Published Papers - Fukushima Takuya

Heat Shock Enhances the Expression of the Human T Cell Leukemia Virus Type-I (HTLV-I) Trans-Activator (Tax) Antigen in Human HTLV-I Infected Primary and Cultured T Cells.

Kunihiro M, Fujii H, Miyagi T, Takahashi Y, Tanaka R, Fukushima T, Ansari AA, Tanaka Y

Viruses ( MDPI AG )  8 ( 7 ) E191   2016.07 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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The environmental factors that lead to the reactivation of human T cell leukemia virus type-1 (HTLV-I) in latently infected T cells in vivo remain unknown. It has been previously shown that heat shock (HS) is a potent inducer of HTLV-I viral protein expression in long-term cultured cell lines. However, the precise HTLV-I protein(s) and mechanisms by which HS induces its effect remain ill-defined. We initiated these studies by first monitoring the levels of the trans-activator (Tax) protein induced by exposure of the HTLV-I infected cell line to HS. HS treatment at 43 degrees C for 30 min for 24 h led to marked increases in the level of Tax antigen expression in all HTLV-I-infected T cell lines tested including a number of HTLV-I-naturally infected T cell lines. HS also increased the expression of functional HTLV-I envelope gp46 antigen, as shown by increased syncytium formation activity. Interestingly, the enhancing effect of HS was partially inhibited by the addition of the heat shock protein 70 (HSP70)-inhibitor pifithlin-mu (PFT). In contrast, the HSP 70-inducer zerumbone (ZER) enhanced Tax expression in the absence of HS. These data suggest that HSP 70 is at least partially involved in HS-mediated stimulation of Tax expression. As expected, HS resulted in enhanced expression of the Tax-inducible host antigens, such as CD83 and OX40. Finally, we confirmed that HS enhanced the levels of Tax and gp46 antigen expression in primary human CD4(+) T cells isolated from HTLV-I-infected humanized NOD/SCID/gamma c null (NOG) mice and HTLV-I carriers. In summary, the data presented herein indicate that HS is one of the environmental factors involved in the reactivation of HTLV-I in vivo via enhanced Tax expression, which may favor HTLV-I expansion in vivo.

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Absolute quantification of HTLV-1 basic leucine zipper factor (HBZ) protein and its plasma antibody in HTLV-1 infected individuals with different clinical status.

Shiohama Y, Naito T, Matsuzaki T, Tanaka R, Tomoyose T, Takashima H, Fukushima T, Tanaka Y, Saito M

Retrovirology ( BIOMED CENTRAL LTD )  13 ( 1 ) 29   2016.04 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Background: Human T cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ), which is encoded by a minus strand mRNA, is thought to play important roles in the development of adult T-cell leukemia (ATL) and HTLV1- associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, a comprehensive analysis of HBZ, including mRNA and protein expression, humoral immunoreactivity against HBZ, and HTLV-1 proviral load (PVL), in HTLV1- infected individuals with different clinical status has not been reported previously. Results: In this study, using novel monoclonal antibody-based in-house enzyme-linked immunosorbent assay systems, we report the absolute quantification of HBZ protein and its plasma antibody in clinical samples from HTLV-1-infected individuals with different clinical status. The data were compared to both HBZ mRNA levels and PVL. The results showed that plasma anti-HBZ antibody was detectable only in 10.4 % (5/48) of asymptomatic carriers (ACs), 10.8 % (13/120) of HAM/TSP patients, and 16.7 % (7/42) of ATL patients. HBZ protein was detected in three out of five patients with acute ATL, but was not detected in patients with HAM/TSP (0/10) or ACs (0/4). Thus, an antibody response to HBZ was not associated with the PVL or the expression of HBZ (both at the mRNA and protein levels) or the clinical status of the infection. Conclusions: The present results emphasize the extremely low expression and immunogenicity of HBZ in natural HTLV-1 infection. However, there is a possibility that the low but distinct expression of HBZ protein in PBMCs is associated with the survival of HTLV-1-infected cells and the development of ATL.

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Cord Blood Transplantation Provided Long-term Remission in a Case of Adult T-cell Leukemia-lymphoma (ATL) with Myelofibrosis.

Itonaga H, Taguchi J, Kato T, Sato S, Sawayama Y, Imaizumi Y, Niino D, Hata T, Fukushima T, Ohshima K, Miyazaki Y

Internal medicine (Tokyo, Japan) ( 日本内科学会 )  55 ( 2 ) 197 - 201   2016 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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A 53-year-old man was diagnosed with adult T-cell leukemia-lymphoma (ATL) acute type transformed from chronic type. A bone marrow analysis showed diffuse infiltration of abnormal lymphocytes and diffuse fibrotic change. He received unrelated cord blood transplantation (CBT) following reduced-intensity conditioning with complete remission of ATL after two courses of chemotherapy and achieved neutrophil and platelet engraftment. At 99 days after CBT, a bone marrow biopsy showed apparent resolution of myelofibrosis. These results suggest the therapeutic potential of CBT for patients with chemosensitive ATL with myelofibrosis.<br>

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Recurrence of Psoriasis Vulgaris Accompanied by Treatment with C-C Chemokine Receptor Type 4 (CCR4) Antibody (Mogamulizumab) Therapies in a Patient with Adult T cell Leukemia/ Lymphoma: Insight into Autoinflammatory Diseases.

Morichika K, Tomoyose T, Hanashiro T, Shimabukuro N, Tamaki K, Tedokon I, Nishi Y, Nakachi S, Karube KN, Fukushima T, Katoh T, Ohshima K, Masuzaki H

Internal medicine (Tokyo, Japan) ( 一般社団法人 日本内科学会 )  55 ( 10 ) 1345 - 9   2016 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Adult T cell leukemia / lymphoma (ATL) is one of the most aggressive hematological malignancies caused by human T-lymphotropic virus type-I (HTLV-1). Mogamulizumab is a new defucosylated humanized monoclonal antibody agent which targets C-C chemokine receptor type 4 (CCR4) expressed occasionally on the surface of ATL cells. However, adverse events such as drug eruptions have also been highlighted, at least in part, via the dysfunction of regulatory T cells (Tregs). We herein report a pronounced recurrence of systemic psoriasis vulgaris accompanied by the treatment of mogamulizumab in a patient with ATL. Pathological examinations may suggest a mechanistic link between the recurrence of autoinflammatory diseases and anti-CCR4 antibody therapies.<br>

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Fatal pneumonia and viremia due to human parainfluenza virus type 1 in a patient with adult T-cell leukemia-lymphoma treated with mogamulizumab.

Tamaki K, Kinjo T, Aoyama H, Tomoyose T, Nakachi S, Hanashiro T, Shimabukuro N, Tedokon I, Morichika K, Nishi Y, Taira N, Fujita J, Yoshimi N, Fukushima T, Masuzaki H

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy ( ELSEVIER SCIENCE BV )  21 ( 11 ) 820 - 3   2015.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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We report a case of fatal pneumonia and viremia due to human parainfluenza virus type 1 (HPIV-1) in a 65-year-old male patient with adult T-cell leukemia-lymphoma (ATL) treated with mogamulizumab, a brand-new therapeutic agent for ATL. To our knowledge, this is the first report describing viremia due to HPIV-1. After administering mogamulizumab, lymphocyte count in the blood was drastically decreased and the patient suffered from complicated infections including gram-negative bacterial sepsis, cytomegalovirus antigenemia and aspergillosis. Although these infections were successfully controlled by broad spectrum antimicrobial therapy, patchy ground-grass opacities in the both lungs were gradually worsened. He finally died due to acute respiratory failure. Since findings of the chest CT was consistent with typical patterns of viral pneumonia, we screened major respiratory viruses in the peripheral blood with multiplex PCR, and it turned out that RNA of HPIV-1 was positive. Although ATL cells were not detected in the autopsied lungs and a variety of other tissues, cytoplasmic inclusion bodies, which are commonly observed in RNA viral infection, were abundantly observed in the autopsied lung tissue. These findings suggest that mogamulizumab accomplished complete remission of ATL, while the chemotherapy-induced prolonged lymphopenia caused fatal pneumonia and viremia due to HPIV-1. As it has been well recognized that community respiratory viruses including HPIV-1 often cause fatal pneumonia in patients with leukemia, but also there is no specific treatment for HPIV-1, we have to enforce standard precautions especially when we treat leukemic patients with intensively immunosuppressive agents such as mogamulizumab. (C) 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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Monitoring of Hepatitis B Virus (HBV) DNA and Risk of HBV Reactivation in B-Cell Lymphoma: A Prospective Observational Study.

Kusumoto S, Tanaka Y, Suzuki R, Watanabe T, Nakata M, Takasaki H, Fukushima N, Fukushima T, Moriuchi Y, Itoh K, Nosaka K, Choi I, Sawa M, Okamoto R, Tsujimura H, Uchida T, Suzuki S, Okamoto M, Takahashi T, Sugiura I, Onishi Y, Kohri M, Yoshida S, Sakai R, Kojima M, Takahashi H, Tomita A, Maruyama D, Atsuta Y, Tanaka E, Suzuki T, Kinoshita T, Ogura M, Mizokami M, Ueda R

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America ( OXFORD UNIV PRESS INC )  61 ( 5 ) 719 - 29   2015.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Background. There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs). Methods. We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of &gt;= 11 IU/mL. Results. With a median HBV DNA follow-up of 562 days, HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5-12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of &lt;10 mIU/mL and detectable HBV DNA remaining below the level of quantification at baseline were independent risk factors for HBV reactivation (hazard ratio, 20.6 and 56.2, respectively; P &lt; .001). Even in 6 patients with a rapid increase of HBV due to mutations, the monthly HBV DNA monitoring was effective at preventing HBV-related hepatitis. Conclusions. Monthly monitoring of HBV DNA is useful for preventing HBV reactivation-related hepatitis among B-NHL patients with resolved HBV infection following R-steroid-chemo (UMIN000001299).

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Successful treatment of toxoplasmic encephalitis diagnosed early by polymerase chain reaction after allogeneic hematopoietic stem cell transplantation: two case reports and review of the literature

T. Miyagi, H. Itonaga, F. Aosai, J. Taguchi, K. Norose, K. Mochizuki, H. Fujii, A. Furumoto, M. Ohama, K. Karimata, A. Yamanoha, H. Taniguchi, S. Sato, N. Taira, Y. Moriuchi, T. Fukushima, H. Masuzaki, Y. Miyazaki

TRANSPLANT INFECTIOUS DISEASE ( WILEY-BLACKWELL )  17 ( 4 ) 593 - 598   2015.08 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Toxoplasmic encephalitis represents a rare, but often fatal infection after allogeneic hematopoietic stem cell transplantation. Polymerase chain reaction (PCR)-based preemptive therapy is considered promising for this disease, but is not routinely applied, especially in low seroprevalence countries including Japan. We encountered 2 cases of toxoplasmic encephalitis after transplantation that were successfully treated. The diagnosis of toxoplasmic encephalitis in these cases was confirmed by PCR testing when neurological symptoms were observed. Both patients received pyrimethamine and sulfadiazine treatments within 2weeks of the development of neurological symptoms, and remained free of recurrence for 32 and 12months. These results emphasized the importance of the PCR test and immediate treatment after diagnosis for the management of toxoplasmic encephalitis.

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Human T-cell leukemia virus type-I Tax induces the expression of CD83 on T cells.

Tanaka Y, Mizuguchi M, Takahashi Y, Fujii H, Tanaka R, Fukushima T, Tomoyose T, Ansari AA, Nakamura M

Retrovirology ( BIOMED CENTRAL LTD )  12 ( 1 ) 56   2015.07 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Background: CD83, a cell surface glycoprotein that is stably expressed on mature dendritic cells, can be transiently induced on other hematopoietic cell lineages upon cell activation. In contrast to the membrane form of CD83, soluble CD83 appears to be immunosuppressive. In an analysis of the phenotype of leukemic CD4(+) T cells from patients with adult T-cell leukemia (ATL), we found that a number of primary CD4(+) T cells became positive for cell surface CD83 after short-term culture, and that most of these CD83(+) CD4(+) T cells were positive for human T-cell leukemia virus type-I (HTLV-I) Tax (Tax1). We hypothesized that Tax1 is involved in the induction of CD83. Result: We found that CD83 was expressed selectively on Tax1-expressing human CD4(+) T cells in short-term cultured peripheral blood mononuclear cells (PBMCs) isolated from HTLV-I+ donors, including ATL patients and HTLV-I carriers. HTLV-I-infected T cell lines expressing Tax1 also expressed cell surface CD83 and released soluble CD83. CD83 can be expressed in the JPX-9 cell line by cadmium-mediated Tax1 induction and in Jurkat cells or PBMCs by Tax1 introduction via infection with a recombinant adenovirus carrying the Tax1 gene. The CD83 promoter was activated by Tax1 in an NF-kappa B-dependent manner. Based on a previous report showing soluble CD83-mediated prostaglandin E2 (PGE2) production from human monocytes in vitro, we tested if PGE2 affected HTLV-I propagation, and found that PGE2 strongly stimulated expression of Tax1 and viral structural molecules. Conclusions: Our results suggest that HTLV-I induces CD83 expression on T cells via Tax1 -mediated NF-kappa B activation, which may promote HTLV-I infection in vivo.

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Characteristic patterns of relapse after allogeneic hematopoietic SCT for adult T-cell leukemia-lymphoma: a comparative study of recurrent lesions after transplantation and chemotherapy by the Nagasaki Transplant Group

H. Itonaga, Y. Sawayama, J. Taguchi, S. Honda, H. Taniguchi, J. Makiyama, E. Matsuo, S. Sato, K. Ando, D. Imanishi, Y. Imaizumi, S. Yoshida, T. Hata, Y. Moriuchi, T. Fukushima, Y. Miyazaki

BONE MARROW TRANSPLANTATION ( NATURE PUBLISHING GROUP )  50 ( 4 ) 585 - 591   2015.04 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Allogeneic hematopoietic SCT (allo-SCT) is a promising therapy that may provide long-term durable remission for adult T-cell leukemia-lymphoma (ATL) patients; however, the incidence of relapse associated with ATL remains high. To determine the clinical features of these patients at relapse, we retrospectively analyzed tumor lesions in 30 or 49 patients who relapsed following allo-SCT or chemotherapy (CHT), respectively, at three institutions in Nagasaki prefecture between 1997 and 2011. A multivariate analysis revealed that the development of abnormal lymphocytes in the peripheral blood of patients at relapse was less frequent after allo-SCT than after CHT (P&lt;0.001). Furthermore, relapse with a new lesion only in the absence of the primary lesion was more frequent in allo-SCT (P = 0.014). Lesions were more frequently observed in the central nervous systems of patients who relapsed with new lesions only (P = 0.005). Thus, the clinical manifestation of relapsed ATL was slightly complex, especially in post-transplant patients. Our results emphasized the need to develop adoptive modalities for early and accurate diagnoses of relapsed ATL.

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The intractable intra-abdominal hemorrhage with unknown etiology in a patient with severe hemophilia A.

Morichika K, Tomoyose T, Nishi Y, Nakachi S, Fukushima T, Masuzaki H

The American journal of emergency medicine ( W B SAUNDERS CO-ELSEVIER INC )  33 ( 1 ) 129.e1 - 3   2015.01 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Severe hemophilia patients are more likely to be complicated by intra-articular hemorrhage, subcutaneous hemorrhage, and intra-mascular hemorrhage. Spontaneous intra-abdominal hemorrhage is a rare fatal disease, which is an arterial bleeding of uncertain causes from vessel feeding arteries. In case the spontaneous intra-abdominal hemorrhage is complicated to severe hemophilia patients, the mortality rate increases considerably. We experienced a patient with severe hemophilia A, who made a full recovery from spontaneous intra-abdominal hemorrhagic shock by replacement therapy of coagulation factor VII, a noninvasive procedure.

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Giant Septic Lymphadenitis with Marked Gas Formation Caused by Bacteroides fragilis in a Patient with Adult T-cell Leukemia/lymphoma.

Tomoyose T, Nakachi S, Nishi Y, Morichika K, Tedokon I, Tamaki K, Shimabukuro N, Hanashiro T, Samura H, Fukushima T, Masuzaki H

Internal medicine (Tokyo, Japan) ( 一般社団法人 日本内科学会 )  54 ( 22 ) 2919 - 22   2015 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Adult T-cell leukemia/lymphoma (ATL) sometimes causes opportunistic infections. A 53-year-old woman with systemic lymphadenopathies was diagnosed with ATL by inguinal lymph node biopsies and underwent oral chemotherapy. Two months later, high grade fever, lower abdominal pain and lymphadenopathy recurred. Computed tomography revealed the presence of lymphadenopathy with marked gas formation in the pelvic lesion. Blood cultures were suggestive of septic lymphadenitis by <i>Bacteroides fragilis</i> (<i>BF</i>). This represents the first demonstration of giant lymphadenitis with gas formation caused by <i>BF</i> in a patient with ATL. Notably, septic lymphadenitis is pivotal in the differential diagnosis of systemic lymphadenopathy in ATL.<br>

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Successful treatment of a chronic-phase T-315-mutated chronic myelogenous leukemia patients with a combination of imatinib and interferon-alfa.

Itonaga H, Tsushima H, Hata T, Matsuo E, Imanishi D, Imaizumi Y, Kawaguchi Y, Fukushima T, Doi Y, Mori S, Kamihira S, Tomonaga M, Miyazaki Y.

Int J Hematol ( その他の出版社 )  95   209 - 213   2012 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

High expression of 67-kDa laminin receptor relates to the proliferation of leukemia cells and increases expression of GM-CSF receptor.

Ando K, Miyazaki Y, Sawayama Y, Tominaga S, Matuso E, Yamasaki R, Inoue Y, Iwanaga M, Imanishi D, Tsushima H, Fukushima T, Imaizumi Y, Taguchi J, Yoshida S, Hata T, Tomonaga M.

Exp Heamtol ( その他の出版社 )  39   179 - 186   2011 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

Allogeneic hematopoietic stem cell transplantation for ATL with central nervous system involvement: The Nagasaki Transplant Group experience.

Fukushima T, Taguchi J, Moriuchi Y, Yoshida S, Itonaga H, Ando K, Sawayama Y, Imaizumi Y, Imanishi D, Hata T, Miyazaki Y.

Int J Hematol ( その他の出版社 )  94   390 - 394   2011 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

Expression of myeloperoxidase and gene mutations in AML patients with normal karyotype: durable CEBPA mutations are associated with high percentage of MPO positivity in leukemic blasts.

Tominaga-Sato S, Tsushima H, Ando K, Itonaga H, Imaizumi Y, Imanishi D, Iwanaga M, Taguchi J, Fukushima T, Yoshida S, Hata T, Moriuchi Y, Kuriyama K, Mano H, Tomonaga M, Miyazaki Y.

Int J Hematol ( その他の出版社 )  94   81 - 89   2011 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

Is zidovudine and interferon-alfa the gold standard for adult T-cell leukemia-lymphoma?

Ishitsuka K, Fukushima T, Tsukasaki K, Tobinai K.

J Clin Oncol ( その他の出版社 )  28   e765   2010 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

Relationship between monoclonal gammopathy of undetermined significance and radiation exposure in Nagasaki atomic bomb survivors.

Iwanaga M, Tagawa M, Tsukasaki K, Matsuo T, Yokota K, Miyazaki Y, Fukushima T, Hata T, Imaizumi Y, Imanishi D, Taguchi J, Momita S, Kamihira S, Tomonaga M.

Blood ( その他の出版社 )  113   1639 - 1650   2009 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

Long-term efficacy of imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: a report by the Nagasaki CML Study Group.

Sakai M, Miyazaki Y, Matsuo E, Moriuchi Y, Hata T, Fukushima T, Imaizumi Y, Imanishi D, Taguchi J, Iwanaga M, Tsushima H, Inoue Y, Takasaki Y, Tsuchiya T, Komoda M, Ando K, Horio K, Moriwaki Y, Tominaga S, Itonaga H, Nagai K, Tsukasaki K, Tsutsumi C, Sawayama Y, Yamasaki R, Ogawa D, Kawaguchi Y, Ikeda S, Yoshida S, Onimaru Y, Tawara M, Atogami S, Koida S, Joh T, Yamamura M, Matsuo Y, Soda H, Nonaka H, Jinnai I, Kuriyama K, Tomonaga M.

Int J Hematol ( その他の出版社 )  89   319 - 325   2009 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

Expression of myeloperoxidase enhances the chemosensitivity of leukemia cells through the generation of reactive oxygen species and the nitration of protein.

Sawayama Y, Miyazaki Y, Ando K, Horio K, Tsutsumi C, Imanishi D, Tsushima H, Imaizumi Y, Hata T, Fukushima T, Yoshida S, Onimaru Y, Iwanaga M, Taguchi J, Kuriyama K, Tomonaga M.

Leukemia ( その他の出版社 )  22   956 - 964   2008 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

Successful cord blood transplantation for mycosis fungoides.

Fukushima T, Horio K, Matsuo E, Imanishi D, Yamasaki R, Tsushima H, Imaizumi Y, Ohshima K, Hata T, Yoshida S, Miyazaki Y, Tomonaga M.

Int J Hematol ( その他の出版社 )  88   596 - 598   2008 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)