研究者詳細 - 井山　諭

論文 - 井山　諭

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Establishment of a simple test for iron absorption from the gastrointestinal tract

Masayoshi Kobune, Koji Miyanishi, Kohichi Takada, Yutaka Kawano, Hiroyuki Nagashima, Shohei Kikuchi, Kazuyuki Murase, Satoshi Iyama, Tsutomu Sato, Yasushi Sato, Rishu Takimoto, Junji Kato

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER TOKYO ) 93 ( 6 ) 715 - 719 2011年06月 [査読有り]

Recent studies on iron metabolism have begun to reveal the molecular mechanisms underlying iron absorption, which is dramatically affected in several disorders. In the clinical setting, the ability to determine the status of iron absorption would aid in the diagnosis of pathological conditions. Efforts to develop an oral iron absorption test (OIAT) date back to at least 60 years. However, previous procedures were associated with a number of problems, such as radiation exposure and low reproducibility. In an attempt to resolve these issues, we employed sodium ferrous citrate (SFC), by which the influence of various nutrients and drugs on iron absorption was markedly reduced. We found that OIAT using SFC was simple to perform in both hospitalized patients and outpatients. The increment of serum iron and % transferrin saturation at 120 min after SFC administration was useful in distinguishing iron absorption between healthy volunteers, patients with iron-deficiency anemia, and patients with anemia secondary to chronic disorders, which are respectively characterized by normal, enhanced, and reduced iron absorption. Thus, the SFC-based OIAT may represent a viable screening test for the evaluation of gastrointestinal iron absorption.

DOI PubMed

Tuberculous pleuritis with onset of refractory pleural effusion after chemoradiotherapy for esophageal cancer

Masahiro Hirakawa, Yasushi Sato, Hiroyuki Ohnuma, Tamotsu Sagawa, Hirotoshi Ishiwatari, Kazuyuki Murase, Satoshi Iyama, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Masayoshi Kobune, Rishu Takimoto, Junji Kato

Journal of Japanese Society of Gastroenterology ( 2 ) 108 ( 2 ) 231 - 237 2011年02月 [査読有り]

A 75-year-old man received chemoradiotherapy (CRT) for stage IVa esophageal cancer and complete response (CR) was obtained. However, he was referred to our department for recurrence in an area of esophagus not included in the previously irradiated field. Left pleural effusion increased after admission. Tuberculous pleuritis was eventually diagnosed by thoracoscopic pleural biopsy. It is necessary to accurately diagnose the cause of pleural effusion after CRT, because treatment strategies greatly depend on it. It is also necessary to consider the possible onset of tuberculous pleuritis, in particular, in patients with a history of tuberculosis infection.

DOI PubMed

Immune thrombocytopenia associated with de novo hepatitis B in a follicular lymphoma patient after autologous peripheral blood stem cell transplantation

Hiroyuki Kuroda, Tamaki Sakurai, Michiko Yamada, Naoki Uemura, Michihiro Ono, Tomoyuki Abe, Shigeyuki Fujii, Masahiro Maeda, Kyuhei Kohda, Yasuo Hirayama, Yuko Fujimi, Satoshi Iyama, Junji Kato

Biotherapy 25 ( 1 ) 579 - 583 2011年01月

We report a patient with immune thrombocytopenic purpura (ITP) associated with de novo hepatitis B after cessation of preemptive lamivudine therapy. A 52-year-old man was diagnosed with relapse follicular lymphoma (FL) he had received five courses of rituximab plus CHOP (R-CHOP) following an autologous peripheral blood stem cell transplantation (APBSCT) in January, 2008. As he was hepatitis B virus (HBV) surface antigen-positive, lamivudine was administered simultaneously with both R-CHOP and APBSCT to prevent a HBV reactivation. He developed de novo hepatitis due to HBV reactivation 2 months after cessation of lamivudine in June, 2009. He was admitted to a hospital, complaining of purpura and oral bleeding in July, 2009. Based on his elevated level of platelet-associated IgG (PAIgG), a diagnosis of ITP was made. After intravenous immunoglobulin injections and treatment with entecavir, thrombocytopenia and viral replication were controlled. In an APBSCT recipient whose idiotypic network is still forming, there is a higher likelihood of an expression of cross-reactive auto-antibodies after HBV reactivation.

Effective treatment by both anti-androgen therapy and chemotherapy for a patient with advanced salivary duct carcinoma

Hiroyuki Kuroda, Tamaki Sakurai, Michiko Yamada, Naoki Uemura, Michihiro Ono, Tomoyuki Abe, Shigeyuki Fujii, Masahiro Maeda, Kyuhei Kohda, Masahiko Obata, Masakatsu Ando, Satoshi Iyama, Junji Kato

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. ) 38 ( 4 ) 627 - 630 2011年 [査読有り]

Salivary duct carcinoma (SDC) is a high-grade malignant tumor arising predominantly in the parotid gland. Androgen receptor (AR) expression was mainly restricted to SDC in salivary cancer. We report successful treatment of a patient with advanced SDC using an endocrine chemotherapy. A 76-year-old man was hospitalized with lumbalgia and swelling of left submandibular region. Radiological examination indicated a tumor in left submandibular gland and metastatic tumors in lumbar vertebra, accompanied by swollen lymph nodes of the neck, mediastinum. Needle biopsies of both vertebral tumor and cervical lymph node revealed SDC. Positive nuclear staining was observed against AR in tumor cells of our patient by immunohistochemical analysis. He obtained a partial response after 1 course of treatment with both anti-androgen therapy and palliative chemotherapy using paclitaxel. In contrast to previous reports of poor response to chemotherapy alone and short-term survival of patients with SDC, our patient has demonstrated that chemotherapy combined with anti-androgen therapy may be an effective modality as a therapeutic regimen for SDC.

PubMed

Successful rituximab treatment of methotrexate-associated B-cell lymphoproliferative disorder arising in two patients with latency type II epstein-barr viral infection

Hiroyuki Kuroda, Tamaki Sakurai, Michiko Yamada, Naoki Uemura, Michihiro Ono, Tomoyuki Abe, Shigeyuki Fujii, Masahiro Maeda, Nanase Ishida, Kyuhei Kohda, Masahiko Obata, Masakatsu Ando, Satoshi Iyama, Junji Kato

Biotherapy 24 ( 6 ) 507 - 511 2010年11月

We have encountered two patients with methotrexate (MTX)-associated B-cell lymphoproliferative disorder (B-LPD) as a complication of rheumatoid arthritis (RA). Case 1 was a 68-year-old woman. She complained of right neck swelling during low-dose MTX treatment for RA. Her neck lymph node biopsy revealed polymorphic B-LPD. Case 2 was a 67-year-old man. He has hospitalized for right neck lymph node swelling and throat pain during low-dose MTX treatment for RA. Diffuse large B cell lymphoma was diagnosed by his tonsil biopsy. The immunohistochemical analyses of B-LPD in those patients showed latency type II Epstein-Barr virus (EBV) infection. MTX withdrawal and observation for a month revealed no spontaneous regression of B-LPD in both cases. Therefore, we administered rituximab once, it had been tumor remission of B-LPD in parallel with the EBV-DNA level in peripheral blood. Thus, their arthralgia was improved, and the MMP-3 level decreased. MTX withdrawal does not necessarily lead to spontaneous remission of tumors in B-LPD patients with latency type II EBV infection. Rituximab therapy proved effective for not only MTX-associated B-LPD but also RA in our patients.

ENDOSCOPIC FINDINGS OF ENTEROPATHY-TYPE T-CELL LYMPHOMA BY DOUBLE-BALLOON ENTEROSCOPY AND CAPSULE ENDOSCOPY

Yasushi Sato, Michihiro Ono, Tamotsu Sagawa, Rishu Takimoto, Masahiro Hirakawa, Hiroyuki Ohnuma, Tsutomu Sato, Satoshi Iyama, Kazuyuki Murase, Koji Miyanishi, Masayoshi Kobune, Junji Kato

DIGESTIVE ENDOSCOPY ( WILEY-BLACKWELL ) 22 ( 3 ) 243 - 245 2010年07月 [査読有り]

DOI PubMed

[Evaluation of the efficacy of liposomal amphotericin B].

Iyama S, Murase K, Sato T, Kikuchi S, Sato Y, Kobune M, Takimoto R, Kato J

Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases ( 2 ) 84 ( 2 ) 182 - 186 2010年03月 [査読有り]

2006 年12 月から2008 年4 月までの間に札幌医科大学附属病院第四内科に入院した患者の内，リポソーマルアムホテリシンB（L-AMB）が投与された患者計32 症例を対象にL-AMB の有効性と安全性を評価するために後方視的検討を行った．基礎疾患は血液疾患が87.5％と多数を占め，その内訳は急性骨髄性白血病が最も多く，全体の50％を占めており，次いで悪性リンパ腫が全体の12.5％であった．L-AMB の平均投与期間は14.2±12.9 日，累積投与量は平均1,786±2,181mg であった．予防投与の3 例を除き，何らかの真菌感染症を発症もしくは発熱性好中球減少症を発症した29 例中，21 例（72.4％）で改善効果を認めた．有害事象の重症度は，軽度9 例，中等度7 例であり，重度の副作用を認めた症例はなかった．低カリウム血症が7 例（21.9％）に，クレアチニン上昇が4 例（12.5％）に認められたがいずれも軽度であった．投与を中止した中等度副作用発生例に関しては，いずれも投与中止後に症状の正常化を確認出来た．以上のことから，これまでの海外の報告と同様に，我々の検討においてもL-AMB が高い有効性と安全性を有することが示唆された．特に確定診断がつく前の早期にL-AMB を使用開始することが良好な治療成績に結びつく可能性が考えられた．また生理食塩水の負荷など十分な補液量を行うことや，血清カリウムなどの電解質バランスを管理することでL-AMB を安全に使用できることが示唆された．従来型のアムホテリシンB では，腎毒性などの理由により使用が限られていたが，副作用が大幅に軽減されたL-AMB は真菌感染のリスクを持った血液疾患患者や既に真菌感染症を発症した血液疾患患者の治療薬として有用であると考えられた．

DOI PubMed CiNii

Pure Red Cell Aplasia Associated with Good's Syndrome Accompanied by Decreased Stem Cell Factor Production in the Bone Marrow

Kageaki Kuribayashi, Akihito Fujimi, Masayoshi Kobune, Rishu Takimoto, Shohei Kikuchi, Satoshi Iyama, Junji Kato, Yoshiro Niitsu, Naoki Watanabe

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE ) 49 ( 5 ) 377 - 382 2010年 [査読有り]

DOI PubMed

Therapeutic results in patients with biphenotypic acute leukemia at Sapporo Medical University Hospital

Kazuyuki Murase, Satoshi Iyama, Tsutomu Sato, Rishu Takimoto, Masayoshi Kobune, Junji Kato

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. ) 37 ( 10 ) 2011 - 2013 2010年 [査読有り]

We reviewed the results of 6 patients with biphenotypic acute leukemia (BAL) which the diagnostic standard of the European Group for the Immunological Characterization of Leukemia (EGIL) at Sapporo Medical University Hospital between 2006 and 2008. There were 5 males and 1 females with an average age of 35 years. Among them, 4 were B lymphoid and myeloid, 2 were T lymphoid and myeloid, and one was T/B lymphoid. Two of 4 patients did not attain complete remission, and two relapsed after first treatment with acute myeloblastic leukemia (AML) protocol. On the other hand, two showed complete remission after the acute lymphoblastic leukemia (ALL) protocol. One of 4 patients survived who had been treated with hematopoietic stem cell transplantation as a post-remission therapy. The ALL protocol was good for the induction therapy. However, overall treatment-related deaths were 4 patients and considerable caution was necessary.

PubMed

ヘッジホッグ・シグナル伝達阻害剤は、CD34+白血病細胞の薬剤耐性を解除する

菊地尚平, 小船雅義, 村瀬和幸, 井山諭, 佐藤勉, 瀧本理修, 河野豊, 宮西浩嗣, 佐藤康史, 加藤淳二

臨床血液 ( (一社)日本血液学会-東京事務局 ) 50 ( 9 ) 1113 - 1113 2009年09月 [査読有り]

[Successful induction of complete remission by gemtuzumab ozogamicin following chemotherapy in three patients with relapsed or refractory acute myeloid leukemia].

Hirayama Y, Terui T, Koike K, Neda H, Ishitani K, Kohda K, Kuroda H, Iyama S, Sato T, Kobune M, Takimoto R, Kato J

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 8 ) 50 ( 8 ) 663 - 665 2009年08月 [査読有り]

DOI PubMed CiNii

シクロパミンは、CD34陽性白血病細胞の薬剤耐性を解除する(Cyclopamine dramatically restores drug resistance of CD34+ leukemic cells)

小船雅義, 井山諭, 佐藤勉, 瀧本理修, 菊地尚平, 村瀬和幸, 河野豊, 宮西浩嗣, 佐藤康史, 加藤淳二

日本癌学会総会記事 ( 日本癌学会 ) 68回 480 - 480 2009年08月 [査読有り]

Drug resistance is dramatically restored by hedgehog inhibitors in CD34(+) leukemic cells

Masayoshi Kobune, Rishu Takimoto, Kazuyuki Murase, Satoshi Iyama, Tsutomu Sato, Shohei Kikuchi, Yutaka Kawano, Kohji Miyanishi, Yasushi Sato, Yoshiro Niitsu, Junji Kato

CANCER SCIENCE ( WILEY-BLACKWELL ) 100 ( 5 ) 948 - 955 2009年05月 [査読有り]

Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers and in cancer stem cells. However, the contribution of Hh signaling to leukemic cell regulation has remained unclear. In this study, we assessed the possibility that Hh pathway activation contributes to the survival and drug resistance of cluster of differentiation (CD)34(+) leukemia cells. Hh signaling in leukemic cell lines and primary leukemic cells was screened by reverse transcription - polymerase chain reaction (RT-PCR) and a Hh signaling reporter assay. We found that Hh signaling is active in several human acute myeloid leukemia (AML) cells, especially primary CD34(+) leukemic cells and cytokine-responsive CD34+ cell lines such as Kasumi-1, Kasumi-3 and TF-1. These CD34+ cells express the downstream effectors glioma-associated oncogene homolog (GLI)1 or GLI2, indicative of active Hh signaling. Moreover, inhibition of Hh signaling with the naturally derived Smoothened antagonist cyclopamine, endogenous Hh inhibitor hedgehog-interacting protein or anti-hedgehog neutralizing antibody induced apoptosis after 48 h of exposure, although these CD34(+) cell lines exhibited resistance to cytarabine (Ara-C). In contrast, cyclopamine failed to affect growth or survival in U937 and HL-60 cell lines that lack expression of Hh receptor components, confirming that the effect of Hh inhibition is specific. Furthermore, combination with 10 mu M cyclopamine significantly reduced drug resistance of CD34(+) cell lines and primary CD34(+) leukemic cells to Ara-C. These results suggest that aberrant Hh pathway activation is a feature of some CD34(+) myeloid leukemic cells and Hh inhibitors may have a therapeutic role in the treatment of AML. (Cancer Sci 2009; 100: 948-955).

DOI PubMed

Chronic idiopathic neutropenia associated with granular lymphocytic leukemia effectively treated with immunosuppressants

Yuko Fujimi, Yasuo Hirayama, Hiroyuki Kuroda, Toshiro Sakai, Yuichi Konuma, Kyuhei Kohda, Akihito Fujimi, Satoshi Iyama, Tsutomu Sato, Masayoshi Kobune, Rishu Takimoto, Junji Kato

Biotherapy 23 ( 3 ) 263 - 266 2009年05月

A 64-year-old male was admitted to our hospital with diverticulitis of the large intestine, and a blood test detected neutropenia. Bone marrow aspiration found no hematological malignancy, and we considered idiopathic neutropenia. After he was injected with granulocyte colony-stimulating factor and antibiotics, abdominal pain and high fever disappeared. However, the neutropenia continued. One month after his hospitalization, we found monoclonal rearrangement of TCRβ and predominant granular lymphocyte in the peripheral blood. The diagnosis was granular lymphocytic leukemia (GLL) with neutropenia. After he was treated with immunosuppressants, the neutrophil count was normalized. We conclude that some cases of chronic idiopathic neutropenia are associated with GLL.

Treatment of hepatocellular carcinoma by AdAFPep/Rep, AdAFPep/p53, and 5-fluorouracil in mice

Tamotsu Sagawa, Yasuyuki Yamada, Minoru Takahashi, Yasushi Sato, Masayoshi Kobune, Rishu Takimoto, Junki Fukaura, Satoshi Iyama, Tsutomu Sato, Koji Miyanishi, Takuya Matsunaga, Tetsuji Takayama, Junji Kato, Katsunori Sasaki, Hirofumi Hamada, Yoshiro Niitsu

HEPATOLOGY ( JOHN WILEY & SONS INC ) 48 ( 3 ) 828 - 840 2008年09月 [査読有り]

Although conditionally replicable adenovirus (CRAd) has been used in the clinical treatment of hepatocellular carcinoma (HCC), it suffers from the inherent drawback of having relatively low antitumor activity. Here, we have sought to overcome this drawback. First, we combined CRAd (AdAFPep/Rep) driven by a-fetoprotein enhancer/promoter (ATPep) with a replication-incompetent adenovirus carrying a p53 transgene that is also driven by AFPep. The synergism of this combination produced a significantly improved tumoricidal effect on the human HCC cell line Hep3B, which has a relatively short doubling time in comparison with other human HCC cell lines, through the transactivation of p53 by early region 1A transcribed by AdAFPep/Rep. This synergistic interaction was augmented by the addition of a subtumoricidal dose (0.5 mu g/mL) of 5-fluorouracil (5-FU), which enhanced p53 expression and facilitated the release of virions from tumor cells. When relatively large (10-mm-diameter) Hep3B tumors grown in nude mice were injected with the two viruses in combination, they showed significantly impaired growth in comparison with those treated with each virus separately. The growth suppression effect of the virus combination was enhanced by a low dose (600 mu g) of 5-FU. Survival of the tumor-bearing mice treated with these three agents was significantly longer than that of control mice. Moreover, the tumor completely disappeared with the repeated injection of these agents. Conclusion: This combination strategy holds promise for the treatment of relatively large and rapidly growing HCCs that may be encountered clinically.

DOI PubMed

[A case of hepatosplenic gammadelta T-cell lymphoma associated hemophagocytic syndrome].

Iyama S, Matsunaga T, Sato T, Sato Y, Sagawa T, Murase K, Kida M, Kobune M, Takimoto R, Kato J, Niitsu Y

Gan to kagaku ryoho. Cancer & chemotherapy ( 9 ) 35 1623 - 1627 2008年09月 [査読有り]

PubMed

ヒト骨髄間質細胞は臍帯血CD34陰性細胞のCXCR4発現増強と長期造血再建能を誘導する

小船雅義, 村瀬和幸, 井山諭, 佐藤勉, 河野豊, 瀧本理修, 松永卓也, 加藤淳二

臨床血液 ( (一社)日本血液学会-東京事務局 ) 49 ( 9 ) 940 - 940 2008年09月 [査読有り]

アデノウイルスベクターを用いたヘッジホッグ遺伝子の高発現は、TおよびBリンパ球の分化抑制を誘導する

加藤淳二, 小船雅義, 村瀬和幸, 井山諭, 佐藤勉, 河野豊, 瀧本理修, 松永卓也

臨床血液 ( (一社)日本血液学会-東京事務局 ) 49 ( 9 ) 1085 - 1085 2008年09月 [査読有り]

Apoptosis supercedes necrosis in mitochondrial DNA-depleted Jurkat cells by cleavage of receptor-interacting protein and inhibition of lysosomal cathepsin

Tsutomu Sato, Takuro Machida, Sho Takahashi, Kazuyuki Murase, Yutaka Kawano, Tsuyoshi Hayashi, Satoshi Iyama, Kohich Takada, Kageaki Kuribayashi, Yasushi Sato, Masayoshi Kobune, Rishu Takimoto, Takuya Matsunaga, Junji Kato, Yoshiro Niitsu

JOURNAL OF IMMUNOLOGY ( AMER ASSOC IMMUNOLOGISTS ) 181 ( 1 ) 197 - 207 2008年07月 [査読有り]

In the present study, we used mitochondrial DNA-depleted Jurkat subclones (rho(0) cells) to demonstrate that Fas agonistic Ab (CH-11), at the concentrations that evoke apoptotic death of the parental Jurkat cells, induced necrosis mainly through generation of excess reactive oxygen species, lysosomal rupture, and sequential activation of cathepsins B and D, and in minor part through activation of receptor-interacting protein (RIP). In the rho(0) cells treated with CH-11, ATP supplementation converted necrosis into apoptosis by the formation of the apoptosome and subsequent activation of procaspase-3. In these ATP-supplemented rho(0) cells (ATP-rho(0)), generation of excess ROS and lysosomal rupture were still seen, yet cathepsins B and D were inactivated and RIP was degraded. The conversion of necrosis to apoptosis, RIP degradation, and cathepsin inactivation in ATP-rho(0) cells were blocked by caspase-3 inhibitors. Activities of cathepsins B and D in the lysate of necrotic rho(0) cells were inhibited by the addition of apoptotic parental Jurkat cell lysate. Thus, apoptosis may supercede necrosis.

PubMed

Ex vivo large-scale generation of human red blood cells from cord blood CD34(+) cells by co-culturing with macrophages

Akihito Fujimi, Takuya Matsunaga, Masayoshi Kobune, Yutaka Kawano, Taiko Nagaya, Ikuta Tanaka, Satoshi Iyama, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Tamotsu Sagawa, Yasushi Sato, Rishu Takimoto, Tetsuji Takayama, Junji Kato, Shinsei Gasa, Hiromi Sakai, Eishun Tsuchida, Kenji Ikebuchi, Hirofumi Hamada, Yoshiro Niitsu

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER TOKYO ) 87 ( 4 ) 339 - 350 2008年05月 [査読有り]

We generated red blood cells (RBC) from cord blood (CB) CD34(+) cells using a four-phase culture system. We first cultured CB CD34(+) cells on telomerase gene-transduced human stromal cells in serum-free medium containing stem cell factor (SCF), Flt-3/Flk-2 ligand, and thrombopoietin to expand CD34(+) cells (980-fold) and the total cells (10,400-fold) (first phase). Expanded cells from the first phase were liquid-cultured with SCF, interleukin-3 (IL-3), and erythropoietin (EPO) to expand (113-fold) and differentiate them into erythroblasts (second phase). To obtain macrophages for the next phase, we expanded CD34(+) cells from a different donor using the same co-culture system. Expanded cells from the first phase were liquid-cultured with granulocyte-macrophage colony stimulating factor, macrophage-colony stimulating factor (M-CSF), IL-3, and SCF to generate monocytes/macrophages (75-fold), which were incubated with type AB serum and M-CSF to fully differentiate them into macrophages. Erythroblasts were then co-cultured with macrophages in the presence of EPO to expand (threefold) and fully differentiate them (61% orthochromatic erythroblasts plus 39% RBC) (third phase). RBC were purified from erythroblasts and debris through a deleukocyting filter to generate 6.0 x 10(12) RBC from 1.0 unit of CB (3.0 transfusable units). Qualitatively, these RBC showed a hemoglobin content, oxygenation of hemoglobin, and in vivo clearance similar to those of adult peripheral RBC. Finally, an almost complete enucleation of orthochromatic erythroblasts (99.4%) was achieved by the cultivation method recently described by Miharada et al. in the absence of macrophages and cytokines (fourth phase). RBC were purified from remnant erythroblasts and debris by passage through a deleukocyting filter to generate 1.76 x 10(13) RBC from 1.0 unit of CB (8.8 transfusable units), the highest yield ever reported. Thus, this method may be useful for generating an alternative RBC supply for transfusions, investigating infectious agents that target erythroid cells, and as a general in vitro hematopoietic model system.

DOI PubMed

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