Researchers Database

omine ken

    InternalMedicineHematology Associate Professor
Last Updated :2021/11/23

Researcher Information


J-Global ID

Research Interests

  • CD19   T-cell therapy   chimeric antigen receptor   

Research Areas

  • Life sciences / Hematology and oncology
  • Life sciences / Tumor diagnostics and therapeutics

Academic & Professional Experience

  • 2014  Jichi Medical UniversitySchool of Medicine講師

Association Memberships

  • Society of Immunotherapy for Hematological Malignancies   The Japanese Society of Myeloma   THE JAPANESE CANCER ASSOCIATION   The Japan Society of Gene and Cell Therapy   THE JAPANESE SOCIETY OF INTERNAL MEDICINE   THE JAPANESE SOCIETY OF HEMATOLOGY   

Published Papers

  • Mashima K, Ikeda T, Kawaguchi SI, Toda Y, Ito S, Ochi SI, Nagayama T, Umino K, Minakata D, Nakano H, Yamasaki R, Morita K, Kawasaki Y, Sugimoto M, Ishihara Y, Ashizawa M, Yamamoto C, Fujiwara SI, Hatano K, Sato K, Oh I, Ohmine K, Muroi K, Kanda Y
    Annals of hematology 98 (5) 1127 - 1133 0939-5555 2019/05 [Refereed][Not invited]
    It is controversial whether blast percentage based on all nucleated cells (ANC) or non-erythroid cells (NEC) more accurately reflects the prognosis of patients with myelodysplastic syndromes (MDS). We considered that the impact of blast percentage on survival should be similar in MDS with erythroid hyperplasia (MDS-E) and MDS with no erythroid hyperplasia (MDS-NE), and from this perspective, we retrospectively analyzed 322 patients, including 44 with MDS-E and 278 with MDS-NE. Overall survival was similar between the MDS-E and MDS-NE groups (P = 0.94). In a subgroup of patients with bone marrow (BM) blasts of < 5%, no difference in survival was found between MDS-E and MDS-NE by either calculation method. However, in patients with a blast percentage between 5 and 10%, a significant difference in survival was observed only when the blast percentage in MDS-E was calculated from ANC (P < 0.001 by ANC and P = 0.66 by NEC). A similar result was observed when we analyzed the remaining patients with higher blasts together with those with blasts between 5 and 10%. These results suggest that the calculation of the BM blast percentage based on NEC in MDS-E provides a blast percentage value with a clinical impact consistent with that in MDS-NE.
  • Kawasaki Y, Kimura SI, Nakano H, Mashima K, Shirato Y, Kawaguchi SI, Toda Y, Ochi SI, Nagayama T, Minakata D, Yamasaki R, Morita K, Ashizawa M, Yamamoto C, Hatano K, Sato K, Oh I, Fujiwara SI, Ohmine K, Kako S, Muroi K, Kanda Y
    International journal of hematology 109 (4) 470 - 476 0925-5710 2019/04 [Refereed][Not invited]
    Neutropenia is a major risk factor for opportunistic infections in patients with acute myeloid leukemia (AML) who undergo chemotherapy. In the present study, we retrospectively compared the D-index, which reflects both the depth and duration of neutropenia, between two different chemotherapy regimens for AML. Sixty-seven patients with AML were included: 37 received an induction regimen of daunorubicin (DNR) and cytarabine followed by consolidation therapies consisting of standard-dose cytarabine (SDAC) and other antineoplastic agents; the remaining 30 received idarubicin (IDR) and cytarabine as remission induction therapy followed by high-dose cytarabine (HDAC). The duration of neutropenia was shorter, but the D-index was higher, with IDR than with DNR. The total D-index during the entire consolidation therapies was significantly higher with SDAC than with HDAC. In conclusion, the neutropenia profile differs between treatment regimens, and thus, physicians should plan the management of infectious complications according to the neutropenia profile for each regimen.
  • Umino K, Fujiwara SI, Ikeda T, Kawaguchi SI, Toda Y, Ito S, Ochi SI, Nagayama T, Mashima K, Minakata D, Nakano H, Yamasaki R, Morita K, Kawasaki Y, Yamamoto C, Ashizawa M, Hatano K, Sato K, Oh I, Ohmine K, Muroi K, Kanda Y
    Leukemia & lymphoma 60 (8) 1 - 8 1042-8194 2019/04 [Refereed][Not invited]
    This study sought to investigate the impact of the soluble interleukin-2 receptor level in the relapsed or refractory phase (r/r sIL-2R) on the clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL). We determined the optimal cutoff value of r/r sIL-2R for disease progression within 6 months from salvage chemotherapy to be 861 U/mL. The high r/r sIL-2R group exhibited a significantly lower survival rate than the low r/r sIL-2R group (1-year event-free survival [EFS], 22.6% vs. 55.7%, p < .001 and 1-year overall survival [OS], 45.9% vs. 75.1%, p < .001). Independent significant correlations were observed between r/r sIL-2R and both inferior 1-year EFS and OS in a multivariate analysis (hazard ratio [HR]: 2.69, 95% CI: 1.61-4.51, p < .001 and HR: 2.99, 95% CI: 1.57-5.70, p < .001). This study demonstrates that r/r sIL-2R could be useful for predicting a poor prognosis in patients with r/r DLBCL.
  • Ryosuke Uchibori, Takeshi Teruya, Hiroyuki Ido, Ken Ohmine, Yoshihide Sehara, Masashi Urabe, Hiroaki Mizukami, Junichi Mineno, Keiya Ozawa
    Molecular therapy oncolytics 12 16 - 25 2019/03 [Refereed][Not invited]
    Adoptive transfer of T cells expressing a chimeric antigen receptor (CAR) is a promising cell-based anticancer therapy. Although clinical studies of this approach show therapeutic efficacy, additional genetic modification is necessary to enhance the efficacy and safety of CAR-T cells. For example, production of an antitumor cytokine from CAR-T cells can potentially enhance their tumor-killing activity, but there are concerns that constitutive expression of anticancer molecules will cause systemic side effects. Therefore, it is important that exogenous gene expression is confined to the tumor locality. Here, we aimed to develop an inducible promoter driven by activation signals from a CAR. Transgene expression in T cells transduced with the CD19-targeted CAR and an inducible promoter, including inducible reporter genes (CAR-T/iReporter), was only induced strongly by co-culture with CD19-positive target cells. CAR-T/iReporter cells also showed redirected cytolysis toward CD19-positive, but not CD19-negative, tumor cells. Overall, our study indicated that the inducible promoter was selectively driven by activation signals from the CAR, and transduction with the inducible promoter did not affect original effector activities including interleukin-2 and interferon-γ production and the antitumor activity of CAR-redirected cytotoxic T lymphocytes. Moreover, this inducible promoter permits visualization and quantification of the activation status in CAR-T cells.
  • Mashima K, Ikeda T, Toda Y, Ito S, Umino K, Minakata D, Nakano H, Morita K, Yamasaki R, Kawasaki Y, Sugimoto M, Ashizawa M, Yamamoto C, Fujiwara S, Hatano K, Sato K, Oh I, Ohmine K, Muroi K, Kanda Y
    Leukemia & lymphoma 60 (3) 703 - 710 1042-8194 2019/03 [Refereed][Not invited]
    Wilms tumor gene 1 (WT1) is highly expressed in myelodysplastic syndrome (MDS) cells and is known to reflect the tumor burden in MDS. We evaluated the usefulness of WT1 mRNA levels for predicting the prognosis of MDS. At diagnosis, WT1 levels were strongly correlated with the percentage of blasts calculated based on non-erythroid cells, but not with that based on all nucleated cells (r = 0.57, p < .05 vs r = 0.42, p = .13). Among the allogeneic transplant recipients, the presence of two consecutive WT1 levels ≥100 copies/μg RNA with a median interval of one month was associated with a 77.8% relapse rate at nine months from the first detection of a high WT1 level, and the median time to relapse was only 114 [36-257] days. WT1 levels at diagnosis were correlated with known prognostic factors. In addition, the presence of two consecutive high WT1 levels after allogeneic transplantation may predict early relapse of MDS.
  • Umino K, Fujiwara SI, Minakata D, Yamamoto C, Meguro A, Matsuyama T, Sato K, Ohmine K, Izumi T, Muroi K, Kanda Y
    Leukemia & lymphoma 60 (3) 734 - 741 1042-8194 2019/03 [Refereed][Not invited]
  • Minakata D, Fujiwara SI, Ikeda T, Kawaguchi SI, Toda Y, Ito S, Ochi SI, Nagayama T, Mashima K, Umino K, Nakano H, Yamasaki R, Morita K, Kawasaki Y, Sugimoto M, Yamamoto C, Ashizawa M, Hatano K, Sato K, Oh I, Ohmine K, Muroi K, Ohmori T, Kanda Y
    International journal of hematology 109 (2) 141 - 146 0925-5710 2019/02 [Refereed][Not invited]
    We evaluated clinical outcomes of disseminated intravascular coagulation (DIC) in patients with hematological malignancies treated with synthetic protease inhibitors (SPIs) and compared the effects of gabexate mesilate (FOY) and nafamostat mesilate (FUT). We retrospectively examined 127 patients [acute myeloid leukemia (n = 48), acute lymphoblastic leukemia (n = 25), and non-Hodgkin lymphoma (n = 54)] with DIC, who were diagnosed according to Japanese Ministry of Health, Labour and Welfare criteria and treated with SPIs [FOY (n = 55) and FUT (n = 72)] at our hospital from 2006 to 2015. The DIC resolution rates on days 7 and 14 were 42.6% and 62.4%, respectively. No significant differences were observed in DIC resolution rates between the FUT and FOY groups [40.3% vs. 45.5% (day 7), P = 0.586; 56.3% vs. 69.8% (day 14), P = 0.179, respectively]. Multivariate analysis revealed that response to chemotherapy was the only independent predictor of DIC resolution on days 7 and 14 (ORR 2.81, 95% CI 1.32-5.98, P = 0.007; ORR 2.51, 95% CI 1.12-5.65, P = 0.026). Resolution of DIC was correlated with improvement of background hematological malignancies, and no significant differences were observed between the two SPIs.
  • Morita K, Fujiwara SI, Ikeda T, Kawaguchi SI, Toda Y, Ito S, Ochi SI, Nagayama T, Mashima K, Umino K, Minakata D, Nakano H, Yamasaki R, Kawasaki Y, Sugimoto M, Ashizawa M, Yamamoto C, Hatano K, Sato K, Oh I, Ohmine K, Muroi K, Ashizawa K, Yamamoto Y, Oshiro H, Kanda Y
    Acta haematologica 141 (3) 158 - 163 0001-5792 2019 [Refereed][Not invited]
    TAFRO syndrome, a rare systemic inflammatory disease, can lead to multiorgan failure without appropriate treatment. Although thrombocytopenia is frequently seen in patients with TAFRO syndrome, little is known about its pathogenesis. Moreover, while recent studies have reported the presence of an anterior mediastinal mass in some patients, the pathological status of this remains unclear. Here, we report a case of fatal bleeding in a patient with TAFRO syndrome accompanied by an anterior mediastinal mass. A 55-year-old female was transferred to our hospital with a 2-week history of fever, epistaxis, and dyspnea. Laboratory tests revealed severe thrombocytopenia, computed tomography (CT) showed pleural effusions, and bone marrow biopsy revealed reticulin myelofibrosis. We suspected TAFRO syndrome, but the CT scan showed an anterior mediastinal mass that required a biopsy to exclude malignancy. She soon developed severe hemorrhagic diathesis and died of intracranial hemorrhage despite intensive treatment. She had multiple autoantibodies against platelets, which caused platelet destruction. An autopsy of the mediastinal mass revealed fibrous thymus tissues with infiltration by plasma cells. Our case suggests that thrombocytopenia could be attributed to antibody-mediated destruction and could be lethal. Hence, immediate treatment is imperative in cases of severe thrombocytopenia, even when accompanied by an anterior mediastinal mass.
  • Ken Ohmachi, Kensei Tobinai, Tomohiro Kinoshita, Takayuki Ishikawa, Kiyohiko Hatake, Satoshi Ichikawa, Ken Ohmine, Yuri Kamitsuji, Ilseung Choi, Takaaki Chou, Kunihiro Tsukasaki, Kyoya Kumagai, Masafumi Taniwaki, Toshiki Uchida, Yoshitaka Kikukawa, Kohmei Kubo, Keichiro Mihara, Norifumi Tsukamoto, Koji Izutsu, Isao Yoshida, Fumihiro Ishida, Noriko Usui, Shinsuke Iida, Tohru Murayama, Eisuke Ueda, Hiroshi Kuriki, Kiyoshi Ando
    International journal of hematology 108 (5) 499 - 509 0925-5710 2018/11 [Refereed][Not invited]
    GALLIUM is a global phase III study that demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with obinutuzumab plus chemotherapy (G-chemo) versus rituximab plus chemotherapy (R-chemo) in previously untreated patients with follicular lymphoma (FL). In this single-country subgroup analysis, we explored patterns of efficacy and safety in patients enrolled in the GALLIUM study in Japan (Japanese subgroup). Patients were randomized to open-label induction treatment with G-chemo or R-chemo. Responders received maintenance monotherapy with their randomized antibody for up to 2 years. The primary endpoint was investigator-assessed PFS. Overall, 123 patients with FL were randomized in the Japanese subgroup (G-chemo, n = 65; R-chemo, n = 58). The majority of patients received cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (82.9 vs 33.1% in the global GALLIUM FL population). PFS at 3 years was 89.9% (G-chemo) vs. 74.7% (R-chemo); hazard ratio 0.42; 95% confidence interval 0.15, 1.15; P = 0.08. Higher rates of grade 3-5 adverse events (96.9 vs. 89.7%) and serious adverse events (35.4 vs. 22.4%) were observed with G-chemo vs R-chemo, respectively. Neutropenia was frequent in the Japanese subgroup (92.3% G-chemo; 79.3% R-chemo). Overall, the results in the Japanese subgroup were consistent with those in the global GALLIUM population.
  • Shoko Ito, Masahiro Ashizawa, Ryo Sasaki, Takashi Ikeda, Yumiko Toda, Kiyomi Mashima, Kento Umino, Daisuke Minakata, Hirofumi Nakano, Ryoko Yamasaki, Yasufumi Kawasaki, Miyuki Sugimoto, Chihiro Yamamoto, Shin-Ichiro Fujiwara, Kaoru Hatano, Kazuya Sato, Iekuni Oh, Ken Ohmine, Kazuo Muroi, Jun Suzuki, Shuji Hatakeyama, Yuji Morisawa, Toshiyuki Yamada, Yoshinobu Kanda
    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 24 (10) 812 - 814 1341-321X 2018/10 [Refereed][Not invited]
    The 1,3-beta-D-Glucan (BDG) assay is widely used for the diagnosis of fungal infections, especially in patients with hematologic malignancies. Some antimicrobials have been reported to cause false-positive results for BDG, but there has been no report on the effect of penicillin G (PCG) on BDG levels. We experienced a patient who developed false-positive BDG elevation during the administration of PCG for osteomyelitis due to Streptococcus pneumoniae infection. The serum BDG level increased up to 81.0 pg/ml during the continuous administration of PCG at 24 million units per day. However, chest and paranasal CT scan showed no evidence of fungal infection. The BDG level decreased to 38.0 pg/ml at 14 hours after the discontinuation of PCG. The amount of BDG in one vial of PCG inferred from these serum BDG levels is very similar to the actual BDG concentration in a vial of PCG. Therefore, during the administration of PCG, elevated BDG levels should be interpreted with caution, as they may be false-positive results.
  • Umino K, Fujiwara SI, Ikeda T, Toda Y, Ito S, Mashima K, Minakata D, Nakano H, Yamasaki R, Kawasaki Y, Sugimoto M, Yamamoto C, Ashizawa M, Hatano K, Sato K, Oh I, Ohmine K, Muroi K, Kanda Y
    Hematology (Amsterdam, Netherlands) 23 (8) 470 - 477 1024-5332 2018/09 [Refereed][Not invited]
  • Shin-ichiro Fujiwara, Yuya Shirato, Takashi Ikeda, Shin-ichiro Kawaguchi, Yumiko Toda, Shoko Ito, Shin-ichi Ochi, Takashi Nagayama, Kiyomi Mashima, Kento Umino, Daisuke Minakata, Hirofumi Nakano, Kaoru Morita, Ryoko Yamasaki, Yasufumi Kawasaki, Miyuki Sugimoto, Masahiro Ashizawa, Chihiro Yamamoto, Kaoru Hatano, Kazuya Sato, Iekuni Oh, Ken Ohmine, Kazuo Muroi, Yoshinobu Kanda
    International Journal of Hematology 107 (6) 712 - 715 1865-3774 2018/06 [Refereed][Not invited]
    Tyrosine kinase inhibitors (TKIs) are standard therapy for chronic myeloid leukemia (CML). However, the effects of these agents on mature B cell lymphoma are not well known. We describe a 50-year-old man who was diagnosed with CML in the chronic phase and treated with imatinib. After 3 years of imatinib therapy that achieved a complete cytogenetic response of CML, he developed Philadelphia-negative follicular lymphoma (FL). Rituximab monotherapy induced a partial response of FL, and he subsequently achieved a major molecular response (MMR) of CML. Three years later, however, the MMR was lost, followed by the progression of FL. Imatinib was switched to nilotinib for the treatment of CML, while we chose watchful waiting for FL. He achieved MMR again under treatment with nilotinib for 8 months including one month of substitutional use of dasatinib due to adverse events, but thereafter nilotinib was switched to bosutinib due to hyperbilirubinemia. With the administration of second-generation TKIs (2G-TKIs) for a total of 18 months, he achieved a complete response to FL without antilymphoma treatment. This is the first report to suggest that 2G-TKIs may have direct or indirect effects on FL.
  • Hirohisa Nakamae, Tetsuya Fukuda, Chiaki Nakaseko, Yoshinobu Kanda, Ken Ohmine, Takaaki Ono, Itaru Matsumura, Akira Matsuda, Makoto Aoki, Kazuo Ito, Hirohiko Shibayama
    International Journal of Hematology 107 (3) 327 - 336 1865-3774 2018/03 [Refereed][Not invited]
    In the ongoing, international, phase 3 study Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd), nilotinib 300 and nilotinib 400 mg, both twice daily, are compared with imatinib 400 mg once daily for the treatment of newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP). Results for the overall population in ENESTnd (n = 846) showed that nilotinib resulted in higher response rates vs. imatinib and was well tolerated. Outcomes among Japanese patients in ENESTnd were specifically analyzed after 1 year of follow-up, and showed similar trends to the overall population we present updated analysis of the Japanese subgroup based on 5 years of follow-up. Among Japanese patients in the nilotinib 300-mg (n = 29), nilotinib 400-mg (n = 23), and imatinib (n = 25) arms, 86.2, 78.3, and 60.0%, respectively, achieved major molecular response [BCR-ABL1 ≤ 0.1% on the International Scale (BCR-ABL1IS)] by 5 years, and 65.5, 69.6, and 40.0%, respectively, achieved MR4.5 (BCR-ABL1IS ≤ 0.0032%). Safety results were consistent with prior reports. In this subgroup, one death occurred during treatment in the nilotinib 400-mg twice-daily arm (unknown cause), and one patient in each arm progressed to accelerated phase/blast crisis by the data cutoff.
  • Daisuke Minakata, Kazuya Sato, Takashi Ikeda, Yumiko Toda, Shoko Ito, Kiyomi Mashima, Kento Umino, Hirofumi Nakano, Ryoko Yamasaki, Kaoru Morita, Yasufumi Kawasaki, Miyuki Sugimoto, Chihiro Yamamoto, Masahiro Ashizawa, Kaoru Hatano, Iekuni Oh, Shin-ichiro Fujiwara, Ken Ohmine, Hirotoshi Kawata, Kazuo Muroi, Ikuo Miura, Yoshinobu Kanda
    Cancer Genetics 220 44 - 48 2210-7770 2018/01 [Refereed][Not invited]
    Double-hit lymphoma (DHL) is defined as lymphoma with concurrent BCL2 and MYC translocations. While the most common histological subtype of DHL is diffuse large B-cell lymphoma, the present patient had leukemic follicular lymphoma (FL). A 52-year-old man was admitted to our hospital due to general fatigue and cervical and inguinal lymph node swelling. The patient was leukemic and the pathological diagnosis of the inguinal lymph node was FL grade 1. Chromosomal analysis revealed a complex karyotype including a rare three-way translocation t(8 14 18)(q24 q32 q21) involving the BCL2, MYC, and IGH genes. Based on a combination of fluorescence in situ hybridization (FISH), using BCL2, MYC and IGH, and spectral karyotyping (SKY), the karyotype was interpreted as being the result of a multistep mechanism in which the precursor B-cell gained t(14 18) in the bone marrow and acquired a translocation between der(14)t(14 18) and chromosome 8 in the germinal center, resulting in t(8 14 18). The pathological diagnosis was consistently FL, not only at presentation but even after a second relapse. The patient responded well to standard chemotherapies but relapsed after a short remission. This patient is a unique case of leukemic DH-FL with t(8 14 18) that remained in FL even at a second relapse.
  • Yasufumi Kawasaki, Kazuya Sato, Hiroko Hayakawa, Norihito Takayama, Hirofumi Nakano, Ryoji Ito, Kiyomi Mashima, Iekuni Oh, Daisuke Minakata, Ryoko Yamasaki, Kaoru Morita, Masahiro Ashizawa, Chihiro Yamamoto, Kaoru Hatano, Shin-ichiro Fujiwara, Ken Ohmine, Kazuo Muroi, Yoshinobu Kanda
    Biology of Blood and Marrow Transplantation 24 (8) 1563 - 1574 1523-6536 2018 [Refereed][Not invited]
    Xenogeneic graft-versus-host disease (GVHD) models in highly immunodeficient mice are currently being used worldwide to investigate human immune responses against foreign antigens in vivo. However, the individual roles of CD4+ and CD8+ T cells, and donor/host hematopoietic and nonhematopoietic antigen-presenting cells (APCs) in the induction and development of GVHD have not been fully investigated. In the present study, we comprehensively investigated the immune responses of human T cells and the antigen presentation capacity of donor/host hematopoietic and nonhematopoietic APCs in xenogeneic GVHD models using nonobese diabetic/Shi-scid-IL2rgnul l mice. CD4+ T cells and, to a lesser extent, CD8+ T cells individually mediated potentially lethal GVHD. In addition to inflammatory cytokine production, CD4+ T cells also supported the activation and proliferation of CD8+ T cells. Using bone marrow chimeras, we demonstrated that host hematopoietic, but not nonhematopoietic, APCs play a critical role in the development of CD4+ T cell-mediated GVHD. During early GVHD, we detected 2 distinct populations in memory CD4+ T cells. One population was highly activated and proliferated in major histocompatibility complex antigen (MHC)+/+ mice but not in MHC−/− mice, indicating alloreactive T cells. The other population showed a less activated and slowly proliferative status regardless of host MHC expression, and was associated with higher susceptibility to apoptosis, indicating nonalloreactive T cells in homeostasis-driven proliferation. These observations are clinically relevant to donor T cell response after allogeneic hematopoietic stem cell transplantation. Our findings provide a better understanding of the immunobiology of humanized mice and support the development of novel options for the prevention and treatment for GVHD.
  • Ohmine K
    [Rinsho ketsueki] The Japanese journal of clinical hematology 59 (8) 1058 - 1065 0485-1439 2018 [Refereed][Not invited]
  • Hirofumi Nakano, Shin-ichiro Fujiwara, Shoko Ito, Kiyomi Mashima, Kento Umino, Daisuke Minakata, Ryoko Yamasaki, Yasufumi Kawasaki, Miyuki Sugimoto, Masahiro Ashizawa, Chihiro Yamamoto, Kaoru Hatano, Kiyoshi Okazuka, Kazuya Sato, Iekuni Oh, Ken Ohmine, Takahiro Suzuki, Kazuo Muroi, Yoshinobu Kanda
    HEMATOLOGICAL ONCOLOGY 35 (3) 357 - 364 0278-0232 2017/09 [Refereed][Not invited]
    The early clearance of blast cells in peripheral blood (PB) during induction chemotherapy can predict the clinical outcome in acute leukemia. We retrospectively analyzed the kinetics of white blood cell (WBC) count, blast cell percentage (BCP), and blast cell count (BCC) in PB in 78 patients with de novo acute myeloid leukemia who underwent a uniform induction chemotherapy between December 2001 and December 2015 at Jichi Medical University. By a repeated-measures analysis of variance, the interaction of the decline in BCP with the achievement of complete remission (CR) was stronger than those of the decline in WBC or BCC. A receiver operating characteristic curve analysis for the achievement of CR showed that the areas under the curve for the decline in WBC, BCP, and BCC were 0.592, 0.703, and 0.634, respectively, and a decline in BCP of 9.25%/day within 4 or 5days from induction chemotherapy was the optimal cutoff value. A multivariate analysis showed that a rapid decline in BCP (9.25%/day) was a significant predictive factor for CR, independent of the cytogenetic risk (p=0.0096). A rapid decline in BCP during the first 5days of induction chemotherapy may be a good predictor of CR. Copyright (c) 2015 John Wiley & Sons, Ltd.
  • Daisuke Minakata, Shin-ichiro Fujiwara, Takashi Ikeda, Yumiko Toda, Shoko Ito, Kiyomi Mashima, Kento Umino, Hirofumi Nakano, Ryoko Yamasaki, Kaoru Morita, Yasufumi Kawasaki, Miyuki Sugimoto, Chihiro Yamamoto, Masahiro Ashizawa, Kaoru Hatano, Kazuya Sato, Iekuni Oh, Ken Ohmine, Kazuo Muroi, Yoshinobu Kanda
    INTERNATIONAL JOURNAL OF HEMATOLOGY 106 (3) 411 - 417 0925-5710 2017/09 [Refereed][Not invited]
    We retrospectively analyzed the relationship between white blood cell (WBC) count elevation after priming and clinical response in 115 patients with AML (61 untreated and 54 relapsed or refractory) treated with low-dose cytarabine, aclarubicin, and G-CSF priming. Receiver operating characteristic curve analysis showed that the ratio of maximum WBC count to pretreatment WBC count (WBCratio) was most strongly associated with complete remission (CR) in previously untreated patients among several parameters we analyzed in this study; however, the prediction accuracy was not clinically significant considering the area under the curve of 0.694. Based on the cutoff value of the WBCratio, CR rate and event-free survival in the high WBCratio group were significantly better than those in the low WBCratio group in untreated patients. Regarding the WBC differential counts, a high ratio of the maximum to pretreatment value of neutrophils rather than that of peripheral blasts was associated with a superior CR rate. In addition, an increase in blasts after G-CSF priming had a significant negative impact on CR rate in untreated patients. In conclusion, an increase in blast counts after G-CSF priming was not predictive of achieving CR.
  • Shoko Ito, Shin-ichiro Fujiwara, Kiyomi Mashima, Kento Umino, Daisuke Minakata, Hirofumi Nakano, Ryoko Yamasaki, Yasufumi Kawasaki, Miyuki Sugimoto, Masahiro Ashizawa, Chihiro Yamamoto, Kaoru Hatano, Kiyoshi Okazuka, Kazuya Sato, Iekuni Oh, Ken Ohmine, Takahiro Suzuki, Kazuo Muroi, Yoshinobu Kanda
    ANNALS OF HEMATOLOGY 96 (5) 719 - 724 0939-5555 2017/05 [Refereed][Not invited]
    The development of acute myeloid leukemia (AML) in patients with untreated chronic lymphocytic leukemia (CLL) is rare. We experienced a 65-year-old man who developed AML with aberrant CD7 expression and monoallelic CEBPA mutation during watchful waiting for CLL. He failed to achieve complete response (CR) by standard induction therapy for AML. We retrospectively reviewed 27 patients who developed AML with untreated CLL published between 1973 and 2016. The median age at diagnosis of AML was 68 years, and the median duration between the diagnoses of AML and CLL was 4.2 years. Diagnosis of AML and CLL was made simultaneously in 16 patients. The CR rate of AML was 42.9%, and the median survival was only 1.5 months after the diagnosis of AML. Patients who achieved CR tended to survive longer than those who did not. Our results demonstrated that the development of AML in patients with untreated CLL was associated with a poor response to chemotherapy and an extremely poor prognosis.
  • Kento Umino, Shin-Ichiro Fujiwara, Shoko Ito, Kiyomi Mashima, Daisuke Minakata, Hirofumi Nakano, Ryoko Yamasaki, Yasufumi Kawasaki, Miyuki Sugimoto, Masahiro Ashizawa, Kaoru Hatano, Kiyoshi Okazuka, Kazuya Sato, Iekuni Oh, Ken Ohmine, Takahiro Suzuki, Kazuo Muroi, Yoshinobu Kanda
    LEUKEMIA & LYMPHOMA 58 (2) 316 - 323 1042-8194 2017/02 [Refereed][Not invited]
    We evaluated 121 patients with follicular lymphoma (FL) and analyzed the association between the soluble interleukin-2 receptor (sIL-2R) level at diagnosis and the cumulative incidence of transformation. By a receiver-operating characteristic analysis, we determined a cutoff value of sIL-2R for transformation at 4360U/mL to classify patients into two groups. Patients in the high sIL-2R group showed a shorter progression-free survival (PFS) and shorter disease-specific survival (DSS) (p<0.001 and p=0.018). Furthermore, the cumulative incidence of transformation in the high sIL-2R group was higher than that in the low sIL-2R group (40.9% vs. 7.3% at 5 years, p<0.001). In a multivariate analysis, high sIL-2R was an independent predictive risk factor for transformation (HR 7.42, 95% CI: 2.75-20.0, p<0.001). This study showed that the sIL-2R level at diagnosis may be a prognostic factor for transformation, PFS, and DSS in patients with FL.
  • Shin-ichiro Fujiwara, Kazuo Muroi, Chihiro Yamamoto, Kaoru Hatano, Kiyoshi Okazuka, Kazuya Sato, Iekuni Oh, Ken Ohmine, Takahiro Suzuki, Keiya Ozawa
    HEMATOLOGY 22 (6) 347 - 353 1024-5332 2017 [Refereed][Not invited]
    Objectives: CD25 has been reported to be highly expressed in leukemia stem cells and correlated with adverse outcomes in young patients with acute myeloid leukemia (AML). However, the significance of CD25 expression in elderly patients with AML has not yet been investigated. Methods: We retrospectively analyzed 154 newly diagnosed AML patients aged 60 years or over by flow cytometry. Results: CD25-positive AML was characterized by high white blood cell counts, secondary AML, rare favorable karyotypes, and positivity for CD34 and CD7 antigens, compared with CD25-negative AML. CD25 positivity was significantly correlated with an inferior complete remission (CR), event-free survival (EFS), and overall survival. Multivariate analysis showed CD25 positivity to be a significant prognostic predictor of CR and EFS. A regimen of low-dose cytarabine and aclarubicin combined with granulocyte-colony-stimulating factor (CAG) led to higher CR rates in the CD25-positive AML patients than intensive chemotherapies. CD25 expression was increased at relapse and in the development of leukemic status from myelodysplastic syndrome or myeloproliferative neoplasm. Discussion: An effective treatment strategy for elderly patients with CD25-positive AML has not been established. Further studies are needed to evaluate the effect of a CAG regimen and allogenic stem cell transplantation in patients. Conclusion: CD25 is an independent prognostic factor in elderly AML patients. Alternative therapies for CD25-positive elderly AML patients are needed.
  • Kento Umino, Shin-ichiro Fujiwara, Kazuya Sato, Daisuke Minakata, Hirofumi Nakano, Ryoko Yamasaki, Yasufumi Kawasaki, Miyuki Sugimoto, Chihiro Yamamoto, Kaoru Hatano, Kiyoshi Okazuka, Lekuni Oh, Ken Ohmine, Takahiro Suzuki, Kazuo Muroi, Yoshinobu Kanda
    ACTA HAEMATOLOGICA 137 (2) 93 - 99 0001-5792 2017 [Refereed][Not invited]
    The prognosis of patients with systemic lymphoma with central nervous system (CNS) involvement is very poor and there is no established standard therapy. We retrospectively analyzed 18 patients (4 untreated and 14 relapsed) with systemic lymphoma with CNS involvement who received methotrexate and cytarabine-based multiagent chemotherapy (modified Bonn protocol). Complete and partial responses were achieved in 56 and 22% of the patients, respectively. The 1-year overall survival (OS) and progression-free survival (PFS) was 81.0 and 39.2%, respectively. Patients with parenchymal involvement showed a better 1-year PFS than those with either leptomeningeal involvement or both. In a multivariate analysis, poor performance status (PS) was the only independent prognostic factor for the 1-year OS and PFS (HR 10.8, 95% CI 1.09-108, p = 0.042; HR 20.8, 95% CI 2.39-181, p = 0.006, respectively). Grade 4 neutropenia and thrombocytopenia occurred in 17 patients each (94%), but there were no grade 4 nonhematopoietic adverse events. The modified Bonn pro-tocol resulted in relatively favorable response and survival, and provided clinical benefits to patients with good PS, in particular. This study demonstrated that the modified Bonn protocol could be a feasible and encouraging treatment approach for lymphoma with CNS and systemic involvement. (C) 2017 S. Karger AG, Basel
  • Kento Umino, Shin-ichiro Fujiwara, Takashi Ikeda, Yumiko Toda, Shoko Ito, Kiyomi Mashima, Daisuke Minakata, Hirofumi Nakano, Ryoko Yamasaki, Yasufumi Kawasaki, Miyuki Sugimoto, Chihiro Yamamoto, Masahiro Ashizawa, Kaoru Hatano, Kazuya Sato, Iekuni Oh, Ken Ohmine, Kazuo Muroi, Yoshinobu Kanda
    HEMATOLOGY 22 (9) 521 - 526 1024-5332 2017 [Refereed][Not invited]
    Objectives: Follicular lymphoma (FL) is a clinically and biologically heterogeneous disease. Therefore, it is important to identify factors that can predict its clinical outcome. Methods: We retrospectively evaluated the usefulness of soluble interleukin-2 receptor (sIL-2R) levels after R-CHOP (posttreatment sIL-2R) in 72 patients with newly diagnosed FL who had either a complete response (CR) or partial response. With the use of a recursive partitioning analysis, we determined the cut-off values of post- and pretreatment sIL-2R levels that were associated with disease progression, which corresponded to 486.5 and 5405U/mL, respectively. Results: The high posttreatment sIL-2R group showed a significantly inferior progression-free survival (PFS) compared to the low posttreatment sIL-2R group in all patients (3-year PFS 52.6% vs. 77.4%, P=0.003), and in patients with CR (3-year PFS 57.1% vs. 82.1%, P=0.034). Although a multivariate analysis showed that pretreatment sIL-2R, but not posttreatment sIL-2R, was an independently significant predictive factor for disease progression, among patients with low pretreatment sIL-2R levels, those with high posttreatment sIL-2R levels tended to have inferior PFS. There was a significant trend in PFS among the high pretreatment sIL-2R group, the low pre- and high posttreatment sIL-2R group, and the low pre- and low posttreatment sIL-2R group (P<0.001). Conclusion: Among patients with a low pretreatment sIL-2R level who exhibited a positive response to R-CHOP, the posttreatment sIL-2R level may help to identify those with a poor prognosis.
  • Chihiro Yamamoto, Shoko Ito, Kiyomi Mashima, Kento Umino, Daisuke Minakata, Ryoko Yamasaki, Yasufumi Kawasaki, Miyuki Sugimoto, Hirofumi Nakano, Masahiro Ashizawa, Kiyoshi Okazuka, Kaoru Hatano, Kazuya Sato, Lekuni Oh, Shin-Ichiro Fujiwara, Ken Ohmine, Takahiro Suzuki, Kazuo Muroi, Yoshinobu Kanda
    LEUKEMIA & LYMPHOMA 57 (11) 2541 - 2547 1042-8194 2016/11 [Refereed][Not invited]
    The combination of mitoxantrone (MIT), etoposide (ETP), and cytarabine (Ara-C) (MEC) is a frequently used salvage therapy for acute leukemia, but has been associated with severe myelosuppression. Therefore, we investigated the miniMEC regimen with reduced doses of AraC and MIT. Thirteen ALL and 44 AML patients, all relapsed or refractory, received miniMEC, which consisted of MIT at 8 mg/m(2) for 3 d, ETP at 100 mg/m(2) for 5 d, and Ara-C at 100 mg/m(2) infused over 24 h for 7 d. CR + CRi was achieved in eight ALL patients (61.5%) and 16 AML patients (36.4%). Median duration of neutropenia was 30 d (range, 1-50). Thirty-one patients (54.4%) subsequently received allogeneic stem cell transplantation (SCT), and overall survival was significantly improved in this group (median OS 161 versus 481 d, p=0.006). We concluded that miniMEC is a safe and effective bridging therapy to SCT.
  • Takahiro Suzuki, Hiroyuki Kobayashi, Yasufumi Kawasaki, Kiyoshi Okazuka, Kaoru Hatano, Shin-ichiro Fujiwara, Iekuni Oh, Ken Ohmine, Yoshinobu Kanda
    INTERNATIONAL JOURNAL OF HEMATOLOGY 104 (4) 446 - 453 0925-5710 2016/10 [Refereed][Not invited]
    Anti-thymocyte globulin (ATG) is a key drug in immunosuppressive therapy for patients with aplastic anemia. The mainstay of ATG therapy had been a horse ATG (hATG) formulation, Lymphoglobulin or ATGAM, but Lymphoglobulin was recently discontinued, and Thymoglobulin, a rabbit ATG (rATG) formulation, is currently used as the first-line drug in many countries, including Japan. However, a recent randomized clinical trial reported significantly unfavorable outcomes associated with the use of rATG regimens. We retrospectively analyzed clinical outcomes of adult patients with moderate to severe aplastic anemia who were treated with 3.5 mg/kg of Thymoglobulin (n = 22) or 15 mg/kg of Lymphoglobulin (n = 25) in our facility. The estimated overall response rates in the rATG and hATG groups were 64.6 versus 56.0 % at 6 months, and 76.4 versus 69.2 % at 12 months, respectively; and there was no statistical difference between the two groups (P = 0.32). Overall survival at 24 months was not significantly different: rATG 89.8 % versus hATG 96.0 % (P = 0.39). Early phase infection was observed in 37.5 % of cases in the rATG and 14.8 % in the hATG group, but the frequency was not statistically different (P = 0.107). Our data indicate that Thymoglobulin at a dose of 3.5 mg/kg is a viable alternative when hATG is not available.
  • Miyuki Sugimoto, Shoko Ito, Kiyomi Mashima, Kento Umino, Daisuke Minakata, Hirofumi Nakano, Ryoko Yamasaki, Yasufumi Kawasaki, Masahiro Ashizawa, Chihiro Yamamoto, Shin-ichiro Fujiwara, Kiyoshi Okazuka, Kaoru Hatano, Kazuya Sato, Iekuni Oh, Ken Ohmine, Takahiro Suzuki, Kazuo Muroi, Shinichi Kako, Yoshinobu Kanda
    ANNALS OF HEMATOLOGY 95 (9) 1513 - 1519 0939-5555 2016/09 [Refereed][Not invited]
    The BEAM regimen consisting of carmustine (BCNU), etoposide, cytarabine, and melphalan (MEL) is widely used before autologous hematopoietic stem cell transplantation (auto-HSCT) for lymphoma. However, intravenous BCNU is not available in Japan, and therefore, ranimustine (MCNU) has been used instead of BCNU (the MEAM regimen). We retrospectively analyzed the outcome of 79 adult patients who underwent auto-HSCT for lymphoma using this regimen in two centers, with 1- and 2-day dosing of MEL, respectively. Three-year overall survival (OS) and progression-free survival (PFS) probabilities were 77.3 and 56.5 % in the entire population and 71.7 and 58.0 % in patients with diffuse large B cell lymphoma. These outcomes were at least equivalent to those with the BEAM regimen. There was no regimen-related pulmonary toxicity. In a multivariate analysis, older age was the only factor that was significantly associated with for OS. In a comparison of the two MEL dosing schedules, while there was no significant differences in either OS or PFS, diarrhea was observed more frequently with 1-day dosing of MEL. In conclusion, the MEAM regimen appeared to be a promising conditioning regimen in auto-HSCT for lymphoma. A large prospective study is warranted to confirm the current findings.
  • Daisuke Minakata, Shin-ichiro Fujiwara, Shoko Ito, Kiyomi Mashima, Kento Umino, Hirofumi Nakano, Yasufumi Kawasaki, Miyuki Sugimoto, Ryoko Yamasaki, Chihiro Yamamoto, Masahiro Ashizawa, Kaoru Hatano, Kiyoshi Okazuka, Kazuya Sato, Iekuni Oh, Ken Ohmine, Takahiro Suzuki, Kazuo Muroi, Yoshinobu Kanda
    LEUKEMIA RESEARCH 42 82 - 87 0145-2126 2016/03 [Refereed][Not invited]
    This retrospective analysis compared the efficacy of intensive induction therapy consisting of daunorubicin and cytarabine (DNR-AraC) to that of less-intensive therapy including low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming (CAG). Patients aged 60 years or older who were newly diagnosed as acute myeloid leukemia (AML) were analyzed. Sixty-four and 48 patients were treated with DNR-AraC and CAG, respectively. The complete remission rates, 3-year overall survival and event-free survival in the DNR-AraC group were significantly superior to those in the CAG group (65.6% vs. 29.2%, p < 0.001, 38.4% vs. 12.3%, p = 0.0033, and 20.3% vs. 7.8%, p = 0.0030, respectively), although these differences were not statistically significant in multivariate analyses. Next, we calculated a propensity score for selecting the CAG regimen from six factors. The DNR-AraC regimen was associated with better survival than the CAG regimen in a low propensity score group, but there was no difference in survival between regimens in a high propensity score group. Intensive therapy should be performed for patients with sufficient general and comorbid conditions, but less-intensive therapy may be sufficient for patients with higher age, myelodysplasia-related changes, and lower white blood cell counts, which were relevant factors in the propensity score calculation. (C) 2015 Elsevier Ltd. All rights reserved.
  • Ohmine K
    [Rinsho ketsueki] The Japanese journal of clinical hematology 57 (11) 2345  0485-1439 2016 [Refereed][Not invited]
  • Oh I, Oh Y, Ohmine K
    [Rinsho ketsueki] The Japanese journal of clinical hematology 57 (11) 2365 - 2372 0485-1439 2016 [Refereed][Not invited]
  • Yuki Iwayanagi, Tomoyuki Igawa, Atsuhiko Maeda, Kenta Haraya, Naoko A. Wada, Norihito Shibahara, Ken Ohmine, Takeru Nambu, Genki Nakamura, Futa Mimoto, Hitoshi Katada, Shunsuke Ito, Tatsuhiko Tachibana, Kou-ichi Jishage, Kunihiro Hattori
    JOURNAL OF IMMUNOLOGY 195 (7) 3198 - 3205 0022-1767 2015/10 [Refereed][Not invited]
    Fc engineering can modulate the Fc-Fc gamma R interaction and thus enhance the potency of Abs that target membrane-bound Ags, but it has not been applied to Abs that target soluble Ags. In this study, we revealed a previously unknown function of inhibitory Fc gamma RII in vivo and, using an Ab that binds to Ag pH dependently, demonstrated that the function can be exploited to target soluble Ag. Because pH-dependent Ab dissociates Ag in acidic endosome, its Ag clearance from circulation reflects the cellular uptake rate of Ag/Ab complexes. In vivo studies showed that Fc gamma R but not neonatal FcR contributes to Ag clearance by the pHdependent Ab, and when Fc binding to mouse Fc gamma RII and III was increased, Ag clearance was markedly accelerated in wild-type mice and FcR g-chain knockout mice, but the effect was diminished in Fc gamma RII knockout mice. This demonstrates that mouse Fc gamma RII efficiently promotes Ab uptake into the cell and its subsequent recycling back to the cell surface. Furthermore, when a human IgG1 Fc variant with selectively increased binding to human Fc gamma RIIb was tested in human Fc gamma RIIb transgenic mice, Ag clearance was accelerated without compromising the Ab half-life. Taken together, inhibitory Fc gamma RIIb was found to play a prominent role in the cellular uptake of monomeric Ag/Ab immune complexes in vivo, and when the Fc of a pH-dependent Ab was engineered to selectively enhance human Fc gamma RIIb binding, the Ab could accelerate soluble Ag clearance from circulation. We assume such a function would enhance the therapeutic potency of Abs that target soluble Ags.
  • Atsushi Yoshida, Meri Watanabe, Ken Ohmine, Hidetoshi Kawashima
    INTERNATIONAL OPHTHALMOLOGY 35 (3) 429 - 432 0165-5701 2015/06 [Refereed][Not invited]
    We report in this article central retinal vein occlusion (CRVO) caused by hyperviscosity syndrome (HVS) in a young patient with mucosa-associated lymphoid tissue (MALT) lymphoma and Sjogren's syndrome (SjS). A 32-year-old female was referred to our hospital from a local ophthalmologist. Fundoscopic examination and fluorescein angiogram revealed she had a serous retinal detachment in the right eye, together with CRVO (nonischemic type) in both eyes. Systemic examinations revealed hyperglobulinemia, increased blood viscosity, increased antinuclear antibody, increased rheumatoid arthritis particle aggregation, and increased anti-SS-A antibody. Together with a decreased salivary gland secretory function, she was eventually diagnosed as suffering from SjS. Moreover, a large cystic mass was found in the anterior mediastinum on the chest X-ray. Fine needle biopsy soon revealed she had MALT lymphoma. After eight courses of the administration of rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP), most laboratory values were normalized, including blood viscosity. Cystic mass in the anterior mediastinum decreased, and the conditions of CRVO in both eyes had much improved. Decreased best-corrected visual acuity (BCVA) in the right eye was fully restored by sixth month. Not only MALT lymphoma, but also SjS can cause secondary hyperglobulinemia. Indeed, immunoelectrophoresis-serum test showed a polyclonal pattern of hyperglobulinemia. Therefore, SjS was thought to be the primary reason of hyperglobulinemia in this patient, which induced HVS, eventually causing CRVO. R-CVP therapy was effective for not only MALT lymphoma but also SjS accompanied with HVS. Consequently, R-CVP therapy led to the improvement of CRVO.
  • Takahiro Suzuki, Iekuni Oh, Ken Ohmine, Akiko Meguro, Masaki Mori, Shin-ichiro Fujiwara, Chihiro Yamamoto, Tadashi Nagai, Keiya Ozawa
    INTERNATIONAL JOURNAL OF HEMATOLOGY 101 (1) 32 - 36 0925-5710 2015/01 [Refereed][Not invited]
    Erythropoiesis-stimulating agents (ESAs) are used to ameliorate anemia in lower-risk myelodysplastic syndromes (MDS). Serum erythropoietin (EPO) level < 500 IU/L is widely accepted as a major predictive factor for response to ESAs. However, few data about EPO levels in the Japanese population are available. We therefore evaluated distribution of serum EPO levels in Japanese patients with MDS. Forty-three cases were analyzed; 30 were classified as lower-risk MDS (low or intermediate-1 by the international prognostic scoring system). Twenty-two cases were transfusion dependent. The overall median hemoglobin level was 7.7 g/dL. The median value of serum EPO was 254 IU/L (range: 16.4-23,000). Serum EPO levels had a strong inverse correlation with hemoglobin levels, and a significantly larger proportion of patients showed high EPO levels (> 500 IU/L) in the transfusion-dependent group. In the higher-risk group, no significant correlation between EPO and hemoglobin was observed. Regression analyses showed that serum EPO of 500 IU/L corresponds to 8.29 g/dL of hemoglobin in lower-risk MDS. The results indicate that patients with hemoglobin levels of 8.0 g/dL or more, who are still transfusion independent, may be good candidates for ESA treatment.
  • Ishihara A, Ohmine K, Weisbrode SE, Bertone AL
    Orthopedic & muscular system : current research 3 (3) 2014/11 [Refereed][Not invited]
  • Piyanuch Sripayap, Tadashi Nagai, Mitsuyo Uesawa, Hiroyuki Kobayashi, Tomonori Tsukahara, Ken Ohmine, Kazuo Muroi, Keiya Ozawa
    EXPERIMENTAL HEMATOLOGY 42 (4) 294 - 306 0301-472X 2014/04 [Refereed][Not invited]
    The DNA methylation inhibitor azacitidine (5-azacytidine) is used against myelodysplastic syndrome and acute myeloid leukemia, but drug resistance is an ongoing, intractable problem. To investigate resistance mechanisms, we generated two azacitidine-resistant cell lines, THP-1/AR and HL60/AR, and studied genetic disparities between them and their corresponding parental lines. In cells treated with azacitidine, significant mitotic variations were noted in parental cells which were absent in resistant cells, suggesting that resistance arises from negating azacitidine-mediated activation of apoptosis signaling and reestablishing G2/M checkpoint. Importantly, both resistant cell lines have common point mutations in the uridine-cytidine kinase 2 (UCK2) gene, which encodes the rate-limiting enzyme of the azacitidine activation pathway. Forced expression of mutated UCK2 in parental THP-1 cells abrogated azacitidine-induced apoptosis, whereas overexpression of wild type UCK2 in resistant THP-1/AR cells restored sensitivity to azacitidine, implying that UCK2 gene mutations perturb azacitidine activation and advance azacitidine resistance. Our study provides new insights into azacitidine resistance and establishes models useful in developing effective strategies to overcome it. (C) 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
  • Ryosuke Uchibori, Tomonori Tsukahara, Ken Ohmine, Keiya Ozawa
    INTERNATIONAL JOURNAL OF HEMATOLOGY 99 (4) 377 - 382 0925-5710 2014/04 [Refereed][Not invited]
    Cellular and gene therapies represent promising treatment strategies at the frontier of medicine. Hematopoietic stem cells, lymphocytes, and mesenchymal stem cells (MSCs) can all serve as sources of cells for use in such therapies. Strategies for gene therapy are often based on those of cell therapy, and it is anticipated that some examples will be put to practical use in the near future. Given their ability to support hematopoiesis, MSCs may be useful for the enhancement of stem cell engraftment, and the acceleration of hematopoietic reconstitution. Furthermore, MSCs may advance the treatment of severe graft-versus-host disease, based on their immunosuppressive ability. This application is also based on the homing behavior of MSCs to sites of injury and inflammation. Interestingly, MSCs possess tumor-homing ability, opening up the possibility of applications in the targeted delivery of anti-cancer genes to tumors. Many reports have indicated that MSCs can be utilized to target tumors and to deliver anti-cancer molecules locally, as tumors are recognized as non-healing wounds with inflammatory tissue. Here, we review both the potential of MSCs as cellular vehicles for targeted cancer therapy and the molecular mechanisms underlying MSC accumulation at tumor sites.
  • Shin-ichiro Fujiwara, Kazuo Muroi, Raine Tatara, Tomohiro Matsuyama, Ken Ohmine, Takahiro Suzuki, Masaki Mori, Tadashi Nagai, Akira Tanaka, Keiya Ozawa
    LEUKEMIA & LYMPHOMA 55 (2) 307 - 313 1042-8194 2014/02 [Refereed][Not invited]
    CD25 expression in follicular lymphoma (FL) has not yet been investigated. Eighty-five patients with newly diagnosed FL were retrospectively evaluated. On two-color flow cytometric analysis, CD25 was detected on CD19 + and CD20 + lymphoma cells. CD25 expression in FL tended to be higher than in reactive lymphadenopathy, but was lower than in diffuse large B-cell lymphoma. Patients with CD25 + FL (n = 12) showed clinical features of elevated soluble interleukin-2 receptor (IL-2R) levels, B symptoms and an advanced age compared with CD25 - FL (n = 73). The overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) in patients with CD25 + FL were significantly inferior to those with CD25 - FL (ORR, 60 vs. 93%; 2-year PFS, 32 vs. 80.3%; 6-year OS, 47.4 vs. 85.9%, respectively). Multivariate analysis demonstrated that CD25 positivity is an independent prognostic factor for PFS and OS in FL. CD25 + FL may constitute a distinct subgroup associated with aggressiveness and an inferior prognosis.
  • Fujiwara S, Muroi K, Tatara R, Ohmine K, Matsuyama T, Mori M, Nagai T, Ozawa K
    Case reports in hematology 2014 272458  2090-6560 2014 [Refereed][Not invited]
  • Muroi K, Fujiwara S, Tatara R, Sato K, Oh I, Ohmine K, Suzuki T, Nagai T, Ozawa K, Kanda Y
    Journal of clinical and experimental hematopathology : JCEH 54 (3) 243 - 245 1346-4280 2014 [Refereed][Not invited]
  • Tomonori Tsukahara, Ken Ohmine, Chihiro Yamamoto, Ryosuke Uchibori, Hiroyuki Ido, Takeshi Teruya, Masashi Urabe, Hiroaki Mizukami, Akihiro Kume, Masataka Nakamura, Junichi Mineno, Kazutoh Takesako, Isabelle Riviere, Michel Sadelain, Renier Brentjens, Keiya Ozawa
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 438 (1) 84 - 89 0006-291X 2013/08 [Refereed][Not invited]
    Adoptive T-cell therapy with CD19-specific chimeric antigen receptors (CARs) is promising for treatment of advanced B-cell malignancies. Tumor targeting of CAR-modified T-cells is likely to contribute therapeutic potency; therefore we examined the relationship between the ability of CD19-specific CAR (CD19-CAR)-transduced T-cells to accumulate at CD19(+) tumor lesions, and their ability to provide antitumor effects in xenograft mouse models. Normal human peripheral blood lymphocytes, activated with immobilized RetroNectin and anti-CD3 antibodies, were transduced with retroviral vectors that encode CD19-CAR. Expanded CD19-CAR T-cells with a high transgene expression level of about 75% produced IL-2 and IFN-gamma in response to CD19, and lysed both Raji and Daudi CD19(+) human B-cell lymphoma cell lines. Furthermore, these cells efficiently accumulated at Raji tumor lesions where they suppressed tumor progression and prolonged survival in tumor-bearing Rag2(-/-)gamma c(-/-) immunodeficient mice compared to control cohorts. These results show that the ability of CD19-CAR T-cells to home in on tumor lesions is pivotal for their anti-tumor effects in our xenograft models, and therefore may enhance the efficacy of adoptive T-cell therapy for refractory B-cell lymphoma. (C) 2013 Elsevier Inc. All rights reserved.
  • Shin-ichiro Fujiwara, Kazuo Muroi, Yuji Hirata, Kazuya Sato, Tomohiro Matsuyama, Ken Ohmine, Takahiro Suzuki, Katsutoshi Ozaki, Masaki Mori, Tadashi Nagai, Akira Tanaka, Keiya Ozawa
    HEMATOLOGY 18 (1) 14 - 19 1024-5332 2013/01 [Refereed][Not invited]
    CD25 (interluekin-2 receptor) expression in diffuse large B-cell lymphoma (DLBCL) cells has been not examined. To characterize CD25(+) DLBCL, 123 patients, who were newly diagnosed with DLBCL, were analyzed by single-color flow cytometry (FCM). CD25-positivity was significantly higher in DLBCL patients (n = 123; mean +/- SD, 27.8 +/- 30.6%) than in those with reactive lymphadenopathy (n = 16; mean +/- SD, 8.6 +/- 4.3%) and follicular lymphoma (n = 60; mean +/- SD, 12.7 +/- 12.4%). By two-color FCM, CD25/CD19 or CD25/CD20 dual positivity in DLBCL patients was shown: mean +/- SD, 63.7 +/- 25.5% (n = 13) and 55.0 +/- 28.1% (n = 14), respectively. Eighty-two percent of the patients with DLBCL received rituximab combined with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. A cut-off value of 60% with CD25-positivity clearly divided patients with DLBCL into two groups: CD25-high or CD25-low DLBCL. Although clinical and immunophenotypic features were not significantly different in both groups, the former showed a significantly poorer response and more inferior progression-free survival than the latter. CD25 may be a new prognostic marker and could be a therapeutic target in DLBCL.
  • Muroi K, Fujiwara S, Tatara R, Sugimoto M, Yamamoto C, Uehara E, Meguro A, Hatano K, Okazuka K, Oh I, Ohmine K, Suzuki T, Mori M, Nagai T, Ozawa K
    Journal of clinical and experimental hematopathology : JCEH 53 (3) 247 - 250 1346-4280 2013 [Refereed][Not invited]
  • Akiko Meguro, Katsutoshi Ozaki, Kazuya Sato, Iekuni Oh, Shinichiro Fujiwara, Rie Hosonuma, Miyuki Sasazaki, Yuji Kikuchi, Yuji Hirata, Chihiro Yamamoto, Mitsuyo Uesawa, Hiroyuki Kobayashi, Haruko Matsu, Hiroshi Okabe, Eisuke Uehara, Akinori Nishikawa, Raine Tatara, Kaoru Hatano, Chizuru Yamamoto, Tomohiro Matsuyama, Masaki Toshima, Masuzu Ueda, Ken Ohmine, Takahiro Suzuki, Masaki Mori, Tadashi Nagai, Kazuo Muroi, Keiya Ozawa
    LEUKEMIA & LYMPHOMA 53 (1) 43 - 49 1042-8194 2012/01 [Refereed][Not invited]
    In the rituximab era, several large studies have suggested that full-dose rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) might be the best treatment for patients with diffuse large B-cell lymphoma (DLBCL) aged 60 years and older. However, it remains unclear whether this is also the case for those aged 70 years and older. Previously untreated patients with DLBCL aged 70 years and older (elderly) were treated with R-70%CHOP, and patients younger than 70 years (younger) were treated with full-dose R-CHOP every 3 weeks, for a total of 6-8 cycles. Complete remission (CR) rates in elderly versus younger patients were 75 vs. 78% (p = 0.7), respectively. The 3-year overall survival, event-free survival and progression-free survival of elderly versus younger patients were 58 vs. 78% (p < 0.05), 45 vs. 70% (p < 0.05) and 64 vs. 72% (p = 0.43), respectively. Severe adverse events were more frequent in the elderly, even with the dose reduction in that age group. Three-year PFS with R-70% CHOP for patients aged 70 years and older was not significantly worse than that with full-dose R-CHOP for younger patients, suggesting that R-70% CHOP might be a reasonable choice for patients with DLBCL aged 70 years and older, especially for those with comorbidities.
  • Oka S, Muroi K, Fujiwara S, Oh I, Matsuyama T, Ohmine K, Suzuki T, Ozaki K, Mori M, Nagai T, Ozawa K, Hanafusa T
    Journal of clinical and experimental hematopathology : JCEH 52 (1) 63 - 66 1346-4280 2012 [Refereed][Not invited]
  • Kazuya Sato, Tadashi Nagai, Tohru Izumi, Ken Ohmine, Katsutoshi Ozaki, Kazuo Muroi, Keiya Ozawa
    ACTA HAEMATOLOGICA 128 (2) 107 - 109 0001-5792 2012 [Refereed][Not invited]
  • Oka S, Muroi K, Sato K, Fujiwara S, Oh I, Matsuyama T, Ohmine K, Suzuki T, Ozaki K, Mori M, Nagai T, Fukushima N, Fukushima N, Tanaka A, Ozawa K
    Journal of clinical and experimental hematopathology : JCEH 52 (2) 127 - 131 1346-4280 2012 [Refereed][Not invited]
  • Kozue Yoshida, Tadashi Nagai, Ken Ohmine, Mitsuyo Uesawa, Piyanuch Sripayap, Yoji Ishida, Keiya Ozawa
    BIOCHEMICAL PHARMACOLOGY 82 (12) 1884 - 1890 0006-2952 2011/12 [Refereed][Not invited]
    Aurora kinases play an essential role in the regulation of mitosis. The kinases are overexpressed in a variety of cancer cells and are involved in tumorgenesis. Although aurora kinase inhibitors are potential agents for treatment of leukemia, the establishment of efficacious combination therapies is an attractive approach for making good use of these agents. In this study, we examined the effects of a specific aurora kinase inhibitor, VE-465, in combination with various conventional anti-leukemia agents, including doxorubicin, daunorubicin, idarubicin, mitoxantron, cytosine arabinoside, vincristine and etoposide, on acute myeloid leukemia cell lines (HL60, U937, THP-1 and KY821), chronic myeloid leukemia cell lines (KCL22, K562 and KU812) and primary leukemia cells. We found that a combination of VE-465 and vincristine had a synergistic/additive inhibitory effect on the growth of leukemia cells. VE-465 initially increased G2/M-phase cells, followed by induction of sub-G1 cells. Vincristine enhanced this effect of VE-465. The combination of VE-465 and vincristine increased the levels of cleaved caspase 3, cleaved caspase 7, cleaved caspase 9, cleaved PARP and Phospho-Chk2, suggesting that the combination caused Chk2-mediated activation of the G2/M checkpoint, resulting in sequential induction of apoptosis. Interestingly, the combination markedly decreased the level of Phospho-ERK1/2, suggesting that the combination alters a network of cellular signaling pathways. In contrast, combinations of VE-465 and other agents showed no synergistic inhibitory effect but rather had an antagonistic effect. In conclusion, our results indicate the utility of the combination of VE-465 and vincristine as a potential therapy for myeloid leukemia. (C) 2011 Elsevier Inc. All rights reserved.
  • Ken Ohmine, Yi Li, Thomas R. Bauer, Dennis D. Hickstein, David W. Russell
    HUMAN GENE THERAPY 22 (2) 217 - 224 1043-0342 2011/02 [Refereed][Not invited]
    Vector integration can lead to proto-oncogene activation and malignancies during hematopoietic stem cell gene therapy. We previously used foamy virus vectors to deliver the CD18 gene under the control of an internal murine stem cell virus promoter and successfully treated dogs with canine leukocyte adhesion deficiency. Here we have tracked the copy numbers of 11 specific proviruses found in these animals for 36-42 months after transplantation, including examples within or near proto-oncogenes, tumor suppressor genes, and genes unrelated to cancer. We found no evidence for clonal expansion of any of the clones, including those with proviruses in the MECOM gene (MDS1-EVI1 complex). These results suggest that although foamy virus vectors may integrate near proto-oncogenes, this does not necessarily lead to clonal expansion and malignancies. Additionally, we show that copy number estimates of these specific proviruses based on linker-mediated PCR results are different from those obtained by quantitative PCR, but can provide a qualitative assessment of provirus levels.
  • Kazuya Sato, Katsutoshi Ozaki, Shin-ichiro Fujiwara, Iekuni Oh, Tomohiro Matsuyama, Ken Ohmine, Takahiro Suzuki, Masaki Mori, Tadashi Nagai, Kazuo Muroi, Keiya Ozawa
    INTERNATIONAL JOURNAL OF HEMATOLOGY 92 (4) 647 - 650 0925-5710 2010/11 [Refereed][Not invited]
    According to the international working group response criteria for malignant lymphoma revised in 2007, 18F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) combined with or without computed tomography (CT) is recommended for pre-treatment staging and response assessment among patients with diffuse large B-cell lymphoma and Hodgkin lymphoma. Recently, along with the widespread use of PET/CT, unexpected uptake and accumulation of (18)FDG has been reported. Discussed in the present report are patients with malignant lymphoma and second primary carcinomas that were incidentally found by PET/CT. A total of 497 consecutive PET/CT were performed on 290 patients with malignant lymphoma in our institution from April 2008 through March 2010. Eight patients (2.8%) had pathologically confirmed second primary carcinomas consisting of 4 colon cancers, 3 lung cancers, and 1 pancreatic cancer. Two cases were diagnosed at the initial staging, and the others were detected after treatment for lymphoma. It is noteworthy that PET revealed high accumulations of (18)FDG in 5 (62.5%) of the 8 patients without corresponding tumors in conventional CT. All of the 4 patients with colon carcinoma underwent curative surgery. The present study suggests that incidental findings by PET in malignant lymphoma can lead to early detection and successful treatment of second malignancies.
  • Tadashi Nagai, Ken Ohmine, Shin-ichiro Fujiwara, Mitsuyo Uesawa, Chihiro Sakurai, Keiya Ozawa
    LEUKEMIA RESEARCH 34 (8) 1057 - 1063 0145-2126 2010/08 [Refereed][Not invited]
    Small molecules are attractive agents for the treatment of leukemia. We found that a combination of a farnesyltransferase inhibitor, tipifarnib, and an mTOR inhibitor, rapamycin, synergistically inhibited the growth of myeloid leukemia cell lines and primary leukemia cells by inducing apoptosis and cell-cycle blockage. The combined agents reduced the level of phospho-ERK1/2, suggesting that they altered the network of signaling pathways. They also showed synergistic effects in tipifarnib-resistant K562/RR cells. The results support the utility of this combination as a potential therapy for leukemia. The combination might also be effective in overcoming resistance to tipifarnib. (C) 2010 Elsevier Ltd. All rights reserved.
  • Tadashi Nagai, Satoru Kikuchi, Ken Ohmine, Takuji Miyoshi, Makiko Nakamura, Takahito Kondo, Kazumichi Furuyama, Norio Komatsu, Keiya Ozawa
    JOURNAL OF CELLULAR BIOCHEMISTRY 104 (2) 680 - 691 0730-2312 2008/05 [Refereed][Not invited]
    Heme plays an important biomodulating role in various cell functions. In this study, we examined the effects of hemin on cellular sensitivity to imatinib and other anti-leukemia reagents. Hemin treatment of human BCR/ABL-positive KCL22 leukemia cells increased IC50 values of imatinib, that is, the drug resistance, in a dose-dependent manner without any change in the BCR/ABL kinase activity. Imatinib-induced apoptosis was also suppressed by hemin treatment in KCL22 cells. Hemin treatment increased the activity of gamma-glutamylcysteine synthetase (gamma-GCS) light subunit gene promoter, which contains a Maf recognition element (MARE). Protein levels of gamma-GCS and heme oxygenase-1 (HO-1), two MARE-containing genes, were also increased after hemin treatment. Knockdown of Nrf2 expression by RNA interference largely abolished the effect of hemin on imatinib-treated cells, suggesting that Nrf2 recognition of MARE is essential for the hemin-mediated protective effect. Similar to hemin, treatment of cells with delta-aminolevulinic acid (delta-ALA), the obligatory heme precursor, also increased IC50 values of imatinib. In contrast, inhibition of cellular heme synthesis by succinylacetone increased the sensitivity of cells to imatinib in two imatinib-resistant cell lines, KCL22/SR and KU812/SR. Hemin treatment also decreased the sensitivity of cells to four anthracyclins, daunorubicin, idarubicin, doxorubicin, and mitoxantrone, in BCR/ABL-negative leukemia U937 and THP-1 cells, as well as in KCL22 cells. These findings thus indicate that cellular heme level plays an important role in determining the sensitivity of cells to imatinib and certain other anti-leukemia drugs and that the effect of heme may be mediated via its ability to upregulate Nrf2 activity.
  • Hayato Tamai, Hiroki Yamaguchi, Hiroyuki Hamaguchi, Fumiharu Yagasaki, Masami Bessho, Takeshi Kobayashi, Hideki Akiyama, Hisashi Sakamaki, Satoshi Takahashi, Arinobu Tojo, Ken Ohmine, Keiya Ozawa, Hirokazu Okumura, Shinji Nakao, Ayako Arai, Osamu Miura, Shigeo Toyota, Seiji Gomi, Yoshiro Murai, Noriko Usui, Keisuke Miyazawa, Kazuma Ohyashiki, Naoto Takahashi, Kenichi Sawada, Atsushi Kato, Kazuo Oshimi, Koiti Inokuchi, Kazuo Dan
    INTERNATIONAL JOURNAL OF HEMATOLOGY 87 (2) 195 - 202 0925-5710 2008/03 [Refereed][Not invited]
    To clarify the clinical features of adult patients with acute leukemia (AL) with 11q23 abnormalities, we performed a retrospective analysis of data from 58 adult Japanese patients: 51 with acute myeloid leukemia (AML), and 7 with acute lymphoblastic leukemia (ALL). The incidences according to fusion partners in AML were: t(9;11), 31.3%; t(11;19), 27.4%; t(6;11), 21.5%. The incidence of patients with t(11;19) was higher than those in the US and Europe, and the incidence of t(4;11) was lower than that in childhood. The results indicated the poor prognosis of AML with 11q23 abnormalities regardless of the fusion partners. AML patients with 11q23 aged < 60 years in the first CR who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) showed a more favorable outcome than those treated without allo-HSCT, although the differences were not statistically significant (P = 0.322 for DFS, P = 0.138 for OS). This result suggests that treatment strategies including allo-HSCT may be considered in the first CR in cases of AML with 11q23 abnormalities. However, further studies involving a large number of cases are required to assess the effect of allo-HSCT on adult AL with 11q23 abnormalities.
  • Miyuki Akutsu, Saburo Tsunoda, Tohru Izumi, Masaru Tanaka, Susumu Katano, Koichi Inoue, Seiji Igarashi, Kaoru Hirabayashi, Yusuke Furukawa, Ken Ohmine, Kazuya Sato, Hiroyuki Kobayashi, Keiya Ozawa, Keita Kirito, Takahiro Nagashima, Satoshi Teramukai, Masanori Fukushima, Yasuhiko Kano
    ONCOLOGY RESEARCH 17 (3) 137 - 149 0965-0407 2008 [Refereed][Not invited]
    We evaluated the long-term outcome of very dose-intensive chemotherapy (TCC-NHL-91) for advanced intermediate-grade lymphoma, in which an eight-cycle regimen with 11 drugs was given with granulocyte colony-stimulating factor (G-CSF) support (total 18 weeks). Fifty-nine patients were treated during February 1, 1991 and March 31, 2001 (median age: 48 years). Forty-three patients (73%) were in a high-intermediate risk or high-risk group (HI/H) according to the age-adjusted International Prognostic Index (aa-IPI). Forty-six patients received 7 or 8 cycles of therapy. Ten of 15 patients over age 60 stopped before 7 cycles. Forty-three patients with an initial bulky mass or a residual mass received involved-field radiation. Overall, 56 patients (95%) achieved complete remission (CR). Grade 4 hematotoxicity was observed in all patients. With a median follow-up of 128 months, the 10-year overall survival (OS) and progression-free survival (PFS) rates were 76% and 61%, respectively. Neither aa-IPI risk factors nor the index itself was associated with response, OS, or PFS. One patient died of sepsis during the therapy and one died of secondary leukemia. This retrospective study suggests that the TCC-NHL-91 regimen achieves high CR, OS, and PFS in patients with advanced intermediate-grade lymphoma up to 60 years old and may be a valuable asset in the management of this disease. Further evaluation and prospective studies of the TCC-NHL-91 are warranted.
  • Takuji Miyoshi, Tadashi Nagai, Satoru Kikuchi, Ken Ohmine, Makiko Nakamura, Toshiaki Hanafusa, Norio Komatsu, Keiya Ozawa
    EXPERIMENTAL HEMATOLOGY 35 (9) 1358 - 1365 0301-472X 2007/09 [Refereed][Not invited]
    Objective. Results of previous studies have suggested that tipifarnib (Zarnestra), a farnesyltransferase inhibitor, is useful for treating various hematological disorders, including chronic myeloid leukemia. However, acquisition of resistance may be a problem for patients being treated with tipifarnib. Methods. We generated a tipifarnib-resistant BCR/ABL-positive cell line, K562/RR, and examined its characteristics. Results. While levels of cleaved caspase-3, cleaved caspase-7, cleaved caspase-9, and cleaved poly (ADP-ribose) polymerase were significantly increased in K562 cells, the levels were not changed in K562/RR cells with tipifarnib treatment, indicating that induction of apoptosis signaling mediated by tipifarnib is much less in K562/RR cells than in K562 cells. In addition, tipifarnib-mediated induction of cell-cycle blockage was abrogated in K562/RR cells. No mutation of farnesyltransferase alpha and beta genes was found and the level of unprocessed HDJ-2, which is a substrate of farnesyltransferase, was increased by tipifarnib treatment in K562/ RR cells, suggesting that tipifarnib inhibits protein farnesylation in K562/RR cells in the same manner as in K562 cells and that mechanisms independent of farnesyltransferase activity are involved in the acquisition of resistance to tipifarnib in these cells. By DNA microarray analyses using a cDNA microarray comprising 25,000 genes, we identified 5 genes with higher expression levels in K562/RR cells than in K562 cells. These genes include P-globin, calcium channel Caveolin 2, and FEN1, which is involved in DNA replication and repair, and CUGBP2, which may affect expression of cyclooxygenase 2. C onclusion. The results of this study provide useful information for clarification of the mechanisms of resistance to tipifarnib. (c) 2007 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
  • Akiko Meguro-Hashimoto, Masaaki Takatoku, Ken Ohmine, Masaki Toshima, Masaki Mori, Tadashi Nagai, Kazuo Muroi, Keiya Ozawa
    Journal of Infection 53 (3) e135 - e138 0163-4453 2006/09 [Refereed][Not invited]
    A 30-year-old man with acute myeloid leukemia who was pancytopenic after undergoing intensive chemotherapy developed pyrexia and severe pain of both lower legs. We immediately started empiric therapy with cefepime, vancomycin, and fluconazole for febrile neutropenia. However, symptoms progressed. After 4 days, Trichosporon was isolated from venous blood cultures. MRI showed hyperintense lesions within both gastrocnemius muscles and demonstrated reactive vasodilatation and interstitial tissue edema, thought to be induced by hyperpermeability of vessel membranes due to the local fungal infection. Amphotericin B was very effective against this organism. Trichosporosis is a rare infectious disease generally occurring in immunocompromized hosts. To the best of our knowledge, this is first reported case of bilateral Trichosporon infection of lower leg muscles. Severe leg pain was one of the most important signs of fungal infection in this patient with hematologic malignancy. © 2005 The British Infection Society.
  • Takahiro Nagashima, Kazuo Muroi, Chizuru Kawano-Yamamoto, Takuji Miyoshi, Raine Tatara, Akiko Meguro, Shin-Ichiro Fujiwara, Yoko Obara, Iekuni Oh, Satoru Kikuchi, Kazuya Sato, Tomohiro Matsuyama, Masaki Toshima, Ken Ohmine, Katsutoshi Ozaki, Masaaki Takatoku, Masaki Mori, Tadashi Nagai, Keiya Ozawa
    LEUKEMIA & LYMPHOMA 47 (8) 1613 - 1617 1042-8194 2006/08 [Refereed][Not invited]
    Frequency and clinical significance of cerebrospinal fluid (CSF) pleocytosis in hemopoietic stem cell (HSC) transplantation were surveyed. Cyclosporine (CSA)- or tacrolimus (FK506)-based regimens were used as graft-vs-host disease (GVHD) prophylaxis in allogeneic HSC transplantation. CSF pleocytosis with or without neurologic symptoms was detected in 12 of 25 patients receiving allogeneic HSC transplants but in none of 11 patients receiving autologous HSC transplants. Of the 12 patients with CSF pleocytosis, only one patient developed leukoencephalopathy later. There was a correlation between CSF cell numbers and trough levels of CSA but not with those of FK506. In patients receiving allogeneic HSC transplants, CSF pleocytosis may be relatively common and may reflect neurologic damage associated with calcineurin inhibitors.
  • T Miyoshi, T Nagai, K Ohmine, M Nakamura, Y Kano, K Muroi, N Komatsu, K Ozawa
    BIOCHEMICAL PHARMACOLOGY 69 (11) 1585 - 1594 0006-2952 2005/06 [Refereed][Not invited]
    The combination of imatinib and a famesyltransferase inhibitor might be effective for reducing the number of BCR/ABL-positive leukemia cells. In this study, we examined the differences in the mechanisms of the growth inhibitory effect of the combination of imatinib and R115777 (Zarriestra (TM)) among BCR/ABL-positive cell lines. Steel and Peckham isobologram analysis indicated that this combination had a strong synergistic inhibitory effect on growth in all imatinib-resistant cell lines and their parental cell lines. Levels of cleaved caspase 3 were increased by the combination treatment in all cell lines. However, both the level of cleaved PARP and the number of annexin-V-positive cells were much less increased in KCL22 and KCL22/SR cells than in K562, KU812, K562/SR and KU812/SR cells. The combination treatment promoted p27(KIP1) accumulation and induced a significant increase in the percentage of G0/G1 KCL22 and KCL22/SR cells. In other cell lines, the percentage of G0/G1 cells was not increased but rather decreased. The results indicate that induction of apoptosis and blockage of the cell cycle were major mechanisms of the synergistic inhibitory effect of the combination treatment. but the relative importance of these mechanisms differed among cell types. Additional treatment for overriding the G1 checkpoint may be required to eradicate leukemia cells, in which the combination induces cell cycle arrest. (c) 2005 Elsevier Inc. All rights reserved.
  • Nagashima T, Muroi K, Kawano-Yamamoto C, Miyoshi T, Ohmine K, Toshima M, Miyazato A, Takatoku M, Nagai T, Mori M, Komatsu N, Ozawa K
    Medical science monitor : international medical journal of experimental and clinical research 11 (3) CR91 - 4 1234-1010 2005/03 [Refereed][Not invited]
  • T Tarumoto, T Nagai, K Ohmine, T Miyoshi, M Nakamura, T Kondo, K Mitsugi, S Nakano, K Muroi, N Komatsu, K Ozawa
    EXPERIMENTAL HEMATOLOGY 32 (4) 375 - 381 0301-472X 2004/04 [Refereed][Not invited]
    Objective. Imatinib, a BCR/ABL tyrosine kinase inhibitor, has shown remarkable clinical effects in chronic myelogenous leukemia. However, the leukemia cells become resistant to this drug in most blast crisis cases. The transcription factor Nrf2 regulates the gene expression of a number of detoxifying enzymes such as gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme in glutathione (GSH) synthesis, via the antioxidant response element (ARE). In this study, we examined the involvement of Nrf2 in the acquisition of resistance to imatinib. Since oxidative stress promotes the translocation of Nrf2 from the cytoplasm to the nucleus, we also examined whether ascorbic acid, a reducing reagent, can overcome the resistance to imatinib by inhibiting Nrf2 activity. Results. Binding of Nrf2 to the ARE of the gamma-GCS light subunit (gamma-GCSI) gene promoter was much stronger in the imatinib-resistant cell line KCL22/SR than in the parental imatinib-sensitive cell line KCL22. The levels of gamma-GCSI mRNA and GSH were higher in KCL22/SR cells, a finding consistent with the observation of an increase in Nrf2-DNA binding. Addition of a GSH monoester to KCL22 cells resulted in an increase in the IC50 value of imatinib. In contrast, addition of ascorbic acid to KCL22/SR cells resulted in a decrease in Nrf2-DNA binding and decreases in levels of T-GCSI mRNA and GSH. Consistent with these findings, ascorbic acid partly restored imatinib sensitivity to KCL22/SR. Conclusion. Changes in the redox state caused by antioxidants such as ascorbic acid can overcome resistance to imatinib via inhibition of Nrf2-mediated gene expression. (C) 2004 International Society for Experimental Hematology. Published by Elsevier Inc.
  • T Nagai, T Tarumoto, T Miyoshi, K Ohmine, K Muroi, N Komatsu, S Sassa, K Ozawa
    BRITISH JOURNAL OF HAEMATOLOGY 121 (4) 657 - 661 0007-1048 2003/05 [Refereed][Not invited]
    Hydroxyurea (HU), an inhibitor of DNA synthesis, can also induce haemoglobinization in certain erythroid cell lines. In this study, we report that intracellular peroxides levels were increased in HU-treated murine erythroleukaemia (MEL) cells and that l-acetyl-N-cysteine (LNAC), a potent reducing reagent, had a significant inhibitory effect on the HU-mediated induction of beta-globin, delta-aminolaevulinate synthase mRNA expression and haemoglobinization of MEL cells. In contrast, the addition of LNAC to dimethyl sulphoxide (DMSO)-treated MEL cells had a much smaller effect on the number of haemoglobinized cells. These findings suggest that oxidative stress is involved in HU-mediated induction of erythroid differentiation and that HU induces MEL cell differentiation by a mechanism different to that involved in DMSO-mediated differentiation. Our findings also suggest that the induction of MEL cell differentiation by HU does not involve RAS-MAP (mitogen-activated protein) kinase signalling.
  • K Yoshida, S Ueno, T Iwao, S Yamasaki, A Tsuchida, K Ohmine, R Ohki, YL Choi, K Koinuma, T Wada, J Ota, Y Yamashita, K Chayama, K Sato, H Mano
    CANCER SCIENCE 94 (3) 263 - 270 1347-9032 2003/03 [Refereed][Not invited]
    Pancreatic ductal carcinoma (PDC) is one of the most intractable human malignancies. Surgical resection of PDC at curable stages is hampered by a lack of sensitive and reliable detection methods. Given that DNA microarray analysis allows the expression of thousands of genes to be monitored simultaneously, it offers a potentially suitable approach to the identification of molecular markers for the clinical diagnosis of PDC. However, a simple comparison between the transcriptomes of normal and cancerous pancreatic tissue is likely to yield misleading pseudopositive data that reflect mainly the different cellular compositions of the specimens. Indeed, a microarray comparison of normal and cancerous tissue identified the INSULIN gene as one of the genes whose expression was most specific to normal tissue. To eliminate such a "population-shift" effect, the pancreatic ductal epithelial cells were purified by MUC1-based affinity chromatography from pancreatic juice isolated from both healthy individuals and PDC patients. Analysis of these background-matched samples with DNA microarrays representing 3456 human genes resulted in the identification of candidate genes for PDC-specific markers, including those for AC133 and carcinoembryonic antigen-related cell adhesion molecule 7 (CEACAM7). Specific expression of these genes in the ductal cells of the patients with PDC was confirmed by quantitative real-time polymerase chain reaction analysis. Microarray analysis with purified pancreatic ductal cells has thus provided a basis for the development of a sensitive method for the detection of PDC that relies on pancreatic juice, which is routinely obtained in the clinical setting.
  • Ohmine K, Nagai T, Tarumoto T, Miyoshi T, Muroi K, Mano H, Komatsu N, Takaku F, Ozawa K
    Stem cells (Dayton, Ohio) 21 (3) 315 - 321 1066-5099 2003 [Refereed][Not invited]
  • H Makishima, F Ishida, T Ito, K Kitano, S Ueno, K Ohmine, Y Yamashita, J Ota, M Ota, K Yamauchi, H Mano
    BRITISH JOURNAL OF HAEMATOLOGY 118 (2) 462 - 469 0007-1048 2002/08 [Refereed][Not invited]
    Lymphoproliferative disease of granular lympho- cytes (LDGL) is characterized by the clonal proliferationoflarge granular lymphocytes of either T- or natural killer cell origin. To better understand the nature of T cell-type LDGL, we purified the CD4(-) CD8(+) proliferative fractions from LDGL patients (n =4) and the surface marker-matched T cells isolated from healthy volunteers (n =4), and compared the expression profiles of 3456 genes using DNA microarray. Through this analysis, we identified a total of six genes whose expression was active in the LDGL T cells, but silent in the normal ones. Interestingly, expression of the gene for interleukin (IL) 1beta was specific to LDGL T cells, which was further confirmed by the examination of the serum level of IL-1beta protein. Given its important role in inflammatory reactions, the disease-specific expression of IL-1beta may have a causative relationship with the LDGL- associated rheumatoidarthritis. Spectratyping analysis of the T-cell receptor repertoire also proved the monoclonal or oligoclonal natureof LDGL cells. These data have shown that microarray analysis with a purified T-cell subset is an efficient approach to investigate the pathological condition of Tcell-type LDGL.
  • S Imagawa, N Suzuki, K Ohmine, N Obara, HY Mukai, K Ozawa, M Yamamoto, T Nagasawa
    INTERNATIONAL JOURNAL OF HEMATOLOGY 75 (4) 376 - 381 0925-5710 2002/05 [Refereed][Not invited]
    The promoter and enhancer elements of the mouse erythropoietin (mEpo) gene, which have high homology with those of the human erythropoietin (hEpo) gene, were fused with luciferase. ne construct was transfected into erythropoietin-producing hepatoma cell line (Hep3B) cells by lipofectin with lacZ as an internal standard. The wild type (TGATA) showed a 39.5-fold increase in induction by hypoxia. Mouse GATA-2 inhibited the hypoxic induction of the wild-type (m3), promoter-luciferase construct but not the hypoxic induction of the mutant (m4, 5) promoter-luciferasc constructs. N-G-Monomethyl L-arginine (L-NMMA) inhibited the hypoxic induction of the m3 promoter-luciferase construct, but this inhibition was recovered by L-arginine. H2O2 also inhibited the hypoxic induction of the m3 promoter-luciferase construct, but this inhibition was recovered by catalase. Gel shift assays performed on nuclear extracts of 293 cells overexpressing mGATA-1, -2, and -3 revealed that mGATA-1, -2, and -3 bind to the TGATA element of the mEpo promoter. These results indicate that mGATA binds to the TGATA site of the mEpo promoter and negatively regulates mEpo gene expression. Negative regulation of mEpo gene by GATA transcriptional factors is discussed. Int J Hematol. 2002;75:376-381. (C)2002 The Japanese Society of Hematology.

Conference Activities & Talks

  • Clinical development of chimeric antigen receptor-modified T-cell therapy for Acute Lymphoblastic Leukemia  [Invited]
    Ken Ohmine
    7th Thai Society of Hematology International Symposium  2019/05
  • Clinical development of CAR therapy in patients with hematological malignancies in Japan: the current status and challenges  [Invited]
    Ken Ohmine
    The 9th Asian Cellular Therapy Organization Meeting  2018/10


  • Kazuya Sato, Kazuo Muroi, Satoko Oka, Miyuki Sasazaki, Rie Hosonuma, Katsutoshi Ozaki, Shin-ichiro Fujiwara, Iekuni Oh, Tomohiro Matsuyama, Ken Ohmine, Takahiro Suzuki, Masaki Mori, Tadashi Nagai, Keiya Ozawa  Jichi Medical University journal  34-  149  -157  2012/03  [Not refereed][Not invited]
    Mesenchymal stromal cells (MSCs) have been reported to have immunomodulatory effects and ameliorate severe graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). We have conducted a pilot study using human MSCs for the treatment of steroid-resistant GVHD. Between January 2006 and December 2010, 10 patients (7 males and 3 females) with a median age of 37.9 years (range: 23-65 years) who had steroid-resistant GVHD were enrolled in this study. MSCs were isolated from bone marrow of the patient's relatives. Among these 10 patients, three were treated with MSCs. The other seven did not receive MSC treatment because of an improvement in GVHD due to the addition of immunosuppressants including methylprednisolone, spontaneous GVHD regression, or early death. Of the three patients treated with MSCs, one showed an improvement in his intestinal GVHD, another showed no change in his intestinal GVHD and third had his dose of prednisolone successfully decreased without progression of his intestinal GVHD. No immediate adverse reactions associated with MSC infusions were observed. Since the present study was limited to a small number of patients, it is difficult to evaluate the efficacy of MSCs for steroid-resistant GVHD. Further investigations are needed to establish the clinical application of MSCs for steroid-resistant GVHD.
  • Miyuki Sasazaki, Masaki Mori, Mituyo Uesawa, Shinitirou Fuziwara, Yuuzi Kikuti, Kazuya Satou, Tomohiro Matuyama, Ken Oomine, Masuzu Ueda, Takahiro Suzuki, Katutosi Ozaki, Tadashi Nagai, Kazuo Muroi, Keiya Ozawa  Jichi Medical University journal  33-  23  -28  2011/03  [Not refereed][Not invited]
    Burkitt lymphoma/leukemia (BL) was formerly recognized as an aggressive malignant lymphoma with a poor prognosis. To confirm whether the prognosis of BL is improved by the Hyper-CVAD/HD-MTX/Ara-C regimen with or without rituximab (group B) compared with the classical treatment regimen for acute lymphoblastic leukemia or non-Hodgkin lymphoma (group A), the outcomes of 10 patients treated in our hospital from 1997 to 2009 were analyzed. The results showed that both groups had achieved complete remission with each induction therapy; however, 5 of 6 patients in group B had long-term remission, while 3 of 4 patients in group A who received bone marrow transplantation relapsed. In conclusion, the new strategy with short-duration combination chemotherapy is safe and useful for BL.
  • Tatara Raine, Mori Masaki, Fujiwara Shin-ichiro, Miyoshi Takuji, Sato Kazuya, Yamamoto Chizuru, Matsuyama Tomohiro, Toshima Masaki, Ohmine Ken, Ozaki Katsutoshi, Takatoku Masaaki, Nagai Tadashi, Ozawa Keiya, Muroi Kazuo  Jichi Medical University journal  30-  81  -87  2007/12  [Not refereed][Not invited]
  • Oka Satoko, Muroi Kazuo, Sato Kazuya, Yamamoto Kawano Chizuru, Ueda Masuzu, Ono Yoko, Matsuyama Tomohiro, Toshima Masaki, Ohmine Ken, Ozaki Katsutoshi, Takatoku Masaaki, Mori Masaki, Nagai Tadashi, Ozawa Keiya  Jichi Medical University journal  30-  173  -180  2007/12  [Not refereed][Not invited]
    Based on histological examinations of endoscopic biopsy specimens, gastrointestinal (GI) tract B-cell lymphoma was diagnosed in 18 patients who had GI tract symptoms as their initial presentation. The affected sites were the stomach, small intestine and large intestine in nine, seven, and two patients, respectively. The histological classifications were as follows: thirteen patients had diffuse large B-cell lymphoma, one had mucosa-associated with lymphoid tissue (MALT) lymphoma, one had mantle cell lymphoma, while three patients had other types. The flow cytometric analysis of biopsy specimens showed restricted light chain expression in the specimens from seven out of nine patients. The specimens from three out of the another seven patients showed a high expression of CD19 or CD20, however, no light chain expression was determined in any of the seven patients because of insufficient cell numbers. Abnormal karyotypes were observed in the specimens from two of five patients. The analyses using histological examinations combined with flow cytometry (FCM) for ordinary endoscopy and biopsy specimens were thus found to have a significant value for the diagnosis of GI tract B-cell lymphoma.
  • Yamamoto-Kawano Chizuru, Muroi Kazuo, Izumi Tohru, Sato Kazuya, Ueda Masuzu, Matsuyama Tomohiro, Ohmine Ken, Toshima Masaki, Ozaki Katsutoshi, Takatoku Masaaki, Mori Masaki, Nagai Tadashi, Ozawa Keiya  Jichi Medical University journal  29-  105  -113  2006/12  [Not refereed][Not invited]
    Bone marrow of 85 patients with B-cell lymphomas at initial presentation or at relapse was examined simultaneously using both two-color flow cytometry with a CD 19 gate (FCM) and pathologic examination (PTH) including bone marrow aspiration with or without core biopsy. Diffuse large-cell lymphoma (29 patients) and follicular lymphoma (20 patients) were two major subtypes. CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)-based regimens were most frequently used to 47 patients. The median follow-up was 10.5 months. The estimated 2-year overall survival (OS) of the FCM- and PTH-negative group (49 patients), the FCM-positive but PTH-negative group (23 patients) and the FCM-and PTH-positive group (13 patients) was 69±7%, 45±11% and 31±15%, respectively. The estimated 2-year progression-free survival (PFS) of the first, second and third group was 69±7 %, 30±11% and 21±13%, respectively. These results suggest that FCM together with PTH predict the prognosis of B-cell lymphoma. Prospective studies are needed to define the role of flow cytometirc identification of bone marrow lymphoma involvement.
  • Obara Y, Mori M, Nagashima T, Sato K, Toshima M, Omine K, Kirito K, Takatoku M, Muroi K, Komatsu N, Nagai T, Ozawa K  Jichi Medical School journal  28-  11  -16  2005/12  [Not refereed][Not invited]
    We considered the outcome of adult acute lymphoblastic leukemia (ALL) patients treated with Hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethazone)/high dose MTX-Ara-C (methotrexate and cytarabine) as consolidation therapy. Between 1994 and 2004, twenty-seven ALL patients received standard induction therapy, and 23 achieved complete remission. Of the 23 patients, 12 were treated with Hyper-CVAD/high dose MTX-Ara-C (H-CVAD/HD-MA) regimen as consolidation therapy; of these patients, 7 (58%) underwent allogeneic stem cell transplantations. As a result, all but 1 of these 12 patients survived, especially 8 (67%) survived without the relapse of ALL. The other 11 patients who achieved CR were treated with other regimens. And three (27%) underwent allogeneic stem cell transplantations. Of these patients, 2 (18%) survived without relapse ; unfortunately, 6 (67%) died. The H-CVAD/HD-MA group produced better outcomes in both disease free survival (42.0% versus 12.0%, p=0.02) and overall survival (85.0% versus 24.0%, p=0.01) compared with the others. There were no significant differences in the treatment-related toxicity between the two groups. We concluded that H-CVAD/HD-MA regimen is beneficial and safe for ALL patients, and they give the patients to the chance of stem cell transplantation to the patients.
  • OBARA Yoko, NAGAI Tadashi, MORI Masaki, OHMINE Ken, TOSHIMA Masaki, KOMATSU Norio, OZAWA Keiya  臨床血液 = The Japanese Journal of Clinical Hematology  45-  (10)  1138  -1140  2004/10  [Not refereed][Not invited]
  • MIYOSHI Takuji, OTSUKI Tetsuya, OMINE Ken, KIRITO Keita, NAGAI Tadashi, IZUMI Tohru, KOMATSU Norio, MADOIWA Seiji, MIMURO Jun, SAKATA Yoichi, OZAWA Keiya  臨床血液  43-  (10)  954  -959  2002/10  [Not refereed][Not invited]
  • OHMINE Ken, IZUMI Tohru, MUROI Kazuo, SHIMIZU Ritsuko, IMAGAWA Shigehiko, KOMATSU Norio, SASAKI Ryuhei, HATAKE Kiyohiko, MIURA Yasusada, OZAWA Keiya  臨床血液  41-  (1)  8  -11  2000/01  [Not refereed][Not invited]
  • TARUMOTO Takahisa, IMAGAWA Shigehiko, OHMINE Ken, NAGAI Tadashi, SUZUKI Norio, YAMAMOTO Masayuki, HIGUCHI Masato, IMAI Nobuo, OZAWA Keiya  日本分子生物学会年会プログラム・講演要旨集  21-  1998/12  [Not refereed][Not invited]
  • TABATA Masahiko, YOSHIDA Minoru, IZUMI Toru, KAWANO Chizuru, KURIBARA Ryoko, TOSHIMA Masaki, OMINE Ken, TAKATOKU Masaaki, UCHIDA Mie, KIRITO Keita, MIYAZATO Akira, TAKAHASHI Hironori, HOSHINO Mitsuaki, TERUI Yasuhito, TOMIZUKA Hiroshi, OTSUKI Tetsuya, SHIMIZU Ritsuko, TSUNODA Jyun-ichi, MUROI Kazuo, FURUKAWA Yusuke, AMEMIYA Youichi, IMAGAWA Shigehiko, KOMATSU Norio, SUZUKI Toshiyuki, SASAKI Ryuhei, HATAKE Kiyohiko, MIURA Yasusada  臨床血液  39-  (3)  176  -184  1998/03  [Not refereed][Not invited]

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