2023/03/27 更新

写真a

シマダ カズユキ
島田 和之
SHIMADA Kazuyuki
所属
医学部附属病院 血液内科 講師
大学院担当
大学院医学系研究科
職名
講師
連絡先
メールアドレス

学位 1

  1. 博士(医学) ( 2009年3月   名古屋大学 ) 

研究キーワード 2

  1. 微小環境

  2. 悪性リンパ腫

経歴 6

  1. 名古屋大学   医学部附属病院血液内科   講師

    2016年4月 - 現在

  2. 名古屋大学   高等研究院   特任講師

    2012年3月 - 2016年3月

  3. University of Southampton   Cancer Sciences Unit

    2010年4月 - 2012年3月

  4. 名古屋大学   難治感染症部   医員

    2009年10月 - 2010年3月

  5. University of Southampton   Cancer Sciences Division

    2009年5月 - 2009年9月

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    国名:グレートブリテン・北アイルランド連合王国(英国)

  6. 名古屋大学   血液内科   医員

    2007年4月 - 2007年10月

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学歴 2

  1. 名古屋大学   医学系研究科

    - 2009年3月

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    国名: 日本国

  2. 名古屋大学   医学部

    - 2001年3月

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    国名: 日本国

所属学協会 9

  1. 日本内科学会

  2. 日本血液学会   評議員

  3. 日本癌学会   評議員

  4. 日本リンパ網内系学会   評議員

  5. American Society of Clinical Oncology

  6. American Society of Hematology

  7. 日本臨床腫瘍学会

  8. 日本造血・免疫細胞療法学会

  9. 日本骨髄腫学会

▼全件表示

受賞 3

  1. 日本癌学会奨励賞

    2012年9月   日本癌学会  

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    受賞国:日本国

  2. 日本血液学会奨励賞

    2009年10月   日本血液学会  

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    受賞国:日本国

  3. 日本白血病研究基金一般研究賞

    2009年10月   日本白血病研究基金  

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    受賞国:日本国

 

論文 83

  1. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): a multicentre, single-arm, phase 2 trial. 査読有り

    Shimada K, Yamaguchi M, Atsuta Y, Matsue K, Sato K, Kusumoto S, Nagai H, Takizawa J, Fukuhara N, Nagafuji K, Miyazaki K, Ohtsuka E, Okamoto M, Sugita Y, Uchida T, Kayukawa S, Wake A, Ennishi D, Kondo Y, Izumi T, Kin Y, Tsukasaki K, Hashimoto D, Yuge M, Yanagisawa A, Kuwatsuka Y, Shimada S, Masaki Y, Niitsu N, Kiyoi H, Suzuki R, Tokunaga T, Nakamura S, Kinoshita T

    The Lancet. Oncology   21 巻 ( 4 ) 頁: 593 - 602   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:The Lancet Oncology  

    Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. Methods: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20–79 years, had an Eastern Cooperative Group performance status of 0–3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1–5 of cycle one and days 2–6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. Findings: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5–5·5). 2-year progression-free survival was 76% (95% CI 58–87). The most frequent adverse events of grade 3–4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. Interpretation: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. Funding: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.

    DOI: 10.1016/S1470-2045(20)30059-0

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  2. Frequent genetic alterations in immune checkpoint-related genes in intravascular large B-cell lymphoma. 査読有り

    Shimada K, Yoshida K, Suzuki Y, Iriyama C, Inoue Y, Sanada M, Kataoka K, Yuge M, Takagi Y, Kusumoto S, Masaki Y, Ito T, Inagaki Y, Okamoto A, Kuwatsuka Y, Nakatochi M, Shimada S, Miyoshi H, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Shiozawa Y, Nannya Y, Okabe A, Kohno K, Atsuta Y, Ohshima K, Nakamura S, Ogawa S, Tomita A, Kiyoi H

    Blood   137 巻 ( 11 ) 頁: 1491 - 1502   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood  

    Key Points: • Genetic alterations in immune checkpoint–related genes are frequent in IVLBCL. • Plasma cfDNA is an alternative tumor DNA source of IVLBCL to detect genetic alterations by comprehensive analyses.

    DOI: 10.1182/blood.2020007245

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  3. A phase 2 study of axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma in Japan: 1-year follow-up and biomarker analysis.

    Kato K, Fujii N, Makita S, Goto H, Kanda J, Shimada K, Akashi K, Izutsu K, Teshima T, Fukuda N, Sumitani T, Nakamura S, Sumi H, Shimizu S, Kakurai Y, Yoshikawa K, Tobinai K, Usui N, Hatake K

    International journal of hematology   117 巻 ( 3 ) 頁: 409 - 420   2023年3月

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    記述言語:英語   出版者・発行元:International Journal of Hematology  

    Axicabtagene ciloleucel (axi-cel) is an autologous, CD19-targeting chimeric antigen receptor T‑cell therapy. We recently reported the 3-month follow-up results of a phase 2, multicenter, open‑label, single-arm study of axi-cel in Japanese patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) (JapicCTI-183914). Here, we present 1-year efficacy and safety data and biomarker analysis data regarding mechanisms of resistance to axi-cel. Primary and secondary endpoints included investigator-assessed objective response rate (ORR), serious adverse events, and treatment-emergent adverse events. Axi-cel pharmacokinetics were also examined. Biomarker analysis was performed by cytokine measurement, immunohistochemistry, RNA sequencing, and whole-exome sequencing. At a median follow-up of 13.4 months, ORR was 86.7% (13/15 patients), and the complete response (CR) rate improved to 53.3% (8/15 patients) due to response conversion. Seven patients experienced disease progression, and one achieved CR after re-treatment with axi-cel. No new safety concerns were detected. Plausible resistance mechanisms to axi-cel varied among patients but included CD19 downregulation, programmed death-ligand 1 upregulation, and increased macrophage and angiogenesis signatures. The 1-year efficacy and safety of axi-cel were confirmed in Japanese patients with R/R LBCL. Resistance to treatment may involve multiple factors, including target antigen loss and an unfavorable tumor environment. Clinical trial registration: Japan Clinical Trials Information; JapicCTI-183914.

    DOI: 10.1007/s12185-022-03494-7

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  4. Long-term outcomes and central nervous system relapse in extranodal natural killer/T-cell lymphoma. 査読有り

    Miyazaki K, Suzuki R, Oguchi M, Taguchi S, Amaki J, Maeda T, Kubota N, Maruyama D, Terui Y, Sekiguchi N, Takizawa J, Tsukamoto H, Murayama T, Ando T, Matsuoka H, Hasegawa M, Wada H, Sakai R, Kameoka Y, Tsukamoto N, Choi I, Masaki Y, Shimada K, Fukuhara N, Utsumi T, Uoshima N, Kagami Y, Asano N, Ejima Y, Katayama N, Yamaguchi M

    Hematological oncology   40 巻 ( 4 ) 頁: 667 - 677   2022年10月

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    記述言語:英語   出版者・発行元:Hematological Oncology  

    To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60–343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78–30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.

    DOI: 10.1002/hon.2977

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  5. Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma in the Gastrointestinal Tract in the Modern Era. 招待有り 査読有り

    Ishikawa E, Nakamura M, Satou A, Shimada K, Nakamura S

    Cancers   14 巻 ( 2 )   2022年1月

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    記述言語:英語   出版者・発行元:Cancers  

    Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) typically arises from sites such as the stomach, where there is no organized lymphoid tissue. Close associations between Helicobacter pylori and gastric MALT lymphoma or Campylobacter jejuni and immunoproliferative small intestinal disease (IPSID) have been established. A subset of tumors is associated with chromosomal rearrangement and/or genetic alterations. This disease often presents as localized disease, requiring diverse treatment approaches, from antibiotic therapy to radiotherapy and immunochemotherapy. Eradication therapy for H. pylori effectively cures gastric MALT lymphoma in most patients. However, treatment strategies for H. pylori-negative gastric MALT lymphoma are still challenging. In addition, the effectiveness of antibiotic therapy has been controversial in intestinal MALT lymphoma, except for IPSID. Endoscopic treatment has been noted to usually achieve complete remission in endoscopically resectable colorectal MALT lymphoma with localized disease. MALT lymphoma has been excluded from post-transplant lymphoproliferative disorders with the exception of Epstein–Barr virus (EBV)-positive marginal zone lymphoma (MZL). We also describe the expanding spectrum of EBV-negative MZL and a close association of the disease with the gastrointestinal tract.

    DOI: 10.3390/cancers14020446

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  6. Phase 2 study of axicabtagene ciloleucel in Japanese patients with relapsed or refractory large B-cell lymphoma. 査読有り

    Kato K, Makita S, Goto H, Kanda J, Fujii N, Shimada K, Akashi K, Izutsu K, Teshima T, Fukuda N, Sumitani T, Sumi H, Shimizu S, Kakurai Y, Yoshikawa K, Tobinai K, Usui N, Hatake K

    International journal of clinical oncology   27 巻 ( 1 ) 頁: 213 - 223   2022年1月

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    記述言語:英語   出版者・発行元:International Journal of Clinical Oncology  

    Background: Axicabtagene ciloleucel (axi-cel) is an autologous chimeric antigen receptor T-cell based anti-CD19 therapy. The ZUMA-1 study, multicenter, single-arm, registrational Phase 1/2 study of axi-cel demonstrated high objective response rate in patients with relapsed/refractory large B-cell lymphoma. Here, we present the results of the bridging study to evaluate the efficacy and safety of axi-cel in Japanese patients (JapicCTI-183914). Methods: This study was the phase 2, multicenter, open-label, single-arm trial. Following leukapheresis, axi-cel manufacturing and lymphodepleting chemotherapy, patients received a single infusion of axi-cel (2.0 × 106 cells/kg). Bridging therapy between leukapheresis and conditioning chemotherapy was not allowed. The primary endpoint was objective response rate. Results: Among 17 enrolled patients, 16 received axi-cel infusion. In the 15 efficacy evaluable patients, objective response rate was 86.7% (95% confidence interval: 59.5–98.3%); complete response/partial response were observed in 4 (26.7%)/9 (60.0%) patients, respectively. No dose-limiting toxicities were observed. Grade ≥ 3 treatment-emergent adverse events occurred in 16 (100%) patients—most commonly neutropenia (81.3%), lymphopenia (81.3%) and thrombocytopenia (62.5%). Cytokine release syndrome occurred in 13 (81.3%) patients (12 cases of grade 1 or 2 and 1 case of grade 4). No neurologic events occurred. Two patients died due to disease progression, but no treatment-related death was observed by the data-cutoff date (October 23, 2019). Conclusion: The efficacy and safety of axi-cel was confirmed in Japanese patients with relapsed/refractory large B-cell lymphoma who have otherwise limited treatment options. Trial registration: JapicCTI-183914.

    DOI: 10.1007/s10147-021-02033-4

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  7. Diagnostic utility of programmed cell death ligand 1 (clone SP142) immunohistochemistry for malignant lymphoma and lymphoproliferative disorders: A brief review. 査読有り

    Sakakibara A, Kohno K, Ishikawa E, Suzuki Y, Tsuyuki Y, Shimada S, Shimada K, Satou A, Takahara T, Ohashi A, Takahashi E, Kato S, Nakamura S, Asano N

    Journal of clinical and experimental hematopathology : JCEH   61 巻 ( 4 ) 頁: 182 - 191   2021年12月

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    記述言語:英語  

    DOI: 10.3960/jslrt.21003

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  8. Clinicopathologic Analysis of Primary Adrenal Diffuse Large B-Cell Lymphoma: A Reappraisal of 23 Japanese Patients Based on EBV Association and PD-L1 Expression in Tumor Cells. 査読有り

    Kawano T, Tsuyuki Y, Suzuki Y, Shimada K, Kato S, Takahara T, Mori M, Nakaguro M, Sakakibara A, Nakamura S, Satou A

    The American journal of surgical pathology   45 巻 ( 12 ) 頁: 1606 - 1615   2021年12月

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    記述言語:英語   出版者・発行元:The American journal of surgical pathology  

    Primary adrenal diffuse large B-cell lymphoma (PA-DLBCL) is rare. We investigate 23 Japanese patients with PA-DLBCL to understand the clinicopathologic features and biological behavior of this disease. The 17 males and 6 females had a median age of 74 years (range: 40 to 86 y). Tumor cells harbored Epstein-Barr virus-encoded small RNA (EBER) in 9 (39%) samples, including samples from the 2 patients with methotrexate-associated B-cell lymphoproliferative disorder. Programmed cell death ligand 1 (PD-L1) expression was detected in tumor cells of 6 (26%) samples, including 1 EBER+ and 5 EBER- samples. Four (17%) patients exhibited an intravascular proliferating pattern, and all 4 patient samples showed positive staining for PD-L1 in tumor cells. Among those patients, 3 showed intravascular proliferating pattern accompanied by a diffuse extravascular proliferation of tumor cells, and 1 patient was diagnosed with intravascular large B-cell lymphoma. We divided the 23 patients into 3 groups: EBER+ (n=9, 39%), EBER-PD-L1+ (n=5, 22%), and EBER-PD-L1- (n=9, 39%). A comparison of the outcomes among the 3 groups showed significant differences in overall survival (P=0.034). The EBER+ group had the worst prognosis, and the EBER-PD-L1- group had the best prognosis. We also compared the outcomes among the 3 groups that received rituximab-containing chemotherapies. Both the overall survival and progression-free survival were significantly different among these groups (P<0.001 and P=0.002, respectively). In conclusion, we evaluated 3 types of PA-DLBCL and found that each had unique clinical, pathologic, and prognostic features. Our results suggested that immune senescence, iatrogenic immunodeficiency, and immune evasion contribute to the development of PA-DLBCL.

    DOI: 10.1097/PAS.0000000000001809

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  9. Current progress and future perspectives of research on intravascular large B-cell lymphoma. 招待有り 査読有り

    Shimada K, Kiyoi H

    Cancer science   112 巻 ( 10 ) 頁: 3953 - 3961   2021年10月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   出版者・発行元:Cancer Science  

    Intravascular large B-cell lymphoma is a rare disease of the large B cells characterized by selective growth in the lumina of small vessels in systemic organs. Since first reported in 1959, the difficulty of obtaining sufficient tumor cells from biopsy specimens has hampered the elucidation of its underlying biology. Recent progress using xenograft models and plasma cell-free DNA has uncovered genetic features that are similar to those of activated B-cell type diffuse large B-cell lymphoma, including MYD88 and CD79B mutations and frequent alterations in immune check point-related genes such as PD-L1 and PD-L2. Given the improvement in clinical outcomes and a higher risk of secondary central nervous system (CNS) involvement in the rituximab era, a phase 2 trial of R-CHOP combined with high-dose methotrexate and intrathecal chemotherapy as a CNS-oriented therapy has been conducted. This trial, the PRIMEUR-IVL study, has displayed good progression-free survival and a low cumulative incidence of secondary CNS involvement. Long-term follow-up within this trial is still ongoing. Further understanding of the pathophysiology of the disease and improvements in clinical outcomes are still needed.

    DOI: 10.1111/cas.15091

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  10. Spacer Length Modification Facilitates Discrimination between Normal and Neoplastic Cells and Provides Clinically Relevant CD37 CAR T Cells. 査読有り

    Okuno S, Adachi Y, Terakura S, Julamanee J, Sakai T, Umemura K, Miyao K, Goto T, Murase A, Shimada K, Nishida T, Murata M, Kiyoi H

    Journal of immunology (Baltimore, Md. : 1950)   206 巻 ( 12 ) 頁: 2862 - 2874   2021年6月

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    記述言語:英語   出版者・発行元:Journal of Immunology  

    Despite the remarkable initial efficacy of CD19 chimeric Ag receptor T (CAR-T) cell therapy, a high incidence of relapse has been observed. To further increase treatment efficacy and reduce the rate of escape of Ag-negative cells, we need to develop CAR-T cells that target other Ags. Given its restricted expression pattern, CD37 was considered a preferred novel target for immunotherapy in hematopoietic malignancies. Therefore, we designed a CD37-targeting CAR-T (CD37CAR-T) using the single-chain variable fragment of a humanized anti-CD37 Ab, transmembrane and intracellular domains of CD28, and CD3f signaling domains. High levels of CD37 expression were confirmed in B cells from human peripheral blood and bone marrow B cell precursors at late developmental stages; by contrast, more limited expression of CD37 was observed in early precursor B cells. Furthermore, we found that human CD37CAR-T cells with longer spacer lengths exhibited high gene transduction efficacy but reduced capacity to proliferate; this may be due to overactivation and fratricide. Spacer length optimization resulted in a modest transduction efficiency together with robust capacity to proliferate. CD37CAR-T cells with optimized spacer length efficiently targeted various CD37+ human tumor cell lines but had no impact on normal leukocytes both in vitro and in vivo. CD37CAR-T cells effectively eradicated Raji cells in xenograft model. Collectively, these results suggested that spacer-optimized CD37CAR-T cells could target CD37-high neoplastic B cells both in vitro and in vivo, with only limited interactions with their normal leukocyte lineages, thereby providing an additional promising therapeutic intervention for patients with B cell malignancies.

    DOI: 10.4049/jimmunol.2000768

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  11. Follicular T-cell lymphoma mimicking lymphocyte-rich classic Hodgkin lymphoma: a case report of a diagnostic pitfall. 査読有り

    Sakakibara A, Suzuki Y, Kato H, Yamamoto K, Sakata-Yanagimoto M, Ishikawa Y, Furukawa K, Shimada K, Kohno K, Nakamura S, Satou A, Kato S

    Journal of clinical and experimental hematopathology : JCEH   61 巻 ( 2 ) 頁: 97 - 101   2021年6月

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    記述言語:英語  

    DOI: 10.3960/jslrt.20052

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  12. The Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma. 査読有り

    Morichika K, Karube K, Sakihama S, Watanabe R, Kawaki M, Nishi Y, Nakachi S, Okamoto S, Takahara T, Satou A, Shimada S, Shimada K, Tsuzuki T, Fukushima T, Morishima S, Masuzaki H

    The American journal of surgical pathology   45 巻 ( 6 ) 頁: 832 - 840   2021年6月

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    記述言語:英語   出版者・発行元:American Journal of Surgical Pathology  

    On the basis of immunohistochemistry, diffuse large B-cell lymphoma (DLBCL) is categorized as a germinal center B-cell (GCB) or non-GCB subtype. Recent integrated genomic analyses have highlighted the importance of the JAK-STAT3 pathway in the molecular pathogenesis of DLBCL. However, its relevance to clinical outcomes remains controversial. Therefore, we evaluated the extent of the nuclear expression of phosphorylated STAT3 (pSTAT3), a surrogate marker of signal transducer and activator of transcription 3 (STAT3) activation, by immunohistochemistry. We also analyzed the potential relationship between pSTAT3 positivity (defined as ≥ 40% positive neoplastic cells) and clinicopathologic characteristics in 294 patients with DLBCL. pSTAT3 was detected in 122 patients (42%), with a higher rate in the non-GCB subtype than in the GCB subtype (57% vs. 28%, P < 0.001). Factors potentially activating STAT3, MYD88L265P, and Epstein-Barr virus-encoded small RNA were identified in the pSTAT3-positive non-GCB subtype, whereas the pSTAT3-positive GCB subtype often showed STAT3 mutations and lacked EZH2 mutations and the rearrangements of BCL2 and MYC. Multivariate analyses revealed that the pSTAT3-positive GCB subtype showed a favorable prognosis (HR: 0.17; 95% confidence interval, 0.04-0.7; P = 0.014). These findings suggest that pSTAT3 positivity may have a unique impact on the clinicopathologic characteristics of DLBCL, making it a promising novel marker for the favorable prognosis of patients with the GCB subtype.

    DOI: 10.1097/PAS.0000000000001691

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  13. Exosomes secreted from cancer-associated fibroblasts elicit anti-pyrimidine drug resistance through modulation of its transporter in malignant lymphoma. 査読有り

    Kunou S, Shimada K, Takai M, Sakamoto A, Aoki T, Hikita T, Kagaya Y, Iwamoto E, Sanada M, Shimada S, Hayakawa F, Oneyama C, Kiyoi H

    Oncogene   40 巻 ( 23 ) 頁: 3989 - 4003   2021年6月

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    担当区分:責任著者   記述言語:英語   出版者・発行元:Oncogene  

    The tumor microenvironment is deeply involved in the process of tumor growth and development. In this study, we focused on cancer-associated fibroblasts (CAFs) and their derived exosomes on the lymphoma microenvironment to uncover their clinical significance. CAFs were established from primary lymphoma samples, and exosomes secreted from CAFs were obtained by standard procedures. We then investigated the roles of CAFs and their derived exosomes in the survival and drug resistance of lymphoma cells. CAFs supported the survival of lymphoma cells through increased glycolysis, and the extent differed among CAFs. Exosomes were identified as a major component of the extracellular vesicles from CAFs, and they also supported the survival of lymphoma cells. The suppression of RAB27B, which is involved in the secretion of exosomes, using a specific siRNA resulted in reduced exosome secretion and decreased survival of lymphoma cells. Moreover, anti-pyrimidine drug resistance was induced in the presence of exosomes through the suppression of the pyrimidine transporter, equilibrative nucleoside transporter 2 (ENT2), and the suppression of ENT2 was significant in in vivo experiments and clinical samples. RNA sequencing analysis of miRNAs in exosomes identified miR-4717-5p as one of the most abundant miRNAs in the exosome, which suppressed the expression of ENT2 and induced anti-pyrimidine drug resistance in vitro. Our results suggest that exosomes including miR-4717-5p secreted from CAFs play a pivotal role in the lymphoma microenvironment, indicating that they are a promising therapeutic target.

    DOI: 10.1038/s41388-021-01829-y

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  14. Expression of programmed cell death ligand-1 by immune cells in the microenvironment is a favorable prognostic factor for primary diffuse large B-cell lymphoma of the central nervous system. 査読有り

    Tsuyuki Y, Ishikawa E, Kohno K, Shimada K, Ohka F, Suzuki Y, Mabuchi S, Satou A, Takahara T, Kato S, Miyagi S, Ozawa H, Kawano T, Takagi Y, Hiraga J, Wakabayashi T, Nakamura S

    Neuropathology : official journal of the Japanese Society of Neuropathology   41 巻 ( 2 ) 頁: 99 - 108   2021年4月

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    記述言語:英語   出版者・発行元:Neuropathology  

    Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNS-DLBCL) is rare. Thirty-nine patients consecutively diagnosed as having PCNS-DLBCL were analyzed to highlight the prognostic value of the expression of programmed cell death ligand-1 (PD-L1) by neoplastic cells and immune cells in the microenvironment. They were positive for CD20 in all (100%), CD5 in two (5%), CD10 in nine (23%), BCL-2 in 27 (69%), BCL-6 in 34 (87%), and MUM-1 in 37 (95%). Only one case was positive for neoplastic PD-L1, with an unexpectedly long clinical course of 92 months. The remaining 38 cases were further divided into three groups based on the percentage of PD-L1+ cells among microenvironmental immune cells. Cutoffs of < 5%, 5–40%, and ≥ 40% successfully stratified mean prognoses with three-year overall survival (OS) of 21%, 63%, and 100% (P = 0.009), respectively. Progression-free survival (PFS) and OS were different between the groups with and without methotrexate (MTX)-containing chemotherapy (P = 0.007 and P < 0.001, respectively). Multivariate analysis identified three independent adverse factors of OS: PD-L1 negativity (< 5%) on microenvironmental immune cells (P = 0.027), deep structure involvement (P = 0.034), and performance status (PS) 2–4 (P = 0.009). The study showed that PD-L1 expression on immune cells in the microenvironment was associated with prognosis among patients with PCNS-DLBCL.

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  15. Severe myasthenia gravis with anti-LRP4 antibodies and Hodgkin lymphoma. 査読有り

    Hayashi N, Sone J, Fukami Y, Yoshida Y, Kuno S, Shimada K, Atsuta N, Nakamura T, Higuchi O, Katsuno M

    Muscle & nerve   63 巻 ( 1 ) 頁: E2 - E4   2021年1月

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    記述言語:英語   出版者・発行元:Muscle and Nerve  

    DOI: 10.1002/mus.27079

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  16. [Current achievements and future perspectives in the research on intravascular large B-cell lymphoma]. 招待有り 査読有り

    Shimada K

    [Rinsho ketsueki] The Japanese journal of clinical hematology   62 巻 ( 6 ) 頁: 631 - 640   2021年

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    担当区分:筆頭著者, 責任著者   記述言語:日本語  

    DOI: 10.11406/rinketsu.62.631

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  17. [Current status of diagnosis and treatment in diffuse large B-cell lymphoma]. 招待有り 査読有り

    Shimada K

    [Rinsho ketsueki] The Japanese journal of clinical hematology   62 巻 ( 8 ) 頁: 1077 - 1084   2021年

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    担当区分:筆頭著者, 責任著者   記述言語:日本語  

    DOI: 10.11406/rinketsu.62.1077

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  18. Dose-adjusted EPOCH with or without rituximab for aggressive lymphoma patients: real world data. 査読有り

    Matsuda S, Suzuki R, Takahashi T, Suehiro Y, Tomita N, Izutsu K, Fukuhara N, Imaizumi Y, Shimada K, Nakazato T, Yoshida I, Miyazaki K, Yamaguchi M, Suzumiya J

    International journal of hematology   112 巻 ( 6 ) 頁: 807 - 816   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) −/+ rituximab (R) is the standard chemotherapeutic regimen for aggressive lymphoma, but is insufficient for aggressive lymphoma with adverse prognostic factors. Dose-adjusted (DA)-EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisolone) −/+ R demonstrates excellent efficacy against some aggressive lymphoma. Thus, we conducted a retrospective study to evaluate the feasibility and efficacy of this therapy in clinical practice. We enrolled 149 patients from 17 institutions diagnosed between 2007 and 2015. The median follow-up period for survivors was 27 months (range 0.2–123). The complete response (CR) rate of newly diagnosed patients was 79% (95% CI 68–87%). All patients were hospitalized to receive this therapy and 94% of patients also received granulocyte-colony-stimulating factor support. There were no treatment-related deaths. Febrile neutropenia (FN) and grade 3 or 4 infection occurred in 55% and 28% of patients, respectively. There were no significant differences in FN or infection between young (≤ 65 years) and elderly patients (> 65 years). In newly diagnosed diffuse large B-cell lymphoma-not otherwise specified patients (n = 46), the CR rate was 80% (95% CI 64–91%) and the 2-year OS rate was 81% (95% CI 66–90%). In the present study, DA-EPOCH −/+ R exhibited excellent efficacy and feasibility for aggressive lymphoma.

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  19. Phase I study of duvelisib in Japanese patients with relapsed or refractory lymphoma.

    Izutsu K, Kato K, Kiyoi H, Yamamoto G, Shimada K, Akashi K

    International journal of hematology   112 巻 ( 4 ) 頁: 504 - 509   2020年10月

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    記述言語:英語   出版者・発行元:International Journal of Hematology  

    Duvelisib is a novel dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ. This single-arm, multicenter phase I study investigated its safety, pharmacokinetics, and preliminary efficacy in Japanese patients with relapsed or refractory lymphoma. Duvelisib was administered orally twice daily at 25 mg in 28-day cycles. Seven patients, comprising 4 with follicular lymphoma (FL), 2 with diffuse large B-cell lymphoma, and 1 with mantle cell lymphoma (MCL) were enrolled. No dose-limiting toxicity occurred in any patient. The most commonly experienced treatment-related adverse events of any grade were neutropenia and thrombocytopenia, occurring in 3 patients each (42.9%); followed by lymphopenia, diarrhea, enterocolitis, stomatitis, hepatic function abnormal, ALT increased, and AST increased, occurring in 2 patients each (28.6%). The most common grade ≥ 3 treatment-related adverse events were neutropenia, which occurred in 3 patients (42.9%), and thrombocytopenia, lymphopenia, and hepatic function abnormal, which occurred in 2 patients each (28.6%). One patient with FL achieved a complete response; the remaining 3 with FL and the 1 with MCL achieved a partial response. The overall response rate was 71.4% (5/7 patients). Duvelisib was well tolerated in Japanese patients with relapsed or refractory lymphoma. Safety and preliminary efficacy data support further development of duvelisib in Japanese patients.

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  20. R-CHOP-14 versus R-CHOP-14/CHASER for upfront autologous transplantation in diffuse large B-cell lymphoma: JCOG0908 study.

    Kagami Y, Yamamoto K, Shibata T, Tobinai K, Imaizumi Y, Uchida T, Shimada K, Minauchi K, Fukuhara N, Kobayashi H, Yamauchi N, Tsujimura H, Hangaishi A, Tominaga R, Suehiro Y, Yoshida S, Inoue Y, Suzuki S, Tokuhira M, Kusumoto S, Kuroda J, Yakushijin Y, Takamatsu Y, Kubota Y, Nosaka K, Morishima S, Nakamura S, Ogura M, Maruyama D, Hotta T, Morishima Y, Tsukasaki K, Nagai H

    Cancer science   111 巻 ( 10 ) 頁: 3770 - 3779   2020年10月

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    記述言語:英語   出版者・発行元:Cancer Science  

    The efficiency of upfront consolidation with high-dose chemotherapy/autologous stem-cell transplantation (HDCT/ASCT) for newly diagnosed high-risk diffuse large B-cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high-risk DLBCL patients having an age-adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R-CHOP-14 (arm A) or 3 cycles of R-CHOP-14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2-y progression-free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow-up of 40.3 mo, 2-y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%-81.2%) and 66.7% (95% CI: 48.8%-79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%-85.7%) and 83.3% (95% CI: 66.6%-92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non-hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R-CHOP-14 showed higher 2-y PFS and less toxicity compared with R-CHOP-14/CHASER in patients with high-risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN-CTR, UMIN000003823).

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  21. Reappraisal of Primary Epstein-Barr Virus (EBV)-positive Diffuse Large B-Cell Lymphoma of the Gastrointestinal Tract: Comparative Analysis Among Immunosuppressed and Nonimmunosuppressed Stage I and II-IV Patients.

    Miyagi S, Ishikawa E, Nakamura M, Shimada K, Yamamura T, Furukawa K, Tanaka T, Mabuchi S, Tsuyuki Y, Kohno K, Sakakibara A, Satou A, Kato S, Fujishiro M, Nakamura S

    The American journal of surgical pathology   44 巻 ( 9 ) 頁: 1173 - 1183   2020年9月

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    記述言語:英語   出版者・発行元:American Journal of Surgical Pathology  

    Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoproliferation encompasses a broad range of clinicopathologic findings, including specific subtypes, for example, EBV+ mucocutaneous ulcer. Here we reassessed 36 cases of primary EBV+ diffuse large B-cell lymphomas (16 men and 20 women; median age, 69.5 y; range, 35 to 84 y), including 8 immunosuppressed patients (Lugano stage II-IV; median age, 74 y), 7 nonimmunosuppressed patients with stage I disease (median age, 69 y), and 21 nonimmunosuppressed patients with stage II-IV disease (median age, 69 y). All immunosuppressed patients exhibited iatrogenic immunodeficiency and an ulcerative appearance, with ulcer sites including the stomach (1 patient), small intestine (6 patients), and rectum (1 patient). Four patients were in the setting of treated lymphoma-associated immunosuppression. Immunosuppressed patients had higher incidences of intestinal involvement (P=0.001) and perforation (n=2) compared with advanced stage nonimmunosuppressed patients. Among nonimmunosuppressed stage I patients, lesions were restricted to the stomach, none showed multiple lesions or elevated serum lactate dehydrogenase, and the overall survival curve plateaued, although it was not statistically significant (P=0.0581). One nonimmunosuppressed stage I patient with a polypoid lesion exhibited spontaneous regression within 2 months after diagnosis, while another with bulky disease pursued an aggressive clinical course. Nonimmunosuppressed stage I cases without bulky masses may be considered EBV mucocutaneous ulcer with local progression. Our results demonstrated that primary EBV+ gastrointestinal diffuse large B-cell lymphoma could be delineated into 3 groups based on immune status and clinical stage, revealing distinguishing features useful as a pragmatic guide for diagnostic and therapeutic approaches.

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  22. PD-L1 expression on tumor or stromal cells of nodal cytotoxic T-cell lymphoma: A clinicopathological study of 50 cases.

    Yamashita D, Shimada K, Kohno K, Kogure Y, Kataoka K, Takahara T, Suzuki Y, Satou A, Sakakibara A, Nakamura S, Asano N, Kato S

    Pathology international   70 巻 ( 8 ) 頁: 513 - 522   2020年8月

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    記述言語:英語   出版者・発行元:Pathology International  

    Inhibitors of programmed cell-death 1 (PD-1) and programmed cell-death ligand 1 (PD-L1) have revolutionized cancer therapy. Nodal cytotoxic T-cell lymphoma (CTL) is characterized by a poorer prognosis compared to nodal non-CTLs. Here we investigated PD-L1 expression in 50 nodal CTL patients, with and without EBV association (25 of each). We identified seven patients (14%) with neoplastic PD-L1 (nPD-L1) expression on tumor cells, including three males and four females, with a median age of 66 years. One of the seven cases was TCRαβ type, three were TCRγδ type and three were TCR-silent type. Six of the seven cases exhibited a lethal clinical course despite multi-agent chemotherapy, of whom four patients died within one year of diagnosis. Morphological findings were uniform, with six cases showing centroblastoid appearance. Among nPD-L1+ cases, two of three examined had structural variations of PD-L1 disrupting 3′-UTR region. Notably, all of the TCRγδ-type nodal CTL cases showed nPD-L1 or miPD-L1 positivity (3 and 10 cases, respectively). TCRγδ-type cases comprised 42% of nPD-L1+ cases (P = 0.043 vs. PD-L1−), and 35% of miPD-L1+ cases (P = 0.037 vs. PD-L1−). The results indicate that PD-L1+ nodal CTL cases, especially of the TCRγδ type, are potential candidates for anti-PD-1/PD-L1 therapies.

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  23. PD-L1 (SP142) expression in neoplastic cells predicts a poor prognosis for patients with intravascular large B-cell lymphoma treated with rituximab-based multi-agent chemotherapy.

    Suzuki Y, Kohno K, Matsue K, Sakakibara A, Ishikawa E, Shimada S, Shimada K, Mabuchi S, Takahara T, Kato S, Nakamura S, Satou A

    Cancer medicine   9 巻 ( 13 ) 頁: 4768 - 4776   2020年7月

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    記述言語:英語   出版者・発行元:Cancer Medicine  

    Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse large B-cell lymphoma (DLBCL) arising in extranodal sites. PD-L1 expression of tumor cells has been reported in IVLBCL cells, but its clinicopathological relevance remains to be elucidated. Aims: This study was aimed to reveal the characteristics of PD-L1+ IVLBCL. Methods and results: Neoplastic PD-L1 expression was examined in 34 cases of IVLBCL and clinicopathological characteristics between patients with PD-L1+ and PD-L1− IVLBCL were compared. We assessed PD-L1 expression with SP142 antibody. Twelve (35%) of 34 cases showed positivity for PD-L1. The PD-L1+ group had significantly lower survival rates compared to the PD-L1− group. The PD-L1+ IVLBCL group also had a significantly lower age distribution and a lower frequency of patients older than 60 years compared to the PD-L1− group. Very recently, we speculate that there is possible link between PD-L1+ IVLBCL and PD-L1+ extranodal DLBCL-NOS (eDLBCL) because features of the two groups showed overlapping. Therefore, we compared the clinicopathological characteristics of the PD-L1+ IVLBCL and PD-L1+ eDLBCL. There were no significant differences in clinicopathological parameters and prognosis. Conclusion: The worse prognosis of the PD-L1+ group might be caused by immune evasion mechanisms, which are linked to PD-L1 expression. Therefore, PD-L1+ IVLBCL cases might be regarded as good candidates for targeted immunotherapy. We also highlighted the overlapping features of PD-L1+ IVLBCL and PD-L1+ eDLBCL. This result suggests that they should be regarded as one entity, immune evasion-related extranodal large B-cell lymphoma.

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  24. EBV status has prognostic implication among young patients with angioimmunoblastic T-cell lymphoma.

    Eladl AE, Shimada K, Suzuki Y, Takahara T, Kato S, Kohno K, Elsayed AA, Wu CC, Tokunaga T, Kinoshita T, Sakata-Yanagimoto M, Nakamura S, Satou A

    Cancer medicine   9 巻 ( 2 ) 頁: 678 - 688   2020年1月

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    記述言語:英語   出版者・発行元:Cancer Medicine  

    Epstein-Barr virus (EBV)-positive B cells have been detected in 66%-86% of patients with angioimmunoblastic T-cell lymphoma (AITL). However, it remains controversial whether EBV status has an impact on the survival of patients with AITL. In this study, we aimed to reevaluate the impact of EBV on the clinicopathological characteristics of AITL. In particular, we focused on the impact of EBV in younger patients with AITL. In total, 270 cases of AITL were studied. Epstein-Barr virus-positive B cells were detected in 191 (71%) cases (EBER+ group). Among the patients who received anthracycline-based therapy, the EBER status did not affect the overall survival (OS) or progression-free survival (PFS). In the younger group of AITL (≤60 years), PFS was significantly worse in the EBER− group compared to the EBER+ group (P =.0013). Furthermore, the multivariate analysis identified EBER-negative status, thrombocytopenia, and elevated serum IgA level as significant adverse prognostic factors for PFS (P <.001, P <.001, and P =.002). Based on these findings, we constructed new prognostic model for the younger group, based on three adverse factors. We classified the patients into two risk groups: low risk (no or 1 adverse factor) and high risk (2 or 3 adverse factors). This new model for younger patients with AITL showed that both OS and PFS were significantly related to the level of risk (P <.0001). In summary, this study showed that, among younger patients with AITL, an EBER+ status significantly improved prognosis compared to an EBER− status. Our new prognostic model should be applicable to younger patients with AITL.

    DOI: 10.1002/cam4.2742

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  25. Prognostic impact of PD-L1 expression in primary gastric and intestinal diffuse large B-cell lymphoma.

    Ishikawa E, Nakamura M, Shimada K, Tanaka T, Satou A, Kohno K, Sakakibara A, Furukawa K, Yamamura T, Miyahara R, Nakamura S, Kato S, Fujishiro M

    Journal of gastroenterology   55 巻 ( 1 ) 頁: 39 - 50   2020年1月

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    記述言語:英語   出版者・発行元:Journal of Gastroenterology  

    Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and the most common gastrointestinal lymphoma. The prognostic/predictive indicators among patients with gastric and intestinal DLBCL (giDLBCL) are controversial beyond their anatomical sites. We compared giDLBCL cases and investigated the clinical utility of newly emerging indicators with an emphasis on programmed cell death ligand 1 (PD-L1) expression. Methods: This retrospective study included 174 patients with primary gastric (n = 129) or intestinal (n = 45) DLBCL treated with rituximab-containing chemotherapy between 1995 and 2018. Results: Compared with gastric DLBCL (gDLBCL) cases, patients with intestinal DLBCL (iDLBCL) had a significantly higher rate of advanced Lugano stage (71% vs 37%, P < 0.001), perforation (13% vs. 0.8%, P = 0.001), PD-L1 expression on microenvironment immune cells (miPD-L1, 70% vs 46%, P = 0.008), CD10 positivity (47% vs 28%, P = 0.027), and CD5 positivity (9% vs 1.6%, P = 0.040). The iDLBCL patients showed significantly worse progression-free survival (PFS) and overall survival (OS) than gDLBCL cases (P = 0.0338 and P = 0.0077, respectively). PD-L1 expression on tumor cells was detected in only 3 (2%) of 174 cases with early relapse and/or an aggressive clinical course; whereas, miPD-L1-positive cases had significantly better OS than the miPD-L1-negative gDLBCL and iDLBCL cases (P = 0.0281 and P = 0.0061, respectively). Multivariate analysis revealed that miPD-L1 negativity (P = 0.030) was an independent adverse prognostic factor for OS in giDLBCL. Conclusions: The anatomical site of disease did not influence outcome in giDLBCL cases treated with rituximab-containing chemotherapy; while, miPD-L1 expression had a favorable impact on the outcome.

    DOI: 10.1007/s00535-019-01616-3

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  26. Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas. 査読有り

    Kataoka K, Miyoshi H, Sakata S, Dobashi A, Couronné L, Kogure Y, Sato Y, Nishida K, Gion Y, Shiraishi Y, Tanaka H, Chiba K, Watatani Y, Kakiuchi N, Shiozawa Y, Yoshizato T, Yoshida K, Makishima H, Sanada M, Onozawa M, Teshima T, Yoshiki Y, Ishida T, Suzuki K, Shimada K, Tomita A, Kato M, Ota Y, Izutsu K, Demachi-Okamura A, Akatsuka Y, Miyano S, Yoshino T, Gaulard P, Hermine O, Takeuchi K, Ohshima K, Ogawa S

    Leukemia   33 巻 ( 7 ) 頁: 1687 - 1699   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Leukemia  

    Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3′-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.

    DOI: 10.1038/s41375-019-0380-5

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  27. Methotrexate-associated lymphoproliferative disorders of T-cell phenotype: clinicopathological analysis of 28 cases.

    Satou A, Tabata T, Miyoshi H, Kohno K, Suzuki Y, Yamashita D, Shimada K, Kawasaki T, Sato Y, Yoshino T, Ohshima K, Takahara T, Tsuzuki T, Nakamura S

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   32 巻 ( 8 ) 頁: 1135 - 1146   2019年7月

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    記述言語:英語   出版者・発行元:Modern Pathology  

    Methotrexate-associated lymphoproliferative disorders are categorized as “other immunodeficiency-associated lymphoproliferative disorders in the WHO classification. Methotrexate-associated lymphoproliferative disorder is mainly a B-cell lymphoproliferative disorders or Hodgkin lymphoma type, whereas T-cell lymphoproliferative disorders are relatively rare (4–8%). Only a small number of methotrexate-associated T-cell lymphoproliferative disorders have been detailed thus far. Because of the rarity, methotrexate-associated T-cell lymphoproliferative disorder has not been well studied and its clinicopathological characteristics are unknown. A total of 28 cases of methotrexate-associated T-cell lymphoproliferative disorders were retrospectively analyzed. Histologically and immunohistochemically, they were divided into three main types: angioimmunoblastic T-cell lymphoma (n = 19), peripheral T-cell lymphoma, NOS (n = 6), and CD8+ cytotoxic T-cell lymphoma (n = 3). Among the 28 cases, only one CD8+ cytotoxic T-cell lymphoma case was Epstein-Barr virus-positive. The other 27 cases were negative for Epstein-Barr virus on tumor cells, but scattered Epstein-Barr virus-infected B-cells were detected in 24 cases (89%), implying the reactivation of Epstein-Barr virus caused by immunodeficient status of the patients. After the diagnosis of methotrexate-associated T-cell lymphoproliferative disorder, methotrexate was immediately withdrawn in 26 cases. Twenty (77%) cases presented with spontaneous regression. Compared to methotrexate-associated B-cell lymphoproliferative disorder, patients with methotrexate-associated T-cell lymphoproliferative disorder had a significantly higher proportion of males (p = 0.035) and presence of B-symptoms (p = 0.036), and lower proportion of Epstein-Barr virus+ tumor cells (p < 0.001). Although the difference was not significant, the methotrexate-associated T-cell lymphoproliferative disorder also had more frequent spontaneous regression (p = 0.061). In conclusion, methotrexate-associated T-cell lymphoproliferative disorder was divided into three main types: angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, NOS, and CD8+ cytotoxic T-cell lymphoma. Angioimmunoblastic T-cell lymphoma was the most common type. Methotrexate-associated T-cell lymphoproliferative disorder was characterized by a high rate of spontaneous regression after methotrexate cessation. Epstein-Barr virus positivity was relatively rare in methotrexate-associated T-cell lymphoproliferative disorder, significantly less frequent than methotrexate-associated B-cell lymphoproliferative disorder, suggesting different pathogenesis.

    DOI: 10.1038/s41379-019-0264-2

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  28. Divergence and heterogeneity of neoplastic PD-L1 expression: Two autopsy case reports of intravascular large B-cell lymphoma. 査読有り

    Sakakibara A, Inagaki Y, Imaoka E, Sakai Y, Ito M, Ishikawa E, Shimada S, Shimada K, Suzuki Y, Nakamura S, Satou A, Kohno K

    Pathology international   69 巻 ( 3 ) 頁: 148 - 154   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pathology International  

    Intravascular large B-cell lymphoma (IVLBCL) is a distinct disease, but the neoplastic PD-L1 expression on tumor cells may vary among cases. We evaluated 10 IVLBCL autopsy cases for neoplastic PD-L1 expression, and had positive results in two cases. In one case, neoplastic PD-L1 expression (SP142, 28-8, and E1J2J clones) was dependent on the organ and anatomical site (capillaries vs. vessels) of the tumor tissue. Neoplastic PD-L1 expression was found in tumor cells located in capillaries in the central nervous system, pituitary gland, kidneys, lung, and gastrointestinal tract; sinuses/sinusoids of the spleen, liver, bone marrow, and lymph nodes; and an extravascular location. However, this expression was not detected in tumor cells located in the adrenal gland, thyroid gland, pancreas, ovaries, uterus, pleura, and small or larger-sized vessels of the lung. The other case showed constant neoplastic PD-L1 expression on the tumor cells, and in addition to the affected organs, capillaries, and vessels with two anti-PD-L1 antibodies (28-8 and E1J2J, but not SP142). The divergence and heterogeneity of neoplastic PD-L1 expression were clearly demonstrated in our cases. To the best of our knowledge, this is the first description of divergent neoplastic PD-L1 expression among the affected organs and anatomical sites in IVLBCL.

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  29. Pyruvate secreted from patient-derived cancer-associated fibroblasts supports survival of primary lymphoma cells. 査読有り

    Sakamoto A, Kunou S, Shimada K, Tsunoda M, Aoki T, Iriyama C, Tomita A, Nakamura S, Hayakawa F, Kiyoi H

    Cancer science   110 巻 ( 1 ) 頁: 269 - 278   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    Cancer-associated fibroblasts (CAF) are a key component in the tumor microenvironment and play functional roles in tumor metastasis and resistance to chemotherapies. We have previously reported that CAF isolated from lymphoma samples increase anaerobic glycolysis and decrease intracellular production of reactive oxygen species, promoting the survival of tumor cells. Herein, we analyzed the mechanisms underlying this support of tumor-cell survival by CAF. As direct contact between lymphoma cells and CAF was not indispensable to survival support, we identified that the humoral factor pyruvate was significantly secreted by CAF. Moreover, survival of lymphoma cells was promoted by the presence of pyruvate, and this promotion was canceled by inhibition of monocarboxylate transporters. Metabolome analysis of lymphoma cells in coculture with CAF demonstrated that intermediates in the citric acid cycle were significantly increased, indicating that tumor cells produced energy by aerobic metabolism. These findings indicate that energy production in lymphoma cells is regulated in coordination not only with anaerobic glycolysis, but also with aerobic metabolism termed the reverse-Warburg effect, involving the secretion of pyruvate from CAF resulting in increased use of the citric acid cycle in lymphoma cells.

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  30. Immune evasion-related extranodal large B-cell lymphoma: A report of six patients with neoplastic PD-L1-positive extranodal diffuse large B-cell lymphoma.

    Suzuki Y, Sakakibara A, Shimada K, Shimada S, Ishikawa E, Nakamura S, Kato S, Takahara T, Asano N, Satou A, Kohno K

    Pathology international   69 巻 ( 1 ) 頁: 13 - 20   2019年1月

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    記述言語:英語   出版者・発行元:Pathology International  

    We identified six patients with Epstein-Barr virus (EBV)-negative extranodal diffuse large B-cell lymphoma (DLBCL) and immunohistochemical expression of PD-L1 on their tumor cells by examining 283 DLBCL cases with the PD-L1 SP142 clone between 2015 and 2017. They consisted of two men and four women with a median age of 71 years, and were examined in an autopsy (n = 1) and biopsies from the adrenal gland (n = 2), skin (n = 1), pelvic cavity (n = 1), and kidney (n = 1). All showed a monomorphic population of large transformed B-cells leading to diagnoses of DLBCL with two intravascular large B-cell lymphoma (IVLBCL) and one de novo CD5+ type and were featured by an invariable immunephenotype: CD3-, CD20+, BCL-2+, and MUM1+. In addition, CD5 and CD10 were each detected in one case. All cases expressed PD-L1 on >10% to >90% of tumor cells, which was confirmed with two other PD-L1 antibodies (E1J2J and 28-8). Three untreated patients had a rapid, lethal clinical course within 7 months after diagnosis; while, the remaining three achieved complete remission after treatment and were alive at the last follow-up. We suggest immune evasion-related extranodal large B-cell lymphoma should be recognized beyond the currently identified entities of IVLBCL and de novo CD5+ DLBCL.

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  31. Clinicopathological analysis of primary intestinal diffuse large B-cell lymphoma: Prognostic evaluation of CD5, PD-L1, and Epstein-Barr virus on tumor cells.

    Ishikawa E, Kato S, Shimada K, Tanaka T, Suzuki Y, Satou A, Kohno K, Sakakibara A, Yamamura T, Nakamura M, Miyahara R, Goto H, Nakamura S, Hirooka Y

    Cancer medicine   7 巻 ( 12 ) 頁: 6051 - 6063   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Medicine  

    Background: Primary intestinal diffuse large B-cell lymphoma (iDLBCL) is rare. In this study, we investigated the clinicopathological features of this disease to further understand the prognostic value of CD5, programmed cell death ligand 1 (PD-L1), and Epstein-Barr virus (EBV) on tumor cells. Methods: Tumor specimens from 62 patients consecutively diagnosed with primary iDLBCL at a single institution were analyzed. Results: Our series consisted of EBV-positive (EBV + ) iDLBCL (n = 10), de novo CD5 + iDLBCL (n = 4), and DLBCL, not otherwise specified (DLBCL-NOS; n = 48). Notably, seven of 10 EBV + cases had treated lymphoma-associated (n = 4) or iatrogenic immunodeficiency (n = 3). Two of 10 EBV + cases expressed PD-L1 on tumor cells, whereas the remaining eight were positive for PD-L1 on microenvironment immune cells. Only one DLBCL-NOS case had neoplastic PD-L1 expression with a giant cell-rich appearance. Both EBV-harboring and PD-L1 expression on tumor cells, but not CD5, were associated with worse overall survival (OS) in iDLBCL patients receiving rituximab-containing chemotherapy (P = 0.0354, P = 0.0092, and P = 0.1097, respectively). Multivariate analysis identified PD-L1 positivity on tumor cells (P = 0.0106), PD-L1 negativity on microenvironment immune cells (P = 0.0193), and EBV positivity (P = 0.0324) as poor independent prognostic factors for OS. Among iDLBCL cases without any EBV association, CD5 positivity, or neoplastic PD-L1 expression, high PD-L1 expression (≥40%) on microenvironment immune cells predicted an extremely favorable outcome. Conclusion: EBV + iDLBCL mainly comprised immunodeficiency-associated patients, which may highlight the specificity of the intestine. PD-L1 expression on tumor cells or microenvironment immune cells was found to have an opposite prognostic impact in iDLBCL.

    DOI: 10.1002/cam4.1875

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  32. Biology and management of primary effusion lymphoma. 招待有り 査読有り

    Shimada K, Hayakawa F, Kiyoi H

    Blood   132 巻 ( 18 ) 頁: 1879 - 1888   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood  

    Primary effusion lymphoma (PEL) is a rare B-cell malignancy that most often occurs in immunocompromised patients, such as HIV-infected individuals and patients receiving organ transplantation. The main characteristic of PEL is neoplastic effusions in body cavities without detectable tumor masses. The onset of the disease is associated with latent infection of human herpes virus 8/ Kaposi sarcoma–associated herpes virus, and the normal counterpart of tumor cells is B cells with plasmablastic differentiation. A condition of immunodeficiency and a usual absence of CD20 expression lead to the expectation of the lack of efficacy of anti-CD20 monoclonal antibody; clinical outcomes of the disease remain extremely poor, with an overall survival at 1 year of ∼30%. Although recent progress in antiretroviral therapy has improved outcomes of HIV-infected patients, its benefit is still limited in patients with PEL. Furthermore, the usual high expression of programmed death ligand 1 in tumor cells, one of the most important immune-checkpoint molecules, results in the immune escape of tumor cells from the host immune defense, which could be the underlying mechanism of poor treatment efficacy. Molecular-targeted therapies for the activating pathways in PEL, including NF-kB, JAK/STAT, and phosphatidylinositol 3-kinase/AKT, have emerged to treat this intractable disease. A combination of immunological recovery from immune deficiency, overcoming the immune escape, and the development of more effective drugs will be vital for improving the outcomes of PEL patients in the future.

    DOI: 10.1182/blood-2018-03-791426

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  33. Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial

    Watanabe T., Tobinai K., Wakabayashi M., Morishima Y., Kobayashi H., Kinoshita T., Suzuki T., Yamaguchi M., Ando K., Ogura M., Taniwaki M., Uike N., Yoshino T., Nawano S., Terauchi T., Hotta T., Nagai H., Tsukasaki K., Kurosawa M., Yamagishi K., Kobayashi N., Minauchi K., Harigae H., Fukuhara N., Takahashi N., Kameoka Y., Matsuda S., Saitoh Y., Tsukamoto N., Yokohama A., Kubota N., Minami Y., Yamauchi N., Kumagai K., Tsujimura H., Izutsu K., Maruyama D., Takayama N., Ohyashiki K., Akahane D., Shimoyama T., Shimada T., Kamiyama Y., Dobashi N., Wasada I., Sano F., Takimoto M., Chou T., Ishiguro T., Masaki Y., Yamauchi T., Ono T., Yamamoto K., Kato H., Tokunaga T., Shimada K., Ushijima Y., Iida S., Kusumoto S., Uchida T., Hanamura I., Kanasugi J., Kagami Y., Hiraga J., Miyazaki K., Utsumi T., Kuroda J., Kobayashi T., Matsumura I., Rai S., Murayama T., Gomyo H., Sunami K., Makita M., Ichinohe T., Fukushima N., Yoshida I., Yakushijin Y., Asai H., Suehiro Y., Choi I., Takamatsu Y., Sasaki H., Yamasaki S., Tsukada J., Morimoto H., Kimura S., Yokoo M., Yoshida S., Moriuchi Y., Miyazaki Y., Imaizumi Y., Jo T., Nosaka K., Tatetsu H., Hidaka M., Harada N., Ohtsuka E., Ishitsuka K., Yoshimitsu M.

    The Lancet Haematology   5 巻 ( 11 ) 頁: e520 - e531   2018年11月

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    記述言語:日本語   出版者・発行元:The Lancet Haematology  

    Background: Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial. Methods: In the phase 2–3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1–3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m2], given on day 1, plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], vincristine [1·4 mg/m2, capped at 2·0 mg] given intravenously on day 3, and oral prednisone [100 mg once daily on days 3–7]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121. Findings: Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25–41; R-CHOP-14 39%, 31–47; hazard ratio 0·89, 95% CI 0·67–1·17). In 248 patients with grade 1–3a follicular lymphoma, progression-free survival was 39% (33–45) at 8 years and 36% (30–42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5–6·0) at 5 years, 8·5% (5·4–12·4) at 8 years, and 9·3% (6·1–13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1–12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3–5·5). Interpretation: R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up—both of which could lead to death. Funding: National Cancer Center and Ministry of Health, Labour and Welfare of Japan.

    DOI: 10.1016/S2352-3026(18)30155-8

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  34. Reappraisal of nodal Epstein-Barr Virus-negative cytotoxic T-cell lymphoma: Identification of indolent CD5(+) diseases. 査読有り

    Yamashita D, Shimada K, Takata K, Miyata-Takata T, Kohno K, Satou A, Sakakibara A, Nakamura S, Asano N, Kato S

    Cancer science   109 巻 ( 8 ) 頁: 2599 - 2610   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    Nodal cytotoxic molecule (CM)-positive peripheral T-cell lymphoma (CTL) has recently been recognized as a clinicopathologically distinct disease. To further characterize this disease, here we compared 58 patients with Epstein-Barr virus (EBV)-negative CTL to 48 patients with EBV-positive CTL. The two groups did not differ in histopathology, T-cell receptor (TCR) expression or rearrangement incidences, or survival curves. However, patients with EBV-negative CTL less frequently showed hepatic involvement (P =.007), B symptoms (P =.020), hemophagocytosis (P =.024), and detectable CD4 (P =.002) and CD5 (P =.009). Univariate and multivariate analyses identified three factors that independently predicted favorable survival, onset age <60 years (P =.002), CD5 expression (P =.002), and mixed morphology (P =.013), TCRαβ was not an independent predictor (P =.30), but was strongly linked with long survivorship among patients younger than 60 years old. A prognostic model incorporating these factors worked well for prognostic delineation, independently of the International Prognostic Index (P =.007 vs P =.082) and Prognostic Index for PTCL (P =.020 vs P =.15). Moreover, this constellation of findings indicated two nodal indolent diseases: CD5+TCRαβ (n = 13), and CD5+ NK-cell type lacking TCR expression or clonal TCRγ rearrangement (n = 4). The survival curves for these two groups were significantly superior to others (n = 29, P <.001). These diseases appear to be unique in their indolent clinical behavior, and should be managed differently from other diseases.

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  35. A prognostic model, including the EBV status of tumor cells, for primary gastric diffuse large B-cell lymphoma in the rituximab era. 査読有り

    Ishikawa E, Tanaka T, Shimada K, Kohno K, Satou A, Eladl AE, Sakakibara A, Furukawa K, Funasaka K, Miyahara R, Nakamura M, Goto H, Nakamura S, Kato S, Hirooka Y

    Cancer medicine   7 巻 ( 7 ) 頁: 3510 - 3520   2018年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Medicine  

    EBV-positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), often affects the gastrointestinal tract. However, the prognostic significance of EBV associated with primary gastric DLBCL (gDLBCL) has not been established. This retrospective study included 240 patients with primary gDLBCL, diagnosed between 1995 and 2015. Tumor specimens were analyzed with EBER in situ hybridization. In 25 (10%) cases, tumor cells harbored EBV. The EBV+ group more frequently exhibited programmed death-ligand 1 (PD-L1) expression in microenvironment immune cells, but not tumor cells, compared to the EBV− group (86% vs 43%, P =.006). Among 156 patients that received rituximab-containing chemotherapy, the EBV+ group had a significantly worse overall survival (OS) than the EBV− group (P =.0029). Multivariate analyses identified 3 independent adverse prognostic factors of OS: multiple gastric lesions (P =.002), EBER positivity (P =.003), and B symptoms (P =.018). These factors were combined to develop a gDLBCL prognostic (gDLP) model that significantly stratified the patients into 3 distinct risk groups (Scores: good = 0, intermediate = 1, and poor = 2/3, P <.0001) with 5-year OS rates of 100%, 81%, and 39%, respectively. Patients with EBV+ gDLBCL commonly exhibited microenvironmental PD-L1 expression and showed a significantly worse prognosis than subjects with EBV− gDLBCL. Our gDLP model, which included EBV+ tumor cells, provided good predictions of clinical outcome and may be useful for selecting patients in trials in the immune-oncology era.

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  36. Early disease progression in patients with localized natural killer/T-cell lymphoma treated with concurrent chemoradiotherapy. 査読有り

    Yamaguchi M, Suzuki R, Kim SJ, Ko YH, Oguchi M, Asano N, Miyazaki K, Terui Y, Kubota N, Maeda T, Kobayashi Y, Amaki J, Soejima T, Saito B, Shimoda E, Fukuhara N, Tsukamoto N, Shimada K, Choi I, Utsumi T, Ejima Y, Kim WS, Katayama N

    Cancer science   109 巻 ( 6 ) 頁: 2056 - 2062   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    Prognosis of patients with localized nasal extranodal natural killer/T-cell lymphoma, nasal type (ENKL) has been improved by non-anthracycline-containing treatments such as concurrent chemoradiotherapy (CCRT). However, some patients experience early disease progression. To clarify the clinical features and outcomes of these patients, data from 165 patients with localized nasal ENKL who were diagnosed between 2000 and 2013 at 31 institutes in Japan and who received radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) were retrospectively analyzed. Progression of disease within 2 years after diagnosis (POD24) was used as the definition of early progression. An independent dataset of 60 patients with localized nasal ENKL who received CCRT at Samsung Medical Center was used in the validation analysis. POD24 was documented in 23% of patients who received RT-DeVIC and in 25% of patients in the validation cohort. Overall survival (OS) from risk-defining events of the POD24 group was inferior to that of the reference group in both cohorts (P <.00001). In the RT-DeVIC cohort, pretreatment elevated levels of serum soluble interleukin-2 receptor (sIL-2R), lactate dehydrogenase, C-reactive protein, and detectable Epstein-Barr virus DNA in peripheral blood were associated with POD24. In the validation cohort, no pretreatment clinical factor associated with POD24 was identified. Our study indicates that POD24 is a strong indicator of survival in localized ENKL, despite the different CCRT regimens adopted. In the treatment of localized nasal ENKL, POD24 is useful for identifying patients who have unmet medical needs.

    DOI: 10.1111/cas.13597

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  37. Bortezomib plus dexamethasone vs thalidomide plus dexamethasone for relapsed or refractory multiple myeloma. 査読有り

    Iida S, Wakabayashi M, Tsukasaki K, Miyamoto K, Maruyama D, Yamamoto K, Takatsuka Y, Kusumoto S, Kuroda J, Ando K, Kikukawa Y, Masaki Y, Kobayashi M, Hanamura I, Asai H, Nagai H, Shimada K, Tsukamoto N, Inoue Y, Tobinai K

    Cancer science   109 巻 ( 5 ) 頁: 1552 - 1561   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    A randomized phase II selection design study (JCOG0904) was carried out to evaluate the more promising regimen between bortezomib (Bor) plus dexamethasone (Dex; BD) and thalidomide (Thal) plus Dex (TD) in Bor and Thal-naïve patients with relapsed or refractory multiple myeloma (RRMM). Patients ≥20 and <80 years old with a documented diagnosis of symptomatic multiple myeloma (MM) who received one or more prior therapies were randomized to receive BD (Bor 1.3 mg/m2) or TD (Thal 200 mg/d). In both arms, 8 cycles of induction (3-week cycle) were followed by maintenance phase (5-week cycle) until disease progression, unacceptable toxicity, or patient refusal. The primary end-point was 1-year progression-free survival (PFS). Forty-four patients were randomized and assigned to receive BD and TD (n = 22, each group). At a median follow-up of 34.3 months, the 1-year PFS in the BD and TD arms were 45.5% (95% confidence interval (CI), 24.4%-64.3%) and 31.8% (95% CI, 14.2%-51.1%), respectively, and the overall response rates were 77.3% and 40.9%, respectively. The 3-year overall survival (OS) was 70.0% (95% CI, 44.9%-85.4%) in the BD, and 48.8% (95% CI, 25.1%-69.0%) in the TD arm. Among grade 3/4 adverse events, thrombocytopenia (54.5% vs 0.0%) and sensory peripheral neuropathy (22.7% vs 9.1%) were more frequent in BD when compared with the TD arm. Patients treated with BD had better outcomes than those treated with TD with regard to 1-year PFS and 3-year OS. Thus, BD was prioritized over TD for further investigations in Bor and Thal-naïve RRMM patients. (Clinical trial registration no. UMIN000003135.).

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  38. Phase I study of cord blood transplantation with intrabone marrow injection of mesenchymal stem cells: A clinical study protocol. 査読有り

    Goto T, Murata M, Terakura S, Nishida T, Adachi Y, Ushijima Y, Shimada K, Ishikawa Y, Hayakawa F, Nishio N, Nishiwaki S, Hirakawa A, Kato K, Takahashi Y, Kiyoi H

    Medicine   97 巻 ( 17 ) 頁: e0449   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Medicine (United States)  

    Introduction: Delayed hematological recovery, graft failure, and acute graft-versus-host disease (GVHD) still remain major problems in cord blood transplantation (CBT). Mesenchymal stem cells (MSCs) are known to support bone marrow stroma and promote hematopoiesis. Additionally, MSCs possess immunomodulatory properties and are used clinically for the treatment of acute GVHD. Therefore, the use of MSCs to enhance engraftment and prevent GVHD after allogeneic hematopoietic cell transplantation has been explored. Recent clinical trials have shown the feasibility and safety of intravenous cotransplantation of MSCs with cord blood cells in pediatric patients, but not in adult patients, who are at greater risk of graft failure. As for the route of administration of MSCs, direct intrabone marrow injection of MSCs is thought to enhance the engraftment of cord blood cells more than intravenous injection. Based on these background findings, this clinical trial was designed to develop a new strategy to enhance engraftment and prevent GVHD after CBT. Methods and analysis: This is a single-center, phase I, clinical study to evaluate the safety of CBT combined with intrabone marrow injection of ex vivo expanded MSCs from bone marrow of a third-party donor. Adult patients with hematological disorders are eligible for this study. The target sample size is 5, and the registration period is 3 years. The target dose of MSCs infused is 0.5 × 10 6 cells/kg of patient body weight. On the day of CBT, MSCs are injected into the intrabone marrow of the patient 4 hours before the infusion of a single cord blood unit. The conditioning regimen varies according to patient age and disease. GVHD prophylaxis consists of a combination of tacrolimus and methotrexate. The primary endpoint of this study is infusional toxicity of MSCs within 14 days after transplantation.

    DOI: 10.1097/MD.0000000000010449

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  39. Altered EZH2 splicing and expression is associated with impaired histone H3 lysine 27 tri-Methylation in myelodysplastic syndrome. 査読有り

    Shirahata-Adachi M, Iriyama C, Tomita A, Suzuki Y, Shimada K, Kiyoi H

    Leukemia research   63 巻   頁: 90 - 97   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Leukemia Research  

    Background EZH2 (enhancer of zeste homolog 2) is a histone H3K27 methyltransferase involved in the pathogenesis of various hematological malignancies. In myelodysplastic syndromes (MDS), loss of function of EZH2 is known to contribute to pathogenesis, however the pattern of EZH2 mRNA and protein expression in MDS has not been extensively characterized. Material and methods A total of 26 patients diagnosed with MDS were analyzed in this study. The relationship between EZH2 expression in patient bone marrow samples, evaluated by RT-PCR and immunoblotting, and patient characteristics were analyzed. The function of truncated EZH2 proteins was examined in vitro. Results EZH2 expression levels and transcript sizes varied considerably between patients, but there was no relationship with the percentage blast component of patient samples. Cloning and sequencing of amplified RT-PCR fragments demonstrated that patients expressed multiple EZH2 transcripts containing insertions or deletions, with or without frameshift, mainly induced by altered splicing. All identified frameshift mutations were found to be 5′ to the functional SET domain, and resulted in truncated protein translation. Altered patterns of EZH2 expression was observed in patients with or without alterations in genes involved with RNA splicing, SRSF2, U2AF1 and SF3B1. Functional analysis in vitro revealed that C-terminally truncated EZH2, lacking the SET domain, may impair the methyltransferase function of wild-type EZH2 in a dominant negative fashion. Conclusion Our findings suggest that the loss of function of EZH2 induced by aberrant splicing, and/or EZH2 mutations resulting in the production of C-terminally truncated proteins, may be involved in MDS pathogenesis.

    DOI: 10.1016/j.leukres.2017.10.015

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  40. YM155 induces apoptosis through proteasome-dependent degradation of MCL-1 in primary effusion lymphoma. 査読有り

    Kojima Y, Hayakawa F, Morishita T, Sugimoto K, Minamikawa Y, Iwase M, Yamamoto H, Hirano D, Imoto N, Shimada K, Okada S, Kiyoi H

    Pharmacological research   120 巻   頁: 242 - 251   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pharmacological Research  

    Primary effusion lymphoma (PEL) is a lymphoma that shows malignant effusion in body cavities without contiguous tumor masses and has a very poor prognosis. We recently developed a novel drug screening system using patient-derived xenograft (PDX) cells that maintained the primary cell phenotype better than cell lines. This screening is expected to discover anti-tumor drugs that have been overlooked by conventional screening using cell lines. We herein performed this screening to identify new therapeutic agents for PEL. We screened 3518 compounds with known pharmaceutical activities based on cytotoxic effects on PDX cells of PEL and selected YM155, a possible survivin inhibitor. It exerted strong anti-tumor effects in PDX cells and three cell lines of PEL; the GI50 of YM155 was 1.2–7.9 nM. We found that YM155 reduced myeloid cell leukemia-1 (MCL-1) protein levels prior to decreasing survivin levels, and this was inhibited by a proteasome inhibitor. The knockdown of MCL-1 by siRNA induced cell death in a PEL cell line, suggesting the involvement of decreased MCL-1 levels in YM155-induced cell death. YM155 also induced the phosphorylation of ERK1/2 and MCL-1, and a MEK1 inhibitor inhibited the phosphorylation of ERK1/2, degradation of MCL-1, and YM155-induced apoptosis. These results indicate that YM155 induces the proteasome-dependent degradation of MCL-1 through its phosphorylation by ERK1/2 and causes apoptosis in PEL cells. Furthermore, a treatment with YM155 significantly inhibited the development of ascites in PEL PDX mice. These results suggest the potential of YM155 as an anti-cancer agent for PEL.

    DOI: 10.1016/j.phrs.2017.04.006

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  41. Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism. 査読有り

    Aoki T, Shimada K, Sakamoto A, Sugimoto K, Morishita T, Kojima Y, Shimada S, Kato S, Iriyama C, Kuno S, Harada Y, Tomita A, Hayakawa F, Kiyoi H

    Oncotarget   8 巻 ( 8 ) 頁: 13085 - 13098   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oncotarget  

    Despite improved clinical outcomes of diffuse large B-cell lymphoma, a certain proportion of patients still develop a primary refractory disease. To overcome these lymphomas that are intractable to existing treatment strategies, the tumor microenvironment has been identified as a potential therapeutic target. Here we describe our search for effective drugs for primary refractory lymphoma cells with MYC rearrangement. Through the drug screening of 3,440 known compounds, we identified a unique compound, emetine. This compound was effective against lymphoma cells with MYC rearrangement from two different patients that were co-cultured with cancer associated fibroblasts. Emetine induced the death of these cells with a half maximal inhibitory concentration of 312 nM and 506 nM, respectively. Subsequent analyses of the mechanism of action of emetine showed that the drug induced apoptosis of tumor cells via alteration of glucose metabolism through inhibition of hypoxia inducible factor-1α. Moreover, emetine inhibited the potential of cancer associated fibroblasts to support tumor cell viability in vitro and demonstrated significant inhibition of tumor growth in in vivo analyses. Emetine also induced cell death in other primary refractory lymphoma cells with MYC rearrangement. Our combined data indicate that emetine is a potential promising drug for the treatment of intractable lymphomas, which targets both the tumor and its microenvironment.

    DOI: 10.18632/oncotarget.14393

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  42. [Malignant lymphoma with cardiac involvement]. 査読有り

    Terakura S, Onji M, Iriyama C, Goto T, Ushijima Y, Shimada K, Ishikawa Y, Nishida T, Hayakawa F, Murata M, Kiyoi H

    [Rinsho ketsueki] The Japanese journal of clinical hematology   58 巻 ( 3 ) 頁: 239 - 242   2017年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.11406/rinketsu.58.239

    PubMed

  43. [Molecular pathogenesis and treatment strategy in diffuse large B-cell lymphoma]. 招待有り 査読有り

    Shimada K

    [Rinsho ketsueki] The Japanese journal of clinical hematology   58 巻 ( 10 ) 頁: 2033 - 2042   2017年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.11406/rinketsu.58.2033

    PubMed

  44. SPIB is a novel prognostic factor in diffuse large B-cell lymphoma that mediates apoptosis via the PI3K-AKT pathway. 査読有り

    Takagi, Yusuke; Shimada, Kazuyuki; Shimada, Satoko; Sakamoto, Akihiko; Naoe, Tomoki; Nakamura, Shigeo; Hayakawa, Fumihiko; Tomita, Akihiro; Kiyoi, Hitoshi

    Cancer science   107 巻 ( 9 ) 頁: 1270-80   2016年9月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cas.13001

  45. Development and analysis of patient-derived xenograft mouse models in intravascular large B-cell lymphoma. 査読有り

    Shimada, K; Shimada, S; Sugimoto, K; Nakatochi, M; Suguro, M; Hirakawa, A; Hocking, T D; Takeuchi, I; Tokunaga, T; Takagi, Y; Sakamoto, A; Aoki, T; Naoe, T; Nakamura, S; Hayakawa, F; Seto, M; Tomita, A; Kiyoi, H

    Leukemia   30 巻 ( 7 ) 頁: 1568-79   2016年7月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/leu.2016.67

  46. Efficacy of ofatumumab against rituximab-resistant B-CLL/SLL cells with low CD20 protein expression 査読有り

    Shimada, K. Tomita, A. Saito, S. Kiyoi, H.

    Br J Haematol   166 巻 ( 3 ) 頁: 455-457   2014年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  47. Retrospective analysis of prognostic factors for angioimmunoblastic T-cell lymphoma: a multicenter cooperative study in Japan 査読有り

    Tokunaga, T. Shimada, K. Yamamoto, K. Chihara, D. Ichihashi, T. Oshima, R. Tanimoto, M. Iwasaki, T. Isoda, A. Sakai, A. Kobayashi, H. Kitamura, K. Matsue, K. Taniwaki, M. Tamashima, S. Saburi, Y. Masunari, T. Naoe, T. Nakamura, S. Kinoshita, T.

    Blood   119 巻 ( 12 ) 頁: 2837-43   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1182/blood-2011-08-374371

  48. Presentation and management of intravascular large B-cell lymphoma 招待有り 査読有り

    Shimada, K. Kinoshita, T. Naoe, T. Nakamura, S.

    Lancet Oncol   10 巻 ( 9 )   2009年9月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/S1470-2045(09)70140-8

  49. Retrospective analysis of intravascular large B-cell lymphoma treated with rituximab-containing chemotherapy as reported by the IVL study group in Japan 査読有り

    Shimada, K. Matsue, K. Yamamoto, K. Murase, T. Ichikawa, N. Okamoto, M. Niitsu, N. Kosugi, H. Tsukamoto, N. Miwa, H. Asaoku, H. Kikuchi, A. Matsumoto, M. Saburi, Y. Masaki, Y. Yamaguchi, M. Nakamura, S. Naoe, T. Kinoshita, T.

    J Clin Oncol   26 巻 ( 19 )   2008年5月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1200/JCO.2007.15.4278

  50. Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial

    Watanabe Takashi, Tobinai Kegsei, Wakabayashi Masashi, Morishima Yasuo, Kobayashi Hirofumi, Kinoshita Tomohiro, Suzuki Takayo, Yamaguchi Motoko, Ando Kiyoshi, Ogura Michinori, Taniwadi Masafumi, Uike Naokuni, Yoshino Tadashi, Nawano Sigeru, Terauchi Takeshi, Hotta Tomomitsu, Nagai Hirokazu, Tsukasaki Kunihiro

    LANCET HAEMATOLOGY   5 巻 ( 11 ) 頁: E520 - E531   2018年11月

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  51. Autopsy case report of intravascular large B-cell lymphoma with neoplastic PD-L1 expression. 査読有り

    Sakakibara A, Inagaki Y, Imaoka E, Ishikawa E, Shimada S, Shimada K, Suzuki Y, Nakamura S, Satou A, Kohno K

    Journal of clinical and experimental hematopathology : JCEH   58 巻 ( 1 ) 頁: 32 - 35   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3960/jslrt.17037

    Web of Science

    PubMed

  52. Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism. 査読有り

    Aoki T, Shimada K, Sakamoto A, Sugimoto K, Morishita T, Kojima Y, Shimada S, Kato S, Iriymaya C, Kuno S, Harada Y, Tomita A, Hayakawa F, Kiyoi H.

    Oncotarget.   8 巻   頁: 13085-13098   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.18632/oncotraget.14393

  53. Peripheral blood cell-free DNA is an alternative tumor DNA source reflecting disease status in myelodysplastic syndromes 査読有り

    Suzuki, Yasuhiro; Tomita, Akihiro; Nakamura, Fumika; Iriyama, Chisako; Shirahata-Adachi, Mizuho; Shimada, Kazuyuki; Akashi, Akimi; Ishikawa, Yuichi; Kaneda, Norio; Kiyoi, Hitoshi

    Cancer science   107 巻 ( 9 ) 頁: 1329-37   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cas.12994

  54. Live-cell single-molecule imaging of the cytokine receptor MPL for analysis of dynamic dimerization. 査読有り

    Sakamoto A, Tsukamoto T, Furutani Y, Sudo Y, Shimada K, Tomita A, Kiyoi H, Kato T, Funatsu T.

    J Mol Cell Biol.   8 巻   頁: 553-555   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  55. High-dose chemotherapy followed by autologous stem cell transplantation for relapsed/refractory primary mediastinal large B-cell lymphoma 査読有り

    T Aoki, K Shimada, R Suzuki, K Izutsu, A Tomita, Y Maeda, J Takizawa, K Mitani, T Igarashi, K Sakai, K Miyazaki, K Mihara, K Ohmachi, N Nakamura, H Takasaki, H Kiyoi, S Nakamura, T Kinoshita, M Ogura

    Blood cancer journal   5 巻 ( 12 ) 頁: e372   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/bcj.2015.101

  56. Discovery of a drug targeting microenvironmental support for lymphoma cells by screening using patient-derived xenograft cells. 査読有り

    Sugimoto K, Hayakawa F*, Shimada S, Morishita T, Shimada K, Katakai T, Tomita A, Kiyoi H, Naoe T

    Sci Rep     2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/srep13054.

  57. Current understanding and future prospects for intravascular large B-cell lymphoma 招待有り 査読有り

    Shimada, Kazuyuki

      56 巻 ( 8 ) 頁: 1032-7   2015年8月

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    担当区分:筆頭著者   記述言語:日本語  

    DOI: 10.11406/rinketsu.56.1032

  58. Target Antigen Density Governs the Efficacy of Anti-CD20-CD28-CD3 zeta Chimeric Antigen Receptor-Modified Effector CD8+ T Cells 査読有り

    Watanabe, K. Terakura, S. Martens, A. C. van Meerten, T. Uchiyama, S. Imai, M. Sakemura, R. Goto, T. Hanajiri, R. Imahashi, N. Shimada, K. Tomita, A. Kiyoi, H. Nishida, T. Naoe, T. Murata, M.

    J Immunol   194 巻 ( 3 ) 頁: 911-920   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  59. Prognostic significance of pleural or pericardial effusion and the implication of optimal treatment in primary mediastinal large B-cell lymphoma: a multicenter retrospective study in Japan 査読有り

    Aoki, T. Izutsu, K. Suzuki, R. Nakaseko, C. Arima, H. Shimada, K. Tomita, A. Sasaki, M. Takizawa, J. Mitani, K. Igarashi, T. Maeda, Y. Fukuhara, N. Ishida, F. Niitsu, N. Ohmachi, K. Takasaki, H. Nakamura, N. Kinoshita, T. Nakamura, S. Ogura, M.

    Haematologica   99 巻 ( 12 ) 頁: 1817-1825   2014年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  60. De novo DLBCL with a CD20 IHC(+) and FCM(-) phenotype: molecular mechanisms and correlation with rituximab sensitivity 査読有り

    Tokunaga, T. Tomita, A. Sugimoto, K. Shimada, K. Iriyama, C. Hirose, T. Shirahata-Adachi, M. Suzuki, Y. Mizuno, H. Kiyoi, H. Asano, N. Nakamura, S. Kinoshita, T. Naoe, T.

    Cancer Sci     2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cas.12307

  61. Chemically modified synthetic microRNA-205 inhibits the growth of melanoma cells in vitro and in vivo 査読有り

    Noguchi, S. Iwasaki, J. Kumazaki, M. Mori, T. Maruo, K. Sakai, H. Yamada, N. Shimada, K. Naoe, T. Kitade, Y. Akao, Y.

    Mol Ther   21 巻 ( 6 )   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/mt.2013.70

  62. CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737 査読有り

    Shimada, K. Tomita, A. Minami, Y. Abe, A. Hind, C. K. Kiyoi, H. Cragg, M. S. Naoe, T.

    Exp Hematol   40 巻 ( 9 )   2012年5月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.exphem.2012.05.007

  63. Phase II study of dose-modified busulfan by real-time targeting in allogeneic hematopoietic stem cell transplantation for myeloid malignancy 査読有り

    Kuwatsuka, Y. Kohno, A. Terakura, S. Saito, S. Shimada, K. Yasuda, T. Inamoto, Y. Miyamura, K. Sawa, M. Murata, M. Karasuno, T. Taniguchi, S. Nagafuji, K. Atsuta, Y. Suzuki, R. Fukumoto, M. Naoe, T. Morishita, Y.

    Cancer Sci   103 巻 ( 9 )   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1349-7006.2012.02342.x

  64. Retrospective analysis of primary gastric diffuse large B cell lymphoma in the rituximab era: a multicenter study of 95 patients in Japan 査読有り

    Tanaka, T. Shimada, K. Yamamoto, K. Hirooka, Y. Niwa, Y. Sugiura, I. Kitamura, K. Kosugi, H. Kinoshita, T. Goto, H. Nakamura, S.

    Ann Hematol   91 巻 ( 3 )   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s00277-011-1306-0

  65. A case report of angioimmunoblastic T cell lymphoma (AITL) with localization of neoplastic clear cells in the outer zone of germinal centers 査読有り

    Murakami, Y. Shimada, K. Kosugi, H. Mori, N.

    Pathol Int   61 巻 ( 5 )   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1440-1827.2011.02655.x

  66. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies 査読有り

    Alduaij, W. Ivanov, A. Honeychurch, J. Cheadle, E. J. Potluri, S. Lim, S. H. Shimada, K. Chan, C. H. Tutt, A. Beers, S. A. Glennie, M. J. Cragg, M. S. Illidge, T. M.

    Blood   117 巻 ( 17 )   2011年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1182/blood-2010-07-296913

  67. Virus-associated hemophagocytic syndrome caused by pandemic swine-origin influenza A (H1N1) in a patient after unrelated bone marrow transplantation. 査読有り

    Katsumi, Akira; Nishida, Tetsuya; Murata, Makoto; Terakura, Seitaro; Shimada, Kazuyuki; Saito, Shigeki; Kobayashi, Miki; Kodaira, Akari; Shibata, Shinichiro; Oda, Isao; Yagi, Tetsuya; Kiyoi, Hitoshi; Matsushita, Tadashi; Kojima, Tetsuhito; Naoe, Tomoki.

    Journal of clinical and experimental hematopathology   51 巻 ( 1 ) 頁: 63-5   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  68. Central nervous system involvement in intravascular large B-cell lymphoma: a retrospective analysis of 109 patients 査読有り

    Shimada, K. Murase, T. Matsue, K. Okamoto, M. Ichikawa, N. Tsukamoto, N. Niitsu, N. Miwa, H. Asaoku, H. Kosugi, H. Kikuchi, A. Matsumoto, M. Saburi, Y. Masaki, Y. Yamamoto, K. Yamaguchi, M. Nakamura, S. Naoe, T. Kinoshita, T.

    Cancer Sci   101 巻 ( 6 )   2010年4月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1349-7006.2010.01555.x

  69. Concurrent chemoradiotherapy for limited-stage extranodal natural killer/t-cell lymphoma, nasal type

    Shimada, K. Suzuki, R.

    J Clin Oncol   28 巻 ( 14 )   2010年3月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1200/JCO.2009.27.7574

  70. Escape mechanisms from antibody therapy to lymphoma cells: downregulation of CD20 mRNA by recruitment of the HDAC complex and not by DNA methylation 査読有り

    Sugimoto, T. Tomita, A. Hiraga, J. Shimada, K. Kiyoi, H. Kinoshita, T. Naoe, T.

    Biochem Biophys Res Commun   390 巻 ( 1 )   2009年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbrc.2009.09.059

  71. Comparative clinicopathological study of primary CNS diffuse large B-cell lymphoma and intravascular large B-cell lymphoma 査読有り

    Imai, H. Shimada, K. Shimada, S. Abe, M. Okamoto, M. Kitamura, K. Kinoshita, T. Shiraishi, T. Nakamura, S.

    Pathol Int   59 巻 ( 7 )   2009年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1440-1827.2009.02390.x

  72. Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance 査読有り

    Hiraga, J. Tomita, A. Sugimoto, T. Shimada, K. Ito, M. Nakamura, S. Kiyoi, H. Kinoshita, T. Naoe, T.

    Blood   113 巻 ( 20 )   2009年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1182/blood-2008-08-175208

  73. Evaluation of organ involvement in intravascular large B-cell lymphoma by 18F-fluorodeoxyglucose positron emission tomography 査読有り

    Shimada, K. Kosugi, H. Shimada, S. Narimatsu, H. Koyama, Y. Suzuki, N. Yuge, M. Nishibori, H. Iwata, Y. Nakamura, S. Naoe, T. Kinoshita, T.

    Int J Hematol   88 巻 ( 2 )   2008年5月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s12185-008-0102-7

  74. Nodal T/NK-cell lymphoma of nasal type: a clinicopathological study of six cases 査読有り

    Takahashi, E. Asano, N. Li, C. Tanaka, T. Shimada, K. Shimada, S. Yoshino, T. Kojima, M. Hara, K. Eimoto, T. Nakamura, S.

    Histopathology   52 巻 ( 5 )   2008年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1365-2559.2008.02997.x

  75. High incidence of secondary failure of platelet recovery after autologous and syngeneic peripheral blood stem cell transplantation in acute promyelocytic leukemia 査読有り

    Narimatsu, H. Emi, N. Kohno, A. Iwai, M. Yanada, M. Yokozawa, T. Saito, S. Shimada, K. Kiyoi, H. Naoe, T. Yamamoto, K. Morishita, Y.

    Bone Marrow Transplant   40 巻 ( 8 )   2007年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/sj.bmt.1705820

  76. Mutations of N-RAS, FLT3 and p53 genes are not involved in the development of acute leukemia transformed from myeloproliferative diseases with JAK2 mutation 査読有り

    Suzuki, M. Abe, A. Kiyoi, H. Murata, M. Ito, Y. Shimada, K. Morishita, Y. Kinoshita, T. Naoe, T.

    Leukemia   20 巻 ( 6 )   2006年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/sj.leu.2404186

  77. Severe regimen-related toxicity of second transplantation for graft failure following reduced-intensity cord blood transplantation in an adult patient 査読有り

    Shimada, K. Narimatsu, H. Morishita, Y. Kohno, A. Saito, S. Kato, Y.

    Bone Marrow Transplant   37 巻 ( 8 )   2006年2月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/sj.bmt.1705312

  78. Solid tumors after hematopoietic stem cell transplantation in Japan: incidence, risk factors and prognosis 査読有り

    Shimada, K. Yokozawa, T. Atsuta, Y. Kohno, A. Maruyama, F. Yano, K. Taji, H. Kitaori, K. Goto, S. Iida, H. Morishima, Y. Kodera, Y. Naoe, T. Morishita, Y.

    Bone Marrow Transplant   36 巻 ( 2 )   2005年5月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/sj.bmt.1705020

  79. Conditioning regimen of melphalan, fludarabine and total body irradiation in unmanipulated HLA haploidentical stem cell transplantation based on feto-maternal tolerance 査読有り

    Narimatsu, H. Morishita, Y. Saito, S. Shimada, K. Ozeki, K. Kohno, A. Kato, Y.

    Intern Med   43 巻 ( 11 )   2004年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 1063-7

  80. Adenocarcinomatosis of the bone marrow and secondary acute myeloid leukemia 査読有り

    Narimatsu, H. Morishita, Y. Watanabe, N. Saito, S. Shimada, K. Ozeki, K. Kohno, A. Kato, Y. Nagasaka, T.

    Intern Med   43 巻 ( 8 ) 頁: 764-5   2004年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  81. Usefulness of bone marrow aspiration for definite diagnosis of Asian variant of intravascular lymphoma: four autopsied cases 査読有り

    Narimatsu, H. Morishita, Y. Saito, S. Shimada, K. Ozeki, K. Kohno, A. Kato, Y. Nagasaka, T.

    Leuk Lymphoma   45 巻 ( 8 )   2004年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1080/10428190410001683769

  82. Primary cutaneous diffuse large B cell lymphoma: a clinically aggressive case 査読有り

    Narimatsu, H. Morishita, Y. Shimada, K. Ozeki, K. Kohno, A. Kato, Y. Nagasaka, T.

    Intern Med   42 巻 ( 4 ) 頁: 354-7   2003年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  83. Genomic analysis of a murine cell-surface sialomucin, MGC-24/CD164.

    Kurosawa N, Kanemitsu Y, Matsui T, Shimada K, Ishihama H, Muramatsu T.

    Eur J Biochem   265 巻   頁: 466-472   1999年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

▼全件表示

MISC 1

  1. A case of reexpansion pulmonary edema and acute pulmonary thromboembolism associated with diffuse large B-cell lymphoma treated with venovenous extracorporeal membrane oxygenation.

    Kazama S, Hiraiwa H, Kimura Y, Ozaki R, Shibata N, Arao Y, Oishi H, Kato H, Kuwayama T, Yamaguchi S, Kondo T, Furusawa K, Morimoto R, Okumura T, Bando YK, Sato T, Shimada K, Kiyoi H, Nakamura G, Yasuda Y, Kasugai D, Ogawa H, Higashi M, Yamamoto T, Jingushi N, Ozaki M, Numaguchi A, Goto Y, Matsuda N, Murohara T  

    Journal of cardiology cases23 巻 ( 1 ) 頁: 53 - 56   2021年1月

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    記述言語:英語   出版者・発行元:Journal of Cardiology Cases  

    A 37-year-old man diagnosed with diffuse large B-cell lymphoma two weeks previously, visited our emergency department with sudden dyspnea. He had a severe respiratory failure with saturated percutaneous oxygen at 80% (room air). Chest radiography showed a large amount of left pleural effusion. After 1000 mL of the effusion was urgently drained, reexpansion pulmonary edema (RPE) occurred. Despite ventilator management, oxygenation did not improve and venovenous extracorporeal membrane oxygenation (VV-ECMO) was initiated in the intensive care unit. The next day, contrast-enhanced computed tomography showed a massive thrombus in the right pulmonary artery, at this point the presence of pulmonary thromboembolism (PTE) was revealed. Fortunately, the patient's condition gradually improved with anticoagulant therapy and VV-ECMO support. VV-ECMO was successfully discontinued on day 4, and chemotherapy was initiated on day 8. We speculated the following mechanism in this case: blood flow to the right lung significantly reduced due to acute massive PTE, and blood flow to the left lung correspondingly increased, which could have caused RPE in the left lung. Therefore, our observations suggest that drainage of pleural effusion when contralateral blood flow is impaired due to acute PTE may increase the risk of RPE. <Learning objective: This is a case of reexpansion pulmonary edema (RPE) in the left lung following acute pulmonary thromboembolism (PTE) in the right lung associated with malignant lymphoma, managed by venovenous extracorporeal membrane oxygenation. Contralateral pleural drainage could increase the risk of RPE because contralateral pulmonary blood flow is assumed to increase when PTE obstructs blood flow. Pleural drainage should be performed carefully in patients with malignant tumors because PTE may be hidden.>

    DOI: 10.1016/j.jccase.2020.08.013

    Scopus

    PubMed

講演・口頭発表等 10

  1. Favorable outcomes of newly diagnosed intravascular large B-cell lymphoma patients treated with R-CHOP combined with high-dose methotrexate plus intrathecal chemotherapy: results from a multicenter phase 2 trial (PRIMEUR-IVL) 国際会議

    Kazuyuki Shimada, Motoko Yamaguchi, Yoshiko Atsuta, Kosei Matsue, Keijiro Sato, Shigeru Kusumoto, Hirokazu Nagai, Jun Takizawa, Noriko Fukuhara, Koji Nagafuji, Kana Miyazaki, Eiichi Ohtsuka, Masataka Okamoto, Yasumasa Sugita, Toshiki Uchida, Satoshi Kayukawa, Atsushi Wake, Daisuke Ennishi, Yukio Kondo, Tohru Izumi, Yoshihiro Kin, Kunihiro Tsukasaki, Daigo Hashimoto, Masaaki Yuge, Atsumi Yanagisawa, Yachiyo Kuwatsuka, Satoko Shimada, Yasufumi Masaki, Nozomi Niitsu, Hitoshi Kiyoi, Ritsuro Suzuki, Takashi Tokunaga, Shigeo Nakamura, Tomohiro Kinoshita, on behalf of IVL study group in Japan

    The 61st ASH Annual Meeting and Exposition  2019年12月8日 

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    開催年月日: 2019年12月

    記述言語:英語   会議種別:口頭発表(一般)  

  2. Current achievement of research and clinical practice in intravascular large B-cell lymphoma 招待有り

    Kazuyuki Shimada

    2020年10月 

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    開催年月日: 2020年10月 - 2020年11月

    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

  3. Significance of exosomes secreted from cancer-associated fibroblasts in lymphoma microenvironment

    Kunou Shunsuke, Shimada Kazuyuki, Hikita Tomoya, Sakamoto Akihiko, Oneyama Chitose, Kiyoi Hitoshi

    CANCER SCIENCE 

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    開催年月日: 2018年12月

    記述言語:日本語   会議種別:口頭発表(一般)  

  4. 異種移植マウスモデルを用いた血管内大細胞型B細胞リンパ腫の病態解析 招待有り

    島田和之

    第54回日本癌治療学会学術集会 

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    開催年月日: 2016年10月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(公募)  

    国名:日本国  

  5. 悪性リンパ腫におけるWHO分類とその運用 招待有り

    杉浦由姫乃, 島田和之

    第16回日本検査血液学会学術集会 

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    開催年月日: 2015年7月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(指名)  

    国名:日本国  

  6. Development and Analysis of Novel Intravascular Large B-Cell Lymphoma NOD/Shi-Scid IL2Rγnull Mouse Xenograft Model 国際会議

    7. Shimada K*, Shimada S, Sugimoto K, Hayakawa F, Katayama M, Hirakawa A, Takagi Y, Nakamura S, Seto M, Naoe T, Tomita A, Kiyoi H.

    The 56th Annual Meeting of the American Society of Hematology. 

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    開催年月日: 2014年12月

    記述言語:英語   会議種別:口頭発表(一般)  

    国名:アメリカ合衆国  

  7. Intravascular large B-cell lymphoma-from bench to bedside. 招待有り

    Shimada K.

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    開催年月日: 2014年11月

    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

    国名:日本国  

  8. 血管内大細胞型B細胞リンパ腫の治療戦略 招待有り

    島田和之, 木下朝博

    第53回日本リンパ網内系学会総会 

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    開催年月日: 2013年5月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(指名)  

    国名:日本国  

  9. 血管内大細胞型B細胞リンパ腫の臨床成績の向上に関する研究 招待有り

    島田和之

    第71回日本癌学会学術総会 

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    開催年月日: 2012年9月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  10. Presentation and management of intravascular large B-cell lymphoma 招待有り

     詳細を見る

    開催年月日: 2011年10月

    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

    国名:日本国  

▼全件表示

共同研究・競争的資金等の研究課題 3

  1. 悪性リンパ腫の臓器指向性を規定する腫瘍細胞と微小環境構成細胞の相互作用の解明と革新的な分子標的治療法の開発

    2017年4月 - 現在

  2. 悪性リンパ腫の腫瘍細胞と微小環境構成細胞の比較解析と微小環境構成細胞による腫瘍支持機構を標的とする新規治療法の開発

    2014年8月 - 2017年3月

    革新的がん医療実用化研究事業 

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    資金種別:競争的資金

  3. 悪性リンパ腫細胞の臓器指向性のメカニズム解明と責任遺伝子を標的とした革新的治療法の開発

    2014年1月 - 2015年3月

科研費 6

  1. 悪性リンパ腫の多様性から解く臓器指向性の解明と新規治療への応用

    研究課題/研究課題番号:20K08751  2020年4月 - 2023年3月

    科学研究費助成事業  基盤研究(C)

    島田 和之

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    担当区分:研究代表者 

    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    悪性リンパ腫は、リンパ節を病変の主座とする節性リンパ腫、節外臓器を病変の主座とする節外性リンパ腫に大別される。本研究では、節性リンパ腫病変においては、微小環境を構成するがん関連線維芽細胞(CAF)より分泌されるエクソソームに焦点をおき、エクソソームがもたらす腫瘍細胞への薬剤感受性変化および周囲の免疫担当細胞への影響について検討する。節外性リンパ腫病変においては、これまでの検討で見出した中枢神経病変に強発現する遺伝子の機能を解析するとともに、中枢神経病変形成に関連する腫瘍細胞のクローン性について検討する。また血管内病変を形成する血管内リンパ腫に対する新たな免疫療法の可能性を探索する。
    2021年度においては、節性病変の微小環境を構成するがん関連線維芽細胞(CAF)より分泌されるエクソソームの役割の解明として、エクソソームにより感受性変化を来すHDAC阻害剤の作用機序の解明に取り組んだ。HDAC阻害薬存在下において、エクソソームの有無による難治性B細胞リンパ腫患者由来PDX(patient-derived xenograft)細胞の遺伝子発現を比較した。発現変化を来す遺伝子を同定し、現在その検証を行っている。また、エクソソームの腫瘍微小環境への影響の探索として、CAF共培養下/エクソソーム存在下における抗体医薬の作用変化について検討した。まず、CAF共培養下/エクソソーム存在下において、非存在下と比較して抗体医薬による直接細胞死作用や補体依存性細胞傷害活性に差異が認められないことを確認した。次に抗体依存性細胞傷害活性を検討し、CAF共培養下・エクソソーム存在下において、NK細胞による抗CD20抗体医薬への作用変化が認められることを確認した。
    また、中枢神経病変形成機序の解明については、これまでの検討で見出した中枢神経病変にて発現が認められる遺伝子について検討を進めた。当該遺伝子を形質導入したB細胞リンパ腫細胞株によるPDXモデルを作成し、中枢神経を含む各臓器に形成された腫瘍の当該遺伝子発現の検討を行っている。IVLBCLにおけるPD-L1構造異常への治療応用への可能性の探索については、シングルセルレベルでの解析を可能とするcell barcodingシステムの構築に取り組んだ。作成されたプラスミドが、難治性B細胞リンパ腫由来PDX細胞に対して、形質導入可能であることを確認したが、IVLBCL由来PDX細胞に対する形質導入効率については改善の必要があることを見出し、現在導入効率を向上させるための試みを行っている。
    CAFより分泌されるエクソソームの役割の解明と標的治療の開発については、エクソソームによる薬剤感受性変化と関連するHDAC classを同定し、当該classを阻害するHDAC阻害薬の存在下において、エクソソームによる腫瘍細胞の発現変化を検討した。発現変化を来す遺伝子を抽出し、現在その検証を行うことにより、エクソソームの標的分子を検討している。エクソソームによる薬剤感受性変化の分子機構の一端を解明するものと考えている。また、エクソソームの微小環境への影響についても、CAF共培養下/エクソソーム存在下における抗体医薬の作用について検討し、CAF共培養下/エクソソーム存在下において抗CD20抗体医薬における抗体依存性細胞傷害活性に変化が認められることを確認した。現在、CAF共培養下/エクソソーム存在下における免疫担当細胞の機能解析に着手している。
    中枢神経病変形成機序の解明については、中枢神経病変に特徴的に発現する遺伝子に着目して検討を進めている。当該遺伝子を形質導入させたB細胞リンパ腫細胞株を作成し、PDXモデルにおける野生株移植モデルとの病変部位、各臓器病変における当該遺伝子の発現に比較検討している。今年度も比較して当該遺伝子の妥当性について検討を進める。PD-L1を高発現するIVLBCLに対しては、抗PD-1抗体についてのPDX評価モデルを作成し、治療効果について検討を進めている。シングルセル解析を可能とするcell barcodingシステムの構築も進んでおり、概ね順調に進展していると考えている。
    最終年度となる2022年度については、本研究課題の成果発表に着手していく。エクソソームによる薬剤感受性変化とその分子機構の解明については、HDAC阻害薬の感受性変化の背景にある分子機構の解明を推進し、成果発表の準備を進めていく。エクソソーム存在下・非存在下における抗体医薬の感受性変化については、作用変化が認められた抗体依存性細胞傷害活性について、検証を進めるとともに、作用変化をもたらす免疫担当細胞の機能変化を確認していく。
    中枢神経病変形成機序の解明、血管内リンパ腫へのPD-L1を標的とした新規治療法の探索については、引き続きcell barcodingを用いた評価系の構築に取り組んでいく。2021年度に明らかとなったIVLBCL PDX細胞への形質導入効率の向上について取り組むとともに、cell barcodingの評価系についてIVLBCL以外のB細胞リンパ腫も含めて検討し、評価系の実証に取り組んでいく。中枢神経病変形成の機序の解明についても、cell barcodingシステムは応用可能であり、現在解析中のモデルを解析するとともに、新たな評価系も組み合わせることにより、中枢神経病変形成の機序を明らかにしていく。

  2. 悪性リンパ腫の臓器指向性に関わる腫瘍細胞と微小環境の相互作用の解明と新規治療開発

    2017年4月 - 2020年3月

    科学研究費補助金  基盤研究(C)

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    担当区分:研究代表者 

  3. 悪性リンパ腫の臓器指向性に関わる腫瘍細胞と微小環境の相互作用の解明と新規治療開発

    研究課題/研究課題番号:17K09922  2017年4月 - 2020年3月

    島田 和之

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    担当区分:研究代表者 

    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    悪性リンパ腫の節性病変において、腫瘍関連線維芽細胞(CAF)がピルビン酸やエクソソームを分泌することにより、腫瘍細胞の糖代謝を亢進させ、その生存支持に関与していることを明らかにした。催吐薬であるemetineが、腫瘍細胞の糖代謝を阻害することにより、難治性B細胞リンパ腫細胞に対して治療効果を示すことを明らかにした。さらに、エクソソームが、抗ピリミジン薬の膜輸送タンパクの発現変化を通して、抗ピリミジン薬の感受性変化に関与していることを明らかにした。節外病変形成においては、中枢神経病変特異的に発現する遺伝子を同定し、当該遺伝子が中枢神経病変形成に関与していることを明らかにした。
    悪性リンパ腫の節性病変におけるCAFについては、知見がそれほど集積しておらず、CAFより分泌されるピルビン酸およびエクソソームが、腫瘍細胞への生存に関与していることを明らかにしたことには学術的意義があると考えられる。さらに本研究では、エクソソームが、抗ピリミジン薬の膜輸送タンパクの発現変化を通して、その感受性に関与し、実際の臨床検体においても、膜輸送タンパク発現が抗ピリミジン薬の感受性予測因子となり得ることを示した。抗ピリミジン薬は、悪性リンパ腫診療における救援療法のキードラッグの一つであり、膜輸送タンパク発現を評価することにより、実際の診療における適切な治療選択に有用となる可能性がある。

  4. 悪性リンパ腫の臓器指向性のメカニズム解明と節外臓器浸潤を抑制する新規治療法の開発

    2014年4月 - 2017年3月

    科学研究費補助金  若手研究(B)

      詳細を見る

    担当区分:研究代表者 

  5. 創薬に向けた白血病のトランスレーショナルリサーチ

    2014年4月 - 2016年3月

    科学研究費補助金  基盤研究(B)

      詳細を見る

    担当区分:研究分担者 

  6. 悪性リンパ腫における微小環境依存性と治療開発に関する研究

    2013年4月 - 2015年3月

    科学研究費補助金 

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    担当区分:研究分担者 

▼全件表示

産業財産権 1

  1. 血液関連疾患患者のリンパ節由来の間質細胞

    清井仁, 冨田章裕, 早川文彦, 島田和之, 坂本明彦

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    出願番号:2015-132000  出願日:2015年6月

    公開番号:2017-012078  公開日:2017年1月

    出願国:国内