Naoki Harada

Kyushu Medical Center, Hukuoka, Fukuoka, Japan

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Publications (27)78.29 Total impact

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    ABSTRACT: The introduction of reduced-intensity conditioning (RIC) regimens has made possible allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML). However, the optimal timing of allo-HCT in these patients and its relative risks and benefits when compared with chemotherapies have not been determined. This retrospective study by the Fukuoka Blood and Marrow Transplant Group compared RIC allo-HSCT with non-transplant therapies, the choice based on donor availability, in AML patients in their first complete remission (CR1). The prognostic value of various patient characteristics and disease-specific variables were investigated in 299 patients aged ≥60 years with AML in CR1. Among the 107 patients aged 60-65 years, 54 of whom received allo-HCT and 53 of whom continued chemotherapies; allo-HCT, adverse-risk group, and hematopoietic cell transplantation-comorbidity index were significant predictors of survival outcomes. Among 192 patients aged ≥66 years deemed ineligible for allo-HCT, relapse and Karnofsky performance status after induction therapy were significant predictors of survival outcomes. Findings from this study may facilitate a new standard of care for older AML patients in CR1 who are considered candidates for allo-HCT.
    Annals of Hematology 02/2015; 94(7). DOI:10.1007/s00277-015-2338-7 · 2.63 Impact Factor
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    ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic cells by bone marrow macrophages activated presumably by systemic inflammatory hypercytokinemia. We here show that the pathogenesis of HLH involves impairment of the anti-phagocytic system operated by interaction of surface CD47 and signal regulatory protein alpha (SIRPA). In HLH patients, the changes of expression levels, or HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy individuals. The number of bone marrow HSCs in HLH patients was reduced to ~20% of normal controls, and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients but not those from normal controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficient to be engulfed by macrophages. The expression of pro-phagocytic calreticulin was kept suppressed at the HSC stage in both HLH and normal controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA anti-phagocytic system plays a key role in maintenance of HSCs, and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development.
    Blood 09/2012; 120(19). DOI:10.1182/blood-2012-02-408864 · 10.45 Impact Factor
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    ABSTRACT: Preemptive therapy for cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplant (HSCT) patients is effective in decreasing the incidence of CMV disease. Intravenous ganciclovir is a commonly used preemptive therapy, but as we have recently shown, oral valganciclovir (VGC) is a useful alternative. However, the optimal dose of VGC has not been determined. We prospectively evaluated the efficacy and toxicity of an initial low-dose of VGC (900 mg QD) as preemptive therapy in 20 patients with low-level CMV antigenemia following allogeneic HSCT. Patients were screened weekly for CMV pp65 antigenemia after engraftment. Preemptive therapy with VGC (900 mg QD) was initiated if more than two CMV antigen-positive cells per 50,000 leukocytes were detected. CMV antigen-positive cells disappeared from all 20 patients after 14-29 days (median 20 days) of VGC treatment. None of the patients developed CMV disease nor did they require more than the conventional VGC dose (900 mg BID). Neutropenia (<500/μL) developed in three patients who required granulocyte-colony-stimulating factor support, but there were no other significant side effects. These observations suggest that the initial dose of VGC in preemptive therapy for CMV can be safely decreased to 900 mg QD for patients with low-level CMV antigenemia.
    International journal of hematology 05/2012; 96(1):94-100. DOI:10.1007/s12185-012-1087-9 · 1.92 Impact Factor
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    ABSTRACT: Virus-associated hemorrhagic cystitis (HC) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Although numerous studies have attempted to identify factors that predispose patients to viral HC, its causes remain controversial. We analyzed retrospectively the results of 266 allogeneic HSCTs to identify factors associated with HC. Of this group, 42 patients (15.8%) were diagnosed with viral HC, because of either adenovirus (ADV; n = 26; 9.8%) or BK virus (BKV; n = 16; 6.0%). ADV-HC was frequently associated with T cell purging, and was less common in patients with acute graft-versus-host-disease (GVHD). Conversely, BKV-HC was more frequently observed in patients with excessive immune reactions such as GVHD, preengraftment immune reaction, and hemophagocytic syndrome. These observations indicate that ADV- and BKV-HC may differ significantly in their risk factors and pathogenesis. Profound immune deficiency is more likely to be associated with ADV-HC, whereas immune hyperactivity might play a key role in BKV-HC.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2011; 18(3):458-65. DOI:10.1016/j.bbmt.2011.07.025 · 3.40 Impact Factor
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    ABSTRACT: Procalcitonin (PCT) has been increasingly used as a biomarker of infection. The purpose of this study was to evaluate its diagnostic value after hematopoietic stem cell transplantation (HSCT), where non-infectious febrile complications such as graft-versus-host disease frequently develop. We retrospectively analyzed 144 febrile episodes (infections: 82, and noninfections: 62) in adult patients with hematological disorders, including 57 and 87 episodes in HSCT and non-HSCT patients, respectively. Of 57 febrile episodes in HSCT patients, 46 (86%) and 25 (44%) revealed positivity for C-reactive protein (CRP) and PCT, respectively. Among 87 febrile episodes in non-HSCT patients, 81 (93%) and 22 (25%) events showed positive results of CRP and PCT. Both of these biomarkers were associated with infectious episodes in univariate analysis. Multivariate analysis showed that a high cut-off level (>9.5 mg/dL) of CRP was a better indicator for infections than PCT in HSCT patients, while PCT positivity was more diagnostic for infections than any cutoff CRP level in non-HSCT patients. It may be necessary to interpret the results of these biomarkers with different orders of priority in transplant versus nontransplant patients.
    Internal Medicine 01/2011; 50(19):2149-55. DOI:10.2169/internalmedicine.50.5798 · 0.90 Impact Factor
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    ABSTRACT: Human herpes virus (HHV)6-associated limbic encephalitis and/or myelitis is one of the life-threatening central nervous system complications following allogeneic hematopoietic stem cell transplantation (HSCT). Recent reports have shown significant correlations of these complications with unrelated cord blood transplantation (UCBT). We retrospectively analyzed 228 allogeneic HSCT recipients in our single institution; 13 patients (5.7%) were diagnosed with HHV6-associated encephalitis/myelitis. This complication was documented in 8 of 51 UCBT recipients (15.7%) and 5 of 177 recipients (2.8%) transplanted with bone marrow or peripheral blood stem cells, indicating a higher incidence of this complication occurring in UCBT recipients (P = .0005). In addition, HHV6-associated encephalitis/myelitis occurred more frequently in recipients who underwent 2 or more HSCTs (7 of 59 recipients [11.9%]), compared to those who received only 1 HSCT (6 of 169 recipients [3.6%], P = .018). Of note, the incidence of this complication increased to 28.6% (6 of 21 recipients), when the analysis was restricted to a second or more UCBT recipients. All 13 patients presented preengraftment immune response prior to the onset of encephalitis. Two patients manifested typical symptoms at the onset of HHV6-associated encephalitis/myelitis, such as memory dysfunction, disorientation, and consciousness disturbance. However, 4 patients presented only with dysesthesia and pruritus, described as typical manifestations of patients with calcineurin-inhibitor-induced pain syndrome (CIPS), and the remaining 7 showed both symptoms, indicating that CIPS-like symptoms might be manifestations of HHV6-associated myelitis. Thus, physicians should be alert to this rare but often fatal complication, particularly for those who receive 2 or more HSCTs using UCB.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2010; 16(11):1596-602. DOI:10.1016/j.bbmt.2010.05.009 · 3.40 Impact Factor
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    ABSTRACT: Invasive aspergillosis (IA) is an important cause of infectious morbidity and mortality in patients who undergo haematopoietic stem cell transplantation (HSCT). History of IA before allogeneic HSCT is still challenging because of the high risk of recurrence after HSCT. Recent advances in early-stage diagnosis and new, more effective classes of antifungal agents have improved the management of IA in the HSCT recipients. We report two cases with acute myelogenous leukaemia after primary failure of induction chemotherapy with the patients developing pulmonary IA. They responded well to a combination of voriconazole (VCZ) and micafungin, resulting in a remarkable reduction of pulmonary IA lesions at short intervals. Thereafter, antifungal therapy was switched to liposomal amphotericin B (L-AmB), followed by conditioning regimen for allogeneic HSCT, because of the possibility of VCZ altering the metabolism of chemotherapeutic agents and calcineurin inhibitors. Successful engraftment was achieved without severe adverse side-effects or aggravation of IA after HSCT. Combining VCZ with micafungin followed by L-AmB throughout HSCT could be advantageous in stabilising IA in HSCT patients.
    Mycoses 03/2010; 54(4):e255-9. DOI:10.1111/j.1439-0507.2010.01858.x · 2.24 Impact Factor
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    ABSTRACT: Invasive aspergillosis (IA) remains one of the most significant causes of morbidity and mortality in patients with hematological malignancies undergoing chemotherapy and hematopoietic stem cell transplantation (HSCT), mainly due to the difficulty in its early diagnosis. Monitoring of galactomannan (GM) antigen, an exoantigen of Aspergillus, in the blood by sandwich ELISA is a useful and noninvasive method for early diagnosis of IA. The GM test has a sensitivity of 67-100% with a specificity of 81-99% in neutropenic patients and allogeneic transplant recipients [1-3]. Although it has been widely used as a diagnostic criterion for IA [4,5], one of the major limitations of this assay is false-positivity, particularly in pediatric patients [1], patients with graft-versus-host disease (GVHD) [6,7], and those taking dietary GM [8,9] or fungus-derived antibiotics, such as piperacillin-tazobactam (PIPC/TAZ) [10-12].
    American Journal of Hematology 01/2010; 85(6):449-51. DOI:10.1002/ajh.21697 · 3.80 Impact Factor
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    ABSTRACT: The chronic graft-versus-host disease often requires unceasing immunosuppressive therapy (IST), which increases a risk of infectious complications in hematopoietic stem cell transplantation (HSCT) recipients. We report an adult T-cell leukemia/lymphoma case who developed pulmonary nocardiosis, a rare pulmonary complication, after allogeneic HSCT despite administration of the prophylactic trimethoprim-sulfamethoxazole (TMP/STX). The inhaled corticosteroid in addition to systemic IST had been started for bronchiolitis obliterance 4 months prior to nocardiosis development. The patient was successfully treated with an increased dose of TMP/STX combined with meropenem. Transplantation physicians should keep this rare pulmonary complication in mind during sustained IST.
    Internal Medicine 01/2010; 49(14):1441-4. DOI:10.2169/internalmedicine.49.3658 · 0.90 Impact Factor
  • Naoki Harada · Koichi Akashi
    Nihon Naika Gakkai Zasshi 01/2010; 99(12):2990-2995. DOI:10.2169/naika.99.2990
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    ABSTRACT: Nasal natural killer (NK)/T cell lymphoma is a rare disease with a poor prognosis. We report the case of a 52-year-old woman with progressive advanced nasal NK/T cell lymphoma, with local invasiveness and bone marrow involvement, who was successfully treated with unrelated cord blood transplantation (UCBT). The patient was initially refractory to conventional chemotherapy. She was therefore treated with local irradiation, which induced a partial response. The patient then underwent UCBT using a conditioning regimen consisting of cyclophosphamide and total body irradiation. Acute graft-versus-host disease involving the skin was observed, but it was well controlled without systemic administration of corticosteroids. The patient remained in complete remission for 18 months after UCBT. Although the observation period has been relatively short and longer follow-up is needed, our observations suggest that incorporating focal irradiation to conditioning regimen for local control might be an effective treatment option for advanced nasal NK/T cell lymphoma in the setting of UCBT.
    International journal of hematology 12/2009; 91(1):107-11. DOI:10.1007/s12185-009-0453-8 · 1.92 Impact Factor
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    ABSTRACT: Gemtuzumab ozogamicin (GO) is an effective molecular-targeted agent for CD33-positive acute myelogenous leukemia (AML) patients who are resistant to conventional chemotherapy. Recent prospective trials have revealed the safety and efficacy of GO as part of conditioning following allogeneic bone marrow or peripheral blood stem cell transplantation (SCT). We report here for the first time three AML cases that relapsed after allogeneic SCT and underwent unrelated cord blood transplantation (UCBT) following reduced-intensity conditioning (RIC) comprising fludarabine, melphalan, and low-dose total body irradiation combined with GO. Primary neutrophil engraftment occurred in all cases, while recovery of platelet count was delayed. Only one case of reversible hepatic sinusoidal obstruction syndrome was documented. Non-relapse mortality at day 100 was not documented. Notably, one patient who responded to GO survived for 6 months after UCBT in remission with excellent performance status, while the remaining cases relapsed early. These data suggest that GO may be safely combined with RIC for UCBT after previous allogeneic SCT.
    International journal of hematology 09/2009; 90(3):416-20. DOI:10.1007/s12185-009-0405-3 · 1.92 Impact Factor
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    ABSTRACT: Between March 2007 and January 2008, the safety and efficacy of oral valganciclovir (VGC) preemptive therapy for cytomegalovirus (CMV) infection was evaluated in ten consecutive patients who received allogeneic hematopoietic stem cell transplantation (HSCT). Patients were screened once or twice per week after engraftment using CMV pp65 antigenemia assay. When more than 2 CMV antigen-positive cells per 50,000 leukocytes were detected, preemptive therapy with oral VGC was initiated at a dose of 900 mg twice daily for 3 weeks. Nine patients (90%) completed the 3-week VGC treatment except for one patient who developed febrile neutropenia. There was no other significant toxicity. CMV antigen-positive cells were rapidly decreased in all nine patients and became undetectable by the end of the VGC treatment. None of the patients developed CMV disease. CMV infection relapsed in four of the ten patients (40%) after the VGC treatment. These observations suggest that preemptive therapy with VGC is effective for preventing CMV disease in allogeneic HSCT patients. Further studies with a large number of patients will be necessary to determine the optimal initial- and maintenance-dose of VGC.
    International journal of hematology 02/2009; 89(2):231-7. DOI:10.1007/s12185-008-0249-2 · 1.92 Impact Factor
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    ABSTRACT: We describe a case of encephalomyelitis mimicking multiple sclerosis associated with chronic graft-versus-host disease (GVHD) occurring after allogeneic bone marrow transplantation (BMT) for myelodysplastic syndrome. Immunosuppressive therapy, consisting of a therapeutic dose of cyclosporine A and a maintenance dose of methylprednisolone, was effective in treating symptoms. Although central nervous system GVHD is very rare and remains controversial, presentation of neurological symptoms after allogeneic BMT warrants consideration of GVHD in the differential diagnosis.
    Internal Medicine 02/2009; 48(16):1453-6. DOI:10.2169/internalmedicine.48.2003 · 0.90 Impact Factor
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    ABSTRACT: We report a 29-year-old Japanese male with acute myelogenous leukemia (AML)-M4 with a cryptic t(7;11)(p15;p15), in which a chimeric NUP98-HOXA9 fusion was detected by polymerase chain reaction analysis and a chromosomal analysis showed 46,XY. The patient received intensive chemotherapy and underwent autologous stem cell transplantation, and remission was confirmed by the disappearance of NUP98-HOXA9. However, 6 months after transplantation, the patient relapsed; NUP98-HOXA9 was detected again and karyotypic analysis revealed 46,XY, t(1;21)(p32;q22). Fluorescent in situ hybridization (FISH) analysis using an AML1-ETO translocation dual probe, showed that the 21q22 breakpoint involved AML1 locus. A retrospective FISH analysis showed that t(1;21) was absent at onset. This is the first reported case with AML who had a cryptic t(7;11)(p15;p15), and additionally acquired t(1;21)(p32;q22) at relapse.
    International journal of hematology 12/2008; 88(5):571-4. DOI:10.1007/s12185-008-0198-9 · 1.92 Impact Factor
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    ABSTRACT: We report a case of severe parainfluenza (PIV) 3 pneumonia in a hematopoietic stem cell transplant recipient that was successfully treated with oral ribavirin and methylprednisolone. A 42-year-old woman diagnosed with acute myelogenous leukemia (FAB M5a) in first complete remission underwent allogeneic bone marrow transplantation from an HLA-matched unrelated donor in May 2006. In July 2007, she developed PIV3 pneumonia. Her respiratory status progressively worsened and she required O(2) inhalation at 6 L/min. After an informed consent was obtained, oral ribavirin was initiated (16 mg/kg per day) for 1 week on July 31. By day 3 of treatment, the high-grade fever had disappeared. However, it recurred after ribavirin was discontinued. In addition, the patient's hypoxia continued to worsen, requiring O(2) inhalation at 9 L/min. To suppress the inflammatory reaction in the lung caused by PIV3 pneumonia, intravenous methylprednisolone (1,000 mg once a day for 3 days) was started along with high-dose oral ribavirin (16 mg/kg per day) on August 11. The patient showed dramatic clinical improvement, and oxygen inhalation was discontinued on September 3. Our case suggests that with concomitant effective anti-viral treatment, corticosteroids may suppress host inflammatory or immune reactions that lead to respiratory failure.
    International journal of hematology 09/2008; 88(3):336-40. DOI:10.1007/s12185-008-0148-6 · 1.92 Impact Factor
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    ABSTRACT: Primary plasma cell leukaemia (PCL) is a rare, aggressive neoplasm of plasma cell dyscrasia. Conventional chemotherapy is usually ineffective, with an overall survival of only 8 months. Here, we describe a 42-year-old man with primary PCL, who was successfully treated with haploidentical (2-HLA loci mismatched) haematopoietic stem-cell transplantation (HSCT). To overcome the human leukocyte antigen (HLA) disparity, in vivo T-cell purging by the pre-transplant administration of antithymocyte globulin followed by a conventional prophylactic treatment against graft-versus-host disease (GVHD) resulted in an avoidance of severe GVHD as well as infectious complications. The patient has maintained complete remission for 13 months after haploidentical HSCT, indicating that a graft-versus-PCL effect might be preserved. Haploidentical HSCT can be a potentially curative treatment for patients with primary PCL who do not have an HLA-identical donor.
    Japanese Journal of Clinical Oncology 01/2008; 37(12):969-72. DOI:10.1093/jjco/hym130 · 2.02 Impact Factor
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    ABSTRACT: Toxoplasmosis is a rare but rapidly fatal complication that can occur following hematopoietic stem cell transplantation (HSCT). Over a 17-yr period at our institutions, a definite diagnosis of toxoplasmosis was made in only two of 925 allogeneic HSCT recipients (0.22%) and none of 641 autologous HSCT recipients. These two patients received a conventional conditioning regimen followed by transplantation from an HLA-matched donor; however, they developed severe graft-vs.-host disease, which required intensive immunosuppressive therapy. Despite prophylactic treatment with trimethoprim/sulfamethoxazole, their immunosuppressive state, as indicated by a low CD4(+) cell count, might have resulted in toxoplasmosis encephalitis. Rapid and non-invasive methods such as a polymerase chain reaction (PCR) test of their cerebrospinal fluid for Toxoplasma gondii and magnetic resonance imaging of the brain were useful for providing a definitive diagnosis and prompt therapy in these patients: one patient stabilized and survived after responding to treatment with pyrimethamine/sulfodiazine whereas the other died of bacterial infection. In addition, retrospective PCR analyses of the frozen stored peripheral blood samples disclosed that detection of T. gondii preceded the onset of disease, indicating routine PCR testing of peripheral blood specimens may be an early diagnostic tool. It should be noted that when patients receiving HSCT have an unexplained fever and/or neurological complications, PCR tests should be considered to avoid cerebral lesions and improve the outcome of the patients.
    European Journal Of Haematology 11/2007; 79(4):317-21. DOI:10.1111/j.1600-0609.2007.00919.x · 2.07 Impact Factor
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    ABSTRACT: Patients with acute myelogenous leukaemia (AML) show co-existing frequently internal tandem duplications of FLT3 (FLT3-ITD) and mutations of nucleophosmin (NPM1-Mt). We investigated the biological and clinical significance of FLT3-ITD and/or NPM1-Mt in this context. We analysed 89 AML patients according to whether NPM1 and FLT3-ITD were single mutants, double mutants, or wild type for both. FLT3-ITD was detected in 19 of 89 patients (21.3%), while NPM1-Mt was detected in 19 of 89 patients (21.3%); eight of 89 patients (9.0%) carried both FLT3-ITD and NPM1-Mt. By multivariate analysis, white blood cell count and peripheral blood blast cell count at diagnosis were significantly higher in patients with FLT3-ITD but not in those with only NPM1-Mt. NPM1-Mt was significantly related to female gender, normal karyotype, and M4 or M5 disease according to French-American-British criteria. In addition, leukaemic blast cells with NPM1-Mt, FLT3-ITD, or both expressed CD34 less frequently than wild-type blasts (P < 0.0001 and P = 0.005 respectively), while myelomonocytic markers such as CD11b and CD14 were expressed more frequently in patients with NPM1-Mt. FLT3-ITD may increase potential for cell proliferation to produce a leukaemic population; NPM1-Mt may cause cells to develop along the myelomonocytic lineage. Extensive analyses and detailed experiments will be required to clarify how NPM1 and FLT3 mutations interact in leukaemogenesis.
    European Journal Of Haematology 08/2007; 79(1):17-24. DOI:10.1111/j.1600-0609.2007.00866.x · 2.07 Impact Factor
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    ABSTRACT: Between 1999 and 2005, 285 patients received new diagnoses of myelofibrosis with myeloid metaplasia (MMM) in Japan. Anemic symptoms were present in 162 patients, and hemoglobin (Hb) concentrations were <10 g/dL in 197 patients. Fifty-five MMM patients were treated with anabolic steroids, and their effect on anemia during MMM was evaluated in 39 patients. A "good" response was defined as an Hb increase of >or=1.5 g/dL, cessation of transfusion dependence, and an Hb concentration of >10 g/dL maintained for at least 8 weeks. A "minimum" response was defined as an Hb increase of >or=1.5 g/dL and transfusion independence for at least 8 weeks. Both good and minimum responses were considered "favorable." Favorable responses were achieved in 17 patients (44%, 8 good and 9 minimum responses). None of the pretreatment variables, such as the lack of transfusion dependence, a higher Hb concentration at the start of treatment, or the absence of cytogenetic abnormalities, were associated with a response to anabolic steroid therapy. Adverse events associated with anabolic steroid therapy were moderate and transient. Two patients required definitive withdrawal of treatment. Thus, anabolic steroids are well tolerated and effective for the treatment of anemia in a subset of MMM patients.
    International Journal of Hematology 06/2007; 85(4):338-43. DOI:10.1532/IJH97.06135 · 1.92 Impact Factor

Publication Stats

208 Citations
78.29 Total Impact Points


  • 2012
    • Kyushu Medical Center
      Hukuoka, Fukuoka, Japan
  • 1994–2012
    • Kyushu University
      • • Graduate School of Medical Sciences
      • • Division of Internal Medicine
      Hukuoka, Fukuoka, Japan
  • 2011
    • Osaka City University
      Ōsaka, Ōsaka, Japan
  • 2007–2010
    • St.Mary's Hospital (Fukuoka - Japan)
      Hukuoka, Fukuoka, Japan