研究等業績 - その他 - 髙橋　直人

骨髄腫細胞において低酸素で上昇するコーディング・ノンコーディング遺伝子の網羅的探索とその機能解析

池田 翔, 北舘 明宏, 阿部 史人, 小林 敬宏, 高橋 直人, 田川 博之

International Journal of Myeloma ( 日本骨髄腫学会 )  7 ( 1 ) 54 - 54   2017年04月

J-GLOBAL

Assessing the safety and efficacy of ruxolitinib in a multicenter, open-label study in Japanese patients with myelofibrosis

Komatsu N.

International Journal of Hematology ( International Journal of Hematology )  105 ( 3 ) 309 - 317   2017年03月

DOI

DISTRIBUTION PATTERN OF GLOMERULAR IGG SUBCLASS DEPOSITS IN MEMBRANOUS NEPHROPATHY PATIENTS WITH CRESCENT FORMATION AND POSITIVE MPO-ANCA

Masaya Saitoh, Atsushi Komatsuda, Yuhta Oyama, Masato Sawamura, Masatoyo Ozawa, Hideki Wakui, Naoto Takahashi

RHEUMATOLOGY ( OXFORD UNIV PRESS )  56   138 - 138   2017年03月

Erratum to: Assessing the safety and efficacy of ruxolitinib in a multicenter, open-label study in Japanese patients with myelofibrosis (International Journal of Hematology, (2017), 105, 3, (309-317), 10.1007/s12185-016-2130-z)

Komatsu N.

International Journal of Hematology ( International Journal of Hematology )  105 ( 3 )   2017年03月

DOI

ANCA-ASSOCIATED VASCULITIS COMPLICATING WITH LARGE VESSEL INVOLVEMENT AND HYPERTROPHIC PACHYMENINGITIS: REPORT OF AN AUTOPSY CASE AND REVIEW OF THE LITERATURE

Hajime Kaga, Atsushi Komatsuda, Masaya Saitoh, Mizuho Nara, Ayumi Omokawa, Masaru Togashi, Shin Okuyama, Hideki Wakui, Naoto Takahashi

RHEUMATOLOGY ( OXFORD UNIV PRESS )  56   70 - 70   2017年03月

Evaluation of the safety and efficacy of recombinant soluble thrombomodulin for patients with disseminated intravascular coagulation associated with acute leukemia: multicenter prospective study by the Tohoku Hematology Forum.

Yokoyama H, Takahashi N, Katsuoka Y, Inomata M, Ito T, Meguro K, Kameoka Y, Tsumanuma R, Murai K, Noji H, Ishizawa K, Ito S, Onishi Y, Harigae H, Tohoku Hematology Forum

International Journal of Hematology   105 ( 5 ) 606 - 613   2017年02月

DOI

Clinicopathological characteristics of malignant lymphoma in patients with hepatitis C virus infection in the Tohoku district in Eastern Japan.

Tajima K, Takahashi N, Ishizawa K, Murai K, Akagi T, Noji H, Sasaki O, Wano M, Itoh J, Kato Y, Shichishima T, Harigae H, Ishida Y, Tohoku Hematology Forum

Leuk Lymphoma.   58 ( 6 ) 1509 - 1511   2017年01月

DOI

[Refractory CD20-positive peripheral T-cell lymphoma showing loss of CD20 expression after rituximab therapy and gain of CD20 expression after administration of vorinostat and gemcitabine].

Teshima K, Ohyagi H, Kume M, Takahashi S, Saito M, Takahashi N

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 一般社団法人 日本血液学会 )  58 ( 11 ) 2227 - 2231   2017年

<p>79歳，男性。全身リンパ節腫脹で発症したT細胞受容体β鎖遺伝子再構成陽性，CD20陽性末梢性T細胞性リンパ腫（peripheral T-cell lymphoma, PTCL）, NOSに対してR-CHOP療法6コース施行し部分寛解を得た。2ヶ月後に早期再発を来たし，頸部リンパ節および皮膚の再生検でCD20陰転化を確認した。リンパ節病変はCCR4陽性であった。救援療法のGDP療法は奏効しなかった。皮膚病変に対してvorinostatを投与したが骨髄抑制のため中止，その後さらに皮膚病変は増悪した。増大した頸部リンパ節の生検を再度行ったところ，CD20再発現を認めた。CCR4陽性に対してmogamulizumabを投与したが病勢増悪し，再発から8ヶ月で死亡した。本例はCD20の発現がrituximab，vorinostat，gemcitabine治療の経過中に変化した興味深い症例と考えられる。</p>

DOI PubMed

Effects of denosumab on bone metabolic markers and bone mineral density in patients treated with glucocorticoids

Sawamura M.

Internal Medicine ( Internal Medicine )  56 ( 6 ) 631 - 636   2017年

Objective We performed a prospective study to determine the efficacy and safety of denosumab on bone metabolic indices and bone mineral density (BMD) in 29 patients receiving long-term glucocorticoids (GCs) who had clinical risk factors for fracture. Methods Among these patients, 16 had systemic lupus erythematosus (SLE), 6 RA, 4 other autoimmune diseases, and 3 renal diseases. All patients received donosumab 60 mg at baseline and 6 months. Serum N-terminal cross-linked telopeptide of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) levels were measured as bone metabolic indices. BMD at the lumbar spine (LSBMD) and femoral neck (FNBMD) were measured using dual energy X-ray absorptiometry and expressed as a percentage of the young adult mean (%YAM). Results Denosumab therapy significantly reduced serum NTX and BAP levels from baseline after 12 months (from 19.2 to 13.9 nmol BCE/L
from 11.9 to 9.2 U/L, respectively). In 18 patients treated with bisphosphonates before the start of denosumab therapy, the improvements in the LSBMD and FNBMD values were 1.5%YAM/year and 1.1%YAM/year, respectively. The LSBMD and FNBMD values were both significantly higher 12 months after denosumab therapy (3.5%YAM/year and 3.0%YAM/year, respectively). The LSBMD gain was significantly higher after denosumab therapy than during bisphosphonate therapy. No fractures were observed in any patients during denosumab therapy. Conlusion Denosumab is effective and safe in preventing bone resorption and BMD loss in patients treated with long-term GCs for inflammatory diseases. This is the first study showing a significant increase in not only LSBMD but also FNBMD in GC-induced osteoporosis after denosumab therapy.

DOI PubMed

Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia

Togasaki E.

Blood Cancer Journal ( Blood Cancer Journal )  7 ( 4 ) e559   2017年

Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1-17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations &gt;= 6 showed higher rate of achieving major molecular response than thoseo6 (P = 0.0381). Mutations in epigenetic regulator, ASXL1, TET2, TET3, KDM1A and MSH6 were found in 25% of patients. TET2 or TET3, AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1.

DOI PubMed

Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma

Abe F.

Oncotarget ( Oncotarget )  8 ( 5 ) 7572 - 7585   2017年

Tumor suppressive microRNA (miR)-150 inhibits metastasis by combining with the C-C chemokine receptor 6 (CCR6) "seed sequence" mRNA of the 3'-untranslated region (3'-UTR) in advanced cutaneous T-cell lymphoma (CTCL). Because the histone deacetylase inhibitor (HDACI) vorinostat showed excellent outcomes for treating advanced CTCL, HDACIs may reduce the metastasis of CTCL by targeting miR-150 and/ or CCR6. To examine whether these candidate molecules are essential HDACI targets in advanced CTCL, we used the My-La, HH, and HUT78 CTCL cell lines for functional analysis because we previously demonstrated that their xenografts in NOD/Shi-scid IL-2γnul mice (CTCL mice) induced multiple metastases. We found that pan- HDACIs (vorinostat and panobinostat) inhibited the migration of CTCL cells and downregulated CCR6. The miRNA microarray analysis against CTCL cell lines demonstrated that these pan-HDACIs commonly upregulated 161 miRNAs, including 34 known tumor suppressive miRNAs such as miR-150. Although 35 miRNAs possessing the CCR6 "seed sequence" were included in these 161 miRNAs, miR-150 and miR-185-5p were downregulated in CTCL cells compared to in normal CD4+ T-cells. The transduction of 12 candidate miRNAs against CTCL cells revealed that miR-150 most efficiently inhibited their migration capabilities and downregulated CCR6. Quantitative reverse transcriptase-polymerase chain reaction demonstrated that miR-150 was downregulated in advanced but not early CTCL primary cases. Finally, we injected miR-150 or siCCR6 into CTCL mice and found that mouse survival was significantly prolonged. These results indicate that miR-150 and its target, CCR6, are essential therapeutic targets of pan-HDACIs in advanced CTCL with metastatic potential.

DOI PubMed

Successful management of splenomegaly with ruxolitinib prior to allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia transformed from post-polycythemia vera myelofibrosis.

Masumi Fujishima, Naohito Fujishima, Akihiro Kitadate, Yongmei Guo, Atsushi Watanabe, Kumi Ubukawa, Miho Nara, Tomoko Yoshioka, Yoshihiro Kameoka, Naoto Takahashi

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 一般社団法人 日本血液学会 )  58 ( 7 ) 743 - 748   2017年

A 64-year-old woman was admitted to our hospital to undergo allogeneic stem cell transplantation. She was diagnosed with polycythemia vera with a JAK2 V617F mutation 7 years ago. She was administered ruxolitinib for splenomegaly two years prior to admission but this was discontinued because of progressive pancytopenia. One months after cessation of ruxolitinib, she developed acute myeloid leukemia transformed from post-polycythemia vera myelofibrosis. Although she achieved complete remission after induction therapy, 8-finger-breadth splenomegaly remained below the left costal margin. Ruxolitinib was re-administered following two courses of consolidation therapy. She underwent unrelated peripheral blood stem cell transplantation. Ruxolitinib was administered until the day before transplantation, and the spleen was palpated in 4-finger breadth below costal arc. Neutrophil engraftment was achieved 13 days after transplantation. In allogeneic stem cell transplantation, splenomegaly is one of the risk factors for engraftment failure and/or therapy-related mortality. Hence, a smaller spleen size can theoretically improve the outcome after transplantation. The administration of ruxolitinib prior to transplantation may have contributed to engraftment with a non-invasive reduction in the size of the spleen.

DOI PubMed

TAFRO Syndrome with Bilateral Adrenal Hemorrhage

Ito F, Kameoka Y, Nara M, Ubukawa K, Fujishima M, Yoshioka T, Fujishima N, Takahashi N

Nihon Naika Gakkai Zasshi. ( 日本内科学会 )  106 ( 2 ) 288 - 294   2017年

Two cases of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome with high serum procalcitonin levels, including the first case complicated with adrenal hemorrhaging

Nara M.

Internal Medicine ( Internal Medicine )  56 ( 10 ) 1247 - 1252   2017年

Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis/Renal failure, and Organomegaly (TAFRO) syndrome is a recently described systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly. It has an acute or subacute onset of unknown etiology, although some pathological features resemble those of multicentric Castleman disease. We here report two cases of TAFRO syndrome. The symptoms and pathological findings in these cases met the 2015 diagnostic criteria. Our cases showed high serum procalcitonin levels, suggesting bacterial infection as an onset trigger. In addition, Case 1 is the first case complicated with adrenal hemorrhaging. Case 2 is the second case of tocilizumab-resistant TAFRO syndrome successfully treated with rituximab.

DOI

両側副腎出血を合併したTAFRO症候群

伊藤 史子, 亀岡 吉弘, 奈良 美保, 鵜生川 久美, 藤島 眞澄, 吉岡 智子, 藤島 直仁, 高橋 直人

日本内科学会雑誌 ( 一般社団法人 日本内科学会 )  106 ( 2 ) 288 - 294   2017年

<p>48歳，男性．発熱，全身性浮腫とリンパ節腫脹で発症し，炎症反応高値，副腎出血，血小板減少，骨髄線維化を認めた．副腎出血による副腎不全を合併した悪性リンパ腫を疑ったが，リンパ節生検にてCastleman病の病理所見と一致し，多彩な臨床症状と検査所見を総合的に判断し，TAFRO症候群と診断した．Prednisolone（PSL）により症状の改善がみられた．頻度は稀だが，本症例のような多彩な臨床症状と特徴的な検査所見を示す場合，TAFRO症候群を念頭に置く必要がある．</p>

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