研究者詳細 - 島田　和之

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

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

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

Zanubrutinib in Japanese treatment-naive and relapsed/refractory patients with Waldenström macroglobulinemia and CLL/SLL. 査読有り Open Access

Izutsu K, Ishikawa T, Shimada K, Kubo K, Kondo T, Fujimoto K, Fujisaki T, Kurahashi S, Nagafuji K, Sakai R, Jo T, Nakazato T, Sunami K, Kasahara S, Cohen A, Takai M, Zhong J, Takeuchi M

International journal of hematology 2025年2月

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

Zanubrutinib is a selective second-generation Bruton tyrosine kinase inhibitor approved in various B-cell malignancies globally. The phase 1/2 BGB-3111-111 study evaluated the efficacy and safety of zanubrutinib 160 mg twice daily orally in Japanese patients with treatment-naive or relapsed/refractory mature B-cell malignancies. Here, efficacy results from Part 2 in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 19) and Waldenström macroglobulinemia (WM; n = 19), and safety results from Parts 1 (N = 6) and 2 (N = 49) are presented, with the first dose between 30 January, 2020, and 31 October, 2022. As of 10 May, 2023, investigator-assessed overall response rates were 100% (19/19) and 94.7% (18/19) in CLL/SLL and WM, respectively, with median follow-up of 27.9 and 26.8 months; 24-month progression-free survival rates were 71.4% and 100% in treatment-naive and relapsed/refractory CLL/SLL and 83.9% and 100% in treatment-naive and relapsed/refractory WM, respectively. In patients with B-cell malignancies, any-grade treatment-emergent adverse events (TEAEs) occurred in 53 (96.4%) and serious TEAEs in 18 (32.7%). Common TEAEs were platelet count decreased (18.2%), pyrexia (18.2%), COVID-19 (14.5%), and neutrophil count decreased (12.7%). With median follow-up > 2 years, zanubrutinib demonstrated durable efficacy in Japanese patients with CLL/SLL or WM and a favorable safety profile consistent with global phase 3 studies.

DOI： 10.1007/s12185-025-03925-1

Open Access

Multicenter randomized phase III study of high-dose therapy with autologous stem cell transplantation versus observation for patients with newly diagnosed peripheral T-cell lymphoma who achieved complete metabolic response after induction therapy (JCOG2210, TRANSFER study). 査読有り

Kita R, Shimada K, Machida R, Sekita T, Sasaki K, Ishitsuka K, Fukuda H, Maruyama D, Munakata W, Nagai H, Japan Clinical Oncology Group Lymphoma Study Group

Japanese journal of clinical oncology 55 巻 ( 2 ) 頁： 183 - 188 2025年2月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Journal of Clinical Oncology

Patients with peripheral T-cell lymphoma demonstrated a poor prognosis after obtaining a complete response with induction treatment compared to those with B-cell lymphoma. Once it relapsed, curative treatment is frequently limited to invasive treatments with significant treatment-related mortality, including allogeneic stem cell transplantation. The limitations of these treatment choices indicate the necessity for developing optimal consolidation therapies to prevent relapse. This multicenter randomized phase III trial aims to confirm the superiority of the high-dose therapy with autologous stem cell transplantation over observation alone in terms of progression-free survival for patients with newly diagnosed peripheral T-cell lymphoma who achieved complete metabolic response after induction therapy. A total of 140 patients from 52 hospitals will be enrolled in Japan over 5.5 years. This trial is registered in the Japan Registry of Clinical Trials as jRCTs031240169 (https://jrct.niph.go.jp/latest-detail/jRCTs031240169).

DOI： 10.1093/jjco/hyae144

Efficacy and safety of mosunetuzumab monotherapy for Japanese patients with relapsed/refractory follicular lymphoma: FLMOON-1. 査読有り Open Access

Goto H, Kumode T, Mishima Y, Kataoka K, Ogawa Y, Kanemura N, Shimada K, Uchida T, Kuroe Y, Kawasaki A, Sato J, Teshima T

International journal of clinical oncology 30 巻 ( 2 ) 頁： 389 - 396 2025年2月

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 Clinical Oncology

Background: In a global phase I/II study (GO29781; NCT02500407), single-agent mosunetuzumab had a manageable safety profile and induced durable complete responses in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma, including in patients with R/R follicular lymphoma (FL). In this analysis, the efficacy and safety of mosunetuzumab monotherapy were evaluated in an expansion cohort, FLMOON-1, in Japanese patients with R/R FL who had received ≥ 2 prior lines of therapy in a phase I study (JO40295, jRCT2080223801). Methods: Mosunetuzumab was administered intravenously at the recommended phase II dose (with cycle 1 step-up dosing) for eight cycles or up to 17 cycles, or until disease progression or unacceptable toxicity. The pre-specified primary endpoint was Independent Review Facility (IRF)-assessed complete response rate (CRR; as best overall response). Secondary objectives included investigator (INV)-assessed CRR, INV- and IRF-assessed objective response rate (ORR), and safety. Results: At the data cutoff (October 13, 2023), 19 patients (median age 72 years) were evaluated. The IRF-assessed CRR and ORR were 68.4% and 78.9%, respectively; the INV-assessed CRR and ORR were 63.2% and 84.2%, respectively. Grade 3–4 adverse events (AEs) were observed in 89.5% of patients, with a low incidence of AEs leading to mosunetuzumab discontinuation (10.5%) and one fatal AE unrelated to mosunetuzumab. Cytokine release syndrome occurred in 47.4% of patients and were mostly Grade 1 in severity. Conclusion: These findings indicate mosunetuzumab has a consistent efficacy and manageable safety profile in Japanese patients with R/R FL compared with previously reported data from the global phase I/II study.

DOI： 10.1007/s10147-024-02662-5

Open Access

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

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

EClinicalMedicine 80 巻頁： 103078 2025年2月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：eClinicalMedicine

Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma for which prognosis is typically poor without a timely diagnosis. To explore the safety and efficacy of standard chemotherapy combined with central nervous system (CNS)-directed therapy, we conducted a multicentre, single-arm, phase 2 trial in untreated IVLBCL patients without CNS involvement at diagnosis (PRIMEUR-IVL). In the primary analysis, the PRIMEUR-IVL study demonstrated 2-year progression-free survival (PFS) of 76% and 2-year overall survival (OS) of 92% with a low incidence (3%) of secondary CNS involvement (sCNSi). Methods: We present a prespecified final analysis of the PRIMEUR-IVL study including 5-year PFS, OS and cumulative incidence of sCNSi. Participants were enrolled between June 2011 and July 2016, and the data cutoff date for the final analysis was 16 November 2021. The trial was registered in the UMIN Clinical Trial Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165). Findings: With a median follow-up of 7.1 years (interquartile range 5.6–8.7), 5-year PFS in all 37 eligible patients was 68% (95% confidence interval [CI] 50%–80%) and OS was 78% (95% CI 61%–89%). No additional sCNSi was observed after the primary analysis. Severe adverse events after the primary analysis were grade 4 neutropenia (n = 1) and grade 4 myelodysplastic syndrome that did not require specific treatment (n = 1). Eight deaths occurred during the observation period after enrolment, due to primary disease (n = 6), sepsis (n = 1) and unknown sudden death (n = 1). Interpretation: Long-term follow-up data demonstrated durable response for PFS and OS, and low cumulative incidence of sCNSi, indicating the efficacy of standard chemotherapy combined with CNS-directed therapy for untreated IVLBCL patients. Funding: This study received financial support from the Japan Agency for Medical Research and Development, Center for Supporting Hematology-Oncology Studies, and National Cancer Center.

DOI： 10.1016/j.eclinm.2025.103078

Open Access

Primary large B-cell lymphoma of the central nervous system: A reappraisal of CD5-positive cases based on clinical, pathological, and molecular evaluation. 査読有り

Yamada S, Satou A, Tsuyuki Y, Iba S, Okumura Y, Ishikawa E, Ito H, Kogure Y, Goto N, Tanikawa M, Shimada K, Tsukamoto T, Karube K, Yokoo H, Kataoka K, Tomita A, Mase M, Nakamura S

Pathology international 75 巻 ( 1 ) 頁： 11 - 20 2025年1月

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

CD5 expression is seen in 5%–10% of de novo diffuse large B-cell lymphomas (DLBCLs). Primary large B-cell lymphoma of the central nervous system (PCNS-LBCL) also exhibits CD5 expression in a minority of cases, however, clinicopathological and molecular features remain largely unclarified. Here we present the clinical, molecular, and pathological features of 11 CD5-positive (+) PCNS-LBCL cases, occupying 6.7% of all 165 PCNS-LBCLs diagnosed in our institutions. While CD5+ systemic DLBCL has been recognized as a distinctive subgroup showing an aggressive clinical course, no obvious differences were found between CD5+ and CD5-negative subgroups among the present CNS patients clinically. MYD88 p.L265P and CD79B p.Y196 mutations were detected in eight (73%) and seven (64%) cases, respectively, supporting previous reports. Notably, the microenvironmental immune cells were universally PD-L1/CD274-positive, and the higher levels tended to present favorable overall survival, as already evidenced in the PCNS-LBCL series. In contrast, neoplastic PD-L1/CD274 expression was undetectable in all cases. Indeed, no structural variations or copy number alterations involving PD-1 ligands were detected by targeted-capture sequencing and fluorescence in situ hybridization. While further studies are warranted, we may have confirmed similarity between PCNS-LBCLs and intravascular large B-cell lymphomas from a molecular standpoint.

DOI： 10.1111/pin.13496

Spheroid culture to select theoretical therapeutic drugs in intravascular large B-cell lymphoma. 査読有り

Takai M, Shimada K, Furukawa K, Yamaga Y, Yoshiyama S, Kagaya Y, Suzuki T, Hayashi K, Shimada S, Karube K, Kiyoi H

Cancer science 116 巻 ( 1 ) 頁： 214 - 225 2025年1月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Science

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma that is characterized by the proliferation of lymphoma cells in the lumina of small vessels. Recent progress uncovering the genetic characteristics associated with MYD88/CD79B mutations has stimulated interest in the use of drugs targeting B-cell receptor signaling, including Bruton's tyrosine kinase. However, difficulties in culturing ex vivo IVLBCL cells has hampered research on the development of novel therapies. In the present study, we demonstrated the establishment of an ex vivo culture system of IVLBCL cells obtained from patient-derived xenograft (PDX) models. The spheroid culture enabled us to culture IVLBCL PDX cells for more than 10 days and to explore the efficacy of drug treatments acting on these cells. We found that carfilzomib and ibrutinib were effective for treating IVLBCL in ex vivo experiments and conducted in vivo analyses to assess the efficacy of these drugs. Although the efficacy of carfilzomib was difficult to confirm due to its toxicity in our models, ibrutinib showed comparable efficacy to a standard combination of chemotherapy drugs. Together, our data provide a new culture method for IVLBCL PDX cells and a rationale for translating ibrutinib to clinical use in IVLBCL patients.

DOI： 10.1111/cas.16310

Analyzing the risk factors for disease progression within 2 years and histological transformation in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone as first-line treatment: A 15-year follow-up of patients with advanced follicular lymphoma in JCOG0203. 査読有り Open Access

Secondary central nervous system involvement in patients with diffuse large B-cell lymphoma treated with rituximab combined CHOP therapy - a supplementary analysis of JCOG0601. 査読有り Open Access

Shimada K, Ohmachi K, Machida R, Ota S, Itamura H, Tsujimura H, Takayama N, Shimada T, Kurosawa M, Tabayashi T, Shimoyama T, Ohshima K, Miyazaki K, Maruyama D, Kinoshita T, Ando K, Hotta T, Tsukasaki K, Nagai H

Annals of hematology 103 巻 ( 6 ) 頁： 2021 - 2031 2024年6月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Annals of Hematology

Abstract: Secondary central nervous system involvement (sCNSi) in diffuse large B-cell lymphoma (DLBCL) is fatal. However, its features in patients with sCNSi who are categorized as lower risk by international prognostic index (IPI) or CNS-IPI are not yet fully understood. In the present analysis, we evaluated DLBCL patients who developed sCNSi at their first progression and who participated in JCOG0601, most of whom were lower risk by IPI. Of 409 patients, 21 (5.1%) developed sCNSi during a median follow-up of 4.9 years. Five-year cumulative incidence of sCNSi were 5.1%; and 4.0%, 5.3%, and 11.5% at low, intermediate, and high risk of CNS-IPI, respectively. The most common locations of extranodal lesions at the time of registration in patients with sCNSi were the stomach (n = 4), paranasal cavity (n = 3), and bone marrow (n = 2). In univariable analysis, paranasal cavity lesion was a high-risk factor for sCNSi (subdistribution hazard ratio, 4.34 [95% confidence interval 1.28–14.73]). Median overall survival after sCNSi was 1.3 years, with a 2-year overall survival rate of 39.3%. The incidence of sCNSi in DLBCL patients at lower risk of CNS-IPI was low, as previously reported, but paranasal cavity lesion might indicate high risk for organ involvement. Clinical trial registration: JCOG0601 was registered in the UMIN Clinical Trials Registry (UMIN000000929, date of registration; December 04, 2007) and the Japan Registry of Clinical Trials (jRCTs031180139, date of registration; February 20, 2019).

DOI： 10.1007/s00277-024-05620-3

Watanabe T, Matsuno Y, Wakabayashi M, Maruyama D, Yamamoto K, Kubota N, Shimada K, Asagoe K, Yamaguchi M, Ando K, Ogura M, Kuroda J, Suehiro Y, Tsukasaki K, Tobinai K, Nagai H

Hematological oncology 42 巻 ( 3 ) 頁： e3272 2024年5月

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

Follicular lymphoma (FL) is an indolent lymphoma that becomes aggressive due to histological transformation (HT), leading to reduced survival. Patients with FL have different clinical courses and various treatment options. Some patients exhibit shorter survival and experience disease progression within 24 months of diagnosis/treatment (POD24); the optimal treatment remains an unmet needs. Thus, identifying factors that predict shorter survival is essential to stratify treatment and prolong the survival of patients with FL. To analyze risk factors for POD24 and HT in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment, we performed this post-hoc analysis of patients with advanced indolent B-cell lymphoma in a randomized clinical trial wherein six cycles of R-CHOP were administered every 2–3 weeks. The primary analysis showed no differences in outcomes, which enabled the analysis of 248 patients with FL, assigned to two arms. All histopathological specimens from the 300 enrolled patients were reviewed by three expert hematopathologists. Multivariable analysis implicated Follicular Lymphoma International Prognostic Index (FLIPI) intermediate (odds ratio [OR] 2.531, 95% confidence interval [CI] 0.676–9.466) and high- (OR 2.236, 95% CI 0.160–31.226) risks, B symptoms (OR 2.091, 95% CI 0.747–5.851), and grade 3A (G3A) (OR 1.833, 95% CI 0.634–5.299) as risk factors for POD24. Furthermore, multivariable analysis through a median follow-up of 15.9 years implicated G3A (OR 2.628, 95% CI 0.806–8.575) and high-risk FLIPI (OR 4.401, 95% CI 0.186–104.377) as risk factors for HT. However, an analysis limited to the first 10 years revealed that the prognostic factors elucidated from the longer-term analysis had a greater impact on HT. G3A and high-risk FLIPI may independently predict POD24 and HT, thereby informing treatment stratification of patients with untreated advanced-stage FL in future trials, particularly to address the unmet needs of patients with POD24.

DOI： 10.1002/hon.3272

Dual CAR-T Cells Targeting CD19 and CD37 Are Effective in Target Antigen Loss B-cell Tumor Models. 査読有り

Imai K, Takeuchi Y, Terakura S, Okuno S, Adachi Y, Osaki M, Umemura K, Hanajiri R, Shimada K, Murata M, Kiyoi H

Molecular cancer therapeutics 23 巻 ( 3 ) 頁： 381 - 393 2024年3月

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

Chimeric antigen receptor T (CAR-T) cells targeting multiple antigens (Ag), may reduce the risk of immune escape following the loss of the target Ag and further increase the efficacy of treatment. We developed dual-targeting CAR-T cells that target CD19 and CD37 Ags and evaluated their antitumor effects. CD19/CD37 dual CAR-T cells were generated using cotransduction and simultaneous gene transfer of two types of lentiviral vectors transferring CD19CAR or CD37CAR genes, including the intracellular domains of CD28 and CD3z signaling domains. These dual CAR-T cells contained three fractions: CD19/CD37 bispecific CAR-T cells, single CD19CAR-T cells, and single CD37CAR-T cells. In the functional evaluation of CAR-T cells in vitro, CD19/CD37 dual CAR-T cells showed adequate proliferation and cytokine production in response to CD19 and CD37 antigen stimulation alone or in combination. Evaluation of intracellular signaling revealed that dual CAR-T cell-mediated signals were comparable with single CAR-T cells in response to CD19- and CD37-positive B-cell tumors. Although the cytotoxicity of CD19/CD37 dual CAR-T cells in both CD19- and CD37-positive B-cell tumors was similar to that of single CD19 and CD37CAR-T cells, against CD19 and CD37 Ag-heterogeneous tumor, dual CAR-T cells demonstrated significantly superior tumor lysis compared with single CAR-T cells. Furthermore, CD19/CD37 dual CAR-T cells effectively suppressed Ag-heterogeneous Raji cells in a xenograft mouse model. Collectively, these results suggest that CD19/CD37 dual CAR-T cells may be effective target-Ag-loss B-cell tumor models in vitro and in vivo, which represents a promising treatment for patients with relapsed/refractory B-cell malignancies.

DOI： 10.1158/1535-7163.MCT-23-0408

Correction: “The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms” Leukemia. 2022 Jul;36(7):1720–1748 (Leukemia, (2022), 36, 7, (1720-1748), 10.1038/s41375-022-01620-2) Open Access

R-CHOP treatment for patients with advanced follicular lymphoma: Over 15-year follow-up of JCOG0203. 査読有り Open Access

Watanabe T, Tobinai K, Wakabayashi M, Maruyama D, Yamamoto K, Kubota N, Shimada K, Asagoe K, Yamaguchi M, Ando K, Ogura M, Kuroda J, Suehiro Y, Matsuno Y, Tsukasaki K, Nagai H

British journal of haematology 204 巻 ( 3 ) 頁： 849 - 860 2024年3月

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

Anti-CD20 antibody in combination with chemotherapy extends overall survival (OS) in untreated advanced-stage follicular lymphoma (FL), yet the optimal associated therapy is unclear. Data on the cumulative incidence of secondary malignancies postrelapse after conventional immunochemotherapy are scarce. A long-term analysis of rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) as first-line treatment was conducted in a randomised clinical trial. A six-cycle R-CHOP regimen was administered every 2 or 3 weeks without rituximab maintenance. A prespecified evaluation was conducted 15 years after the completion of enrolment, following initial analysis results that showed no significant differences in outcomes at the 3-year mark. In-depth analyses were performed on the cohort of 248 patients with FL who were allocated to the two treatment arms. With a median follow-up period of 15.9 years, the 15-year OS was 76.2%. There were no protocol treatment-related deaths, nor were there any fatal infections attributable to subsequent lymphoma treatment. At 15 years, the cumulative incidence of non-haematological and haematological malignancies was 12.8% and 3.7% respectively. Histological transformation appeared after a median of 8 years. R-CHOP maintains safety and efficacy in patients with advanced FL over extended follow-up, making it a viable first-line option for patients with advanced-stage FL.

DOI： 10.1111/bjh.19213

Alaggio R., Amador C., Anagnostopoulos I., Attygalle A.D., de Oliveira Araujo I.B., Berti E., Bhagat G., Borges A.M., Boyer D., Calaminici M., Chadburn A., Chan J.K.C., Cheuk W., Chng W.J., Choi J.K., Chuang S.S., Coupland S.E., Czader M., Dave S.S., de Jong D., Di Napoli A., Du M.Q., Elenitoba-Johnson K.S., Ferry J., Geyer J., Gratzinger D., Guitart J., Gujral S., Harris M., Harrison C.J., Hartmann S., Hochhaus A., Jansen P.M., Karube K., Kempf W., Khoury J., Kimura H., Klapper W., Kovach A.E., Kumar S., Lazar A.J., Lazzi S., Leoncini L., Leung N., Leventaki V., Li X.Q., Lim M.S., Liu W.P., Louissaint A., Marcogliese A., Medeiros L.J., Michal M., Miranda R.N., Mitteldorf C., Montes-Moreno S., Morice W., Nardi V., Naresh K.N., Natkunam Y., Ng S.B., Oschlies I., Ott G., Parrens M., Pulitzer M., Rajkumar S.V., Rawstron A.C., Rech K., Rosenwald A., Said J., Sarkozy C., Sayed S., Saygin C., Schuh A., Sewell W., Siebert R., Sohani A.R., Suzuki R., Tooze R., Traverse-Glehen A., Vega F., Vergier B., Wechalekar A.D., Wood B., Xerri L., Xiao W., Akinola N.O., Akkari Y., Allende L.M., Aozasa K., Arcaini L., Ardeshna K.M., Asano N., Attarbaschi A., Bacon C.M., Barrans S.L., Batchelor T., Battistella M., Baughn L.B., Behdad A., Berentsen S.

Leukemia 37 巻 ( 9 ) 頁： 1944 - 1951 2023年9月

Clinicopathological characteristics associated with the engraftment of patient lymphoma cells in NOG mice. 査読有り

Sahashi S, Shimada K, Takagi Y, Aoki T, Kunou S, Sakamoto A, Murase A, Furukawa K, Kagaya Y, Yamaga Y, Takai M, Tokuyama K, Shimada S, Nakamura S, Kiyoi H

International journal of hematology 118 巻 ( 2 ) 頁： 221 - 230 2023年8月

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

Patient-derived xenograft (PDX) mouse models are useful for deepening our understanding of the biology of malignant lymphoma; however, factors associated with the success of the PDX lymphoma model are largely unknown. We retrospectively analyzed the characteristics of 66 xenotransplantations from 65 patients. In all, 43 (65%) specimens were obtained from patients aged > 60 years, and 42 (64%) specimens were obtained at diagnosis. Specimens were obtained from patients with the following diseases: diffuse large B-cell lymphoma (n = 30), intravascular large B-cell lymphoma (n = 12), follicular lymphoma (n = 8), peripheral T-cell lymphoma (n = 7), mantle cell lymphoma (n = 2), and other (n = 7). The specimens were sourced mainly from bone marrow (n = 31, 47%) and extranodal tumors (n = 13, 20%). Engraftment was successful in 33/66 (50%) xenotransplantations. The median age of patients who provided successful specimens was significantly higher than that for unsuccessful specimens (p = 0.013). Specimens with a high proportion of tumor cells in the graft and those obtained from patients with relapsed/refractory disease showed higher tendencies toward successful engraftment. Taken together, these data suggest that tumor cells with a highly malignant potential might have a high likelihood of engraftment.

DOI： 10.1007/s12185-023-03604-z

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

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

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）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

Methods for confirming the safety of radiation therapy in patients with left ventricular assist device: a case of extranodal NK/T-cell lymphoma, nasal type.

Oishi H, Kondo T, Kawamura M, Shimada K, Mutsuga M, Kurokawa T, Kuwayama T, Hiraiwa H, Morimoto R, Okumura T, Nishida T, Kiyoi H, Naganawa S, Usui A, Murohara T

Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs 25 巻 ( 3 ) 頁： 274 - 278 2022年9月

記述言語：英語出版者・発行元：Journal of Artificial Organs

A left ventricular assist device (LVAD) is a treatment option for patients with end-stage heart failure; however, a certain number of patients on durable LVADs are diagnosed with malignancy. Radiation therapy (RT) for patients with durable LVADs has safety concerns, because RT may interfere with the device. Herein, we report a case of RT during durable LVAD management. A 48-year-old man with a durable LVAD was diagnosed with sinusitis. As his symptoms were resistant to drug therapy, endoscopic sinus surgery was performed, and extranodal NK/T-cell lymphoma, nasal type (ENKL) was pathologically detected. Since RT was the first-line treatment for ENKL, we conducted two types of irradiation experiments to determine whether RT can be safely performed in patients with durable LVADs as follows: (1) assessing the extent of the radiation levels at each site and evaluating device malfunction by irradiating the lesion sites in the patient model with the same protocol as planned, and (2) evaluating device malfunction by directly irradiating the durable LVAD equipment once at the scheduled total dose. The radiation doses at the pump, driveline, system controller, power cable, and power module of the durable LVAD reached 7.86 cGy, 6.34 cGy, 0.66 cGy, 0.38 cGy, and 0.14 cGy, respectively. In both experiments, durable LVAD malfunction or any type of alarm was not observed. We concluded that RT could be safely performed with chemotherapy in this patient and our irradiation experiments can be applied to RT for other malignancies.

DOI： 10.1007/s10047-022-01312-9

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

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

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

Cancers 14 巻 ( 2 ) 2022年1月

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

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

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

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 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

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

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

記述言語：英語出版者・発行元：Journal of Clinical and Experimental Hematopathology

The programmed cell death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in tumor cell escape from immune con-trol and has been most extensively investigated for therapeutic purposes. However, PD-L1 immunohistochemistry is still not used widely for diagnosis. We review the diagnostic utility of PD-L1 (by clone SP142) immunohistochemistry in large-cell lymphomas, mainly consisting of classic Hodgkin lymphoma (CHL) and diffuse large B-cell lymphoma (DLBCL). Neoplastic PD-L1 (nPD-L1) expression on Hodgkin and Reed-Sternberg cells is well-established among prototypic CHL. Of note, EBV+ CHL often poses a challenge for differential diagnosis from peripheral T-cell lymphoma with EBV+ non-malignant large B-cells; their distinction is based on the lack of PD-L1 expression on large B-cells in the latter. The nPD-L1 expression further provides a good diagnostic consensus for CHL with primary extranodal disease conceivably characterized by a combined pathogenesis of immune escape of tumor cells and immunodeficiency. Compared with CHL, the nPD-L1 expression rate is much lower in DLBCL, highlighting some specific subgroups of intravascular large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and EBV+ DLBCL. They consist of nPD-L1-positive and-negative subgroups, but their clinicopatho-logical significance remains to be elucidated. Microenvironmental PD-L1 positivity on immune cells may be associated with a favorable prognosis in extranodal DLBCL. PD-L1 (by SP142) immunohistochemistry has helped us to understand the immune biology of lymphoid neoplasms possibly related by immune escape and/or immunodeficiency. However, knowledge of these issues remains limited and should be clarified for diagnostic consensus in the future.

DOI： 10.3960/jslrt.21003

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

記述言語：英語出版者・発行元：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

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

Shimada K, Kiyoi H

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

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

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

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

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

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

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

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

記述言語：英語出版者・発行元：Journal of Clinical and Experimental Hematopathology

Follicular T-cell lymphoma (FTCL), one of the nodal T-cell lymphomas with T follicular helper (TFH) phenotype, is an uncom-mon disease. The diagnosis of FTCL is challenging on the distinction from the morphological mimics mostly exemplified by follicular lymphoma. Here, we described a case of FTCL that mimicked lymphocyte-rich classic Hodgkin lymphoma (LRCHL). A 47-year-old male presented with cervical lymphadenopathy. The biopsy specimen demonstrated nodular lym-phoid proliferation, which included scattered CD30+ CD15-CD20-PAX5 weakly+ Hodgkin and Reed-Sternberg (HRS)-like cells and a rich distribution of CD3+ CD4+ PD1+ T-cells. Epstein Barr virus was not detected in HRS-like cells, but it was detected in a small proportion of the scattered lymphocytes. The large cells were also negative for programmed cell death ligand 1, which appeared to be coincidental as described in our previous report of LRCHL. However, flow cytometry showed a CD3-CD4+ T-cell population that constituted 37.4% of all gated lymphocytes. A PCR analysis showed a clonal T-cell recep-tor-gamma gene rearrangement, but not a clonal immunoglobulin heavy chain gene rearrangement, and showed RHOA G17V mutation. The constellation of these findings led us to revise the diagnosis to FTCL. This result indicated that our case belonged to a relatively indolent subgroup of nodal peripheral T-cell lymphoma of TFH phenotype, which affects patients ≤60 years old, recently proposed by our group. This case report expands our understanding of the morphologic spectrum of FTCL and its clinicopathologic significance.

DOI： 10.3960/jslrt.20052

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

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

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

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

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

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

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

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.

DOI： 10.1111/neup.12705

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

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

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 cases 23 巻 ( 1 ) 頁： 53 - 56 2021年1月

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

[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

[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

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

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.

DOI： 10.1007/s12185-020-02984-w

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

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.

DOI： 10.1007/s12185-020-02929-3

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

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

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).

DOI： 10.1111/cas.14604

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

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.

DOI： 10.1097/PAS.0000000000001499

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

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

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.

DOI： 10.1111/pin.12950

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. Open Access

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

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.

DOI： 10.1002/cam4.3104

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

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

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

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

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

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

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

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

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

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

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

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

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.

DOI： 10.1111/pin.12757

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

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

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

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.

DOI： 10.1111/cas.13873

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

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.

DOI： 10.1111/pin.12742

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

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

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

Biology and management of primary effusion lymphoma. 招待有り査読有り Open Access

Shimada K, Hayakawa F, Kiyoi H

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

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

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

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

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

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

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

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.

DOI： 10.1111/cas.13652

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 Open Access

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

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.

DOI： 10.1002/cam4.1595

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

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

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

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

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

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.).

DOI： 10.1111/cas.13550

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

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

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

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

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

Leukemia research 63 巻頁： 90 - 97 2017年12月

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

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

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