3 immature teratoma disseminated into the abdomen and pelvis. Chemotherapy resulted in the tumor maker levels returning to their normal ranges, although the tumors had grown slightly. DIAGNOSIS: The specimens resected by laparotomy after the chemotherapy consisted of mature tissue predominantly, although primitive neuroepithelium was observed in a small part of the specimen. The pathological diagnosis was grade 1 immature teratoma, notwithstanding the clinical diagnosis was growing teratoma syndrome based on the clinical features and pathogenesis. INTERVENTIONS: Laparotomy was performed at 7 months after the first operation, with resection of various tumors as well as the rectum, sigmoid colon, residual left fallopian duct, and a small part of the ileum and omentum. Some small tumors at the parietal peritoneum were ablated, although many tiny tumors around the uterus were left untreated. OUTCOMES: The patient has been free from recurrence for 5 years. LESSONS: Growing teratoma syndrome can develop in children, and their tumor size is comparable to that in adolescents and adults. Furthermore, development of growing teratoma syndrome from a primary germ cell tumor is presumably faster in children than in adolescents and adults. Complete resection of all growing teratoma tissue is recommended, although fertility-sparing surgery should be considered when possible.
  • Takayuki Hamabata, Katsutsugu Umeda, Kagehiro Kouzuki, Takayuki Tanaka, Tomoo Daifu, Seishiro Nodomi, Satoshi Saida, Itaru Kato, Shiro Baba, Hidefumi Hiramatsu, Mitsujiro Osawa, Akira Niwa, Megumu K Saito, Yasuhiko Kamikubo, Souichi Adachi, Yoshiko Hashii, Akira Shimada, Hiroyoshi Watanabe, Kenji Osafune, Keisuke Okita, Tatsutoshi Nakahata, Kenichiro Watanabe, Junko Takita, Toshio Heike
    Scientific reports 10 1 14859 - 14859 2020年09月 
    Shwachman-Diamond syndrome (SDS), an autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, which plays a role in ribosome biogenesis. Although the causative genes of congenital disorders frequently involve regulation of embryogenesis, the role of the SBDS gene in early hematopoiesis remains unclear, primarily due to the lack of a suitable experimental model for this syndrome. In this study, we established induced pluripotent stem cells (iPSCs) from patients with SDS (SDS-iPSCs) and analyzed their in vitro hematopoietic and endothelial differentiation potentials. SDS-iPSCs generated hematopoietic and endothelial cells less efficiently than iPSCs derived from healthy donors, principally due to the apoptotic predisposition of KDR+CD34+ common hemoangiogenic progenitors. By contrast, forced expression of SBDS gene in SDS-iPSCs or treatment with a caspase inhibitor reversed the deficiency in hematopoietic and endothelial development, and decreased apoptosis of their progenitors, mainly via p53-independent mechanisms. Patient-derived iPSCs exhibited the hematological abnormalities associated with SDS even at the earliest hematopoietic stages. These findings will enable us to dissect the pathogenesis of multiple disorders associated with ribosomal dysfunction.
  • Kiichiro Kanamitsu, Hisashi Ishida, Kaori Fujiwara, Kana Washio, Akira Shimada, Hirokazu Tsukahara
    Pediatric blood & cancer 67 9 e28323  2020年09月
  • Hisashi Ishida, Yuji Miyajima, Nobuyuki Hyakuna, Satoru Hamada, Takeo Sarashina, Risa Matsumura, Katsutsugu Umeda, Tetsuo Mitsui, Naoto Fujita, Daisuke Tomizawa, Kevin Y. Urayama, Yasushi Ishida, Takashi Taga, Masatoshi Takagi, Souichi Adachi, Atsushi Manabe, Toshihiko Imamura, Katsuyoshi Koh, Akira Shimada
    eJHaem 1 1 86 - 93 2020年07月
  • Tetsuo Mitsui, Naoto Fujita, Yuhki Koga, Reiji Fukano, Tomoo Osumi, Asahito Hama, Katsuyoshi Koh, Harumi Kakuda, Masami Inoue, Takahiro Fukuda, Hiromasa Yabe, Junko Takita, Akira Shimada, Yoshiko Hashii, Atsushi Sato, Yoshiko Atsuta, Yoshinobu Kanda, Junji Suzumiya, Ryoji Kobayashi
    Pediatric blood & cancer 67 4 e28129  2020年04月 
    BACKGROUND: Patients with relapsed or refractory lymphoblastic lymphoma (LBL) have a poor prognosis. The efficacy of allogeneic blood stem cell transplantation for treatment of this disease remains unclear in terms of transplantation-related toxicity. Acute and chronic graft-versus-host diseases (GVHD) are both harmful to patients after allogeneic transplantation, but may have some positive effects through a substitute graft-versus-lymphoma effect. METHODS: To investigate the effect of GVHD on the survival of patients with refractory LBL, we retrospectively studied the outcomes of 213 patients with LBL who underwent first allogeneic stem cell transplantation before the age of 18 years, between 1990 and 2015 in Japan. RESULTS: The five-year overall survival (OS) and event-free survival rates after stem cell transplantation were 50.3% (95% confidence interval [CI], 43.2-56.9) and 47.8% (95% CI, 40.8-54.4), respectively. In univariate landmark analyses, the probability of OS was significantly better in patients with aGVHD than in those without (P = 0.002, five-year OS 58.1% vs 39.0%). The probability of OS was also better in patients with cGVHD than in those without (P = 0.036, five-year OS 72.2% vs 54.7%). Multivariate analysis demonstrated that only aGVHD was associated with better OS (hazard ratio, 0.63; 95% CI, 0.42-0.94, P = 0.024). Progression and recurrence statuses at SCT were associated with poor prognosis. The patients with grade II aGVHD showed the best prognosis (five-year OS: 65.6%). CONCLUSION: Our results suggest that the occurrence of aGVHD may be associated with better outcomes in patients with relapsed/refractory LBL who undergo allogeneic transplantation.
  • Akihito Shinohara, Kumi Oshima, Shigeo Fuji, Katsutsugu Umeda, Shinichi Kako, Mineo Kurokawa, Nobuhiro Tsukada, Masanobu Kasai, Takakazu Kondo, Yoshiko Hashii, Hirohisa Nakamae, Kazuhiro Ikegame, Yoshiyuki Kosaka, Akira Shimada, Yuichiro Nawa, Yoshimitsu Makoto, Atsuta Yoshiko, Takahiro Fukuda, Junji Tanaka, Masao Ogata
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 26 1 66 - 75 2020年01月 
    Little is known about stem cell transplantation in solid organ transplantation (SOT) recipients. We conducted a nationwide retrospective survey of Japan Society for Hematopoietic Stem Cell Transplantation centers. A total of 19 patients who underwent 22 hematopoietic stem cell transplantations (HSCTs) after SOT were identified: 5 autologous HSCTs and 17 allogeneic HSCTs were performed. Patients who underwent autologous HSCT received a liver (n = 4) or kidney (n = 1) transplant. All 5 patients achieved neutrophil engraftment, and 2 of 3 patients with hepatoblastoma were alive at 1 year after HSCT. Allogeneic HSCT was performed in 16 patients (7 liver transplant recipients and 9 kidney transplant recipients). Among these, 2 donors were identical for both transplantations. All but 1 patient achieved neutrophil engraftment. The 5-year overall survival rate was 41.7%, but that in patients with malignant disease (n = 13) was much lower than the overall rate (23.1%). Only 1 patient with malignant disease underwent allogeneic HSCT in nonremission. In allogeneic HSCT after kidney transplantation, post-transplantation (1 year) kidney function in 5 evaluable patients was significantly lower than that before allogeneic HSCT, and 3 patients experienced renal rejection. However, no severe hepatic rejection was noted. In SOT recipients, HSCT is a potentially curable treatment for hematologic disorders, but it must be performed with caution, especially in patients with malignancy.
  • Kazuko Kudo, Miho Maeda, Nobuhiro Suzuki, Hirokazu Kanegane, Shouichi Ohga, Eiichi Ishii, Yoko Shioda, Toshihiko Imamura, Shinsaku Imashuku, Yukiko Tsunematsu, Mikiya Endo, Akira Shimada, Yuuki Koga, Yoshiko Hashii, Maiko Noguchi, Masami Inoue, Ken Tabuchi, Akira Morimoto
    International journal of hematology 111 1 137 - 148 2020年01月 
    The efficacy of and indications for hematopoietic stem cell transplantation (HSCT) in pediatric Langerhans cell histiocytosis (LCH) remain undetermined. This retrospective study analyzed 30 children with refractory LCH who underwent HSCT in Japan between 1996 and 2014. Eleven patients received a myeloablative conditioning (MAC) regimen, while 19 patients received a reduced-intensity conditioning (RIC) regimen. Among the 26 patients with complete data, 23 patients had risk organ (RO) involvement during clinical course. Disease status at HSCT was no active disease (NAD) (4), active disease-regression (AD-r) (2), active disease-stable (AD-s) (4), and active disease-progressive (AD-p) (16). Seventeen of the 30 patients (57%) were alive with a median follow-up of 433 days (range 9-5307) after HSCT. Death occurred within 3 months after HSCT in eight of 13 patients. RIC and MAC patients were similar in both overall survival (OS) (56.8% vs. 63.6%, respectively, p = 0.789) and failure-free survival (56.8% vs. 54.6%, respectively, p = 0.938). Regarding disease status at HSCT, the six patients with NAD/AD-r experienced better outcomes than the 20 with AD-s/AD-p (5-year OS, 100% vs. 54.5%, respectively, p = 0.040). Disease state at the time of HSCT was the most important prognostic factor.
  • Akira Shimada
    European journal of pharmacology 862 172641 - 172641 2019年11月 
    Recent genetic analysis using next-generation sequencing (NGS) vastly improved the understanding of molecular mechanism of hematological malignancies. Many molecular targeting drugs have since been used in the clinic, which is timely as clinical outcomes using conventional chemotherapy and hematopoietic stem cell transplantation (HSCT) reached a plateau. The first memorable success in this field was imatinib, a first-generation tyrosine kinase inhibitor (TKI), which has been applied in chronic myeloid leukemia (CML) since 2001. Imatinib drastically changed CML treatment and many CML patients no longer require HSCT. Recently, the second generation TKIs, dasatinib, nilotinib, and ponatinib, have also been available for CML patients. Acute lymphoblastic leukemia (ALL) is sub-categorized based on cytogenetic or molecular genetic abnormalities. Chemotherapy and HSCT combined with TKI improved the event-free survival rate from 20% to 80% in Philadelphia (Ph) chromosome-positive ALL. Reportedly, another Ph-like ALL subgroup with poor prognosis can also be treated by TKIs; additionally, cell therapies that include bispecific T-cell engagers or chimeric antigen receptor (CAR)-T therapy are emerging. Acute myeloid leukemia (AML) is a heterogenous disease and FMS-like related tyrosine kinase-3 (FLT3)-internal tandem duplication, is the most robust marker for poor prognosis. Several first-generation TKIs have been studied for clinical use. Notably, chemotherapy plus midostaurin improved survival compared with chemotherapy alone. Therefore, midostaurin was approved to treat adult AML patients with FLT3-ITD in 2017. Gemtuzumab ozogamicin, a selective anti-CD33 antibody-calicheamicin conjugate, is approved for clinical practice. Many molecular targeting agents are now being used for hematological malignancies.
  • Norio Shiba, Kenichi Yoshida, Yusuke Hara, Genki Yamato, Yuichi Shiraishi, Hidemasa Matsuo, Yusuke Okuno, Kenichi Chiba, Hiroko Tanaka, Taeko Kaburagi, Masanobu Takeuchi, Kentaro Ohki, Masashi Sanada, Jun Okubo, Daisuke Tomizawa, Tomohiko Taki, Akira Shimada, Manabu Sotomatsu, Keizo Horibe, Takashi Taga, Souichi Adachi, Akio Tawa, Satoru Miyano, Seishi Ogawa, Yasuhide Hayashi
    Blood advances 3 20 3157 - 3169 2019年10月 [査読有り][通常論文]
     
    Recent advances in the genetic understanding of acute myeloid leukemia (AML) have improved clinical outcomes in pediatric patients. However, ∼40% of patients with pediatric AML relapse, resulting in a relatively low overall survival rate of ∼70%. The objective of this study was to reveal the comprehensive genetic background of pediatric AML. We performed transcriptome analysis (RNA sequencing [RNA-seq]) in 139 of the 369 patients with de novo pediatric AML who were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial and investigated correlations between genetic aberrations and clinical information. Using RNA-seq, we identified 54 in-frame gene fusions and 1 RUNX1 out-of-frame fusion in 53 of 139 patients. Moreover, we found at least 258 gene fusions in 369 patients (70%) through reverse transcription polymerase chain reaction and RNA-seq. Five gene rearrangements were newly identified, namely, NPM1-CCDC28A, TRIP12-NPM1, MLLT10-DNAJC1, TBL1XR1-RARB, and RUNX1-FNBP1. In addition, we found rare gene rearrangements, namely, MYB-GATA1, NPM1-MLF1, ETV6-NCOA2, ETV6-MECOM, ETV6-CTNNB1, RUNX1-PRDM16, RUNX1-CBFA2T2, and RUNX1-CBFA2T3. Among the remaining 111 patients, KMT2A-PTD, biallelic CEBPA, and NPM1 gene mutations were found in 11, 23, and 17 patients, respectively. These mutations were completely mutually exclusive with any gene fusions. RNA-seq unmasked the complexity of gene rearrangements and mutations in pediatric AML. We identified potentially disease-causing alterations in nearly all patients with AML, including novel gene fusions. Our results indicated that a subset of patients with pediatric AML represent a distinct entity that may be discriminated from their adult counterparts. Based on these results, risk stratification should be reconsidered.
  • Kaori Fujiwara, Junya Shimizu, Hirokazu Tsukahara, Akira Shimada
    Rheumatology international 39 10 1811 - 1819 2019年10月 
    Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare bleeding disorder caused by antiprothrombin antibodies. LAHPS is associated with systemic lupus erythematosus (SLE) or infections. We describe two Japanese brothers with immunoglobulin-A vasculitis (IgAV) who met the diagnostic criteria of LAHPS. They presented with palpable purpura and abdominal pain, and had a prolonged activated partial thromboplastin time (APTT) and prothrombin deficiency with the presence of lupus anticoagulant. Pediatric LAHPS was reviewed in abstracts from the Japan Medical Abstracts Society that were written in Japanese and PubMed or Web of Science-listed articles in English between 1996 and 2019. Including our cases, pediatric LAHPS has been reported in 40 Japanese and 46 non-Japanese patients. We summarized the clinical and laboratory characteristics of all 86 cases, and found only one Japanese LAHPS case with IgAV, except for our cases. Of the 86 cases, most were associated with infections followed by SLE. The presence of SLE, older age, lower prothrombin levels, severe bleeding symptoms, and positivity of immunoglobulin G anticardiolipin antibodies and anticardiolipin/β2-glycoprotein I antibodies and/or β2-glycoprotein I-dependent anticardiolipin antibodies had higher odds of requiring treatment. Measuring the APTT and prothrombin time (PT) might be required in patients with IgAV when they do not have a typical clinical course or distinctive symptoms. LAHPS should be considered with prolongation of the APTT and/or PT. Additionally, it is important to maintain a balance between the risk of thrombosis and hemorrhage when normalization of the PT and FII levels occurs in LAHPS cases under treatment.
  • Kazuhiko Kurozumi, Yoshiko Nakano, Joji Ishida, Takehiro Tanaka, Masatomo Doi, Junko Hirato, Akihiko Yoshida, Kana Washio, Akira Shimada, Takashi Kohno, Koichi Ichimura, Hiroyuki Yanai, Isao Date
    Brain tumor pathology 36 3 121 - 128 2019年07月 
    Here, we report a highly unusual case of high-grade glioneuronal tumor with a neurotrophic tropomyosin receptor kinase (NTRK) fusion gene. A 13-year-old girl presented with headache and vomiting and MRI detected two cystic lesions bilaterally in the frontal areas with surrounding edema. The left larger tumor was removed by left frontal craniotomy. The tumor was diagnosed as a high-grade glioneuronal tumor, unclassified. Methylation profiling classified it as a diffuse leptomeningeal glioneuronal tumor (DLGNT) with low confidence. This tumor showed genotypes frequently found in DLGNT such as 1p/19q codeletion without IDH mutation and, however, did not have the typical DLGNT clinical and histological features. RNA sequencing identified an ARHGEF2 (encoding Rho/Rac guanine nucleotide exchange factor 2)-NTRK1 fusion gene. The presence of recurrent NTRK fusion in glioneuronal tumors has an important implication in the clinical decision making and opens up a possibility of novel targeted therapy.
  • ARHGEF2-NTRK1融合遺伝子を有する高悪性度glioneuronal tumorの1例
    黒住 和彦, 中野 嘉子, 鷲尾 佳奈, 嶋田 明, 吉田 朗彦, 市村 幸一, 伊達 勲
    小児の脳神経 44 2 218 - 218 (一社)日本小児神経外科学会 2019年04月
  • Ikuya Usami, Toshihiko Imamura, Yoshihiro Takahashi, So-Ichi Suenobu, Daiichiro Hasegawa, Yoshiko Hashii, Takao Deguchi, Tsukasa Hori, Akira Shimada, Koji Kato, Eturou Ito, Akiko Moriya-Saito, Hirohide Kawasaki, Hiroki Hori, Keiko Yumura-Yagi, Junichi Hara, Atsushi Sato, Keizo Horibe
    International journal of hematology 109 4 477 - 482 2019年04月 
    ETV6-RUNX1-positive B precursor acute lymphoblastic leukemia (B-ALL) is a common subtype of pediatric B-ALL that has shown excellent outcomes in contemporary clinical trials for pediatric B-ALL. Examinations of the possibility of reducing therapeutic intensity may thus be explored. This prospective study examined outcomes in 205 pediatric patients with ETV6-RUNX1-positive B-ALL uniformly treated following the Japan Association of Childhood Leukemia Study Group (JACLS) ALL-02 protocol. The JACLS ALL-02 protocol does not employ minimal residual disease detected by polymerase chain reaction (PCR-MRD)-based risk stratification; however, 4-year event-free survival (EFS) and overall survival (OS) were 94.4 ± 1.6 and 97.5 ± 1.1%, respectively. In particular, 92 of 205 (44.9%) patients were successfully treated with a less intensive regimen involving only two cycles of high dose methotrexate and one course of re-induction therapy comprising vincristine, L-asparaginase (L-asp), pirarubicin, and prednisolone. Multivariate analysis revealed that discontinuation of L-asp and poor response to prednisolone was, respectively, associated with poor EFS (HR 6.3; 95% CI 1.3-27.0) and OS (HR 17.5; 95% CI 2.3-130), suggesting that the majority of ETV6-RUNX1-positive B-ALL cases may be cured by a less-intensive chemotherapy regimen if the risk stratification system including PCR-MRD monitoring and insufficient use of L-asp is avoided.
  • Tomoka Okamura, Yousuke Washio, Junko Yoshimoto, Kazumasa Tani, Hirokazu Tsukahara, Akira Shimada
    Acta medica Okayama 73 2 181 - 188 2019年04月 
    Most cases of transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) resolve spontaneously; however, DS-TAM neonates with hydrops fetalis (HF) show poor clinical outcomes. We report three infants with DS-TAM and HF who were treated with exchange transfusion (ET) followed by low-dose cytarabine (LD-CA). All of them survived without developing liver failure, acute leukemia, or other serious adverse events. Our results suggest that this combination treatment with ET and LD-CA would be safe, tolerable and effective as an novel approach for DS-TAM patients with HF.
  • Takako Miyamura, Hiroshi Moritake, Hideki Nakayama, Shiro Tanaka, Daisuke Tomizawa, Norio Shiba, Akiko M Saito, Akio Tawa, Akira Shimada, Shotaro Iwamoto, Yasuhide Hayashi, Takashi Koike, Keizo Horibe, Atsushi Manabe, Shuki Mizutani, Takashi Taga, Souichi Adachi
    British journal of haematology 185 2 284 - 288 2019年04月 [査読有り][通常論文]
     
    The prognosis of paediatric acute myeloid leukaemia (AML) with primary induction failure (PIF) is extremely poor, and effective treatment strategies have not been established. We investigated the clinical and biological features of paediatric AML patients with PIF registered to the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study. The 3-year overall survival rate of the 41 PIF patients was 19.0%. High leucocyte count, M7 morphology, and unfavourable genetic aberrations, such as FLT3-internal tandem duplication, NUP98-NSD1 and high MECOM or PRDM16 expression, were risk factors for PIF. More effective treatment strategies based on leukaemia biology need to be urgently explored.
  • Hisashi Ishida, Akihiro Iguchi, Michinori Aoe, Takahide Takahashi, Kosuke Tamefusa, Kiichiro Kanamitsu, Kaori Fujiwara, Kana Washio, Takehiro Matsubara, Hirokazu Tsukahara, Masashi Sanada, Akira Shimada
    Annals of hematology 98 3 657 - 668 2019年03月 [査読有り][通常論文]
     
    Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although the cure rate of ALL has greatly improved, a considerable number of patients suffer from relapse of leukemia. Therefore, ALL remains the leading cause of death from cancer during childhood. To improve the cure rate of these patients, precisely detecting patients with high risk of relapse and incorporating new targeted therapies are urgently needed. This study investigated inexpensive, rapid, next-generation sequencing of more than 150 cancer-related genes for matched diagnostic, remission, and relapse samples of 17 patients (3 months to 15 years old) with relapsed ALL. In this analysis, we identified 16 single-nucleotide variants (SNVs) and insertion/deletion variants and 19 copy number variants (CNVs) at diagnosis and 28 SNVs and insertion/deletion variants and 22 CNVs at relapse. With these genetic alterations, we could detect several B cell precursor ALL patients with high-risk gene alterations who were not stratified into the highest-risk group (5/8, 62.5%). We also detected potentially actionable genetic variants in about half of the patients (8/17, 47.1%). Among them, we found that one patient harbored germline TP53 mutation as a secondary finding. This inexpensive, rapid method can be immediately applied as clinical sequencing and could lead to better management of these patients and potential improvement in the survival rate in childhood ALL.
  • Hisashi Ishida, Ryoichi Araki, Takashi Iwase, Tomoko Naito, Akira Shimada
    Pediatrics international : official journal of the Japan Pediatric Society 61 2 208 - 210 2019年02月
  • Kosuke Tamefusa, Hisashi Ishida, Kana Washio, Toshiaki Ishida, Hirosuke Morita, Akira Shimada
    Acta medica Okayama 73 1 61 - 65 2019年02月 
    Patients with multi-system (MS)-type langerhans cell histiocytosis (LCH) show poor outcomes, especially congenital MS LCH cases were shown in high mortality rate. We experienced a congenital case of MS LCH with high risk organs, who needed intensive respiratory support after birth. Even though intensive chemotherapy was discontinued, this patient's lung LCH lesions gradually became reduced and his respiratory condition recovered; therefore, we restarted and completed maintenance chemotherapy. The patient maintained complete remission for more than 4 years after the end of chemotherapy. Our case suggests that congenital MS LCH even with severe organ involvement can be treated successfully with chemotherapy.
  • Kiichiro Kanamitsu, Kousuke Chayama, Kana Washio, Ryuichi Yoshida, Yuzo Umeda, Takahito Yagi, Akira Shimada
    Acta medica Okayama 72 5 515 - 518 2018年10月 [査読有り][通常論文]
     
    Hepatitis-associated aplastic anemia (HAAA) is an acquired bone marrow failure syndrome that develops after seronegative fulminant hepatitis. Abnormal cytotoxic T-cell activation with cytokine release is a possible pathophysiology. We present the case of a 16-month-old Japanese male who developed HAAA following living-donor liver transplantation for fulminant hepatitis. His aplastic anemia was successfully treated with immunosuppressive therapy. He had been administered tacrolimus for prophylaxis against hepatic allograft rejection. Ten years after the HAAA onset, the patient's bone marrow was found to be slightly hypoplastic. Tacrolimus may be effective in controlling abnormal immune reactions that can cause recurrent impaired hematopoiesis.
  • Chihiro Tomoyasu, Toshihiko Imamura, Toshihiro Tomii, Mio Yano, Daisuke Asai, Hiroaki Goto, Akira Shimada, Masashi Sanada, Shotaro Iwamoto, Junko Takita, Masayoshi Minegishi, Takeshi Inukai, Kanji Sugita, Hajime Hosoi
    International journal of hematology 108 3 312 - 318 2018年09月 [査読無し][通常論文]
     
    In this study, we performed genetic analysis of 83 B cell precursor acute lymphoblastic leukemia (B-ALL) cell lines. First, we performed multiplex ligation-dependent probe amplification analysis to identify copy number abnormalities (CNAs) in eight genes associated with B-ALL according to genetic subtype. In Ph+ B-ALL cell lines, the frequencies of IKZF1, CDKN2A/2B, BTG1, and PAX5 deletion were significantly higher than those in Ph- B-ALL cell lines. The frequency of CDKN2A/2B deletion in KMT2A rearranged cell lines was significantly lower than that in non-KMT2A rearranged cell lines. These findings suggest that CNAs are correlated with genetic subtype in B-ALL cell lines. In addition, we determined that three B-other ALL cell lines had IKZF1 deletions (YCUB-5, KOPN49, and KOPN75); we therefore performed comprehensive genetic analysis of these cell lines. YCUB-5, KOPN49, and KOPN75 had P2RY8-CRLF2, IgH-CRLF2, and PAX5-ETV6 fusions, respectively. Moreover, targeted capture sequencing revealed that YCUB-5 had JAK2 R683I and KRAS G12D, and KOPN49 had JAK2 R683G and KRAS G13D mutations. These data may contribute to progress in the field of leukemia research.
  • Kazumasa Zensho, Hisashi Ishida, Hiroki Nagai, Hirokazu Tsukahara, Akira Shimada
    Pediatrics international : official journal of the Japan Pediatric Society 60 8 757 - 758 2018年08月 [査読無し][通常論文]
  • Akira Shimada, Yuka Iijima-Yamashita, Akio Tawa, Daisuke Tomizawa, Miho Yamada, Shiba Norio, Tomoyuki Watanabe, Takashi Taga, Shotaro Iwamoto, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Hiroyuki Takahashi, Hideki Nakayama, Katsuyoshi Koh, Hiroaki Goto, Yoshiyuki Kosaka, Akiko Moriya Saito, Nobutaka Kiyokawa, Keizo Horibe, Yusuke Hara, Kentaro Oki, Yasuhide Hayashi, Shiro Tanaka, Souichi Adachi
    International journal of hematology 107 5 586 - 595 2018年05月 [査読無し][通常論文]
     
    Acute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis. We evaluated the results of the AML-05 study, in which all AMLFLT3-ITD patients were assigned to receive hematopoietic stem cell transplantation (HSCT) in the first remission (1CR). We also investigated the effects of additional genetic alterations on FLT3-ITD. The 5-year overall survival (OS) and event-free survival (EFS) rates among the 47 AMLFLT3-ITD patients were 42.2 and 36.8%, respectively. The 5-year disease-free survival rate among 29 patients without induction failure was 58.4%. We defined the allelic ratio (AR) of FLT3-ITD to WT > 0.7 as high. Significant differences were found in OS (AR-high, 20% vs. AR-low, 66%, p < 0.001) and EFS (13 vs. 50%, p = 0.004). All five patients with concurrent NPM1 mutations survived, while seven of eight patients who expressed the NUP98-NSD1 chimera failed to achieve 1CR and died. Multivariate analysis revealed that AR > 0.7 and expression of the NUP98-NSD1 chimera strongly impacted OS and EFS. Although all the AMLFLT3-ITD patients received HSCT at 1CR, the treatment outcome of AMLFLT3-ITD patients did not improve compared with those in a previous study. Heterogeneity was observed among AMLFLT3-ITD patients.
  • Yachiyo Kuwatsuka, Daisuke Tomizawa, Rika Kihara, Yasunobu Nagata, Norio Shiba, Yuka Iijima-Yamashita, Akira Shimada, Takao Deguchi, Hayato Miyachi, Akio Tawa, Takashi Taga, Akitoshi Kinoshita, Hideki Nakayama, Nobutaka Kiyokawa, Akiko Moriya Saito, Katsuyoshi Koh, Hiroaki Goto, Yoshiyuki Kosaka, Norio Asou, Shigeki Ohtake, Shuichi Miyawaki, Yasushi Miyazaki, Toru Sakura, Yukiyasu Ozawa, Noriko Usui, Heiwa Kanamori, Yoshikazu Ito, Kiyotoshi Imai, Youko Suehiro, Shinichi Kobayashi, Kunio Kitamura, Emiko Sakaida, Seishi Ogawa, Tomoki Naoe, Yasuhide Hayashi, Keizo Horibe, Atsushi Manabe, Shuki Mizutani, Souichi Adachi, Hitoshi Kiyoi
    International journal of hematology 107 2 201 - 210 2018年02月 [査読有り][通常論文]
     
    Clinical outcomes and the genetic background of acute myeloid leukemia (AML) in adolescent and young adults (AYAs) are known to differ in younger children and older adults. To clarify the impact of genetic mutations on clinical outcomes of AYAs with AML, we analyzed data from the JPLSG AML-05 and JALSG AML201 studies. AYAs aged 15-39 years (n = 103) were included. FLT3-ITD, KIT, CEBPA, NRAS, KRAS, WT1, MLL-PTD, and NPM1 mutations were analyzed. Overall survival (OS) of the AYAs was 61% and event-free survival was 38% at 3 years. FLT3-ITD (HR 2.10; 95% CI 1.07-4.12; p = 0.031) and NPM1 (HR 0.24; 95% CI 0.06-1.00; p = 0.050) mutations were associated with risk of overall mortality in multivariate analysis. OS was significantly different according to FLT3-ITD and NPM1 mutation status (p = 0.03). Survival was 100% with NPM1 mutations in the absence of FLT3-ITD and 35% (95% CI 14-57%) with FLT3-ITD in the absence of NPM1 mutations. The OS of AYAs, children (n = 413) and older adults (n = 124) of the AML-05 and AML201 participants were significantly different (p < 0.0001). This is the first report to combine clinical and genetic data of AYA AML from the major Japanese pediatric and adult study groups.
  • Takaki Asano, Satoshi Okada, Miyuki Tsumura, Tzu-Wen Yeh, Kanako Mitsui-Sekinaka, Yuki Tsujita, Youjiro Ichinose, Akira Shimada, Kunio Hashimoto, Taizo Wada, Kohsuke Imai, Osamu Ohara, Tomohiro Morio, Shigeaki Nonoyama, Masao Kobayashi
    Frontiers in immunology 9 568 - 568 2018年 
    Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production. Heterozygous mutations in PIK3CD, PIK3R1, or PTEN, which are related to the hyperactive phosphoinositide 3-kinase (PI3K) signaling, were recently presented to cause APDS1 or APDS2 (APDSs), or APDS-like (APDS-L) disorder. In this study, we examined the AKT phosphorylation of peripheral blood lymphocytes and monocytes in patients with APDSs and APDS-L by using flow cytometry. CD19+ B cells of peripheral blood in APDS2 patients showed the enhanced phosphorylation of AKT at Ser473 (pAKT) without any specific stimulation. The enhanced pAKT in CD19+ B cells was normalized by the addition of a p110δ inhibitor. In contrast, CD3+ T cells and CD14+ monocytes did not show the enhanced pAKT in the absence of stimulation. These findings were similarly observed in patients with APDS1 and APDS-L. Among CD19+ B cells, enhanced pAKT was prominently detected in CD10+ immature B cells compared with CD10- mature B cells. Enhanced pAKT was not observed in B cells of healthy controls, patients with common variable immunodeficiency, and hyper IgM syndrome due to CD40L deficiency. These results suggest that the enhanced pAKT in circulating B cells may be useful for the discrimination of APDS1, APDS2, and APDS-L from other antibody deficiencies.
  • Hidemasa Matsuo, Yuka Iijima-Yamashita, Miho Yamada, Takao Deguchi, Nobutaka Kiyokawa, Akira Shimada, Akio Tawa, Daisuke Tomizawa, Takashi Taga, Akitoshi Kinoshita, Souichi Adachi, Keizo Horibe
    Pediatrics international : official journal of the Japan Pediatric Society 60 1 41 - 46 2018年01月 [査読有り][通常論文]
     
    BACKGROUND: In acute myeloid leukemia (AML), accurate detection of minimal residual disease (MRD) enables better risk-stratified therapy. There are few studies, however, on the monitoring of multiple fusion transcripts and evaluation of their accuracy as indicators of MRD at multiple time points. METHODS: We retrospectively examined RNA obtained from 82 pediatric AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study. The expression of six important fusion transcripts (AML1(RUNX1)-ETO, CBFB-MYH11, MLL(KMT2A)-AF9, MLL-ELL, MLL-AF6, and FUS-ERG) was analyzed at five time points 30-40 days apart following diagnosis. RESULTS: In patients with AML1-ETO (n = 36 at time point 5), all six patients with >3,000 copies and four of 30 patients with ≤3,000 copies relapsed. AML1-ETO transcripts persisted during treatment even in patients without relapse, as well as CBFB-MYH11 transcripts. In contrast, in patients with MLL-AF9 (n = 9 at time point 5), two patients were positive for MLL-AF9 expression (>50 copies) and both relapsed. Only one of seven MLL-AF9-negative patients relapsed. In the AML1-ETO group, MRD-positive patients (>3,000 copies at time point 5) had significantly lower relapse-free survival (RFS; P < 0.0001) and overall survival (OS; P = 0.009) than MRD-negative patients. Similarly, in the MLL-AF9 group, MRD-positive patients (>50 copies at time point 5) had significantly lower RFS (P = 0.002) and OS (P = 0.002) than MRD-negative patients. CONCLUSIONS: Detection of MLL-AF9 transcripts on real-time quantitative polymerase chain reaction is a promising marker of relapse in pediatric AML. In contrast, the clinical utility of detecting AML1-ETO and CBFB-MYH11 expression is limited, although higher AML1-ETO expression can be a potential predictor of relapse when assessed according to an optimal threshold.
  • Yuka Iijima-Yamashita, Hidemasa Matsuo, Miho Yamada, Takao Deguchi, Nobutaka Kiyokawa, Akira Shimada, Akio Tawa, Hiroyuki Takahashi, Daisuke Tomizawa, Takashi Taga, Akitoshi Kinoshita, Souichi Adachi, Keizo Horibe
    Pediatrics international : official journal of the Japan Pediatric Society 60 1 47 - 51 2018年01月 [査読有り][通常論文]
     
    BACKGROUND: Gene abnormalities, particularly chromosome rearrangements generating gene fusion, are associated with clinical characteristics and prognosis in pediatric acute myeloid leukemia (AML). Karyotyping is generally performed to enable risk stratification, but the results are not always consistent with those of reverse transcription-polymerase chain reaction (RT-PCR), and more accurate and rapid methods are required. METHODS: A total of 487 samples from de novo AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study (n = 448), and from acute promyelocytic leukemia (APL) patients enrolled in the JPLSG AML-P05 study (n = 39) were available for this investigation. Multiplex quantitative RT-PCR was performed to detect eight important fusion genes: AML1(RUNX1)-ETO(RUNX1T1), CBFB-MYH11, MLL(KMT2A)-AF9(MLLT3), MLL-ELL, MLL-AF6(MLLT4), FUS(TLS)-ERG, NUP98-HOXA9, and PML-RARA. RESULTS: Fusion genes were detected in 207 (46.2%) of the 448 AML-05 patient samples. After exclusion of two samples with PML-RARA, no chromosomal abnormalities were identified on karyotyping in 19 of 205 patients (9.3%) positive for fusion genes on RT-PCR. Fusion genes were confirmed on fluorescence in situ hybridization (FISH) in 11 of these 19 patients. In contrast, fusion genes were detected in 37 of 39 patients (94.9%) from the AML-P05 study, and 33 of these results were consistent with the karyotyping. There were discrepancies in four patients (10.8%), three with normal karyotypes and one in whom karyotyping was not possible. All four of these patients were PML-RARA positive on FISH. CONCLUSIONS: Multiplex quantitative RT-PCR-based fusion gene screening may be effective for diagnosis of pediatric AML.
  • Yousuke Higuchi, Takayuki Motoki, Hisashi Ishida, Kiichiro Kanamitsu, Kana Washio, Takanori Oyama, Takuo Noda, Yasuko Tsurumaru, Ayumi Okada, Hirokazu Tsukahara, Akira Shimada
    BMC cancer 17 1 775 - 775 2017年11月 [査読無し][通常論文]
     
    BACKGROUND: Pediatric papillary thyroid carcinoma frequently presents with lymph node involvement and distant metastases. Sorafenib, an oral multikinase inhibitor, has been used to treat radioactive iodine (RAI) therapy-refractory thyroid carcinoma in adults; however, pediatric experience is limited. Medical procedures and hospitalization for children with autism spectrum disorder may be challenging. CASE PRESENTATION: An 11-year-old boy with autism spectrum disorder and moderate intellectual impairment presented with dyspnea on exertion with thyroid carcinoma and diffuses lung metastases. Total thyroidectomy and adjuvant RAI therapy is the standard treatment; however, the latter therapy was impractical because of his respiratory status and challenging behaviors. He was therefore started on sorafenib 200 mg/day (150 mg/m2/day) and this dosage was increased to 400 mg/day (300 mg/m2/day). The adverse effects were mild and tolerable. After administration of medication, his dyspnea improved and surgery was performed. We attempted to administer RAI therapy after surgery; however, we abandoned it because he had difficulty taking care of himself according to isolation room rules. Thyrotropin suppression therapy was therefore started and sorafenib treatment (400 mg/day) resumed. Follow-up imaging showed regression of pulmonary metastases. The metastases have remained stable for over 24 months on continuous sorafenib treatment without serious adverse events. CONCLUSION: We inevitably used sorafenib as an alternative to standard therapy because of the patient's specific circumstances. Individualized strategies for pediatric cancer patients with autism spectrum disorder are needed.
  • Naoko Iwai, Akira Shimada, Atsushi Iwai, Sonoe Yamaguchi, Hirokazu Tsukahara, Megumi Oda
    Pediatrics international : official journal of the Japan Pediatric Society 59 11 1140 - 1150 2017年11月 [査読無し][通常論文]
     
    BACKGROUND: Childhood cancer survivors (CCS) and their family members continue to live in fear even after treatment is concluded due to concerns about late effects and recurrences. The consequent long-term psychological burden requires long-term follow up suited to the anxieties and needs of CCS, hence the need for the present survey. METHODS: We conducted a questionnaire survey at medical facilities in the Chugoku and Shikoku regions of Japan with CCS who had survived for at least 5 years following treatment, and their family members. RESULTS: A total of 30 CCS (53%) and 27 CCS family members (47%) answered the questionnaires. The median age of the CCS and their family members (CCS parents) was 23 years and 51.5 years, respectively. The most common diagnosis was acute lymphoblastic leukemia (47%) and the median length of follow up after the conclusion of treatment was 11 years. The percentage of participants who responded that they knew about late effects was significantly lower among CCS than among CCS parents. Almost no significant difference was observed between CCS and CCS parents regarding anxieties at specific life stages. The main consultants for CCS and CCS parents were their family, but they sought opportunities for casual consultation for current worries outside the family. CONCLUSIONS: It is necessary for medical facilities not only to provide medical support, but also to establish a place where they can provide centralized consultation for the anxieties of CCS and their parents.
  • Kana Washio, Takashi Oka, Lamia Abdalkader, Michiko Muraoka, Akira Shimada, Megumi Oda, Hiaki Sato, Katsuyoshi Takata, Yoshitoyo Kagami, Norio Shimizu, Seiichi Kato, Hiroshi Kimura, Kazunori Nishizaki, Tadashi Yoshino, Hirokazu Tsukahara
    Leukemia & lymphoma 58 11 2683 - 2694 2017年11月 [査読有り][通常論文]
     
    The human herpes virus, Epstein-Barr virus (EBV), is a known oncogenic virus and plays important roles in life-threatening T/NK-cell lymphoproliferative disorders (T/NK-cell LPD) such as hypersensitivity to mosquito bite (HMB), chronic active EBV infection (CAEBV), and NK/T-cell lymphoma/leukemia. During the clinical courses of HMB and CAEBV, patients frequently develop malignant lymphomas and the diseases passively progress sequentially. In the present study, gene expression of CD16(-)CD56(+)-, EBV(+) HMB, CAEBV, NK-lymphoma, and NK-leukemia cell lines, which were established from patients, was analyzed using oligonucleotide microarrays and compared to that of CD56brightCD16dim/- NK cells from healthy donors. Principal components analysis showed that CAEBV and NK-lymphoma cells were relatively closely located, indicating that they had similar expression profiles. Unsupervised hierarchal clustering analyses of microarray data and gene ontology analysis revealed specific gene clusters and identified several candidate genes responsible for disease that can be used to discriminate each category of NK-LPD and NK-cell lymphoma/leukemia.
  • Jun-Ichi Ueyama, Mizuka Miki, Keisuke Okuno, Shohei Eto, Akira Shimada
    Pediatrics international : official journal of the Japan Pediatric Society 59 10 1103 - 1105 2017年10月 [査読無し][通常論文]
  • Hideki Nakayama, Daisuke Tomizawa, Shiro Tanaka, Shotaro Iwamoto, Akira Shimada, Akiko M Saito, Yuka Yamashita, Hiroshi Moritake, Kiminori Terui, Takashi Taga, Hidemasa Matsuo, Yoshiyuki Kosaka, Katsuyoshi Koh, Hajime Hosoi, Hidemitsu Kurosawa, Keiichi Isoyama, Keizo Horibe, Shuki Mizutani, Souichi Adachi
    Pediatrics international : official journal of the Japan Pediatric Society 59 10 1046 - 1052 2017年10月 [査読無し][通常論文]
     
    BACKGROUND: The combination of fludarabine (Flu), high-dose cytarabine (Ara-C) and granulocyte colony-stimulating factor (G-CSF; FLAG), with anthracyclines has become standard chemotherapy for refractory acute myeloid leukemia (AML) in European children and adults. To clarify the efficacy and the safety of FLAG-idarubicin (IDA) for children prospectively, we planned a multicenter phase II study (AML-R11) by the Japanese Pediatric Leukemia/Lymphoma Study Group. METHODS: Patients with AML aged between 2 and 20 years old, who had the first bone marrow (BM) relapse or induction failure, were enrolled. The FLAG-IDA regimen consisted of Flu 30 mg/m2 for 5 days, Ara-C 2 g/m2 for 5 days, G-CSF (lenograstim) 5 μg/kg for 6 days and IDA 10 mg/m2 for 3 days. The primary endpoint was remission rate after therapy. RESULTS: Due to drug supply issues, the trial was suspended after the inclusion of seven eligible patients. There were six cases of early relapse within 1 year of the first remission. All seven patients completed the therapy and no early death was observed. Hematological toxicity was common, and one patient developed grade 4 non-hematological toxicity of bacterial meningitis. Although only one patient with late relapse achieved complete remission, minimal residual disease was positive on both flow cytometry and Wilms' tumor 1 mRNA. Two patients were alive in remission following hematopoietic stem cell transplantation, whereas the other five patients died of either the disease or treatment-related causes. CONCLUSION: FLAG-IDA might be tolerable for children with refractory AML although the efficacy should be further investigated.
  • Hiroshi Moritake, Shiro Tanaka, Hideki Nakayama, Takako Miyamura, Shotaro Iwamoto, Akira Shimada, Kiminori Terui, Akiko Saito, Norio Shiba, Yasuhide Hayashi, Daisuke Tomizawa, Takashi Taga, Hiroaki Goto, Daisuke Hasegawa, Keizo Horibe, Shuki Mizutani, Souichi Adachi
    Pediatric blood & cancer 64 10 883 - 890 2017年10月 [査読無し][通常論文]
  • Hisashi Ishida, Kousuke Chayama, Kiichiro Kanamitsu, Kana Washio, Takehiro Tanaka, Akira Shimada
    Pediatrics international : official journal of the Japan Pediatric Society 59 5 624 - 626 2017年05月 [査読無し][通常論文]
     
    Patients with Down syndrome (DS) have a markedly higher incidence of childhood leukemia, but a lower incidence of most solid tumors, compared with age-matched euploid individuals. Trisomy 21 might be protective against tumorigenesis because of several tumor suppressive mechanisms. Desmoid-type fibromatosis (DF) is a rare monoclonal, fibroblastic proliferation characterized by a variable clinical course. In recent reports, almost all cases of DF involved genomic alterations associated with activation of the Wnt/β-catenin pathway. Here, we report the case of a boy with DS who developed DF without activation of the Wnt/β-catenin pathway. To the best of our knowledge, this is the first case of DS involving DF.
  • Masahiro Kameda, Yoshihiro Otani, Tomotsugu Ichikawa, Akira Shimada, Koichi Ichimura, Isao Date
    World neurosurgery 101 817.e5-817.e14  2017年05月 [査読無し][通常論文]
     
    BACKGROUND: The molecular diagnosis of brain tumors is important in classifying tumors and determining appropriate treatment. Congenital glioblastoma multiforme (GBM) is a rare tumor that occurs in infants, and the prognosis is poor. Approximately 60 patients diagnosed with congenital GBM have been reported. However, few reports have conducted molecular analyses of congenital GBM. CASE DESCRIPTION: We describe 2 congenital GBM patients treated in our hospital, and report results of immunohistochemistry, fluorescent in situ hybridization (FISH), direct sequencing, and methylation analyses. Surgery was performed on both patients at 2 months old, and the cases were diagnosed as glioblastoma. Immunohistochemical staining, FISH, and direct sequencing were positive for glial fibrillary acidic protein and ATRX, partially positive for p53, showed no alteration of isocitrate dehydrogenase 1 R132H, H3F3A, HIST1H3B, and BRAF, and indicated no codeletion of 1p and 19q. Methylation analysis of 1 patient identified copy number aberrations of 4 genes: deletions of CDK6 and CDKN2A/B, and a fusion of MET. One patient received chemotherapy consisting of ranimustine, interferon-beta, carboplatin, and etoposide, whereas the other patient received chemotherapy with the modified Children's Cancer Group study-9921 protocol. Residual tumors in both patients were decreased, and they achieved 18-year- and 9-month progression-free survival, respectively. In addition, we reviewed 65 previously reported congenital GBM patients, and found they have better prognosis than pediatric and adult GBM, and long-term survival can be expected. CONCLUSIONS: Congenital GBM demonstrates clinical and molecular characteristics that are different from those of pediatric or adult GBM.
  • N. Yoshida, H. Sakaguchi, H. Muramatsu, Y. Okuno, C. Song, S. Dovat, A. Shimada, M. Ozeki, H. Ohnishi, T. Teramoto, T. Fukao, N. Kondo, Y. Takahashi, K. Matsumoto, K. Kato, S. Kojima
    LEUKEMIA 31 5 1221 - 1223 2017年05月 [査読無し][通常論文]
  • Kiichiro Kanamitsu, Akira Shimada, Ritsuo Nishiuchi, Tomonari Shigemura, Yozo Nakazawa, Kenichi Koike, Yuichi Kodama, Yuichi Shinkoda, Yoshifumi Kawano, Kozo Yasui, Koji Sasaki, Ryosuke Kajiwara, Hirokazu Tsukahara, Atsushi Manabe
    International journal of hematology 105 3 377 - 382 2017年03月 [査読無し][通常論文]
     
    Behçet disease (BD) is rarely seen in children. Its clinical manifestations are believed to differ between pediatric and adult patients. The characteristics of BD complicated by myelodysplastic syndrome (MDS) are well established for adult patients; however, because only a few cases of pediatric-onset BD complicated by MDS have been reported, its clinical characteristics remain unknown. We here retrospectively review pediatric-onset BD complicated by myeloid malignancies in Japan, having identified five such patients. All patients were female and had gastrointestinal involvements, but lacked both major features of BD, i.e., uveitis and association with HLA-B51. All patients had advanced MDS or acute myeloid leukemia and received chemotherapy followed by hematopoietic stem cell transplantation. These five cases suggest that intestinal BD and myeloid malignancies have one or more pathophysiological mechanisms in common.
  • Akira Shimada
    [Rinsho ketsueki] The Japanese journal of clinical hematology 58 8 983 - 990 2017年 [査読無し][通常論文]
     
    Annually, it is estimated that approximately 150-200 children aged 0-16 years are diagnosed with acute myeloid leukemia (AML). In Japan, clinical studies with ANLL91, AML99, CCLSG-AML9805, and JPLSG-AML05 protocols were performed historically, and the risk stratification with a combination of chemotherapy and hematopoietic stem cell transplantation resulted in the improvement of clinical outcomes. Regarding the onset of pediatric AML at the molecular level, mutations in FLT3-ITD or KIT (Class I mutation) showed a poor prognosis, but the ratio of mutations in Class III-V genes was smaller than that in adult AML. In contrast, several pediatric AML cases are complicated due to chromosome fragility syndrome or congenital bone marrow failure syndrome. To improve the clinical outcomes, clinical application of next generation sequencing may allow for personalized therapy in each patient in the future.
  • Everolimus for Treatment of Pseudomyogenic Hemangioendothelioma
    Ozeki M, Nozawa A, Kanda K, Hori T, Nagano A, Shimada A, Miyazaki T, Fukao T
    J. Pediatric Hematol Oncol 39 6 e328-e331  2017年 [査読無し][通常論文]
  • Kana Washio, Michiko Muraoka, Kiichiro Kanamitsu, Megumi Oda, Akira Shimada
    ACTA MEDICA OKAYAMA 71 3 249 - 254 2017年 [査読無し][通常論文]
     
    We diagnosed a female infant with Langerhans cell histiocytosis (LCH) who was refractory to conventional chemotherapy. She showed refractory inflammation that was complicated with hemophagocytic lymphohistiocytosis (HLH) during LCH chemotherapy; therefore, we changed the protocol to HLH2004 (dexamethasone, cyclosporine A and VP16). However, there were no signs of hematological recovery. We therefore performed cord blood transplantation with reduced-intensity conditioning, and she achieved complete remission for over 2 years. As salvage therapy for refractory LCH, hematopoietic stem cell transplantation may be a good therapeutic choice, especially when LCH is complicated with HLH.
  • Five Cases of Pediatric-Onset Bechet’s disease complicated with Myelodysplastic Syndrome.
    Kanamitsu K, Shimada A, Nishiuchi R, Shigemura T, Nakazawa Y, Koike K, Kodama Y, Shinkoda Y, Kawano Y, Yasui K, Sasaki K, Kajiwara R, Tsukahara H, Manabe A
    International Journal of Hematology 105 3 377 - 382 2017年 [査読無し][通常論文]
  • Yoshihiro Otani, Tomotsugu Ichikawa, Kazuhiko Kurozumi, Takao Yasuhara, Kana Washio, Akira Shimada, Norihisa Katayama, Kuniaki Katsui, Hiroyuki Yanai, Isao Date
    Neurological Surgery, No shinkei geka. Neurological surgery 45 2 147 - 154 2017年 [査読無し][通常論文]
     
    Atypical teratoid/rhabdoid tumor(AT/RT)is a rare and lethal childhood cancer. Although radiation therapy in children less than three years of age is generally deferred because of its neural toxicity, recent studies have shown that multimodal therapies, including radiation therapy, are effective in pediatric patients with AT/RT less than three years of age. We treated four infant AT/RT patients and investigated the impact of radiation therapy and genetic classification on the prognosis. The mean age at the time of the operation was 9.3 months and all patients were female. All patients underwent surgical resection. Of the four patients, two received combined irradiation and chemotherapy. Specifically, one patient received conformal craniospinal radiation therapy and the other received craniospinal irradiation with proton beams. Immunohistochemical analyses of tumor specimens revealed that the two patients were positive for ASCL1, a regulator of Notch signaling. Patients who received radiation therapy and exhibited ASCL1-positive tumors had a better prognosis. We conclude that radiation therapy may prolong survival in AT/RT patients who are less than 3 years of age. However, further study is required to evaluate long-term functional outcomes.
  • Nakayama H, Tomizawa D, Tanaka S, Iwamoto S, Shimada A, Saito AM, Yamashita Y, Moritake H, Terui K, Taga T, Matsuo H, Kosaka Y, Koh K, Hosoi H, Kurosawa H, Isoyama K, Horibe K, Mizutani S, Adachi S
    Pediatr Int. 2017 Oct;59(10):1046-1052. 2017年 [査読有り][通常論文]
  • Yui Kanazawa, Yuka Yamashita, Mitsuhiro Fujiwara, Michiko Muraoka, Kana Washio, Kiichiro Kanamitsu, Hisashi Ishida, Takae Nakano, Miho Yamada, Keizo Horibe, Takehiro Tanaka, Tadashi Yoshino, Akira Shimada
    Acta medica Okayama 70 6 503 - 506 2016年12月 [査読無し][通常論文]
     
    Childhood anaplastic large cell lymphoma (ALCL) accounts for approx. 10-30% of cases of non-Hodgkin lymphoma, and the ALCL99 study reported 60-75 disease-free survival; however, a relatively high relapse rate was observed (25-30% ). We report 2 patients with Stage III ALCL who relapsed 6-18 months after the end of ALCL99 chemotherapy. A retrospective molecular analysis identified the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) fusion gene in the first diagnostic bone marrow samples taken from both patients. However, antibodies against the ALK protein appeared to be relatively low in the serum of both patients (×100 and ×750). An increase in chemotherapy intensity may be beneficial if Stage III ALCL patients are shown to be NPM-ALK chimera-positive in the first diagnostic bone marrow sample.
  • Norio Shiba, Kenichi Yoshida, Yuichi Shiraishi, Yusuke Okuno, Genki Yamato, Yusuke Hara, Yasunobu Nagata, Kenichi Chiba, Hiroko Tanaka, Kiminori Terui, Motohiro Kato, Myoung-Ja Park, Kentaro Ohki, Akira Shimada, Junko Takita, Daisuke Tomizawa, Kazuko Kudo, Hirokazu Arakawa, Souichi Adachi, Takashi Taga, Akio Tawa, Etsuro Ito, Keizo Horibe, Masashi Sanada, Satoru Miyano, Seishi Ogawa, Yasuhide Hayashi
    British journal of haematology 175 3 476 - 489 2016年11月 [査読無し][通常論文]
     
    Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease. Targeted sequencing efforts have identified several mutations with diagnostic and prognostic values in KIT, NPM1, CEBPA and FLT3 in both adult and paediatric AML. In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH1/2 and DNMT3A) in adult AML. In this study, whole-exome sequencing (WES) of 22 paediatric AML patients revealed mutations in components of the cohesin complex (RAD21 and SMC3), BCORL1 and ASXL2 in addition to previously known gene mutations. We also revealed intratumoural heterogeneities in many patients, implicating multiple clonal evolution events in the development of AML. Furthermore, targeted deep sequencing in 182 paediatric AML patients identified three major categories of recurrently mutated genes: cohesion complex genes [STAG2, RAD21 and SMC3 in 17 patients (8·3%)], epigenetic regulators [ASXL1/ASXL2 in 17 patients (8·3%), BCOR/BCORL1 in 7 patients (3·4%)] and signalling molecules. We also performed WES in four patients with relapsed AML. Relapsed AML evolved from one of the subclones at the initial phase and was accompanied by many additional mutations, including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process causing leukaemia recurrence.
  • Hisashi Ishida, Kiichiro Kanamitsu, Kana Washio, Michiko Muraoka, Kanae Sakakibara, Takehiro Matsubara, Hirotaka Kanzaki, Akira Shimada
    Pediatric blood & cancer 63 11 2059 - 60 2016年11月 [査読無し][通常論文]
  • 大杉 夕子, 山口 悦子, 長谷川 大一郎, 今村 俊彦, 早川 晶, 安井 昌博, 坂口 大俊, 堀 司, 嶋田 明, 岩本 彰太郎, 橋井 佳子, 田村 真一, 力石 健, 照井 君典, 金井 理恵, 佐藤 篤, 堀部 敬三, 小林 良二, 足立 壯一
    日本小児血液・がん学会雑誌 53 4 274 - 274 2016年11月
  • Ai Yamada, Hiroshi Moritake, Mariko Kinoshita, Daisuke Sawa, Sachiyo Kamimura, Shotaro Iwamoto, Yuka Yamashita, Jiro Inagaki, Takahide Takahashi, Akira Shimada, Megumi Obara, Hiroyuki Nunoi
    Pediatrics international : official journal of the Japan Pediatric Society 58 9 905 - 8 2016年09月 [査読無し][通常論文]
     
    Inversion of chromosome 16 [inv(16)] has a good prognosis in acute myeloid leukemia (AML), but additional genetic aberrations influence the outcome. We herein describe the case of a 15-year-old Japanese boy with inv(16) harboring a low-allelic burden internal tandem duplication of FLT3 (FLT3-ITD) and KIT mutations. Conventional chemotherapy eradicated a clone with a low-allelic burden FLT3-ITD mutation, although another clone with a KIT mutation occurred 17 months later. Further investigation is necessary to identify AML with inv(16) conferring poor prognosis, to facilitate appropriate treatment with additional drugs, such as dasatinib or gemtuzumab ozogamicin.
  • Yuko Sekiya, Yusuke Okuno, Hideki Muramatsu, Olfat Ismael, Nozomu Kawashima, Atsushi Narita, Xinan Wang, Yinyan Xu, Asahito Hama, Hiroyuki Fujisaki, Toshihiko Imamura, Daiichiro Hasegawa, Yoshiyuki Kosaka, Shosuke Sunami, Yoshitoshi Ohtsuka, Shouichi Ohga, Yoshiyuki Takahashi, Seiji Kojima, Akira Shimada
    International journal of hematology 104 2 266 - 7 2016年08月 [査読無し][通常論文]
  • Hiroyuki Takahashi, Tomoyuki Watanabe, Akitoshi Kinoshita, Yuki Yuza, Hiroshi Moritake, Kiminori Terui, Shotaro Iwamoto, Hideki Nakayama, Akira Shimada, Kazuko Kudo, Tomohiko Taki, Miharu Yabe, Hiromichi Matsushita, Yuka Yamashita, Kazutoshi Koike, Atsushi Ogawa, Yoshiyuki Kosaka, Daisuke Tomizawa, Takashi Taga, Akiko M. Saito, Keizo Horibe, Tatsutoshi Nakahata, Hayato Miyachi, Akio Tawa, Souichi Adachi
    BRITISH JOURNAL OF HAEMATOLOGY 174 3 437 - 443 2016年08月 [査読無し][通常論文]
     
    We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 836% [95% confidence interval (CI): 686-918%] and 907% (95% CI: 771-964%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 333% (95% CI: 193-676%) and 546% (95% CI: 229-780%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered.
  • Michiko Muraoka, Chiho Okuma, Kiichiro Kanamitsu, Hisashi Ishida, Yui Kanazawa, Kana Washio, Masafumi Seki, Motohiro Kato, Junko Takita, Yusuke Sato, Seishi Ogawa, Hirokazu Tsukahara, Megumi Oda, Akira Shimada
    Journal of human genetics 61 6 523 - 6 2016年06月 [査読無し][通常論文]
     
    Juvenile myelomonocytic leukemia (JMML) appears to be a life-threatening disease and showed poor prognosis even after hematopoietic stem cell transplantation (HSCT) because of high relapse rate. On the other hand, recent molecular analysis revealed the heterogeneity of JMML. Here we report that two JMML patients survived >20 years without HSCT and both patients had uniparental disomy of 11q23 where CBL is located without the phenomenon found in neither Noonan syndrome nor Noonan syndrome-like disorder. We think that some JMML patients with CBL mutation might show the good prognosis in later life after remission of JMML.
  • Takashi Taga, Tomoyuki Watanabe, Daisuke Tomizawa, Kazuko Kudo, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Shotaro Iwamoto, Hideki Nakayama, Hiroyuki Takahashi, Akira Shimada, Tomohiko Taki, Tsutomu Toki, Etsuro Ito, Hiroaki Goto, Katsuyoshi Koh, Akiko M. Saito, Keizo Horibe, Tatsutoshi Nakahata, Akio Tawa, Souichi Adachi
    PEDIATRIC BLOOD & CANCER 63 2 248 - 254 2016年02月 [査読無し][通常論文]
     
    Background. On the basis of results of previous Japanese trials for myeloid leukemia in Down syndrome (ML-DS), the efficacy of risk-oriented therapy was evaluated in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-D05 study. Procedure. All patients received induction chemotherapy that consisted of pirarubicin, intermediate-dose cytarabine, and etoposide. Patients who achieved complete remission (CR) after initial induction therapy were stratified to the standard risk (SR) group and received four courses of reduced-dose intensification therapy. Patients who did not achieve CR were stratified to the high risk (HR) group and received intensified therapy that consisted of continuous or high-dose cytarabine. Results. A total of 72 patients were eligible and evaluated. One patient died of sepsis during initial induction therapy. Sixty-nine patients were stratified to SR and two patients to HR. No therapy-related deaths were observed during intensification therapy. The 3-year event-free and overall survival rates were 83.3% +/- 4.4% and 87.5% +/- 3.9 %, respectively. Age at diagnosis less than 2 years was a significant favorable prognostic factor for risk of relapse (P = 0.009). Conclusions. The attempt of risk-oriented prospective study for ML-DS was unsuccessful, but despite the dose reduction of chemotherapeutic agents, the overall outcome was good, and further dose reduction might be possible for specific subgroups. (c) 2015 Wiley Periodicals, Inc.
  • Norio Shiba, Kentaro Ohki, Tohru Kobayashi, Yusuke Hara, Genki Yamato, Reo Tanoshima, Hitoshi Ichikawa, Daisuke Tomizawa, Myoung-ja Park, Akira Shimada, Manabu Sotomatsu, Hirokazu Arakawa, Keizo Horibe, Souichi Adachi, Takashi Taga, Akio Tawa, Yasuhide Hayashi
    BRITISH JOURNAL OF HAEMATOLOGY 172 4 581 - 591 2016年02月 [査読無し][通常論文]
     
    Recent reports described the NUP98-NSD1 fusion as an adverse prognostic marker for acute myeloid leukaemia (AML) and PRDM16 (also known as MEL1) as the representative overexpressed gene in patients harbouring NUP98-NSD1 fusion. PRDM16 gene expression levels were measured via real-time polymerase chain reaction in 369 paediatric patients with de novo AML, of whom 84 (23%) exhibited PRDM16 overexpression (PRDM16/ABL1 ratio 0010). The frequencies of patients with high or low PRDM16 expression differed widely with respect to each genetic alteration, as follows: t(8;21), 4% vs. 96%, P<0001; inv(16), 0% vs. 100%, P<0001; KMT2A (also termed MLL)- partial tandem duplication, 100% vs. 0%, P<0001; NUP98-NSD1, 100% vs. 0%, P<0001. The overall survival (OS) and event-free survival (EFS) among PRDM16-overexpressing patients were significantly worse than in patients with low PRDM16 expression (3-year OS: 51% vs. 81%, P<0001, 3-year EFS: 32% vs. 64%, P<0001) irrespective of other cytogenetic alterations except for NPM1. PRDM16 gene expression was particularly useful for stratifying FLT3-internal tandem duplication-positive AML patients (3-year OS: high=30% vs. low=70%, P<0001). PRDM16 overexpression was highly recurrent in de novo paediatric AML patients with high/intermediate-risk cytogenetic profiles and was independently associated with an adverse outcome.
  • Takae Hanada, Kiichiro Kanamitsu, Kosuke Chayama, Takako Miyamura, Yui Kanazawa, Michiko Muraoka, Kana Washio, Masahide Imada, Misao Kageyama, Akihito Takeuchi, Kei Tamai, Megumi Oda, Akira Shimada
    Acta medica Okayama 70 1 31 - 5 2016年 [査読無し][通常論文]
     
    The treatment of patients with congenital leukemia is difficult and often results in a poor prognosis. We present here the case of a female child with congenital acute myeloid leukemia (AML) with t(8 ; 16) (p11 ; p13) who received chemotherapy and survived for more than 10 years without relapse. A novel MOZ-CBP chimera was found in her diagnostic sample. Although adult AML patients with MOZ-CBP have mainly been reported as having therapy-related AML and showed poor prognoses, the present case supports the idea that AML with MOZ-CBP in the pediatric population might show better prognoses.
  • Relapsed AML patient with inv(16) harboring a low FLT3-ITD allelic burden and KIT mutations
    Yamada A, Moritake H, Kinoshita M, Sawa D, Kamimura S, Iwamoto S, Yamashita Y, Inagaki J, Takahashi T, Shimada A, Obara M, Nunoi H.
    Pediatric International 58 9 905 - 908 2016年 [査読無し][通常論文]
  • Tokumasu M, Murata C, Shimada A, Ohki K, Hayashi Y, Saito AM, Fujimoto J, Horibe K, Nagao M, Itoh H, Kamikubo Y, Nakayama H, Kinoshita A, Tomizawa D, Taga T, Tawa A, Tanaka S, Heike T, Adachi S
    Leukemia 29 12 2438 - 2441 2015年12月 [査読有り][通常論文]
  • Takahide Takahashi, Akira Inoue, Junko Yoshimoto, Kiichiro Kanamitsu, Tomohiko Taki, Masahide Imada, Mutsuko Yamada, Shinsuke Ninomiya, Tsutomu Toki, Kiminori Terui, Etsuro Ito, Akira Shimada
    Pediatric blood & cancer 62 11 2021 - 4 2015年11月 [査読有り][通常論文]
     
    Myeloid malignancy with Down syndrome (ML-DS) is estimated to have a step-wise leukemogenesis including GATA1 mutation. Trisomy 21 is essential for ML-DS; however, we do not know exactly which gene or genes located on chromosome 21 are necessary for the ML-DS. We report a female infant with transient myeloproliferative disorder (TMD) and partial trisomy 21. SNP array analysis showed 10 Mb amplification of 21q22.12-21q22.3, which included DYRK1A, ERG, and ETS but not the RUNX1 gene. With two other reported TMD cases having partial trisomy 21, DYRK1A, ERG, and ETS were the most likely genes involved in collaboration with the GATA1 mutation.
  • 富澤 大輔, 多和 昭雄, 清河 信敬, 木下 明俊, 宮地 勇人, 山下 友加, 岩本 彰太郎, 出口 隆生, 柴 徳生, 盛武 浩, 嶋田 明, 長谷川 大輔, 多賀 崇, 石井 榮一, 足立 壮一, 日本小児白血病リンパ腫研究グループ(JPLSG)
    日本小児血液・がん学会雑誌 52 4 249 - 249 2015年10月
  • Daisuke Tomizawa, Tomoyuki Watanabe, Ryoji Hanada, Keizo Horibe, Yasuo Horikoshi, Shotaro Iwamoto, Akitoshi Kinoshita, Hiroshi Moritake, Hideki Nakayama, Akira Shimada, Takashi Taga, Hiroyuki Takahashi, Akio Tawa, Kiminori Terui, Hiroki Hori, Yoshifumi Kawano, Atsushi Kikuta, Atsushi Manabe, Souichi Adachi
    International journal of hematology 102 3 318 - 26 2015年09月 [査読無し][通常論文]
     
    As past studies of adolescent and young adults (AYA) with acute myeloid leukemia (AML) reported conflicting results, we conducted a retrospective analysis using data from three Japanese pediatric AML studies. Among the 782 patients with de novo AML, 44 were classified as AYA (age ≥15 years at diagnosis), 164 as infants (0-1 year), 413 as younger children (2-11 years), and 161 as older children (12-14 years). While the 5-year event-free survival rate of AYA was not different among the groups, the five-year survival rate (54.7 %) was significantly lower than that of the other three groups (P = 0.019): 68.7 % for infants, 73.2 % for younger children, and 75.5 % for older children. No difference in the 5-year cumulative incidence of relapse was observed, but treatment-related death (TRD) of AYA was significantly higher (29.4 %) than that in infants (14.8 %), younger children (10.2 %), and older children (13.8 %). Multivariate analysis showed age ≥15 years old at diagnosis was associated with both poor survival rate and high TRD. Adolescents with AML had inferior survival due to a higher incidence of TRD, especially after failure of initial frontline treatment.
  • 栗山 絢子, 吉本 優里, 平林 真介, 長谷川 大輔, 小澤 美和, 草川 功, 真部 淳, 嶋田 明, 末延 聡一
    日本小児科学会雑誌 119 2 419 - 419 (公社)日本小児科学会 2015年02月 [査読無し][通常論文]
  • Hiroyuki Takahashi, Tomoyuki Watanabe, Akitoshi Kinoshita, Yuki Yuza, Hiroshi Moritake, Kiminori Terui, Shotaro Iwamoto, Hideki Nakayama, Akira Shimada, Kazuko Kudo, Tomohiko Taki, Miharu Yabe, Hiromichi Matsushita, Yuka Yamashita, Kazutoshi Koike, Atsushi Ogawa, Yoshiyuki Kosaka, Daisuke Tomizawa, Takashi Taga, Akiko M. Saito, Keizo Horibe, Tatsutoshi Nakahata, Hayato Miyachi, Akio Tawa, Souichi Adachi
    BLOOD 124 21 2014年12月 [査読有り][通常論文]
  • Takashi Taga, Tomoyuki Watanabe, Kazuko Kudo, Daisuke Tomizawa, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Shotaro Iwamoto, Hideki Nakayama, Hiroyuki Takahashi, Akira Shimada, Tomohiko Taki, Tsutomu Toki, Etsuro Ito, Hiroaki Goto, Katsuyoshi Koh, Akiko M. Saito, Keizo Horibe, Tatsutoshi Nakahata, Akio Tawa, Souichi Adachi
    BLOOD 124 21 2014年12月 [査読有り][通常論文]
  • Hidemasa Matsuo, Mio Kajihara, Daisuke Tomizawa, Tomoyuki Watanabe, Akiko Moriya Saito, Junichiro Fujimoto, Keizo Horibe, Kumi Kodama, Mayu Tokumasu, Hiroshi Itoh, Hideki Nakayama, Akitoshi Kinoshita, Takashi Taga, Akio Tawa, Tomohiko Taki, Norio Shiba, Kentaro Ohki, Yasuhide Hayashi, Yuka Yamashita, Akira Shimada, Shiro Tanaka, Souichi Adachi
    HAEMATOLOGICA 99 11 e225-e227  2014年11月 [査読無し][通常論文]
  • Hideki Nakayama, Ken Tabuchi, Akio Tawa, Ichiro Tsukimoto, Masahiro Tsuchida, Akira Morimoto, Hiromasa Yabe, Keizo Horibe, Ryoji Hanada, Masue Imaizumi, Yasuhide Hayashi, Kazuko Hamamoto, Ryoji Kobayashi, Kazuko Kudo, Akira Shimada, Takako Miyamura, Hiroshi Moritake, Daisuke Tomizawa, Takashi Taga, Souichi Adachi
    International journal of hematology 100 2 171 - 9 2014年08月 [査読無し][通常論文]
     
    The outcomes of children with relapsed acute myeloid leukemia (AML) are known to be poor, but remain obscure. We retrospectively analyzed 71 patients who had relapsed following first-line treatment under the AML99 protocol. We investigated the time and site of recurrence, response to re-induction therapy, and performance of hematopoietic stem cell transplantation (HSCT) in relapsed cases, and performed a multivariate analysis to identify prognostic factors. The 5-year overall-survival (OS) rate after relapse was 37 %. Of 71 patients, three died without any anti-leukemic therapy and two underwent allogeneic HSCT. The remaining 66 patients received re-induction chemotherapy, and 33 (50 %) achieved second CR (CR2). Twenty-two of 25 (88 %) late relapse patients and 11 of 41 (27 %) early relapse patients achieved CR2 (P < 0.001). Twenty-nine CR2 cases and 35 non-CR2 cases underwent allogeneic HSCT. The 5-year OS rate was significantly higher in patients who underwent HSCT in CR2 than those in non-CR2 (66 vs. 17 %, P < 0.000001). Multivariate analysis indicated that early relapse (P < 0.05) and the positivity of the FMS-like tyrosine kinase 3--internal tandem duplication (P < 0.05) were adverse prognostic factors for survival. In conclusion, the etiology of relapsed pediatric AML needs to be elucidated and effective chemotherapy should be administered to obtain CR2.
  • Olfat Ismael, Akira Shimada, Shaimaa Elmahdi, Momen Elshazley, Hideki Muramatsu, Asahito Hama, Yoshiyuki Takahashi, Miho Yamada, Yuka Yamashita, Keizo Horide, Seiji Kojima
    International journal of hematology 99 2 169 - 74 2014年02月 [査読無し][通常論文]
     
    TLS/FUS-ERG chimeric fusion transcript resulting from translocation changes involving chromosomes 16 and 21 is a rare genetic event associated with acute myeloid leukemia (AML). The distinct t(16;21) AML subtype exhibits unique clinical and morphological features and is associated with poor prognosis and a high relapse rate; however, the underlying mechanism remains to be clarified. Recently, whole-genome sequencing revealed a large set of genetic alterations that may be relevant for the dynamic clonal evolution and relapse pathogenesis of AML. Here, we report three pediatric AML patients with t(16;21) (p11; q22). The TLS/FUS-ERG fusion transcript was detected in all diagnostic and relapsed samples, with the exception of one relapsed sample. We searched for several genetic lesions, such as RUNX1, FLT3, c-KIT, NRAS, KRAS, TP53, CBL, ASXL1, IDH1/2, and DNMT3A, in primary and relapsed AML samples. Interestingly, we found RUNX1 mutation in relapsed sample of one patient in whom cytogenetic analysis showed the emergence of a new additional clone. Otherwise, there were no genetic alterations in FLT3, c-KIT, NRAS, KRAS, TP53, CBL, ASXL1, IDH1/2, or DNMT3A. Our results suggest that precedent genetic alterations may be essential to drive the progression and relapse of t(16;21)-AML patients.
  • Akiko Takeda, Akira Shimada, Kazuko Hamamoto, Syuuji Yoshino, Tomoko Nagai, Yousuke Fujii, Mutsuko Yamada, Yoshimi Nakamura, Toshiyuki Watanabe, Yuki Watanabe, Yuko Yamamoto, Kanae Sakakibara, Megumi Oda, Tsuneo Morishima
    Acta medica Okayama 68 2 119 - 23 2014年 [査読無し][通常論文]
     
    Acute megakaryocytic leukemia (AMKL) with t(1;22)(p13;q13) is a distinct category of myeloid leukemia by WHO classification and mainly reported in infants and young children. Accurate diagnosis of this type of AMKL can be difficult, because a subset of patients have a bone marrow (BM) blast percentage of less than 20% due to BM fibrosis. Therefore, it is possible that past studies have underestimated this type of AMKL. We present here the case of a 4-month-old female AMKL patient who was diagnosed by presence of the RBM15-MKL1 (OTT-MAL) fusion transcript by RT-PCR. In addition, we monitored RBM15-MKL1 fusion at several time points as a marker of minimal residual disease (MRD), and found that it was continuously negative after the first induction chemotherapy even by nested RT-PCR. Detection of the RBM15-MKL1 fusion transcript thus seems to be useful for accurate diagnosis of AMKL with t(1;22)(p13;q13). We recommend that the RBM15-MKL1 fusion transcript be analyzed for all suspected AMKL in infants and young children. Furthermore, monitoring of MRD using this fusion transcript would be useful in treatment of AMKL with t(1;22)(p13;q13).
  • Michinori Aoe, Akira Shimada, Michiko Muraoka, Kana Washio, Yoshimi Nakamura, Takahide Takahashi, Masahide Imada, Toshiyuki Watanabe, Ken Okada, Ritsuo Nishiuchi, Takako Miyamura, Kosuke Chayama, Misako Shibakura, Megumi Oda, Tsuneo Morishima
    International journal of hematology 99 5 609 - 15 2014年 [査読無し][通常論文]
     
    The tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) revolutionized the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL), which had showed poor prognosis before the dawn of IM treatment. However, if Ph-ALL patients showed IM resistance due to ABL kinase mutation, second-generation TKI, dasatinib or nilotinib, was recommended. We treated 4 pediatric Ph-ALL patients with both IM and bone marrow transplantation (BMT); however, 3 relapsed. We retrospectively examined the existence of ABL kinase mutation using PCR and direct sequencing methods, but there was no such mutation in all 4 diagnostic samples. Interestingly, two relapsed samples from patients who were not treated with IM before relapse did not show ABL kinase mutation and IM was still effective even after relapse. On the other hand, one patient who showed resistance to 3 TKI acquired dual ABL kinase mutations, F359C at the IM-resistant phase and F317I at the dasatinib-resistant phase, simultaneously. In summary, Ph-ALL patients relapsed with or without ABL kinase mutation. Furthermore, ABL kinase mutation was only found after IM treatment, so an IM-resistant clone might have been selected during the IM treatment and intensive chemotherapy. The appropriate combination of TKI and BMT must be discussed to cure Ph-ALL patients.
  • Michio Suzuki, Yoshinori Ito, Akira Shimada, Mika Saito, Hideki Muramatsu, Asahito Hama, Yoshiyuki Takahashi, Hirokazu Kimura, Seiji Kojima
    Journal of pediatric hematology/oncology 36 1 e65-8 - E68 2014年01月 [査読無し][通常論文]
     
    A 5-month-old girl was diagnosed with Langerhans cell histiocytosis and received unrelated umbilical cord blood transplantation at the age of 14 months. After cord blood transplantation, CD4(+) lymphocytopenia from unknown causes was observed, and persistent infections with human parvovirus B19 (B19) occurred. We performed repeated longitudinal genetic analysis for B19, which revealed 6 nucleotide mutations in B19 nonstructural protein regions in the patient. The resulting changes of the nonstructural 1 structure may have altered antigenicity of the virus and could play a role in the pathogenesis of persistent infection under immunocompromised conditions.
  • Daisuke Tomizawa, Akio Tawa, Tomoyuki Watanabe, Akiko Moriya Saito, Kazuko Kudo, Takashi Taga, Shotaro Iwamoto, Akira Shimada, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Hiroyuki Takahashi, Hideki Nakayama, Nobutaka Kiyokawa, Keiichi Isoyama, Shuki Mizutani, Junichi Hara, Keizo Horibe, Tatsutoshi Nakahata, Souichi Adachi
    International journal of hematology 98 5 578 - 88 2013年11月 [査読有り][通常論文]
     
    Infants (<1 year old) with acute myeloid leukemia (AML) are particularly vulnerable to intensive cytotoxic therapy. Indeed, the mortality rate was high among infants enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study, which prompted us to temporarily suspend patient enrollment and amend the protocol. Forty-five infants with AML were enrolled. For patients aged <2 years, drug doses were adjusted for body weight. Following the protocol amendments, doses for infants were reduced by a further 33 % in the initial induction course. Six infants died during the induction phase (including five early deaths), mainly due to pulmonary complications. The 3-year probability of overall survival (pOS) in all 45 infants [55.9 %, 95 % confidence interval (CI) 37.9-70.6 %] was significantly lower than that of patients aged 1 to <2 years (77.0 %, 95 % CI 62.7-86.3 %) and those aged ≥2 years (74.7 %, 95 % CI 69.2-79.4 %) (P = 0.037), mainly due to the higher non-relapse mortality rate in infants. No early deaths occurred after the protocol amendments, and the 3-year pOS of the 17 infants enrolled thereafter was 76.4 % (95 % CI 48.8-90.4 %). In conclusion, appropriate dose reduction is essential to avoid early deaths when treating infants with AML.
  • Yuka Yamashita, Akira Shimada, Tomomi Yamada, Kazutaka Yamaji, Toshinori Hori, Masahito Tsurusawa, Arata Watanabe, Atsushi Kikuta, Keiko Asami, Akiko M Saito, Keizo Horibe
    Pediatric blood & cancer 60 10 1587 - 92 2013年10月 [査読有り][通常論文]
     
    BACKGROUND: Genome-wide analysis studies have demonstrated that IKZF1, CRLF2, and JAK2 gene alterations correlate with poor prognosis in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the prognostic significance for these gene alterations has not been clarified in Japanese patients. PROCEDURE: A total of 194 patients with BCP-ALL enrolled in the Japanese Children's Cancer & Leukemia Study Group ALL 2004 clinical trial were assessed for the presence of three different gene alterations: IKZF1 deletions, CRLF2 expression and JAK2 mutation. RESULTS: IKZF1 deletions and CRLF2-high expression were identified in 22 of 177 (12%) patients and in 15 of 141 (11%) patients, respectively. However, JAK2 R683 mutation was detected only one of 177 patients. The 4-year event-free survival (4y-EFS) was different when comparing patients with or without IKZF1 deletions (68.2% vs. 85.2%; P = 0.04) and was also different when comparing patients with different CRLF2 expression levels (high, 66.7% vs. low, 88.1%; P = 0.03). The differences in 4y-EFS were statistically significant in patients with ALL in the National Cancer Institute (NCI)-high risk group (HR-ALL) (IKZF1 deletions: yes, 58.3% vs. no, 87.0%, P = 0.02; CRLF2 expression: high, 55.6% vs. low, 85.3%, P = 0.04) but not in patients with ALL in the NCI-standard risk group (SR-ALL; IKZF1 deletions: yes, 80.0% vs. no, 84.4%, P = 0.75; CRLF2 expression: high, 83.3% vs. low, 89.2%, P = 0.77). Coexistence of IKZF1 deletions and CRLF2-high expression associated with poor outcomes. CONCLUSIONS: IKZF1 deletions and CRLF2-high expression predicted poor outcomes in patients with HR-ALL but not in patients with SR-ALL in our Japanese cohort.
  • Hirozumi Sano, Akira Shimada, Ken Tabuchi, Tomohiko Taki, Chisato Murata, Myoung-ja Park, Kentaro Ohki, Manabu Sotomatsu, Souichi Adachi, Akio Tawa, Ryoji Kobayashi, Keizo Horibe, Masahiro Tsuchida, Ryoji Hanada, Ichiro Tsukimoto, Yasuhide Hayashi
    International journal of hematology 98 4 437 - 45 2013年10月 [査読有り][通常論文]
     
    Mutations in Wilms tumor 1 (WT1) have been reported in 10-22 % of patients with cytogenetically normal acute myeloid leukemia (CN-AML), but the prognostic implications of these abnormalities have not been clarified in either adults or children. One hundred and fifty-seven pediatric AML patients were analyzed for WT1 mutations around hotspots at exons 7 and 9; however, amplification of the WT1 gene by the reverse transcriptase-polymerase chain reaction was not completed in four cases (2.5 %). Of the 153 evaluable patients, 10 patients (6.5 %) had a mutation in WT1. The incidence of WT1 mutations was significantly higher in CN-AML than in others (15.2 vs. 4.5 %, respectively, P = 0.03). Of the 10 WT1-mutated cases, eight (80 %) had mutations in other genes, including FLT3-ITD in two cases, FLT3-D835 mutation in two, KIT mutation in three, MLL-PTD in three, NRAS mutation in one, and KRAS mutation in two (in some cases, more than one additional gene was mutated). The incidences of KIT and FLT3-D835 mutations were significantly higher in patients with than in those without WT1 mutation. No significant differences were observed in the 3-year overall survival and disease-free survival; however, the presence of WT1 mutation was related to a poor prognosis in patients with CN-AML, excluding those with FLT3-ITD and those younger than 3 years.
  • Atsushi Narita, Hideki Muramatsu, Hirotoshi Sakaguchi, Sayoko Doisaki, Makito Tanaka, Asahito Hama, Akira Shimada, Yoshiyuki Takahashi, Nao Yoshida, Kimikazu Matsumoto, Koji Kato, Kazuko Kudo, Yoko Furukawa-Hibi, Kiyofumi Yamada, Seiji Kojima
    JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY 35 5 E219 - E223 2013年07月 
    Background:Voriconazole is a triazole antifungal agent with potent activity against a broad spectrum of pathogens, including Aspergillus and Candida species. In human adults, allelic polymorphisms of CYP2C19 are known to correlate with significant variation in voriconazole plasma concentration. Here, we report an analysis of CYP2C19 phenotype and voriconazole plasma concentrations in children.Methods:This retrospective study included 37 children who had voriconazole plasma concentrations measured from May 2006 to June 2011. All had single-nucleotide polymorphisms that define the 3 major CYP2C19 alleles. Patients were classified as follows: normal metabolizers, intermediate metabolizers, poor metabolizers, or hypermetabolizers.Results:The frequencies of the 3 CYP2C19 genetic polymorphisms were similar to those previously reported for Japanese adults. Trough plasma concentrations of voriconazole were significantly higher in the poor metabolizer and intermediate metabolizer groups compared with the normal metabolizer and hypermetabolizer groups (P=0.004). Two patients with high plasma concentrations experienced voriconazole-related severe adverse events (syndrome of inappropriate antidiuretic hormone secretion and cardiac toxicities).Conclusions:The current study suggests that a significant association exists in children between the voriconazole plasma concentration and the CYP2C19 phenotype. Dose adjustment based on CYP2C19 phenotype may be useful during voriconazole therapy, especially for Japanese children, who as a group have a higher incidence of the poor metabolizer and intermediate metabolizer phenotypes.
  • Norio Shiba, Hitoshi Ichikawa, Tomohiko Taki, Myoung-Ja Park, Aoi Jo, Sachiyo Mitani, Tohru Kobayashi, Akira Shimada, Manabu Sotomatsu, Hirokazu Arakawa, Souichi Adachi, Akio Tawa, Keizo Horibe, Masahiro Tsuchida, Ryoji Hanada, Ichiro Tsukimoto, Yasuhide Hayashi
    Genes, chromosomes & cancer 52 7 683 - 93 2013年07月 [査読有り][通常論文]
     
    The cryptic t(5;11)(q35;p15.5) creates a fusion gene between the NUP98 and NSD1 genes. To ascertain the significance of this gene fusion, we explored its frequency, clinical impact, and gene expression pattern using DNA microarray in pediatric acute myeloid leukemia (AML) patients. NUP98-NSD1 fusion transcripts were detected in 6 (4.8%) of 124 pediatric AML patients. Supervised hierarchical clustering analyses using probe sets that were differentially expressed in these patients detected a characteristic gene expression pattern, including 18 NUP98-NSD1-negative patients (NUP98-NSD1-like patients). In total, a NUP98-NSD1-related gene expression signature (NUP98-NSD1 signature) was found in 19% (24/124) and in 58% (15/26) of cytogenetically normal cases. Their 4-year overall survival (OS) and event-free survival (EFS) were poor (33.3% in NUP98-NSD1-positive and 38.9% in NUP98-NSD1-like patients) compared with 100 NUP98-NSD1 signature-negative patients (4-year OS: 86.0%, 4-year EFS: 72.0%). Interestingly, t(7;11)(p15;p15)/NUP98-HOXA13, t(6;11)(q27;q23)/MLL-MLLT4 and t(6;9)(p22;q34)/DEK-NUP214, which are known as poor prognostic markers, were found in NUP98-NSD1-like patients. Furthermore, another type of NUP98-NSD1 fusion transcript was identified by additional RT-PCR analyses using other primers in a NUP98-NSD1-like patient, revealing the significance of this signature to detect NUP98-NSD1 gene fusions and to identify a new poor prognostic subgroup in AML.
  • Kimiko Wakai, Hirozumi Sano, Akira Shimada, Yusuke Shiozawa, Myoung-ja Park, Manabu Sotomatsu, Ryu Yanagisawa, Kenichi Koike, Kunihisa Kozawa, Akihide Ryo, Hiroyuki Tsukagoshi, Hirokazu Kimura, Yasuhide Hayashi
    Journal of pediatric hematology/oncology 35 2 162 - 3 2013年03月 [査読有り][通常論文]
  • Tomizawa D, Tawa A, Watanabe T, Saito A.M, Kudo K, Taga T, Iwamoto S, Shimada A, Terui K, Moritake H, Kinoshita A, Takahashi H, Nakayama H, Koh K, Kigasawa H, Kosaka Y, Miyachi H, Horibe K, Nakahata T, Adachi S
    Leukemia 27 12 2413 - 2416 2013年 [査読有り][通常論文]
  • Daisuke Tomizawa, Akio Tawa, Tomoyuki Watanabe, Akiko Moriya Saito, Kazuko Kudo, Takashi Taga, Shotaro Iwamoto, Akira Shimada, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Hiroyuki Takahashi, Hideki Nakayama, Katsuyoshi Koh, Hisato Kigasawa, Yoshiyuki Kosaka, Hayato Miyachi, Keizo Horibe, Tatsutoshi Nakahata, Souichi Adachi
    BLOOD 120 21 2012年11月 [査読有り][通常論文]
  • Daisuke Tomizawa, Akio Tawa, Tomoyuki Watanabe, Akiko Moriya Saito, Kazuko Kudo, Takashi Taga, Shotaro Iwamoto, Akira Shimada, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Hiroyuki Takahashi, Hideki Nakayama, Katsuyoshi Koh, Hisato Kigasawa, Yoshiyuki Kosaka, Hayato Miyachi, Keizo Horibe, Tatsutoshi Nakahata, Souichi Adachi
    BLOOD 120 21 2012年11月 [査読有り][通常論文]
  • Daisuke Tomizawa, Akio Tawa, Tomoyuki Watanabe, Akiko Moriya Saito, Kazuko Kudo, Takashi Taga, Shotaro Iwamoto, Akira Shimada, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Hiroyuki Takahashi, Hideki Nakayama, Katsuyoshi Koh, Hisato Kigasawa, Yoshiyuki Kosaka, Hayato Miyachi, Keizo Horibe, Tatsutoshi Nakahata, Souichi Adachi
    BLOOD 120 21 2012年11月 [査読有り][通常論文]
  • Daiichiro Hasegawa, Akio Tawa, Daisuke Tomizawa, Tomoyuki Watanabe, Akiko Saito, Kazuko Kudo, Takashi Taga, Shotaro Iwamoto, Akira Shimada, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Hiroyuki Takahashi, Hideki Nakayama, Katsuyoshi Koh, Hisato Kigasawa, Yoshiyuki Kosaka, Hayato Miyachi, Keizo Horibe, Tatsutoshi Nakahata, Souichi Adachi
    BLOOD 120 21 2012年11月 [査読有り][通常論文]
  • Akira Shimada, Tomohiko Taki, Daisuke Koga, Ken Tabuchi, Akio Tawa, Ryoji Hanada, Masahiro Tsuchida, Keizo Horibe, Ichiro Tsukimoto, Souichi Adachi, Seiji Kojima, Yasuhide Hayashi
    International journal of hematology 96 4 469 - 76 2012年10月 [査読有り][通常論文]
     
    The prognostic value of WT1 mRNA expression in pediatric acute myeloid leukemia (AML) remains controversial. A sample of newly diagnosed (n = 158) AML patients from the Japanese Childhood AML Cooperative Treatment Protocol, AML 99, were simultaneously analyzed for WT1 expression, cytogenetic abnormalities and gene alterations (FLT3, KIT, MLL, and RAS). WT1 expression (including more than 2,500 copies/μgRNA) was detected in 122 of the 158 (77.8 %) initial diagnostic AML bone marrow samples (median 45,500 copies/μgRNA). Higher WT1 expression was detected in French American British (FAB)-M0, M3, M7 and lower expression in M4 and M5. Higher WT1 expression was detected in AML with inv(16), t(15;17) and Down syndrome and lower in AML with 11q23 abnormalities. Multivariate analyses demonstrated that FLT3-internal tandem duplication (ITD), KIT mutation, MLL-partial tandem duplication were correlated with poor prognosis; however, higher WT1 expression was not. FLT3-ITD was correlated with WT1 expression and prognosis. Furthermore, 74 WT1 expression after induction chemotherapy was analyzed. Higher WT1 expression after induction chemotherapy was significantly correlated with M1 or M2/M3 marrow, FLT3-ITD and poor prognosis. Multivariate analyses in 74 AML patients revealed that FLT3-ITD, MLL-PTD, and KIT mutations were associated with poor prognosis; however, NRAS Mutation, KRAS mutation and high WT1 expression (>10,000 copies/μgRNA) did not show poor prognosis. Our findings suggest that higher WT1 expression at diagnosis does not correlate with poor prognosis, but that WT1 expression after induction chemotherapy is considered to be a useful predictor of clinical outcome in pediatric AML.
  • Toshihiko Imamura, Shotaro Iwamoto, Rie Kanai, Akira Shimada, Kiminori Terui, Yuko Osugi, Ryoji Kobayashi, Akio Tawa, Yoshiyuki Kosaka, Koji Kato, Hiroki Hori, Keizo Horibe, Megumi Oda, Souichi Adachi
    British journal of haematology 159 2 204 - 10 2012年10月 [査読有り][通常論文]
     
    The acute myeloid leukaemia (AML) 99 trial conducted previously in Japan for the treatment of de novo paediatric AML showed excellent results, with a 5-year overall survival (OS) and event-free survival (EFS) of 75·6% and 61·6%, respectively. To examine reproducibility of these results in another cohort, the outcome of 146 newly diagnosed AML paediatric patients prospectively registered in the Japan Association of Childhood Leukaemia Study (JACLS) from 2003 to 2006 was compared to that of 240 patients in the original AML 99 clinical trial. The 5-year EFS and OS achieved in the new cohort was 66·7 ± 4·0% and 77·7 ± 8·0% respectively, which were comparable to those obtained in the original AML 99 clinical trial, although less frequent core-binding factor (CBF) AML (29·5% vs. 37%) and an almost equal frequency of allogeneic haematopoietic stem cell transplantation (allo-HSCT) during first complete remission (16·5% vs. 19%) were observed. The 5-year EFS in patients with a normal karyotype (NK) (n = 35, 54·9 ± 15·1%) was inferior in the present cohort when compared to the original AML99 trial. This study confirmed the excellent outcome of the original AML99 protocol.
  • Olfat Ismael, Akira Shimada, Asahito Hama, Hiroshi Sakaguchi, Sayoko Doisaki, Hideki Muramatsu, Nao Yoshida, Masafumi Ito, Yoshiyuki Takahashi, Naohiro Akita, Shosuke Sunami, Yoshitoshi Ohtsuka, Youji Asada, Hiroyuki Fujisaki, Seiji Kojima
    Pediatric blood & cancer 59 3 530 - 5 2012年09月 
    BACKGROUND: Acquired somatic mutations of JAK2 have been reported to play a pivotal role in the pathogenesis of BCR-ABL1-negative myeloproliferative neoplasm (MPN). However, the molecular characteristics of childhood MPN remain to be elucidated. PATIENT AND METHODS: We investigated a group of pediatric patients diagnosed either with essential thrombocythemia (ET; N = 9) or polycythemia vera (PV; N = 4) according to WHO criteria (median age = 10 years; range 1.5-15 years) in whom direct sequencing was performed for the existence of genetic alterations in JAK2, MPL, TET2, ASXL1, CBL, IDH1, and IDH2. More sensitive allele specific polymerase chain reaction was used for JAK2(V617F) genotyping. RESULTS: We found three patients harbor JAK2(V617F) mutation (2/9 ET and 1/4 PV). Bone marrow examination showed small and large megakaryocytes with dysplastic features in JAK2(V617F)-positive ET patients compared to those without JAK2(V617F). We identified a previously unrecognized missense mutation at codon 1230 in exon 12 of ASXL1 gene in ET and PV patients (1/9 ET and 1/4 PV). Otherwise, no genetic alterations could be detected in JAK2 exon 12, MPL, TET2, CBL, IDH1, and IDH2 in all ET and PV patients. CONCLUSION: Although JAK2 mutations in childhood ET and PV are not as frequent as reported in adult patients, JAK2 is the most frequently mutated gene in childhood MPN known so far. Owing to the presence of childhood MPN without any genetic alterations in JAK2, MPL, TET2, ASXL1, CBL, IDH1, and IDH2, new biological markers have to be found.
  • Takashi Taga, Akiko Moriya Saito, Kazuko Kudo, Daisuke Tomizawa, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Shotaro Iwamoto, Hideki Nakayama, Hiroyuki Takahashi, Akio Tawa, Akira Shimada, Tomohiko Taki, Hisato Kigasawa, Katsuyoshi Koh, Souichi Adachi
    Blood 120 9 1810 - 5 2012年08月 [査読有り][通常論文]
     
    Myeloid leukemia in Down syndrome (ML-DS) is associated with good response to chemotherapy and favorable prognosis. Because little research has been focused on refractory/relapsed (R/R) cases, we conducted a retrospective analysis for R/R ML-DS. Among ML-DS patients diagnosed between 2000 and 2010 in Japan, 26 relapsed (25 in the BM and 1 in the skin), and 3 refractory patients were enrolled. The male/female ratio was 18/11. The median age at initial diagnosis of ML-DS was 2 years, and the median time to relapse was 8.6 months. Each patient initially had been treated with ML-DS-specific protocols. Thirteen of the 26 patients achieved complete remission with various kinds of reinduction chemotherapies; 2 of 8 survived without further recurrence after receiving allogeneic hematopoietic stem cell transplantation, and 4 of 5 maintained complete remissions with chemotherapy alone. Treatment failures mostly were associated with disease progression rather than treatment-related toxicities. The 3-year OS rate was 25.9% ± 8.5%. A longer duration from initial diagnosis to relapse was a significant favorable prognostic factor (P < .0001). We conclude that clinical outcome for patients with R/R ML-DS generally are unfavorable, even in those receiving hematopoietic stem cell transplantation. Novel methods to identify poor prognostic factors for ML-DS are necessary.
  • Sayoko Doisaki, Hideki Muramatsu, Akira Shimada, Yoshiyuki Takahashi, Makiko Mori-Ezaki, Masanori Sato, Hiroyuki Kawaguchi, Akitoshi Kinoshita, Manabu Sotomatsu, Yasuhide Hayashi, Yoko Furukawa-Hibi, Kiyofumi Yamada, Hideaki Hoshino, Hitoshi Kiyoi, Nao Yoshida, Hirotoshi Sakaguchi, Atsushi Narita, Xinan Wang, Olfat Ismael, Yinyan Xu, Nobuhiro Nishio, Makito Tanaka, Asahito Hama, Kenichi Koike, Seiji Kojima
    Blood 120 7 1485 - 8 2012年08月 [査読無し][通常論文]
     
    Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. Somatic mutations in genes involved in GM-CSF signal transduction, such as NRAS, KRAS, PTPN11, NF1, and CBL, have been identified in more than 70% of children with JMML. In the present study, we report 2 patients with somatic mosaicism for oncogenic NRAS mutations (G12D and G12S) associated with the development of JMML. The mutated allele frequencies quantified by pyrosequencing were various and ranged from 3%-50% in BM and other somatic cells (ie, buccal smear cells, hair bulbs, or nails). Both patients experienced spontaneous improvement of clinical symptoms and leukocytosis due to JMML without hematopoietic stem cell transplantation. These patients are the first reported to have somatic mosaicism for oncogenic NRAS mutations. The clinical course of these patients suggests that NRAS mosaicism may be associated with a mild disease phenotype in JMML.
  • 2遺伝子の発現に基づく高リスク小児急性骨髄性白血病の同定(Identification of high risk patients in pediatric AML by two aberrantly expressed genes)
    三谷 幸代, 城 青衣, 嶋田 明, 柴 徳生, 林 泰秀, 市川 仁
    日本癌学会総会記事 71回 166 - 166 2012年08月
  • Xinan Wang, Hideki Muramatsu, Hirotoshi Sakaguchi, Yinyan Xu, Atsushi Narita, Yusuke Tsumura, Sayoko Doisaki, Makito Tanaka, Olfat Ismael, Akira Shimada, Asahito Hama, Yoshiyuki Takahashi, Seiji Kojima
    British journal of haematology 158 4 553 - 5 2012年08月
  • Olfat Ismael, Akira Shimada, Asahito Hama, Momen Elshazley, Hideki Muramatsu, Aya Goto, Hirotoshi Sakaguchi, Makito Tanaka, Yoshiyuki Takahashi, Xu Yinyan, Minoru Fukuda, Yuji Miyajima, Yuka Yamashita, Keizo Horibe, Ryoji Hanada, Masafumi Ito, Seiji Kojima
    British journal of haematology 158 1 129 - 37 2012年07月 
    Myelodysplastic/myeloproliferative uclassifiable (MDS/MPN-U) is a rare myeloid neoplasm characterized by myelodysplasia and myeloproliferation at the time of initial presentation, which is usually a diagnosis of exclusion. The molecular pathogenesis of MDS/MPN-U patients remains to be elucidated. Among five patients diagnosed with MDS/MPN-U, three patients harboured RUNX1 (AML1) mutations; one carried somatic mosaicism of RUNX1 mutation with JAK2(V617F) mutation and one had dual RUNX1 and FLT3-internal tandem duplication mutations with progression to acute myeloid leukaemia (AML). Germline mutation of TP53 was detected as a sole genetic lesion in one patient. JAK2(V617F) and somatic mosaicism of KRAS and TET2 mutations co-existed in one patient. Otherwise, no alterations were detected in PTPN11, NRAS, CBL and ASXL1 genes. ETV6-PDGFRB fusion transcript was not detected in all patients. Four patients recieved haematopoietic stem cell transplantation (HSCT); three patients relapsed and one achieved complete remission after three donor lymphocyte infusions. Our findings suggest that the mutational spectrum observed in childhood MDS/MPN-U is quite different from that seen in juvenile myelomonocytic leukaemia and, to some extent, resemble chronic myelomonocytic leukaemia. Moreover, two patients had constitutional alterations of genes frequently found in AML. Further investigations are required to define the roles of these genetic alterations in the pathogenesis of childhood MDS/MPN-U.
  • Akira Shimada, Yoshiyuki Takahashi, Hideki Muramatsu, Asahito Hama, Olfat Ismael, Atsushi Narita, Hiroshi Sakaguchi, Sayoko Doisaki, Nobuhiro Nishio, Makito Tanaka, Nao Yoshida, Kimikazu Matsumoto, Koji Kato, Nobuhiro Watanabe, Seiji Kojima
    International journal of hematology 95 6 675 - 9 2012年06月 
    Fanconi anemia (FA) is a disorder characterized by developmental anomalies, bone marrow failure and a predisposition to malignancy. It has recently been shown that hematopoietic stem cell transplantation using fludarabine (FLU)-based reduced-intensity conditioning is an efficient and quite safe therapeutic modality. We retrospectively analyzed the outcome of bone marrow transplantation (BMT) in eight patients with FA performed in two institutes between 2001 and 2011. There were seven females and one male with a median age at diagnosis = 4.5 years (range 2-12 years). The constitutional characteristics associated with FA, such as developmental anomalies, short stature and skin pigmentation, were absent in three of the patients. One patient showed myelodysplastic features at the time of BMT. All patients received BMT using FLU, cyclophosphamide (CY) and rabbit anti-thymocyte globulin (ATG) either from a related donor (n = 4) or an unrelated donor (n = 4). Acute graft-versus-host disease (GVHD) of grade I developed in one patient, while chronic GVHD was not observed in any patient. All patients are alive and achieved hematopoietic recovery at a median follow-up of 72 months (range 4-117 months). BMT using FLU/low-dose CY/ATG -based regimens regardless to the donor is a beneficial therapeutic approach for FA patients.
  • Nozomu Kawashima, Akira Shimada, Takeshi Taketani, Yasuhide Hayashi, Nao Yoshida, Kimikazu Matsumoto, Yoshiyuki Takahashi, Seiji Kojima, Koji Kato
    International journal of hematology 95 5 577 - 80 2012年05月 
    Acute myeloid leukemia with abnormal bone marrow eosinophilia (AML-M4Eo) is often reported in core binding factor (CBF) leukemia, with translocations such as inv(16)(p13q22), t(16;16)(p13;q22) or t(8;21)(q22;q22); however, it is rarely reported with t(16;21)(q24;q22), which produces the RUNX1-CBFA2T3 (AML1-MTG16) chimera. The similarity between this chimera and RUNX1-RUNXT1 (AML1-MTG8) by t(8;21)(q22;q22) remains controversial. Adult leukemia with t(16;21)(q24;q22) was primarily therapy related, and shows poor prognosis; however, pediatric AML with this translocation was quite rare and tended to be de novo AML. We present here a 4-year-old boy with de novo AML-M4Eo and t(16;21)(q24;q22). He received chemotherapy and survived for more than 70 months without transplantation. We speculated that pediatric AML with t(16;21)(q24;q22) showed favorable prognosis, as with t(8;21)(q22;q22).
  • Hirozumi Sano, Akira Shimada, Tomohiko Taki, Chisato Murata, Myoung-Ja Park, Manabu Sotomatsu, Ken Tabuchi, Akio Tawa, Ryoji Kobayashi, Keizo Horibe, Masahiro Tsuchida, Ryoji Hanada, Ichiro Tsukimoto, Yasuhide Hayashi
    International journal of hematology 95 5 509 - 15 2012年05月 [査読有り][通常論文]
     
    Mutations in RAS are frequent in acute myeloid leukemia (AML), and are thought to contribute to leukemogenesis in a subset of patients; however, their prognostic significance has not been firmly established. One hundred and fifty-seven pediatric patients with AML were analyzed for NRAS and KRAS mutations around hot spots at codons 12, 13, and 61. Twenty-nine patients (18.5%) had an activating mutation of RAS. We found KRAS mutations to be more frequent than NRAS mutations (18/29, 62.1% of patients with RAS mutation), in contrast to previous reports (18-40%). The frequency of RAS mutation was higher in French-American-British types M4 and M5 than other types (P = 0.02). There were no significant differences in other clinical manifestations or distribution in cytogenetic subgroups, or aberrations of other genes, including KIT mutation, FLT3-ITD, and MLL-PTD, between patients with and without RAS mutations. No significant differences were observed in the 3-year overall survival and disease-free survival; however, the presence of RAS mutation was related to late relapse. The occurrence of clinical events at relatively late period should be monitored for in AML patients with mutations in RAS.
  • 発現アレイを用いた小児急性骨髄性白血病における、NUP98-NSD1融合遺伝子の解析
    柴 徳生, 市川 仁, 滝 智彦, 朴 明子, 嶋田 明, 田渕 健, 荒川 浩一, 足立 壮一, 堀部 敬三, 林 泰秀
    日本小児科学会雑誌 116 2 245 - 245 (公社)日本小児科学会 2012年02月
  • Norio Shiba, Tomohiko Taki, Myoung-Ja Park, Akira Shimada, Manabu Sotomatsu, Souichi Adachi, Akio Tawa, Keizo Horibe, Masahiro Tsuchida, Ryoji Hanada, Ichiro Tsukimoto, Hirokazu Arakawa, Yasuhide Hayashi
    British journal of haematology 156 3 413 - 4 2012年02月 [査読有り][通常論文]
  • 小児急性骨髄性白血病におけるNUP98-NSD転座の解析
    柴 徳生, 朴 明子, 村田 知里, 嶋田 明, 滝 智彦, 外松 学, 田渕 健, 足立 壮一, 多和 昭雄, 堀部 敬三, 土田 昌宏, 花田 良二, 月本 一郎, 荒川 浩一, 林 泰秀
    小児がん 48 プログラム・総会号 204 - 204 (NPO)日本小児がん学会 2011年11月
  • Asahito Hama, Ayami Yoshimi, Hirotoshi Sakaguchi, Sayoko Doisaki, Hideki Muramatsu, Akira Shimada, Yoshiyuki Takahashi, Kazue Nozawa, Masafumi Ito, Masahiro Tsuchida, Atsushi Manabe, Akira Ohara, Seiji Kojima
    [Rinsho ketsueki] The Japanese journal of clinical hematology 52 8 653 - 8 2011年08月 [査読有り][通常論文]
     
    The revised WHO classification proposed the term "refractory cytopenia of childhood (RCC)" for children with myelodysplastic syndrome (MDS) with a low blast count. The differential diagnosis between RCC and aplastic anemia (AA) is challenging, especially when bone marrow is hypoplastic and there is no detectable chromosomal abnormality. To reveal the difference between AA and RCC with respect to the clinical and biological features, we retrospectively reviewed the bone marrow smears of 140 patients registered for childhood AA-97 study, which were classified into three groups as follows; the AA group was defined as having no morphologically dysplastic changes; the AA-RCC borderline group was defined as having <10% dysplastic changes in the erythroid lineage only; and the RCC group was defined as having dysplastic changes in more than two cell lineages or >10% in a single cell lineage. The patients were classified into the AA group (n=96, 69%), AA-RCC borderline group (n=20, 14%) and RCC group (n=24, 17%). Most of the patients in the AA group were classified as having very severe disease, whereas most of the patients in the RCC group were classified as non-severe disease. Only 2 patients in the AA group developed acute myeloid leukemia. The response rate to immunosuppressive therapy did not differ among the 3 groups. To demonstrate whether the two diseases are truly different entities, it is necessary to compare molecular backgrounds between the AA and RCC groups.
  • Hideki Muramatsu, Yoshiyuki Takahashi, Hirotoshi Sakaguchi, Akira Shimada, Nobuhiro Nishio, Asahito Hama, Sayoko Doisaki, Hiroshi Yagasaki, Kimikazu Matsumoto, Koji Kato, Seiji Kojima
    International journal of hematology 93 2 186 - 191 2011年02月 [査読無し][通常論文]
     
    Allogeneic hematopoietic stem cell transplantation (HSCT) and tyrosine kinase inhibitor have revolutionized the treatment of patients with chronic myeloid leukemia (CML). In this study, the clinical impact of HSCT and imatinib mesylate (IM) was retrospectively analyzed in 28 children with CML treated in our institutes from 1984 to 2008. Twelve patients were given oral IM. At 36 months after initiation of IM therapy, the complete cytogenetic response rate was 90.9%, and the major molecular response rate was 36.4%. Sixteen children received allogeneic HSCT without administration of IM. The stage of disease at transplantation was: first chronic phase (n = 10), second chronic phase (n = 2), accelerated phase (n = 2), and blastic crisis (n = 2). The progression rate was significantly lower in patients treated with IM than in those treated without IM (0 vs. 28.6%, p = 0.006). In summary, the survival outcomes of pediatric patients with CML were dramatically improved by treatment with IM compared to HSCT.
  • Machiko Kawamura, Hidefumi Kaku, Tateki Ito, Nobuaki Funata, Tomohiko Taki, Akira Shimada, Yasuhide Hayashi
    Cancer genetics and cytogenetics 203 2 292 - 6 2010年12月 
    Patients diagnosed with t(8;21)-acute myeloid leukemia (AML) are currently considered to have good prognoses, but about half of these patients relapse. FLT3-internal tandem duplication (ITD) is generally thought to be strongly associated with poor prognosis in AML, but is rarely reported in patients with t(8;21)-AML. Expression of the neural cell-adhesion molecule (CD56) is also associated with a significantly shorter complete remission duration and survival in patients with t(8;21)-AML. Patients with t(8;21)-AML expressing CD56 have been reported to exhibit a higher incidence of granulocytic sarcoma (GS), and t(8;21)-AML with GS results in a less favorable prognosis than AML with this translocation alone. Here, we report on a 15-year-old girl with t(8;21)-AML having both CD56 expression and FLT3-ITD. This patient underwent unrelated donor bone marrow transplantation and achieved complete remission, but thereafter presented with obstructive jaundice caused by GS compression of the common bile duct without bone marrow invasion at relapse. Autopsy revealed multiple nodules of the stomach membrane and invasion into the head of the pancreas. For earlier detection of relapse, we suggest that it would be useful to examine existence of GS in CD56-positive t(8;21)-AML patients at diagnosis and hematologic remission. Even though t(8;21)-AML is less likely to co-occur with FLT3-ITD in pediatric patients, this report suggests that prognostic factors, including FLT3 and KIT genes and the surface marker CD56, should be analyzed in these patients.
  • Rika Kanezaki, Tsutomu Toki, Kiminori Terui, Gang Xu, Runan Wang, Akira Shimada, Asahito Hama, Hirokazu Kanegane, Kiyoshi Kawakami, Mikiya Endo, Daisuke Hasegawa, Kazuhiro Kogawa, Souichi Adachi, Yasuhiko Ikeda, Shotaro Iwamoto, Takashi Taga, Yoshiyuki Kosaka, Seiji Kojima, Yasuhide Hayashi, Etsuro Ito
    Blood 116 22 4631 - 8 2010年11月 [査読有り][通常論文]
     
    Twenty percent to 30% of transient abnormal myelopoiesis (TAM) observed in newborns with Down syndrome (DS) develop myeloid leukemia of DS (ML-DS). Most cases of TAM carry somatic GATA1 mutations resulting in the exclusive expression of a truncated protein (GATA1s). However, there are no reports on the expression levels of GATA1s in TAM blasts, and the risk factors for the progression to ML-DS are unidentified. To test whether the spectrum of transcripts derived from the mutant GATA1 genes affects the expression levels, we classified the mutations according to the types of transcripts, and investigated the modalities of expression by in vitro transfection experiments using GATA1 expression constructs harboring mutations. We show here that the mutations affected the amount of mutant protein. Based on our estimates of GATA1s protein expression, the mutations were classified into GATA1s high and low groups. Phenotypic analyses of 66 TAM patients with GATA1 mutations revealed that GATA1s low mutations were significantly associated with a risk of progression to ML-DS (P < .001) and lower white blood cell counts (P = .004). Our study indicates that quantitative differences in mutant protein levels have significant effects on the phenotype of TAM and warrants further investigation in a prospective study.
  • Kaoru Okazaki, Jun Unemoto, Masatoshi Kondo, Takashi Kusaka, Kunihisa Kozawa, Masakazu Yoshizumi, Akira Shimada, Junko Takita, Takashi Kaneko, Takehiro Hama, Hirokazu Kimura
    Leukemia research 34 9 e226-8  2010年09月
  • Mitsuru Seki, Hirokazu Kimura, Akio Mori, Akira Shimada, Yoshiyuki Yamada, Kenichi Maruyama, Yasuhide Hayashi, Kazunaga Agematsu, Tomohiro Morio, Akihiro Yachie, Masahiko Kato
    Pediatrics international : official journal of the Japan Pediatric Society 52 4 e196-9  2010年08月
  • Yasuhiro Mizushima, Tomohiko Taki, Akira Shimada, Yoshihiro Yui, Yoshimi Hiraumi, Hiroshi Matsubara, Motonobu Watanabe, Ken-ichiro Watanabe, Yuri Kamitsuji, Yasuhide Hayashi, Ichiro Tsukimoto, Ryoji Kobayashi, Keizo Horibe, Akio Tawa, Tatsutoshi Nakahata, Souichi Adachi
    International journal of hematology 91 5 831 - 7 2010年06月 [査読有り][通常論文]
     
    High BAALC (brain and acute leukemia, cytoplasmic) gene expression may indicate an adverse prognosis for adults who have acute myeloid leukemia (AML) and a normal karyotype, but its prognostic significance for pediatric AML cases is unclear. Whether different BAALC isoform patterns are of prognostic significance is also unclear. Newly diagnosed AML patients with normal karyotype who were treated by the Japanese Childhood AML Cooperative Treatment Protocol AML 99 were analyzed in terms of their BAALC expression levels (n = 29), BAALC isoforms (n = 29), and CEBPA mutations (n = 49). Eleven and 18 patients exhibited high and low BAALC expression, respectively, but these groups did not differ significantly in terms of overall survival (54.6 vs. 61.1%, P = 0.55) or event-free survival (61.4 vs. 50.0%, P = 0.82). Three of these 29 patients (10.3%) expressed the exon 1-5-6-8 BAALC isoform along with the expected 1-6-8 isoform and had adverse clinical outcomes. Novel CEBPA mutations were also identified in four of 49 patients (8.2%). All four patients have maintained complete remission for at least 5 years. Thus, 1-5-6-8 isoform expression may be associated with an adverse prognosis in pediatric AML with normal karyotype. CEBPA mutations may indicate a favorable prognosis.
  • Aoi Jo, Ichiro Tsukimoto, Eiichi Ishii, Norio Asou, Sachiyo Mitani, Akira Shimada, Takashi Igarashi, Yasuhide Hayashi, Hitoshi Ichikawa
    British journal of haematology 144 6 917 - 29 2009年03月 
    Acute myeloid leukaemia, French-American-British M4 and M5 subtypes (AML-M4/M5) is frequently associated with MLL gene rearrangement and its incidence is relatively high among infants. Clinically, paediatric AML-M4/M5 has been considered as an intermediate or undefined prognostic group. In this study, we analysed gene expression of 40 paediatric AML-M4/M5 patients excluding inv(16) and t(8;21) patients, and found striking differences among the patients in an age-associated manner. In particular, most of the infants displayed very distinct gene expression. On the basis of this difference, we divided paediatric patients into three subgroups (A, B and C) with the average age of 0.3, 3.1 and 6.6 years old respectively. All subgroups included patients with MLL gene rearrangement as well as normal and other karyotypes. Surprisingly, gene expression signatures of MLL gene rearrangement differed substantially among these subgroups. In addition, subgroup C presented extremely poor outcome (3-year event-free survival 28%) whilst eight patients with MLL gene rearrangement in subgroup C had all relapsed within 18 months. These results suggest that age is an important factor contributing to the biology of AML-M4/M5 and the sub-grouping procedures developed in this study could be a powerful tool to identify unfavourable risk patients within paediatric AML-M4/M5.
  • Minoru Kuroiwa, Jun Sakamoto, Akira Shimada, Norio Suzuki, Junko Hirato, Myoung-Ja Park, Manabu Sotomatsu, Yasuhide Hayashi
    Journal of pediatric surgery 44 3 e31-5  2009年03月 
    We report a rare case of neonatal Beckwith-Wiedemann syndrome (BWS) associated with alveolar rhabdomyosarcoma (RMS). Alveolar RMS was diagnosed on the basis of excisional biopsy. Chemotherapy was initiated and followed by bone marrow transplantation. The patient, who is now 3 years and 11 months of age, is alive 46 months after the initial diagnosis, albeit with disease. We could not detect the PAX3-FKHR or PAX7-FKHR transcripts; however, we could observe hypomethylation of the differentially methylated region of the long QT intronic transcript 1. Thus, neonatal alveolar RMS with BWS may result from an alternate molecular pathway.
  • 金澤 崇, 田村 一志, 塚田 昌大, 柴 徳生, 森川 昭廣, 嶋田 明, 朴 明子, 外松 学, 林 泰秀
    The Kitakanto Medical Journal 58 4 432 - 432 北関東医学会 2008年11月
  • Akira Shimada, Masahiko Kato, Kazushi Tamura, Junko Hirato, Hirokazu Kanegane, Yasuhiko Takechi, Myoung-Ja Park, Manabu Sotomatsu, Shinitsu Hatakeyama, Yasuhide Hayashi
    Journal of pediatric hematology/oncology 30 10 785 - 7 2008年10月 [査読有り][通常論文]
  • 柴 徳生, 金澤 崇, 塚田 昌大, 田村 一志, 森川 昭廣, 朴 明子, 嶋田 明, 外松 学, 林 泰秀
    The Kitakanto Medical Journal 58 2 239 - 240 北関東医学会 2008年05月
  • Akira Shimada, Tomohiko Taki, Ken Tabuchi, Takeshi Taketani, Ryoji Hanada, Akio Tawa, Masahiro Tsuchida, Keizo Horibe, Ichiro Tsukimoto, Yasuhide Hayashi
    Pediatric blood & cancer 50 2 264 - 9 2008年02月 
    BACKGROUND: Mixed-lineage leukemia (MLL)-partial tandem duplication (PTD) is associated with poor prognosis in adult acute myeloid leukemia (AML), but its relationship to pediatric AML is unknown. PROCEDURE: One hundred fifty-eight newly diagnosed AML patients, including 13 FAB-M3 and 10 Down syndrome (DS) patients, who were treated on the Japanese Childhood AML Cooperative Treatment Protocol AML 99 were analyzed for MLL-PTD, as well as internal tandem duplication (ITD) and the kinase domain mutation (D835Mt) in the FLT3 gene. RESULTS: We found MLL-PTD in 21 (13.3%) of 158 AML patients, but not in FAB-M3 or DS patients. The differences between patients with and without MLL-PTD were significant for 3-year overall survival (OS) (56.3% vs. 83.2%, P = 0.018), disease-free survival (DFS) (41.7% vs. 69.6%, P = 0.010), and relapse rate (RR) (54.3% vs. 27.6%, P = 0.0085) of 135 AML patients excluding the FAB-M3 and DS patients. Furthermore, ITD and D835Mt in the FLT3 gene were found in 17 (12.6%) and 8 (5.9%) of these 135 patients, respectively. The differences between patients with FLT3-ITD and the wild-type allele were significant for 3-year OS (35.3% and 84.3%, P < 0.0000001), DFS (40.0% and 66.9%, P < 0.003), and RR (52.4% and 30.3%, P < 0.005). Coduplication of both genes was found in only 3 (1.9%) patients. CONCLUSION: AML patients with FLT3-ITD, but not D835Mt, showed a poor prognosis. AML patients with MLL-PTD were also correlated with poor prognosis in this study.
  • Akira Shimada, Junko Hirato, Minoru Kuroiwa, Akira Kikuchi, Ryoji Hanada, Kimiko Wakai, Yasuhide Hayashi
    Pediatric blood & cancer 50 2 213 - 7 2008年02月 
    BACKGROUND: The clinical outcome of neuroblastoma (NB) depends on age, stage, and MYCN amplification. Receptor tyrosine kinases (RTKs) promote cell growth, migration, and metastasis in cancer cells, including NB. However, the correlation of the expression profile of RTKs with prognosis in NB remains controversial. PROCEDURE: Expression and mutation analysis of KIT, PDGFR, FLT3, RET, and TRKA mRNAs were performed in 24 NB cell lines and 40 tumor samples using RT-PCR followed by direct sequencing. Immunohistochemical analysis of KIT and PDGFR protein expression was also examined in 38 paraffin sections of NB tumor samples. RESULTS: The expression of KIT, PDGFRbeta, and FLT3 mRNA was associated with NB in patients under 1 year (P < 0.02) and TRKA expression (P < 0.001). The loss of expression of these kinases was associated with MYCN amplification (P < 0.02) and advanced stages of disease in patients over 1 year of age (P < 0.005). PDGFRalpha mRNA expression was detected in all cell lines and tumor samples, and RET mRNA expression was not associated with any clinical parameters. Immunohistochemistry results showed the similar findings. We did not find any activating mutations in KIT, PDGFR, FLT3, or RET. Notably, the GNNK(-) isoform of KIT was predominant in all cell lines and clinical samples. CONCLUSION: Expression of KIT, PDGFRbeta, and FLT3 was associated with a good prognosis in NB. The loss of expression of these RTKs might correlate to the disease progression of NB.
  • Machiko Kawamura, Hidefumi Kaku, Takeshi Taketani, Tomohiko Taki, Akira Shimada, Yasuhide Hayashi
    Cancer genetics and cytogenetics 180 1 74 - 8 2008年01月 [査読有り][通常論文]
     
    The prognosis of leukemia developed in Down syndrome (DS) patients has improved markedly. Most DS leukemia occurs before 3 years of age and is classified as acute megakaryocytic leukemia (AMKL). Mutations in the GATA1 gene have been found in almost all DS patients with AMKL. In contrast, it has been shown that occurrence of DS acute myeloid leukemia (DS-AML) after 3 years of age may indicate a higher risk for a poor prognosis, but its frequency is very low. Age is one of the significant prognostic indicators in DS-AML. The prognostic factor of gene alterations has not been reported in older DS-AML patients. We here describe the case of a 7-year-old DS boy with AML-M2, who had no history of transient abnormal myelopoiesis or any clinical poor prognostic factors, such as high white blood cell counts or extramedullary infiltration. We molecularly analyzed the GATA1, FLT3, MLL-partial tandem duplication, NRAS, and RUNX1 (previously AML1) genes and did not detect any alterations. The patient has lived for more than 5 years after treatment on the AML99-Down protocol in Japan. This suggests that a patient lacking these genes alterations might belong to a subgroup of older DS-AML patients with good prognosis. Accumulation of more data on older pediatric DS-AML patients is needed.
  • 当科で経験した再発TEL/AML1陽性ALL 3例の検討
    柴 徳生, 金澤 崇, 塚田 昌大, 田村 一志, 朴 明子, 嶋田 明, 外松 学, 林 泰秀, 小川 千登世, 森川 昭廣
    小児がん 44 プログラム・総会号 281 - 281 (NPO)日本小児がん学会 2007年12月
  • Akira Shimada, Hitoshi Ichikawa, Tomohiko Taki, Chisato Kubota, Teruaki Hongo, Masahiro Sako, Akira Morimoto, Akio Tawa, Ichiro Tsukimoto, Yasuhide Hayashi
    International journal of hematology 86 3 289 - 90 2007年10月
  • Akira Shimada, Yasuhide Hayashi, Mizuho Ogasawara, Myoung-Ja Park, Masahiko Katoh, Hisanori Minakami, Toshiyuki Kitoh, Seiji Kojima, Keisei Kawa, Hirokazu Kimura
    Leukemia research 31 9 1199 - 203 2007年09月 [査読有り][通常論文]
     
    Down syndrome (DS) patients are frequently complicated with infections, autoimmune phenomena and hematological disorders, including transient abnormal myelopoiesis (TAM) in infancy and acute megakaryoblastic leukaemia (AMKL) in later life. In this study, serum levels of cytokines from 23 TAM and 15 AMKL patients were examined using the highly sensitive microsphere fluorescence system. Statistical differences between DS neonates with or without TAM were found in IL-1beta [median 7.0 pg/ml (0.34-271.6) verses 0.05 pg/ml (0.0-2.4), p=0.034], TNF-alpha [8.11 pg/ml (0.1-253.0) verses 0.41 pg/ml (0.1-1.5), p=0.041], and IFN-gamma [20.0 pg/ml (0.14-406.3) verses 1.5 pg/ml (0.14-5.79), p=0.036]. Moreover, abnormal inflammatory cytokinemia was also found in myelodysplastic syndrome (MDS) and AMKL with DS. These abnormal cytokinemia may have a role in the pathophysiology of TAM, MDS and AMKL in DS, especially in liver fibrosis or myelofibrosis.
  • Akira Shimada, Takeshi Taketani, Akira Kikuchi, Ryoji Hanada, Hiroshi Arakawa, Hirokazu Kimura, Yuyan Chen, Yasuhide Hayashi
    Journal of pediatric hematology/oncology 29 9 666 - 7 2007年09月 [査読有り][通常論文]
  • Kazuyuki Matsuda, Akira Shimada, Nao Yoshida, Atsushi Ogawa, Akihiro Watanabe, Shuhei Yajima, Susumu Iizuka, Kazutoshi Koike, Fumio Yanai, Keiichiro Kawasaki, Masakatsu Yanagimachi, Akira Kikuchi, Yoshitoshi Ohtsuka, Eiko Hidaka, Kazuyoshi Yamauchi, Miyuki Tanaka, Ryu Yanagisawa, Yozo Nakazawa, Masaaki Shiohara, Atsushi Manabe, Seiji Kojima, Kenichi Koike
    Blood 109 12 5477 - 80 2007年06月 [査読有り][通常論文]
     
    Of 11 children with juvenile myelomonocytic leukemia (JMML) carrying RAS mutations (8 with NRAS mutations, 3 with KRAS2 mutations), 5 had a profound elevation in either or both the white blood cells and spleen size at diagnosis. Three patients had no or modest hepatosplenomegaly and mild leukocytosis at presentation but subsequently showed a marked increase in spleen size with or without hematologic exacerbation, for which nonintensive chemotherapy was initiated. The other three patients with NRAS or KRAS2 glycine to serine substitution received no chemotherapy, but hematologic improvement has been observed during a 2- to 4-year follow up. In the third group, all hematopoietic cell lineages analyzed had the RAS mutations at the time of hematologic improvement, whereas DNA obtained from the nails had the wild type. Additionally, numbers of circulating granulocyte-macrophage progenitors were significantly reduced during the clinical course. Thus, some patients with JMML with specific RAS mutations may have spontaneously improving disease.
  • Masahiko Kato, Hirokazu Kimura, Mitsuru Seki, Akira Shimada, Yasuhide Hayashi, Tomohiro Morio, Satoru Kumaki, Yasushi Ishida, Yoshiro Kamachi, Akihiro Yachie
    Allergology international : official journal of the Japanese Society of Allergology 55 2 115 - 9 2006年06月 
    Omenn syndrome (OS) is a form of severe combined immunodeficiency (SCID) characterized by erythrodermia, hepatosplenomegaly, lymphadenopathy, and alopecia. In patients with OS, B cells are mostly absent, T-cell counts are normal to elevated, and T cells are frequently activated and express a restricted T-cell receptor (TCR) repertoire. Thus far, inherited hypomorphic mutations of the recombination activating genes either 1 or 2 (RAG1/2) have been detected in most OS patients. We have recently experienced a rare case of OS showing the revertant mosaicism due to multiple second-site mutations leading to typical OS clinical features with RAG1-deficient SCID. In this review, we will focus on the variation of several phenotypes of OS.
  • Yuyan Chen, Junko Takita, Mitsuteru Hiwatari, Takashi Igarashi, Ryoji Hanada, Akira Kikuchi, Teruaki Hongo, Tomohiko Taki, Mizuho Ogasawara, Akira Shimada, Yasuhide Hayashi
    Genes, chromosomes & cancer 45 6 583 - 91 2006年06月 [査読有り][通常論文]
     
    PTPN11 has been identified as a causative gene in Noonan syndrome (NS), responsible for about 50% of cases of NS. Given the association between NS and an increased risk of some malignancies, notably leukemia and probably some solid tumors including neuroblastoma (NB) and rhabdomyosarcoma (RMS), recent studies have reported that gain-of-function somatic mutations in PTPN11 occur in some hematological malignancies, especially de novo juvenile myelomonocytic leukemia (JMML) and in some solid tumors such as NB, although at a low frequency. In a screen for mutations of PTPN11 in 7 cell lines and 30 fresh tumors of RMS and in 25 cell lines and 40 fresh tumors of NB, we identified a missense mutation (A72T) in an embryonal RMS patient. In the RMS samples, we also detected mutations of NRAS in 1 cell line and 1 patient; both mutations were in embryonal RMSs and had no PTPN11 mutations. No mutations of PTPN11 were detected in NB. In 95 leukemia cell lines and 261 fresh leukemia samples including 22 JMMLs, 9 kinds of missense mutations were detected in 17 leukemia samples, which included 11 (50.0%) mutations in JMML samples and lower frequencies in other hematological malignancies. Furthermore, we identified 4 (18.2%) NRAS mutations and 1 (4.5%) KRAS mutation in 5 JMML samples, 1 of which had a concomitant PTPN11 mutation. Our data suggest that mutations of PTPN11 as well as RAS play a role in the pathogenesis of not only myeloid hematological malignancies but also a subset of RMS malignancies.
  • Akira Shimada, Tomohiko Taki, Ken Tabuchi, Akio Tawa, Keizo Horibe, Masahiro Tsuchida, Ryoji Hanada, Ichiro Tsukimoto, Yasuhide Hayashi
    Blood 107 5 1806 - 9 2006年03月 
    Patients with t(8;21) acute myeloid leukemia (AML) are considered to have a good prognosis; however, approximately 50% of them relapse. The genetic alterations associated with a poor outcome in t(8;21) AML remain unknown. Recently, aberrations of receptor tyrosine kinases (RTKs) were frequently found in patients with AML. However, the prevalence and prognostic impact of RTK aberrations in pediatric t(8;21) AML remains undetermined. Here, we found the kinase domain mutations of the KIT gene in 8 (17.4%) of 46 patients with t(8;21) AML among newly diagnosed pediatric patients with AML treated on the AML99 protocol in Japan. Significant differences between patients with or without KIT mutations were observed in the 4-year overall survival (50.0% versus 97.4%, P = .001), disease-free survival (37.5% versus 94.7%, P < .001) and relapse rate (47.0% versus 2.7%, P < .001). Furthermore, FLT3 internal tandem duplication was found in only 2 (4.3%) patients. These results suggested that KIT mutations are strongly associated with a poor prognosis in pediatric t(8;21) AML.
  • Toshiji Shitara, Akira Shimada, Ryoji Hanada, Tadashi Matsunaga, Keisei Kawa, Hideo Mugishima, Tohru Sugimoto, Jun-ichi Mimaya, Atsushi Manabe, Masahito Tsurusawa, Yoshiaki Tsuchida
    Pediatric hematology and oncology 23 2 103 - 10 2006年03月 [査読有り][通常論文]
     
    Irinotecan is expected to become a new drug for childhood solid tumors. Sixteen children with relapsed solid tumors received irinotecan 180 mg/m2/day for 3 consecutive days, repeated once after 25 days off. Their original tumors were neuroblastoma in 7, rhabdomyosarcoma in 3, nephroblastoma and undifferentiated sarcoma in 2 each, and primitive neuroectodermal tumor and leiomyosarcoma in 1 each. The average age at trials was 6 years. Partial response was achieved in 5 (31.3%) (neuro-blastoma, rhabdomyosarcoma, nephroblastoma, undifferentiated sarcoma, and leiomyosarcoma), and decrease in tumor marker in the other 2. Irinotecan appears promising, and could become included in the first-line treatment.
  • Minoru Kuroiwa, Mitsuteru Hiwatari, Junko Hirato, Norio Suzuki, Yoshiaki Tsuchida, Akira Shimada, Toshiji Shitara, Tomohiko Taki, Yasuhide Hayashi
    Journal of pediatric surgery 40 11 1798 - 801 2005年11月 
    A 12-year-old girl presented with a large abdominal tumor. At surgery, a huge pedunculated extraluminal tumor was found arising from the greater curvature of the stomach and invading the surrounding structures, and there were also a submucosal tumor measuring 5 x 4 x 4 cm and multiple intramural nodules beside the main tumor. These lesions, which were removed with 1.0-cm surgical margins, were immunohistochemically positive for c-kit (CD117) and CD34. A diagnosis of gastrointestinal stromal tumor (GIST) was made. The huge size of the tumor (3.6 kg in weight and 36 x 25 x 25 cm in diameter), the invasion of the surrounding structures, and the increased mitotic figures indicated the GIST had malignant potential. Sequence analysis of the polymerase chain reaction product of RNAs from the tumor cells revealed a novel platelet-derived growth factor receptor alpha (PDGFRA) mutation, which would exhibit biologic consequences similar to those of the c-kit mutation. The patient underwent a 3-month course of imatinib mesylate as adjuvant chemotherapy because of the possible risk for tumor recurrence. She is now doing well without any evidence of recurrence or metastasis 25 months after the surgery. Only 9 cases of GIST have been reported in children, and a review of those cases revealed GISTs in children would be associated with a better prognosis than in adults and that one third of pediatric GISTs presented with intestinal obstruction in the newborn period.
  • Taizo Wada, Tomoko Toma, Hiroyuki Okamoto, Yoshihito Kasahara, Shoichi Koizumi, Kazunaga Agematsu, Hirokazu Kimura, Akira Shimada, Yasuhide Hayashi, Masahiko Kato, Akihiro Yachie
    Blood 106 6 2099 - 101 2005年09月 
    Omenn syndrome (OS) is a rare primary immunodeficiency characterized by the presence of activated/oligoclonal T cells, eosinophilia, and the absence of circulating B cells. OS patients carry leaky mutations of recombination activating genes (RAG1 or RAG2) resulting in partial V(D)J recombination activity, whereas null mutations cause severe combined immunodeficiency with absence of mature T and B cells (T-B- SCID). Here we describe somatic mosaicism due to multiple second-site mutations in a patient with RAG1 deficiency. We found that he is homozygous for a single base deletion in the RAG1 gene, which results in frameshift and likely abrogates the protein function. However, the patient showed typical OS features. Molecular analysis revealed that several second-site mutations, all of which restored the RAG1 reading frame and resulted in missense mutations, were demonstrated in his T cells. These findings suggest that his revertant T-cell mosaicism is responsible for OS phenotype switched from T-B- SCID.
  • Toshiji Shitara, Yoshiaki Tsuchida, Junko Hirato, Akira Shimada, Hideaki Murai, Norio Suzuki, Minoru Kuroiwa, Mayumi Iwakawa
    Pediatric surgery international 21 6 470 - 3 2005年06月 
    The prognosis for children with Wilms' tumor is reported to be excellent in those who are less than 2 years of age at diagnosis and who have a stage I/favorable-histology tumor with specimen weight less than 550 g. We report on a patient with Wilms' tumor who belonged to this group but who developed pulmonary metastases, and we discuss the diagnostic and therapeutic problems in such patients. The importance of careful evaluation of the renal sinus should be emphasized.
  • Down症候群のtransient myeloproliferative disorderは胎内で発症している?
    嶋田 明, 菊地 水穂, 設楽 利二, 林 泰秀, 藤生 徹, 丸山 憲一, 小林 徹, 徐 剛, 土岐 力, 伊藤 悦朗
    日本小児科学会雑誌 108 2 211 - 211 (公社)日本小児科学会 2004年02月 [査読有り][通常論文]
  • Akira Shimada, Kenichi Maruyama, Toshiji Shitara, Masahiko Kato, Kazutoshi Cho, Tohru Kobayashi, Toru Fujiu, Yoshiaki Tsuchida, Akira Nishida, Yasuhide Hayashi, Hisanori Minakami, Kunihisa Kozawa, Hirokazu Kimura
    Biology of the neonate 85 3 167 - 72 2004年 
    A transient myeloproliferative disorder (TMD) occurs in 10% of the infants with Down syndrome. While most cases resolve within a few months, in 20% of them TMDs are life-threatening or fatal. We encountered 4 patients with TMD, including 1 patient who died of liver failure and disseminated intravascular coagulation. Suspecting involvement of proinflammatory cytokines, we serially assayed them in patients' sera. Cytokines were significantly more abundant in patients than in controls. Interleukins 1 and 2, tumor necrosis factor alpha, interferon gamma, and granulocyte-macrophage colony-stimulating factor were greatly increased, especially in the infant who died. Sustained cytokinemia is likely to participate in TMD pathophysiology, and very high serum concentrations might predict a poor outcome.
  • Akira Shimada, Gang Xu, Tsutomu Toki, Hirokazu Kimura, Yasuhide Hayashi, Etsuro Ito
    Blood 103 1 366 - 366 2004年01月
  • 島田 明
    電気学会論文誌. D, 産業応用部門誌 = The transactions of the Institute of Electrical Engineers of Japan. D, A publication of Industry Applications Society 120 1 1 - 2 The Institute of Electrical Engineers of Japan 2000年01月
  • 島田 明
    日本ロボット学会誌 10 7 983 - 991 The Robotics Society of Japan 1992年11月 
    The aim of this paper is to clear characteristics of the obsever based robot motion controller, which observer estimates disturbance torque and velocity.
    Generally, because of perturbation for moment of inertia, gravity, friction, and low-stiffness by its kinematic structures, robot motion becomes worse. It is well-known that the disturbance observer based controller is robust for not only actually disturbance but unknown perturbation. But we have never full knowledge of that observer, today.
    This paper describes the phisical means of the disturbance torque and velocity estimated observer, at first. Next, it shows how the observer which is used as way of attenuation for additional disturbance, gives influence to not-nominal model. And, I will show the influence of observer and phase-shift for chaging moment of inertia. And for low stiffness manipulators, I will clear that the observer having not-optimal poles gives worse result for motion.
  • 島田 明
    日本ロボット学会誌 10 5 617 - 620 The Robotics Society of Japan 1992年09月

講演・口頭発表等

  • Panel-based NGS Identifies Prognostic and Actionable Genes in Childhood Acute Lymphoblastic Leukemia and Suits for Clinical Sequence.  [通常講演]
    109th Annual Meeting of American Association of Cancer Research 2018年
  • Aberrant Methylation of Tumor Suppressor Genes in Pediatric Myelodysplastic Syndrome / Acute Myeloid Leukemia.  [通常講演]
    109th Annual Meeting of American Association of Cancer Research 2018年
  • The challenge of risk-reclassification of Pediatric AML with FLT3 wild type – JPLSG AML05 study,  [通常講演]
    Annual Meeting of International BFM study group 2016年
  • Poor prognosis with different induction rate was observed in children with acute myeloid leukemia and FLT3-ITD according to the ITD/WT allelic ratio: a result from the Japanese Pediatric Leukemia/Lymphoma Study Group  [通常講演]
    米国血液学会 2013年
  • 末梢血中WT1mRNA定量とFCM-MRDが再発の早期発見に有効であったAML-M7の 一例  [通常講演]
    日本小児血液がん学会 2013年
  • 抗凝固療法抵抗性の肝中心静脈閉塞症2症例の治療経験  [通常講演]
    日本小児血液がん学会 2013年
  • 末梢血中に少数の芽球を認めたPartial trisomy 21を伴うTAM/TMDの一例  [通常講演]
    日本小児血液がん学会 2013年
  • Persistent Chromosomal Abnormalities in Ph-negative cells during Imatinib Therapy - a CML case  [通常講演]
    日本血液学会 2013年
  • ABL kinase mutation correlated to the resistance for imatinib, dasatinib and nilotinib in Philadelphia chromosome-positive pediatric acute lymphoblastic leukemia  [通常講演]
    日本血液学会 2013年
  • Chemotherapy prior to Hematopoietic stem cell transplantation is effective for pediatric RAEB/RAEB-T  [通常講演]
    日本血液学会 2013年
  • Poor prognosis with different induction rate was observed in children with acute myeloid leukemia and FLT3-ITD according to the ITD/WT allelic ratio: a result from the Japanese Pediatric Leukemia/Lymphoma Study Group  [通常講演]
    American Society of Hematology 2013年
  • Treatment experience of 2 veno-occulusive disease cases which were resistant for anti-coagulant therapy  [通常講演]
    2013年
  • Persistent Chromosomal Abnormalities in Ph-negative cells during Imatinib Therapy - a CML case  [通常講演]
    2013年
  • ABL kinase mutation correlated to the resistance for imatinib, dasatinib and nilotinib in Philadelphia chromosome-positive pediatric acute lymphoblastic leukemia  [通常講演]
    2013年
  • Chemotherapy prior to Hematopoietic stem cell transplantation is effective for pediatric RAEB/RAEB-T  [通常講演]
    2013年
  • 乳児AMLの後方視的解析  [通常講演]
    日本小児血液がん学会 2011年
  • Frequent TP53 mutations in pediatric refractory cytopenia of childhood but rare in aplastic anemia  [通常講演]
    日本血液学会 2011年
  • 小児骨髄増殖性疾患の残された課題―真性多血症、本態性血小板血症  [通常講演]
    日本小児科学会 2011年
  • Infant AML  [通常講演]
    International BFM study group annual meeting 2011年
  • Infant AML  [通常講演]
    International BFM study group annual meeting 2011年

MISC

  • TP53遺伝子異常を伴う小児急性骨髄性白血病の臨床像と分子生物学異常の解析(Clinical and molecular characterization of pediatric acute myeloid leukemia with TP53 alterations)
    Hara Yusuke, Taki Tomohiko, Yamato Genki, Yoshida Kenichi, Shiba Norio, Kaburagi Taeko, Shiraishi Yuichi, Ohki Kentaro, Kawamura Machiko, Sotomatsu Manabu, Arakawa Hirokazu, Matsuo Hidemasa, Shimada Akira, Toki Tsutomu, Kiyokawa Nobutaka, Tomizawa Daisuke, Taga Takashi, Ito Etsuro, Horibe Keizo, Miyano Satoru, Ogawa Seishi, Adachi Souichi, Hayashi Yasuhide 日本小児血液・がん学会雑誌 56 (4) 192 -192 2019年10月 [査読無し][通常論文]
  • 小児急性骨髄性白血病患者におけるKMT2C変異とPHF6変異の臨床的意義について(Clinical significances of patients with KMT2C and PHF6 mutations in pediatric acute myeloid leukemia)
    Kaburagi Taeko, Yamato Genki, Shiba Norio, Yoshida Kenichi, Hara Yusuke, Shiraishi Yuichi, Ohki Kentaro, Sotomatsu Manabu, Arakawa Hirokazu, Matsuo Hidemasa, Shimada Akira, Taki Tomohiko, Kiyokawa Nobutaka, Tomizawa Daisuke, Horibe Keizo, Miyano Satoru, Adachi Souichi, Taga Takashi, Ogawa Seishi, Hayashi Yasuhide 日本小児血液・がん学会雑誌 56 (4) 191 -191 2019年10月 [査読無し][通常論文]
  • Ikuya Usami, Toshihiko Imamura, Yoshihiro Takahashi, So-ichi Suenobu, Daiichiro Hasegawa, Yoshiko Hashii, Takao Deguchi, Tsukasa Hori, Akira Shimada, Koji Kato, Etsuro Ito, Akiko Moriya Saito, Hirohide Kawasaki, Hiroki Hori, Keiko Yumura Yagi, Jun-ichi Hara, Atsushi Sato, Keizo Horibe BLOOD 130 2017年12月 
    0
  • 乳児Atypical teratoid/rhabdid tumorに対する放射線治療および分子生物学的分類と予後との関連について.
    大谷理浩, 市川智継, 黒住和彦, 安原隆雄, 鷲尾佳奈, 嶋田 明, 片山敬久, 勝井邦彰, 柳井広之, 伊達 勲 脳神経外科 45 (2) 147 -154 2017年 [査読無し][通常論文]
  • 小児疾患診療のための病態生理 3 改訂第5版】 血液・腫瘍性疾患 急性骨髄性白血病
    嶋田 明 小児内科 48 921 -927 2016年 [査読無し][通常論文]
  • 【血球の増加と減少】 赤血球 赤血球増多症 過粘稠度症候群を含めて
    嶋田 明 小児内科 48 (7) 990 -992 2016年 [査読無し][通常論文]
  • 竹井絵莉菜, 嶋田明, 神崎浩孝, 渡部友紀, 武田達明, 八木健太, 槙田祟志, 正岡康幸, 北村佳久, 千堂年昭 日本薬学会年会要旨集(CD-ROM) 135th (4) ROMBUNNO.26PB-PM214 -203 2015年03月 [査読無し][通常論文]
  • 【Ph陰性骨髄増殖性腫瘍~分子病態と治療の最前線~】 小児骨髄増殖性疾患の分子病態と治療
    嶋田 明 血液フロンティア 25 (7) 987 -992 2015年 [査読無し][通常論文]
  • 先天性白血病(新生児白血病)
    嶋田 明 日本産婦人科・新生児血液学会誌 24 (2) 53 -59 2015年 [査読無し][通常論文]
  • 骨髄系 小児骨髄増殖性疾患の分子メカニズム
    嶋田 明 Annual Review血液 2015 128 -132 2015年 [査読無し][通常論文]
  • 小児急性骨髄性白血病における癌抑制遺伝子のDNAメチル化と脱メチル化剤の抗腫瘍効果(Promotor Hypermethylation of Tumor Suppressor Genes in Pediatric Acute Myeloid Leukemia and Anti-Tumor Effect of Demethylating Agent)
    竹井 絵莉菜, 神崎 浩孝, 武田 達明, 八木 健太, 槇田 崇志, 正岡 康幸, 北村 佳久, 千堂 年昭, 嶋田 明 日本小児血液・がん学会雑誌 51 (4) 269 -269 2014年10月 [査読無し][通常論文]
  • 小児急性骨髄性白血病におけるEVI1関連遺伝子の高発現の予後的影響(The prognostic impact of high EVI1-related genes expression in pediatric acute myeloid leukemia)
    Shiba Norio, Hara Yusuke, Ohki Kentaro, Yamato Genki, Park Myoung-Ja, Kobayashi Tohru, Ichikawa Hitoshi, Tomizawa Daisuke, Taki Tomohiko, Shimada Akira, Sotomatsu Manabu, Arakawa Hirokazu, Horibe Keizo, Adachi Souichi, Tawa Akio, Hayashi Yasuhide 臨床血液 55 (9) 1376 -1376 2014年09月 [査読無し][通常論文]
  • 八木健太, 河崎陽一, 嶋田明, 竹井絵莉菜, 武田達明, 江角悟, 北村佳久, 千堂年昭 日本薬学会年会要旨集(CD-ROM) 134th (4) ROMBUNNO.30PMM-008S -177 2014年03月 [査読無し][通常論文]
  • NUP98-NSD1融合遺伝子陽性例は小児急性骨髄性白血病において予後不良である
    原 勇介, 柴 徳生, 嶋田 明, 工藤 寿子, 富澤 大輔, 多賀 崇, 多和 昭雄, 荒川 浩一, 足立 壮一, 林 泰秀 日本小児科学会雑誌 117 (2) 344 -344 2013年02月 [査読無し][通常論文]
  • 小児再生不良性貧血の骨髄像 140例のセントラルレビューによる検討
    濱 麻人, 吉見 礼美, 坂口 大俊, 土居崎 小夜子, 村松 秀城, 嶋田 明, 高橋 義行, 野沢 和江, 伊藤 雅文, 土田 昌宏, 真部 淳, 小原 明, 小島 勢二 臨床血液 2013年 [査読無し][通常論文]
  • 小児急性白血病におけるDNMT3A遺伝子変異の解析
    柴 徳生, 朴 明子, 村田 知里, 嶋田 明, 滝 智彦, 外松 学, 田渕 健, 足立 壮一, 多和 昭雄, 堀部 敬三, 土田 昌宏, 花田 良二, 月本 一郎, 荒川 浩一, 林 泰秀 小児がん 48 (プログラム・総会号) 203 -203 2011年11月 [査読無し][通常論文]
  • 嶋田 明, 林 泰秀 日本小児血液学会雑誌 24 (5) 276 -282 2010年12月
  • 菊池 陽, 花田 良二, 康 勝好, 嶋田 明, 小埜 良一, 山本 圭子, 岩中 督, 今泉 了彦, 相原 敏則, 岸本 宏志, 小川 恵弘 小児がん 38 (1) 9 -12 2001年06月

受賞

  • 2011年 クレディセゾン賞
     JPN


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