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

DOI： 10.1016/j.stem.2010.11.014

Publisher：南江堂  

DOI： 10.15106/j_naika134_820

CiNii Research

Language：English   Publisher：Expert Review of Clinical Immunology  

Introduction: Castleman disease (CD) is a benign lymphoproliferative disease causing severe systemic inflammation. Interleukin-6 (IL-6) is a major pathogenesis of multicentric CD (MCD), but only 30–60% of patients respond to IL-6 inhibitors. Novel agents for IL-6 inhibitor-refractory cases are needed. Clinical data and samples are being collected on a large scale and the clinical, pathological, and pathogenetic aspects are being elucidated. Areas covered: The pathological and clinical classification of CD is outlined. Focusing on idiopathic MCD (iMCD), this review identifies therapeutic targets and summarizes currently recommended drugs and promising therapeutic candidates. Expert opinion: The pathogenesis of MCD has been implicated in the activation of the Janus kinase (JAK)-transcriptional signaling activator (STAT) 3 pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt/mechanical target of rapamycin (mTOR) signaling pathway. iMCD-TAFRO (thrombocytopenia, anasarca, fever/elevated CRP, reticulin myelofibrosis/renal dysfunction, organ enlargement) is resistant to IL-6 inhibitors, and cyclosporine and mTOR inhibitors are sometimes effective. JAK inhibitors and mTOR inhibitors may be therapeutic agents for iMCD. Recently, we have shown that peripheral helper T (Tph) cell abnormalities are at the core of iMCD pathogenesis. Therapies targeting chemokine (C-X-C motif) ligand 13 (CXCL13) produced by Tph cells and blocking the Tph-CXCL13-B cell pathway may satisfy unmet need in refractory cases.

DOI： 10.1080/1744666X.2024.2357689

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Language：English   Publisher：Cancer Science  

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20–65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high-dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent-to-treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1-year maintenance, respectively. With a median follow-up of 38 months, the 3-year progression-free survival (PFS) rate was 83.5% and the 3-year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment-related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high-risk cytogenetics showed a trend toward lower 3-year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra-high-risk cytogenetics (≥2 high-risk cytogenetics) had an even worse prognosis, with 61.2% 3-year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38-antibody should be assessed in future studies.

DOI： 10.1111/cas.16158

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：English   Publisher：Bone Marrow Transplantation  

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.

DOI： 10.1038/s41409-023-02183-1

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

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

Language：English   Publisher：Blood Advances  

Immunomodulatory drugs (IMiDs) are key drugs for treating multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the interaction between cell-specific substrates and cereblon, a substrate receptor of the E3 ubiquitin ligase complex. Thus, identification of cell-specific substrates is important for understanding the effects of IMiDs. IMiDs increase the risk of thromboembolism, which sometimes results in fatal clinical outcomes. In this study, we sought to clarify the molecular mechanisms underlying IMiDs-induced thrombosis. We investigated cereblon substrates in human megakaryocytes using liquid chromatography–mass spectrometry and found that thrombospondin-1 (THBS-1), which is an inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, functions as an endogenous substrate in human megakaryocytes. IMiDs inhibited the proteasomal degradation of THBS-1 by impairing the recruitment of cereblon to THBS-1, leading to aberrant accumulation of THBS-1. We observed a significant increase in THBS-1 in peripheral blood mononuclear cells as well as larger von Willebrand factor multimers in the plasma of patients with myeloma, who were treated with IMiDs. These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.

DOI： 10.1182/bloodadvances.2023010080

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

Language：English   Publisher：Nature Communications  

Castleman disease (CD) is a rare lymphoproliferative disorder. Among subtypes of CD, idiopathic multicentric CD-not otherwise specified (iMCD-NOS) has a poor prognosis and its pathogenesis is largely unknown. Here we present a xenotransplantation model of iMCD-NOS pathogenesis. Immunodeficient mice, transplanted with lymph node (LN) cells from iMCD-NOS patients, develop iMCD-like lethal inflammation, while mice transplanted with LN cells from non-iMCD patients without inflammation serve as negative control. Grafts depleted of human CD3+ T cells fail to induce inflammation in vivo. Upon engraftment, peripheral helper T (Tph) cells expand and levels of human CXCL13 substantially increase in the sera of mice. A neutralizing antibody against human CXCL13 blocks development of inflammation and improves survival in the recipient mice. Our study thus indicates that Tph cells, producing CXCL13 play a critical role in the pathogenesis of iMCD-NOS, and establishes iMCD-NOS as an immunoregulatory disorder.

DOI： 10.1038/s41467-023-42718-0

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

Language：English   Publisher：Communications Biology  

Protection of telomeres 1a (POT1a) is a telomere binding protein. A decrease of POT1a is related to myeloid-skewed haematopoiesis with ageing, suggesting that protection of telomeres is essential to sustain multi-potency. Since mesenchymal stem cells (MSCs) are a constituent of the hematopoietic niche in bone marrow, their dysfunction is associated with haematopoietic failure. However, the importance of telomere protection in MSCs has yet to be elucidated. Here, we show that genetic deletion of POT1a in MSCs leads to intracellular accumulation of fatty acids and excessive ROS and DNA damage, resulting in impaired osteogenic-differentiation. Furthermore, MSC-specific POT1a deficient mice exhibited skeletal retardation due to reduction of IL-7 producing bone lining osteoblasts. Single-cell gene expression profiling of bone marrow from POT1a deficient mice revealed that B-lymphopoiesis was selectively impaired. These results demonstrate that bone marrow microenvironments composed of POT1a deficient MSCs fail to support B-lymphopoiesis, which may underpin age-related myeloid-bias in haematopoiesis.

DOI： 10.1038/s42003-023-05374-0

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

Language：English   Publisher：Cancer Science  

Metabolic alterations, especially in the mitochondria, play important roles in several kinds of cancers, including acute myeloid leukemia (AML). However, AML-specific molecular mechanisms that regulate mitochondrial dynamics remain elusive. Through the metabolite screening comparing CD34+ AML cells and healthy hematopoietic stem/progenitor cells, we identified enhanced lysophosphatidic acid (LPA) synthesis activity in AML. LPA is synthesized from glycerol-3-phosphate by glycerol-3-phosphate acyltransferases (GPATs), rate-limiting enzymes of the LPA synthesis pathway. Among the four isozymes of GPATs, glycerol-3-phosphate acyltransferases, mitochondrial (GPAM) was highly expressed in AML cells, and the inhibition of LPA synthesis by silencing GPAM or FSG67 (a GPAM-inhibitor) significantly impaired AML propagation through the induction of mitochondrial fission, resulting in the suppression of oxidative phosphorylation and the elevation of reactive oxygen species. Notably, inhibition of this metabolic synthesis pathway by FSG67 administration did not affect normal human hematopoiesis in vivo. Therefore, the GPAM-mediated LPA synthesis pathway from G3P represents a critical metabolic mechanism that specifically regulates mitochondrial dynamics in human AML, and GPAM is a promising potential therapeutic target.

DOI： 10.1111/cas.15835

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

急性骨髄性白血病(AML)に特異的なミトコンドリア機能の制御に関与する分子メカニズムを検討した。CD34陽性AML細胞と健常な造血幹/前駆細胞を比較した代謝物スクリーニングを通じて、AMLにおけるリゾホスファチジン酸(LPA)合成活性の亢進を同定した。LPAは、LPA合成経路の律速酵素であるグリセロール-3-リン酸アシルトランスフェラーゼ(GPAT)によってグリセロール-3-リン酸から合成される。GPATの4つのアイソザイムのうち、グリセロール-3-リン酸アシルトランスフェラーゼ、ミトコンドリア(GPAM)がAML細胞で高発現していた。GPAMサイレンシングまたはFSG67(GPAM阻害剤)でLPA合成を阻害すると、ミトコンドリア分裂が誘導され、その結果、酸化的リン酸化が抑制され、活性酸素種が増加することで、AMLの増殖が著しく阻害された。さらに、FSG67によるGPAM阻害は、in vivoでの正常な造血に影響を与えることなく、AMLに対して有効であることが示された。以上より、GPAMを介したグリセロール-3-リン酸からのLPA合成経路は、AMLにおけるミトコンドリア動態を特異的に制御する重要な代謝機構であり、GPAMは有望な治療標的であることが示唆された。

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

大腸癌幹細胞の中で増殖状態にあるものの特徴を決定するため、オルガノイドと大腸癌組織を材料に、それらのトランスクリプトミクスを解析した。その結果、CD44陽性を示す通常のヒト大腸癌幹細胞の分画の中に、ヒアルロン酸媒介運動性受容体(RHAMM)を発現している亜集団があることを発見した。細胞種の多様性を再構成することで腫瘍組織のミニチュア版としたオルガノイドを材料に、単一細胞トランスクリプトミクス解析を施行したところ、増殖性を示し、様々な細胞種の中にあって独特の特徴を示すRHAMM陽性細胞があることに注目された。ヒト大腸癌組織からRHAMM陽性CD44陽性の細胞を予期的に分離した結果、分離された同細胞は他の癌細胞と比較して高い増殖特性と自己新生能を現した。RHAMMを阻害するとin vitroでのオルガノイド形成は強く抑制され、in vivoでは腫瘍成長が阻害された。RHAMMは、通常の癌幹細胞分画内に含まれる増殖性の亜集団への特異的マーカーになりうると考えられた。

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

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

DOI： 10.1111/cas.15795

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

DOI： 10.1007/s12185-022-03458-x

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Language：English   Publisher：(一社)日本血液学会  

症例は31歳女性で、inv(16)(p13.1q22)を有する急性骨髄性白血病(AML)と診断された。臨床試験で自家造血幹細胞移植(ASCT)後に大量化学療法を受けたが、ASCTから2年後に再発した。そこで、HLA一致の非血縁者男性ドナーから、強度減弱前処置を用いた同種造血幹細胞移植(HSCT)を受けた。タクロリムス(Tac)とメトトレキサートによる予防下で急性移植片対宿主病(GVHD)発症したため、プレドニゾロン(PSL)で対処した。その後、中等度の慢性GVHDに進行したため、PSLとリツキシマブによる追加の免疫抑制剤、および修正フルチカゾン/アリスロマイシン/モンテルカスト(mFAM)併用療法を施行した。慢性GVHDに対してTac療法とmFAM療法を継続していたが、同種HSCT後9年目に食欲不振、寝汗、右下腹部痛を呈した。ドナー由来のバーキットリンパ腫と診断した。リツキシマブ併用集中化学療法により部分奏効が得られた。再発リスクの低減と化学療法の反復による臓器毒性を回避するため、アップフロント大量化学療法後にドナー由来のCD34+細胞を用いた幹細胞救済療法(疑似自家造血幹細胞移植[pASCT])を施行し、免疫抑制剤を適切に調整した。pASCT後23ヵ月間、cGVHDの増悪もなく、無病状態が維持された。

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DOI： 10.1038/s41375-023-01879-z

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

DOI： 10.1182/bloodadvances.2022008405

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Language：Japanese   Publisher：The Japanese Society of Hematology  

<p>Acute myeloid leukemia (AML) is one of the most common hematologic malignancies derived from self-renewing and highly propagating leukemic stem cells (LSCs). We have previously identified T-cell immunoglobulin mucin-3 (TIM-3) as an AML LSC-specific surface molecule by comparing the gene expression profiles of LSCs and hematopoietic stem cells (HSCs). TIM-3 expression clearly discriminates LSCs from HSCs within the CD34⁺CD38^- stem cell fraction. Furthermore, AML cells secrete galectin-9 (Gal-9, a TIM-3 ligand) in an autocrine manner, resulting in constitutive TIM-3 signaling, which maintains LSC self-renewal capacity through <i>β</i>-catenin accumulation. In this study, we investigated the LSC-specific mechanisms of TIM-3 signaling. We found that TIM-3 signaling drove the canonical Wnt pathway, which was independent of Wnt ligands, to maintain cancer stemness in LSCs. Gal-9 ligation activated the cytoplasmic Src homology 2 (SH2) binding domain of TIM-3 to recruit hematopoietic cell kinase (HCK), a Src family kinase that is highly expressed in LSCs. HCK phosphorylated p120-catenin to promote the formation of the LDL receptor-related protein 6 (LRP6) signalosome, hijacking the canonical Wnt pathway. This TIM-3/HCK/p120-catenin axis was employed principally in immature LSCs compared to TIM-3-expressing exhausted T-cells.</p>

DOI： 10.11406/rinketsu.64.547

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CiNii Research

Language：English  

DOI： 10.31547/bct-2022-010

PubMed

DOI： 10.1182/blood-2022-170782

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

Clonal hematopoiesis (CH) refers to the disproportionate expansion of hematopoietic stem cell clones and their corresponding progeny following the acquisition of somatic mutations. CH is common at the time of diagnosis in patients with blood cancers, including multiple myeloma (MM) and lymphoma. The presence of CH mutations correlates with IL-6 mediated inflammation and may result in lymphoma or MM modulation through microenvironment effects or by manifestations of the mutations themselves within the founding tumor clone. As might be expected with a variety of mutations and multiple potential mechanisms, CH exerts context-dependent effects, being protective in some settings and harmful in others. Though CH is very common in patients with hematologic malignancies, how it intersects with therapy and the natural disease course of these cancers are active areas of investigation. In lymphomas and MM specifically, patients have high rates of CH at diagnosis and are subsequently exposed to therapies, such as cytotoxic chemotherapy, that can cause CH progression to overt hematologic malignancy. The expanding diversity of treatment modalities for these cancers also increases the opportunities for CH to impact clinical outcome and modulate clinical responses. Here we review the basic biology and known health effects of CH, and we focus on the clinical relevance of CH in lymphoma and MM.

DOI： 10.1016/j.jaccao.2022.01.098

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

DOI： 10.1007/s12185-022-03394-w

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Language：English   Publisher：(一社)日本血液学会  

造血幹細胞移植(HSCT)施行前の再発・難治性(R/R)悪性リンパ腫患者において、18フルオロ-2-デオキシ-グルコース陽電子放出断層撮影法(18FDG-PET/CT)による総代謝腫瘍体積(TMTV)の評価が予後に与える影響を後方視的に検討した。2007年1月～2015年12月に当院においてHSCT施行前の3ヵ月以内にPET/CT検査を実施したR/R悪性リンパ腫患者67例を対象とした。39例(年齢20～65歳)が自家HSCTを受け、28例(年齢22～69歳)が同種HSCTを受けた。その結果、自家HSCT群のTMTVが大きい患者は、再発リスクが高く、予後が不良であった。同種HSCT群では、TMTVが大きい患者は無増悪生存率が低く、再発率も有意に高かった。Deauvilleスコアやその他の臨床パラメータはいずれも両群の予後と関連しなかった。以上より、HSCT前のPET/CTで評価したTMTVはR/Rアグレッシブリンパ腫の予後予測や治療方針の決定に有効であった。

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

DOI： 10.1007/s12185-022-03348-2

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Language：English   Publisher：(一社)日本血液学会  

早期に臨床的に意義のあるサイトメガロウイルス(csCMV)感染がなく、レテルモビル(LMV)予防投与を完了した同種造血細胞移植(allo-HCT)レシピエントにおいて、晩期csCMV感染に関連する危険因子を後方視的に検討した。2018年6月から2021年2月までに当院でallo-HCTを受け、csCMV感染予防のための予防的LMVを受けた患者81例(年齢18～70歳)を対象とした。そのうち23例(28.4%)はCMV再活性化を起こし、抗CMV薬による初回介入までの期間の中央値はallo-HCT後で131日(範囲103～166日)、LMV中止後で30日(範囲5～67日)であった。晩期csCMV初回感染の治療期間中央値は21日(範囲12～43日)であった。晩期csCMVは免疫再構成の遅れと明らかに相関していた。HLA不一致ドナー(HR 13.0、p=0.011)またはCMVに対するIgG陰性ドナー(HR 2.39、p=0.043)からのallo-HCTはリスクが有意に高かった。また、晩期CMV感染の有無による移植成績に差は認められなかった。以上より、より多くのallo-HCTレシピエント、特に「高リスク」ドナーから移植を受けるレシピエントにおいて、LMV長期投与の晩期csCMV感染予防に対する効果を明らかにする必要性が示唆された。

Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.111.1186

CiNii Research

Language：English   Publisher：Cancer Letters  

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.

DOI： 10.1016/j.canlet.2022.215597

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Language：English   Publisher：Blood Advances  

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 (COO), 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 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.

DOI： 10.1182/bloodadvances.2021004618

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DOI： 10.1111/cei.13477

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DOI： 10.1007/s12185-019-02788-7

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DOI： 10.1111/cas.14424.

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DOI： 10.1038/s41388-018-0480-0

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DOI： 10.1038/s41388-018-0480-0

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DOI： 10.1158/1535-7163.MCT-18-1216

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DOI： 10.1158/1535-7163.MCT-18-1216

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Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor–induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve–related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve–related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; P =.049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; P =.036), whereas there was no significant difference among the latter 2 groups (P =.889). The development of HHV6-associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve–related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication.

DOI： 10.1016/j.bbmt.2018.07.017

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

Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor–induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve–related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve–related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; P =.049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; P =.036), whereas there was no significant difference among the latter 2 groups (P =.889). The development of HHV6-associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve–related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication.

DOI： 10.1016/j.bbmt.2018.07.017

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

DOI： 10.3892/or.2018.6464

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

DOI： 10.3892/or.2018.6464

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DOI： 10.1182/blood-2016-09-741611

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DOI： 10.1007/s12185-016-2148-2

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

DOI： 10.1016/j.stemcr.2016.07.002

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DOI： 10.11406/rinketsu.57.412

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DOI： 10.1002/stem.1906

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DOI： 10.1007/s12185-015-1740-1

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DOI： 10.1159/000431062

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DOI： 10.1016/j.exphem.2014.07.267

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DOI： 10.1007/s12185-014-1651-6

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DOI： 10.1158/2159-8290.CD-14-0104

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DOI： 10.2169/internalmedicine.53.1366

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

DOI： 10.1007/s12185-013-1433-6

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

DOI： 10.1016/j.gene.2013.08.015

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DOI： 10.1007/s12185-013-1410-0

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DOI： 10.1182/blood-2012-06-440354

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DOI： 10.1182/blood-2012-02-409607

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DOI： 10.1182/blood-2012-02-408864

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DOI： 10.1002/ajh.23247

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DOI： 10.1371/journal.pone.0035763

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DOI： 10.1182/blood-2011-04-351965

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DOI： 10.1111/j.1749-6632.2012.06550.x

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DOI： 10.1111/j.1365-2141.2010.08249.x

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DOI： 10.1182/blood-2008-12-196055

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DOI： 10.4049/jimmunol.182.3.1490

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DOI： 10.1084/jem.20081756

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DOI： 10.4049/jimmunol.180.11.7358

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DOI： 10.1111/j.1600-0609.2007.00919.x

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DOI： 10.3324/haematol.11233

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DOI： 10.2169/internalmedicine.46.6384

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DOI： 10.1038/sj.bmt.1705649

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Event date： 2021.9 - 2021.10

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2021.9

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2021.5

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2020.10

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：広島   Country：Japan  

Event date： 2020.10

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Turkey  

Event date： 2020.10

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2020.9

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2020.6

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Germany  

Event date： 2010.9

Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2009.10

Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2008.12

Presentation type：Oral presentation (general)  

Country：United States  

Event date： 2007.10

Presentation type：Oral presentation (general)  

Venue：横浜   Country：Japan  

Event date： 2006.12

Presentation type：Oral presentation (general)  

Country：United States  

Language：English  

Language：Japanese  

Language：English  

Language：English  

Language：English  

Language：English  

Language：Japanese  

Language：English  

Language：English  

Language：English  

Language：Japanese   Publisher：(株)羊土社  

近年の質量分析技術の進歩に伴い発展をみせるメタボローム解析をはじめとする、種々の代謝研究の進捗により、がん幹細胞および白血病幹細胞にとって重要な代謝経路、特性が明らかになってきている。近年のがん代謝研究の進歩は著しく、腫瘍細胞が依存する特定の代謝経路を阻害する薬剤の臨床応用も目前である。本稿では、がん、白血病幹細胞に共通する代謝特性の概説を行うと同時に、特に分岐鎖アミノ酸代謝に焦点を当て、その腫瘍における機能や治療応用の可能性についてこれまでの研究を紹介し、考察を行いたい。(著者抄録)

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