Akihiro Takeshita

Publications (57)187.24 Total impact

• Article: Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia.

  Masamitsu Yanada, Motohiro Tsuzuki, Hiroyuki Fujita, Katsumichi Fujimaki, Shin Fujisawa, Kazutaka Sunami, Masafumi Taniwaki, Akira Ohwada, Kosuke Tsuboi, Akio Maeda, Akihiro Takeshita, Shigeki Ohtake, Yasushi Miyazaki, Yoshiko Atsuta, Yukio Kobayashi, Tomoki Naoe, Nobuhiko Emi
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  ABSTRACT: The optimal treatments for relapsed acute promyelocytic leukemia (APL) remain equivocal. We conducted a phase 2 study to evaluate the efficacy and feasibility of a sequential treatment consisting of induction and consolidation with arsenic trioxide (ATO), peripheral blood stem cell (PBSC) harvest after high-dose cytarabine chemotherapy, and autologous hematopoietic cell transplantation (HCT). Between 2005 and 2009, 35 patients (26 with hematologic and 9 with molecular relapse) were enrolled. Induction therapy resulted in complete remission in 81% of those with hematologic relapse, and most patients became negative for PML-RARα after the first ATO consolidation course, but 4 remained positive. Administration of the second ATO consolidation course further decreased the transcript levels in 3 patients. In total, 25 patients proceeded to PBSC harvest, all of whom successfully achieved the target CD34+ cell doses, and 23 underwent autologous HCT with PML-RARα-negative PBSC graft. Post-transplant relapse occurred in 3 patients, and there was no transplant-related mortality. With a median follow-up of 4.9 years, the 5-year event-free and overall survival rates were 65% and 77%, respectively. These findings demonstrate the outstanding efficacy and feasibility of the sequential treatment featuring ATO and autologous HCT for relapsed APL. This study is registered at the UMIN Clinical Trials Registry as C000000302.
  Blood 02/2013; · 9.90 Impact Factor
• Article: Long-term outcome and prognostic factors of elderly patients with acute promyelocytic leukemia.

  Takaaki Ono, Akihiro Takeshita, Yuji Kishimoto, Hitoshi Kiyoi, Masaya Okada, Takahiro Yamauchi, Motohiro Tsuzuki, Kentaro Horikawa, Mitsuhiro Matsuda, Katsuji Shinagawa, Fumihiko Monma, Shigeki Ohtake, Chiaki Nakaseko, Masatomo Takahashi, Yukihiko Kimura, Masako Iwanaga, Norio Asou, Tomoki Naoe
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  ABSTRACT: Studies focused on elderly acute promyelocytic leukemia (APL) are relatively limited. To evaluate prognostic impact in elderly APL, we compared the long-term outcome of elderly APL patients (60-70 years) with younger patients (15-59 years) treated with all-trans retinoic acid combined with anthracycline and cytarabine in the Japan Adult Leukemia Study Group (JALSG) APL97 study. Of 283 evaluable patients, 46 (16.3%) were elderly who had more frequent lower platelet (P = 0.04), lower albumin (P = 0.006) and performance status 3 (P = 0.02), higher induction death rate due to differentiation syndrome (P = 0.03), and non-relapse mortality (NRM) during consolidation therapy (P = 0.001). Overall survival was significantly inferior in elderly patients (P = 0.005), but disease-free survival and cumulative incidence of relapse were not. Better therapeutic approaches should be considered to reduce NRM during induction and consolidation therapy in elderly APL. This study was registered at http://www.umin.ac.jp/ctrj/ under C000000206.
  Cancer Science 07/2012; · 3.33 Impact Factor
• Article: Randomized comparison of fixed-schedule versus response-oriented individualized induction therapy and use of ubenimex during and after consolidation therapy for elderly patients with acute myeloid leukemia: the JALSG GML200 Study.

  Atsushi Wakita, Shigeki Ohtake, Satoru Takada, Fumiharu Yagasaki, Hirokazu Komatsu, Yasushi Miyazaki, Kohmei Kubo, Yukihiko Kimura, Akihiro Takeshita, Yoko Adachi, Hitoshi Kiyoi, Takuhiro Yamaguchi, Minoru Yoshida, Kazunori Ohnishi, Shuichi Miyawaki, Tomoki Naoe, Ryuzo Ueda, Ryuzo Ohno
  [show abstract] [hide abstract]
  ABSTRACT: We conducted a multicenter prospective randomized study to compare a fixed-scheduled induction therapy with a response-oriented individualized induction therapy for elderly patients with acute myeloid leukemia (AML). Newly diagnosed AML patients, aged between 65 and 80, were randomly assigned to receive fixed or individualized induction. Both groups received daunorubicin (DNR) 40 mg/m(2) for 3 days and behenoyl cytarabine (BHAC) 200 mg/m(2) for 8 days. In the individualized group, bone marrow biopsy was done on days 8 and 10, and according to the cellularity and blast ratio, the patients received additional DNR and BHAC for two to four more days. All patients achieving complete remission (CR) were randomized a second time to determine whether they would receive ubenimex. CR was obtained in 60.1 % of the fixed group and 63.6 % of the individualized group. Predicted 4-year relapse-free survival (RFS) was 9 % for the fixed group and 18 % for the individualized group. There were no statistically significant differences in CR and RFS between the fixed and individualized groups. In the ubenimex group, prolonged RFS was observed. Notably, gender was a prognostic factor in this study, as 102 female patients had a significantly higher CR rate (72.5 vs. 54.3 %, p = 0.0048) and better OS (24 vs. 14 % at 4 years, p = 0.018), compared with 140 male patients.
  International journal of hematology 05/2012; 96(1):84-93. · 1.17 Impact Factor
• Article: Phase I trial of gemtuzumab ozogamicin in intensive combination chemotherapy for relapsed or refractory adult acute myeloid leukemia (AML): Japan Adult Leukemia Study Group (JALSG)-AML206 study.

  Noriko Usui, Akihiro Takeshita, Chiaki Nakaseko, Nobuaki Dobashi, Hiroyuki Fujita, Hitoshi Kiyoi, Yukio Kobayashi, Toru Sakura, Yuichi Yahagi, Kazuyuki Shigeno, Chikako Ohwada, Yasushi Miyazaki, Shigeki Ohtake, Shuichi Miyawaki, Tomoki Naoe, Kazunori Ohnishi
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  ABSTRACT: In order to investigate better molecular-target therapy for acute myeloid leukemia (AML), we conducted a phase I trial of a combination of gemtuzumab ozogamicin (GO) with conventional chemotherapy. Between January 2007 and December 2009, a total of 19 adult Japanese patients with relapsed or refractory CD33-positive AML (excluding acute promyelocytic leukemia) were enrolled. All registered patients received a standard dose of cytarabine (Ara-C) (100 mg/m(2) × 7 days), combined with either idarubicin (IDR) (10-12 mg/m(2) × 3 days) or daunorubicin (DNR) (50 mg/m(2) × 3-5 days), and then GO (3-5 mg/m(2) ), which was administered 1 day after the last infusion of IDR (IAG regimen) or DNR (DAG regimen). While doses of both GO and IDR and the administration period of only DNR were increased, the dose-limiting toxicity (DLT) was assessed. Among 19 patients (nine in the IAG regimen, 10 in the DAG regimen), the median age was 59 years (range 33-64), and the relapsed/refractory ratio was 13/6. In the therapy using 3 mg/m(2) GO in the IAG or DAG regimen, grade 3/4 leukopenia and neutropenia were observed in all patients, but none had grade 3/4 non-hematological toxicities, except febrile neutropenia. Three patients in the IAG regimen who were administered 5 mg/m(2) GO showed DLT. No patients had veno-occlusive disease or sinusoidal obstructive syndrome. In conclusion, 3 mg/m(2) GO combined with Ara-C and IDR or DNR can be safely administered, and phase II trials should be conducted to investigate the clinical efficacy of the combination therapy.
  Cancer Science 07/2011; 102(7):1358-65. · 3.33 Impact Factor
• Article: [Analyses of 6 misidentifications in blood sampling in our hospital].

  Chiaki Yamada, Harumi Fujiwara, Naoko Ogawa, Yui Funai, Hiroki Shibata, Hiroko Watanabe, Makoto Kaneko, Akihiro Takeshita
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  ABSTRACT: The initial step of blood transfusion therapy is blood type grouping. ABO-mismatch blood transfusion results in serious adverse effects. 6 incidents in the process of blood type identification, which were caused by misidentification in blood sampling, have experienced in our hospital since October, 2006 to September 2009. We retrospectively examined these incidents, and discussed the reasons and countermeasures. All of 6 incidents were caused by busy residents or nurses during busy hours such as early in the morning or in the emergency. To prevent these incidents, staffs of transfusion unit announced what we have to take care in sampling blood and tied alert tags to sampling tubes. Moreover, we have recently introduced crosschecking computer systems between patients and sampling tubes. We should make continuous efforts to establish safer blood transfusion systems.
  Rinsho byori. The Japanese journal of clinical pathology 01/2011; 59(1):42-5.
• Article: Impact of additional chromosomal abnormalities in patients with acute promyelocytic leukemia: 10-year results of the Japan Adult Leukemia Study Group APL97 study.

  Takaaki Ono, Akihiro Takeshita, Masako Iwanaga, Norio Asou, Tomoki Naoe, Ryuzo Ohno
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  ABSTRACT: Background. We analyzed the clinical features and outcomes of acute promyelocytic leukemia (APL) patients with or without additional chromosomal abnormalities (ACAs) who were treated with all-trans retinoic acid (ATRA) and chemotherapy in a multicenter prospective study, JALSG APL97. Design and Methods. Of 302 registered patients, 225 patients were assessable. Clinical characteristics were compared between patients with or without ACAs. The response to treatment and long-term outcomes were also compared. Results. ACAs were observed in 67 patients (30%). Trisomy 8 was most frequently detected in 21 cases (31%). Although the clinical characteristics did not differ between two groups, the frequency of M3v was significantly lower in patients with ACAs (1% vs. 9%, P = 0.04). Complete remission rate and relapse rate were similar between patients with or without ACAs (97% vs. 95%, P = 0.72 and 26% vs. 22%, P = 0.51, respectively). Overall survival (OS) and disease-free survival (DFS) were similar between two groups (91% vs. 84%, P = 0.18 and 68% vs. 71%, P = 0.59, respectively). Conclusions. ACAs in Japanese APL patients neither showed any prognostic significance in this study involving a substantial number of patients, but should further be followed in keeping with the advent of treatments for this curable disease.
  Haematologica 09/2010; 96(1):174-6. · 6.42 Impact Factor
• Article: Collaborative study of irregular erythrocyte antibodies in Japan: results from the Japanese study group of allo-immunity and antigen diversity in Asian populations.

  Akihiro Takeshita, Hiroko Watanabe, Harumi Fijihara, Machiko Oshida, Kimiko Yurugi, Yutaka Tomoda, Makoto Uchikawa, Shuichi Kino, Hitoshi Ohto
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  ABSTRACT: As a national study, we evaluated the frequencies of irregular erythrocyte antibodies (Abs) by gender and history of transfusion or pregnancy. In total, data from 248,785 patients were analyzed, from whom 4222 irregular erythrocyte Abs were detected in 3554 cases (1.43%). Abs frequencies in these 4222 cases were as follows: anti-E, 26%; anti-Le(a), 26%; anti-P(1), 11%; anti-M, 6%; anti-E+c, 4%; anti-Fy(b), 4%; anti-Di(a), 3%; anti-Le(b), 3%; and anti-D, 2%. In pregnancy, anti-D (5%), anti-Jr(a) (3%) and anti-E+c (6%) Abs were, with statistical significance, more frequent. Among transfused patients, anti-E (38%), anti-E+c (8%), anti-Jk(a) (4%), anti-e+C (2%) and anti-E+Jk(a) (1%) Abs were, with statistical significance, more frequent.
  Transfusion and Apheresis Science 08/2010; 43(1):3-8. · 1.25 Impact Factor
• Article: [Biological markers for diagnosis of myeloid leukemia].

  Akihiro Takeshita, Kaori Shinjo
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  ABSTRACT: There are several important biological markers in myeloid leukemia. In particular, WT1, FLT3, P-glycoprotein (P-gp) and surface antigens are important biologic markers. When we monitor the treatment of leukemia, WT1 is considered to be an important marker, and has been applied to immune therapy. The abnormality of the genes of FLT3 and expression of P-gp are poor prognostic factors, and their inhibitors are developed in progress. The surface antigen analysis of blast cells is also used in the classification and the treatment strategy decision. Recently, as for the treatment of leukemia, stratification by various kinds of factors has been adopted in many prospective studies. The results of these biological markers are utilized for the stratification.
  Nippon rinsho. Japanese journal of clinical medicine 10/2009; 67(10):1916-20.
• Article: CMC-544 (inotuzumab ozogamicin) shows less effect on multidrug resistant cells: analyses in cell lines and cells from patients with B-cell chronic lymphocytic leukaemia and lymphoma.

  Akihiro Takeshita, Kaori Shinjo, Nozomi Yamakage, Takaaki Ono, Isao Hirano, Hirotaka Matsui, Kazuyuki Shigeno, Satoki Nakamura, Tadasu Tobita, Masato Maekawa, Kazunori Ohnishi, Yoshikazu Sugimoto, Hitoshi Kiyoi, Tomoki Naoe, Ryuzo Ohno
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  ABSTRACT: The effect of CMC-544, a calicheamicin-conjugated anti-CD22 monoclonal antibody, was analysed in relation to CD22 and P-glycoprotein (P-gp) in B-cell chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) in vitro. The cell lines used were CD22-positive parental Daudi and Raji, and their P-gp positive sublines, Daudi/MDR and Raji/MDR. Cells obtained from 19 patients with B-cell CLL or NHL were also used. The effect of CMC-544 was analysed by viable cell count, morphology, annexin-V staining, and cell cycle distribution. A dose-dependent, selective cytotoxic effect of CMC-544 was observed in cell lines that expressed CD22. CMC-544 was not effective on Daudi/MDR and Raji/MDR cells compared with their parental cells. The MDR modifiers, PSC833 and MS209, restored the cytotoxic effect of CMC-544 in P-gp-expressing sublines. In clinical samples, the cytotoxic effect of CMC-544 was inversely related to the amount of P-gp (P = 0.003), and to intracellular rhodamine-123 accumulation (P < 0.001). On the other hand, the effect positively correlated with the amount of CD22 (P = 0.010). The effect of CMC-544 depends on the levels of CD22 and P-gp. Our findings will help to predict the clinical effectiveness of this drug on these B-cell malignancies, suggesting a beneficial effect with combined use of CMC-544 and MDR modifiers.
  British Journal of Haematology 05/2009; 146(1):34-43. · 4.94 Impact Factor
• Article: Phase I/II study of humanized anti-CD33 antibody conjugated with calicheamicin, gemtuzumab ozogamicin, in relapsed or refractory acute myeloid leukemia: final results of Japanese multicenter cooperative study.

  Yukio Kobayashi, Kensei Tobinai, Akihiro Takeshita, Kensuke Naito, Osamu Asai, Nobuaki Dobashi, Shinpei Furusawa, Kenji Saito, Kinuko Mitani, Yasuo Morishima, Michinori Ogura, Fumiaki Yoshiba, Tomomitsu Hotta, Masami Bessho, Shin Matsuda, Jin Takeuchi, Shuichi Miyawaki, Tomoki Naoe, Noriko Usui, Ryuzo Ohno
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  ABSTRACT: The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of gemtuzumab ozogamicin (GO) in patients with relapsed and/or refractory CD33-positive acute myeloid leukemia (AML). Patients received 2-h infusions of GO twice with an interval of approximately 14 days. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria Version 2.0. Samples for pharmacokinetics were taken on day 1 and day 8 of the first treatment cycle. The dose was increased stepwise and, in each cohort, patients were treated at the same dose. Forty patients, median age 58 years (range 28-68) were treated; 20 and 20 patients were enrolled to the phase I and II parts, respectively. In the phase I part, dose-limiting toxicities (DLTs) were hepatotoxicities, and the recommended dose was established as 9 mg/m2 given as two intravenous infusions separated by approximately 14 days. The pharmacokinetic study revealed that Cmax and AUC were equivalent to those of non-Japanese patients. In the phase II part, complete remission was observed in 5 patients, and one patient had complete remission without platelet recovery. Four of these 6 in remission and one in the phase I are long-term survivors (alive for at least 44 months). GO is safe and effective as a single agent among Japanese CD33-positive AML patients. Remission lasted longer in a subset of patients than in non-Japanese patients in earlier studies. Further studies of this agent are warranted to establish standard therapy.
  International journal of hematology 05/2009; 89(4):460-9. · 1.17 Impact Factor
• Article: Phase I trial of FLAGM with high doses of cytosine arabinoside for relapsed, refractory acute myeloid leukemia: study of the Japan Adult Leukemia Study Group (JALSG).

  Shuichi Miyawaki, Yasukazu Kawai, Akihiro Takeshita, Norio Komatsu, Noriko Usui, Yukihiro Arai, Fumihiro Ishida, Takeshi Morii, Yasuhiko Kano, Michinori Ogura, Noriko Doki, Ryuzo Ohno
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  ABSTRACT: This study was designed to determine the optimal high dose for cytosine arabinoside (ara-C) in combination with fludarabine, granulocyte colony-stimulating factor, and mitoxantrone (FLAGM) in adult patients with relapsed or refractory acute myeloid leukemia. Nine patients were enrolled at increasing dosage levels of ara-C (8, 12, and 16 g/m2 per dose level). Ara-C and fludarabine were administered once a day at level 1, once or twice a day at level 2, and twice a day at level 3. All patients had grade 4 hematologic toxicity. The most common adverse events were of grade 2 or less, with nausea and vomiting being the most common (6 events), followed by diarrhea (5 events), and rash (5 events). Of the 13 grade 3 nonhematologic toxicities reported, the 2 most common were febrile neutropenia (6 events) and disseminated intravascular coagulation (3 events). No early deaths were observed. FLAGM with high-dose ara-C was considered safe for patients, and the recommended dosage of ara-C in this study was 2 g/m2 every 12 hours for a total dose of 16 g/m2.
  International Journal of Hematology 12/2007; 86(4):343-7. · 1.27 Impact Factor
• Article: A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARalpha transcript after consolidation therapy: the Japan Adult Leukemia Study Group (JALSG) APL97 study.

  Norio Asou, Yuji Kishimoto, Hitoshi Kiyoi, Masaya Okada, Yasukazu Kawai, Motohiro Tsuzuki, Kentaro Horikawa, Mitsuhiro Matsuda, Katsuji Shinagawa, Tohru Kobayashi, Shigeki Ohtake, Miki Nishimura, Masatomo Takahashi, Fumiharu Yagasaki, Akihiro Takeshita, Yukihiko Kimura, Masako Iwanaga, Tomoki Naoe, Ryuzo Ohno
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  ABSTRACT: To examine the efficacy of intensified maintenance chemotherapy, we conducted a prospective multicenter trial in adult patients with newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Of the 302 registered, 283 patients were assessable and 267 (94%) achieved complete remission. Predicted 6-year overall survival in all assessable patients and disease-free survival in patients who achieved complete remission were 83.9% and 68.5%, respectively. A total of 175 patients negative for PML-RARalpha at the end of consolidation were randomly assigned to receive either intensified maintenance chemotherapy (n = 89) or observation (n = 86). Predicted 6-year disease-free survival was 79.8% for the observation group and 63.1% for the chemotherapy group, showing no statistically significant difference between the 2 groups (P = .20). Predicted 6-year survival of patients assigned to the observation was 98.8%, which was significantly higher than 86.2% in those allocated to the intensified maintenance (P = .014). These results indicate that the intensified maintenance chemotherapy did not improve disease-free survival, but rather conferred a significantly poorer chance of survival in acute promyelocytic leukemia patients who have become negative for the PML-RARalpha fusion transcript after 3 courses of intensive consolidation therapy.
  Blood 08/2007; 110(1):59-66. · 9.90 Impact Factor
• Article: Pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia treated with arsenic trioxide.

  Shinya Fujisawa, Ryuzo Ohno, Kazuyuki Shigeno, Naohi Sahara, Satoki Nakamura, Kensuke Naito, Miki Kobayashi, Kaori Shinjo, Akihiro Takeshita, Yoshinari Suzuki, Hisakuni Hashimoto, Kenji Kinoshita, Masahito Shimoya, Toshikazu Kaise, Kazunori Ohnishi
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  ABSTRACT: To investigate the pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia (APL) treated with arsenic trioxide (ATO) at a daily dose of 0.15 mg/kg. Inorganic arsenic (AsIII and AsV) and the major metabolites monomethylarsonic acid (MAA(V)) and dimethylarsinic acid (DMAA(V)) in plasma and urine collected from 12 Japanese patients were quantified by HPLC/ICP-MS. The plasma concentrations of AsIII and AsV on day 1 reached the similar Cmax (12.4 +/- 8.4 and 10.2 +/- 3.9 ng/ml) immediately after completion of administration followed by a biphasic elimination. The AUC(0-infinity) of AsV was about twice that of AsIII. The appearance of methylated metabolites in the blood was delayed. During the repeated administration, the plasma concentrations of inorganic arsenic reached the steady state. In contrast, the MAA(V) and DMAA(V) concentrations increased in relation to increased administration frequency. The mean total arsenic excretion rate including inorganic arsenic and methylated arsenic was about 20% of daily dose on day 1 and remained at about 60% of daily dose during week 1-4. This study demonstrates that ATO is metabolized when administered intravenously to APL patients and methylated metabolites are promptly eliminated from the blood and excreted into urine after completion of administration, indicating no measurable accumulation of ATO in the blood.
  Cancer Chemotherapy and Pharmacology 04/2007; 59(4):485-93. · 2.83 Impact Factor
• Article: [Cell surface marker (CD-phenotype)].

  Akihiro Takeshita
  Nippon rinsho. Japanese journal of clinical medicine 02/2007; 65 Suppl 1:293-8.
• Article: [Antibody therapy for acute leukemia].

  Akihiro Takeshita
  Nippon rinsho. Japanese journal of clinical medicine 02/2007; 65 Suppl 1:408-15.
• Article: Molecular characterization of 8-methoxyfluoroquinolone resistance in a clinical isolate of methicillin-resistant Staphylococcus aureus.

  Toshinobu Horii, Yasuhiro Suzuki, Akihiro Takeshita, Masato Maekawa
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  ABSTRACT: Activity of gatifloxacin against clinical isolates of fluoroquinolone-resistant Staphylococcus aureus is more potent than that of other fluoroquinolones such as norfloxacin and levofloxacin. To date, few reports have described high-level resistance to gatifloxacin in clinical isolates of S. aureus, although in vitro studies have shown that mutations in both DNA gyrase and topoisomerase IV were required for gatifloxacin resistance in S. aureus. Minimum inhibitory concentrations were determined for fluoroquinolones and other antimicrobials in a methicillin-resistant S. aureus isolate that was cultured from blood of a patient with septicemia. Fluoroquinolone resistance was characterized by DNA sequencing and microbiologic assay. The isolate showed high-level resistance to fluoroquinolones including an 8-methoxyfluoroquinolone, gatifloxacin (minimum inhibitory concentration 64 microg/ml). Amino acid mutations of Ser80Tyr and Glu84Lys in GrlA and Ser84Leu and Ser85Pro in GyrA were possibly related to this resistance in methicillin-resistant S. aureus HU2000-062, although efflux may play a minor role in resistance as well. GyrA and GrlA mutations mainly conferred to 8-methoxyfluoroquinolone resistance in this isolate.
  Chemotherapy 02/2007; 53(2):104-9. · 1.82 Impact Factor
• Article: [Significance of WHO classification for acute leukemia and myelodysplastic syndrome].

  Aya Sugiura, Akihiro Takeshita
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  ABSTRACT: The FAB classification, proposed in 1976, is basically a morphological classification of leukemia and is now used worldwide. However, according to chromosome and genetic research development, some important data have been revealed to influence the prognosis of leukemia. Recently, the World Health Organization (WHO), in conjunction with the Society for Hematopathology and the European Association of Hematopathology, published a new classification. The WHO classification incorporated the results of chromosome and genetic analyses of leukemia. Some leukemias and lymphomas revealed genetic abnormalities, establishing a new disease entity in the WHO classification, and several genetic abnormalities affect drug sensitivity and prognosis. As the WHO classification is going to be used worldwide, we should update our understanding of its contents.
  Rinsho byori. The Japanese journal of clinical pathology 12/2006; 54(11):1178-86.
• Source

  Available from: hama-med.ac.jp

  Article: Arrhythmogenic effects of arsenic trioxide in patients with acute promyelocytic leukemia and an electrophysiological study in isolated guinea pig papillary muscles.

  Keisuke Yamazaki, Hajime Terada, Hiroshi Satoh, Kensuke Naito, Akihiro Takeshita, Akihiko Uehara, Hideki Katoh, Kazunori Ohnishi, Hideharu Hayashi
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  ABSTRACT: Arsenic trioxide (As(2)O (3)) is a new promising regimen for patients with a relapse of acute promyelocytic leukemia (APL), but causes life-threatening arrhythmias. This study aimed to investigate the incidence and mechanism of arrythmogenesis caused by As(2)O(3). Standard 12-lead ECGs were monitored throughout As(2)O(3) therapy in 20 APL patients. As(2)O (3) (0.15 mg/kg) significantly prolonged the corrected QT interval (QTc: 445+/-7 to 517+/-17 ms, means+/-SE, p<0.01), and also increased the QTc dispersion and transmural dispersion of repolarization. Non-sustained ventricular tachycardias and torsades de pointes occurred in 4 and 1 patients, respectively. The action potentials and isometric contraction were measured in guinea pig papillary muscles during As(2)O (3) perfusion (350 micromol/L). The action potential duration was prolonged (APD(90): 150+/-11 to 195+/-12 ms at 60 min, p<0.01, n=5) and perfusion of As(2)O(3) in a low K(+) solution with a low stimulation rate augmented the prolongation of APD, and provoked early after-depolarizations and triggered activities. The prolonged exposure to As(2)O(3) induced muscle contracture, aftercontractions, triggered activities and electromechanical alternans. Tetrodotoxin or butylated hydroxytoluene partially prevented the As(2)O(3)-induced prolongation of APD. The prolonged QTc and spatial heterogeneity are responsible for the As(2)O(3)-induced ventricular tachyarrhythmias. In addition to prolongation of the APD, cellular Ca(2+) overload and lipid peroxidation might contribute to the electrophysiological abnormalities caused by As(2)O(3).
  Circulation Journal 11/2006; 70(11):1407-14. · 3.77 Impact Factor
• Source

  Available from: cytometry.com.cn

  Article: Clinicopathological and prognostic characteristics of CD33-positive multiple myeloma.

  Naohi Sahara, Kazunori Ohnishi, Takaaki Ono, Yuya Sugimoto, Miki Kobayashi, Kaori Takeshita, Kazuyuki Shigeno, Satoki Nakamura, Kensuke Naito, Sadahiro Tamashima, Kenji Nara, Tadasu Tobita, Akihiro Takeshita, Ryuzo Ohno
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  ABSTRACT: There have been few reports about the CD33 expression on multiple myeloma (MM) cells so far, showing that only a few patients expressed CD33 homogenously on their MM cells. However, in these reports, neither detailed clinical information nor its prognostic significance was described. Therefore, we analyzed the CD33 expression on MM cells from 63 newly diagnosed patients by flow cytometry and the correlation with other clinical parameters to determine the clinicopathological significance of this molecule. Fourteen (22%) patients were positive for CD33. Of the 14 patients with CD33+ MM, >80% of MM cells were positive in six (9.5%). The CD33+ patients had higher beta 2 microglobulin and lactate dehydrogenase levels and higher incidence of anemia and thrombocytopenia than did CD33- patients. The estimated 3-yr overall survival in CD33+ patients was significantly lower than in the CD33- ones (31% and 50%, respectively, P = 0.042). Especially, mortality within a year from diagnosis in the CD33+patients was higher than that in CD33- patients (43% and 10%, respectively, P = 0.005). Serial evaluation of CD33 expression showed that the amount of CD33 significantly increased after a variety of treatment including melphalan and steroid in individual patients. These results suggest that the CD33 expression might be associated with drug resistance to these conventional agents, and CD33 might be a useful target for the development of new therapeutic agents in MM.
  European Journal Of Haematology 08/2006; 77(1):14-8. · 2.61 Impact Factor
• Article: Role for interleukin-6 and insulin-like growth factor-I via PI3-K/Akt pathway in the proliferation of CD56- and CD56+ multiple myeloma cells.

  Naohi Sahara, Akihiro Takeshita, Takaaki Ono, Yuya Sugimoto, Miki Kobayashi, Kazuyuki Shigeno, Satoki Nakamura, Kaori Shinjo, Kensuke Naito, Kiyoshi Shibata, Takemi Otsuki, Hideharu Hayashi, Kazunori Ohnishi
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  ABSTRACT: Several studies including ours have suggested that lack of CD56 in multiple myeloma (MM) defines a unique patient subset with poorer prognosis. However, the mechanism underlying this aggressive behavior of CD56(-) MM has not been well elucidated. Interleukin-6 (IL-6) or insulin-like growth factor I (IGF-I) induce proliferation of MM cells. In this study, we report about the relationship between CD56 expression and responsiveness to these cytokines. We sorted out both CD56(-) and CD56(+) fractions from MM cell lines such as KMS-21-BM and U-266, and investigated their different responsiveness to IL-6 or IGF-I. Furthermore, we compared the effects of these cytokines on the regulation of cell-cycle distribution between CD56(-) and CD56(+) cells. Although CD56(-) cells in both KMS-21-BM and U-266 cells responded significantly to IL-6, CD56(+) cells did not. Ki-67(+) cells in the CD56(-) cells were significantly increased by IL-6. Western blotting showed that IL-6 phosphorylated Akt, and upregulated and downregulated the level of cyclin D1 and p27 protein in the CD56(-) KMS-21-BM cells, respectively. LY-294002 completely blocked these effects of IL-6. On the other hand, Ki-67(+) cells in the CD56(+) cells did not respond to IL-6. Anti-IGF-I mAb significantly reduced Ki-67(+) cells only in the CD56(+) cells. IGF-I phosphorylated Akt and upregulated cyclin D1 in the CD56(+) KMS-21-BM cells, which was completely blocked by LY294002. These results suggest that CD56(-) and CD56(+) MM cells could be stimulated by IL-6 and IGF-I, respectively, via PI3-K/Akt pathway, and provide useful information for anticytokine therapies.
  Experimental Hematology 07/2006; 34(6):736-44. · 2.90 Impact Factor