Atsushi Makimoto

University of Yamanashi, Kōhu, Yamanashi, Japan

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Publications (83)267.61 Total impact

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    ABSTRACT: Upon analyzing 696 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases, we identified the characteristics of CD66c expression. In addition to the confirmation of strong correlation with BCR-ABL positivity and hyperdiploid, we further observed that CD66c is frequently expressed in CRLF2-positive (11/15, p<0.01 against chimeric gene-negative) as well as hypodiploid cases (3/4), whereas it is never expressed in ETV6-RUNX1, MLL-AF4, MLL-AF9, MLL-ENL, and E2A-PBX1-positive cases. Although the expression of CD66c itself is not directly linked to the prognosis, the accompanying genetic abnormalities are important prognostic factors for BCP-ALL, indicating the importance of CD66c expression in the initial diagnosis of BCP-ALL.
    No preview · Article · Oct 2013 · Leukemia research
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    ABSTRACT: Lymphopenia-induced homeostatic proliferation of T cells after autologous hematopoietic stem cell transplantation (HSCT) skews the T cell repertoire by engaging tumor-associated Ags, leading to an induction of antitumor immunity. However, how HSCT alters the immunosuppressive microenvironment in the tumors is unknown. In this study, we first analyzed the kinetics of regulatory T cells (Tregs) in the tumors after syngeneic HSCT. Unexpectedly, the frequency of CD4(+) cells expressing Foxp3 was increased in the spleens, whereas the frequency was clearly decreased in the tumors after HSCT. The origin of reconstituted CD4(+) and Foxp3(+) cells in the tumors was mainly from the expansion of transferred splenic T cells. Then, to examine the mechanism of Treg suppression after HSCT, we isolated CD11c(+) cells from tumors. A large amount of Treg-inhibitory cytokine IL-6 was secreted from the CD11c(+) cells in the tumors, but not in the spleens in the recipient mice. Furthermore, to understand what factor affects the activity of CD11c(+) cells in the tumors after HSCT, we analyzed the expression of various cytokines/chemokines with mouse cytokine Ab arrays, and noticed that VEGF-D concentration was increased in the tumors in the early period after HSCT. The CD11c(+) cells produced IL-6 in response to VEGF-D stimulation, and an administration of VEGF receptor-3 neutralizing Ab significantly suppressed the production of IL-6 from CD11c(+) cells accompanied with the increase of Tregs in the tumors of HSCT recipients. Autologous HSCT creates an environment that strongly supports the enhancement of antitumor immunity in reconstituted lymphopenic recipients through the suppression of Tregs.
    Preview · Article · Aug 2013 · The Journal of Immunology
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    ABSTRACT: Rhabdomyosarcoma is a rare soft tissue sarcoma that typically affects children, adolescents, and young adults. Despite treatment via a multidisciplinary approach, the prognosis of advance-stage rhabdomyosarcomas remains poor, and a new treatment strategy is needed. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is a potential target for specific inhibitors. In this study, we investigated 116 rhabdomyosarcomas using a polymer-based ALK immunostaining method and correlated the results with clinicopathological parameters. In addition, we examined ALK status using dual-color fluorescence in situ hybridization, PCR, and sequencing. In immunohistochemical analysis, ALK was detected in 2 (6%) of 33 embryonal rhabdomyosarcomas, 42 (69%) of 61 alveolar rhabdomyosarcomas, and 0 (0%) of 22 other subtypes, including pleomorphic, adult-spindle-cell/sclerosing, and epithelioid variants. Compared with ALK-negative alveolar rhabdomyosarcomas, ALK-positive ones are presented with metastatic spread more frequently and showed a greater extent of myogenin reactivity. Overall survival was not associated with ALK expression. FOXO1 rearrangement was significantly associated with ALK immunoreactivity. The median ALK copy number was greater in ALK-positive tumors than in ALK-negative tumors. Most (93%) cases tested showed no selective increase in the ALK gene dosage. ALK selective amplification and low-level selective gain were noted in one and three cases, respectively. Further, a high-polysomy pattern (≥4 ALK copies in ≥40% of cells) was observed in seven cases. A significant increase in the ALK copy number was exclusive to the ALK-immunopositive cohort, but it was uncommon, accounting for only 30% of the 37 ALK-positive rhabdomyosarcomas. ALK gene rearrangement was not observed in either cohort, while an ALK somatic mutation (I1277T) was found in one ALK-negative embryonal case. Although it remains controversial whether ALK expression without gene rearrangement is therapeutically relevant, this comprehensive analysis may help future studies on the utility of ALK-targeted therapy for patients with rhabdomyosarcoma.Modern Pathology advance online publication, 11 January 2013; doi:10.1038/modpathol.2012.222.
    No preview · Article · Jan 2013 · Modern Pathology
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    ABSTRACT: The prognosis of adult rhabdomyosarcoma (RMS) has been considered dismal. The question is raised that vincristine, d-actinomycin, and cyclophosphamide (VAC) chemotherapy may not be administered as per schedule for adult RMS; consequently, low dose intensity (DI) leads to poor prognosis. Herein, we examined whether the administration of VAC chemotherapy for adults and children with RMS is feasible with regard to the DIs of VAC. Chart review was retrospectively performed for all identified patients. The percentage of relative DI (RDI) was calculated according to the Children's Oncology Group D9803 protocol. Further, we examined the RDI in the first 6 cycles of VAC (induction phase) and the DI after the first 6 cycles of VAC (maintenance phase). We identified a total of 27 adults and 18 children with RMS, respectively. The mean RDIs of vincristine in total phase were significantly lower in adults than that in children (P = 0.04). In induction phase, the mean RDIs of vincristine and cyclophosphamide were similar for both groups; however, they were dropped significantly in adults during maintenance phase (P < 0.05). Mean RDIs of vincristine in elderly patients tended to become low. Low RDI was mainly attributable to hematologic toxicity, infection, and peripheral neuropathy. The prognosis of low versus high RDI was similar. The RDIs of vincristine and cyclophosphamide in the maintenance phase were significantly lower than that in children. VAC chemotherapy for adults was not feasible; these patients require a different regimen.
    No preview · Article · Jul 2012 · Cancer Chemotherapy and Pharmacology
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    Yuki Yamamoto · Atsushi Makimoto

    Preview · Article · Apr 2012 · Japanese Journal of Clinical Oncology
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    ABSTRACT: Outcomes in adult patients with rhabdomyosarcoma are poor, with a 5-year survival rate of approximately 30 %. The current study aimed to compare the clinical outcomes of adult and childhood rhabdomyosarcoma patients with local and metastatic disease and to examine the impact and timing of local therapy on metastasis. Clinicopathological features and patient outcomes were reviewed retrospectively for rhabdomyosarcoma patients receiving chemotherapy between 1981 and 2010 at our institution. Adults were defined as those aged 21 years or older. Of the 98 patients identified, 36 were adults (median age, 29; range, 21-72) and 62 were children (median age, 11; range, 0.6-20). Median progression-free survival of localized and metastatic disease for children and adults was as follows: localized disease, 166.9 versus 22.4 months (p = 0.005), and metastatic disease, 13.3 versus 13.3 months (p = 0.949), respectively. Multivariate regression analysis revealed that older age (≥ 21 vs. <21) was a significant poor prognostic factor in localized disease. Conversely, age was not related to survival in metastatic disease. Receiving radiotherapy to the primary site was an independent factor indicating a better prognosis. An analysis of the optimal timing of local therapy was performed for 53 patients; however, its significance on survival could not be determined. Age was a negative prognostic factor in rhabdomyosarcoma patients with localized disease, but it did not affect the survival in metastatic disease. For metastatic disease, although local therapies may be effective for survival, the timing of such therapies should be determined individually.
    No preview · Article · Mar 2012 · Journal of Cancer Research and Clinical Oncology
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    ABSTRACT: Sarcoma at advanced stages remains a clinically challenging disease. Interferons (IFNs) can target cancer cells by multiple antitumor activities, including the induction of cancer cell death and enhancement of immune response. However, the development of an effective cancer immunotherapy is often difficult, because cancer generates an immunotolerant microenvironment against the host immune system. An autologous hematopoietic stem cell transplantation (HSCT) is expected to reconstitute a fresh immune system, and expand tumor-specific T cells through the process of homeostatic proliferation. Here we examined whether a combination of autologous HSCT and IFNs could induce an effective tumor-specific immune response against sarcoma. First, we found that a type I IFN gene transfer significantly suppressed the cell growth of various sarcoma cell lines, and that IFN-β gene transfer was more effective in inducing cell death than was IFN-α in sarcoma cells. Then, to examine the antitumor effect in vivo, human sarcoma cells were inoculated in immune-deficient mice, and a lipofection of an IFN-β-expressing plasmid was found to suppress the growth of subcutaneous tumors significantly. Finally, the IFN gene transfer was combined with syngeneic HSCT in murine osteosarcoma models. Intratumoral IFN-β gene transfer markedly suppressed the growth of vector-injected tumors and inhibited formation of spontaneous lung and liver metastases in syngeneic HSCT mice, and an infiltration of many immune cells was recognized in metastatic tumors of the treated mice. The treated mice showed no significant adverse events. A combination of intratumoral IFN gene transfer with autologous HSCT could be a promising therapeutic strategy for patients with sarcoma.
    No preview · Article · Sep 2011 · Human gene therapy
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    ABSTRACT: The safety, tolerability, pharmacokinetics and efficacy of nelarabine were evaluated in adult and pediatric patients with relapsed or refractory T-ALL/T-LBL. Adult patients received nelarabine i.v. over 2 hours on days 1, 3 and 5 in every 21 days, and pediatric patients received this regimen over 1 hour for 5 consecutive days in every 21 days. Safety was evaluated in 7 adult and 6 pediatric patients. Adverse events (AEs) were reported in all patients. Most frequently reported AEs included somnolence and nausea in adult patients and leukopenia and lymphocytopenia in pediatric patients. Five grade 3/4 AEs were reported in both adult and pediatric patients, most of which were hematologic events. There were no dose-limiting toxicities. Efficacy was evaluated in 7 adult and 4 pediatric patients. Complete response was noted in 1 adult and 2 pediatric patients. Higher intracellular ara-GTP concentrations were suggested to be associated with efficacy. Japanese adult and pediatric patients with T-ALL/T-LBL well tolerated nelarabine treatment, warranting further investigation.
    No preview · Article · Jun 2011 · [Rinshō ketsueki] The Japanese journal of clinical hematology
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    Preview · Article · Mar 2011 · Pediatric Blood & Cancer
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    ABSTRACT: Little is known about the incidence of secondary neoplasms among survivors of retinoblastoma in Japan. The objective of our study was to analyze the cumulative incidence rate of secondary neoplasms following retinoblastoma and to investigate the risk factors of developing secondary neoplasms. We conducted a retrospective cohort study of 754 retinoblastoma patients who visited the National Cancer Center Hospital in Tokyo between 1964 and 2007. The cumulative incidence rate curves were drawn using the competing risk method and compared with the Gray's test. Using competing risk regression analysis, multivariate analysis estimated the subdistribution hazard ratio of factors related to the development of secondary neoplasms. The median length of follow-up was 108 months (0-594 months). Twenty-one (2.8%) patients developed 23 secondary neoplasms in total. The cumulative incidence rates of secondary neoplasms after retinoblastoma treatment were 2.4% at 10 years after diagnosis, 4.3% at 20 years, 6.4% at 30 years and 19.1% at 40 years. Ten patients (1.3%) died and 723 (95.9%) were alive without developing secondary neoplasms. The subdistribution hazard ratios of hereditary retinoblastoma and external beam irradiation were 4.85 (95% confidence interval = 0.74-31.85) and 4.76 (95% confidence interval = 0.69-33.09), respectively. We demonstrated the cumulative incidence rate of secondary neoplasms following retinoblastoma in Japan. The subdistribution hazards ratios of hereditary retinoblastoma and external beam irradiation were high but not significant because of statistical power. The long-term follow-up of retinoblastoma survivors is warranted to understand secondary neoplasm risk.
    No preview · Article · Nov 2010 · Japanese Journal of Clinical Oncology
  • Atsuko Watanabe · Ako Hosono · Atsushi Makimoto

    No preview · Article · Oct 2010 · Pediatrics International
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    ABSTRACT: We present a case of a 12-year-old female with a germline TP53 mutation who presented with anaplastic astrocytoma and subsequent acute lymphoblastic leukemia (ALL) 13 months after starting treatment with temozolomide (TMZ). The patient had no family history of malignancy except her grand father and his siblings. Although alkylating agents such as TMZ are known to induce secondary hematologic malignancy, only several cases of treatment-related acute leukemia have been reported after TMZ-alone chemotherapy for malignant gliomas. We demonstrate a rare case of TMZ-related ALL in a child with glioma possibly associated with a germline TP53 mutation.
    No preview · Article · Sep 2010 · Pediatric Blood & Cancer
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    ABSTRACT: A multicenter Phase I/II study of Irinotecan hydrochloride (CPT-11; 40-45 mg/m(2)/dose) was conducted for the treatment of refractory pediatric solid tumors. The pharmacokinetics of CPT-11 and its metabolites were characterized using both traditional noncompartmental analysis and population pharmacokinetics using NONMEM VI; pharmacokinetic pharmacodynamic relationships of SN-38 with indices of toxicity were also evaluated. 11 patients between 3 and 18 years were enrolled. Pharmacokinetic parameters and consideration of relevant covariates (performance status (PS), BSA, corrected body weight (CBW), exponent of 3/4 on weight, etc.) were evaluated. Relationships between pharmacokinetic parameters of SN-38 and percentage change from baseline in patient biochemical response data were investigated via regression analysis. CPT-11 exhibited a mean clearance (CL) of 15.31 +/- 5.95 (l/h) (13.06 +/- 3.58 (l/hr/m(2))) and AUC(0-inf) of 3547.0 +/- 1406.5 (ng x h/ml); the AUC ratio of parent CPT-11 to SN-38 was 5.0%. Based on the population pharmacokinetic analysis, decreasing PS was significantly dependent on reduction in CL of CPT-11 (p < 0.001). The final model for CPT-11 are as follows: CL (l/h) = 1.31 x CBW(0.75) (omegaCL = 21.7%), Vss (l) = 2.66 x CBW (omegaVss = 21.2%), Vc (l) = 1.13 x CBW, inter-compartment CL (l/h) = 0.257 x CBW(0.75). Percentage changes of leucocyte and neutrophil count within a first month treatment were significantly correlated with Cmax of SN-38 (r = 0.78 and r = 0.74) and AUC0-2 of SN-38 (r = 0.73 and r = 0.73). Pharmacokinetic parameters were similar to results published in several past reports. An allometric scaling of CBW(0.75) would seem to provide a good index of dosage requirement of CPT-11 in pediatric patients.
    No preview · Article · May 2010 · International journal of clinical pharmacology and therapeutics
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    Preview · Article · Feb 2010 · Biology of Blood and Marrow Transplantation
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    ABSTRACT: Tumor lysis syndrome (TLS), including hyperuricemia, is a frequent serious complication in patients with hematologic malignancies. This study in Japanese patients evaluated the efficacy, safety, and pharmacokinetic profile of rasburicase in pediatric patients with hematologic malignancies. Patients aged <18 years at high risk for TLS, with newly diagnosed hematologic malignancies, were randomized to intravenous rasburicase 0.15 mg/kg/day (n = 15) or 0.20 mg/kg/day (n = 15) for 5 days. Chemotherapy was started 4-24 h after the first rasburicase dose. Response was defined as a reduction in plasma uric acid to < or = 6.5 mg/dL (patients <13 years) or < or = 7.5 mg/dL (patients > or = 13 years) by 48 h after the first administration, lasting until 24 h after the final administration. Response rates were 93.3 and 100% with rasburicase 0.15 and 0.20 mg/kg/day, respectively. Uric acid levels declined rapidly within 4 h of starting rasburicase administration in both groups. Most adverse events were related to the underlying chemotherapy regimens. Two hypersensitivity reactions, including grade 1/2 pruritus, were considered to be related to rasburicase. Rasburicase is effective and well tolerated for the management of hyperuricemia in Japanese pediatric patients at high risk of developing TLS.
    No preview · Article · Aug 2009 · International journal of hematology
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    ABSTRACT: The current study was conducted to compare the diagnostic accuracy between (18)F-fluoro-2-deoxy-D: -glucose (FDG) positron emission tomography (PET)/computed tomography (CT), and conventional imaging (CI) for the staging and re-staging of patients with rhabdomyosarcomas. Thirty-five patients who underwent FDG PET/CT prior to treatment were evaluated retrospectively. CI methods consisted of (99m)Tc-hydroxymethylene diphosphonate bone scintigraphy, chest radiograph, whole body CT, and magnetic resonance imaging of the primary site. The images were reviewed and two boardcertified radiologists reached a diagnostic consensus. Tumor stage was confirmed by histological examination and/or follow-up examinations. Interpretation on the basis of FDG PET/CT, and CI, diagnostic accuracies of the T and N stages were similar. Using FDG PET/CT, the M stage was correctly assigned in 31 patients (89%), whereas the accuracy of CI in M stage was 63%. TNM stage was correctly assessed with FDG PET/CT in 30 of 35 patients (86%) and with CI in 19 of 35 patients (54%). The overall TNM staging and M staging accuracies of FDG PET/CT were significantly higher than that of CI (P < 0.01). FDG PET/CT is more accurate than CI regarding clinical staging and re-staging of patients with rhabdomyosarcomas.
    No preview · Article · Mar 2009 · Annals of Nuclear Medicine

  • No preview · Article · Jul 2008 · EJC Supplements
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    A Hosono · A Makimoto · A Kawai · Y Takaue
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    ABSTRACT: Bone Marrow Transplantation is a high quality, peer-reviewed journal covering all aspects of clinical and basic haemopoietic stem cell transplantation.
    Preview · Article · Jul 2008 · Bone Marrow Transplantation
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    ABSTRACT: There is some unknown reason Ewing family of tumors (EFTs) is much less common on Asia and Africa than in the Western Caucasian population. This study analyzed the prediction of response and prognostic factors for Ewing family of tumors (EFTs) in an Asian population with a low incidence. We retrospectively reviewed 94 patients with EFTs between 1978 and 2006. Fifteen patients received local therapy only. Statistical analyses were performed for 79 patients, including those who received systemic chemotherapy, to identify factors related to chemotherapy responsiveness, event-free survival, and overall survival. Of the 79 patients whose records were analyzed, the 5-year event-free rate and overall survival (OS) rate were 41 and 54%, respectively. The response rate to first-line chemotherapy was 61% in 70 patients with assessable lesions. A significant predictor of response was existence of a non-pelvic primary tumor (P = 0.04). Significant prognostic factors for OS were age, performance status, and metastases at the time of diagnosis (P < 0.01, respectively). Fifty-four patients had disease progression or recurrence after first-line treatment. The time to progression was 3.4 months after salvage treatment. Progression during first-line treatment was significantly associated with time to progression after salvage treatment (P = 0.01). All patients treated without chemotherapy in first-line treatment were recurred with poor prognosis. A non-pelvic primary tumor was a favorable predictor of responsiveness to chemotherapy. Chemo-resistant patients might less benefit from second line chemotherapy. Chemotherapy in first-line treatment should not be omitted, even if primary tumor was extirpated completely.
    No preview · Article · Mar 2008 · Journal of Cancer Research and Clinical Oncology
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    ABSTRACT: The present study was conducted to clarify the diagnostic accuracy of 18F-fluoro-2-deoxy-D-glucose (18FDG) positron emission tomography (PET)/computed tomography (CT) in the staging in pediatric sarcomas. Fifty pediatric patients with histologically proven sarcomas who underwent 18FDG PET/CT before treatment were evaluated retrospectively for the detection of nodal and distant metastases. Diagnostic accuracy of 18FDG PET/CT in detecting nodal and distant metastases was compared with that of 18FDG PET and conventional imaging (CI). The images were reviewed and a diagnostic consensus was reached by 3 observers. REFERENCE standard was histologic examination in 15 patients and confirmation of an obvious progression in size of the lesions on follow-up examinations. Nodal metastasis was correctly assessed in 48 patients (96%) with PET/CT, in contrast to 43 patients (86%) with PET, and 46 patients (92%) with CI. Diagnostic accuracies of nodal metastasis in 3 modalities were similar. Using PET/CT, distant metastasis was correctly assigned in 43 patients (86%), whereas interpretation based on PET alone or CI revealed distant metastasis in 33 patients (66%) and 35 patients (70%), respectively. Diagnostic accuracy of distant metastasis with PET/CT was significantly higher than that of PET (P=0.002) or CI (P=0.008). False negative results regarding distant metastasis by PET/CT in 7 patients (14%) were caused by subcentimetric lesions (n=4), bone marrow lesion (n=2), and soft tissue lesions (n=1). PET/CT is more accurate and probably more cost-effective than PET alone or CI regarding distant metastasis in pediatric sarcomas.
    No preview · Article · Oct 2007 · Journal of Pediatric Hematology/Oncology

Publication Stats

1k Citations
267.61 Total Impact Points


  • 2013
    • University of Yamanashi
      • Department of Pediatrics
      Kōhu, Yamanashi, Japan
  • 2001-2013
    • National Cancer Center, Japan
      • • Center for Cancer Control and Information Services
      • • Research Center for Cancer Prevention and Screening
      • • Endoscopy Division
      Edo, Tōkyō, Japan
    • The University of Tokyo
      • Department of Hematology and Oncology
      Tōkyō, Japan
  • 2007
    • Sapporo Medical University
      Sapporo, Hokkaidō, Japan
  • 1994-2004
    • The University of Tokushima
      • Department of Pediatrics
      Tokusima, Tokushima, Japan
  • 2002
    • National Hospital Organization Kyushu Cancer Center
      Hukuoka, Fukuoka, Japan