Atsushi Makimoto

Saitama Medical University, Saitama, Saitama-ken, Japan

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Publications (76)232.77 Total impact

  • [show abstract] [hide abstract]
    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.
    Modern Pathology 01/2013; · 5.25 Impact Factor
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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.
    Cancer Chemotherapy and Pharmacology 07/2012; 70(3):391-7. · 2.80 Impact Factor
  • Yuki Yamamoto, Atsushi Makimoto
    Japanese Journal of Clinical Oncology 04/2012; 42(4):359. · 1.90 Impact Factor
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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.
    Journal of Cancer Research and Clinical Oncology 03/2012; 138(7):1249-57. · 2.91 Impact Factor
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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.
    [Rinshō ketsueki] The Japanese journal of clinical hematology 06/2011; 52(6):406-15.
  • Pediatric Blood & Cancer 03/2011; 56(3). · 2.35 Impact Factor
  • Atsuko Watanabe, Ako Hosono, Atsushi Makimoto
    Pediatrics International 10/2010; 52(5):836-8. · 0.88 Impact Factor
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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.
    Pediatric Blood & Cancer 09/2010; 55(3):577-9. · 2.35 Impact Factor
  • Biology of Blood and Marrow Transplantation - BIOL BLOOD MARROW TRANSPLANT. 01/2010; 16(2).
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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.
    International journal of hematology 08/2009; 90(4):492-500. · 1.17 Impact Factor
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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.
    Annals of Nuclear Medicine 03/2009; 23(2):155-61. · 1.41 Impact Factor
  • Source
    A Hosono, A Makimoto, A Kawai, Y Takaue
    Bone Marrow Transplantation 07/2008; 41(12):1067-8. · 3.54 Impact Factor
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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.
    Journal of Cancer Research and Clinical Oncology 03/2008; 134(3):389-95. · 2.91 Impact Factor
  • Ejc Supplements - EJC SUPPL. 01/2008; 6(9):159-159.
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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.
    Journal of Pediatric Hematology/Oncology 10/2007; 29(9):608-12. · 0.97 Impact Factor
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    ABSTRACT: To evaluate the potential of allogeneic hematopoietic cell transplantation (HCT) with a reduced-intensity conditioning regimen (RIST) for the treatment of patients with hematologic malignancies not in remission, we retrospectively reviewed the medical records of 132 patients (89 leukemia or myelodysplastic syndrome, 40 malignant lymphoma, and 3 others) who received conventional myeloablative HCT (CST, n=52) or RIST (n=80). The median age of the RIST group was significantly higher than that of the CST group (53 years versus 40 years, P<.01). The RIST group also included a higher proportion of patients with an HCT-specific comorbidity index (HCT-CI) of 1 or more than the CST group (65% versus 37%, P=.03). The probabilities of achieving complete remission and the incidences of grades II-IV and III-IV acute graft-versus-host disease (aGVHD) in the CST and RIST groups were, respectively, 77% and 64%, 50% and 50%, and 23% and 28%, with no significant differences. Similarly, there was no difference in the 2-year probabilities of nonrelapse mortality (NRM, 36% and 38%), progressive disease or relapse (PD 51% and 49%), overall survival (OS, 31% and 38%), and progression-free survival (PFS, 28% and 29%). Multivariate analyses revealed that a higher HCT-CI score and transplant from donors other than HLA-matched relatives were associated with increased risks of NRM and poor OS, and patients who received chemotherapy within 2 months before HCT were associated with increased risks of PD, poor OS, and PFS after transplantation. After adjusting for these variables, the risks of NRM, PD, OS, and PFS in the RIST group were not significantly different from those in the CST group. In conclusion, these results suggest that the antileukemia/lymphoma effect associated with RIST is comparable to that associated with CST. RIST appears to be feasible for the treatment of hematologic malignancies not in remission.
    Biology of Blood and Marrow Transplantation 09/2007; 13(8):932-41. · 3.94 Impact Factor
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    ABSTRACT: To study the immunoexpression of cyclo-oxygenase (COX) 2 in osteoblastomas (OBs) and osteosarcomas (OSs), and to assess the utility of immunohistochemical analysis for COX 2 in the differential diagnosis of the two tumour forms. The immunohistochemical features of COX 2 were studied in 11 OBs and 30 OSs, including 26 high-grade OSs (16 osteoblastic, 7 chondroblastic, and 3 fibroblastic) and 4 low-grade OSs. Tumour cells from all 11 OBs unequivocally showed diffuse, intense and cytoplasmic immunoreactivity for COX 2. Strong cytoplasmic expression of COX 2 was observed in 5 of 26 (19%) high-grade OSs, all chondroblastic. In one osteoblastic-type OS, COX 2 was expressed in the chondroblastic component, but this tumour was considered to be COX 2 negative. No COX 2 expression was noted in atypical osteoblastic cells. Staining in the four low-grade OSs was negative. The results of immunohistochemical analysis of COX 2 suggest that in addition to the routine histopathological evaluation, COX 2 is a valuable diagnostic marker in the distinction between OB and OS.
    Journal of Clinical Pathology 05/2007; 60(4):410-4. · 2.44 Impact Factor
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    ABSTRACT: The incidence of primary bone lymphoma (PBL) is so rare that many of its aspects remain unknown. A number of studies have been reported from Western countries, but only a few reports are available from Asia. We retrospectively analyzed 28 consecutive patients diagnosed with PBL initially treated at our hospital between 1995 and 2004. All patients underwent chemotherapy with half receiving radiotherapy as their initial treatment. A log-rank test was used in a univariate analysis to identify factors affecting overall survival. Fifteen (54%) patients were male and 13 (46%) female with a median age of 47 (range: 5-81). Although 19 (68%) patients had diffuse large B-cell lymphoma (DLBCL), other histopathological subtypes (three B-lymphoblastic lymphoma, two anaplastic large cell lymphoma, two indolent B-cell lymphoma, one NK/T-cell lymphoma (NTCL) and one Hodgkin lymphoma) were also included. The pelvis was the most frequently involved site (54%). While 68% of patients had stage IV disease, none of them showed bone marrow involvement at their initial diagnosis. Despite 61% high intermediate-risk and high-risk patients based on the International Prognostic Index, the estimated 3-year overall and progression-free survival rates were 84% and 77%, respectively. Only 'histopathological subtype (immunoblastic variant of DLBCL or NTCL versus others)' and 'response to initial treatment (progression versus remission)' were factors significantly affecting overall survival. Although the total number of patients was relatively small, the detailed clinical data analyses presented here revealed several new characteristics of PBL and some aspects that may be unique to Japanese patients.
    Japanese Journal of Clinical Oncology 04/2007; 37(3):216-23. · 1.90 Impact Factor
  • Ejc Supplements - EJC SUPPL. 01/2007; 5(4):180-181.
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    ABSTRACT: Patients who exhibit gastrointestinal (GI) involvement due to graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) are often recommended to withhold oral intake (NPO) to avoid further damage to the GI mucosa. However, it is possible that continuing oral intake could be beneficial in many patients compared to total parenteral nutrition (TPN). The primary objective of this prospective study was to evaluate whether programmed step-ladder oral dieting (enteral nutrition; EN) is feasible and beneficial for these patients. A total of 18 patients who exhibited GI-acute GVHD (stage I to III gut GVHD) after SCT received an EN dieting program, and changes in clinical and laboratory parameters were compared to those in a control cohort of 17 patients who were placed on NPO with TPN. Patients with GVHD were included prospectively and those with intestinal bleeding/obstruction, severe pancreatitis, and cytomegalovirus enterocolitis were excluded. None of the patients in the EN group experienced significant adverse events, including exacerbation of GI symptoms. Although there was no statistically significant difference in the volume or frequency of diarrhea or the time to complete dietary recovery, parameters including body weight and serum levels of total protein and albumin tended to improve faster in the EN group. The EN diet is safely applicable to patients suffering from GI involvement by GVHD.
    American Journal of Hematology 11/2006; 81(10):747-52. · 4.00 Impact Factor

Publication Stats

698 Citations
232.77 Total Impact Points

Institutions

  • 2010
    • Saitama Medical University
      • Department of Internal Medicine
      Saitama, Saitama-ken, Japan
  • 2002–2009
    • National Cancer Center, Japan
      • • Research Center for Cancer Prevention and Screening
      • • Center for Cancer Control and Information Services
      • • Endoscopy Division
      Edo, Tōkyō, Japan
  • 2007
    • Sapporo Medical University
      Sapporo, Hokkaidō, Japan
  • 2001–2006
    • National Hospital Organization Kyushu Cancer Center
      Hukuoka, Fukuoka, Japan
    • The University of Tokyo
      Edo, Tōkyō, Japan
  • 2004
    • Kagoshima University
      • Department of Pediatrics
      Kagosima, Kagoshima, Japan
  • 1995–2004
    • The University of Tokushima
      • Department of Pediatrics
      Tokusima, Tokushima, Japan