Faculty Profiles - FUJIWARA Hideaki

Papers - FUJIWARA Hideaki

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Computational analysis of continuous body temperature provides early discrimination of graft-versus-host disease in mice. Reviewed International journal

Kuang He, Zhenke Wu, Hideaki Fujiwara, Steven Whitesall, Cynthia K Zajac, Sung Won Choi, Pavan Reddy, Muneesh Tewari

Blood advances 3 ( 23 ) 3977 - 3981 2019.12

miR-142 controls metabolic reprogramming that regulates dendritic cell activation. Reviewed International journal

Yaping Sun, Katherine Oravecz-Wilson, Sydney Bridges, Richard McEachin, Julia Wu, Stephanie H Kim, Austin Taylor, Cynthia Zajac, Hideaki Fujiwara, Daniel Christopher Peltier, Thomas Saunders, Pavan Reddy

The Journal of clinical investigation 129 ( 5 ) 2029 - 2042 2019.4

Language：English Publishing type：Research paper (scientific journal)

DCs undergo metabolic reprogramming from a predominantly oxidative phosphorylation (OXPHOS) to glycolysis to mount an immunogenic response. The mechanism underpinning the metabolic reprogramming remains elusive. We demonstrate that miRNA-142 (miR-142) is pivotal for this shift in metabolism, which regulates the tolerogenic and immunogenic responses of DCs. In the absence of miR-142, DCs fail to switch from OXPHOS and show reduced production of proinflammatory cytokines and the ability to activate T cells in vitro and in in vivo models of sepsis and alloimmunity. Mechanistic studies demonstrate that miR-142 regulates fatty acid (FA) oxidation, which causes the failure to switch to glycolysis. Loss- and gain-of-function experiments identified carnitine palmitoyltransferase -1a (CPT1a), a key regulator of the FA pathway, as a direct target of miR-142 that is pivotal for the metabolic switch. Thus, our findings show that miR-142 is central to the metabolic reprogramming that specifically favors glycolysis and immunogenic response by DCs.

DOI： 10.1172/JCI123839

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A Pipeline for Faecal Host DNA Analysis by Absolute Quantification of LINE-1 and Mitochondrial Genomic Elements Using ddPCR. Reviewed

Scientific reports 2019.4

Mitochondrial Deacetylase SIRT3 Plays an Important Role in Donor T Cell Responses after Experimental Allogeneic Hematopoietic Transplantation. Reviewed International journal

Tomomi Toubai, Hiroya Tamaki, Daniel C Peltier, Corinne Rossi, Katherine Oravecz-Wilson, Chen Liu, Cynthia Zajac, Julia Wu, Yaping Sun, Hideaki Fujiwara, Israel Henig, Stephanie Kim, David B Lombard, Pavan Reddy

Journal of immunology (Baltimore, Md. : 1950) 201 ( 11 ) 3443 - 3455 2018.12

Language：English Publishing type：Research paper (scientific journal)

Allogeneic hematopoietic cell transplantation (allo-HCT) through its graft-versus-tumor (GVT) effects is a curative therapy against many hematological malignancies. However, GVT is linked to harmful graft-versus-host disease (GVHD) after allo-HCT. Both GVT and GVHD require allogeneic T cell responses, which is an energetically costly process that causes oxidative stress. Sirtuin 3 (SIRT3), a mitochondrial histone deacetylase (HDAC), plays an important role in cellular processes through inhibition of reactive oxygen species (ROS). Nonmitochondrial class of HDACs regulate T cell responses, but the role of mitochondrial HDACs, specifically SIRT3, on donor T cell responses after allo-HCT remains unknown. In this study, we report that SIRT3-deficient (SIRT3-/-) donor T cells cause reduced GVHD severity in multiple clinically relevant murine models. The GVHD protective effect of allogeneic SIRT3-/- T cells was associated with a reduction in their activation, reduced CXCR3 expression, and no significant impact on cytokine secretion or cytotoxic functions. Intriguingly, the GVHD protective effect of SIRT3-/- T cells was associated with a reduction in ROS production, which is contrary to the effect of SIRT3 deficiency on ROS production in other cells/tissues and likely a consequence of their deficient activation. Notably, the reduction in GVHD in the gastrointestinal tract was not associated with a substantial reduction in the GVT effect. Collectively, these data reveal that SIRT3 activity promotes allogeneic donor T cell responses and ROS production without altering T cell cytokine or cytolytic functions and identify SIRT3 as a novel target on donor T cells to improve outcomes after allo-HCT.

DOI： 10.4049/jimmunol.1800148

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SAG/RBX2 E3 Ubiquitin Ligase Differentially Regulates Inflammatory Responses of Myeloid Cell Subsets. Reviewed International journal

Xiufang Xiong, Nathan D Mathewson, Hua Li, Mingjia Tan, Hideaki Fujiwara, Haomin Li, Pavan Reddy, Yi Sun

Frontiers in immunology 9 2882 - 2882 2018.12

Language：English Publishing type：Research paper (scientific journal)

Macrophages form an important component of the innate immune system and serve as first responders against invading pathogens. While pathways critical for initiation of inflammatory responses between macrophages and other LysM+ myeloid cells are largely similar, it remains unknown whether a specific pathway has differential effects on inflammatory responses mediated between these cells. Recent studies demonstrated that depletion of SAG (Sensitive to Apoptosis Gene), an E3 ubiquitin ligase, blocked inflammatory responses generated by macrophages and dendritic cells in response to LPS in cell culture settings. However, the in vivo role of Sag on modulation of macrophages and neutrophil is not known. Here we generated LysM-Cre/Sag fl/fl mice with selective Sag deletion in myeloid lineage, and found that in contrast to in vitro observations, LysM-Cre/Sag fl/fl mice showed increased serum levels of proinflammatory cytokines and enhanced mortality in response to LPS. Interestingly, while Sag -/- macrophages released less proinflammatory cytokines, Sag -/- neutrophils released more. Mechanistically, expression of a list of genes response to LPS was significantly altered in bone marrow cells from LysM-Cre +/Sag fl/fl mice after LPS challenge. Specifically, induction by LPS of myeloperoxidase (Mpo), a key neutrophil enzyme, and Elane, neutrophil expressed elastase, was significantly decreased upon Sag depletion. Collectively, our study revealed that Sag plays a differential role in the activation of macrophages and neutrophils.

DOI： 10.3389/fimmu.2018.02882

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Murine Models of Steroid Refractory Graft-versus-Host Disease. Reviewed International journal

Tomomi Toubai, Corinne Rossi, Isao Tawara, Chen Liu, Cynthia Zajac, Katherine Oravecz-Wilson, Daniel Peltier, Yaping Sun, Hideaki Fujiwara, Shin-Rong Wu, Mary Riwes, Israel Henig, Stephanie Kim, Pavan Reddy

Scientific reports 8 ( 1 ) 12475 - 12475 2018.8

Language：English Publishing type：Research paper (scientific journal)

Corticosteroids are the first line therapy for acute graft-versus-host disease (GVHD). However, the outcome of steroid refractory GVHD (SR-GVHD) is poor due to a lack of effective treatments. The development of therapies for SR-GVHD is limited by an incomplete understanding of its pathophysiology partly because of the absence of clinically relevant animal models of SR-GVHD. Here we addressed the need for a SR-GVHD animal model by developing both MHC matched multiple minor histocompatibility antigens (miHAs) mismatched and MHC mismatched haploidentical murine models of SR-GVHD. We demonstrate that animals can develop SR-GVHD regardless of whether steroids are initiated early or late post allogeneic bone marrow transplantation (allo-BMT). In general, we observed increased GVHD specific histopathological damage of target organs in SR-GVHD animals relative to steroid responsive animals. Interestingly, we found no significant differences in donor T cell characteristics between steroid refractory and responsive animals suggesting that donor T cell independent mechanisms may play more prominent roles in the pathogenesis of SR-GVHD than was considered previously.

DOI： 10.1038/s41598-018-30814-x

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IAPs protect host target tissues from graft-versus-host disease in mice. Reviewed International journal

Tomomi Toubai, Corinne Rossi, Katherine Oravecz-Wilson, Chen Liu, Cynthia Zajac, Shin-Rong Julia Wu, Yaping Sun, Hideaki Fujiwara, Hiroya Tamaki, Daniel Peltier, Mary Riwes, Israel Henig, Stuart Brabbs, Colin S Duckett, Shaomeng Wang, Pavan Reddy

Blood advances 1 ( 19 ) 1517 - 1532 2017.8

Language：English Publishing type：Research paper (scientific journal)

Inhibitors of apoptosis proteins (IAPs) regulate apoptosis, but little is known about the role of IAPs in the regulation of immunity. Development of IAP inhibition by second mitochondria-derived activator of caspase (SMAC) mimetics is emerging as a novel therapeutic strategy to treat malignancies. We explored the role of IAPs in allogeneic immunity with 2 distinct yet complementary strategies, namely, chemical and genetic approaches, in clinically relevant models of experimental bone marrow transplantation (BMT). The small-molecule pan-IAP inhibitor SMAC mimetic AT-406 aggravated gastrointestinal graft-versus-host disease (GVHD) in multiple models. The role of specific IAPs in various host and donor cellular compartments was explored by utilizing X-linked IAP (XIAP)- and cellular IAP (cIAP)-deficient animals as donors or recipients. Donor T cells from C57BL/6 cIAP1-/- or XIAP-/- animals demonstrated equivalent GVHD severity and allogeneic responses, both in vivo and in vitro, when compared with B6 wild-type (B6-WT) T cells. By contrast, when used as recipient animals, both XIAP-/- and cIAP1-/- animals demonstrated increased mortality from GVHD when compared with B6-WT animals. BM chimera studies revealed that cIAP and XIAP deficiency in host nonhematopoietic target cells, but not in host hematopoietic-derived cells, is critical for exacerbation of GVHD. Intestinal epithelial cells from IAP-deficient animals showed reduced levels of antiapoptotic proteins as well as autophagy-related protein LC3 after allogeneic BMT. Collectively, our data highlight a novel immune cell-independent but target tissue-intrinsic role for IAPs in the regulation of gastrointestinal damage from GVHD.

DOI： 10.1182/bloodadvances.2017004242

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Siglec-G represses DAMP-mediated effects on T cells. Reviewed International journal

Tomomi Toubai, Corinne Rossi, Katherine Oravecz-Wilson, Cynthia Zajac, Chen Liu, Thomas Braun, Hideaki Fujiwara, Julia Wu, Yaping Sun, Stuart Brabbs, Hiroya Tamaki, John Magenau, Pang Zheng, Yang Liu, Pavan Reddy

JCI insight 2 ( 14 ) 2017.7

Language：English Publishing type：Research paper (scientific journal)

The role of negative regulators or suppressors of the damage-associated molecular pattern-mediated (DAMP-mediated) stimulation of innate immune responses is being increasingly appreciated. However, the presence and function of suppressors of DAMP-mediated effects on T cells, and whether they can be targeted to mitigate T cell-dependent immunopathology remain unknown. Sialic acid-binding immunoglobulin-like lectin G (Siglec-G) is a negative regulator of DAMP-mediated responses in innate immune cells, but its T cell-autonomous role is unknown. Utilizing loss-of-function-based (genetic knockout) and gain-of-function-based (agonist) approaches, we demonstrate that in the presence of certain DAMPs, Siglec-G suppressed in vitro and in vivo T cell responses. We also demonstrate that its T cell-autonomous role is critical for modulating the severity of the T cell-mediated immunopathology, graft-versus-host disease (GVHD). Enhancing the Siglec-G signaling in donor T cells with its agonist, a CD24Fc fusion protein, ameliorated GVHD while preserving sufficient graft-versus-tumor (GVT) effects in vivo. Collectively, these data demonstrate that Siglec-G is a potentially novel negative regulator of T cell responses, which can be targeted to mitigate GVHD.

DOI： 10.1172/jci.insight.92293

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A Critical Analysis of the Role of SNARE Protein SEC22B in Antigen Cross-Presentation. Reviewed International journal

S Julia Wu, Yashar S Niknafs, Stephanie H Kim, Katherine Oravecz-Wilson, Cynthia Zajac, Tomomi Toubai, Yaping Sun, Jayendra Prasad, Daniel Peltier, Hideaki Fujiwara, Israel Hedig, Nathan D Mathewson, Rami Khoriaty, David Ginsburg, Pavan Reddy

Cell reports 19 ( 13 ) 2645 - 2656 2017.6

Language：English Publishing type：Research paper (scientific journal)

Cross-presentation initiates immune responses against tumors and viral infections by presenting extracellular antigen on MHC I to activate CD8+ T cell-mediated cytotoxicity. In vitro studies in dendritic cells (DCs) established SNARE protein SEC22B as a specific regulator of cross-presentation. However, the in vivo contribution of SEC22B to cross-presentation has not been tested. To address this, we generated DC-specific Sec22b knockout (CD11c-Cre Sec22bfl/fl) mice. Contrary to the paradigm, SEC22B-deficient DCs efficiently cross-present both in vivo and in vitro. Although in vitro small hairpin RNA (shRNA)-mediated Sec22b silencing in bone-marrow-derived dendritic cells (BMDCs) reduced cross-presentation, treatment of SEC22B-deficient BMDCs with the same shRNA produced a similar defect, suggesting the Sec22b shRNA modulates cross-presentation through off-target effects. RNA sequencing of Sec22b shRNA-treated SEC22B-deficient BMDCs demonstrated several changes in the transcriptome. Our data demonstrate that contrary to the accepted model, SEC22B is not necessary for cross-presentation, cautioning against extrapolating phenotypes from knockdown studies alone.

DOI： 10.1016/j.celrep.2017.06.013

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SAG/Rbx2-Dependent Neddylation Regulates T-Cell Responses. Reviewed International journal

Nathan D Mathewson, Hideaki Fujiwara, Shin-Rong Wu, Tomomi Toubai, Katherine Oravecz-Wilson, Yaping Sun, Corinne Rossi, Cynthia Zajac, Yi Sun, Pavan Reddy

The American journal of pathology 186 ( 10 ) 2679 - 91 2016.10

Language：English Publishing type：Research paper (scientific journal)

Neddylation is a crucial post-translational modification that depends on the E3 cullin ring ligase (CRL). The E2-adapter component of the CRL, sensitive to apoptosis gene (SAG), is critical for the function of CRL-mediated ubiquitination; thus, the deletion of SAG regulates neddylation. We examined the role of SAG-dependent neddylation in T-cell-mediated immunity using multiple approaches: a novel T-cell-specific, SAG genetic knockout (KO) and chemical inhibition with small-molecule MLN4924. The KO animals were viable and showed phenotypically normal mature T-cell development. However, in vitro stimulation of KO T cells revealed significantly decreased activation, proliferation, and T-effector cytokine release, compared with WT. Using in vivo clinically relevant models of allogeneic bone marrow transplantation also demonstrated reduced proliferation and effector cytokine secretion associated with markedly reduced graft-versus-host disease. Similar in vitro and in vivo results were observed with the small-molecule inhibitor of neddylation, MLN4924. Mechanistic studies demonstrated that SAG-mediated effects in T cells were concomitant with an increase in suppressor of cytokine signaling, but not NF-κB translocation. Our studies suggest that SAG is a novel molecular target that regulates T-cell responses and that inhibiting neddylation with the clinically available small-molecule MLN4924 may represent a novel strategy to mitigate T-cell-mediated immunopathologies, such as graft-versus-host disease.

DOI： 10.1016/j.ajpath.2016.06.014

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Treatment of thrombotic microangiopathy after hematopoietic stem cell transplantation with recombinant human soluble thrombomodulin. Reviewed International journal

Hideaki Fujiwara, Yoshinobu Maeda, Yasuhisa Sando, Makoto Nakamura, Katsuma Tani, Tatsunori Ishikawa, Hisakazu Nishimori, Ken-Ichi Matsuoka, Nobuharu Fujii, Eisei Kondo, Mitsune Tanimoto

Transfusion 56 ( 4 ) 886 - 92 2016.4

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Transplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic stem cell transplantation (HSCT) remains a severe complication associated with underlying endothelial damage. TMA has a high mortality rate with no definite treatments and effective treatments are needed. STUDY DESIGN AND METHODS: The study objective was to retrospectively analyze the outcome of patients receiving recombinant human soluble thrombomodulin (rTM), which has cytoprotective effects against calcineurin inhibitor-induced endothelial cell damage, or other therapeutics for TA-TMA from 254 consecutive HSCT recipients between 2009 to 2014 at a single institution. We hypothesized that patients receiving rTM as a first-line treatment would receive a benefit. RESULTS: Sixteen patients were diagnosed as TA-TMA. Of these 16 patients, nine were treated with rTM (rTM group), and seven received treatment other than rTM (control group) as a first-line therapy. Seven of the nine patients in the rTM group recovered from TA-TMA without complications, but none in the control group recovered. The rTM group showed a significantly better overall survival after TA-TMA onset than did the control group (median, 123.0 days vs. 45.5 days, respectively; p = 0.045). The cumulative incidence of acute graft-versus-host disease was the same in both groups (56% vs. 57%, respectively; p = 0.52) on Day 100 after TA-TMA onset. CONCLUSION: This is the first report evaluating rTM administration for TA-TMA compared with previous treatments. Our data suggests that rTM might offer a better clinical outcome in patients with TA-TMA.

DOI： 10.1111/trf.13437

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Vigorous inflammatory responses in noninfectious pulmonary complication induced by donor lymphocyte infusion. Reviewed International journal

Miyuki Nishie, Nobuharu Fujii, Yusuke Mimura, Takeru Asano, Yuka Mimura-Kimura, Keisuke Aoe, Michinori Aoe, Hiromi Nakashima, Hideaki Fujiwara, Hisakazu Nishimori, Ken-Ichi Matsuoka, Eisei Kondo, Yoshinobu Maeda, Mitsune Tanimoto

Transfusion 56 ( 1 ) 231 - 6 2016.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Donor lymphocyte infusion (DLI) is used for treatment of hematologic malignancy relapse or mixed chimerism after allogeneic hematopoietic stem cell transplantation. Although graft-versus-host disease is well recognized as one of the adverse effects of DLI, there are limited reports on noninfectious pulmonary complications (NIPCs) after DLI. CASE REPORT: A 55-year-old woman with acute myeloid leukemia received DLI for conversion from recipient predominant to complete donor chimerism on Day +193 after allogeneic HSCT. Eight weeks later, she complained of dyspnea with fever; chest computed tomography revealed diffuse, bilateral, ground glass opacity and reticular appearance. She was diagnosed as having NIPC based on serum and bronchoalveolar lavage fluid (BALF) findings. She was successfully treated with prednisolone (PSL) and completely recovered. DISCUSSION: We analyzed the cell profile from the BALF and 27 cytokines and chemokines in the serum using the Bio-Plex platform. The cells consisted of recipient predominant macrophages and T cells. The serum cytokine and chemokine profile showed significant elevation of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, macrophage inflammatory protein (MIP)-1α, and MIP-1β, which declined with the improvement of symptoms after initiation of PSL treatment. CONCLUSION: Inflammatory effectors by recipient cells, rather than allogeneic responses by donor cells, played an important role in the pathogenesis of NIPCs after DLI in the present case.

DOI： 10.1111/trf.13283

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末梢血幹細胞採取時の健常人ドナーにおけるクエン酸中毒発現、電解質異常についての解析

藤井敬子, 石川立則, 吉岡尚徳, 廻勇輔, 藤原英晃, 小林優人, 高木尚江, 閘結稀, 池田亮, 浅野尚美, 小郷博昭, 藤井伸治, 大塚文男

日本輸血細胞治療学会誌 61 ( 6 ) 593 - 593 2015.12

Intravascular lymphomaの肺病変に関する検討

二宮貴一朗, 藤原英晃, 前田嘉信, 高田尚良, 吉野正, 木浦勝行, 谷本光音

日本リンパ網内系学会会誌 55 100 - 100 2015.6

Contribution of the PD-1-PD-L Pathway to Chronic Graft-Versus-Host Disease Reviewed

Hideaki Fujiwara, Koichiro Kobayashi, Hisakazu Nishimori, Masaaki Nishinohara, Sachiyo Okamoto, Ken-ichi Matsuoka, Eisei Kondo, Nobuharu Fujii, Katsuji Shinagawa, Mitsune Tanimoto, Yoshinobu Maeda

BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION 19 ( 2 ) S324 - S325 2013.4

CD5陽性限局期び漫性大細胞型リンパ腫の特徴と治療成績. Reviewed

藤原英晃, 前田嘉信, 山根弘路, 海野正俊, 矢野朋文, 増成太郎, 朝倉昇司, 品川克至, 谷本光音.

日本内科学会雑誌. 102 ( Suppl. ) 186 - 186 2013.4

High frequency of neurolymphomatosis as a relapse disease of intravascular large B-cell lymphoma. Reviewed International journal

Kosei Matsue, Brian Y Hayama, Kan-Ichi Iwama, Takafumi Koyama, Hideaki Fujiwara, Masayuki Yamakura, Masami Takeuchi, Toshihiro O'uchi

Cancer 117 ( 19 ) 4512 - 21 2011.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Intravascular large B-cell lymphoma (IVL) is characterized by lymphoma cell proliferation in the lumina of small vessels in various organs. A high incidence of neurologic symptoms associated with the central nervous system has been reported, but peripheral nerve involvement (neurolymphomatosis [NL]) rarely has been described. METHODS: The medical records from patients who were diagnosed with IVL over the past 4 years were reviewed. A diagnosis of NL was made based on the combination of neurologic symptoms and their correspondence with imaging studies, such as magnetic resonance imaging (MRI), (18) F-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography (PET/CT), and/or the histologic confirmation of lymphoma cells within the peripheral nerves, nerve root/plexuses, or cranial nerves. RESULTS: Four patients with NL were identified among 11 patients who had IVL. All cases of NL occurred as relapsed disease during or shortly after the completion of chemotherapy. Although MRI studies of the brains and whole spines revealed nerve infiltration by gadolinium enhancement in 2 patients, the technology was not sensitive enough to detect such infiltration in the remaining 2 patients. In contrast, FDG-PET/CT studies successfully revealed cranial or peripheral nerve lesions in all 4 patients and was useful for evaluating therapeutic response. Patients received treatment with high-dose methotrexate with or without other systemic chemotherapy, which achieved varied success. Further studies will be needed to determine the optimal treatment. CONCLUSIONS: Considering the rarity of IVL and NL, the current observations suggested that IVL may have a predilection not only for the vessels but also for both the central and peripheral nervous systems.

DOI： 10.1002/cncr.26090

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The utility of positron emission tomography/computed tomography in the staging of extranodal natural killer/T-cell lymphoma. Reviewed International journal

Hideaki Fujiwara, Yoshinobu Maeda, Yuichiro Nawa, Masayuki Yamakura, Daisuke Ennishi, Yukihiro Miyazaki, Katsuji Shinagawa, Masamichi Hara, Kosei Matsue, Mitsune Tanimoto

European journal of haematology 87 ( 2 ) 123 - 9 2011.8

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Natural killer (NK)/T-cell lymphoma cases are rarely discovered using positron emission tomography/computed tomography (PET/CT). We compared the utility of PET/CT and that of conventional methods (CMs; CT with IV contrast, biopsies from primary sites, and bone marrow examinations) in the staging of extranodal NK/T-cell lymphoma. Nineteen untreated patients with extranodal NK/T-cell lymphoma at three institutions were analyzed. PET/CT and CMs were applied for initial workups following diagnosis. PET/CT and CMs were compared and evaluated for their ability to detect tumor lesions and their influence on the staging and treatment strategies. In total, 116 lesions were detected by CM and PET/CT. Using PET/CT, 108 lesions (93%) were discovered. The number of nodal lesions was 28: all were positive by PET/CT and 26 (93%) by CMs. The number of extranodal lesions was 89: 84 (94%) and 54 (61%) lesions were positive by PET/CT and CMs, respectively. PET/CT was superior to CMs in detecting cutaneous lesions [31/31 lesions (100%) vs. 20/31 lesions (65%), respectively; P=0.042]. Bone marrow involvement was confirmed pathologically in only seven patients; four cases (57%) were positive by PET/CT. Using CMs, ten patients (53%) were stages I-II and nine (47%) were stages III-IV. Using PET/CT, eight patients (42%) were in stages I-II and 11 (58%) were in stages III-IV. PET/CT findings altered the stage and treatment strategy in two cases (11%). Our study demonstrated that PET/CT is a useful tool for detecting extranodal lesions in NK/T-cell lymphoma, particularly cutaneous lesions. PET/CT may therefore influence future staging and treatment strategies.

DOI： 10.1111/j.1600-0609.2011.01645.x

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Random skin biopsy and bone marrow biopsy for diagnosis of intravascular large B cell lymphoma Reviewed

MATSUE K

Ann Hematol 90 417 - 421 2011.4

Reactivation of hepatitis B virus after rituximab-containing treatment in patients with CD20-positive B-cell lymphoma. Reviewed International journal

Kosei Matsue, Shun-ichi Kimura, Yoko Takanashi, Kan-ichi Iwama, Hideaki Fujiwara, Masayuki Yamakura, Masami Takeuchi

Cancer 116 ( 20 ) 4769 - 76 2010.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Reactivation of hepatitis B virus (HBV) after rituximab-containing chemotherapy in patients with B-cell lymphoma has been recognized as a potentially serious complication in HBV immune patients. METHODS: To determine the HBV reactivation in patients treated with rituximab, a retrospective study of HBV-related markers was performed before and after rituximab-containing treatment in 261 consecutive patients with CD20-positive B-cell lymphoma. RESULTS: Of the 261 patients, 230 patients were tested for both hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc) before treatment. Fifty-six (24.3%) of 230 patients were anti-HBc positive, and the remaining 174 (75.6%) patients were anti-HBc negative. Among the 56 anti-HBc-positive patients, 5 (8.9%) became HBsAg positive (HBV reactivation), whereas none of the 174 anti-HBc-negative patients became HBsAg positive with a median follow-up of 24 months (P = .001). Among the 5 patients with HBV reactivation, 4 were negative for antibody to HBsAg (anti-HBs), and 1 patient was positive for anti-HBs. All 5 of these patients were treated successfully with entecavir on detection of HBsAg, although 4 of the 5 patients exhibited mild to moderate elevation of alanine aminotransferase. Among 56 anti-HBc-positive patients, those negative for anti-HBs had a higher probability of developing HBV reactivation compared with those positive for anti-HBs (4 of 19; 21.1% vs 1 of 37; 2.7%, P = .014). CONCLUSIONS: Patients with isolated anti-HBc are at high risk of HBV reactivation and should be monitored closely for HBsAg, anti-HBs, HBV-DNA, and transaminase levels during and after rituximab-containing treatment. Although preemptive use of entecavir enabled successful management of HBV reactivation, mild to moderate hepatic flare was still observed. These approaches should be further evaluated in a prospective study with regard to clinical usefulness, safety, and cost-effectiveness.

DOI： 10.1002/cncr.25253

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