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

DOI： 10.1182/blood-2018-02-835991

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Cyclin-dependent kinase 9 (CDK9), a subunit of the positive transcription elongation factor b (P-TEFb) complex, regulates gene transcription elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). The deregulation of CDK9/PTEFb has important implications for many cancer types. BAY 1143572 is a novel and highly selective CDK9/P-TEFb inhibitor currently being investigated in phase 1 studies. Weevaluated the therapeutic potential ofBAY1143572 in adult T-cell leukemia/lymphoma (ATL). As a result of CDK9 inhibition and subsequent inhibition of phosphorylation at serine 2 of the RNAPII CTD, BAY1143572 decreased c-Mycand Mcl-1 levels in ATL-derived or human T-cell lymphotropic virus type-1 (HTLV-1)-transformed lines and primary ATL cells tested, leading to their growth inhibition and apoptosis. Median inhibitory concentrations for BAY 1143572 in ATL-derived or HTLV-1-transformed lines (n = 8), primary ATL cells (n=11), and CD4 1 cells fromhealthy volunteers (n=5) were 0.535, 0.30, and 0.36 mM, respectively. Next, NOG mice were used as recipients of tumor cells from an ATL patient. BAY 1143572-treated ATL-bearing mice (once daily 12.5 mg/kg oral application) demonstrated significantly decreased ATL cell infiltration of the liver and bone marrow, as well as decreased human soluble interleukin-2 receptor levels in serum (reflecting the ATL tumor burden), compared with untreated mice (n = 8 for both). BAY 1143572-treated ATL-bearingmice demonstrated significantly prolonged survival compared with untreated ATL-bearing mice (n=7 for both). Collectively, this study indicates thatBAY1143572showedstrongpotential as anovel treatmentof ATL.

DOI： 10.1182/blood-2016-09-741983

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL ONCOLOGY  

Purpose
Few treatment options exist for adult T-cell leukemia/lymphoma (ATL), and the prognosis for this disease is poor. A phase I study of lenalidomide demonstrated preliminary antitumor activity in patients with relapsed ATL. The current phase II study evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed or recurrent ATL.
Patients and Methods
Patients 20 years of age or older with acute, lymphoma, or unfavorable chronic subtype ATL, who had received one or more prior anti-ATL systemic chemotherapy and achieved stable disease or better on their last anti-ATL therapy with subsequent relapse or recurrence, were eligible. Patients received oral lenalidomide 25mg/d continuously until disease progression or unacceptable toxicity. The primary end point was overall response rate; secondary end points included safety, tumor control rate (stable disease or better), time to response, duration of response, time to progression, progression-free survival, and overall survival.
Results
Objective responses were noted in 11 of 26 patients (overall response rate, 42%; 95% CI, 23% to 63%), including four complete responses and one unconfirmed complete response. The tumor control rate was 73%. The median time to response and duration of response were 1.9 months and not estimable, respectively, and the median time to progression was 3.8 months. The median progression-free survival and overall survival were 3.8 and 20.3 months, respectively. The most frequent grade >= 3 adverse events were neutropenia (65%), leukopenia (38%), lymphopenia (38%), and thrombocytopenia (23%), which were all manageable and reversible.
Conclusion
Lenalidomide demonstrated clinically meaningful antitumor activity and an acceptable toxicity profile in patients with relapsed or recurrent aggressive ATL, hinting at its potential to become a treatment option. Further investigations of lenalidomide in ATL and other mature T-cell neoplasms are warranted. (C) 2016 by American Society of Clinical Oncology

DOI： 10.1200/JCO.2016.67.7732

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n=29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n=24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

DOI： 10.1111/bjh.13338

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL ONCOLOGY  

Purpose CC chemokine receptor 4 (CCR4) is expressed by peripheral T-cell lymphomas (PTCLs) and is associated with poor outcomes. Mogamulizumab (KW-0761) is a defucosylated humanized anti-CCR4 antibody engineered to exert potent antibody-dependent cellular cytotoxicity. This multicenter phase II study evaluated the efficacy and safety of mogamulizumab in patients with relapsed PTCL and cutaneous T-cell lymphoma (CTCL).
Patients and Methods Mogamulizumab (1.0 mg/kg) was administered intravenously once per week for 8 weeks to patients with relapsed CCR4-positive PTCL or CTCL. The primary end point was the overall response rate, and the secondary end points included safety, progression-free survival (PFS), and overall survival (OS).
Results A total of 38 patients were enrolled, and 37 patients received mogamulizumab. Objective responses were noted for 13 of 37 patients (35%; 95% CI, 20% to 53%), including five patients (14%) with complete response. The median PFS was 3.0 months (95% CI, 1.6 to 4.9 months), and the median OS was not calculated. The mean maximum and trough mogamulizumab concentrations ( standard deviation) after the eighth infusion were 45.9 +/- 9.3 and 29.0 +/- 13.3 g/mL, respectively. The most common adverse events were hematologic events, pyrexia, and skin disorders, all of which were reversible and manageable.
Conclusion Mogamulizumab exhibited clinically meaningful antitumor activity in patients with relapsed PTCL and CTCL, with an acceptable toxicity profile. Further investigation of mogamulizumab for treatment of T-cell lymphoma is warranted. J Clin Oncol 32:1157-1163. (C) 2014 by American Society of Clinical Oncology

DOI： 10.1200/JCO.2013.52.0924

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

We document human T lymphotropic virus type 1 (HTLV-1) bZIP factor (HBZ)-specific CD4 T cell responses in an adult T cell leukemia/lymphoma (ATL) patient after allogeneic hematopoietic stem cell transplantation (HCT) and identified a novel HLA-DRB1* 15:01-restricted HBZ-derived naturally presented minimum epitope sequence, RRRAEKKAADVA (HBZ114-125). This peptide was also presented on HLA-DRB1*15:02, recognized by CD4 T cells. Notably, HBZ-specific CD4 T cell responses were only observed in ATL patients after allogeneic HCT (4 of 9 patients) and not in nontransplanted ATL patients (0 of 10 patients) or in asymptomatic HTLV-1 carriers (0 of 10 carriers). In addition, in one acute-type patient, HBZ-specific CD4 T cell responses were absent in complete remission before HCT, but they became detectable after allogeneic HCT. We surmise that HTLV-1 transmission from mothers to infants through breast milk in early life induces tolerance to HBZ and results in insufficient HBZ-specific T cell responses in HTLV-1 asymptomatic carriers or ATL patients. In contrast, after allogeneic HCT, the reconstituted immune system from donor-derived cells can recognize virus protein HBZ as foreign, and HBZ-specific immune responses are provoked that contribute to the graft-versus-HTLV-1 effect.

DOI： 10.4049/jimmunol.1301952

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

We report an adult T-cell leukemia/lymphoma patient suffering from Stevens-Johnson Syndrome (SJS) during mogamulizumab (humanized anti-CCR4 monoclonal antibody) treatment. There was a durable significant reduction of the CD4+CD25highFOXP3+ regulatory T (Treg) cell subset in the patient's PBMC, and the affected inflamed skin almost completely lacked FOXP3-positive cells. This implies an association between reduction of the Treg subset by mogamulizimab and occurrence of SJS. The present case should contribute not only to our understanding of human pathology resulting from therapeutic depletion of Treg cells, but also alert us to the possibility of immune-related severe adverse events such as SJS when using mogamulizumab. We are currently conducting a clinical trial of mogamulizumab for CCR4-negative solid cancers (UMIN000010050), specifically aiming to deplete Treg cells. © 2013 Japanese Cancer Association.

DOI： 10.1111/cas.12116

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL ONCOLOGY  

Purpose
Adult T-cell leukemia-lymphoma (ATL) is usually resistant to conventional chemotherapies, and there are few other treatment options. Because CC chemokine receptor 4 (CCR4) is expressed on tumor cells from most patients with ATL, KW-0761, a humanized anti-CCR4 monoclonal antibody, which markedly enhances antibody-dependent cellular cytotoxicity, was evaluated in the treatment of patients with relapsed ATL.
Patients and Methods
A multicenter phase II study of KW-0761 for patients with relapsed, aggressive CCR4-positive ATL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary end point was overall response rate, and secondary end points included progression-free and overall survival from the first dose of KW-0761. Patients received intravenous infusions of KW-0761 once per week for 8 weeks at a dose of 1.0 mg/kg.
Results
Of 28 patients enrolled onto the study, 27 received at least one infusion of KW-0761. Objective responses were noted in 13 of 26 evaluable patients, including eight complete responses, with an overall response rate of 50% (95% CI, 30% to 70%). Median progression-free and overall survival were 5.2 and 13.7 months, respectively. The mean half-life period after the eighth infusion was 422 +/- 147 hours (+/- standard deviation). The most common adverse events were infusion reactions (89%) and skin rashes (63%), which were manageable and reversible in all cases.
Conclusion
KW-0761 demonstrated clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile. Further investigation of KW-0761 for treatment of ATL and other T-cell neoplasms is warranted. J Clin Oncol 30: 837-842. (C) 2012 by American Society of Clinical Oncology

DOI： 10.1200/JCO.2011.37.3472

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: Adult T-cell leukemia/lymphoma (ATLL) has a very poor prognosis. We have developed the humanized defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody KW-0761 as a next generation immunotherapeutic agent. The first aim of the present study was to evaluate whether the antitumor activity of KW-0761 would likely be sufficient for therapeutic clinical application against ATLL. The second aim was to fully elucidate the mechanism of antibody-dependent cellular cytotoxicity (ADCC) mediated by this defucosylated monoclonal antibody.
Experimental Design: The antitumor activity of KW-0761 against ATLL cell lines was evaluated in vitro using human cells and in mice in vivo. Primary ATLL cells from 23 patients were evaluated for susceptibility to autologous ADCC with KW-0761 by two independent methods.
Results: KW-0761 showed potent antitumor activity against ATLL cell lines both in vitro and in the ATLL mouse model in vivo. In addition, KW-0761 showed potent antitumor activity mediated by highly enhanced ADCC against primary ATLL cells both in vitro and ex vivo in an autologous setting. The degree of KW-0761 ADCC against primary ATLL cells in an autologous setting was mainly determined by the amount of effector natural killer cells present, but not the amount of the target molecule CCR4 on the ATLL cell surface.
Conclusion: KW-0761 should be sufficiently active for therapeutic clinical application for ATLL. In addition, combination treatment strategies that augment natural killer cell activity should be promising for amplifying the effect of KW-0761. In the near future, the actual efficacy of KW-0761 will be established in pivotal clinical trials. Clin Cancer Res; 16(5); 1520-31. (C)2010 AACR.

DOI： 10.1158/1078-0432.CCR-09-2697

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Adult T-cell leukemia/lymphoma (ATLL) patients are highly immunocompromised, but the underlying mechanism responsible for this state remains obscure. Recent studies demonstrated that FOXP3, which is a master control gene of naturally occurring regulatory T (Treg) cells, is expressed in the tumor cells from a subset of patients with ATLL. Since most ATLL cells express both CD4 and CD25, these tumors might originate from CD4(+)CD25(+)FOXP3(+) Treg cells, based on their phenotypic characteristics. However, whether ATLL cells actually function as Treg cells has not yet been clearly demonstrated. Here, we show that ATLL cells from a subset of patients are not only hypo-responsive to T-cell receptor-mediated activation, but also suppress the proliferation of autologous CD4(+) non-ATLL cells. Furthermore, ATLL cells from this subset of patients secrete only small amounts of IFN-gamma, and suppress IFN-gamma production by autologous CD4(+) non-ATLL cells. These are the first data showing that ATLL cells from a subset of patients function as Treg cells in an autologous setting. The present study provides novel insights into understanding the immunopathogenesis of ATLL, i.e., how HTLV-1-infected cells can survive in the face of host immune responses. It also adds to our understanding of ATLL patients' severely immunocompromised state. (c) 2007 Wiley-Liss, Inc.

DOI： 10.1002/ijc.22536

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Hodgkin lymphoma (HL) is characterized by the presence of a small number of tumor cells in a rich background of inflammatory cells, but the contribution of the abundant nontumor cells to HL pathogenesis is poorly understood. We showed that migratory CD4(+) cells induced by HL cells were hyporesponsive to T-cell receptor stimulation and suppressed the activation/proliferation of the effector CD4(+) T cells in an autologous setting. We further showed that HL cells in the affected lymph nodes were surrounded by a large number of lymphocytes expressing both CC chemokine receptor 4 (CCR4) and FOXP3. These findings indicate that the migratory cells induced by HL cells function as regulatory T (Treg) cells so that these cells create a favorable environment for the tumor cells to escape from host immune system. In addition, we showed that a chimeric anti-CCR4 monoclonal antibody (mAb) could deplete CCR4(+) T cells and inhibit the migration of CD4(+)CD25(+) T cells in vitro. Recognition of the importance of CCR4(+) Treg cells in the pathogenesis of HL will allow rational design of more effective treatments, such as use of an anti-CCR4 mAb, to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.

DOI： 10.1158/0008-5472.CAN-06-0261

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

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm with dismal prognosis, and no optimal therapy has been developed. We tested the defucosylated chimeric anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, KM2760, to develop a novel immunotherapy for this refractory tumor. In the presence of peripheral blood mononuclear cells (PBMCs) from healthy adult donors, KM2760 induced CCR4-specific antibody-dependent cellular cytotoxicity (ADCC) against CCR4-positive ATLL cell lines and primary tumor cells obtained from ATLL patients. We next examined the KM2760-induced ADCC against primary ATLL cells in an autologous setting. Antibody-dependent cellular cytotoxicity mediated by autologous effector cells was generally lower than that mediated by allogeneic control effector cells. However, a robust ADCC activity was induced in some cases, which was comparable with that mediated by allogeneic effector cells. It suggests that the ATLL patients' PBMCs retain substantial ADCC-effector function, although the optimal conditions for maximal effect have not yet been determined. In addition, we also found a high expression of FoxP3 mRNA and protein, a hallmark of regulatory T cells, in ATLL cells, indicating the possibility that ATLL cells originated from regulatory T cells. KM2760 reduced FoxP3 mRNA expression in normal PBMCs along with CCR4 mRNA by lysis of CCM4+ T cells in vitro. Our data suggest not only that the CCR4 molecule could be a suitable target for the novel antibody-based therapy for patients with ATLL but also that KM2760 may induce effective tumor immunity by reducing the number of regulatory T cells.

DOI： 10.1158/1078-0432.CCR-04-0983

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

We recently reported expression of the chemokine receptors CXC chemokine receptor 3 (CXCR3) and CC chemokine receptor 4 (CCR4) in adult T-cell leukemia/ lymphoma and showed a preferential expression of CCR4 and its association with an unfavorable outcome. In the present study, we extend our adult T-cell leukemia/lymphoma study to other subtypes of T- and NK-cell lymphoma, to clarify whether a characteristic chemokine receptor expression pattern is obtained for each of the subtypes defined by the WHO classification. CXCR3 and CCR4 were rarely expressed in three well-defined subtypes, precursor T-lymphoblastic lymphoma, anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, and extranodal NK/T -cell lymphoma. A CXCR3-dominant expression pattern was observed in angioimmunoblastic T-cell lymphoma, while a CCR4-dominant expression pattern was observed in mycosis fungoides in transformation and in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. CXCR3 and CCR4 were heterogeneously expressed in peripheral T-cell lymphomas, unspecified (PTCLU). We next focused on PTCLU and analyzed the clinical significance of the chemokine receptors and their association with FoxP3, a hallmark of immunoregulatory T (Treg) cells. Multivariate analysis showed that CCR4 expression was an independent and significant unfavorable prognostic factor (P < 0.001). A significant correlation was found between mRNA expression of CCR4 and FoxP3, suggesting a possible association of CCR4-positive tumors with Treg cells and thereby with an immunocompromised state. Chemokine receptors may be useful not only for further characterization of the T- and NK-cell lymphomas but also in predicting clinical outcomes for patients. We suggest that a specific therapy targeting the CCR4 molecule may be developed as an alternative treatment for patients with CCR4-positive tumors.

DOI： 10.1158/1078-0432.CCR-04-0371

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Adult T-cell leukemia/lymphoma (ATLL) is a distinct clinical entity among mature T-cell neoplasms, and its causative agent has been confirmed to be long-term infection by human T-lymphotropic virus type 1. A recent study demonstrated frequent expression of a chemokine receptor, CC chemokine receptor (CCR)4, which is known as a Th2 marker but not CXC chemokine receptor (CXCR)3, which is known as a Th1 marker, among both ATLL- and human T-lymphotropic virus type 1-immortalized T cells. In this study, immunostaining analysis for CCR4 and CXCR3 expression in ATLL cells obtained from 103 patients with ATLL was performed, and the clinical parameters and overall survival of the CCR4-positive and -negative cases were compared. Ninety-one (88.3%) of the 103 cases were positive for CCR4 staining, whereas only 5 (4.9%) were positive for CXCR3 staining. Positivity for CCR4 was significantly associated with skin involvement (P < 0.05), although there were no significant differences in clinical characteristics between the CCR4-positive and -negative cases at the time of initial diagnosis. CCR4(+) ATLL cells may accumulate in the skin because of the expression of a CCR4 ligand, thymus and activation-regulated chemokine (TARC), on normal and inflamed cutaneous endothelia. As for survival analysis, positivity for CCR4 expression was extracted as an unfavorable prognostic factor as well as other factors, including the presence of B symptoms and extranodal involvement of more than one site. Multivariate analysis confirmed that CCR4 expression was an independent and significant prognostic factor (P < 0.05). Thus, our finding may provide a novel insight into not only the biological but also the clinical features of ATLL.

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Authorship：Corresponding author  

DOI： 10.1002/hon.3072

Authorship：Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/hon.3072

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DOI： 10.1038/s41375-022-01655-5

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CD28, one of the costimulatory molecules, has a pivotal role in T-cell activation, and its expression is strictly regulated in normal T cells. Gain-of-function genetic alterations involving CD28 have been frequently observed in adult T-cell leukemia/lymphoma (ATLL). These abnormalities, such as CD28 fusions and copy number variations, may not only confer continuous, prolonged, and enhanced CD28 signaling to downstream pathways but also induce overexpression of the CD28 protein. In this study, 120 ATLL cases were examined by immunohistochemistry for CD28 and its ligands CD80 and CD86, and their expression on tumor cells was semiquantitatively evaluated. CD28 was overexpressed in 55 (46%) cases, and CD80 or CD86 (CD80/CD86) was infrequently overexpressed in 12 (11%). Compared with non-overexpressers, CD28 overexpressers showed a higher frequency of CD28 genetic alterations and had an increased number of CD80/CD86-positive non-neoplastic cells infiltrating tumor microenvironment. In the entire ATLL patient cohort, CD28 overexpressers showed a significantly poorer overall survival (OS) compared with non-overexpressers (P = .001). The same was true for a subgroup who were treated with multidrug regimens with or without mogamulizumab. CD28 overexpression had no prognostic impact in the group who received allogeneic hematopoietic stem cell transplantation. In the multivariate analysis for OS, CD28 overexpression was selected as an independent risk factor. These results suggest ATLL patients with CD28 overexpression have more aggressive clinical course and are more refractory to treatment with multidrug chemotherapy. CD28 overexpression appears to be a novel unfavorable prognostic marker in ATLL patients, and further prospective studies are warranted to establish its prognostic significance.

DOI： 10.1111/cas.15191

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.15191

Authorship：Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/bjh.17895

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bjh.17895

Authorship：Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/bjh.17749

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bjh.17749

Language：Japanese   Publisher：Bone Marrow Transplantation  

In the original version of this article, the legends to Figs. 1 and 2 were incorrect. This has now been corrected in the PDF and HTML versions of the article.

DOI： 10.1038/s41409-020-01037-4

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Language：Japanese   Publisher：Bone Marrow Transplantation  

The outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult T-cell leukemia/lymphoma (ATL) is still unsatisfactory. To illustrate the advantages and disadvantages of each donor source, we performed a nationwide retrospective study of graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) of patients with allo-HSCT-treated ATL. One-year GRFS did not significantly differ between patients who received related bone marrow transplantation (R-BMT; 26%, n = 117), related peripheral blood stem cell transplantation (R-PBSCT; 22%, n = 225), unrelated bone marrow transplantation (UR-BMT; 26%, n = 619), and cord blood transplantation (CBT; 21%, n = 359; p = 0.09). This was attributable to a low incidence of systemically-treated chronic GVHD after CBT (9% at 1 year) and reduced non-GVHD/relapse mortality after R-PBSCT (9% at 1 year). Among patients transplanted in complete remission (CR), 1-year overall survival after CBT (52%, n = 132) was not inferior to that after R-BMT (55%, n = 51), R-PBSCT (57%, n = 79), and UR-BMT (58%, n = 280; p = 0.15), and relapse rates were equivalent among the four sources (p = 0.19). Our results suggest that all donor sources are feasible for CR patients and that GRFS provides important clues toward optimizing allo-HSCT for ATL.

DOI： 10.1038/s41409-020-00996-y

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Authorship：Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/bjh.17211

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DOI： 10.1111/cas.14658

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Authorship：Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/cjp2.180

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cjp2.180

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

The enzyme, indoleamine 2,3-dioxygenase 1 (IDO), catabolizes tryptophan (Trp) in the kynurenine (Kyn) pathway, and is important in suppressing antitumor immune responses in the tumor microenvironment. With regard to previously untreated patients with follicular lymphoma (FL), we sought to establish the prognostic significance of Trp catabolism in this disease. Serum Trp and Kyn levels in 110 patients with FL were quantified, and their relationship to different clinical parameters studied. IDO expression in the lymph nodes of affected patients was studied. Study participants included 54 males and 56 females (age range 39-86, median 62 years), showing a 5-year overall survival (OS) rate of 78.5%. Patients with a high Kyn level (5-year OS, 65.0% versus 81.7%; P = 0.026), high Kyn/Trp ratio (71.1% versus 81.7%; P = 0.002), and low hemoglobin (Hb) level (< 12.0 g/dL; P = 0.001; a component of FL international prognostic indexes) demonstrated a significantly shorter OS. Multivariate analysis included the following 10 variables: age, sex, serum β2-microglobulin, Hb, longest diameter of the largest involved node, Ann Arbor stage, serum lactate dehydrogenase, histologic grading, B symptoms, and serum Kyn/Trp ratio; a lower Hb level and a high Kyn/Trp ratio (HR, 3.239; 95% CI, 1.296-8.096) led to a significantly inferior OS. In the microenvironment, some CD11c-positive myeloid dendritic cells but not FL tumor cells were found to produce IDO. Overall, measuring levels of serum Kyn and Trp in individual patients with FL contributed to predicting their prognosis. This article is protected by copyright. All rights reserved.

DOI： 10.1002/hon.2804

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/s41388-020-01393-x

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Other Link： http://www.nature.com/articles/s41388-020-01393-x

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DOI： 10.1111/nph.16521

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DOI： 10.1002/cam4.2974

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Language：Japanese   Publisher：Journal of Low Temperature Physics  

We are developing an ultra-wideband spectroscopic instrument, DESHIMA (DEep Spectroscopic HIgh-redshift MApper), based on the technologies of an on-chip filter bank and microwave kinetic inductance detector (MKID) to investigate dusty starburst galaxies in the distant universe at millimeter and submillimeter wavelengths. An on-site experiment of DESHIMA was performed using the ASTE 10-m telescope. We established a responsivity model that converts frequency responses of the MKIDs to line-of-sight brightness temperature. We estimated two parameters of the responsivity model using a set of skydip data taken under various precipitable water vapor (PWV 0.4–3.0 mm) conditions for each MKID. The line-of-sight brightness temperature of sky is estimated using an atmospheric transmission model and the PWVs. As a result, we obtain an average temperature calibration uncertainty of 1 σ= 4 %, which is smaller than other photometric biases. In addition, the average forward efficiency of 0.88 in our responsivity model is consistent with the value expected from the geometrical support structure of the telescope. We also estimate line-of-sight PWVs of each skydip observation using the frequency response of MKIDs and confirm the consistency with PWVs reported by the Atacama Large Millimeter/submillimeter Array.

DOI： 10.1007/s10909-020-02338-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society of Hematology  

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive hematological malignancy derived from mature CD4+ T-lymphocytes. Here, we demonstrate the transcriptional regulatory network driven by 2 oncogenic transcription factors, IRF4 and NF-κB, in ATL cells. Gene expression profiling of primary ATL samples demonstrated that the IRF4 gene was more highly expressed in ATL cells than in normal T cells. Chromatin immunoprecipitation sequencing analysis revealed that IRF4-bound regions were more frequently found in super-enhancers than in typical enhancers. NF-κB was found to co-occupy IRF4-bound regulatory elements and formed a coherent feed-forward loop to coordinately regulate genes involved in T-cell functions and development. Importantly, IRF4 and NF-κB regulated several cancer genes associated with super-enhancers in ATL cells, including MYC, CCR4, and BIRC3. Genetic inhibition of BIRC3 induced growth inhibition in ATL cells, implicating its role as a critical effector molecule downstream of the IRF4-NF-κB transcriptional network.

DOI： 10.1182/blood.2019002639

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DOI： 10.1007/s12185-019-02754-3

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Language：Japanese  

DOI： 10.11406/rinketsu.61.912

PubMed

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

CCR4 is expressed on tumor cells of most patients with adult T-cell leukemia/lymphoma (ATL). Gain-of-function mutations of the CCR4 gene in ATL patients may be associated with alterations at the carboxyl terminus, a finding which led to a high efficacy anti-CCR4 antibody, mogamulizumab. Only a few studies have reported CCR4 protein expression and genomic CCR4 mutations in non-ATL T/NK-cell lymphomas. Furthermore, an association between CCR4 protein expression, genomic CCR4 mutations, and transcript CCR4 mutations has not been well analyzed. The T/NK-cell lymphomas (n = 226) enrolled in this study were examined for CCR4 expression by immunohistochemistry. CCR4 mutations in the codons 322-348 were detected by direct sequencing and a SNaPshot Multiplex assay. CCR4 protein expression was positive in 48/52 (92%) and 58/174 (33%) of ATL and non-ATL cases, respectively, and genomic CCR4 mutations were detected in 17/52 (33%) and 6/174 (3.4%), respectively. While all 17 ATL cases with genomic CCR4 mutations were positive for CCR4 protein expression, five of six mutated non-ATL cases were negative for CCR4 protein expression and transcript CCR4 mutations. This study suggests that frequencies of CCR4 expression and genomic CCR4 mutations and an association between the two may be considerably different between ATL cases and non-ATL T/NK-cell lymphomas.

DOI： 10.1007/s12185-019-02728-5

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PubMed

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

DOI： 10.1111/cas.14139

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

Infectious diseases, including those caused by fungi, remain important issues in patients receiving malignant lymphoma chemotherapy. We herein report a rare case of Exophiala dermatitidis fungemia during chemotherapy in a 67-year-old woman admitted to our hospital. She had a fever that could not be resolved despite antifungal therapy. Yeast-like fungi were detected in blood culture samples, but biochemical identification was difficult. E. dermatitidis, a black mold, was identified using time-of-flight mass spectrometry. The patient finally improved after her treatment was switched to voriconazole. Fungal infection is difficult to diagnose and treat, but this novel approach can improve patients' outcomes.

DOI： 10.2169/internalmedicine.2082-18

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PubMed

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

DOI： 10.1038/s41409-018-0400-5

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

Lenalidomide is an effective therapeutic agent for multiple myeloma (MM). However, its efficacy in the context of chromosomal abnormalities (CA) is poorly understood. We retrospectively analyzed 83 patients with relapsed/refractory (RR) MM, who received lenalidomide plus low-dose dexamethasone (Ld), in the context of CA. The median age and number of prior therapies were 69 and 2, respectively. Three, 11, 45, and 19 patients achieved complete response, very good partial response, partial response, and stable disease, respectively. Median progression-free survival (PFS) and overall survival (OS) were 11.1 and 38.8 months, respectively. Seventy-two patients were evaluated for frequently observed translocations; median PFS was 24.4 months in 20 patients with t(11;14), 13.0 months in 16 patients with t(4;14), and 3.7 months in seven patients with t(14;16). G-banded karyotype analysis detected 11 hypodiploid patients, who had shorter PFS and OS (2.5 and 6.2 months, respectively) compared to others (13.0 and 43.7 months, respectively). Hypodiploid patients showed poor clinical outcome, whereas patients with t(11;14) showed favorable outcome. In summary, the present study presents the clinical impact of chromosomal abnormalities on the outcome of Ld therapy, and contributes to understanding the appropriate choice of lenalidomide-based therapy to achieve effective treatment of RR MM.

DOI： 10.1007/s12185-019-02669-z

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

A 42-year-old female complaining of fever and night sweats was diagnosed with acute megakaryoblastic blast phase chronic myeloid leukemia (CML-BP). She had massive splenomegaly, left pleural effusion with leukemia infiltration, and moderate myelofibrosis. She received dasatinib monotherapy (140 mg/day) as for induction, after which her pleural effusion rapidly resolved and hematological remission was achieved. However, CML relapsed 4 months after starting dasatinib due to increased BCR-ABL fusion signals in the peripheral blood. The T315I mutation was also detected at the recurrence of CML. As a salvage treatment, ponatinib monotherapy (45 mg/day) was started immediately. After 5 months, BCR-ABL fusion signals decreased to 5%, and myelofibrosis improved from MF Grade 2 to 1; she then underwent allogeneic bone marrow transplantation from an unrelated donor. However, the graft failed, and cord blood transplantation (CBT) was performed. Ponatinib (15 mg/day) was continued after CBT as a maintenance treatment, with molecular complete response continuing for more than 1 year with no severe adverse events, including cardiovascular events. There is limited evidence regarding the optimal dose and schedule of ponatinib before and after allogeneic hematopoietic stem cell transplantation, especially in patients with CML-BP having T315I mutation; thus, well-designed clinical trials are warranted.

DOI： 10.1007/s12185-019-02628-8

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PubMed

Language：Japanese   Publisher：(一社)日本病理学会  

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

DOI： 10.1200/JCO.18.00501

PubMed

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

DOI： 10.1111/bjh.15123

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PubMed

Authorship：Last author  

DOI： 10.1002/cia2.12070

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

DOI： 10.3324/haematol.2018.191395

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PubMed

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

DOI： 10.1002/hon.2559

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

Web of Science

Language：English   Publisher：日本癌学会  

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

DOI： 10.1056/NEJMc1807852

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PubMed

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

DOI： 10.1111/cas.13654

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

Afuresertib (AFU), a novel inhibitor of the serine/threonine kinase AKT, has clinical efficacy as a mono­therapy against hematological malignancies and is expected to be used in combination with standard therapies for multiple myeloma (MM). To develop a more effective and less toxic combination of immunomodulatory drugs (IMiDs) for therapy, the antitumor effect of sub-optimal doses of AFU, pomalidomide plus dexamethasone (PD), and the AFU-PD combination on MM cells were examined in the present study. Two MM cell lines, XG‑7 and U266, with low sensitivity to both PD and AFU monotherapies, were subjected to these combinations and analyzed. Although the cell lines showed a slight reduction in viability with the sub‑optimal doses of each monotherapy, the combination of the treatments resulted in a reduction in cell viability and the progression of apoptosis. Co-treatment with sub-optimal doses of PD and AFU enhanced caspase activation and highly suppressed the expression of IKZF1 and IKZF3. In addition, this combination promoted the dephosphorylation and stabilization of 4EBP1, an inhibitor of eIF4E activation, which led to the impairment of eIF4E-mediated translational activity. Furthermore, AFU showed a sufficient inhibitory effect on the phosphorylation of FOXO1, a tumor suppressor, in monotherapy or in combination with PD, which may be attributable to the activation of FOXO1, the subsequent inhibition of tumor growth, and the induction of cell death. In conclusion, the combination therapy with sub-optimal doses of PD and AFU exhibited potent antitumor activity in MM cells and may provide a novel strategy for the treatment of patients who experienced intolerable toxicity or insufficient response during IMiD therapy.

DOI： 10.3892/ol.2018.8501

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Cancer cells are highly reliant on certain molecular pathways, which support their survival and proliferation. The fundamental concept of molecularly targeted therapy is to target a protein that is specifically deregulated or overexpressed in cancer cells. However, drug resistance and tumor heterogeneity are major obstacles in the development of specific inhibitors. Additionally, many driver oncogenes exert their oncogenic property via abnormal expression without having genetic mutations. Interestingly, recent accumulating evidence has demonstrated that many critical cancer genes are driven by a unique class of enhancers termed super-enhancers. Genes associated with super-enhancers are relatively more susceptible to the inhibition of general transcriptional machinery compared with genes that are regulated by typical enhancers. Cancer cells are more sensitive to treatment with small-molecule inhibitors of CDK7 or BRD4 than non-transformed cells. These findings proposed a novel strategy to identify functionally important genes as well as novel therapeutic modalities in cancer. This approach would be particularly useful for genetically complicated cancers, such as adult T-cell leukemia (ATL), whereby a large mutational burden is present, but the functional consequences of each mutation have not been well-studied. In this review, we discuss recent findings on super-enhancers, underlying mechanisms, and the efficacy of small-molecule transcriptional inhibitors in ATL.

DOI： 10.3390/molecules23051057

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc.  

Disease status at allogeneic hematopoietic cell transplantation (HCT) is an important pretransplant prognostic factor of HCT in adult T cell leukemia/lymphoma (ATL)
however, other prognostic factors, including comorbidities, were not predictive in small cohort analyses. Several scoring systems (HCT-specific comorbidity index [HCT-CI]/modified European Group for Blood and Marrow Transplantation risk score [mEBMT]) have been adopted to predict HCT outcomes in other hematologic malignancies. We retrospectively evaluated HCT-CI and mEBMT to predict nonrelapse mortality (NRM) in 824 ATL patients registered in the Japan Society for Hematopoietic Cell Transplantation TRUMP database, from 2008 until 2013. A higher HCT-CI was associated with greater NRM when comparing HCT-CI 0 versus HCT-CI 1 to 3 and HCT-CI 0 versus HCT-CI ≥ 4. A higher mEBMT score was not associated with higher NRM when comparing mEBMT 0 to 3 with 4 to 6. Because ATL patients are older and consequently at risk of additional complications, we developed an optimized prognostic index for ATL (ATL-HCT-PI) using known risk factors: age, HCT-CI, and donor–recipient sex combination. The ATL-HCT-PI scores effectively predicted the 2-year NRM (22.0%, 27.7%, and 44.4%, respectively). Therefore, the newly developed ATL-HCT-PI, in combination with other risk factors, is more useful for predicting NRM in HCT for ATL patients.

DOI： 10.1016/j.bbmt.2017.11.005

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PubMed

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

DOI： 10.1007/s12185-017-2339-5

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Impact Journals LLC  

Proteasome inhibitors (PI), mainly targeting the β5 subunit of the 20S proteasome, are widely used in the treatment of multiple myeloma (MM). However, PI resistance remains an unresolved problem in the therapy of relapsed and refractory MM. To develop a new PI that targets other proteasome subunits, we examined the anti-MM activity of a novel syringolin analog, syringolog-1, which inhibits the activity of both the β5 and β2 subunits. Syringolog-1 exhibited marked cytotoxicity against various MM cell lines and anti-tumor activity towards bortezomib (Btz)-resistant MM cells through the dual inhibition of chymotrypsin-like (β5 subunit) and trypsin-like (β2 subunit) activities. MM cells, including Btz-resistant cells, showed elevated CHOP and NOXA expression after syringolog-1 treatment, indicating the induction of excessive endoplasmic reticulum stress during syringolog-1 treatment. Similar activities of syringolog-1 were also observed in freshly prepared MM cells derived from patients. To clarify the anti-tumor mechanism of dual inhibition of both the β5 and β2 subunits of the proteasome, PSMB5 and PSMB7 were co-inhibited in MM cells. This resulted in increased apoptosis of MM cells accompanied by accumulation of ubiquitinated proteins compared to inhibition of either PSMB7 or PSMB5 alone, indicating an enhanced effect by double inhibition of β2 and β5 activities. In conclusion, this syringolin analog, a dual inhibitor of proteasome β2 and β5 activities, exhibited potent anti-tumor effects on MM cells and may be useful for overcoming Btz-resistance in the treatment of MM.

DOI： 10.18632/oncotarget.24160

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press  

Background: Medical staffoften overlook or underestimate the presence or severity of cognitive dysfunction. The purpose of this study was to clarify the frequency, clinical indicators and predictors of cognitive dysfunction among newly diagnosed older patients with hematologic malignancy receiving first-line chemotherapy. Methods: Patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were consecutively recruited. Cognitive dysfunction was evaluated using the Mini-Mental State Examination (MMSE) twice: before starting chemotherapy (T1) and 1 month later (T2). Participants also underwent a comprehensive geriatric assessment at T1. Potential clinical indicators that were associated with cognitive dysfunction were explored via cross-sectional analysis at T1. Predictors of cognitive dysfunction at T2 were also investigated among patients without cognitive dysfunction at T1. Results: A total of 145 participants participated in the study
cognitive dysfunction at T1 was present in 20%. Multivariate analysis demonstrated that lower educational attainment and poorer instrumental activities of daily living were significant clinical indicators of cognitive dysfunction. Among 99 patients who did not have cognitive dysfunction at T1 and underwent cognitive assessment at T2, 7% developed dysfunction. Subjective perception of difficulty remembering at T1 was the only factor which significantly predicted new-onset cognitive dysfunction at T2. Conclusions: The prevalence rate of cognitive dysfunction was non-negligible among older patients with hematologic malignancy before and immediately after initial chemotherapy. Attention to the clinical indicators and predictors found in this study may provide facilitate the identification of cognitive dysfunction in patients with cancer.

DOI： 10.1093/jjco/hyx159

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PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Indoleamine 2,3-dioxygenase 1 (IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway. The purpose of the present study was to determine the clinical significance of Trp catabolism in newly diagnosed Hodgkin lymphoma (HL) patients. We quantified serum Trp and Kyn in 52 HL patients, and analyzed their associations with different clinical parameters including serum soluble CD30 concentration. The IDO expression was evaluated in the patients’ affected lymph nodes. The cohort comprised 22 male and 30 female patients (age range, 15-81 years
median, 45 years), with a 5-year overall survival (OS) of 88.6%. The OS was significantly shorter for patients with a high Kyn/Trp ratio (OS at 5 years, 60.0% vs 92.2%), for those with stage IV disease, and for those with lymphocytopenia (&lt
600/mm3 and/or &lt
8% white blood cell count). The latter two parameters are components of the international prognostic score for advanced HL. In contrast, there were no significant differences in OS according to age, serum albumin, hemoglobin, sex, white blood cell count, or serum soluble CD30 (≥ or &lt
285.6 ng/mL). Multivariate analysis using the three variables stage, lymphocytopenia, and serum Kyn/Trp ratio showed that only the latter significantly affected OS. Indoleamine 2,3-dioxygenase 1 was produced by macrophages/dendritic cells, but not by HL tumor cells, and IDO levels determined by immunohistochemistry had a significant positive correlation with the serum Kyn/Trp ratio. In conclusion, quantification of serum Kyn and Trp is useful for predicting prognosis of individual HL patients.

DOI： 10.1111/cas.13432

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

DOI： 10.11406/rinketsu.59.2136

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Hematology  

<p>A 40-year-old female presented with a skin rash, hepatosplenomegaly, hypothyroidism, IgG-λ monoclonal gammopathy, slightly elevated serum VEGF levels, and >1-year history of weakness in the posterior cervical muscles. Based on these symptoms and her clinical course, she was suspected of having POEMS syndrome. However, because there was no sign of peripheral neuropathy (PN), the criteria for the diagnosis of POEMS syndrome were not met. Consequently, she continued follow-up and was under close observation as an outpatient. She complained of slowly progressive dyspnea that was identified as type 2 respiratory failure requiring non-invasive positive pressure ventilation. She received systemic chemotherapy, including thalidomide and dexamethasone, as the respiratory failure was predominantly a result of POEMS-associated PN. Although the skin eruptions improved upon treatment, respiratory failure gradually worsened, and she required mechanical ventilation. The patient was suspected of having sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance (SLONM-MGUS), because of resistant to chemotherapy and second opinion suggestion. A thigh muscle biopsy revealed the presence of nemaline rods and led to the definitive diagnosis of SLONM-MGUS. Unfortunately, she was unable to receive autologous stem cell transplantation, and finally died because of progressive respiratory failure. SLONM-MGUS is an extremely rare disease but should be considered as a critical, monoclonal-protein related condition.</p>

DOI： 10.11406/rinketsu.59.161

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science  

Bortezomib (Btz) is an active agent used to treat multiple myeloma (MM). Not all patients who receive Btz-containing therapy show a favorable response. Interaction of cellular adhesion molecules with MM and bone marrow stromal cells is crucial for the survival of MM cells. However, little is known about the role of these molecules in the sensitivity of MM to Btz-containing therapy. Thus, we evaluated the correlation between the level of cellular adhesion molecules in MM cells and the efficacy of Btz plus dexamethasone (Bd) therapy. The expression of the neural cell adhesion molecule gene (NCAM, also known as CD56), ITGA4, CXCR4, and other genes were analyzed in 74 samples of primary MM cells collected from patients before they received Bd therapy. Of the eight genes tested, expression of NCAM was lower among patients who responded poorly to Bd therapy. In vitro expression of NCAM induced by transfection of MM cells enhanced their sensitivity to Btz treatment by causing accumulation of polyubiquitinated proteins. Our results indicate that expression of NCAM is associated with better response to Btz treatment and is a promising candidate biomarker for predicting response to therapies involving Btz.

DOI： 10.1371/journal.pone.0196780

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Adult T-cell leukemia-lymphoma (ATL) is a mature T-cell malignancy associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Japan is the most endemic country for HTLV-1 and ATL in the world. Recent nationwide studies of Japanese blood donors reported that HTLV-1 carriers spread from endemic areas to non-endemic areas. Therefore, the latest information on nationwide epidemiological and clinical data for ATL is necessary to guide clinical practice. We undertook a multicenter, hospital-based survey of newly diagnosed ATL patients from 2010 to 2011. A total of 996 patients with ATL were registered from 126 hospitals across Japan. Of those, 922 (487 men and 435 women) were included in the analysis. The median age at diagnosis was 68 years (interquartile range, 60-75 years). Overall, 67.2% of ATL was diagnosed in the Kyushu-Okinawa area. The most common subtype was acute (49.5%), followed by lymphoma (25.7%), chronic (14.2%), and smoldering (10.6%). Lymphoma type was more prevalent in men (60%), whereas chronic was more prevalent in women (60%). Half of patients with lymphoma type were aged over 70 years, whereas one-third of patients with the chronic type were aged under 60 years. All of these characteristics were different from those of the previous nationwide surveys in the 1980s and 1990s. This survey clarified that half of current patients with ATL are aged over 68 years who were unable to receive intensive cytotoxic therapies. New less toxic agents for aged patients and further strategies to prevent the development of ATL from HTLV-1 carrier status are needed.

DOI： 10.1111/cas.13398

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

A number of studies have recently demonstrated that super-enhancers, which are large cluster of enhancers typically marked by a high level of acetylation of histone H3 lysine 27 and mediator bindings, are frequently associated with genes that control and define cell identity during normal development. Super-enhancers are also often enriched at cancer genes in various malignancies. The identification of such enhancers would pinpoint critical factors that directly contribute to pathogenesis. In this study, we performed enhancer profiling using primary leukemia samples from adult T-cell leukemia/lymphoma (ATL), which is a genetically heterogeneous intractable cancer. Super-enhancers were enriched at genes involved in the T-cell activation pathway, including IL2RA/CD25, CD30, and FYN, in both ATL and normal mature T cells, which reflected the origin of the leukemic cells. Super-enhancers were found at several known cancer gene loci, including CCR4, PIK3R1, and TP73, in multiple ATL samples, but not in normal mature T cells, which implicated those genes in ATL pathogenesis. A small-molecule CDK7 inhibitor, THZ1, efficiently inhibited cell growth, induced apoptosis, and downregulated the expression of super-enhancer-associated genes in ATLcells. Furthermore, enhancer profiling combined with gene expression analysis identified a previously uncharacterized gene, TIAM2, that was associated with super- enhancers in all ATL samples, but not in normal T cells. Knockdown of TIAM2 induced apoptosis in ATL cell lines, whereas overexpression of this gene promoted cell growth. Our study provides a novel strategy for identifying critical cancer genes.

DOI： 10.1182/blood-2017-06-792184

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Recognizing the significant biological and clinical heterogeneity of mature T cell and natural killer (NK)/T cell lymphomas, the American Society for Blood and Marrow Transplantation invited experts to develop clinical practice recommendations related to the role of autologous hematopoietic cell transplantation (auto-HCT) and allogeneic HCT (allo-HCT) for specific histological subtypes. We used the GRADE methodology to aid in moving from evidence to decision making and ultimately to generating final recommendations. Auto-HCT in front-line consolidation is recommended in peripheral T cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T cell lymphoma (AITL), anaplastic large cell lymphoma-anaplastic lymphoma kinase (ALCL-ALK)-negative, NK/T cell (disseminated), enteropathy-associated T cell lymphoma (EATL), and hepatosplenic lymphomas. Auto-HCT in relapsed-sensitive disease is recommended for NK/T cell (localized and disseminated), EATL, subcutaneous panniculitis-like T cell, and ALCL-ALK-positive lymphomas. Auto-HCT is also recommended for PTCL-NOS, AITL, and ALCL-ALK-negative lymphomas if not performed as front-line therapy. Auto-HCT in refractory (primary or relapsed) disease is not recommended for any of the histological subtypes discussed. Allo-HCT in front-line consolidation is recommended for NK/T cell (disseminated), adult T cell leukemia/lymphoma (ATLL; acute and lymphoma type), and hepatosplenic lymphomas. Allo-HCT for relapsed sensitive disease is recommended for PTCL-NOS, AITL, ALCL-ALK-negative, ALCL-ALK-positive, NK/T cell (localized and disseminated), ATLL (acute, lymphoma type, smoldering/chronic), mycosis fungoides/Sezary syndrome (advanced stage IIB-IVB or tumor stage/extracutaneous), EATL, subcutaneous panniculitis-like T cell, and hepatosplenic lymphoma. Allo-HCT in refractory (primary or relapsed refractory) disease is recommended for any aforementioned histological subtypes. Emerging novel therapies will likely be incorporated into the pretransplantation, peritransplantation, and post-transplantation algorithms (auto-HCT or allo-HCT) with the goals of optimizing efficacy and improving outcomes. We acknowledge that there are unique clinical scenarios not covered by these recommendations that may require individualized decisions. (C) 2017 American Society for Blood and Marrow Transplantation.

DOI： 10.1016/j.bbmt.2017.07.027

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

This phase I/II multicenter study evaluated romidepsin treatment in Japanese patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Patients aged ae&lt;yen&gt;20 years received romidepsin via a 4-h intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Phase I used a 3 + 3 design to identify any dose-limiting toxicity (DLT) for regimens of romidepsin 9 and 14 mg/m(2). The primary endpoints for phase I and II were DLT and overall response rate (ORR), respectively. Intent-to-treat patients were those who received ae&lt;yen&gt;1 romidepsin dose (PTCL, n = 48; CTCL, n = 2). In phase I, none of the patients (n = 3, 9 mg/m(2); n = 6, 14 mg/m(2)) exhibited DLT. In phase II, 40 patients with PTCL were treated with 14 mg/m(2) romidepsin. The most common treatment-emergent grade ae&lt;yen&gt;3 adverse events were lymphopenia (74%), neutropenia (54%), leukopenia (46%), and thrombocytopenia (38%). Patients in phase II showed a 43% ORR, including 25% complete responses. Median progression-free survival was 5.6 months and median duration of response was 11.1 months. This phase I/II study identified a well-tolerated dose of romidepsin, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with relapsed/refractory PTCL.
ClinicalTrials.gov Identifier NCT01456039.

DOI： 10.1007/s12185-017-2286-1

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

The present study sought to elucidate the prognosis of adult T-cell leukemia–lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti-CCR4 monoclonal antibody. Progression-free survival (PFS) and overall survival (OS) of ATL patients enrolled in two studies are herein updated, namely NCT00355472 (phase I study of mogamulizumab in relapsed patients with ATL and peripheral T-cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived &gt
3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1-year PFS was 26%, whereas median OS was 14.4 months, and 3-year OS was 23%. For patients without a rash or who developed a grade 1 rash only, median PFS was 0.8 months, and 1-year PFS was zero, with a median OS of 6.0 months, and 3-year OS of 8%. In contrast, for patients who developed a rash ≥grade 2, median PFS was 11.7 months, and 1-year PFS was 50%, with a median OS of 25.6 months, and 3-year OS of 36%. Thus, we conclude that mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune-related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of mogamulizumab.

DOI： 10.1111/cas.13343

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

Background & Aims: Occult hepatitis B virus (HBV) infection should be evaluated before systemic chemotherapy to prevent HBV reactivation-related hepatitis. We investigated HBV reactivation using high sensitivity HB surface antigen (HBsAg) chemiluminescent enzyme immunoassay (HBsAg-HQ) and ultra-high sensitive HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA).
Methods: Of 120 HBV-resolved patients with haematological malignancy receiving systemic chemotherapy from 2012 to 2015 in our hospital, 13 patients had HBV DNA reactivation (in 12/13 patients HBV DNA became quantifiable) according to HBV DNA monitoring. These patients were applied for Architect HBsAg-QT (detection limit: 50 mIU/mL), HBsAg-HQ (5 mIU/mL) and ICT-CLEIA (0.5 mIU/mL) using stored samples.
Results: When HBV DNA was firstly quantifiable by regular HBV DNA monitoring, HBsAg-QT was detected in 1/12 patients (8%), HBsAg-HQ was detected in 4/12 patients (33%) and ICT-CLEIA was detected in all 12 patients (100%), suggesting that the sensitivity of ICT-CLEIA was comparable to that of HBV DNA quantification. Interestingly, two patients were HBsAg positive by ICT-CLEIA before HBV DNA became detectable. Median difference of detectable point between HBV DNA and ICT-CLEIA was zero (range from -28 to 56 days), while median delay by HBsAg-QT or HBsAg-HQ was 52.5 days after HBV DNA became detectable. Although anti-HBs titres were high (131.9 mIU, 80.4 mIU) in two patients with escape mutations (Saa126V, Saa145R), HBsAg by ICT-CLEIA and HBV DNA were detectable concurrently.
Conclusions: ICT-CLEIA is a novel assay for HBV monitoring to prevent hepatitis caused by HBV reactivation.

DOI： 10.1111/liv.13349

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

Aim: Cognitive decline is common among older adults with cancer. The present study aimed to investigate the impact of cognitive decline on health utility value in older adults suffering from cancer.
Methods: Consecutive patients aged 65 years or older with a primary diagnosis of malignant lymphoma or multiple myeloma were recruited. Patients were asked to complete the EuroQoL-5 (EQ-5D) scale to measure health utility and the Mini-Mental State Examination to assess cognitive decline. The potential impact of cognitive decline was investigated with univariate analysis. A multivariate regression analysis was conducted to control for potential confounding factors.
Results: Complete data were obtained from 87 patients, 29% of whom had cognitive decline. The mean perpendicular to SE EQ-5D score for patients with cognitive decline was significantly lower than that for those without cognitive decline (0.67 +/- 0.04 vs 0.79 +/- 0.03, t = 2.38, P = 0.02). However, multiple regression analysis showed that cognitive decline was not significantly associated with EQ-5D scores. Female sex and lower performance scores (worse physical condition) were significantly associated with EQ-5D scores.
Conclusions: Cognitive decline may be involved in decreased health utility value in older adult patients with cancer. However, this effect does not seem to be independent, and the patient's physical condition may be a relevant confounding factor.

DOI： 10.1111/psyg.12205

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Language：Japanese   Publisher：Cancer Science  

Weekly administration of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has been shown to be a safe and effective treatment for metastatic breast cancer (MBC) in clinical studies. We conducted a multicenter, randomized, open-label phase II study to compare the efficacy and safety of weekly nab-paclitaxel and docetaxel in Japanese patients with human epidermal growth factor receptor 2-negative MBC. The primary endpoint was progression-free survival (PFS). Patients were randomized to receive nab-paclitaxel (150 mg/m2 nab-paclitaxel once per week for 3 of 4 weeks; n = 100) or docetaxel (75 mg/m2 docetaxel every 3 weeks; n = 100). The median PFS by independent radiologist assessment was 9.8 months (90% confidence interval [CI]: 8.5–11.2) for nab-paclitaxel and 11.2 months (90% CI: 8.4–13.8) for docetaxel (hazard ratio: 1.25, P = 0.363), and the median overall survival was 42.4 months and 34.0 months, respectively. The overall response rate was 56.1% for nab-paclitaxel and 52.5% for docetaxel. Adverse events in both treatment arms were similar to previous reports. Neutropenia was the most common adverse event in both arms, with 35.0% of patients in the nab-paclitaxel arm and 89.0% in the docetaxel arm experiencing grade 4 neutropenia. Grade 3 peripheral sensory neuropathy occurred in 22.0% of patients in the nab-paclitaxel and 5.0% in the docetaxel arm. In this study, although weekly nab-paclitaxel 150 mg/m2 did not show superiority in PFS compared with docetaxel, efficacy outcomes were similar in patients treated with weekly nab-paclitaxel and docetaxel.

DOI： 10.1111/cas.13221

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

DOI： 10.1111/cas.13166

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

DOI： 10.1007/s00535-016-1244-7

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Language：English   Publisher：AMER SOC HEMATOLOGY  

Web of Science

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Detection of HTLV-1 provirus using paraffin tumor sections may assist the diagnosis of adult T-cell leukemia/lymphoma (ATLL). For the detection, non-quantitative PCR assay has been reported, but its usefulness and limitations remain unclear. To our knowledge, quantitative PCR assay using paraffin tumor sections has not been reported. Using paraffin sections from ATLLs and non-ATLL T-cell lymphomas, we first performed non-quantitative PCR for HTLV-1 provirus. Next, we determined tumor ratios and carried out quantitative PCR to obtain provirus copy numbers. The results were analyzed with a simple regression model and a novel criterion, cut-off using 95 % rejection limits. Our quantitative PCR assay showed an excellent association between tumor ratios and the copy numbers (r = 0.89, P &lt; 0.0001). The 95 % rejection limits provided a statistical basis for the range for the determination of HTLV-1 involvement. Its application suggested that results of non-quantitative PCR assay should be interpreted very carefully and that our quantitative PCR assay is useful to estimate the status of HTLV-1 involvement in the tumor cases. In conclusion, our quantitative PCR assay using paraffin tumor sections may be useful for the screening of ATLL cases, especially in HTLV-1 non-endemic areas where easy access to serological testing for HTLV-1 infection is limited.

DOI： 10.1111/pin.12462

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本血液学会-東京事務局  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA(+)-M2BP) was developed recently as a predictive marker of progression to liver fibrosis and hepatocellular carcinoma (HCC) in patients seropositive for hepatitis C virus (HCV). We retrospectively analyzed 16 HCV-seropositive patients who received systemic chemotherapy for hematologic malignancies to evaluate the usefulness of WFA(+)-M2BP for predicting HCV-related complications. These were defined as the onset of significant liver damage (LD) with increased HCV RNA levels, leading to interrupted or discontinued chemotherapy or the occurrence of HCC after chemotherapy. Baseline WFA(+)-M2BP levels were determined using preserved serum samples. The median level of WFA(+)-M2BP was 1.59 [cutoff index (C.O.I.) value range 0.38-6.66]. With a median follow-up of 623 days (range 120-2404), LD and HCC were observed in three and two patients, respectively. Detectable HCV RNA and WFA(+)-M2BP aeyen2.0 C.O.I. at baseline were identified as risk factors for these HCV-related complications (P = 0.034 and P = 0.005, respectively). The sensitivity, specificity, and positive and negative predictive values of the WFA(+)-M2BP level (cutoff point: 2.0 C.O.I.) for the occurrence of HCV-related complications were 100.0, 81.8, 71.4, and 100.0 %, respectively. WFA(+)-M2BP may be a useful marker for the prediction of HCV-related complications in HCV-seropositive patients following systemic chemotherapy.

DOI： 10.1007/s12185-016-2033-z

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Language：English  

DOI： 10.1084/jem.20151493

PubMed

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

Natural killer (NK) cells are well known to be the most important effector cells mediating antibody-dependent cellular cytotoxicity (ADCC) which is an important mechanism of action of antibody drugs. We evaluated the effects of chemotherapy on the cell number and activity of NK cells from patients who received the vincristine-cyclophosphamide-doxorubicin-prednisone (VCAP), doxorubicin-ranimustine-prednisone (AMP), and vindesine-etoposide-carboplatin-prednisone (VECP) (mLSG15) or mLSG15-like (-L) regimen, which is one of the standard of cares for newly diagnosed adult T-cell leukemia-lymphoma (ATL), or the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) or CHOP-L regimen which is another standard of care for ATL and peripheral T-cell lymphoma (PTCL).
The number of lymphocytes and NK cells, and NK cell activity, were assessed using flow cytometry and a Cr-51 release assay, respectively.
A total of 26 patients with untreated ATL or PTCL were enrolled, and blood samples from 25 patients were evaluable. NK cell number in ATL decreased after mLSG15/-L treatment, and the degree of decrease in the NK cell number was more prominent just before VECP therapy (Day 15-17 of each cycle) than just before VCAP therapy (Day 1 of each cycle). The NK cell number in ATL after CHOP/-L treatment also decreased. Interestingly, the NK cell activity showed a tendency to increase after the treatment. NK cell number in PTCL did not decrease by CHOP/-L regimen, but the activity was slightly decreased after the treatment.
These results indicate that the effects of chemotherapeutic agents on NK cells vary according to the disease type and intensity of chemotherapy.

DOI： 10.1007/s00280-016-3070-2

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Language：English   Publisher：OXFORD UNIV PRESS  

The successful use of immune checkpoint inhibitors has been big breakthrough in the development of cancer immunotherapy. Anti-CTLA-4 monoclonal antibody, ipilimumab, is the first-approved immune checkpoint inhibitor and has shown durable objective responses for advanced melanoma beyond the effect of dacarbazine. Anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, are other immune checkpoint inhibitors that have demonstrated more effective results than conventional drugs in clinical trials for a variety of advanced solid tumors including melanoma, non-small cell lung carcinoma and renal carcinoma. These studies have indicated that the enhancement of anti-cancer immunity by controlling the immune suppressive environment in cancer tissues is an important issue for the development of cancer immune-therapy. Accordingly, in recent years, the enthusiasm for research of cancer immunology has shifted to studies regarding the formation of the immune suppressive environment, immune suppression mechanisms in cancer tissues and the molecules and cells involved in these pathways. Novel findings from these studies might lead to the development of cancer immunotherapy based on control of the immune suppressive environment.

DOI： 10.1093/jjco/hyv201

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Proteasome inhibitors (PIs) in combination with immunomodulatory drugs (IMiDs) have been shown to be effective against relapsed/refractory multiple myeloma (RRMM). To determine the optimal dosing schedule of once weekly bortezomib (BTZ) combined with lenalidomide (LEN) and dexamethasone (DEX), especially in the outpatient setting, we conducted a phase I dose escalation study. A 21-day cycle of BTZ 1.3 mg/m(2) on days 1 and 8, LEN 10 mg/day (cohort 1) or 15 mg/day (cohort 2) on days 1-14, and DEX 20 mg/day on days 1, 2, 8, and 9 was administered. Three patients were enrolled in each cohort. No dose-limiting toxicity was observed in either cohort. Although hematological toxicities estimated as &gt; grade 3 were common, non-hematological toxicities of grade 3 or higher were rare. Two cases of newly diagnosed peripheral neuropathy (PN) were observed, while no grade 3/4 PN was observed. Two patients achieved partial response and two achieved stable disease. The recommended doses of BTZ and LEN were determined to be 1.3 mg/m(2) and 15 mg, respectively. Combination therapy of once weekly BTZ with LEN and DEX was well tolerated and shows promise as a regimen for patients with RRMM previously treated with both PIs and IMiDs.

DOI： 10.1007/s12185-015-1925-7

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PubMed

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

Our goal was to evaluate the usefulness of labial salivary gland (LSG) biopsy for diagnosing immunoglobulin light chain (AL) amyloidosis, by comparing bone marrow and skin biopsies in the same patient population. This retrospective study included 34 consecutive patients who showed evidence of monoclonal proteins and symptoms considered to be due to amyloidosis, and who underwent a tissue biopsy from LSG between January 2005 and December 2012 at Nagoya City University Hospital. All samples of superficial tissues, including LSG, bone marrow, and skin, were independently evaluated as having amyloid deposits by a central review, which was blind to clinical information. An AL amyloidosis diagnosis was based on evidence of amyloid deposition in any biopsied tissue. Eighteen patients were diagnosed with AL amyloidosis. The sensitivity for detecting amyloid deposition was highest in biopsies of LSG at 89 %, followed by 77 % for bone marrow, and 72 % for skin. Amyloid deposition was detected in at least one superficial tissue of all the 18 patients. An LSG biopsy may be appropriate as a first-choice procedure to diagnose AL amyloidosis. Multiple biopsies of superficial tissues, including LSG, bone marrow, and skin, are recommended to increase the sensitivity for diagnosing AL amyloidosis.

DOI： 10.1007/s00277-015-2549-y

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

We report an adult T-cell leukemia-lymphoma (ATL) patient suffering from fatal reactivation of hepatitis B virus (HBV) infection after treatment with the anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, mogamulizumab. HBV reactivation occurred without liver damage in this hepatitis B surface antigen (HBsAg) negative patient, who was seropositive for antibodies against the viral core and surface antigens at baseline, after two cycles of CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone) followed by six cycles of THP-COP regimen (cyclophosphamide, pirarubicin, vincristine and prednisolone). Unexpectedly, mogamulizumab monotherapy for relapsed CCR4 positive ATL induced sudden and fatal liver failure due to HBV reactivation, despite antiviral prophylaxis with entecavir. This clinical course may not only offer important suggestions to prevent critical HBV reactivation in HBsAg positive cancer patients who receive immune-enhancing drugs such as anti-CCR4 antibody, but also provide a clue to understanding the pathogenesis of HBV reactivation following systemic chemotherapy.

DOI： 10.1111/hepr.12513

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Bortezomib (BTZ), a proteasome inhibitor, is widely used in the treatment of multiple myeloma (MM), but a fraction of patients respond poorly to this agent. To identify factors predicting the duration of progression-free survival (PFS) of MM patients on BTZ treatment, the expression of proteasome and endoplasmic reticulum (ER) stress-related genes was quantified in primary samples from patients receiving a combination of BTZ and dexamethasone (BD). Fifty-six MM patients were stratified into a group with PFS&lt;6 months (n = 33) and a second group with PFS &gt;= 6 months (n = 23). Of the 15 genes analyzed, the expression of activating transcription factor 3 (ATF3) and ATF4 was significantly lower in patients with shorter PFS (P = 0.0157 and P = 0.0085, respectively). Chromatin immunoprecipitation analysis showed that these ATFs bind each other and transactivate genes encoding the proapoptotic transcription factors, CHOP and Noxa, which promote ER stress-associated apoptosis. When either ATF3 or ATF4 expression was silenced, MM cells partially lost sensitivity to BTZ treatment. This was accompanied by lower levels of Noxa, CHOP and DR5. Thus low basal expression of ATF3 and ATF4 may attenuate BTZ-induced apoptosis. Hence, ATF3 and ATF4 could potentially be used as biomarkers to predict efficacy of BD therapy in patients with MM.

DOI： 10.1038/bcj.2015.98

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：HARBORSIDE PRESS  

Objectives: To investigate the screening performance for frailty of the Vulnerable Elders Survey-13 (VES-13) and the 2-step approach consisting of the VES-13 plus the anhedonia (loss of interest or pleasure) item from Patient Health Questionnaire-9 (PHQ-9) among older patients with newly diagnosed cancer. Methods: This study involved 106 consecutive inpatients aged 65 years or older, newly diagnosed with malignant lymphoma or multiple myeloma, just before chemotherapy initiation. The participants were administered the VES-13, and also underwent a comprehensive geriatric assessment (CGA), including for depression and 6 other geriatric conditions, using validated measures, just before initiation of chemotherapy. We defined frailty as the presence of 2 or more geriatric conditions as determined by the CGA. Receiver operating characteristic analysis was performed. The 2-step screening approach was examined by post hoc analysis. Results: The average age of the subjects was 74 years. Among the 106 subjects, 50% met the criteria for frailty. Using a cutoff score of 2 to 3 on the VES-13, a sensitivity and negative predictive value (NPV) of 72% of the screening tool was obtained for the condition of frailty. When the second step of the screening, consisting of the VES-13 plus anhedonia, was applied to the VES-13 negative patients, the sensitivity and NPV improved to 90% and 88%, respectively. Conclusions: The 2-step approach exhibited better screening performance for frailty among patients with cancer than existing methods. Large prospective studies are required in the future to confirm this ability of the 2-step approach.

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PubMed

Language：English   Publisher：JNCCN Journal of the National Comprehensive Cancer Network  

Objectives: To investigate the screening performance for frailty of the Vulnerable Elders Survey-13 (VES-13) and the 2-step approach consisting of the VES-13 plus the anhedonia (loss of interest or pleasure) item from Patient Health Questionnaire-9 (PHQ-9) among older patients with newly diagnosed cancer. Methods: This study involved 106 consecutive inpatients aged 65 years or older, newly diagnosed with malignant lymphoma or multiple myeloma, just before chemotherapy initiation. The participants were administered the VES-13, and also underwent a comprehensive geriatric assessment (CGA), including for depression and 6 other geriatric conditions, using validated measures, just before initiation of chemotherapy. We defined frailty as the presence of 2 or more geriatric conditions as determined by the CGA. Receiver operating characteristic analysis was performed. The 2-step screening approach was examined by post hoc analysis. Results: The average age of the subjects was 74 years. Among the 106 subjects, 50% met the criteria for frailty. Using a cutoff score of 2 to 3 on the VES-13, a sensitivity and negative predictive value (NPV) of 72% of the screening tool was obtained for the condition of frailty. When the second step of the screening, consisting of the VES-13 plus anhedonia, was applied to the VES-13-negative patients, the sensitivity and NPV improved to 90% and 88%, respectively. Conclusions: The 2-step approach exhibited better screening performance for frailty among patients with cancer than existing methods. Large prospective studies are required in the future to confirm this ability of the 2-step approach.

DOI： 10.6004/jnccn.2015.0180

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PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Hematology  

PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, and is an important micro-environmental factor suppressing antitumor immune responses. We investigated the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL). EXPERIMENTAL DESIGN: We quantified serum Trp and Kyn in 96 ATL patients, 38 human T-cell lymphotropic virus type-1 asymptomatic carriers (HTLV-1 ACs), and 40 healthy adult volunteers. The relationships between various clinical parameters were analyzed. IDO expression was evaluated in the affected lymph nodes of ATL patients. RESULTS: Serum Kyn concentrations and Kyn/Trp ratios were significantly higher in HTLV-1 ACs than in healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. There were no significant differences in serum Trp concentrations between ATL patients, HTLV-1 ACs and controls. IDO was possibly produced by ATL and/or cells in the microenvironment. Multivariate analyses demonstrated a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, to be significant independent detrimental prognostic factors in ATL and aggressive variant ATL. CONCLUSIONS: Quantification of serum Kyn and Trp is prognostically useful for individual ATL patients. Furthermore, ATL is an appropriate disease for testing novel cancer immunotherapies targeting IDO.

DOI： 10.11406/rinketsu.56.2295

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PubMed

Language：English   Publisher：日本癌学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: FoxP3(+) Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of CCR4-expressing FoxP3(+) CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients.
Experimental Design: We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, including Tregs, and induction of immune responses were analyzed.
Results: The results showed that KW-0761 infusion in a dose range between0.1mg/kg and 1.0mg/kgwas safe andwell tolerated. Nodose-limiting toxicitywas observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3(+) Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients.
Conclusions: The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3(+) Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses. (C) 2015 AACR.

DOI： 10.1158/1078-0432.CCR-15-0357

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of peripheral T-lymphocytes with a poor prognosis. This multicenter, two-stage, single-arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression-free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17-31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression-free survival (PFS) was 38 (95% CI
18-106) days. All patients developed ≥1 adverse events (AEs), and 80% of patients had ≥1 grade 3/4 AEs
however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients.

DOI： 10.1111/cas.12735

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PubMed

Language：Japanese   Publisher：Cancer Science  

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of peripheral T-lymphocytes with a poor prognosis. This multicenter, two-stage, single-arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression-free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17-31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression-free survival (PFS) was 38 (95% CI; 18-106) days. All patients developed ≥1 adverse events (AEs), and 80% of patients had ≥1 grade 3/4 AEs; however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients.

DOI： 10.1111/cas.12735

Scopus

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

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of peripheral T-lymphocytes with a poor prognosis. This multicenter, two-stage, single-arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression-free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17-31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression-free survival (PFS) was 38 (95% CI; 18-106) days. All patients developed &gt;= 1 adverse events (AEs), and 80% of patients had &gt;= 1 grade 3/4 AEs; however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients.

DOI： 10.1111/cas.12735

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Language：English  

DOI： 10.1111/cas.12735

PubMed

Language：Japanese   Publisher：PLoS ONE  

Background Decision-making capacity to provide informed consent regarding treatment is essential among cancer patients. The purpose of this study was to identify the frequency of decisionmaking incapacity among newly diagnosed older patients with hematological malignancy receiving first-line chemotherapy, to examine factors associated with incapacity and assess physicians' perceptions of patients' decision-making incapacity. Methods Consecutive patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were recruited. Decision-making capacity was assessed using the Structured Interview for Competency and Incompetency Assessment Testing and Ranking Inventory-Revised (SICIATRI-R). Cognitive impairment, depressive condition and other possible associated factors were also evaluated. Results Among 139 eligible patients registered for this study, 114 completed the survey. Of these, 28 (25%, 95%confidence interval [CI]: 17%-32%) were judged as having some extent of decision-making incompetency according to SICIATRI-R. Higher levels of cognitive impairment and increasing age were significantly associated with decision-making incapacity. Physicians experienced difficulty performing competency assessment (Cohen's kappa-0.54). Conclusions Decision-making incapacity was found to be a common and under-recognized problem in older patients with cancer. Age and assessment of cognitive impairment may provide the opportunity to find patients that are at a high risk of showing decision-making incapacity. Copyright:

DOI： 10.1371/journal.pone.0136163

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background
Decision-making capacity to provide informed consent regarding treatment is essential among cancer patients. The purpose of this study was to identify the frequency of decision-making incapacity among newly diagnosed older patients with hematological malignancy receiving first-line chemotherapy, to examine factors associated with incapacity and assess physicians' perceptions of patients' decision-making incapacity.
Methods
Consecutive patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were recruited. Decision-making capacity was assessed using the Structured Interview for Competency and Incompetency Assessment Testing and Ranking Inventory-Revised (SICIATRI-R). Cognitive impairment, depressive condition and other possible associated factors were also evaluated.
Results
Among 139 eligible patients registered for this study, 114 completed the survey. Of these, 28 (25%, 95% confidence interval [CI]: 17%-32%) were judged as having some extent of decision- making incompetency according to SICIATRI-R. Higher levels of cognitive impairment and increasing age were significantly associated with decision-making incapacity. Physicians experienced difficulty performing competency assessment (Cohen's kappa -0.54).
Conclusions
Decision-making incapacity was found to be a common and under-recognized problem in older patients with cancer. Age and assessment of cognitive impairment may provide the opportunity to find patients that are at a high risk of showing decision-making incapacity.

DOI： 10.1371/journal.pone.0136163

Web of Science

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background
Decision-making capacity to provide informed consent regarding treatment is essential among cancer patients. The purpose of this study was to identify the frequency of decision-making incapacity among newly diagnosed older patients with hematological malignancy receiving first-line chemotherapy, to examine factors associated with incapacity and assess physicians' perceptions of patients' decision-making incapacity.
Methods
Consecutive patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were recruited. Decision-making capacity was assessed using the Structured Interview for Competency and Incompetency Assessment Testing and Ranking Inventory-Revised (SICIATRI-R). Cognitive impairment, depressive condition and other possible associated factors were also evaluated.
Results
Among 139 eligible patients registered for this study, 114 completed the survey. Of these, 28 (25%, 95% confidence interval [CI]: 17%-32%) were judged as having some extent of decision- making incompetency according to SICIATRI-R. Higher levels of cognitive impairment and increasing age were significantly associated with decision-making incapacity. Physicians experienced difficulty performing competency assessment (Cohen's kappa -0.54).
Conclusions
Decision-making incapacity was found to be a common and under-recognized problem in older patients with cancer. Age and assessment of cognitive impairment may provide the opportunity to find patients that are at a high risk of showing decision-making incapacity.

DOI： 10.1371/journal.pone.0136163

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Language：English  

DOI： 10.1016/j.lungcan.2015.04.012

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

Reduced-intensity conditioning (RIC) has been shown to facilitate allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with comorbidities and the elderly. However, there are some concerns about transplant-related mortality (TRM). We retrospectively analyzed 37 consecutive patients who received allo-HSCT using RIC from January 2005 to December 2012 in our hospital. All patients received fludarabine (FLU), 180 mg/m2, and intravenous busulfan (BU), 6.4 mg/kg (or oral BU 8 mg/kg), with or without TBI (2 or 4 Gy). Cyclosporine or tacrolimus alone, or in combination with shortterm methotrexate therapy was used for GVHD prophylaxis. Donor sources included related peripheral blood donors (n=4), and related (n=8) and unrelated (n=25) bone marrow donors. The underlying diseases were various, and 27 patients were considered to be at standard risk. Although one patient died of early disease progression, engraftment was achieved for the others. With a median follow-up of 28.5 months, the estimated 1-year and 5-year TRMs were 13% and 20%, respectively. Five patients died of transplant-related complications, which consisted of 2 cases of acute GVHD and 1 case each of interstitial pneumonitis, bronchiolitis obliterans, and infectious pneumonia. In conclusion, FLU/BU-based RIC is tolerable, but further optimization is needed to prevent transplant-related complications.

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PubMed

Language：Japanese   Publisher：Japanese Journal of Cancer and Chemotherapy  

Reduced-intensity conditioning (RIC) has been shown to facilitate allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with comorbidities and the elderly. However, there are some concerns about transplant-related mortality (TRM). We retrospectively analyzed 37 consecutive patients who received allo-HSCT using RIC from January 2005 to December 2012 in our hospital. All patients received fludarabine (FLU), 180 mg/m2, and intravenous busulfan (BU), 6.4 mg/kg (or oral BU 8 mg/kg), with or without TBI (2 or 4 Gy). Cyclosporine or tacrolimus alone, or in combination with shortterm methotrexate therapy was used for GVHD prophylaxis. Donor sources included related peripheral blood donors (n=4), and related (n=8) and unrelated (n=25) bone marrow donors. The underlying diseases were various, and 27 patients were considered to be at standard risk. Although one patient died of early disease progression, engraftment was achieved for the others. With a median follow-up of 28.5 months, the estimated 1-year and 5-year TRMs were 13% and 20%, respectively. Five patients died of transplant-related complications, which consisted of 2 cases of acute GVHD and 1 case each of interstitial pneumonitis, bronchiolitis obliterans, and infectious pneumonia. In conclusion, FLU/BU-based RIC is tolerable, but further optimization is needed to prevent transplant-related complications.

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Language：Japanese  

PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO), an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, is increasingly being recognized as an important micro-environmental factor suppressing antitumor immune responses. The purpose of the present study was to determine the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL).
Experimental Design: We quantified serum Trp and Kyn in 96 ATL patients, 38 human T-cell lymphotropic virus type-1 asymptomatic carriers (HTLV-1 ACs), and 40 healthy adult volunteer controls. The relationships between various clinical parameters including overall survival were analyzed. IDO expression was evaluated in the affected lymph nodes of ATL patients.
Results: Serum Kyn concentrations and Kyn/Trp ratios were significantly higher in HTLV-1 ACs than healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. However, there were no significant differences in the serum Trp concentrations between ATL patients, HTLV-1 ACs, and controls. IDO was possibly produced by ATL and/or cells of the microenvironment. Multivariate analyses demonstrated that a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, were significantly independent detrimental prognostic factors in ATL, as well as in that subset of patients with aggressive variant ATL.
Conclusions: Quantification of serum Kyn and Trp is useful for predicting prognosis of an individual ATL patient. Furthermore, ATL, especially in patients with a high serum Kyn/Trp ratio, is an appropriate disease for testing novel cancer immunotherapies targeting IDO. (C)2015 AACR.

DOI： 10.1158/1078-0432.CCR-14-2275

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PubMed

Language：Japanese   Publisher：PHARMACEUTICAL SOC JAPAN  

Mogamulizumab (Moga; KW-0761) is a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody engineered to exert potent antibody-dependent cellular cytotoxicity (ADCC). A collaborative investigation with industry in preclinical studies has demonstrated in vitro and in vivo efficacy via ADCC for adult T-cell leukemia/lymphoma (ATLL) and CCR4-positive peripheral T-cell lymphoma (PTCL). In a phase I study, once-weekly administration of mogamulizumab (0.01-1.0 mg/kg) for 4 weeks was well tolerated. In a phase II study of once-weekly mogamulizumab (1.0 mg/kg) for 8 weeks in relapsed/refractory ATLL patients, an overall response rate of 50% including 30% complete response rate with a median progression-free survival of 5.2 months was observed. The drug was subsequently approved by Pharmaceuticals and Medical Devices Agency (PMDA) in March 2012. Because CCR4 is abundantly expressed on the surface of effector regulatory T cells, a phase I study is being conducted to enhance antitumor immune response in patients with solid tumors. However, approximately 60% of patients receiving mogamulizumab experience skin eruption with 19% showing grade &gt;= 3 rash. Postmarketing surveillance of mogamulizumab revealed a 3-4% incidence rate of skin-related serious adverse events (SAEs) such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Therefore we initiated a search for predictive genomic biomarkers in the blood of patients with ATLL or solid tumors prior to treatment with mogamulizumab for not only efficacy but also immune-related SAEs. We believe the results of this study may lead to safer and more efficient use of this agent in the near future.

DOI： 10.1248/yakushi.14-00230-3

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Language：Japanese   Publisher：日本骨髄腫学会  

Language：Japanese   Publisher：Microscopy  

A phase reconstruction method based on multiple scanning transmission electron microscope (STEM) images was evaluated quantitatively using image simulations. The simulation results indicated that the phase shift caused by a single atom was proportional to the 0.6th power of the atomic number Z. For a thin SrTiO3 [001] crystal, the reconstructed phase at each atomic column increased according to the specimen thickness. The STEM phase images can quantify the oxygen vacancy concentration if the thickness is less than several nanometers.

DOI： 10.1093/jmicro/dfu113

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Reactivation of hepatitis B virus (HBV) infection may occur in adult T-cell leukemia-lymphoma (ATL) patients with resolved HBV infection who receive monotherapy with the anti-CC chemokine receptor 4 monoclonal antibody, mogamulizumab. However, there is little evidence regarding the incidence and characteristics of HBV reactivation in ATL patients receiving systemic chemotherapy, including the use of this antibody. We conducted a retrospective study for 24 ATL patients with resolved HBV infection underwent regular HBV DNA monitoring to assess HBV reactivation in Nagoya City University Hospital between January 2005 and June 2013. With median HBV DNA follow-up of 238 days (range 57-1420), HBV reactivation (defined as the detection of HBV DNA) was observed in three (12.5 %) of 24 patients with resolved HBV infection. No hepatitis due to HBV reactivation occurred in those patients who were diagnosed with HBV DNA levels below 2.1 log copies/mL and who received antiviral drugs. Mogamulizumab was administered prior to HBV reactivation in two of three HBV-reactivated patients. In the mogamulizumab era, further well-designed prospective studies are warranted to estimate the incidence of HBV reactivation and to establish regular HBV DNA monitoring-guided preemptive antiviral therapy for such patients.

DOI： 10.1007/s12185-015-1750-z

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Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.104.298

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

DOI： 10.1007/s12185-014-1714-8

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Language：Japanese  

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Language：English   Publishing type：Part of collection (book)   Publisher：Springer Japan  

Recent clinical research advances in tumor immunity provide hope for the development of a novel tumor immunotherapy. Many clinical studies of cancer vaccines over the past 10 years have shown the augmentation of tumor immunity in some patients, although the clinical effects have been low. In addition, it was reported that blocking regulatory molecules involved in the immune checkpoint is important for immune activation in both in vitro and in vivo studies. In particular, studies using blocking antibodies to cytotoxic T lymphocyte-associated antigen (CTLA)-4, programmed cell death protein (PD)-1, or PD-1 ligand 1 (PD-L1) observed significant clinical effects including complete remission, suggesting that regulation of regulatory signals in the immune checkpoint is a new direction for the development of new drugs based on tumor immunity. As regulatory T cells (Tregs) also plays a key role in immune regulation, just as the regulatory molecules in the immune checkpoint become targets for the development of novel tumor immunotherapy, they may also become a target for development. Several reports have suggested that Tregs that infiltrate tumor sites as well as regulatory signals for immune checkpoints can inhibit tumor immunity, which is one explanation why treatment by cancer vaccine is limited. CC chemokine receptor 4 (CCR4) is selectively expressed on effector Tregs, and humanized monoclonal antibodies to CCR4 have been developed as a drug, ‘mogamulizumab’, to treat adult T cell leukemia/lymphoma (ATLL). Mogamulizumab depletes both ATLL cells and normal Tregs, resulting in the recovery of immune function in ATLL patients. Mogamulizumab is now expected to be accepted for use as a novel immuno-activator for tumor therapy by depletion of Tregs and is undergoing phase Ia/Ib studies for treatment of solid tumors in the lung, esophagus, intestine, ovary, and melanoma.

DOI： 10.1007/978-4-431-55327-4_17

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Language：English  

DOI： 10.1371/journal.pone.0136163

PubMed

Language：Japanese  

DOI： 10.2134/jeq2014.11.0506

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Language：Japanese  

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive tumor caused by human T-cell leukemia virus type 1. MicroRNAs (miRNAs) are closely involved in the development and progression of various tumors. Here we investigated the dysregulation of miRNAs in ATL and its clinical significance. Studies using miRNA arrays and subsequent real-time reverse transcription polymerase chain reaction showed that, in the 9 ATL cell lines examined, 1 miRNA was consistently up-regulated, whereas another 3 were consistently down-regulated, compared with normal CD4-positive lymphocytes. Next, we analyzed the prognostic impact of these 4 miRNAs in patients with aggressive-type AIL (n = 40). Of the 4 dysregulated miRNAs selected, 3 (miR-130b higher expression, miR-145 lower expression, and miR-223 lower expression) were significantly associated with a worsened overall patient survival. We found that expressions of these 3 miRNAs were correlated with each other. To clarify which of the 3 had the most significant impact on overall survival, we performed a multivariate prognostic analysis that included these 3 miRNAs, and only miR-145 lower expression was selected as an independent risk factor (P = .0005). When overexpressed in an AIL cell line in vitro, miR-145 specifically inhibited tumor cell growth. In conclusion, our study suggests that miR-145 down-regulation provides a growth advantage in ATL and is highly associated with a worsened prognosis for patients with ALT. Hence, miR-145 may be a useful prognostic marker and a potential therapeutic target for ATL. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2014.01.017

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PubMed

Language：English  

DOI： 10.1016/j.humpath.2014.01.017

PubMed

Language：Japanese   Publisher：Human Pathology  

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive tumor caused by human T-cell leukemia virus type 1. MicroRNAs (miRNAs) are closely involved in the development and progression of various tumors. Here we investigated the dysregulation of miRNAs in ATL and its clinical significance. Studies using miRNA arrays and subsequent real-time reverse transcription polymerase chain reaction showed that, in the 9 ATL cell lines examined, 1 miRNA was consistently up-regulated, whereas another 3 were consistently down-regulated, compared with normal CD4-positive lymphocytes. Next, we analyzed the prognostic impact of these 4 miRNAs in patients with aggressive-type ATL (n = 40). Of the 4 dysregulated miRNAs selected, 3 (miR-130b higher expression, miR-145 lower expression, and miR-223 lower expression) were significantly associated with a worsened overall patient survival. We found that expressions of these 3 miRNAs were correlated with each other. To clarify which of the 3 had the most significant impact on overall survival, we performed a multivariate prognostic analysis that included these 3 miRNAs, and only miR-145 lower expression was selected as an independent risk factor (P =.0005). When overexpressed in an ATL cell line in vitro, miR-145 specifically inhibited tumor cell growth. In conclusion, our study suggests that miR-145 down-regulation provides a growth advantage in ATL and is highly associated with a worsened prognosis for patients with ALT. Hence, miR-145 may be a useful prognostic marker and a potential therapeutic target for ATL. © 2014 Elsevier Inc.

DOI： 10.1016/j.humpath.2014.01.017

Scopus

Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive tumor caused by human T-cell leukemia virus type 1. MicroRNAs (miRNAs) are closely involved in the development and progression of various tumors. Here we investigated the dysregulation of miRNAs in ATL and its clinical significance. Studies using miRNA arrays and subsequent real-time reverse transcription polymerase chain reaction showed that, in the 9 ATL cell lines examined, 1 miRNA was consistently up-regulated, whereas another 3 were consistently down-regulated, compared with normal CD4-positive lymphocytes. Next, we analyzed the prognostic impact of these 4 miRNAs in patients with aggressive-type AIL (n = 40). Of the 4 dysregulated miRNAs selected, 3 (miR-130b higher expression, miR-145 lower expression, and miR-223 lower expression) were significantly associated with a worsened overall patient survival. We found that expressions of these 3 miRNAs were correlated with each other. To clarify which of the 3 had the most significant impact on overall survival, we performed a multivariate prognostic analysis that included these 3 miRNAs, and only miR-145 lower expression was selected as an independent risk factor (P = .0005). When overexpressed in an AIL cell line in vitro, miR-145 specifically inhibited tumor cell growth. In conclusion, our study suggests that miR-145 down-regulation provides a growth advantage in ATL and is highly associated with a worsened prognosis for patients with ALT. Hence, miR-145 may be a useful prognostic marker and a potential therapeutic target for ATL. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2014.01.017

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

ObjectiveThe objective of this study was to evaluate the therapeutic potential of bevacizumab with or without systemic chemotherapy for adult T-cell leukemia/lymphoma (ATL) and clarify the significance of angiogenesis for ATL pathogenesis.
MethodsNOD/Shi-scid, IL-2R(null) (NOG) mice were used as recipients of tumor cells from a patient with ATL, which engraft and proliferate in a microenvironment-dependent manner. The ATL cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures.
ResultsInjection of bevacizumab alone significantly increased necrosis and decreased vascularization in the tumor tissue. Levels of human soluble interleukin two receptor in the serum (reflecting the ATL tumor burden) of bevacizumab-treated mice were significantly lower than in untreated mice. Although bevacizumab monotherapy showed these clear anti-angiogenesis effects, it did not prolong survival. In contrast, injection of bevacizumab together with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) led to a significant prolongation of survival of the ATL mice relative to CHOP alone.
ConclusionsThis is the first report to evaluate the efficacy of bevacizumab for ATL in a tumor microenvironment-dependent model. Bevacizumab therapy combined with chemotherapy could be a valuable treatment strategy for that subgroup of ATL probably depending to a large extent on angiogenesis via vascular endothelial growth factor.

DOI： 10.1111/ejh.12231

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

The introduction of molecularly targeted drugs has increased the risk of reactivation of hepatitis B virus (HBV), which is a potentially fatal complication following anticancer chemotherapy even in patients who have previously resolved their HBV infection. CC chemokine receptor 4 (CCR4) has been identified as a novel molecular target in antibody therapy for patients with adult T-cell leukemia-lymphoma (ATL) and peripheral T-cell lymphoma, and the humanized anti-CCR4 monoclonal antibody mogamulizumab has been developed. We reported HBV reactivation of an ATL patient with previously resolved HBV infection after mogamulizumab treatment in a dose-finding study for this antibody. Our retrospective analysis using preserved samples also revealed the detailed kinetics of HBV DNA levels before and just after HBV reactivation.

DOI： 10.1111/hepr.12117

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Language：Japanese   Publisher：The Japanese Society of Hematology  

DOI： 10.11406/rinketsu.55.2257

CiNii Books

Other Link： https://jlc.jst.go.jp/DN/JLC/20000648576?from=CiNii

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQJRT-PCR. CCNDI, FGFR3 and c-MAF were positive in 44(36%), 28(23%) and 16(13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCNDI, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2013.09.026

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Allogeneic hematopoietic cell transplantation (HCT), but not autologous HCT, can provide long-term remission in some patients with adult T cell leukemia-lymphoma (ATL). We retrospectively analyzed the effects of acute graft-versus-host disease (GVHD) among the 616 patients with ATL who survived at least 30 days after allogeneic HCT with other than cord blood grafts. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated an association between grade I-II acute GVHD and favorable overall survival (OS) (hazard ratio [HR], 0.634; 95% confidence interval [Cl], 0.477 to 0.843), whereas grade III-IV acute GVHD showed a trend toward unfavorable OS (HR, 1.380; 95% Cl, 0.988 to 1.927) compared with nonacute GVHD. In subsequent multivariate analyses of patients who survived at least 100 days after HCT (n = 431), the presence of limited chronic GVHD showed a trend toward favorable OS (HR, 0.597; 95% Cl, 0.354 to 1.007), and extensive chronic GVHD had a significant effect on OS (HR, 0.585; 95% CI, 0.389 to 0.880). There were no significant interactions between myeloablative conditioning or reduced-intensity conditioning with OS even when acute GVHD was absent or present at grade I-II or grade or when chronic GVHD was absent, limited, or extensive. This study demonstrates the actual existence of graft-versus-ATL effects in patients with ATL regardless of whether myeloablative conditioning or reduced-intensity conditioning is used. (C) 2013 American Society for Blood and Marrow Transplantation.

DOI： 10.1016/j.bbmt.2013.09.014

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Language：English  

DOI： 10.1016/j.leukres.2013.09.026

PubMed

Language：Japanese   Publisher：Leukemia Research  

CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQ/RT-PCR. CCND1, FGFR3 and c-MAF were positive in 44 (36%), 28 (23%) and 16 (13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCND1, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients. © 2013 Elsevier Ltd.

DOI： 10.1016/j.leukres.2013.09.026

Scopus

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQJRT-PCR. CCNDI, FGFR3 and c-MAF were positive in 44(36%), 28(23%) and 16(13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCNDI, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2013.09.026

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Language：English  

DOI： 10.1183/09031936.00149113

PubMed

Language：Japanese  

Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.102.1744

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PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

We expanded human T-lymphotropic virus type 1 Tax-specific CTL in vitro from PBMC of three individual adult T cell leukemia/lymphoma (ATL) patients and assessed their therapeutic potential in an in vivo model using NOG mice bearing primary ATL cells from the respective three patients (ATL/NOG). In these mice established with cells from a chronic-type patient, treatment by i.p. injection of autologous Tax-CTL resulted in greater infiltration of CD8-positive T cells into each ATL lesion. This was associated with a significant decrease of ATL cell infiltration into blood, spleen, and liver. Tax-CTL treatment also significantly decreased human soluble IL-2R concentrations in the sera. In another group of ATL/NOG mice, Tax-CTL treatment led to a significant prolongation of survival time. These findings show that Tax-CTL can infiltrate the tumor site, recognize, and kill autologous ATL cells in mice in vivo. In ATL/NOG mice with cells from an acute-type patient, whose postchemotherapeutic remission continued for &gt;18 mo, antitumor efficacy of adoptive Tax-CTL therapy was also observed. However, in ATL/NOG mice from a different acute-type patient, whose ATL relapsed after 6 mo of remission, no efficacy was observed. Thus, although the therapeutic effects were different for different ATL patients, to the best of our knowledge, this is the first report that adoptive therapy with Ag-specific CTL expanded from a cancer patient confers antitumor effects, leading to significant survival benefit for autologous primary cancer cell-bearing mice in vivo. The present study contributes to research on adoptive CTL therapy, which should be applicable to several types of cancer. The Journal of Immunology, 2013, 191: 135-144.

DOI： 10.4049/jimmunol.1202692

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Language：English  

DOI： 10.1016/j.lungcan.2013.04.010

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：CIG MEDIA GROUP, LP  

In this study, we analyzed the mechanism that bath-PUVA therapy to CCR4-expressing tumor cells and regulatory T cells (Treg) in patients with mycosis fungoides(MF). The CCR4 positive cell and Treg in patient blood and the skin were analyzed. Both type of cells decreased after bath-PUVA in the skin lesion, in contrast, bath-PUVA did not significantly change the percent circulating Treg. It suggested that bath-PUVA eliminated both pathogenetically relevant cells and Treg and systemic immunosuppression was not induced.
Background: Mycosis fungoides (MF) is a malignant lymphoma characterized by expansion of CD4(+) memory T-cell clones. Infiltrating cells express CCR4, which is attracted to CC chemokine ligands 17 and 22 (thymus and activation-regulated chemokine [TARC]/CCL17 and TARC/CCL22). Bath psoralen plus ultraviolet A (PUVA) is effective against MF. In patients with psoriasis, bath-PUVA induces circulating regulatory T cells (Tregs), which suppress effector T cells. To understand the mechanisms in MF, we analyzed lesion-infiltrating cells before and after bath-PUVA therapy. Patients and Methods: Thirteen patients with MF (12 stage IB, 1 stage ill; mean age 69.2 years, range 35-87 years; 6 men, 7 women) were recruited. Results: Immunohistochemical analysis revealed that lesion CCR4-positive (CCR4) cells and Tregs significantly decreased from 105.1 +/- 164.8 cells/10(-2) mm(2) to 31.4 +/- 39.0 cells/10(-2) mm(2) and from 78.1 +/- 67.8 cells/10(-2) mm(2) to 24.7 +/- 25.0 cells/10(-2) mm(2), respectively. Serum TARC levels significantly correlated with infiltrating CD3(+) (r = 0.997), CCR4(+) (r = 0.991), and forkhead box P3-positive (Foxp3(+)) cells (r = 0.843). Circulating Tregs before bath-PUVA therapy were not significantly different from those in healthy volunteers. Bath-PUVA did not significantly change the percentage of circulating Tregs. Conclusions: Bath-PUVA decreased CCR4(+) cells and Tregs in MF lesions but did not induce circulating Tregs, which might suppress effector T cells. Direct effects through skin lesions might eliminate both pathogenetically relevant cells and Tregs. Systemic immunosuppression was not induced. (c) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clml.2012.12.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Although adult T-cell leukemia (ATL) has a poor prognosis, successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) in some cases suggests that a cellular immune-mediated strategy can be effective. So far, however, no effective target for anti-ATL immunotherapy has been defined. Here we demonstrated for the first time that human telomerase reverse transcriptase (hTERT) is a promising therapeutic target for ATL, and we developed a novel redirected T-cell-based immunotherapy targeting hTERT. hTERT messenger RNA was produced abundantly in ATL tumor cells but not in steady-state normal cells. Rearranged human leukocyte antigen-A*24:02 (HLA-A*24:02) -restricted and hTERT(461-469) nonameric peptide-specific T-cell receptor (TCR) alpha/beta genes were cloned from our previously established cytotoxic T lymphocyte clone (K3-1) and inserted into a novel retroviral TCR expression vector encoding small interfering RNAs for endogenous TCR genes in redirected T cells (hTERT-siTCR vector). Consequently, allogeneic or autologous gene-modified CD8(+) T cells prepared using the hTERT-siTCR vector successfully killed ATL tumor cells, but not normal cells including steady-state hematopoietic progenitors, in an HLA-A*24:02-restricted manner both in vitro and in vivo. Our experimental observations support the development of a novel hTERT-targeting redirected T-cell-based adoptive immunotherapy for ATL patients, especially those for whom suitable allo-HSCT donors are lacking.

DOI： 10.1182/blood-2012-11-465971

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Language：Japanese   Publisher：Respiratory Investigation  

DOI： 10.1016/j.resinv.2012.11.001

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Language：English  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

DOI： 10.1007/s12185-013-1301-4

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PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We established an angioimmunoblastic T-cell lymphoma (AITL) mouse model using NOD/Shi-scid, IL-2R gamma(null) mice as recipients. The immunohistological findings of the AITL mice were almost identical to those of patients with AITL. In addition, substantial amounts of human immunoglobulin G/A/M were detected in the sera of the AITL mice. This result indicates that AITL tumor cells helped antibody production by B cells or plasma cells. This is the first report of reconstituting follicular helper T (TFH) function in AITL cells in an experimental model, and this is consistent with the theory that TFH cell is the cell of origin of AITL tumor cells. (C) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2012.09.009

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PubMed

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

We expanded CTL specific for Tax (a human T-lymphotropic virus type-1-encoded gene product) in vitro from PBMC of several adult T-cell leukemia/lymphoma (ATL) patients, and document its potential significance as a target for ATL immunotherapy. Tax-specific CTL responses against tumor cells were restricted by Tax-expression and the appropriate human leukocyte antigen (HLA) type. Tax-specific CTL recognized HLA/Tax-peptide complexes on autologous ATL cells, even when their Tax expression was so low that it could only be detected by RT-PCR but not by flow cytometry. Recognition resulted in interferon gamma (IFN-γ) production and target cell lysis. This would be the first report that Tax-specific CTL from ATL patients specifically recognized and killed autologous tumor cells that expressed Tax. The Tax-specific CTL responded to as little as 0.01 pM of the corresponding peptide, indicating that their T-cell receptor avidity was much higher than that of any other CTL recognizing viral or other tumor antigens. This is presumably the reason why the Tax-specific CTL recognized and killed autologous ATL cells despite their very low Tax expression. In addition, cell cycle analyses and experiments with primary ATL cell-bearing mice demonstrated that ATL cells present at the site of active cell proliferation, such as in the tumor masses, expressed substantial amounts of Tax, but it was minimally expressed by the tumor cells in a quiescent state, such as in the blood. The present study not only provides a strong rationale for exploiting Tax as a possible target for ATL immunotherapy but also contributes to our understanding of the immunopathogenesis of ATL. © 2012 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2012.02371.x

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PubMed

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

We expanded CTL specific for Tax (a human T-lymphotropic virus type-1-encoded gene product) in similar to vitro from PBMC of several adult T-cell leukemia/lymphoma (ATL) patients, and document its potential significance as a target for ATL immunotherapy. Tax-specific CTL responses against tumor cells were restricted by Tax-expression and the appropriate human leukocyte antigen (HLA) type. Tax-specific CTL recognized HLA/Tax-peptide complexes on autologous ATL cells, even when their Tax expression was so low that it could only be detected by RT-PCR but not by flow cytometry. Recognition resulted in interferon gamma (IFN-?) production and target cell lysis. This would be the first report that Tax-specific CTL from ATL patients specifically recognized and killed autologous tumor cells that expressed Tax. The Tax-specific CTL responded to as little as 0.01 similar to pM of the corresponding peptide, indicating that their T-cell receptor avidity was much higher than that of any other CTL recognizing viral or other tumor antigens. This is presumably the reason why the Tax-specific CTL recognized and killed autologous ATL cells despite their very low Tax expression. In addition, cell cycle analyses and experiments with primary ATL cell-bearing mice demonstrated that ATL cells present at the site of active cell proliferation, such as in the tumor masses, expressed substantial amounts of Tax, but it was minimally expressed by the tumor cells in a quiescent state, such as in the blood. The present study not only provides a strong rationale for exploiting Tax as a possible target for ATL immunotherapy but also contributes to our understanding of the immunopathogenesis of ATL.

DOI： 10.1111/j.1349-7006.2012.02371.x

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Language：Japanese   Publisher：Cancer Science  

We expanded CTL specific for Tax (a human T-lymphotropic virus type-1-encoded gene product) in vitro from PBMC of several adult T-cell leukemia/lymphoma (ATL) patients, and document its potential significance as a target for ATL immunotherapy. Tax-specific CTL responses against tumor cells were restricted by Tax-expression and the appropriate human leukocyte antigen (HLA) type. Tax-specific CTL recognized HLA/Tax-peptide complexes on autologous ATL cells, even when their Tax expression was so low that it could only be detected by RT-PCR but not by flow cytometry. Recognition resulted in interferon gamma (IFN-γ) production and target cell lysis. This would be the first report that Tax-specific CTL from ATL patients specifically recognized and killed autologous tumor cells that expressed Tax. The Tax-specific CTL responded to as little as 0.01 pM of the corresponding peptide, indicating that their T-cell receptor avidity was much higher than that of any other CTL recognizing viral or other tumor antigens. This is presumably the reason why the Tax-specific CTL recognized and killed autologous ATL cells despite their very low Tax expression. In addition, cell cycle analyses and experiments with primary ATL cell-bearing mice demonstrated that ATL cells present at the site of active cell proliferation, such as in the tumor masses, expressed substantial amounts of Tax, but it was minimally expressed by the tumor cells in a quiescent state, such as in the blood. The present study not only provides a strong rationale for exploiting Tax as a possible target for ATL immunotherapy but also contributes to our understanding of the immunopathogenesis of ATL. © 2012 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2012.02371.x

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Adult T-cell leukemia-lymphoma (ATL) is an intractable mature T-cell neoplasm. We performed a nationwide retrospective study of allogeneic hematopoietic stem cell transplantation (HSCT) for ATL in Japan, with special emphasis on the effects of the preconditioning regimen. This is the largest study of ATL patients receiving HSCT. Median overall survival (OS) and 3-year OS of bone marrow or peripheral blood transplantation recipients (n = 586) was 9.9 months (95% confidence interval, 7.4-13.2 months) and 36% (32%-41%), respectively. These values for recipients of myeloablative conditioning (MAC; n = 280) and reduced intensity conditioning (RIC; n = 306) were 9.5 months (6.7-18.0 months) and 39% (33%-45%) and 10.0 months (7.2-14.0 months) and 34% (29%-40%), respectively. Multivariate analysis demonstrated 5 significant variables contributing to poorer OS, namely, older age, male sex, not in complete remission, poor performance status, and transplantation from unrelated donors. Although no significant difference in OS between MAC and RIC was observed, there was a trend indicating that RIC contributed to better OS in older patients. Regarding mortality, RIC was significantly associated with ATL-related mortality compared with MAC. In conclusion, allogeneic HSCT not only with MAC but also with RIC is an effective treatment resulting in long-term survival in selected patients with ATL. (Blood. 2012;120(8):1734-1741)

DOI： 10.1182/blood-2012-03-414490

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Forkhead box P1 protein is a transcription factor involved in cell signaling and regulation of gene expression and is essential for B-cell development. Forkhead box P1 overexpression has been associated with a worsened prognosis in some B-cell lymphomas. However, little is known about the clinicopathologic significance of forkhead box P1 in T-cell malignancies. In this study, immunohistochemistry for forkhead box P1 was performed in peripheral T-cell lymphoma, not otherwise specified, cases (n = 41), which were then divided into lower (n = 15) and higher (n = 26) forkhead box P1 expressers. Results of real-time quantitative reverse transcriptase polymerase chain reaction for forkhead box P1 messenger RNA supported the data on immunohistochemical forkhead box P1 expression. Forkhead box P1 overexpression in lymphoma cells was inversely associated with proliferation activity as evaluated by Ki-67 expression. Double immunostain for forkhead box P1 and a T-cell marker in normal lymph nodes showed forkhead box P1 signals in many of nonneoplastic T cells. Prognostic analysis showed that forkhead box P1 overexpression was associated with an improved overall survival of the patients with peripheral T-cell lymphoma, not otherwise specified, and was independent of the International Prognostic Index in multivariate analysis. Forkhead box P1 overexpression may be associated with less activated phenotype of the tumors and with a better prognosis in patients with peripheral T-cell lymphoma, not otherwise specified. The clinicopathologic significance of forkhead box P1 overexpression in peripheral T-cell lymphoma, not otherwise specified, may be different from that in B-cell lymphomas. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2011.10.013

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Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The IRE1 alpha-XBP1 pathway, a key component of the endoplasmic reticulum (ER) stress response, is considered to be a critical regulator for survival of multiple myeloma (MM) cells. Therefore, the availability of small-molecule inhibitors targeting this pathway would offer a new chemotherapeutic strategy for MM. Here, we screened small-molecule inhibitors of ER stress-induced XBP1 activation, and identified toyocamycin from a culture broth of an Actinomycete strain. Toyocamycin was shown to suppress thapsigargin-, tunicamycin-and 2-deoxyglucose- induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase ( PERK) activation. Furthermore, although toyocamycin was unable to inhibit IRE1 alpha phosphorylation, it prevented IRE1 alpha-induced XBP1 mRNA cleavage in vitro. Thus, toyocamycin is an inhibitor of IRE1 alpha-induced XBP1 mRNA cleavage. Toyocamycin inhibited not only ER stress-induced but also constitutive activation of XBP1 expression in MM lines as well as primary samples from patients. It showed synergistic effects with bortezomib, and induced apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human MM. Taken together, our results suggest toyocamycin as a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-MM therapy.

DOI： 10.1038/bcj.2012.26

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Scopus

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

We established a mouse model of microenvironment-dependent human lymphoma, and assessed the therapeutic potential of bevacizumab, an antitumor agent acting on the microenvironment. NOD/Shi-scid, IL-2R gamma(null) (NOG) mice were used as recipients of primary tumor cells from a patient with diffuse large B-cell lymphoma (DLBCL), which engraft and proliferate in a microenvironment-dependent manner. The lymphoma cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Injection of bevacizumab together with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) significantly increased necrosis and decreased vascularization in the tumor, compared with CHOP alone. Levels of human soluble interleukin-2 receptor (sIL2R) in the serum of bevacizumab+CHOP-treated mice (reflecting the DLBCL tumor burden) were significantly lower than in CHOP recipients. Mice receiving bevacizumab monotherapy also showed significant benefit in terms of tumor necrosis and vascularization, as well as decreased serum sIL2R concentrations. The present DLBCL model reflects the human DLBCL in vivo environment more appropriately than current mouse models using established tumor cell lines. This is the first report to evaluate the efficacy of bevacizumab in such a tumor microenvironment-dependent model. Bevacizumab may be a potential treatment strategy for DLBCL patients.

DOI： 10.1038/bcj.2012.12

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Adult T-cell leukemia/lymphoma (ATLL) is an intractable hematologic malignancy caused by human T-lymphotropic virus type 1 (HTLV-1), which infects approximately 20 million people worldwide. Here, we have explored the possible expression of cancer/testis (CT) antigens by ATLL cells, as CT antigens are widely recognized as ideal targets of cancer immunotherapy against solid tumors. A high percentage (87.7%) of ATLL cases (n = 57) expressed CT antigens at the mRNA level: NY-ESO-1 (61.4%), MAGE-A3 (31.6%), and MAGE-A4 (61.4%). CT antigen expression was confirmed by immunohistochemistry. This contrasts with other types of lymphoma or leukemia, which scarcely express these CT antigens. Humoral immune responses, particularly against NY-ESO-1, were detected in 11.6% (5 of 43) and NY-ESO-1-specific CD8(+) T-cell responses were observed in 55.6% (5 of 9) of ATLL patients. NY-ESO-1-specific CD8(+) T cells recognized autologous ATLL cells and produced effector cytokines. Thus, ATLL cells characteristically express CT antigens and therefore vaccination with CT antigens can be an effective immunotherapy of ATLL. (Blood. 2012;119(13):3097-3104)

DOI： 10.1182/blood-2011-09-379982

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PubMed

Language：English  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Adult T-cell leukemia-lymphoma (ATL) has a very poor prognosis. Since there currently are limited treatment options for ATL patients, several novel agents are being developed and tested clinically. Antibody therapy against ATL was initially started with interleukin-2 receptor alpha-subunit, CD25, as a target molecule in the late 1980s, and is currently ongoing. CC chemokine receptor 4 (CCR4) was postulated as a novel molecular target in ATL antibody therapy, and humanized anti-CCR4 mAb (KW-0761), whose Fc region was defucosylated to enhance antibody-dependent cellular cytotoxicity, was developed. A phase I study of KW-0761 in relapsed ATL and peripheral T-cell lymphoma was started in 2006, and a subsequent phase II study was completed in 2010. KW-0761 showed a clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile. The prognosis of ATL patients should be improved in the near future with clinical applications of novel treatment strategies, including those involving KW-0761 and other promising antibody therapies targeting CD25 or CD30.

DOI： 10.1007/s12185-011-0941-5

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PubMed

Language：English  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Evading immune surveillance is one of the common hallmarks of cancer. Herein we describe two major evasion mechanisms in lymphoma, focusing on regulatory T (Treg) cells and C-C chemokine receptor 4 (CCR4) expressed on these cells. First, the tumor cells themselves function as Treg cells, characterized by expression of CCR4, contributing to tumor survival by downregulating host immunity. Second, CCR4 ligands are produced by tumor cells, which attract other CCR4+ Treg cells to the vicinity of the tumor. CCR4+ adult T-cell leukemia//lymphoma is an example of the former phenomenon, and Hodgkin lymphoma of the latter, for which an almost identical immunopathogenesis has been reported in many types of cancer. Awareness of the importance of CCR4 allows the rational design of more effective cancer treatments. Accordingly, we have developed a defucosylated anti-CCR4 mAb, the first therapeutic agent targeting CCR4 to be used clinically for cancer. The therapeutic anti-CCR4 mAb represents a promising treatment method for patients with CCR4+ neoplasms by directly killing the cancer cells, but could also be used as a novel treatment strategy for many types of CCR4- cancers to overcome the suppressive effect of CCR4+ Treg cells. (Cancer Sci 2011; 102: 44-50).

DOI： 10.1111/j.1349-7006.2010.01767.x

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PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Engineering the Fc region of monoclonal antibodies (mAb) in order to enhance effector functions such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity (CDC) is likely to a be promising approach for next-generation mAb therapy. Here, we report on such an antibody, 113F, a novel CDC-enhancing variant of rituximab, and determine the tumor-associated factors influencing susceptibility to 113F-induced CDC. The latter included the quantity of complement inhibitors present, such as CD55 and CD59. We report that compared to rituximab, 113F mediated highly enhanced CDC against primary CD20-expressing lymphoma cells in vitro. Currently, a major problem in the field of immunotherapy research is the lack of suitable small animal models to evaluate human CDC in vivo. Therefore, we established a novel human tumor-bearing NOD/Shi-scid, IL-2R gamma(null) mouse model, in which human complement functions as the CDC mediator. We demonstrated that rituximab exerted significant antitumor effects via human CDC in this humanized mouse. The finding of specific localization of human C1q on CD20-expressing tumor cell membranes was consistent with the observation that human CDC indeed contributed to the antitumor effect in this model. Moreover, 113F exerted significantly more potent antitumor effects than rituximab in this in vivo model. The detection of more abundant dense signals from C1q using 113F compared to rituximab was consistent with the concept that this reagent represented a CDC-enhancing mAb. In the near future, the efficacy of this type of CDC-enhancing antibody will be determined in clinical trials in humans.

DOI： 10.1007/s00262-010-0905-2

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Bortezomib is an effective agent for treating multiple myeloma (MM). To investigate the underlying mechanisms associated with acquired resistance to this agent, we established two bortezomib-resistant MM cell lines, KMS-11/BTZ and OPM-2/BTZ, the 50% inhibitory concentration values of which were respectively 24.7- and 16.6-fold higher than their parental cell lines. No activation of caspase and BH3-only proteins such as Noxa was noted in bortezomib-resistant cells after exposure to the drug. The accumulation of polyubiquitinated proteins was reduced in bortezomib-resistant cells compared with the parental cells, associated with avoidance of catastrophic ER stress as assessed by downregulation of CHOP expression. These resistant MM cells have a unique point mutation, G322A, in the gene encoding the proteasome beta 5 subunit (PSMB5), likely resulting in conformational changes to the bortezomib-binding pocket of this subunit. KMS-11 parental cells transfected to express mutated PSMB5 also showed reduced bortezomib-induced apoptosis compared with those expressing wild-type PSMB5 or the parental cells. Expression of mutated PSMB5 was associated with the prevention of the accumulation of unfolded proteins. Thus, a fraction of MM cells may acquire bortezomib resistance by suppressing apoptotic signals through the inhibition of unfolded protein accumulation and subsequent excessive ER stress by a mutation of the PSMB5 gene. Leukemia (2010) 24, 1506-1512; doi:10.1038/leu.2010.137;published online 17 June 2010

DOI： 10.1038/leu.2010.137

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Language：English  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

It was recently reported that hepatitis B virus (HBV) reactivation had occurred in HBsAg-negative lymphoma patients who received rituximab plus steroid combination chemotherapy. HBV reactivation in myeloma patients have not been reported extensively. We describe here two cases of HBV reactivation in HBsAg-negative myeloma patients receiving systemic chemotherapy: one from the medical records of 40 patients and another from 61 patients with prospective HBV-DNA monitoring. In the first case positive for anti-HBs, HBV reactivation was diagnosed when hepatitis developed during conventional chemotherapy such as MP and MCP regimen in a relapsed patient after autologous stem cell transplantation (APBSCT); in the second case positive for anti-HBc and anti-HBs, elevation of HBV-DNA was recognized by serial HBV-DNA monitoring performed prospectively following APBSCT. Interestingly, these two cases had the reduction of the titer of anti-HBs during the treatment, followed by HBV reactivation. These clinical data suggest that the HBV-DNA monitoring is necessary for not only HBsAg-positive but also HBsAg-negative myeloma patients with anti-HBc-positive and/or anti-HBs-positive following transplantation and after conventional chemotherapy in the salvage setting. Establishment of a standard strategy to prevent HBV reactivation is important for myeloma patients receiving systemic chemotherapy.

DOI： 10.1007/s12185-010-0592-y

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL ONCOLOGY  

Purpose
KW-0761, a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody, exerts a strong antibody-dependent cellular cytotoxic effect. This phase I study assessed the safety, pharmacokinetics, recommended phase II dose and efficacy of KW-0761 in patients with relapsed CCR4-positive adult T-cell leukemia-lymphoma (ATL) or peripheral T-cell lymphoma (PTCL).
Patients and Methods
Sixteen patients received KW-0761 once a week for 4 weeks by intravenous infusion. Doses were escalated, starting at 0.01, 0.1, 0.5, and finally 1.0 mg/kg by a 3 + 3 design.
Results
Fifteen patients completed the protocol treatment. Only one patient, at the 1.0 mg/kg dose, developed grade 3 dose-limiting toxicities, skin rash, and febrile neutropenia, and grade 4 neutropenia. Other treatment-related grade 3 to 4 toxicities were lymphopenia (n = 10), neutropenia (n = 3), leukopenia (n = 2), herpes zoster (n = 1), and acute infusion reaction/cytokine release syndrome (n = 1). Neither the frequency nor severity of toxicities increased with dose escalation. The maximum tolerated dose was not reached. Therefore, the recommended phase II dose was determined to be 1.0 mg/kg. No patients had detectable levels of anti-KW-0761 antibody. The plasma maximum and trough, and the area under the curve of 0 to 7 days of KW-0761, tended to increase dose and frequency dependently. Five patients (31%; 95% CI, 11% to 59%) achieved objective responses: two complete (0.1; 1.0 mg/kg) and three partial (0.01; 2 at 1.0 mg/kg) responses.
Conclusion
KW-0761 was tolerated at all the dose levels tested, demonstrating potential efficacy against relapsed CCR4-positive ATL or PTCL. Subsequent phase II studies at the 1.0 mg/kg dose are thus warranted.

DOI： 10.1200/JCO.2009.25.3575

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PubMed

DOI： 10.11406/rinketsu.50.1671

PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

There is a lack of suitable small animal models to evaluate human Ab-dependent cellular cytotoxicity (ADCC) in vivo, because of the species incompatibility between humans and animals or due to nonspecific allogeneic immune reactions. To overcome these problems, we established a human tumor-bearing mouse model, using NOD/Shi-scid, IL-2R gamma(null) (NOG) mice as recipients, in which autologous human immune cells are engrafted and mediate ADCC but in which endogenous murine cells are unable to mediate ADCC. In the present study, we used NOG mice bearing primary adult T cell leukemia/lymphoma (ATLL) cells and a therapeutic chimeric anti-CCR4 mAb, the Fc region of which is defucosylated to enhance ADCC. We report significant antitumor activity in vivo associated with robust ADCC mediated by autologous effector cells from the same patients. The present study is the first to report a mouse model in which a potent antitumor effect of the therapeutic mAb against primary tumor cells is mediated by autologous human immune cells. Human autologous ADCC in mice in vivo was confirmed by the depletion of human immune cells before ATLL PBMC inoculation. In addition, NOG mice bearing primary ATLL cells presented features identical with patients with ATLL. In conclusion, this approach makes it possible to model the human immune system active in Ab-based immunotherapy in vivo, and thus to perform more appropriate preclinical evaluations of novel therapeutic mAb. Furthermore, the potent ADCC mediated by defucosylated anti-CCR4 mAb, observed here in vivo in humanized mice, will be exploited in clinical trials in the near future. The Journal of Immunology, 2009, 183: 4782-4791.

DOI： 10.4049/jimmunol.0900699

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

We previously reported that a dominant-positive activating mutation (Asn505) in the transmembrane domain (TMD) of c-MPL, which encodes the thrombopoietin receptor, caused familial essential thrombocythemia. Here, we show that the Asn505 mutation induces both autonomous dimerization of c-Mpl and signal activation in the absence of its ligand. Signal activation was preserved in a truncated mutant of Asn505 that lacked the extracellular domain of c-MPL. We also found that the substitution of the amino acid (AA) residue at position 505 with others of strong polarity (Glu, Asp, or Gln) also resulted in activated dimerization without ligand stimulation. Overall, these data show that the Asn505 mutation transduced the signal through the autonomous dimerization of the c-MPL protein due to strong AA polarity. This finding provides a new insight into the mechanism of disease causation by mutations in the TMD of cytokine/hematopoietic receptors. (Blood. 2009; 114: 3325-3328)

DOI： 10.1182/blood-2008-04-149047

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

We previously reported that a dominant-positive activating mutation (Asn505) in the transmembrane domain (TMD) of c-MPL, which encodes the thrombopoietin receptor, caused familial essential thrombocythemia. Here, we show that the Asn505 mutation induces both autonomous dimerization of c-Mpl and signal activation in the absence of its ligand. Signal activation was preserved in a truncated mutant of Asn505 that lacked the extracellular domain of c-MPL. We also found that the substitution of the amino acid (AA) residue at position 505 with others of strong polarity (Glu, Asp, or Gln) also resulted in activated dimerization without ligand stimulation. Overall, these data show that the Asn505 mutation transduced the signal through the autonomous dimerization of the c-MPL protein due to strong AA polarity. This finding provides a new insight into the mechanism of disease causation by mutations in the TMD of cytokine/hematopoietic receptors. (Blood. 2009; 114: 3325-3328)

DOI： 10.1182/blood-2008-04-149047

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

We previously reported that a dominant-positive activating mutation (Asn505) in the transmembrane domain (TMD) of c-MPL, which encodes the thrombopoietin receptor, caused familial essential thrombocythemia. Here, we show that the Asn505 mutation induces both autonomous dimerization of c-Mpl and signal activation in the absence of its ligand. Signal activation was preserved in a truncated mutant of Asn505 that lacked the extracellular domain of c-MPL. We also found that the substitution of the amino acid (AA) residue at position 505 with others of strong polarity (Glu, Asp, or Gln) also resulted in activated dimerization without ligand stimulation. Overall, these data show that the Asn505 mutation transduced the signal through the autonomous dimerization of the c-MPL protein due to strong AA polarity. This finding provides a new insight into the mechanism of disease causation by mutations in the TMD of cytokine/hematopoietic receptors. (Blood. 2009; 114: 3325-3328)

DOI： 10.1182/blood-2008-04-149047

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Language：Japanese   Publisher：Biotherapy  

Therapeutic monoclonal antibodies (mAb) for the treatment of cancer have begun to fulfill their promise over the last several years, as exemplified by the great success of mAb such as rituximab, trastuzumab, cetuximab, panitumumab, and bevacizumab. For a decade or more after the advent of hybridoma production (1975), important technologies required for the clinical application of therapeutic mAb, such as chimerization, humanization and the generation of fully human antibodies, continued to be developed. Currently, next-generation antibody engineering, such as ADCC or CDC enhancement, and extending the half-life of antibody in vivo is at the translational stage from laboratory to clinic. Of these approaches, we ourselves have focused on ADCC, and have developed a chimeric/humanized anti-CCR4 mAb, the Fc region of which is defucosylated. This results in highly enhanced ADCC due to increased binding affinity of the antibody to the Fcr receptor on effector cells. Based on our laboratory work on CCR4, we are currently conducting clinical trials of this defucosylated humanized anti-CCR4 mAb in Japan. We hope that our translational research on CCR4 will provide a good model for the development of anticancer agents including next-generation therapeutic mAb in Japan. In the future, further development of antibody engineering together with improvement of the infrastructure within which we carry out bench to bedside translational research would result in improved outcomes for patients with different types of cancer.

Scopus

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

There are no suitable small animal models to evaluate human antibody-dependent cellular cytotoxicity (ADCC) in vivo, due to species incompatibilities. Thus, the first aim of this study was to establish a human tumor-bearing mouse model in which human immune cells can engraft and mediate ADCC, but where the endogenous mouse immune cells cannot mediate ADCC. The second aim was to evaluate ADCC mediated in these humanized mice by the defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody (mAb) which we have developed and which is now in phase I clinical trials.
NOD/Shi-scid, IL-2R gamma(null) (NOG) mice were the recipients of human immune cells, and CCR4-expressing Hodgkin lymphoma (HL) and cutaneous T-cell lymphoma (CTCL) cell lines were used as target tumors.
Humanized mice have been established using NOG mice. The chimeric defucosylated anti-CCR4 mAb KM2760 showed potent antitumor activity mediated by robust ADCC in these humanized mice bearing the HL or CTCL cell lines. KM2760 significantly increased the number of tumor-infiltrating CD56-positive NK cells which mediate ADCC, and reduced the number of tumor-infiltrating FOXP3-positive regulatory T (Treg) cells in HL-bearing humanized mice.
Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill CCR4-expressing tumor cells, but also to overcome the suppressive effect of Treg cells on the host immune response to tumor cells. In addition, using our humanized mice, we can perform the appropriate preclinical evaluation of many types of antibody based immunotherapy.

DOI： 10.1007/s00262-008-0632-0

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Anti body-dependent cellular cytotoxicity (ADCC) is a major antitumor mechanism of action of therapeutic monoclonal antibodies (mAbs). The aim of this study was to identify tumor-associated factors which determine susceptibility to rituximab-induced ADCC. Thirty different CD20+ non-Hodgkin lymphoma cell lines were phenotyped for characteristics such as level of expression of NKG2D ligands, and the influence thereof on susceptibility to rituximab-induced ADCC was established. The present study demonstrated that tumor cell susceptibility to rituximab-induced ADCC was determined by 3 major tumor-associated factors: (i) the amount of the target molecule, CD20; (ii) the amount of the ligands for inhibitory killer Ig-like receptors, major histocompatibility complex class 1; and (iii) the amounts of some of the NKG2D ligands, especially UL16-binding protein (ULBP) 1-3. The importance of the ULBPs was confirmed using antibody blockade. In conclusion., this is the first report to show the importance for rituximab-induced ADCC of ULBPs expressed on tumor cells. The ULBPs could be valuable diagnostic biological markers and significant targets for immunotherapy to improve efficacy not only of rituximab but also of other therapeutic mAbs. (C) 2009 UICC

DOI： 10.1002/ijc.24351

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PubMed

Language：English  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Bortezomib, a proteasome inhibitor that was originally developed as an inhibitor of nuclear factor-kappa B pathways, is currently used for the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL). The mechanisms of action of this antitumor agent have been studied by several investigators. Here, we explore the underlying mechanisms of bortezomib-induced apoptosis in cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia/lymphoma (ATLL) at the level of mitochondrial membrane injury. In all cell lines including (KMS-12-PE [MM], HUT78 [CTCL], ATN1 [ATLL], and MT4 [ATLL]), antiapoptotic factors such as c-Flip and XIAP were downregulated after exposure to bortezomib, probably via inhibition of nuclear factor-kappa B signaling. In addition, among the members of the BH3-only family, upregulation of Noxa was consistently seen at both the transcriptional and protein levels in a p53-independent manner after exposure to bortezomib. Repression of Noxa by small interfering RNA partially rescued CTCL and ATLL cells from bortezomib-induced apoptosis. Immunoprecipitation assays indicated time-dependent binding of Noxa and Mcl-1 in all cell types, suggesting that functional repression of Mcl-1 led to the loss of mitochondrial outer membrane potential. Similar results were also obtained in primary tumor cells from patients with ATLL. Taken together, we conclude that bortezomib-induced apoptosis in ATLL and CTCL cells at least partly depends on the upregulation of Noxa and functional repression of Mcl-1, as is also the case in MM and malignant melanoma. (Cancer Sci 2009; 100: 341-348).

DOI： 10.1111/j.1349-7006.2008.01038.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Bortezomib, a proteasome inhibitor that was originally developed as an inhibitor of nuclear factor-kappa B pathways, is currently used for the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL). The mechanisms of action of this antitumor agent have been studied by several investigators. Here, we explore the underlying mechanisms of bortezomib-induced apoptosis in cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia/lymphoma (ATLL) at the level of mitochondrial membrane injury. In all cell lines including (KMS-12-PE [MM], HUT78 [CTCL], ATN1 [ATLL], and MT4 [ATLL]), antiapoptotic factors such as c-Flip and XIAP were downregulated after exposure to bortezomib, probably via inhibition of nuclear factor-kappa B signaling. In addition, among the members of the BH3-only family, upregulation of Noxa was consistently seen at both the transcriptional and protein levels in a p53-independent manner after exposure to bortezomib. Repression of Noxa by small interfering RNA partially rescued CTCL and ATLL cells from bortezomib-induced apoptosis. Immunoprecipitation assays indicated time-dependent binding of Noxa and Mcl-1 in all cell types, suggesting that functional repression of Mcl-1 led to the loss of mitochondrial outer membrane potential. Similar results were also obtained in primary tumor cells from patients with ATLL. Taken together, we conclude that bortezomib-induced apoptosis in ATLL and CTCL cells at least partly depends on the upregulation of Noxa and functional repression of Mcl-1, as is also the case in MM and malignant melanoma. (Cancer Sci 2009; 100: 341-348).

DOI： 10.1111/j.1349-7006.2008.01038.x

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DOI： 10.11406/rinketsu.50.1671

Language：English  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Multiple myeloma (MM) remains an incurable disease and further development of novel agents is needed. Because constitutive expression of topoisomerase I (TopoI) in MM cells and the efficacy of SN-38, an active metabolite of irinotecan (CPT-11), have been reported, we investigated the therapeutic potential of CPT-11. Of the eight MM cell lines analyzed, four showed 50% inhibitory concentration values of less than 2 mu g/mL for CPT-11 and less than 2 ng/mL for SN-38. This efficacy was partly explained by the high expression level of human carboxylesterase-2 (hCE-2) in MM cells. Interestingly, high expression of hCE-2 represented the nature of normal plasma cells, suggesting that hCE-2 could efficiently generate SN-38 within the plasma cells. As expected, higher sensitivity to CPT-11 was observed in hCE-2-overexpressing U266 cells than mock U266 cells. On the other hand, the expression levels of hCE-1, TopoI, UGT1A and ABCG2 did not seem to be associated with the sensitivity of MM cells to CPT-11. In a murine xenograft model inoculated s.c. with RPMI8226 cells, administration of CPT-11 alone significantly reduced the tumor volume. When a combination of CPT-11 and bortezomib was administered, the subcutaneous tumors completely disappeared. Thus, clinical trials on CPT-11 in patients with relapsed or refractory MM are warranted. (Cancer Sci 2008; 99: 2309-2314).

DOI： 10.1111/j.1349-7006.2008.00936.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Multiple myeloma (MM) remains an incurable disease and further development of novel agents is needed. Because constitutive expression of topoisomerase I (TopoI) in MM cells and the efficacy of SN-38, an active metabolite of irinotecan (CPT-11), have been reported, we investigated the therapeutic potential of CPT-11. Of the eight MM cell lines analyzed, four showed 50% inhibitory concentration values of less than 2 mu g/mL for CPT-11 and less than 2 ng/mL for SN-38. This efficacy was partly explained by the high expression level of human carboxylesterase-2 (hCE-2) in MM cells. Interestingly, high expression of hCE-2 represented the nature of normal plasma cells, suggesting that hCE-2 could efficiently generate SN-38 within the plasma cells. As expected, higher sensitivity to CPT-11 was observed in hCE-2-overexpressing U266 cells than mock U266 cells. On the other hand, the expression levels of hCE-1, TopoI, UGT1A and ABCG2 did not seem to be associated with the sensitivity of MM cells to CPT-11. In a murine xenograft model inoculated s.c. with RPMI8226 cells, administration of CPT-11 alone significantly reduced the tumor volume. When a combination of CPT-11 and bortezomib was administered, the subcutaneous tumors completely disappeared. Thus, clinical trials on CPT-11 in patients with relapsed or refractory MM are warranted. (Cancer Sci 2008; 99: 2309-2314).

DOI： 10.1111/j.1349-7006.2008.00936.x

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

Authorship：Corresponding author   Language：English   Publisher：BLACKWELL PUBLISHING  

DOI： 10.1111/j.1365-2141.2007.06947.x

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: Sezary syndrome (SS) and Mycosis fungoides (MF) in the advanced stage have dismal prognoses. Because CC chemokine receptor 4 (CCR4) has an important role in the skin-homing capacity of MF/SS cells, we postulated that anti-CCR4 monoclonal antibody (mAb) could represent a novel therapeutic agent against aggressive/refractory MF/SS.
Experimental Design: The defucosylated next-generation therapeutic mAb KM2760 induces enhanced antibody-dependent cellular cytotoxicity (ADCC). Here, we assessed the therapeutic potential of this antibody against aggressive MF/SS tumor cells in vitro and in animal models in vivo.
Results: KM2760 induced robust ADCC by peripheral blood mononuclear cell (PBMC) from healthy controls against a MF/SS cell line as well as against primary tumor cells from patients with aggressive MF/SS. KM2760 also showed significant antitumor activity in disseminated and nondisseminated MF/SS mouse models. In addition, similar to 30% of autologous MF/SS tumor cells were killed in in vitro assays of KM2760-induced ADCC mediated by patients' PBMC after only 4 h, despite the low numbers of natural killer cells present in these PBMCs. It is also shown that ADCC induced by defucosylated therapeutic mAb can be greatly augmented by the immunomodulatory cytokines interleukin-12, IFN-alpha-2b, and IFN-gamma.
Conclusions: The present study has encouraged us in the conducting of a phase I clinical trial of a completely defucosylated anti-CCR4 mAb in patients with CCR 4-positive T-cell lymphomas, including aggressive MF/SS (ClinicalTrials.gov identifier: NCT00355472). In the near future, the efficacy not only of defucosylated anti-CCR4 mAb single-agent treatment but also of combination therapy with immunomodulatory cytokines will be clinically established to target aggressive/refractory MF/SS.

DOI： 10.1158/1078-0432.CCR-07-1324

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PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We investigated the clinical significance of a blood eosinophilia in a cohort of 158 consecutive patients with adult T-cell leukemia/lymphoma (ATLL), and multivariate analysis revealed that a blood eosinophilia was an independent and a significant unfavorable prognostic factor. Interestingly. a blood eosinophilia was independent of serum LDH level, which might reflect the tumor burden. The present study shows that measurement of the blood eosinophil count is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients. (C) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2006.10.017

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Language：Japanese  

Web of Science

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

In anaplastic large-cell lymphomas positive for anaplastic lymphoma kinase (ALK) protein, the ALK gene is most commonly fused to the NPM gene, and less commonly to TPM3, TFG, ATIC, and other rare genes. Although this lymphoma is generally associated with a favorable clinical outcome, 25% of the patients die of the disease within 5 years. In this study, we developed three assays, all of which can be used with archival formalin-fixed, paraffin-embedded tissues: (1) a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay for various X-ALK fusion genes, (2) a 50 rapid amplification of cDNA ends (RACE) assay to identify unknown fusion partners, and (3) a real-time RT-PCR assay to quantify the amount of the NPM-ALK fusion transcript. In 26 cases of ALK(+) anaplastic large-cell lymphoma, the RT-PCR assay showed that the ALK was fused to NPM in 21 cases, to TPM3 in three, and to TFG in one. The 50 RACE assay detected ATIC-ALK fusion in the remaining case. The real-time quantitative RT-PCR assay showed that the NPM-ALK transcript was over expressed in four of 20 quantifiable cases. Patients with NPM-ALK overexpression showed a significantly unfavorable overall survival compared with those with a low expression of this transcript. The RT-PCR and 50 RACE assays developed here may be useful for identification of known and unknown gene partners fused to the ALK gene. Overexpression of the NPM-ALK fusion transcript may be associated with a poor prognosis of the patients with ALK(+) anaplastic large-cell lymphomas.

DOI： 10.1038/modpathol.3800781

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

In anaplastic large-cell lymphomas positive for anaplastic lymphoma kinase (ALK) protein, the ALK gene is most commonly fused to the NPM gene, and less commonly to TPM3, TFG, ATIC, and other rare genes. Although this lymphoma is generally associated with a favorable clinical outcome, 25% of the patients die of the disease within 5 years. In this study, we developed three assays, all of which can be used with archival formalin-fixed, paraffin-embedded tissues: (1) a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay for various X-ALK fusion genes, (2) a 50 rapid amplification of cDNA ends (RACE) assay to identify unknown fusion partners, and (3) a real-time RT-PCR assay to quantify the amount of the NPM-ALK fusion transcript. In 26 cases of ALK(+) anaplastic large-cell lymphoma, the RT-PCR assay showed that the ALK was fused to NPM in 21 cases, to TPM3 in three, and to TFG in one. The 50 RACE assay detected ATIC-ALK fusion in the remaining case. The real-time quantitative RT-PCR assay showed that the NPM-ALK transcript was over expressed in four of 20 quantifiable cases. Patients with NPM-ALK overexpression showed a significantly unfavorable overall survival compared with those with a low expression of this transcript. The RT-PCR and 50 RACE assays developed here may be useful for identification of known and unknown gene partners fused to the ALK gene. Overexpression of the NPM-ALK fusion transcript may be associated with a poor prognosis of the patients with ALK(+) anaplastic large-cell lymphomas.

DOI： 10.1038/modpathol.3800781

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Language：Japanese  

PubMed

DOI： 10.11406/rinketsu.48.262

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Here, we report that tumor cells from some patients (23.8%) with Hodgkin lymphoma (HL) are positive for CC chemokine receptor 4 (CCR4). We therefore tested the chimeric anti-CCR4 monoclonal antibody (mAb), KM2760, the Fc region of which is defucosylated to enhance antibody-dependent cellular cytotoxicity (ADCC), as a novel immunotherapy for refractory HL. KM2760 demonstrated a promising antitumor activity in the CCR4-positive HL-bearing mouse model in the therapeutic setting. Although KM2760 did not induce any ADCC mediated by mouse natural killer (NK) cells, it significantly enhanced phagocytosis mediated by mouse monocytes/macrophages against the CCR4-positive HL cell line in vitro. Together with the findings that KM2760 did not exhibit any complement-dependent cytotoxicity or direct antiproliferation activity in vitro, these data indicated that KM2760 exerted its robust in vivo antitumor activity via monocytes/macrophages in mice. In the human system, KM2760 enhanced phagocytic activity mediated by monocytes/macrophages. Furthermore, it induced robust ADCC mediated by NK cells against the CCR4-positive HL cell line in vitro. Thus, it is conceivable that KM2760 would have much more potent antitumor activity in humans than in mice. Collectively, this study strongly indicates that anti-CCR4 mAb could be a novel treatment modality for patients with CCR4-positive HL.

DOI： 10.1038/sj.leu.2404415

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Language：English  

Language：English   Publisher：BLACKWELL PUBLISHING  

Leukocyte trafficking, which is critically regulated by chemokines and their receptors, shares many of the characteristics of tumor cell infiltration and metastasis. Expression of CC chemokine receptor 4 (CCR4) by tumor cells is associated with skin involvement, but CCR4 also has an important role in normal and tumor immunity. In a subset of patients with CCR4(+) T-cell leukemia/lymphoma, the tumor cells themselves function as regulatory T (Treg) cells, contributing to tumor survival in the face of host antitumor immune responses. In other types of cancers, the chemokines TARC/CCL17 and MDC/CCL22, specific ligands for CCR4 that are produced by tumor cells and the tumor microenvironment, attract CCR4(+) Treg cells to the tumor, where they create a favorable environment for tumor escape from host immune responses. A novel humanized anti-CCR4 monoclonal antibody (mAb) has been developed, the Fc region of which is defucosylated to enhance antibody-dependent cellular cytotoxicity by increasing its binding affinity to Fc receptor on effector cells. We are now conducting a phase I clinical trial of this anti-CCR4 mAb in patients with CCR4(+) T-cell leukemia/lymphoma in Japan (clinical trials gov. identifier: NCT00355472). Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill the CCR4(+) tumor cells, but also to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.

DOI： 10.1111/j.1349-7006.200.00307

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Language：English  

Leukocyte trafficking, which is critically regulated by chemokines and their receptors, shares many of the characteristics of tumor cell infiltration and metastasis. Expression of CC chemokine receptor 4 (CCR4) by tumor cells is associated with skin involvement, but CCR4 also has an important role in normal and tumor immunity. In a subset of patients with CCR4+ T-cell leukemia/lymphoma, the tumor cells themselves function as regulatory T (Treg) cells, contributing to tumor survival in the face of host antitumor immune responses. In other types of cancers, the chemokines TARC/CCL17 and MDC/CCL22, specific ligands for CCR4 that are produced by tumor cells and the tumor microenvironment, attract CCR4+ Treg cells to the tumor, where they create a favorable environment for tumor escape from host immune responses. A novel humanized anti-CCR4 monoclonal antibody (mAb) has been developed, the Fc region of which is defucosylated to enhance antibody-dependent cellular cytotoxicity by increasing its binding affinity to Fc receptor on effector cells. We are now conducting a phase I clinical trial of this anti-CCR4 mAb in patients with CCR4+ T-cell leukemia/lymphoma in Japan (clinical trials gov. identifier: NCT00355472). Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill the CCR4+ tumor cells, but also to overcome the suppressive effect of CCR4+ Treg cells on the host immune response to tumor cells. © 2006 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2006.00307.x

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PubMed

Language：Japanese  

DOI： 10.1103/PhysRevLett.97.171801

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Patients with adult T-cell leukemia/lyphoma (ATLL) are in a severely immunocompromised state. therefore, it is assumed that ATLL cells either express particular cytokines or induce their expression in host immune cells, disrupting the balanced production of cytokines and causing the host's immune system to break down. We examined the levels of serum cytokines including T helper type 1- (Th1-) associated cytokines [IFN-gamma, TNF-alpha, and interleukin (IL)-2], Th2-associated cytokines (IL-4, -5 and -6) and regulatory T cell-associated cytokines (IL-10 and TGF-beta 1) in 94 ATLL patients, 39 asymptomatic human T-cell lymphotropic -virus type-1 (HTLV-1) carriers and 50 healthy adult volunteers, to clarify whether elevated levels of particular cytokines are associated with the prognosis of ATLL patients. On multivariate analysis, high IL-5 and IL-10 levels were independent and significant unfavorable prognostic factors among the ATLL patients. The IL-10 level significantly increased with disease progression at each step from asymptomatic HTLV-I carrier to ATLL of the indolent variant (chronic and smoldering subtypes) to ATLL of the aggressive variant (acute and lymphoma subtypes). Furthermore, high IL-10 was significantly associated with high lactate dehydrogenase (LDH), indicating that the IL-10 level reflects the tumor burden. The IL-5 level was not associated with disease progression nor LDH. Among ATLL patients with the aggressive variant, high IL-5, but not high IL-10, was an independent and significant unfavorable prognostic factor on multivariate analysis. Measurement of serum IL-5 and IL-10 levels is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/ijc.21688

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Language：English   Publisher：AMER SOC HEMATOLOGY  

DOI： 10.1038/sj.leu.2403754

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Language：English   Publisher：AMER SOC HEMATOLOGY  

DOI： 10.1002/ijc.21688

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：CARDEN JENNINGS PUBL CO LTD  

Leukocyte trafficking is critically regulated by chemokines and their receptors. The involvement of the skin in certain subsets of T-cell malignancies has been explained by the discovery of an interaction between the thymus and activation-regulated chemokine (TARC), which is abundant in the skin, and its receptor, CC chemokine receptor 4 (CCR4), which is expressed in the tumor cells. We describe a diffuse large B-cell lymphoma (DLBCL) that showed CCR4 expression with involvement of the skin. A 55-year-old man presented with a giant skin ulcer of the right axilla, and his disease was diagnosed as DLBCL. Further clinical examination revealed an ulcerated gastric lymphoma lesion. Immunohistochemical and real-time reverse transcriptase-polymerase chain reaction analyses showed that the tumor cells were positive for CCR4, and TARC was expressed at extremely high levels in the lymphoma-affected skin. These observations suggest that the interaction between CCR4 and TARC played a significant role in the involvement of the skin in this case, similar to what has been observed in certain subsets of T-cell malignancies. To the best of our knowledge, this report is the first of a CCR4-positive B-cell lymphoma. The present case provides new insights into the pathogenesis of skin involvement in B-cell lymphomas.

DOI： 10.1532/IJH97.04154

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

MUM1 ( multiple myeloma oncogene 1)/IRF4 ( interferon regulatory factor 4) is a transcription factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas and predicts an unfavorable outcome in some lymphoma subtypes. To elucidate its role in B-cell malignancies, we prepared MUM1-expressing Ba/F3 cells, which proliferated until higher cellular density than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3 (FKBP3), the monokine induced by interferon-gamma(MIG), Fas apoptotic inhibitory molecule (Faim) and Zinc-finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and treatment with neutralizing antibodies against MIG and its receptor, CXCR3, slightly inhibited the proliferation of two MUM1-expressing lines. These results suggest that MUM1 plays roles in the progression of B-cell lymphoma/leukemia by regulating the expression of various genes including MIG.

DOI： 10.1038/sj.leu.2403833

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

MUM1 ( multiple myeloma oncogene 1)/IRF4 ( interferon regulatory factor 4) is a transcription factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas and predicts an unfavorable outcome in some lymphoma subtypes. To elucidate its role in B-cell malignancies, we prepared MUM1-expressing Ba/F3 cells, which proliferated until higher cellular density than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3 (FKBP3), the monokine induced by interferon-gamma(MIG), Fas apoptotic inhibitory molecule (Faim) and Zinc-finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and treatment with neutralizing antibodies against MIG and its receptor, CXCR3, slightly inhibited the proliferation of two MUM1-expressing lines. These results suggest that MUM1 plays roles in the progression of B-cell lymphoma/leukemia by regulating the expression of various genes including MIG.

DOI： 10.1038/sj.leu.2403833

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Amplification and translocation of the Bcl-2 gene has been detected in a certain subset of diffuse large B-cell lymphomas (DLBCL). The correlations among Bcl-2 protein expression, gene translocation or amplification, and the molecular signature determined by cDNA array are poorly understood. This Study examined 25 cases with de novo nodal DLBCL. Interphase fluorescence in situ hybridization (FISH) analysis was performed to evaluate the Bcl-2 gene using IGH/BCL2 and CEP18 centrornere probes (Vysis). When extra Bcl-2 gene signals were observed in each tumor cell and when these signals were in proportion to the extra CEP 18 probe signals, we regarded the findings as indicating the presence of an additional chromosome 18; when extra Bcl-2 signals were observed but additional CEP18 signals were not, we regarded the findings as indicating the presence of gene amplification. A panel of 3 antigens (CD 10, Bcl-6, and MUM-1) was applied to categorize each case as either a "germinal center B-cell (GCB) phenotype" or a "non-GCB phenotype." Of the 25 cases examined, 8 cases (32%) were classified as "GCB phenotype" and 17 cases (68%) were classified as "non-GCB phenotype." A FISH analysis revealed that t(14;18) was detected in 2 of the 8 cases (25%) with the "GCB phenotype" but in none of the 17 "non-GCB phenotype" cases. Extra Bcl-2 gene signals were detected in 7 of the 25 (28%) cases examined: n = 5 for an additional chromosome 18, n I for gene amplification, and n = I for additional chromosome 18 + gene amplification. Extra Bcl-2 gene signals were exclusively detected in DLBCL with the "non-GCB phenotype"; these cases, with the exception of one, stained strongly positive for Bcl-2. The DLBCLs with Bcl-2 protein overexpression were classified into at least two heterogeneous Molecular groups, based on the results of the FISH analysis.

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Language：English  

PubMed

Language：Japanese   Publisher：American Journal of Surgical Pathology  

Amplification and translocation of the Bcl-2 gene has been detected in a certain subset of diffuse large B-cell lymphomas (DLBCL). The correlations among Bcl-2 protein expression, gene translocation or amplification, and the molecular signature determined by cDNA array are poorly understood. This study examined 25 cases with de novo nodal DLBCL. Interphase fluorescence in situ hybridization (FISH) analysis was performed to evaluate the Bcl-2 gene using IGH/BCL2 and CEP18 centromere probes (Vysis). When extra Bcl-2 gene signals were observed in each tumor cell and when these signals were in proportion to the extra CEP18 probe signals, we regarded the findings as indicating the presence of an additional chromosome 18; when extra Bcl-2 signals were observed but additional CEP18 signals were not, we regarded the findings as indicating the presence of gene amplification. A panel of 3 antigens (CD10, Bcl-6, and MUM-1) was applied to categorize each case as either a "germinal center B-cell (GCB) phenotype" or a "non-GCB phenotype." Of the 25 cases examined, 8 cases (32%) were classified as "GCB phenotype" and 17 cases (68%) were classified as "non-GCB phenotype." A FISH analysis revealed that t(14;18) was detected in 2 of the 8 cases (25%) with the "GCB phenotype" but in none of the 17 "non-GCB phenotype" cases. Extra Bcl-2 gene signals were detected in 7 of the 25 (28%) cases examined: n = 5 for an additional chromosome 18, n = 1 for gene amplification, and n = 1 for additional chromosome 18 + gene amplification. Extra Bcl-2 gene signals were exclusively detected in DLBCL with the "non-GCB phenotype"; these cases, with the exception of one, stained strongly positive for Bcl-2. The DLBCLs with Bcl-2 protein over-expression were classified into at least two heterogeneous molecular groups, based on the results of the FISH analysis. Copyright © 2005 by Lippincott Williams & Wilkins.

Scopus

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

In multiple myeloma ( MM), the interaction between myeloma cells and bone marrow microenvironment has an important role in the pathogenesis of MM. We first examined the inducing effect of myeloma cells on migration of human umbilical vein vascular endothelial cells ( HUVECs). Five myeloma cell lines produced varying amounts of VEGF, and migration of HUVECs was induced by coculture with myeloma cells. We next examined the inhibitory effect of a novel synthetic retinoid Am80 ( Tamibarotene) on both myeloma cells and HUVECs. Am80 is specific for the retinoic- acid receptor- alpha/beta, and has therapeutic effects in all- trans retinoic acid resistant acute promyelocytic leukemia. Am80 slightly inhibited the growth of both myeloma cells and HUVECs, and remarkably inhibited the growth of HUVECs stimulated by VEGF. Am80 showed little growth inhibition of bone marrow stromal cells ( BMSCs), but it markedly inhibited migration of HUVECs by cocultured myeloma cells. Am80 inhibited VEGF- induced phosphorylation of VEGF receptor. In addition, VEGF- induced formation of tubelike structures in vitro and neovascularization in mouse corneas were significantly inhibited by Am80. These findings clearly demonstrate that Am80 is a potential inhibitor of angiogenesis caused by the interaction between vascular endothelial cells and myeloma cells, and might be a useful therapeutic agent against MM.

DOI： 10.1038/sj.leu.2403754

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Language：English  

PubMed

Language：Japanese   Publisher：名古屋市立大学医学会  

Language：Japanese   Publisher：日本癌学会  

Language：English  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CANCER ASSOC  

Chromosomal translocations involving the immunoglobulin heavy chain gene (IgH) and nonrandom protooncogene loci are the hallmark of genetic alterations found not only in multiple myeloma (MM), but also in premalignant stages of MM, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). We studied the frequency of IgH (14q32) rearrangements and their partner chromosomes in 16 Japanese patients with MGUS (13 cases), and SMM (3 cases) by means of interphase double-color fluorescence in situ hybridization (DCFISH) applied to purified plasma cells and using CD138-bead selection. IgH rearrangement was recognized in nine of the patients (56.3%). Protooncogene loci juxtaposed to IgH were identified in seven cases including CCND1 (11q13) in six cases and FGFR3 (4p16) in one. Four out of the six t(11;14)-positive cases showed nuclear staining of the cyclin D1 protein, whereas none of the seven t(11;14)-negative cases did. Moreover, neither MUM1(6p25)-IgH nor MAFB(20q11)-IgH fusion signals were observed. This suggests to us that cyclin D1 deregulation due to the presence of t(11;14) is involved in the early development of plasma cell neoplasms, and that this event alone is not enough for the development of symptomatic myeloma.

DOI： 10.1111/j.1349-7006.2003.tb01445.x

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Language：Japanese   Publisher：Clinical Cancer Research  

Adult T-cell leukemia/lymphoma (ATLL) is a distinct clinical entity among mature T-cell neoplasms, and its causative agent has been confirmed to be long-term infection by human T-lymphotropic virus type 1. A recent study demonstrated frequent expression of a chemokine receptor, CC chemokine receptor (CCR)4, which is known as a Th2 marker but not CXC chemokine receptor (CXCR)3, which is known as a Th1 marker, among both ATLL- and human T-lymphotropic virus type 1-immortalized T cells. In this study, immunostaining analysis for CCR4 and CXCR3 expression in ATLL cells obtained from 103 patients with ATLL was performed, and the clinical parameters and overall survival of the CCR4-positive and -negative cases were compared. Ninety-one (88.3%) of the 103 cases were positive for CCR4 staining, whereas only 5 (4.9%) were positive for CXCR3 staining. Positivity for CCR4 was significantly associated with skin involvement (P < 0.05), although there were no significant differences in clinical characteristics between the CCR4-positive and -negative cases at the time of initial diagnosis. CCR4+ ATLL cells may accumulate in the skin because of the expression of a CCR4 ligand, thymus and activation-regulated chemokine (TARC), on normal and inflamed cutaneous endothelia. As for survival analysis, positivity for CCR4 expression was extracted as an unfavorable prognostic factor as well as other factors, including the presence of B symptoms and extranodal involvement of more than one site. Multivariate analysis confirmed that CCR4 expression was an independent and significant prognostic factor (P <0.05). Thus, our finding may provide a novel insight into not only the biological but also the clinical features of ATLL. © 2003, American Association for Cancer Research. All rights reserved.

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Language：English   Publisher：日本癌学会  

Language：Japanese   Publisher：日本癌学会  

Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：CARDEN JENNINGS PUBL CO LTD  

Nasal natural killer (NK)/T-cell lymphoma is characterized by an aggressive clinical course and poor prognosis. The term "NK/T-cell" lymphoma includes both the NK-cell type and the T-cell type, which are classified by immunophenotyping and according to T-cell receptor (TCR) rearrangement. In addition, CD56(+)T-cell lymphoma is defined as NK-like T-cell lymphoma. This report concerns a 54-year-old woman with nasal T-cell lymphoma. Its phenotype showed pure T-cell type with CD3(+), CD56(-), and TCR+ accompanied by Epstein-Barr virus infection. Although the lesions were localized in the nasal mucosa and facial skin (stage IE), local irradiation could not achieve complete remission (CR). We then administered 5 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen followed by high-dose chemotherapy with an autologous peripheral blood stem cell transplantation. This therapy resulted in CR. Our results suggest that this lymphoma subtype may be cured by means of intensive treatment soon after diagnosis. Int J Hematol. 2002;75:195-200. (C)2002 The Japanese Society of Hematology.

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Language：Japanese   Publisher：名古屋市立大学医学会  

Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

Language：Japanese  

CiNii Books

Language：Japanese  

CiNii Books

Other Link： http://search.jamas.or.jp/link/ui/2017341879

Language：Japanese   Publisher：(有)科学評論社  

J-GLOBAL

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2016.34.15_suppl.e19056

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Language：Japanese   Publisher：(一社)日本内科学会  

J-GLOBAL

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publisher：日本癌学会  

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

DOI： 10.1093/annonc/mdu435.73

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：Japanese  

CiNii Books

Other Link： http://search.jamas.or.jp/link/ui/2014274157

Language：Japanese   Publisher：日本がん免疫学会  

Language：English   Publisher：日本癌学会  

Language：Japanese  

CiNii Books

Other Link： http://search.jamas.or.jp/link/ui/2013286825

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC CLINICAL ONCOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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CiNii Books

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publisher：BLACKWELL PUBLISHING  

DOI： 10.1111/j.1349-7006.2007.00522.x

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：FERRATA STORTI FOUNDATION  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：MARY ANN LIEBERT INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：MARY ANN LIEBERT INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：MARY ANN LIEBERT INC  

Web of Science

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：MARY ANN LIEBERT INC  

Web of Science

Language：Japanese  

CiNii Books

Language：Japanese  

J-GLOBAL

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

Web of Science

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

Web of Science

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

Web of Science