Takeshi Sugio

All Publications

• Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy. The New England journal of medicine Hamilton, M. P., Sugio, T., Noordenbos, T., Shi, S., Bulterys, P. L., Liu, C. L., Kang, X., Olsen, M. N., Good, Z., Dahiya, S., Frank, M. J., Sahaf, B., Mackall, C. L., Gratzinger, D., Diehn, M., Alizadeh, A. A., Miklos, D. B. 2024; 390 (22): 2047-2060

  Abstract

  The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern.We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient.A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques.Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).

  View details for DOI 10.1056/NEJMoa2401361

  View details for PubMedID 38865660

• Prognostic impact of HLA supertype mismatch in single-unit cord blood transplantation. Bone marrow transplantation Sugio, T., Uchida, N., Miyawaki, K., Ohno, Y., Eto, T., Mori, Y., Yoshimoto, G., Kikushige, Y., Kunisaki, Y., Mizuno, S., Nagafuji, K., Iwasaki, H., Kamimura, T., Ogawa, R., Miyamoto, T., Taniguchi, S., Akashi, K., Kato, K. 2024

  Abstract

  The "human leukocyte antigen (HLA) supertype" is a functional classification of HLA alleles, which was defined by structural features and peptide specificities, and has been reportedly associated with the clinical outcomes of viral infections and autoimmune diseases. Although the disparity in each HLA locus was reported to have no clinical significance in single-unit cord blood transplantation (sCBT), the clinical significance of the HLA supertype in sCBT remains unknown. Therefore, we retrospectively analyzed clinical data of 1603 patients who received sCBT in eight institutes in Japan between 2000 and 2017. Each HLA allele was categorized into 19 supertypes, and the prognostic effect of disparities was then assessed. An HLA-B supertype mismatch was identified as a poor prognostic factor (PFS: hazard ratio [HR] = 1.23, p=0.00044) and was associated with a higher cumulative incidence (CI) of relapse (HR=1.24, p=0.013). However, an HLA-B supertype mismatch was not associated with the CI of acute and chronic graft-versus-host-disease. The multivariate analysis for relapse and PFS showed the significance of an HLA-B supertype mismatch independent of allelic mismatches, and other previously reported prognostic factors. HLA-B supertype-matched grafts should be selected in sCBT.

  View details for DOI 10.1038/s41409-023-02183-1

  View details for PubMedID 38238452

• An Integrated Multimodal Framework for Noninvasive TCL Disease Detection and Monitoring Sugio, T., Shukla, N., Khodadoust, M. S., Nesselbush, M., Kato, K., Alig, S. K., Boegeholz, J., Schroers-Martin, J., Esfahani, M., Mutter, J. A., Garofalo, A., Jun, S., Hamilton, M. P., Rossi, C., Olsen, M., Liu, C., Akashi, K., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-180492

  View details for Web of Science ID 001159306706091

• Indirectly Recognizable Epitopes Derived from Recipient Mismatched HLA-B Are Associated with Adverse Prognosis in Single-Unit Cord Blood Transplantation Sugio, T., Kato, K., Uchida, N., Miyawaki, K., Niemann, M., Spierings, E., Onizuka, M., Uehara, Y., Tanaka, M., Doki, N., Eto, T., Kobayashi, H., Maruyama, Y., Ichinohe, T., Kanda, J., Atsuta, Y., Morishima, S. AMER SOC HEMATOLOGY. 2022

  View details for DOI 10.1182/blood-2022-164913

  View details for Web of Science ID 000893223200368

• Prognostic value of pre-transplantation total metabolic tumor volume on 18fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography in relapsed and refractory aggressive lymphoma. International journal of hematology Sugio, T., Baba, S., Mori, Y., Yoshimoto, G., Kamesaki, K., Takashima, S., Urata, S., Shima, T., Miyawaki, K., Kikushige, Y., Kunisaki, Y., Numata, A., Takenaka, K., Iawasaki, H., Miyamoto, T., Ishigami, K., Akashi, K., Kato, K. 2022

  Abstract

  Relapsed and refractory aggressive lymphoma have a poor prognosis. High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is effective in chemosensitive patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is among the few options for non-chemosensitive patients. 18Fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18FDG-PET/CT) is the standard tool for evaluating response to chemotherapy and residual tumor volume. However, accurate assessment of residual tumor volume is not currently being achieved in clinical practice, and its value in prognostic and therapeutic stratification remains unclear. To answer this question, we investigated the efficacy of quantitative indicators, including total metabolic tumor volume (TMTV), in predicting prognosis after auto-HSCT and allo-HSCT. We retrospectively analyzed 39 patients who received auto-HSCT and 28 who received allo-HSCT. In the auto-HSCT group, patients with a higher TMTV had a poor prognosis due to greater risk of relapse. In the allo-HSCT group, patients with a higher TMTV had a lower progression-free survival rate and a significantly higher relapse rate. Neither Deauville score nor other clinical parameters were associated with prognosis in either group. Therefore, pre-transplant TMTV on PET is effective for prognostic prediction and therapeutic decision-making for relapsed or refractory aggressive lymphoma.

  View details for DOI 10.1007/s12185-022-03394-w

  View details for PubMedID 35701707

• A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL. Blood advances Miyawaki, K., Kato, K., Sugio, T., Sasaki, K., Miyoshi, H., Semba, Y., Kikushige, Y., Mori, Y., Kunisaki, Y., Iwasaki, H., Miyamoto, T., Kuo, F. C., Aster, J. C., Ohshima, K., Maeda, T., Akashi, K. 2021

  Abstract

  Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of "unfavorable" molecular signatures.

  View details for DOI 10.1182/bloodadvances.2021004618

  View details for PubMedID 34638128

• Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS. Blood advances Sugio, T., Miyawaki, K., Kato, K., Sasaki, K., Yamada, K., Iqbal, J., Miyamoto, T., Ohshima, K., Maeda, T., Miyoshi, H., Akashi, K. 2018; 2 (17): 2242-2252

  Abstract

  Peripheral T-cell lymphoma (PTCL), not otherwise specified (PTCL-NOS) is among the most common disease subtypes of PTCL, one that exhibits heterogeneous clinicopathological features. Although multiple disease-stratification models, including the cell-of-origin or gene-expression profiling methods, have been proposed for this condition, their clinical significance remains unclear. To establish a clinically meaningful stratification model, we analyzed gene-expression signatures of tumors and tumor-infiltrating immune cells using the nCounter system, which enables accurate quantification of low abundance and/or highly fragmented transcripts. To do so, we assessed transcripts of 120 genes related to cancer or immune cells using tumor samples from 68 newly diagnosed PTCL-NOS patients and validated findings by immunofluorescence in tumor sections. We show that gene-expression signatures representing tumor-infiltrating immune cells, but not those of cancerous T cells, dictate patient clinical outcomes. Cases exhibiting both B-cell and dendritic cell (DC) signatures (BD subgroup) showed favorable clinical outcomes, whereas those exhibiting neither B-cell nor DC signatures (non-BD subgroup) showed extremely poor prognosis. Notably, half of the non-BD cases exhibited a macrophage signature, and macrophage infiltration was evident in those cases, as revealed by immunofluorescence. Importantly, tumor-infiltrating macrophages expressed the immune-checkpoint molecules programmed death ligand 1/2 and indoleamine 2, 3-dioxygenase 1 at high levels, suggesting that checkpoint inhibitors could serve as therapeutic options for patients in this subgroup. Our study identifies clinically distinct subgroups of PTCL-NOS and suggests a novel therapeutic strategy for 1 subgroup associated with a poor prognosis. Our data also suggest functional interactions between cancerous T cells and tumor-infiltrating immune cells potentially relevant to PTCL-NOS pathogenesis.

  View details for DOI 10.1182/bloodadvances.2018018754

  View details for PubMedID 30194138

  View details for PubMedCentralID PMC6134219

• Mogamulizumab Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-versus-Host Disease BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Sugio, T., Kato, K., Aoki, T., Ohta, T., Saito, N., Yoshida, S., Kawano, I., Henzan, H., Kadowaki, M., Takase, K., Muta, T., Miyawaki, K., Yamauchi, T., Shima, T., Takashima, S., Mori, Y., Yoshimoto, G., Kamezaki, K., Takenaka, K., Iwasaki, H., Ogawa, R., Ohno, Y., Eto, T., Kamimura, T., Miyamoto, T., Akashi, K. 2016; 22 (9): 1608-1614

  Abstract

  Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development.

  View details for DOI 10.1016/j.bbmt.2016.05.017

  View details for Web of Science ID 000381781400011

  View details for PubMedID 27220263

• Clinicopathological comparison between PTCL-TBX21 and PTCL-GATA3 in Japanese patients. Cancer medicine Shimasaki, Y., Miyoshi, H., Kawamoto, K., Yoshida, N., Mishina, T., Nakashima, K., Imamoto, T., Sugio, T., Yanagida, E., Kato, T., Yamada, K., Takeuchi, M., Suzuki, T., Moritsubo, M., Furuta, T., Imaizumi, Y., Takizawa, J., Kato, K., Suzumiya, J., Suzuki, R., Ohshima, K. 2024

  Abstract

  AIM: Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous disease that can be classified into the PTCL-TBX21 and PTCL-GATA3 subtypes.METHODS: In this study, we compared the clinicopathological features of PTCL-NOS in a Japanese cohort, classified using an IHC algorithm.RESULTS: One hundred patients with PTCL-NOS were categorized as having PTCL-TBX21 (n=55), PTCL-GATA3 (n=24), or PTCL-unclassified (n=21). When comparing PTCL-TBX21 and PTCL-GATA3, PTCL-TBX21 showed significantly lower CD4 positivity (p=0.047), lower counts of high endothelial venules (p=0.032), and a tendency for a better response to initial treatment (p=0.088). Gene expression analysis using the nCounter system showed higher expression of tumor immunity-related genes, such as PD-L1, LAG3, and IDO1, in PTCL-TBX21 than in PTCL-GATA3. PTCL-GATA3 had significantly worse overall survival (OS) than those with PTCL-TBX21 (p=0.047), although a similar tendency was observed for progression-free survival (PFS) (p=0.064). PTCL-GATA3 was a prognostic factor for OS in univariate analysis (HR 2.02; 95% CI, 1.09-3.77; p=0.027), although multivariate analysis did not show significance (HR 2.07; 95% CI, 0.93-4.61; p=0.074). In the PFS analysis, PTCL-GATA3 was an independent prognostic factor by univariate analysis (HR 1.96; 95% CI, 1.08-3.56; p=0.027) and multivariate analysis (HR 2.34; 95% CI, 1.07-5.11; p=0.032).CONCLUSION: The classification of PTCL-NOS into PTCL-TBX21 and PTCL-GATA3 is useful for predicting the prognosis of Japanese patients and stratifying the administration of tumor immune checkpoint inhibitors in clinical practice.

  View details for DOI 10.1002/cam4.6793

  View details for PubMedID 38234210

• Outcomes of allogeneic hematopoietic stem cell transplantation for relapsed or refractory diffuse large B-cell lymphoma. Bone marrow transplantation Kato, K., Sugio, T., Ikeda, T., Yoshitsugu, K., Miyazaki, K., Suzumiya, J., Yamamoto, G., Kim, S. W., Ikegame, K., Uehara, Y., Mori, Y., Ishikawa, J., Hiramoto, N., Eto, T., Nakazawa, H., Kobayashi, H., Serizawa, K., Onizuka, M., Fukuda, T., Atsuta, Y., Suzuki, R. 2023

  Abstract

  Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a currative treatment modality for diffuse large B-cell lymphoma (DLBCL) because of the intrinsic graft-versus-lymphoma effect. However, limited information is available regarding which patients with relapsed or refractory DLBCL are likely to benefit from allo-HSCT. We retrospectively analyzed data from 1268 DLBCL patients who received allo-HSCT. The overall survival and progression-free survival (PFS) rates were 30.3% and 21.6% at 3 years, respectively. Multivariate analysis revealed that stable or progressive disease at transplantation, male patient, poorer performance status at transplantation, and shorter intervals from previous transplantation were associated independently with a lower PFS. Four prognostic factors were used to construct a prognostic index for PFS, predicting 3-year PFS of 55.4%, 43.7%, 20.4% and 6.6%, respectively. The prognostic model predicted relapse rates following allo-HSCT accordingly (P < 0.0001), whereas did not predict transplantation-related mortality (P = 0.249). The prognostic index can identify a subgroup of DLBCL patients who benefit from allo-HSCT and it is worthwhile to evaluate whether this model is also applicable to patients undergoing allo-HSCT in cases of relapse after chimeric antigen receptor engineered T-cell therapy, although the application of allo-HSCT has been declining with the increase of novel immunotherapies.

  View details for DOI 10.1038/s41409-023-02156-4

  View details for PubMedID 38102209

  View details for PubMedCentralID 3664033

• Tumor heterogeneity and immune-evasive T follicular cell lymphoma phenotypes at single-cell resolution. Leukemia Suma, S., Suehara, Y., Fujisawa, M., Abe, Y., Hattori, K., Makishima, K., Sakamoto, T., Sawa, A., Bando, H., Kaji, D., Sugio, T., Kato, K., Akashi, K., Matsue, K., Carreras, J., Nakamura, N., Suzuki, A., Suzuki, Y., Ito, K., Shiiba, H., Chiba, S., Sakata-Yanagimoto, M. 2023

  Abstract

  T follicular helper (TFH) cell lymphomas (TFHLs) are characterized by TFH-like properties and accompanied by substantial immune-cell infiltration into tumor tissues. Nevertheless, the comprehensive understanding of tumor-cell heterogeneity and immune profiles of TFHL remains elusive. To address this, we conducted single-cell transcriptomic analysis on 9 lymph node (LN) and 16 peripheral blood (PB) samples from TFHL patients. Tumor cells were divided into 5 distinct subclusters, with significant heterogeneity observed in the expression levels of TFH markers. Copy number variation (CNV) and trajectory analyses indicated that the accumulation of CNVs, together with gene mutations, may drive the clonal evolution of tumor cells towards TFH-like and cell proliferation phenotypes. Additionally, we identified a novel tumor-cell-specific marker, PLS3. Notably, we found a significant increase in exhausted CD8+ T cells with oligoclonal expansion in TFHL LNs and PB, along with distinctive immune evasion characteristics exhibited by infiltrating regulatory T, myeloid, B, and natural killer cells. Finally, in-silico and spatial cell-cell interaction analyses revealed complex networking between tumor and immune cells, driving the formation of an immunosuppressive microenvironment. These findings highlight the remarkable tumor-cell heterogeneity and immunoevasion in TFHL beyond previous expectations, suggesting potential roles in treatment resistance.

  View details for DOI 10.1038/s41375-023-02093-7

  View details for PubMedID 38012392

  View details for PubMedCentralID 4874220

• Inferred Gene Expression By Cell-Free DNA Profiling Allows Noninvasive Lymphoma Classification Mutter, J. A., Esfahani, M., Schroers-Martin, J., Alig, S. K., Hamilton, M. P., Sworder, B. J., Tessoulin, B., Boegeholz, J., Flerlage, T., Flerlage, J. E., Binkley, M. S., Sugio, T., Rossi, C., Olsen, M., Liu, C., Le Gouill, S., Kurtz, D. M., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-186853

  View details for Web of Science ID 001159306701002

• Longitudinal Noninvasive Surveillance & Fragmentomic Characterization of Follicular Lymphoma Schroers-Martin, J., Mutter, J. A., Esfahani, M., Scherer, F., Soo, J., Alig, S. K., Kurtz, D. M., Sugio, T., Rossi, C., Tessoulin, B., Olsen, M., Liu, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-187116

  View details for Web of Science ID 001159306702041

• Distinct Circulating Genomic Features of Classical Hodgkin Lymphoma of Older Adults Rossi, C., Boegeholz, J., Alig, S. K., Garofalo, A., Esfahani, M., Schroers-Martin, J., Olsen, M., Kang, X., Kurtz, D. M., Sugio, T., Hamilton, M. P., Andre, M., Casasnovas, R., Fornecker, L., Diehn, M., Ghesquieres, H., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-178257

  View details for Web of Science ID 001159740307115

• Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma. Haematologica Kameda, T., Kataoka, K., Kamiunten, A., Hidaka, M., Miyoshi, H., Nakano, N., Nosaka, K., Yoshimitsu, M., Yasunaga, J., Kogure, Y., Shide, K., Miyahara, M., Sakamoto, T., Akizuki, K., Hidaka, T., Kubuki, Y., Koya, J., Kawano, N., Yamashita, K., Kawano, H., Toyama, T., Maeda, K., Marutsuka, K., Imaizumi, Y., Kato, K., Sugio, T., Tokunaga, M., Tashiro, Y., Takaori-Kondo, A., Miyazaki, Y., Akashi, K., Ishitsuka, K., Matsuoka, M., Ohshima, K., Watanabe, T., Kitanaka, A., Utsunomiya, A., Ogawa, S., Shimoda, K. 2023

  Abstract

  The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment. To identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged.

  View details for DOI 10.3324/haematol.2022.281510

  View details for PubMedID 36794502

• Single-cell transcriptome analysis reveals comprehensive immune profiles of T follicular helper cell lymphoma Suma, S., Fujisawa, M., Abe, Y., Suehara, Y., Sugio, T., Akashi, K., Matsue, K., Nakamura, N., Suzuki, A., Suzuki, Y., Chiba, S., Sakata, M. WILEY. 2023: 796

  View details for Web of Science ID 001057570902280

• Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas. Cancer cell Sworder, B. J., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N., Garofalo, A., Macaulay, C. W., Shahrokh Esfahani, M., Olsen, M. N., Hamilton, J., Hosoya, H., Hamilton, M., Spiegel, J. Y., Baird, J. H., Sugio, T., Carleton, M., Craig, A. F., Younes, S. F., Sahaf, B., Sheybani, N. D., Schroers-Martin, J. G., Liu, C. L., Oak, J. S., Jin, M. C., Beygi, S., Hüttmann, A., Hanoun, C., Dührsen, U., Westin, J. R., Khodadoust, M. S., Natkunam, Y., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. 2022

  Abstract

  Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

  View details for DOI 10.1016/j.ccell.2022.12.005

  View details for PubMedID 36584673

• Single-Cell Transcriptome Reveals Comprehensive Immune Profiles of T Follicular Helper Cell Lymphoma Suma, S., Fujisawa, M., Abe, Y., Suehara, Y., Kaji, D., Sugio, T., Kato, K., Akashi, K., Matsue, K., Nakamura, N., Suzuki, A., Suzuki, Y., Chiba, S., Sakata-Yanagimoto, M. AMER SOC HEMATOLOGY. 2022: 8754-8755

  View details for DOI 10.1182/blood-2022-159804

  View details for Web of Science ID 000893230301372

• Lymphoma Microenvironment in DLBCL and PTCL-NOS: the key to uncovering heterogeneity and the potential for stratification. Journal of clinical and experimental hematopathology : JCEH Miyawaki, K., Sugio, T. 2022; 62 (3): 127-135

  Abstract

  Diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are the most common subtypes of mature B cell neoplasm and T/NK cell lymphoma, respectively. They share a commonality in that they are, by definition, highly heterogeneous populations. Recent studies are revealing more about the heterogeneity of these diseases, and at the same time, there is an active debate on how to stratify these heterogeneous diseases and make them useful in clinical practice. The various immune cells and non-cellular components surrounding lymphoma cells, i.e., the lymphoma microenvironment, have been the subject of intense research since the late 2000s, and much knowledge has been accumulated over the past decade. As a result, it has become clear that the lymphoma microenvironment, despite its paucity in tissues, significantly impacts the lymphoma pathogenesis and clinical behavior, such as its prognosis and response to therapy. In this article, we review the role of the lymphoma microenvironment in DLBCL and PTCL-NOS, with particular attention given to its impact on the prognosis and stratification.

  View details for DOI 10.3960/jslrt.22027

  View details for PubMedID 36171096

• Successful pseudo-autologous stem cell transplantation for donor-derived Burkitt lymphoma occurring 9 years after allogeneic transplantation. International journal of hematology Taniguchi, S., Utsumi, S., Kochi, Y., Taya, Y., Mori, Y., Semba, Y., Sugio, T., Miyawaki, K., Kikushige, Y., Kunisaki, Y., Yoshimoto, G., Numata, A., Kato, K., Uchida, N., Maeda, T., Miyamoto, T., Taniguchi, S., Akashi, K. 2022

  Abstract

  Donor-derived hematological malignancies have been recognized as rare but serious late complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Most cases in the literature were diagnosed as myelodysplastic syndrome or acute leukemia, with very few malignant lymphoma reported. We herein present another case of donor-derived Burkitt lymphoma that occurred 9 years after allo-HSCT under continued administration of immunosuppressants for chronic graft-versus-host disease (GVHD). The patient achieved a partial response after rituximab-combined intensive chemotherapy. To reduce the risk of relapse and to avoid organ toxicities due to repeated chemotherapies, we performed upfront high-dose chemotherapy followed by stem cell rescue using donor-derived CD34+ cells, called pseudo-autologous HSCT (pASCT), and adjusted immunosuppressants appropriately. The patient remained disease-free for 23months after pASCT without exacerbation of cGVHD. Although the observation period has been relatively short and longer follow-up is needed, pASCT may be a feasible option for donor-derived lymphoma even in patients with active cGVHD.

  View details for DOI 10.1007/s12185-022-03458-x

  View details for PubMedID 36136227

• Molecular Monitoring of Lymphomas. Annual review of pathology Schroers-Martin, J. G., Alig, S., Garofalo, A., Tessoulin, B., Sugio, T., Alizadeh, A. A. 2022

  Abstract

  Molecular monitoring of tumor-derived alterations has an established role in the surveillance of leukemias, and emerging nucleic acid sequencing technologies are likely to similarly transform the clinical management of lymphomas. Lymphomas are well suited for molecular surveillance due to relatively high cell-free DNA and circulating tumor DNA concentrations, high somatic mutational burden, and the existence of stereotyped variants enabling focused interrogation of recurrently altered regions. Here, we review the clinical scenarios and key technologies applicable for the molecular monitoring of lymphomas, summarizing current evidence in the literature regarding molecular subtyping and classification, evaluation of treatment response, the surveillance of active cellular therapies, and emerging clinical trial strategies. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  View details for DOI 10.1146/annurev-pathol-050520-044652

  View details for PubMedID 36130071

• Human acute leukemia utilizes branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function. Blood advances Kikushige, Y., Miyamoto, T., Kochi, Y., Semba, Y., Ohishi, M., Irifune, H., Hatakeyama, K., Kunisaki, Y., Sugio, T., Sakoda, T., Miyawaki, K., Kato, K., Soga, T., Akashi, K. 2022

  Abstract

  Cancer-specific metabolic activities play a crucial role in the pathogenesis of human malignancies. To investigate human acute leukemia-specific metabolic properties, we comprehensively measured the cellular metabolites within the CD34+ fraction of normal hematopoietic stem progenitor cells (HSPCs), and primary human acute myelogenous leukemia (AML) and lymphoblastic leukemia (ALL) cells. Here we show that human leukemia addicts to the branched-chain amino acid (BCAA) metabolism to maintain their stemness, irrespective of myeloid or lymphoid types. Human primary acute leukemias had BCAA transporters for BCAA uptake, cellular BCAA, α-ketoglutarate (α-KG) and cytoplasmic BCAA transaminase-1 (BCAT1) at significantly higher levels than control HSPCs. Isotope-tracing experiments showed that in primary leukemia cells, BCAT1 actively catabolizes BCAA using α-KG into branched-chain α-ketoacids (BCKAs), whose metabolic processes provide leukemia cells with critical substrates for the TCA cycle and the non-essential amino acids synthesis, both of which reproduce α-KG to maintain its cellular level. In xenogeneic transplantation experiments, deprivation of BCAA from daily diet strongly inhibited expansion, engraftment and self-renewal of human acute leukemia cells. Inhibition of BCAA catabolism in primary AML or ALL cells specifically inactivates polycomb repressive complex 2 (PRC2) function, an epigenetic regulator for stem cell signatures, through inhibiting transcription of PRC components, such as zeste homolog 2 (EZH2) and embryonic ectoderm development (EED). Accordingly, BCAA catabolism plays an important role in maintenance of stemness in primary human AML and ALL, and molecules related to the BCAA metabolism pathway should be critical targets for acute leukemia treatment.

  View details for DOI 10.1182/bloodadvances.2022008242

  View details for PubMedID 36044390

• Single-cell RNA sequencing reveals immune profile and tumor cell heterogeneity of angioimmunoblastic T-cell lymphoma Suma, S., Fujisawa, M., Abe, Y., Suehara, Y., Kusakabe, M., Sugio, T., Akashi, K., Matsue, K., Nakamura, N., Suzuki, A., Suzuki, Y., Chiba, S., Sakatayanagimoto, M. WILEY. 2022: 1273

  View details for Web of Science ID 000778583803149

• Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions. Cancer letters Ito, M., Nakano, M., Ariyama, H., Yamaguchi, K., Tanaka, R., Semba, Y., Sugio, T., Miyawaki, K., Kikushige, Y., Mizuno, S., Isobe, T., Tanoue, K., Taguchi, R., Ueno, S., Kawano, T., Murata, M., Baba, E., Akashi, K. 2022: 215597

  Abstract

  Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45+CD14+ CAMs transdifferentiated into CD45-CD90+ fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45-CD90+ fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFβ signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFβ and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.

  View details for DOI 10.1016/j.canlet.2022.215597

  View details for PubMedID 35150810

• Targeting leukemia-specific dependence on the de novo purine synthesis pathway LEUKEMIA Yamauchi, T., Miyawaki, K., Semba, Y., Takahashi, M., Izumi, Y., Nogami, J., Nakao, F., Sugio, T., Sasaki, K., Pinello, L., Bauer, D. E., Bamba, T., Akashi, K., Maeda, T. 2021

  Abstract

  Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.

  View details for DOI 10.1038/s41375-021-01369-0

  View details for Web of Science ID 000680815500001

  View details for PubMedID 34344987

• Ustekinumab Improves Active Crohn's Disease by Suppressing the T Helper 17 Pathway DIGESTION Ihara, Y., Torisu, T., Miyawaki, K., Umeno, J., Kawasaki, K., Hirano, A., Fujioka, S., Fuyuno, Y., Matsuno, Y., Sugio, T., Sasaki, K., Moriyama, T., Akashi, K., Kitazono, T. 2021: 946-955

  Abstract

  Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn's disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST.Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated.The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action.In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues.

  View details for DOI 10.1159/000518103

  View details for Web of Science ID 000678759300001

  View details for PubMedID 34350861

• Platelet decrease and efficacy of platelet-rich plasma return following peripheral blood stem cell apheresis JOURNAL OF CLINICAL APHERESIS Shima, T., Sakoda, T., Henzan, T., Kunisaki, Y., Sugio, T., Kamezaki, K., Iwasaki, H., Teshima, T., Maeda, T., Akashi, K., Miyamoto, T. 2021; 36 (5): 687-696

  Abstract

  Peripheral blood stem cell (PBSC) transplantation is a key treatment option for hematological diseases and is widely performed in clinical practice. Platelet loss is one of the major complications of PBSC apheresis, and platelet-rich plasma (PRP) return is considered in case of platelet decrease following apheresis; however, little is known about the frequency and severity of platelet loss and the efficacy of PRP return postapheresis.We assessed changes in platelet counts following PBSC-related apheresis in 270 allogeneic (allo)- and 105 autologous (auto)-PBSC settings. We also evaluated the efficacy of PRP transfusion on platelet recovery postapheresis.In both allo- and auto-PBSC settings, the preapheresis platelet count (range, 84-385 and 33-558 × 109 /L, respectively) decreased postapheresis (range, 57-292 and 20-429 × 109 /L, respectively), whereas severe platelet decrease (<50 × 109 /L) was only observed in auto-PBSC patients (n = 9). We confirmed that platelet count before apheresis was a risk factor for severe platelet decrease (<50 × 109 /L) following auto-PBSC apheresis (odds ratio 0.749, P < .049). PRP return postapheresis facilitated platelet recovery in more than 80% of cases in both allo and auto settings.Lower platelet count preapheresis is a useful predictor of severe platelet decrease following auto-PBSC apheresis and PRP return is an effective process to facilitate platelet recovery postapheresis.

  View details for DOI 10.1002/jca.21917

  View details for Web of Science ID 000661969300001

  View details for PubMedID 34133767

• Outcome predictors after retransplantation in relapsed acute lymphoblastic leukemia: a multicenter, retrospective study ANNALS OF HEMATOLOGY Mori, Y., Sasaki, K., Ito, Y., Kuriyama, T., Ueno, T., Kadowaki, M., Aoki, T., Sugio, T., Yoshimoto, G., Kato, K., Maeda, T., Nagafuji, K., Akashi, K., Miyamoto, T., Fukuoka Blood Marrow Transplantat 2021; 100 (1): 197-208

  Abstract

  Retransplantation is the only curative treatment option for patients with acute lymphoblastic leukemia (ALL) that has relapsed after allogeneic hematopoietic cell transplantation (allo-HCT); however, data in this setting remain scant. Hence, this multicenter, retrospective study aims to determine outcome predictors after retransplantation in relapsed ALL. We examined 55 recipients who underwent multiple allo-HCTs during 2006-2018. The 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality rates were 35.9%, 29.1%, and 23.6%, respectively. We observed a trend of better outcome in Ph + ALL (n = 22) patients compared with non-Ph ALL (n = 33) patients; the 2-year PFS was 40.9% versus 21.2%, indicating a beneficial effect of more potent second- or third-generation tyrosine kinase inhibitors. Univariate analysis revealed that late relapse after the previous transplant was the only significant predictor of better transplant outcome among Ph + ALL patients, whereas factors related to prolonged OS/PFS in non-Ph ALL patients were late relapse after the previous transplant, longer duration from disease relapse/progression to second or more allo-HCT, disease status at the transplantation, and good performance status. Nevertheless, further investigations are warranted to determine whether novel molecular-targeted agents with higher efficacy and fewer toxicities could exceed conventional chemotherapies as a bridging strategy to next allo-HCT and improve the outcomes of non-Ph ALL patients.

  View details for DOI 10.1007/s00277-020-04310-0

  View details for Web of Science ID 000585844700001

  View details for PubMedID 33150464

• B cell receptor signaling related to resistance to Helicobacter pylori eradication therapy in gastric diffuse large B cell lymphoma HEMATOLOGICAL ONCOLOGY Torisu, T., Kawano, S., Miyawaki, K., Yamamoto, H., Ihara, Y., Matsuno, Y., Torisu, K., Sugio, T., Sasaki, K., Shimakawa, T., Kato, K., Akashi, K., Nakamura, S., Kitazono, T. 2021; 39 (1): 145-147

  View details for DOI 10.1002/hon.2816

  View details for Web of Science ID 000577761500001

  View details for PubMedID 33034903

• Increasing Diluent Volume Decreases Bendamustine-Induced Venous Irritation without Reducing the Therapeutic Efficacy BIOLOGICAL & PHARMACEUTICAL BULLETIN Ishida, S., Morikawa, H., Watanabe, H., Tsuji, T., Sugio, T., Mori, Y., Miyamoto, T., Masuda, S., Akashi, K., Egashira, N. 2020; 43 (3): 488-492

  Abstract

  The intravenous injection of bendamustine often induces venous irritation, which reduces patients' QOL. We previously reported that the dilution of the final volume of bendamustine from 250 to 500 mL significantly decreased the incidence of venous irritation. However, the influence of this change on the therapeutic efficacy of bendamustine remains unclear. Therefore, the aim of this study was to evaluate the efficacy and safety profiles of bendamustine at different dilutions of the final volume, comparing with the correspondences of previous studies. Thirty-four patients, who received a total of 161 courses of bendamustine and rituximab chemotherapy, were included in this study. The overall response rate of this regimen was 94.1% in this study, which was comparable to that reported in the BRB study (94.2%, a phase II study of bendamustine plus rituximab therapy in Japanese patients). Additionally, the median progression-free survival was not inferior to that reported in the BRB study. Bendamustine-induced venous irritation was observed in 17.6% of the patients during the first treatment cycle administered at a final volume of 500 mL, and was found to be lower than that observed in the control, where bendamustine was administered at a final volume of 250 mL (85.7%). These results suggest that diluting bendamustine to 500 mL, but not to 250 mL, reduces the incidence of venous irritation without a negative impact on its therapeutic efficacy; thus, this simple strategy may be beneficial to ensure efficacy and safety in patients receiving regimens including bendamustine.

  View details for Web of Science ID 000517670400019

  View details for PubMedID 32115507

• Paics, a De Novo Purine Synthetic Enzyme, Is a Novel Target for AML Therapy Yamauchi, T., Miyawaki, K., Semba, Y., Nakao, F., Sugio, T., Sasaki, K., Nogami, J., Canver, M. C., Osborne, S., Pinello, L., Taylor, D., Bauer, D. E., Akashi, K., Maeda, T. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-127047

  View details for Web of Science ID 000577160401207

• Paics Inhibition Is a Potential Therapeutic Strategy for MYC-Positive DLBCL Miyawaki, K., Yamauchi, T., Sugio, T., Sasaki, K., Miyoshi, H., Osborne, S., Taylor, D., Ohshima, K., Kato, K., Maeda, T., Akashi, K. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-129613

  View details for Web of Science ID 000518218500583

• A Fast and Accurate Diagnostic Method for Ph-like ALL Using the Ncounter System Sasaki, K., Miyawaki, K., Semba, Y., Kato, K., Nogami, J., Sugio, T., Miyamoto, T., Ito, Y., Nagafuji, K., Maeda, T., Akashi, K. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-129625

  View details for Web of Science ID 000518218500278

• Comparison of calcineurin inhibitors in combination with conventional methotrexate, reduced methotrexate, or mycophenolate mofetil for prophylaxis of graft-versus-host disease after umbilical cord blood transplantation ANNALS OF HEMATOLOGY Yoshida, S., Ohno, Y., Nagafuji, K., Yoshimoto, G., Sugio, T., Kamimura, T., Ohta, T., Takase, K., Henzan, H., Muta, T., Iwasaki, H., Ogawa, R., Eto, T., Akashi, K., Miyamoto, T. 2019; 98 (11): 2579-2591

  Abstract

  Umbilical cord blood transplantation (UCBT) is a curative treatment for hematological malignancies. However, appropriate prophylaxis against graft-versus-host disease (GVHD), aimed at obtaining rapid and stable engraftment and avoiding toxicity, remains controversial in UCBT. We retrospectively compared outcomes in 409 patients who received calcineurin inhibitors (CIs) plus conventional-dose methotrexate (conv-MTX/CIs, n = 77; methotrexate, 10 mg/m2 on day 1, 7 mg/m2 on days 3 and 6) with those who received CIs plus reduced-dose methotrexate (reduced-MTX/CIs, n = 209; methotrexate, 5 mg/m2 or 5 mg/body on days 1, 3, and 6) or CIs with mycophenolate mofetil (MMF/CIs, n = 123) for GVHD prophylaxis after UCBT. The cumulative incidence of neutrophil engraftment was significantly higher in the reduced-MTX/CI (82.3%) and MMF/CI (86.6%) groups than the conv-MTX/CI (71.4%) group (p = 0.014), although there were no differences in platelet recovery or infectious complications among the three groups. The incidence and severity of GVHD were comparable among the three groups, and there were no significant differences in transplantation-related mortality among the three groups. In conclusion, GVHD prophylaxis with reduced-dose methotrexate and MMF was closely associated with high incidence of neutrophil engraftment without an effect on the incidence and severity of GVHD, which was compared to GVHD prophylaxis with conventional-dose methotrexate.

  View details for DOI 10.1007/s00277-019-03801-z

  View details for Web of Science ID 000491421100002

  View details for PubMedID 31628517

• Genome-Wide CRISPR Screen Identifies PAICS, An Enzyme Involved in De Novo Purine Synthesis, As a Potential Target for AML Therapy Yamauchi, T., Miyawaki, K., Semba, Y., Nakao, F., Sugio, T., Sasaki, K., Nogami, J., Schoonenberg, V. C., Cole, M. A., Macias-Trevino, C., Yao, Q., Canver, M. C., Osborne, S., Pinello, L., Taylor, D., Bauer, D. E., Akashi, K., Takahiro, M. CIG MEDIA GROUP, LP. 2019: S216-S217

  View details for DOI 10.1016/j.clml.2019.07.088

  View details for Web of Science ID 000483480700129

• PAICS Inhibition is a Potential Therapeutic Strategy for MYC-Positive Aggressive DLBCL Miyawaki, K., Yamauchi, T., Sugio, T., Sasaki, K., Miyoshi, H., Osborne, S., Taylor, D., Ohshima, K., Kato, K., Maeda, T., Akashi, K. CIG MEDIA GROUP, LP. 2019: S254

  View details for DOI 10.1016/j.clml.2019.07.163

  View details for Web of Science ID 000483480700203

• Safety and Seropositivity after Live Attenuated Vaccine in Adult Patients Receiving Hematopoietic Stem Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Aoki, T., Kamimura, T., Yoshida, S., Mori, Y., Kadowaki, M., Kohno, K., Ishihara, D., Urata, S., Sugio, T., Kamezaki, K., Kato, K., Ito, Y., Eto, T., Akashi, K., Miyamoto, T. 2019; 25 (8): 1576-1585

  Abstract

  Vaccination against vaccine-preventable diseases (VPDs) is highly recommended for hematopoietic stem cell transplantation (HSCT) recipients by several guidelines; however, the safety and seropositivity after live attenuated vaccines remain unclear in adult HSCT recipients. We analyzed titers of antibodies against measles, rubella, mumps, and varicella zoster virus (VZV) from Japanese adult patients who underwent allogeneic HSCT (allo-HSCT) (n = 74), autologous HSCT (auto-HSCT) (n = 39), or chemotherapy (n = 93). The seropositive rates for measles, rubella, mumps, and VZV in allo-HSCT recipients were 20.2%, 36.4%, 5.4%, and 55.4%, respectively. These rates were equivalent to those in auto-HSCT recipients but were significantly lower than those in patients receiving chemotherapy. Antibody titers tended to gradually decrease with time. Twenty-nine allo-HSCT recipients and 8 auto-HSCT recipients received live attenuated vaccines against VPDs for which they tested seronegative. The titers of antibodies against measles, rubella, and mumps significantly increased after 2 shots of vaccine, and the seropositive rate increased up to 19%, 30%, and 27%, respectively. Three patients (8.1%) experienced mild adverse events, which resolved promptly, indicating safe administration of the live attenuated vaccines. In multivariate analysis, history of chronic graft-versus-host disease was significantly associated with high seropositivity for measles as well as high seroconversion rate for measles after vaccination. Live attenuated vaccines against VPDs were safely administered in seronegative adult HSCT recipients. A further observational study is crucial to evaluate the efficacy of vaccination in seronegative HSCT patients.

  View details for DOI 10.1016/j.bbmt.2019.04.006

  View details for Web of Science ID 000483008500014

  View details for PubMedID 30959161

• Clinicopathological features of HCV-positive splenic diffuse large B cell lymphoma ANNALS OF HEMATOLOGY Shimono, J., Miyoshi, H., Arakawa, F., Yamada, K., Sugio, T., Miyawaki, K., Eto, T., Miyagishima, T., Kato, K., Nagafuji, K., Akashi, K., Teshima, T., Ohshima, K. 2019; 98 (5): 1197-1207

  Abstract

  The hepatitis C virus (HCV) is a single-stranded RNA virus which is thought to be involved in the onset of B cell lymphoma. HCV-positive diffuse large B cell lymphoma (DLBCL) has been reported to clinically manifest in extranodal lesions (e.g., in the liver, spleen, and stomach). Here, we investigated HCV-positive and -negative primary splenic DLBCL (p-spDLBCL) and non-primary splenic DLBCL (ordinary DLBCL). Furthermore, to examine HCV lymphomagenesis, RNA in situ hybridization (ISH), RT-PCR (reverse-transcription polymerase chain reaction), and NS3 immunostaining of HCV viral nonstructural proteins were performed. HCV-positive p-spDLBCL patients presented fewer B symptoms (asymptomatic) and better performance status, with elevated presence of splenic macronodular lesions and more germinal center B cell (GCB) sub-group cases than HCV-negative p-spDLBCL patients. However, HCV-positive ordinary DLBCL patients were found to have more non-GCB sub-group cases than HCV-negative ordinary DLBCL patients. HCV-positive DLBCL patients showed 20.6% (7/34) NS3 positivity, 16.7% (1/6) HCV-RNA in situ positivity, and 22.2% (2/9) detection of HCV-RNA in tumor tissue by RT-PCR. Splenic samples were found to have a higher frequency of HCV detection than lymph node samples, thus suggesting that HCV may be closely related to lymphomagenesis, especially in splenic lymphoma.

  View details for DOI 10.1007/s00277-019-03628-8

  View details for Web of Science ID 000464721200015

  View details for PubMedID 30729289

• Previous exposure to bortezomib is linked to a lower risk of engraftment syndrome after autologous hematopoietic stem cell transplantation LEUKEMIA & LYMPHOMA Mori, Y., Yoshimoto, G., Yuda, J., Hayashi, M., Odawara, J., Kuriyama, T., Sugio, T., Miyawaki, K., Kamezaki, K., Kato, K., Takenaka, K., Iwasaki, H., Maeda, T., Miyamoto, T., Akashi, K. 2019; 60 (1): 271-273

  View details for DOI 10.1080/10428194.2018.1466295

  View details for Web of Science ID 000458399900040

  View details for PubMedID 29741437

• Macrophages in ascites from cancer patients are primed to transdifferentiate into fibroblasts Ito, M., Nakano, M., Ariyama, H., Yamaguchi, K., Semba, Y., Sugio, T., Miyawaki, K., Kikushige, Y., Mizuno, S., Tanaka, R., Baba, E., Akashi, K. WILEY. 2018: 1262

  View details for Web of Science ID 000453773606109

• Analysis of GNA13 Protein in Follicular Lymphoma and its Association With Poor Prognosis AMERICAN JOURNAL OF SURGICAL PATHOLOGY Shimono, J., Miyoshi, H., Yoshida, N., Kato, T., Sato, K., Sugio, T., Miyawaki, K., Kurita, D., Sasaki, Y., Kawamoto, K., Imaizumi, Y., Kato, K., Nagafuji, K., Akashi, K., Seto, M., Teshima, T., Ohshima, K. 2018; 42 (11): 1466-1471

  Abstract

  GNA13 is a G protein involved in modulating tumor proliferative capacity, infiltration, metastasis, and migration. Genomic alteration of GNA13 was frequently observed in follicular lymphoma (FL). In this study, we examined 167 cases of FL by immunostaining of GNA13 using tissue microarray to evaluate the clinical significance. There were 26 GNA13-positive cases (15.6%) and 141 GNA13-negative cases (84.4%). GNA13-positive cases had a higher incidence of early progression of disease for which disease progression was recognized within 2 years compared with GNA13-negative cases (P=0.03). There were no significant differences in other clinicopathologic factors including histological grade, BCL2-IGH translocation, immunohistochemical phenotype, and Follicular Lymphoma International Prognostic Index. In addition, overall survival and progression-free survival were poorer in GNA13-positive cases than in GNA13-negative cases (P=0.009 and 0.005, respectively). In multivariate analysis, GNA13 positivity was found to be a poor prognostic factor for overall survival and progression-free survival. Thus, GNA13 protein expression was an independent prognostic factor and may affect disease progression in FL.

  View details for DOI 10.1097/PAS.0000000000000969

  View details for Web of Science ID 000447699800005

  View details for PubMedID 30307409

  View details for PubMedCentralID PMC6266301

• Gastrointestinal Graft-versus-Host Disease Is a Risk Factor for Postengraftment Bloodstream Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Mori, Y., Yoshimoto, G., Nishida, R., Sugio, T., Miyawaki, K., Shima, T., Nagasaki, Y., Miyake, N., Harada, Y., Kunisaki, Y., Kamezaki, K., Numata, A., Kato, K., Shiratsuchi, M., Maeda, T., Takenaka, K., Iwasaki, H., Shimono, N., Akashi, K., Miyamoto, T. 2018; 24 (11): 2302-2309

  Abstract

  Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P = .013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P < .0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P < .001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants.

  View details for DOI 10.1016/j.bbmt.2018.06.002

  View details for Web of Science ID 000453638700020

  View details for PubMedID 29909153

• Expression of PD-1 and PD-L1 on cytotoxic T lymphocytes and immune deficiency in a patient with adult T cell leukemia/lymphoma ANNALS OF HEMATOLOGY Yanagihara, T., Ikematsu, Y., Kato, K., Yonekawa, A., Ideishi, S., Tochigi, T., Sugio, T., Miyawaki, K., Tanaka, K., Harada, E., Hamada, N., Nakanishi, Y. 2018; 97 (2): 359-360

  View details for DOI 10.1007/s00277-017-3146-z

  View details for Web of Science ID 000419434700018

  View details for PubMedID 28967040

• Hepatitis C virus infection is an independent prognostic factor in follicular lymphoma ONCOTARGET Shimono, J., Miyoshi, H., Kato, T., Sugio, T., Miyawaki, K., Kamimura, T., Miyagishima, T., Eto, T., Imaizumi, Y., Kato, K., Nagafuji, K., Akashi, K., Seto, M., Teshima, T., Ohshima, K. 2018; 9 (2): 1717-1725

  Abstract

  Neoantigens are the main targets of tumor-specific T cells reactivated by immune checkpoint-blocking antibodies or when using tumor-infiltrating T cells for adoptive therapy. While cancers often accumulate hundreds of mutations and harbor several immunogenic neoantigens, the repertoire of mutation-specific T cells in patients might be restricted. To bypass suboptimal conditions, which impede the reactivation of existing T cells or the priming of neoantigen-specific T cells in a patient, we employ T cells of healthy donors with an overlapping HLA repertoire to target cancer neoantigens. In this study, we focus on streamlining the process of in vitro-induction of neoantigen-specific T cells and isolating their T cell receptors (TCRs) to establish a time-efficient protocol that will allow the patient to benefit from subsequent therapy. We first optimized the priming of T cells to omit multiple restimulations and extended culturing. Neoantigen-specific T cells were enriched using specific dextramers and next-generation sequencing was applied to determine the TCR repertoire. This allowed us to circumvent the laborious process of expanding T cell clones. Using this protocol, we successfully identified HLA-A-restricted TCRs specific for neoantigens found in an esophageal cancer cell line (TE-8) and a primary ovarian cancer. To verify TCR specificity, we generated TCR-engineered T cells and confirmed recognition of the tumor-derived neoantigens. Our results also emphasize the importance of neoepitope selection in order to avoid cross-reactivity to corresponding wild-type peptide sequences. In conclusion, we established a 2-week protocol for generating and identifying neoantigen-specific TCRs from third-party donors making this strategy applicable for clinical use.

  View details for DOI 10.18632/oncotarget.23138

  View details for Web of Science ID 000419623200018

  View details for PubMedID 29541393

  View details for PubMedCentralID PMC5834292

• Hepatitis C virus infection is an independent prognostic factor in follicular lymphoma. Oncotarget Shimono, J., Miyoshi, H., Kato, T., Sugio, T., Miyawaki, K., Kamimura, T., Miyagishima, T., Eto, T., Imaizumi, Y., Kato, K., Nagafuji, K., Akashi, K., Seto, M., Teshima, T., Ohshima, K. 2018; 9 (2): 1717-1725

  Abstract

  Hepatitis C virus (HCV) is a single-stranded RNA virus that not only affects hepatocytes, by B cells as well. It is thought that HCV is involved in the onset of B-cell lymphoma. The clinicopathological characteristics of HCV-positive diffuse large B-cell lymphoma (DLBCL) and HCV-positive splenic marginal zone lymphoma (SMZL) are known, but there has been no report on HCV-positive follicular lymphoma (FL). In this study, the clinicopathological characteristics of HCV-positive FL were examined in 263 patients with FL who were classified into a HCV-positive group with HCV antibody and negative groups without one. The number of patients with HCV-positive FL and HCV-negative FL was 10 (3.8%) and 253 (96.2%), respectively. The patients with HCV-positive FL commonly had more than one region of lymphadenopathy, Ann Arbor stage III/IV, hemoglobin <120 g/l, elevated lactate dehydrogenase level, and high-risk categorization of Follicular Lymphoma International Prognostic Index (FLIPI) than in patients with HCV-negative FL. Overall survival and progression-free survival were poorer in patients with HCV-positive FL than in those with HCV-negative FL (p < 0.0001 and 0.006, respectively). Also, multivariate analysis revealed that positive HCV antibody was a poor prognostic factor of OS. In conclusion, HCV-positive FL has unique clinical features and may have a great impact on the overall survival of affected patients.

  View details for DOI 10.18632/oncotarget.23138

  View details for PubMedID 29416725

  View details for PubMedCentralID PMC5788593

• Identification of unipotent megakaryocyte progenitors in human hematopoiesis. Blood Miyawaki, K., Iwasaki, H., Jiromaru, T., Kusumoto, H., Yurino, A., Sugio, T., Uehara, Y., Odawara, J., Daitoku, S., Kunisaki, Y., Mori, Y., Arinobu, Y., Tsuzuki, H., Kikushige, Y., Iino, T., Kato, K., Takenaka, K., Miyamoto, T., Maeda, T., Akashi, K. 2017; 129 (25): 3332-3343

  Abstract

  The developmental pathway for human megakaryocytes remains unclear, and the definition of pure unipotent megakaryocyte progenitor is still controversial. Using single-cell transcriptome analysis, we have identified a cluster of cells within immature hematopoietic stem- and progenitor-cell populations that specifically expresses genes related to the megakaryocyte lineage. We used CD41 as a positive marker to identify these cells within the CD34+CD38+IL-3RαdimCD45RA- common myeloid progenitor (CMP) population. These cells lacked erythroid and granulocyte-macrophage potential but exhibited robust differentiation into the megakaryocyte lineage at a high frequency, both in vivo and in vitro. The efficiency and expansion potential of these cells exceeded those of conventional bipotent megakaryocyte/erythrocyte progenitors. Accordingly, the CD41+ CMP was defined as a unipotent megakaryocyte progenitor (MegP) that is likely to represent the major pathway for human megakaryopoiesis, independent of canonical megakaryocyte-erythroid lineage bifurcation. In the bone marrow of patients with essential thrombocythemia, the MegP population was significantly expanded in the context of a high burden of Janus kinase 2 mutations. Thus, the prospectively isolatable and functionally homogeneous human MegP will be useful for the elucidation of the mechanisms underlying normal and malignant human hematopoiesis.

  View details for DOI 10.1182/blood-2016-09-741611

  View details for PubMedID 28336526

• Delineation of Novel Subtypes Based on Microenvironment Immune Signature Provides Prognostic Stratification Strategy in Peripheral T-Cell Lymphoma Sugio, T., Miyawaki, K., Kato, K., Miyoshi, H., Ohshima, K., Akashi, K. AMER SOC HEMATOLOGY. 2016

  View details for DOI 10.1182/blood.V128.22.4108.4108

  View details for Web of Science ID 000394452307026

• Significance of monitoring trough plasma concentration levels for invasive fungal infection prophylaxis with itraconazole oral solution in patients with hematological malignancies: a prospective study. [Rinsho ketsueki] The Japanese journal of clinical hematology Kawano, I., Matsumoto, K., Jiromaru, T., Jinnochi, F., Semba, Y., Sugio, T., Sakamoto, K., Saito, N., Yoshida, S., Henzan, H., Takase, K., Morita, K., Eto, T. 2016; 57 (12): 2475-2480

  Abstract

  In this prospective study, we examined the prophylactic effect of itraconazole oral solution (ITCZ-OS) against invasive fungal disease in hematologic malignancy patients. The participants were 36 patients, at least 16 years of age, with hematologic malignancies treated at our hospital. ITCZ-OS 200 mg/day was administered orally twice a day with a target trough plasma concentration of 350 ng/ml. If the patient did not achieve the target trough plasma concentration, the dose was increased. The success rate of achieving the target trough plasma concentration of ITCZ with a dose of 200 mg/day was 63.9%. During the observation period, 2 patients (5.6%) were diagnosed with possible invasive fungal disease according to the EORTC/MSG 2008 criteria. Adverse events were observed in 2 patients (5.6%). The results showed administration of ITCZ-OS while monitoring ITCZ trough plasma concentrations to be effective for preventing invasive fungal disease, and no serious adverse events occurred. Since predicting trough levels in response to ITCZ administrations is difficult, its measurement is necessary to maintain the prophylactic effect of ITCZ.

  View details for DOI 10.11406/rinketsu.57.2475

  View details for PubMedID 28090013

• First Preclinical Report of the Efficacy and PD Results of KHK2823, a Non-Fucosylated Fully Human Monoclonal Antibody Against IL-3R alpha Akiyama, T., Takayanagi, S., Maekawa, Y., Miyawaki, K., Jinnouchi, F., Jiromaru, T., Sugio, T., Daitoku, S., Kusumoto, H., Shimabe, M., Nishikawa, S., Yamawaki, K., Iijima, K., Hiura, M., Takahashi, T., Kikushige, Y., Iwasaki, H., Akashi, K., Tawara, T. AMER SOC HEMATOLOGY. 2015

  View details for DOI 10.1182/blood.V126.23.1349.1349

  View details for Web of Science ID 000368019004149

• Prior Use of Mogamulizumab to Allogenic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-Versus-Host Disease Sugio, T., Kato, K., Aoki, T., Ota, T., Saito, N., Yoshida, S., Kawano, I., Henzan, H., Takase, K., Muta, T., Miyawaki, K., Shima, T., Takashima, S., Yamauchi, T., Mori, Y., Yoshimoto, G., Kamezaki, K., Takenaka, K., Kamimura, T., Ohno, Y., Eto, T., Ogawa, R., Iwasaki, H., Miyamoto, T., Akashi, K. AMER SOC HEMATOLOGY. 2015

  View details for DOI 10.1182/blood.V126.23.1940.1940

  View details for Web of Science ID 000368020100105

• [Herpes simplex virus type 2 fulminant hepatitis after umbilical cord blood transplantation for acute myeloid leukemia]. [Rinsho ketsueki] The Japanese journal of clinical hematology Yuasa, M., Ishiwata, K., Sugio, T., Kaji, D., Ota, H., Tsuji, M., Yamamoto, H., Yamamoto, G., Asano-Mori, Y., Uchida, N., Izutsu, K., Taniguchi, S. 2014; 55 (6): 682-6

  Abstract

  This report describes a 41-year-old patient, who developed herpes simplex virus type 2 (HSV-2)-hepatitis after umbilical cord blood transplantation (CBT). The patient had received allogeneic bone marrow transplantation from an unrelated donor for acute myeloid leukemia (AML) not in remission. AML relapsed 18 months after the first transplantation, and CBT was performed. AML relapsed again 5 months later and the patient was given chemotherapy. Although there was no active chronic graft-versus-host disease, liver dysfunction appeared, and one week later, progressed to acute liver failure. Viral screening of blood by PCR including hepatitis B and C viruses, human immunodeficiency virus, Epstein-Barr virus, cytomegalovirus, herpes simplex virus type 1 and HSV-2 revealed elevation of HSV-2 (2.34 * 10⁴ copies/ml). We diagnosed the patient as having HSV-2 acute hepatitis, and initiated treatment with antiviral drugs (acyclovir, foscarnet) and plasma exchange. However, liver functions deteriorated rapidly, and the patient died on day 6 after the onset of acute liver failure. Although HSV hepatitis is very rare after allogeneic stem cell transplantation, it is rapidly progressive and associated with a high mortality rate. Thus, early diagnosis with prompt antiviral intervention is recommended.

  View details for PubMedID 24975337