Kazuhiro Kohno

Oita University, Ōita-shi, Oita-ken, Japan

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Publications (24)68.2 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: High incidences of human herpesvirus (HHV)-6 encephalitis have recently been reported from several Japanese SCT centers. To evaluate the effect of low-dose foscarnet (PFA) in preventing HHV-6 infection among recipients of unrelated BM or cord blood (CB), we examined consecutive cohorts without prophylaxis against HHV-6 (Cohort 1, n=51) and with PFA prophylaxis (Cohort 2, PFA 50 mg/kg/day for 10 days after engraftment, n=67). Plasma real-time PCR assay was performed weekly. High-level reactivation defined as HHV-6 DNA10(4) copies/mL by day 70 was the primary endpoint. No significant reduction of high-level reactivation was seen in Cohort 2 (19.4%) compared with Cohort 1 (33.8%, P=0.095). A trend was identified toward fewer high-level HHV-6 reactivations in Cohort 2 among recipients of unrelated BM (P=0.067), but no difference in incidence was observed among CB recipients (P=0.75). Breakthrough HHV-6 encephalitis occurred following PFA prophylaxis in three patients, and incidence of HHV-6 encephalitis did not differ between Cohort 1 (9.9%) and Cohort 2 (4.5%, P=0.24). In conclusion, 50 mg/kg/day of PFA does not effectively suppress HHV-6 reactivation and cannot prevent all cases of HHV-6 encephalitis. To effectively prevent HHV-6 encephalitis, alternative approaches based on the pathogenesis of HHV-6 encephalitis will probably be required.Bone Marrow Transplantation advance online publication, 2 July 2012; doi:10.1038/bmt.2012.121.
    Bone marrow transplantation 07/2012; · 3.00 Impact Factor
  • British Journal of Haematology 12/2011; 157(2):264-6. · 4.94 Impact Factor
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    ABSTRACT: The etiology of cytomegalovirus (CMV), human herpesvirus-6 (HHV-6), and Epstein-Barr virus (EBV) reactivation and the potential for complications following cytotoxic chemotherapy in the absence of allogeneic transplantation are not clearly understood. Patients with adult T cell leukemia (ATL) are susceptible to opportunistic infections. In this study, the incidence, kinetics and clinical significance of reactivation of CMV, HHV-6, and EBV in ATL patients were investigated. Viral DNA in a total of 468 plasma samples from 34 patients was quantified using real-time PCR. The probability of CMV, HHV-6, and EBV reactivation by 100 days after the start of chemotherapy was 50.6%, 52.3%, and 21.6%, respectively. Although most CMV reactivations were self-limited, plasma CMV DNA tended to persist or increase if the CMV DNA levels in plasma reached ≥ 10(4) copies/ml. CMV reactivation was negatively associated with survival, but the P-value for this association was near the borderline of statistical significance (P=0.052). One patient developed fatal interstitial pneumonia concomitant with peak CMV DNA accumulation (1.6 × 10(6)  copies/ml plasma). Most HHV-6 and EBV reactivations were self-limited, and no disease resulting from HHV-6 or EBV was confirmed. HHV-6 and EBV reactivation were not associated with reduced survival (P=0.35 and 0.11, respectively). These findings demonstrated that subclinical reactivation of CMV, HHV-6, and EBV were common in ATL patients receiving chemotherapy. There were differences in the viral reactivation patterns among the three viruses. A CMV load ≥ 10(4) copies/ml plasma was indicative of subsequent exacerbation of CMV reactivation and developing serious clinical course.
    Journal of Medical Virology 04/2011; 83(4):702-9. · 2.37 Impact Factor
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    ABSTRACT: Thalidomide is now recognized as an important agent for multiple myeloma. In this study, we retrospectively analyzed the effect of thalidomide therapy in 52 patients with relapsed/refractory multiple myeloma. Median age was 70 years. Eight patients were treated with thalidomide alone, 36 with dexamethasone, and 8 with chemotherapy. The maintenance dose of thalidomide was 100 mg/day in 42 cases. The probability of overall survival and progression-free survival one year after the start of thalidomide were 76.2% and 70.9%, respectively. Complete or partial response was obtained in 16 patients (31%). The probability of survival was better in patients who obtained a partial or complete response than in non-responders (P=0.04). Adverse effects (CTCAE criteria Grade 3-4) were somnolence (n=3), constipation (n=5), peripheral neuropathy (n=1), deep vein thrombosis (n=1), anemia (n=10), leukocytopenia (n=10), and thrombocytopenia (n=3). The high incidence of cytopenia in this study suggests that the Japanese population tends to display bone marrow suppression after thalidomide therapy. Some patients developed peripheral neuropathy at the early stage of administration and attention was necessary. In conclusion, thalidomide therapy is safe and effective in patients with refractory multiple myeloma.
    [Rinshō ketsueki] The Japanese journal of clinical hematology 02/2010; 51(2):114-21.
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    ABSTRACT: This study investigated factors associated with the development of human herpesvirus (HHV)-6 encephalitis. Among 111 enrolled subjects, 12 patients developed central nervous system (CNS) dysfunction. CNS dysfunction in four patients was found to have no association with HHV-6. The remaining eight patients displayed HHV-6 encephalitis (n=3), limbic encephalitis (HHV-6 DNA in cerebrospinal fluid was not examined; n=3) or CNS dysfunction because of an unidentified cause (n=2). Real-time PCR showed CNS dysfunction in the latter eight patients, which developed concomitant with the appearance of high plasma levels of HHV-6 DNA (⩾104 copies/ml). Overall, eight of the 24 patients with high-level HHV-6 DNA developed CNS dysfunction, whereas no patients developed CNS dysfunction potentially associated with HHV-6 infection if peak HHV-6 DNA was
    Bone marrow transplantation 01/2010; 45(1):129-136. · 3.00 Impact Factor
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    ABSTRACT: We describe a 62-year-old man infected with human immunodeficiency virus (HIV)-1 who developed primary effusion lymphoma (PEL). Pleural effusion contained atypical lymphoid cells with human herpesvirus (HHV)-8 latent nuclear antigen (LANA)(+). Radiological examination revealed pleural and pericardial effusion, but no evidence of tumor mass or lymph node enlargement. The patient was administered with highly active anti retroviral therapy (HAART) and THP-COP therapy, resulting in complete remission. The prevalence of HHV-8 infection among HIV positive individuals is higher than in the general population in Japan. Although PEL is extremely rare in Japan, the incidence might increase in the future.
    Internal Medicine 01/2010; 49(13):1303-6. · 0.97 Impact Factor
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    ABSTRACT: A 65-year-old woman presented with a 6-month history of abdominal pain and watery diarrhea. Type II enteropathy-associated T-cell lymphoma (EATL) was diagnosed based on the clinical presentation and pathological examination of the tumor. The patient received combination chemotherapy but did not achieve remission. Subsequently, high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) were performed. After these therapies, she achieved complete remission, which has been sustained for 18 months. Although the role of HDT-ASCT for EATL is still controversial, the clinical course of this patient suggests that ASCT can improve the prognosis in some patients with EATL.
    Internal Medicine 01/2010; 49(19):2157-61. · 0.97 Impact Factor
  • Leukemia & lymphoma 05/2009; 50(4):667-9. · 2.61 Impact Factor
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    ABSTRACT: Human herpesvirus 6 (HHV-6) causes life-threatening encephalopathy in recipients of allogeneic SCT, but no consensus has been reached regarding appropriate preventive methods. This study evaluated a plasma HHV-6 viral load-guided preemptive approach against HHV-6-associated encephalopathy. Plasma real-time PCR assay was performed once a week. Among 29 patients, 19 developed positive plasma HHV-6 DNA. Median maximum plasma HHV-6 DNA was 4593.5 copies/ml plasma (range, 150.0-127 891.0 copies/ml plasma). In one of eight events with low-level HHV-6 DNA (defined as <1000 copies/ml plasma) and four of seven events with mid-level HHV-6 DNA (1000-9999.5 copies/ml plasma), HHV-6 loads in plasma subsequently continued increasing. Ganciclovir was administered against six of nine patients with high-level HHV-6 DNA (> or =10,000 copies/ml plasma). High-level HHV-6 DNA resolved similarly in both groups with or without ganciclovir therapy. Among the nine patients with high-level HHV-6 DNA two developed encephalopathy. As encephalopathy developed before the detection of high-level HHV-6 DNA in plasma, these two patients had not received preemptive ganciclovir therapy. In conclusion, our preemptive approach against HHV-6-associated encephalopathy cannot prevent all cases of HHV-6 encephalopathy in SCT recipients due to the dynamic kinetics of plasma HHV-6 viral load.
    Bone Marrow Transplantation 02/2008; 41(3):279-85. · 3.54 Impact Factor
  • Nishi Nihon Hifuka 01/2008; 70(4):381-386.
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    ABSTRACT: A 35-year-old man developed invasive pulmonary aspergillosis (IPA) with severe neutropenia after umbilical cord stem cell transplantation for chronic myelogenous leukemia. Filamentous fungus isolated from his sputum was identified as Aspergillus terreus. Despite systemic amphotericin B (AMPH) administration, IPA progressed. However, intravenous administration of micafungin (MCFG) and oral itraconazole improved clinical data and symptoms, although he later died of massive hemoptysis. Examination of the in vitro susceptibility of this A. terreus isolate to MCFG revealed a good minimum inhibitory concentration and good time-kill assay results compared to AMPH. Thus, MCFG might be useful for IPA caused by A. terreus.
    Internal Medicine 02/2007; 46(11):775-9. · 0.97 Impact Factor
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    ABSTRACT: No established treatments for systemic AL amyloidosis have been determined, and only four reports have described allogeneic stem cell transplantation for this disease. We report the case of a patient with orthostatic hypotension, diarrhea, nephrotic syndrome, and cardiac amyloidosis due to systemic AL amyloidosis. Reduced intensity allogeneic stem cell transplantation (RIST) was performed using a conditioning regimen comprising fludarabine 125 mg/m2 and melphalan 90 mg/m2. Hematologically complete remission and symptomatic improvement were obtained without severe transplantation-related complications. RIST may thus offer a useful treatment strategy for systemic AL amyloidosis complicated by cardiac amyloidosis.
    American Journal of Hematology 05/2006; 81(4):281-3. · 4.00 Impact Factor
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    ABSTRACT: Human herpesvirus 6 (HHV-6) is increasingly recognized as an opportunistic and potentially life-threatening pathogen in recipients of allogeneic stem cell transplants (SCTs). To clarify the incidence and clinical relevance of active HHV-6 infection, serial titers of plasma HHV-6 DNA were determined for 50 allogeneic SCT recipients, using real-time polymerase chain reaction. HHV-6 DNA was detected in plasma from 24 patients (48%). HHV-6 DNA was most frequently apparent approximately 14-27 days after transplantation. An increased risk of a positive result for HHV-6 DNA was associated with transplantation from an allelic-mismatch donor (P = .02) and administration of steroids (P = .04). Steroid use was associated with high HHV-6 DNA loads (P = .02). High HHV-6 DNA loads were correlated with delayed platelet engraftment (P = .04). Among patients who had positive results for HHV-6 DNA, the HHV-6 DNA load was higher in plasma from those who developed limbic encephalitis (n = 4) (P < .0001). Active HHV-6 infection is not rare in SCT recipients. SCT from allelic-mismatch donors is associated with increased risk of active HHV-6 infection. Steroid therapy is associated with not only increased incidence of infection but also accelerated viral replication. Development of limbic encephalitis is associated with high HHV-6 DNA load.
    The Journal of Infectious Diseases 01/2006; 193(1):68-79. · 5.85 Impact Factor
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    ABSTRACT: Cyclosporine (CyA) was administered to 12 patients with myelodysplastic syndrome (MDS), and a response (major erythroid response, according to International Working Group criteria) was observed in 7 patients (58.3%). The median duration of response was 18 months (range, 3-22 months). Two patients are still responding and continuing to take CyA. Three patients stopped because of malignancy complications. To identify variables associated with responsiveness to CyA therapy, we analyzed the treatments of 72 MDS patients, comprising the 12 new patients and 60 patients previously described in the literature. Responses were observed in 44 of the 72 patients (61.1%). Univariate analyses revealed that higher daily dose of CyA (P for trend test, .007) and shorter disease duration (median, 5 months versus 17.5 months, P = .04) were factors significantly associated with response. No significant associations were observed between response and bone marrow features such as erythroid hypoplasia or hypoplastic marrow. Multivariate analysis also demonstrated that high CyA dose (>5 mg/kg per day) was significantly associated with response (P = .02). The present study showed that CyA therapy is useful for MDS patients with any marrow cellularity. Shorter disease duration is a pretreatment variable correlated with response, and a higher CyA dose results in a higher response rate.
    International Journal of Hematology 07/2004; 80(1):35-42. · 1.68 Impact Factor
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    ABSTRACT: We have demonstrated previously the presence of an 8-bp deletion mutant, spanning from nt. 1768 to nt. 1775 in the basic core promoter region of hepatitis B virus (HBV) in patients with anti-HBe positive asymptomatic phase before developing acute exacerbation after immunosuppressive treatment. The transcription and progeny virus production activities of the mutant were examined by transfection of the recombinant plasmid [pUC Del(2)] containing the head-to-tail dimer DNA of the mutant into HepG2 cells. The amounts of hepatitis B surface antigen (HBsAg) and HBe antigens secreted into the culture medium were markedly reduced. Southern blotting of DNAs extracted from the culture medium also showed reduced mutant activity to produce progeny virus. Northern blotting and RNase protection assay of RNAs extracted from transfected cells demonstrated that the transcription of both precore mRNA and pregenome RNA was reduced significantly compared to that of wild-type HBV. The promoter activity examined by transfection of the CAT plasmid containing deletion mutant DNA was much lower than that of wild type. Co-transfection experiments, however, of the CAT plasmid containing wild-type DNA with pUC Del(2) reduced CAT activity induced by wild-type, suggesting that truncated X protein produced by the mutant does not possess a sufficient transactivating activity. Gel shift assay using HepG2 nuclear extract and a probe containing four TA-rich regions in CP and various competitors suggested that the lack of the third TA-rich region was responsible for the transcription reduction of precore mRNA and pregenome RNA. The possible mechanisms are discussed.
    Journal of Medical Virology 06/2000; 61(1):15-22. · 2.37 Impact Factor
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    ABSTRACT: To clarify the mechanism of eosinophilia in adult T-cell leukemia (ATL), we studied three ATL patients having marked eosinophilia. Eosinophil-predominant colony-stimulating activity was detected in the serum of one patient and in the conditioned media (CM) from cultured ATL cells from two patients. Soluble interleukin 5 (IL-5), but no interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), was detected in sera from all patients. On the other hand, GM-CSF was produced in vitro by ATL cells from all cases, whereas detectable IL-3 and IL-5 was produced by cells from only one, suggesting that in the other two cases, the serum IL-5 was produced by the normal reacting lymphocytes. The fact that no patient showed marked neutrophilia supports the possibility that IL-5 may have a leading role in the development of eosinophilia, with GM-CSF produced by ATL cells playing a complementary role. Am. J. Hematol. 59:242–245, 1998. © 1998 Wiley-Liss, Inc.
    American Journal of Hematology 12/1998; 59(3):242 - 245. · 4.00 Impact Factor
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    ABSTRACT: To clarify the mechanism of eosinophilia in adult T-cell leukemia (ATL), we studied three ATL patients having marked eosinophilia. Eosinophil-predominant colony-stimulating activity was detected in the serum of one patient and in the conditioned media (CM) from cultured ATL cells from two patients. Soluble interleukin 5 (IL-5), but no interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), was detected in sera from all patients. On the other hand, GM-CSF was produced in vitro by ATL cells from all cases, whereas detectable IL-3 and IL-5 was produced by cells from only one, suggesting that in the other two cases, the serum IL-5 was produced by the normal reacting lymphocytes. The fact that no patient showed marked neutrophilia supports the possibility that IL-5 may have a leading role in the development of eosinophilia, with GM-CSF produced by ATL cells playing a complementary role.
    American Journal of Hematology 12/1998; 59(3):242-5. · 4.00 Impact Factor
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    ABSTRACT: Bacterial superantigens stimulate T cells in a manner that is restricted to the Vbeta of the T-cell receptor. We examined the ability of adult T-cell leukaemia (ATL) cells to respond to these superantigens. Mononuclear cells from 10 patients were cultured with staphylococcal enterotoxin A (SEA), staphylococcal enterotoxin B (SEB) or toxic shock syndrome toxin-1 (TSST-1), and their response was determined by MTT assay and 3H-thymidine incorporation assay. Cells from six patients showed a specific response to a single superantigen. In two cases the cells responded to TSST-1 and bore Vbeta2, the known target of TSST-1. In three cases the cells responded to SEA with one bearing Vbeta9, a target of SEA, and one bearing Vbeta16. In one case the cells responded to SEB. Most of the cells which proliferated in response to superantigens were determined genetically to be leukaemic. The response to TSST-1 was inhibited by anti-Vbeta2 antibody. The responding cells showed a strongly enhancement expression of interleukin-2 receptor. These findings indicate that leukaemic cells from a proportion of ATL patients have an ability to respond to T-cell receptor-dependent superantigens. This suggests that bacterial infection in such patients may contribute to the expansion of ATL cells.
    British Journal of Haematology 03/1998; 100(3):490-500. · 4.94 Impact Factor
  • Gastroenterology 01/1998; 114. · 12.82 Impact Factor
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    ABSTRACT: The nucleotide sequences of the core upstream and precore regions (371 nucleotide length, nt. 1604-1974) of hepatitis B virus (HBV) were analysed sequentially in three subjects who were positive serologically for anti-HBe and had acute clinical exacerbation after immunosuppressive treatment. These patients were asymptomatic HBV carriers before therapy. The results revealed that the mutant with an 8-bp deletion (nt. 1768-1775) located in the basic core promoter region was dominant in the asymptomatic HBV carrier phase in two of three subjects. After exacerbation, however, such mutant clones possessing 8-bp deletion disappeared or decreased in number and were replaced by the clones possessing a precore stop codon mutation G to A (nt. 1896) or by the clones possessing additional contiguous point mutations A to T (nt. 1762) and G to A (nt. 1764) and a new point mutation C to T (nt. 1653). Possible relationships between acute exacerbation of liver function accompanied by mutation and the transition of the dominant clones were discussed.
    Journal of Medical Virology 12/1997; 53(3):266-72. · 2.37 Impact Factor