Shigeru Chiba

University of Tsukuba, Tsukuba, Ibaraki, Japan

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Publications (331)1630.08 Total impact

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    ABSTRACT: RHOA is a member of RHO family small GTPases. Over the past 2 decades, numerous biochemical and cell biological studies on RHOA have demonstrated signalings such as activation of RHO-associated coiled-coil forming kinases through guanine nucleotide exchange and GTP hydrolysis, cellular responses such as actin fiber formation and myocin activation, biological consequences such as cell motility and cytokineses, etc. There have also been a plenty of active discussion on the roles of RHOA in tumorigenesis, primarily based on gain- and loss-of-function experiments. However, cell-type-specific functions of RHOA have only recently been delineated by conditional gene targeting strategies. Furthermore, very little information had been available on human cancer genetics until we and others recently reported frequent somatic RHOA mutations in a distinct subtype of T-cell-type malignant lymphoma called angioimmunoblastic T-cell lymphoma (AITL), and other T-cell lymphoma with AITL-like features. The RHOA mutations were very specific to these types of lymphoma among hematologic malignancies, and a single hotspot, glycine at the 17th position, was affected by the replacement with valine (G17V). Remarkably, G17V RHOA did not bind GTP, and moreover, it inhibited the GTP binding to wild-type RHOA. How G17V RHOA contributes to T-cell lymphomagenesis needs to be clarified. [199 words; 150-200].
    Small GTPases 06/2015; DOI:10.4161/21541248.2014.988088
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    ABSTRACT: Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100mg/day) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into 2 groups according to those calculated thresholds by receiver operating characteristic curve (407/μL for NK cells and 347/μL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    American Journal of Hematology 06/2015; DOI:10.1002/ajh.24096 · 3.48 Impact Factor
  • Annals of Hematology 05/2015; 94(8). DOI:10.1007/s00277-015-2391-2 · 2.40 Impact Factor
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    ABSTRACT: As the history of the cord blood banking system has lengthened, the number of cord blood units (CBUs) cryopreserved for years has increased. The global expansion of cord blood banking resulted in active international exchange of CBUs. To determine whether long-term cryopreservation and international shipment of CBUs affect the quality of the units and outcome after transplantation, we retrospectively analyzed the quality of 95 CBUs and the hematologic recovery of 127 patients with hematological malignancy following single-unit cord blood transplantation. Of the 127 CBUs used to transplant, 42 units were cryopreserved for long periods (5-11.8 years), and 44 units were shipped from distant countries. We found that length of cryopreservation and origin of CBUs did not affect the ratio of viable total-nucleated cells after thawing. Also, neutrophil engraftment was not affected by long-term cryopreservation (> 5 years) or origin (from distant countries), (hazard ratio, 0.91 and 1.2; P=0.65 and 0.41; respectively). The number of CD34(+) cells before freezing (> 1.4 cells/kg recipient) was the only factor that enhanced neutrophil engraftment (hazard ratio, 1.8; P<0.01). This suggests that length of cryopreservation and origin need not be prioritized over the CD34(+) cell dose when selecting CBUs.Bone Marrow Transplantation advance online publication, 23 March 2015; doi:10.1038/bmt.2015.56.
    Bone marrow transplantation 03/2015; 50(6). DOI:10.1038/bmt.2015.56 · 3.47 Impact Factor
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    ABSTRACT: Recent identification of platelet/megakaryocyte-biased hematopoietic stem/repopulating cells requires revision of the intermediate pathway for megakaryopoiesis. Here, we show a unipotent megakaryopoietic pathway bypassing the bipotent megakaryocyte/erythroid progenitors (biEMP). Cells purified from mouse bone marrow by CD42b (GPIbα) marking were demonstrated to be unipotent megakaryocyte progenitors (MKP) by culture and transplantation. A subpopulation of CD41(+) cells in the lineage(-) Sca1(+) cKit(+) (LSK) fraction (subCD41(+) LSK) isolated from mouse bone marrow differentiated only into MKP and mature megakaryocytes in vitro culture. Although CD41(+) LSK cells as a whole were capable of differentiating into all myeloid and lymphoid cells in vivo, they produced unipotent megakaryocytic progenitors (MKP), mature megakaryocytes, and platelets in vitro and in vivo much more efficiently than Flt3(+) CD41(-) LSK cells, especially at the early phase after transplantation. In single cell PCR and thrombopoietin (TPO) signaling analyses, the MKP and a fraction of CD41(+) LSK, but not the biEMP, showed the similarities in mRNA expression profile and visible TPO mediated phosphorylation. On increased demand of platelet production after 5-FU treatment, a part of CD41(+) LSK population expressed CD42b on the surface, and 90% of them showed unipotent megakaryopoietic capacity in single cell culture and predominantly produced platelets in vivo at the early phase after transplantation. These results suggest that the CD41(+) CD42b(+) LSK are straightforward progenies of megakaryocytes/platelet-biased stem/repopulating cells, but not progenies of biEMP. Consequently, we show a unipotent/highly-biased megakaryopoietic pathway interconnecting stem/repopulating cells and mature megakaryocytes, the one that may play physiologic roles especially in emergency megakaryopoiesis. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
    Stem Cells 03/2015; 33(7). DOI:10.1002/stem.1985 · 7.70 Impact Factor
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    ABSTRACT: To investigate prognosis and effects of first-line therapy in elderly primary central nervous system lymphoma (PCNSL) patients. A systematic review of studies about first-line therapy in immunocompetent patients≥60 years with PCNSL until 2014 and a meta-analysis of individual patient data from eligible studies and international collaborators were performed. We identified 20 eligible studies; from 13 studies we obtained individual data of 405 patients, which were pooled with data of 378 additional patients (N=783). Median age and Karnofsky Performance Score (KPS) was 68 years (range: 60 - 90) and 60% (range: 10% - 100%), respectively. Treatments varied greatly, 573 (73%) patients received high-dose methotrexate (HD-MTX)-based therapy. 276 patients received whole brain radiotherapy (median 36 Gy, range 28.5 - 70). KPS≥70% was the strongest prognostic factor for mortality (hazard ratio [HR] 0.50, 95% CI 0.41 - 0.62). After a median follow-up of 40 months, HD-MTX based therapy was associated with improved survival (HR 0.70, 95% CI 0.53 - 0.93). There was no difference between HD-MTX plus oral chemotherapy and more aggressive HD-MTX based therapies (HR 1.39, 95% CI 0.90 - 2.15). Radiotherapy was associated with an improved survival, but correlated with an increased risk for neurological side effects (odds ratio 5.23, 95% CI 2.33 - 11.74). Elderly PCNSL patients benefit from HD-MTX based therapy, especially if combined with oral alkylating agents. More aggressive HD-MTX protocols do not seem to improve outcome. WBRT may improve outcome, but is associated with increased risk for neurological side effects. Prospective trials for elderly PCNSL patients are warranted. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Annals of Oncology 02/2015; DOI:10.1093/annonc/mdv076 · 6.58 Impact Factor
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    ABSTRACT: Dear Editor,Somatic mutations in DNMT3A, TET2, and RHOA are frequently found in peripheral T cell lymphomas (PTCLs) and other hematological malignancies [1-4]. Among these mutations, RHOA mutations are confined to tumor cells, but TET2 and DNMT3A mutations are found in normal bone marrow and blood cells in multiple lineages in addition to tumor tissues/cells [1, 5]. This has led to an idea that the origin of the TET2 and DNMT3A mutations in some PTCLs may be hematopoietic stem cells (HSCs) or progenitors (HPCs). Here, we report an interesting case of a 74-year-old male patient suffering from PTCL.Tumor tissue was positive for TET2 and DNMT3A mutations (Supplementary Table 1) [1]. CD4+ PD1+ cells, considered to consist of a tumor cell-enriched fraction, were purified from peripheral blood (PB) and showed mutations in TET2 and DNMT3A at allele frequencies of 46.13 and 50.00 %, respectively, indicating that almost all circulating tumor cells had both mutations. The identical TET2 and DNMT ...
    Annals of Hematology 02/2015; 94(7). DOI:10.1007/s00277-015-2332-0 · 2.40 Impact Factor
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    ABSTRACT: To investigate the factors that affect molecular responses on dasatinib treatment in patients with chronic-phase chronic myeloid leukemia (CML-CP), we performed a clinical trial named the 'D-First study'. Fifty-two patients with newly diagnosed CML-CP were enrolled in this study and received 100mg dasatinib once daily. A deep molecular response (DMR) was defined as less than 50 copies/μg RNA of BCR-ABL1 transcript value corrected by GAPDH, which ensures <0.01% of BCR-ABL1 transcript value according to International Scale (BCR-ABL1(IS) ). The halving time for BCR-ABL1 transcripts was calculated using transcript levels before dasatinib treatment, transcript levels after 3 months of treatment, and the treatment time between these two points. In terms of molecular response, 38 of 51 (75%) patients reached major molecular response (MMR) by 12 months, and the rate of DMR by 18 months was 59% (30/51). While both BCR-ABL1 transcript levels before treatment and a shorter halving time of BCR-ABL1 transcripts (≤14 days) were significant factors affecting achievement of MMR by 12 months, the Sokal score at diagnosis was not associated with MMR. Importantly, the halving time was the only factor that predicted achievement of DMR by 18 months. We showed that patients with CML-CP treated with dasatinib can be stratified according to the early treatment response as determined by the halving time of BCR-ABL1 transcripts. These data emphasize the significance of the early response from dasatinib treatment in achieving a DMR. (www.ClinicalTrials.gov; NCT01464411) This article is protected by copyright. All rights reserved. © 2014 Wiley Periodicals, Inc.
    American Journal of Hematology 02/2015; 90(4). DOI:10.1002/ajh.23923 · 3.48 Impact Factor
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    ABSTRACT: We report a 38-year-old Nigerian woman with sickle cell disease. Sickle cell disease had been diagnosed when she experienced her first sickle cell crisis episode at age 8 years. Thereafter, she had infrequent minor episodes. She visited a hospital presenting with fever, anemia, jaundice, and systemic pain, and was then transferred to our hospital. Together with rehydration and red blood cell transfusion, analgesics and antibiotics were prescribed, and produced gradual improvement of all symptoms and signs. The patient was discharged on day 9 of hospitalization. Sickle cell crisis is an acute painful episode caused by occlusion of arterioles. The degree of pain and accompanying symptoms, as well as the frequencies of crises, are variable. Moreover, one third of individuals with sickle cell disease never experience a crisis. As our society becomes increasingly globalized, the probabilities of encountering sickle cell disease patients will be higher.
    [Rinshō ketsueki] The Japanese journal of clinical hematology 01/2015; 56(1):30-4. DOI:10.11406/rinketsu.56.30
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    ABSTRACT: Interdigitating dendritic cell sarcoma (IDCS) is a rare and aggressive neoplasm that is thought to arise from dendritic cells. This disease usually involves the lymph nodes and, rarely, extra-nodal sites. We report a 62-year-old man presenting skin nodules in the head, body, and extremities, as well as bone marrow involvement. Morphologic analysis of a biopsied specimen from the skin lesion was consistent with IDCS. Immunohistochemical staining demonstrated that the tumor cells were positive for IDCS-associated antigens such as CD4, CD45, CD68 (KP-1), and S-100 protein. Complete remission was achieved by treatment with 6 cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) chemotherapy. Although the optimal treatment of IDSC remains unknown, the experience in the current case supports the notion that ABVD chemotherapy may be effective for IDCS, and further extends this idea to rare patients presenting multiple skin lesions.
    Journal of Clinical and Experimental Hematopathology 01/2015; 55(1):33-7. DOI:10.3960/jslrt.55.33
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    ABSTRACT: Hydroxymethylcytosine (hmC) is a natural nucleobase, which is converted from methylcytosine (mC) by tet methylcytosine dioxygenase (TET) family (TET1-3) enzymes. Decrease of genomic hmC is postulated to confer a risk for myeloid-lineage as well as T-cell neoplasms, based on the fact that loss-of-function mutations in the TET2 gene were frequently identified in these diseases. The relationship between hmC and aging remains to be elucidated. Here, we demonstrated that hmC content decreased with age in the peripheral blood T cells of 53 human volunteers. We further identified that the mRNA expression levels of TET1 and TET3 decreased with age, while those of TET2 were not influenced by age. The genomic hmC content was correlated with the mRNA expression level of TET3, but not those of TET1 and TET2. Our study suggests the presence of new epigenetic regulatory mechanisms in aging T cells.
    Journal of Clinical and Experimental Hematopathology 01/2015; 55(1):1-6. DOI:10.3960/jslrt.55.1
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    ABSTRACT: A 52-year-old woman was diagnosed with BJP-λ multiple myeloma (MM) in November 2012. She was treated with six cycles of bortezomib and dexamethasone, resulting in a very good partial response. The patient underwent autologous peripheral blood stem cell transplantation (PBSCT) 6 months after the diagnosis, and clearly achieved a complete response thereafter. She again suffered chronic abdominal pain with spontaneous remission 9 months after the PBSCT, and, 2 months thereafter, was hospitalized due to intestinal obstruction. Two small intestinal intussusceptions and polyposis in the small intestine were found on abdominal computed tomography. As conservative treatment produced no improvement, partial resection of the small intestine was performed. The pathologic review clearly demonstrated the polyps to have atypical plasma cell infiltrates in the mucosa of the small intestine involving all layers. Immunohisto-chemistry and FISH analyses yielded positive results for CD138, CD79a, and λ light chain, consistent with extramedullary relapse of MM. It is very rare for MM to present with polyposis in the small intestine. There have been no reports describing such a case after autologous PBSCT.
    [Rinshō ketsueki] The Japanese journal of clinical hematology 01/2015; 56(4):400-5. DOI:10.11406/rinketsu.56.400
  • Mamiko Sakata-Yanagimoto, Shigeru Chiba
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    ABSTRACT: Notch signaling controls cell-fate specification events in various types of blood cells, and it further regulates the function of particular blood cells. Recent studies have identified the role of Notch signaling as a determinant of mast cell fate from bone marrow progenitors and mast cell maturation towards mucosal type rather than connective tissue type. Furthermore, Notch2 has functional properties for immune defense against Strongyloides venezuelensis through properly distributing intestinal mast cells. The goal of this chapter is to provide the researchers with the comprehensive protocols to examine the functions of Notch signaling in mast cells both in vitro and in vivo.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1220:79-89. DOI:10.1007/978-1-4939-1568-2_6 · 1.29 Impact Factor
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    ABSTRACT: Chronic kidney disease (CKD) is one of the major manifestations of paroxysmal nocturnal hemoglobinuria (PNH). CKD in PNH is induced mainly by intravascular hemolysis of PNH-affected red blood cells (RBC) missing the glycosylphosphatidylinositol-anchored proteins with complement-regulatory activities, CD55 and CD59. CKD develops by heme absorption in the proximal tubules resulting in the interstitial deposition of iron in the kidneys. We administered eculizumab to a patient with PNH, who was one of 29 patients enrolled in the AEGIS clinical trial, an open-label study of eculizumab in Japan. The patient was complicated by stage 3 CKD with impaired estimated glomerular filtration rate (eGFR), at grade G3b, and had obvious proteinuria (2-3+, 1-2 g/day). In a two-year extension to the 12-week AEGIS study, eGFR improved significantly, and the eGFR has since been maintained at grade G2 without proteinuria by sustained eculizumab treatment (>6 years). Renal function improved and maintained by long-term sustained eculizumab treatment, presumably by clearance of iron from the kidney as well as inhibition of the production of anaphylatoxin C5a, even in advanced stages of CKD, is one of the benefits of eculizumab treatment in PNH.
    01/2015; 2015:1-4. DOI:10.1155/2015/673195
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    ABSTRACT: TET2 (Ten Eleven Translocation 2) is a dioxygenase that converts methylcytosine (mC) to hydroxymethylcytosine (hmC). TET2 loss-of-function mutations are highly frequent in subtypes of T-cell lymphoma that harbor follicular helper T (Tfh)-cell-like features, such as angioimmunoblastic T-cell lymphoma (30-83%) or peripheral T-cell lymphoma, not otherwise specified (10-49%), as well as myeloid malignancies. Here, we show that middle-aged Tet2 knockdown (Tet2(gt/gt)) mice exhibit Tfh-like cell overproduction in the spleen compared with control mice. The Tet2 knockdown mice eventually develop T-cell lymphoma with Tfh-like features after a long latency (median 67 weeks). Transcriptome analysis revealed that these lymphoma cells had Tfh-like gene expression patterns when compared with splenic CD4-positive cells of wild-type mice. The lymphoma cells showed lower hmC densities around the transcription start site (TSS) and higher mC densities at the regions of the TSS, gene body and CpG islands. These epigenetic changes, seen in Tet2 insufficiency-triggered lymphoma, possibly contributed to predated outgrowth of Tfh-like cells and subsequent lymphomagenesis. The mouse model described here suggests that TET2 mutations play a major role in the development of T-cell lymphoma with Tfh-like features in humans.
    Blood Cancer Journal 12/2014; 4:e264. DOI:10.1038/bcj.2014.83 · 2.88 Impact Factor
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    ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are subtypes of T-cell lymphoma. Due to low tumor cell content and substantial reactive cell infiltration, these lymphomas are sometimes mistaken for other types of lymphomas or even non-neoplastic diseases. In addition, a significant proportion of PTCL-NOS cases reportedly exhibit features of AITL (AITL-like PTCL-NOS). Thus disagreement is common in distinguishing between AITL and PTCL-NOS. Using whole-exome and subsequent targeted sequencing, we recently identified G17V RHOA mutations in 60-70% of AITL and AITL-like PTCL-NOS cases but not in other hematologic cancers, including other T-cell malignancies. Here, we establish a sensitive detection method for the G17V RHOA mutation using a quantitative allele-specific polymerase chain reaction (qAS-PCR) assay. Mutated allele frequencies deduced from this approach were highly correlated with those determined by deep sequencing. This method could serve as a novel diagnostic tool for 60-70% of AITL and AITL-like PTCL-NOS.
    PLoS ONE 10/2014; 9(10):e109714. DOI:10.1371/journal.pone.0109714 · 3.53 Impact Factor
  • [Rinshō ketsueki] The Japanese journal of clinical hematology 10/2014; 55(10):1715-23.
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    ABSTRACT: In leukemogenesis, Notch signaling can be up- and down-regulated in a context-dependent manner. The transcription factor hairy and enhancer of split-1 (Hes1) is well characterized as a downstream target of Notch signaling. Hes1 encodes a basic helix-loop-helix-type protein, and represses target gene expression. Here we report that deletion of the Hes1 gene in mice promotes acute myeloid leukemia (AML) development induced by the MLL-AF9 fusion protein. We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and down-regulated the promoter activity. FLT3 was consequently up-regulated in MLL-AF9-expressing immortalized and leukemia cells with a Hes1- or RBPJ-null background. MLL-AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL-AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL-AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. We also accessed two independent databases containing mRNA expression profiles and found that the expression level of FLT3 mRNA was negatively correlated with those of HES1 in patient AML samples. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development, probably by down-regulating FLT3 expression.Leukemia accepted article preview online, 19 September 2014. doi:10.1038/leu.2014.281.
    Leukemia 09/2014; 29(3). DOI:10.1038/leu.2014.281 · 9.38 Impact Factor
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    ABSTRACT: Purpose We evaluated the efficacy and safety of febuxostat, a non-purine xanthine oxidase inhibitor, used for prevention of hyperuricemia associated with tumor lysis syndrome (TLS). Methods Records of adult patients with newly diagnosed or relapsed hematologic malignancies who received febuxostat within 7 days before initiation of chemotherapy were retrieved retrospectively at a single institute. The changes in serum uric acid levels from before and 7 days after initiation of febuxostat were evaluated and compared with the historical control group of patients who received allopurinol. We also evaluated non-hematological adverse events during the study period. Results A total of 78 patients’ records were analyzed, 38 in the febuxostat group and 39 in the allopurinol group. There were no significant differences in the incidence of treatment failure, defined as development of clinical TLS or receiving rasburicase, between the febuxostat and allopurinol group (5.2% vs 5.1%, P>0.99). The mean serum uric acid levels were significantly decreased, compared to the baseline (5.6 ± 2.1 mg/dL), at 7 days after initiation of febuxostat (3.1 ± 1.5 mg/dL, last observation carried forward, P<0.001). There were no statistically significant differences in the percent change in the serum uric acid levels between the 40 mg/day febuxostat and the 300 mg/day allopurinol groups (P = 0.57). Grade 3–4 liver dysfunctions were observed in both the febuxostat and allopurinol groups, without significant differences in incidence between the two groups (2.6% vs 5.1%, P>0.99). Neither gout flare nor skin rash occurred in any patients. Conclusions Febuxostat is feasible for prevention of hyperuricemia associated with TLS.
    SpringerPlus 09/2014; 3:501. DOI:10.1186/2193-1801-3-501
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    ABSTRACT: Background: Nearly half of all patients with primary central nervous system lymphoma (PCNSL) are known to be aged over 60 years. However, clinical factors affecting treatment outcomes in elderly patients are under-studied. Methods: We analyzed 38 patients with PCNSL older than 60 years. All patients were treated with a non-radiation, intermediate-dose methotrexate-containing regimen between March 2005 and May 2013 at the University of Tsukuba Hospital. Results: The 3-year overall survival and progression-free survival rates were 56.2% (95% confidence interval (CI) 36.2-76.2%) and 29.8% (95% CI 9-50.6%), respectively, with a median follow-up of 36.5 months. We found that an age > 75 years, a Karnofsky performance score < 70, altered mentation, and a creatinine clearance (CrCl) > 90 ml/min were significant (p < 0.05) factors associated with a worse survival, by univariate analysis. Multivariate analysis revealed that CrCl (p < 0.05; hazard ratio (HR) = 3.39; 95% CI 1.08-10.68) and altered mentation (p < 0.05; HR = 6.27; 95%CI 1.37-28.83) were independent significant association factors. The most frequent adverse event was myelosuppression, with grade 3-4 hematologic toxicities in 28 patients. No delayed neurotoxicities were observed. Conclusion: More intensive therapy may be introduced in selected patients with poor prognosis factors to improve outcomes.
    08/2014; 37(7-8):378-83. DOI:10.1159/000363435

Publication Stats

9k Citations
1,630.08 Total Impact Points

Institutions

  • 2008–2015
    • University of Tsukuba
      • Institute of Clinical Medicine
      Tsukuba, Ibaraki, Japan
  • 2000–2013
    • Tokyo Medical University
      • Division of Hematology
      Edo, Tōkyō, Japan
  • 1989–2011
    • The University of Tokyo
      • • Department of Hematology and Oncology
      • • Department of Cell Therapy and Transplantation Medicine
      • • Division of Internal Medicine
      • • Department of Pathology
      Tōkyō, Japan
  • 2005–2007
    • Institute for Molecular Medicine and Cell Therapy
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2006
    • Saiseikai Maebashi Hospital
      Edo, Tōkyō, Japan
  • 2004
    • Yale University
      New Haven, Connecticut, United States
  • 2000–2002
    • National Institute for Basic Biology
      Okazaki, Aichi, Japan
  • 1996–2002
    • Oita University
      • • Faculty of Medicine
      • • Department of Clinical Pharmacy
      Ōita, Ōita, Japan
  • 2001
    • Toranomon Hospital
      Edo, Tōkyō, Japan