Details of a Researcher - MURASE Kazuyuki

Papers - MURASE Kazuyuki

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Notch signaling genes and CD8+ T-cell dynamics: Their contribution to immune-checkpoint inhibitor therapy in oral squamous cell carcinoma: A retrospective study.

Kazuhiro Ogi, Takahiro Iwamoto, Takashi Sasaya, Koyo Nishiyama, Takaaki Tokura, Takanori Sasaki, Hironari Dehari, Yohei Arihara, Kazuyuki Murase, Masato Saito, Masanori Someya, Kohichi Takada, Akihiro Miyazaki

Cancer medicine 13 ( 5 ) e6985 2024.03 [International journal]

BACKGROUND: Aberrant Notch signaling pathway has been related with the tumorigenesis in head and neck region, involving oral cavity. Here, we report the correlation between mutations in the Notch signaling pathway and CD8+ T-cell infiltration via PD-L1, which lead to enhanced antitumor immunity and may target for immune-checkpoint inhibitors (ICIs) therapy. METHODS: This retrospective study analyzed the results of immunohistochemical staining for PD-L1 and CD8+ T-cell infiltration in 10 patients and whole-exome sequencing (WES) was conducted on five of these patients to identify frequently mutated genes. RESULTS: Four of 10 patients were positive for PD-L1 and CD8+ T. By analyzing WES in three of these four patients, we notably identified the mutations of NOTCH1, FBXW7, and noncoding RNA intronic mutation in NOTCH2NLR in two of these three patients. This study may enable better selection of ICI therapy with CD8+ T-cell infiltration via PD-L1 expression for oral squamous cell carcinoma patients with mutations in Notch signaling pathway.

DOI PubMed

Stage IVa進行食道癌におけるDocetaxel/CDGP/5-FU・放射線同時併用療法(DNF-R)の予後解析

佐藤昌則, 大沼啓之, 早坂尚貴, 濱口孝太, 村瀬和幸, 高田弘一, 宮西浩嗣, 加藤淳二, 染谷正則, 坂田耕一

北海道医学雑誌 ( 北海道医学会 ) 98 ( 2 ) 139 - 139 2023.11

Coefficient of variation of T2-weighted MRI may predict the prognosis of malignant peripheral nerve sheath tumor.

Makoto Emori, Hiroyuki Tsuchie, Hiroyuki Takashima, Atsushi Teramoto, Yasutaka Murahashi, Yoshinori Imura, Hidetatsu Outani, Sho Nakai, Satoshi Takenaka, Ryosuke Hirota, Naoya Nakahashi, Junya Shimizu, Kazuyuki Murase, Akira Takasawa, Hiroyuki Nagasawa, Shintaro Sugita, Kohichi Takada, Tadashi Hasegawa, Seiji Okada, Naohisa Miyakoshi, Toshihiko Yamashita

Skeletal radiology 2023.09 [International journal]

BACKGROUND: We investigated whether non-enhancement MRI features, including measurement of the heterogeneity of the tumor with MR T2 imaging by calculating coefficient of variation (CV) values, were associated with the prognosis of non-metastatic malignant peripheral nerve sheath tumors (MPNST). METHODS: This retrospective study included 42 patients with MPNST who had undergone surgical resection (mean age, 50 years ± 21; 20 male participants). Non-enhancement MR images were evaluated for signal intensity heterogeneity on T1- and T2-weighted imaging, tumor margin definition on T1- and T2-weighted imaging, peritumoral edema on T2-weight imaging, and CV. We measured the signal intensities of MR T2-weighted images and calculated the corresponding CV values. CV is defined as the ratio of the standard deviation to the mean. The associations between factors and overall survival (OS) were investigated via the Kaplan-Meier method with log-rank tests and the Cox proportional hazards model. RESULTS: The mean CV value of MR T2 images was 0.2299 ± 0.1339 (standard deviation) (range, 0.0381-0.8053). Applying receiver operating characteristics analysis, the optimal cut-off level for CV value was 0.137. This cut-off CV value was used for its stratification into high and low CV values. At multivariate survival analysis, a high CV value (hazard ratio = 3.63; 95% confidence interval = 1.16-16.0; p = 0.047) was identified as an independent predictor of OS. CONCLUSION: The CV value of the signal intensity of heterogenous MPNSTs MR T2-weighted images is an independent predictor of patients' OS.

DOI PubMed

Synergistic antitumor effect of histone deacetylase class IIa inhibitor with lenvatinib in hepatocellular carcinoma.

Ryo Ito, Koji Miyanishi, Tomohiro Kubo, Kota Hamaguchi, Takahiro Osuga, Shingo Tanaka, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Minoru Nagayama, Yasutoshi Kimura, Toru Mizuguchi, Ichiro Takemasa, Junji Kato

Hepatology international 17 ( 3 ) 735 - 744 2023.06 [International journal]

BACKGROUND: Histone deacetylase (HDAC) class I and IIa are highly expressed in hepatocellular carcinoma (HCC) and associated with decreased survival. However, clinically used pan and class I inhibitors have serious adverse events. In this study, we assessed the antitumor effects and tolerability of class IIa HDAC inhibitor (HDACI) with lenvatinib, which is a standard therapy for HCC. METHODS AND RESULT: Combination therapy with class IIa HDACI and lenvatinib exerted synergistic antitumor effect in human HCC cell lines. In mouse models, this therapy showed significant antitumor effects, and few adverse events occurred. In immunoblotting, the expression of fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) was high in cell lines that showed a high antitumor effect. In addition, class IIa HDACI administration decreased the expression of FGFR4. In the small interfering RNA (siRNA) analysis, knockdown of HDAC9, which is an isoform of HDAC class IIa, reduced the expression of FGFR4 and induced apoptosis. Immunohistochemistry of human clinical specimens showed a positivity rate of 32% for FGFR4 and 84% for HDAC9 in HCC, and all FGFR4-positive patients were HDAC9 positive. CONCLUSION: Class IIa HDACI and lenvatinib combination therapy induces apoptosis by downregulating FGFR4 and blocking the FGFR signaling in FGFR4-positive HCC cell lines and has demonstrated synergistic antitumor effects and safety. This combination therapy overcomes the problems of conventional therapies and will be beneficial for FGFR4-positive HCC patients.

DOI PubMed

Drastic Multiorgan Dysfunction Due to Severe Leukostasis: A Case Report.

Akinori Tada, Yasuhiro Kikuchi, Kazuyuki Murase, Kohichi Takada, Akira Takasawa

Cureus 14 ( 11 ) e31518 2022.11 [International journal]

DOI PubMed

表在型食道癌ESD後のMM-SM癌における追加化学放射線療法の長期成績

伊藤亮, 大沼啓之, 早坂尚貴, 佐藤昌則, 村瀬和幸, 高田弘一, 福島悠希, 長谷川智一, 土屋高旭, 染谷正則, 宮西浩嗣, 坂田耕一, 加藤淳二

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 131回・125回 56 - 56 2022.09

食道癌化学放射線療法症例における放射線胃炎のリスク因子の検討

佐藤昌則, 大沼啓之, 早坂尚貴, 伊藤亮, 村瀬和幸, 高田弘一, 福島悠希, 長谷川智一, 土屋高旭, 染谷正則, 宮西浩嗣, 坂田耕一, 加藤淳二

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 131回・125回 55 - 55 2022.09

食道癌化学放射線療法症例における放射線胃炎のリスク因子の検討

佐藤昌則, 大沼啓之, 早坂尚貴, 伊藤亮, 村瀬和幸, 高田弘一, 福島悠希, 長谷川智一, 土屋高旭, 染谷正則, 宮西浩嗣, 坂田耕一, 加藤淳二

表在型食道癌ESD後のMM-SM癌における追加化学放射線療法の長期成績

伊藤亮, 大沼啓之, 早坂尚貴, 佐藤昌則, 村瀬和幸, 高田弘一, 福島悠希, 長谷川智一, 土屋高旭, 染谷正則, 宮西浩嗣, 坂田耕一, 加藤淳二

Association between Hepatic Oxidative Stress Related Factors and Activation of Wnt/β-Catenin Signaling in NAFLD-Induced Hepatocellular Carcinoma.

Kota Hamaguchi, Koji Miyanishi, Takahiro Osuga, Shingo Tanaka, Ryo Ito, Hiroki Sakamoto, Tomohiro Kubo, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Minoru Nagayama, Yasutoshi Kimura, Toru Mizuguchi, Ichiro Takemasa, Junji Kato

Cancers 14 ( 9 ) 2022.04 [International journal]

We investigated the association between iron overload, oxidative stress (8-oxo-7,8-dihydroguanine: 8-oxo-dG scores), Wnt/β-catenin pathway activation (expression of glutamine synthetase: GS), and tumor hyperintensity in the Gd-EOB-DTPA-enhanced MRI hepatobiliary phase (relative enhancement ratio: RER). This was a retrospective analysis of 94 hepatocellular carcinoma (HCC) patients who underwent surgical resection. In HBV-, HCV-, and alcohol-associated HCC, serum ferritin levels in the high and low RER groups were equivalent. In contrast, ferritin levels were elevated in the 'high RER' group of patients with nonalcoholic fatty liver disease (NAFLD)-HCC. As predictors of GS positivity, high RER had a sensitivity of 57.2% and a specificity of 100%. High serum ferritin had a sensitivity of 85.7% and a specificity of 85.7%. All cases with serum ferritin ≥275.5 ng/mL and high RER were 8-oxo-dG- and iron staining-positive. Additionally, GS positivity was seen in all cases with "serum ferritin levels above the upper limits or iron staining-positive" and '8-oxo-dG high' cases. Therefore, combining serum ferritin levels with RER may increase the accuracy with which activated Wnt/β-catenin signaling is predicted in NAFLD-HCC. We suggest that 8-oxo-dG accumulates following increased oxidative stress due to hepatic tissue iron deposition; this may activate Wnt/β-catenin signaling and trigger carcinogenesis.

DOI PubMed

A case of acute exacerbation of chronic hepatitis C during the course of adrenal Cushing's syndrome

Takahiro Osuga, Koji Miyanishi, Kota Hamaguchi, Shingo Tanaka, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Junji Kato

Clinical Case Reports ( Wiley ) 10 ( 2 ) 2022.02

DOI

Achievement of a durable response with eribulin for relapsed cardiac metastasis of uterine leiomyosarcoma after surgery: a case report and literature review

Makoto Usami, Kohichi Takada, Hajime Nakamura, Kazuyuki Murase, Yohei Arihara, Naotaka Hayasaka, Tomohiro Kubo, Koji Miyanishi, Junji Kato, Makoto Emori, Shintaro Sugita

Annals of Palliative Medicine ( AME Publishing Company ) 2022.01

DOI

A Case of Unresectable Combined Hepatocellular-Cholangiocarcinoma Successfully Treated with Lenvatinib.

Takahiro Osuga, Koji Miyanishi, Ryo Ito, Shingo Tanaka, Kota Hamaguchi, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Minoru Nagayama, Yasutoshi Kimura, Taro Sugawara, Shintaro Sugita, Ichiro Takemasa, Tadashi Hasegawa, Junji Kato

Case reports in oncology 15 ( 1 ) 318 - 325 2022 [International journal]

A 77-year-old man was referred to our hospital because of a hepatic tumor. Blood biochemistry showed elevated serum alfa-fetoprotein, protein induced by vitamin K absence-II, and carbohydrate antigen 19-9 levels. Gd-EOB-DTPA-enhanced magnetic resonance imaging revealed a 95-mm-sized tumor in liver S7. The tumor showed heterogeneous hyperintensity in the arterial phase, slightly washed out from the portal vein phase, and hypointensity in the hepatocellular phase. Post-enlargement segmental resection was performed, and the pathological diagnosis was combined hepatocellular cholangiocarcinoma. Seven months after surgery, multiple liver tumors were found, and biopsy revealed combined hepatocellular-cholangiocarcinoma. Hepatic arterial infusion chemotherapy with cisplatin was initiated. However, the patient developed a pulmonary abscess, which was treated with antibiotics. He then underwent treatment with lenvatinib, 11 months after surgery. At 8 weeks follow-up, a complete response (according to the modified Response Evaluation Criteria in Solid Tumors [RECIST]) and a partial response (RECIST version 1.1) was noted. To the best of our knowledge, thus far, only a single case of lenvatinib treatment of unresectable mixed liver cancer has been reported. In that case, lenvatinib was used as a third-line treatment. The present report is the first to describe lenvatinib as a first-line therapy for unresectable combined hepatocellular-cholangiocarcinoma, which resulted in a meaningful response. This case provides useful insights into the choice of appropriate drug treatment in this disease in the absence of randomized controlled trials of drug treatment.

DOI PubMed

MUTYH is associated with hepatocarcinogenesis in a non-alcoholic steatohepatitis mouse model

Hiroki Sakamoto, Koji Miyanishi, Shingo Tanaka, Ryo Ito, Kota Hamaguchi, Akira Sakurada, Masanori Sato, Tomohiro Kubo, Takahiro Osuga, Kazuyuki Murase, Kohichi Takada, Yusaku Nakabeppu, Masayoshi Kobune, Junji Kato

Scientific Reports ( Springer Science and Business Media LLC ) 11 ( 1 ) 2021.12

AbstractNon-alcoholic steatohepatitis (NASH)-related HCC is associated with oxidative stress. However, the mechanisms underlying the development of NASH-related HCC is unclear. MUTYH is one of the enzymes that is involved in repair of oxidative DNA damage. The aim of this study was to investigate the association between MUTYH and NASH-related hepatocarcinogenesis. MUTYH wild-type (Mutyh^+/+), heterozygous (Mutyh^+/−), and MUTYH-null (Mutyh^−/−) mice were fed a high-fat high-cholesterol (HFHC) diet or HFHC + high iron diet (20 mice per group) for 9 months. Five of 20 Mutyh^−/− mice fed an HFHC + high iron diet developed liver tumors, and they developed more liver tumors than other groups (especially vs. Mutyh^+/+ fed an HFHC diet, P = 0.0168). Immunohistochemical analysis revealed significantly higher accumulation of oxidative stress markers in mice fed an HFHC + high iron diet. The gene expression profiles in the non-tumorous hepatic tissues were compared between wild-type mice that developed no liver tumors and MUTYH-null mice that developed liver tumors. Gene Set Enrichment Analysis identified the involvement of the Wnt/β-catenin signaling pathway and increased expression of c-Myc in MUTYH-null liver. These findings suggest that MUTYH deficiency is associated with hepatocarcinogenesis in patients with NASH with hepatic iron accumulation.

DOI

Combination of psoas muscle mass index and neutrophil/lymphocyte ratio as a prognostic predictor for patients undergoing nonsurgical hepatocellular carcinoma therapy

Yusuke Sugama, Koji Miyanishi, Takahiro Osuga, Shingo Tanaka, Kota Hamaguchi, Ryo Ito, Hiroki Sakamoto, Tomohiro Kubo, Hiroyuki Ohnuma, Kazuyuki Murase, Kohich Takada, Masayoshi Kobune, Junji Kato

JGH Open ( Wiley ) 5 ( 12 ) 1335 - 1343 2021.12

DOI

Complete Response Induced by Concurrent Chemoradiotherapy in a Patient with NUT Carcinoma: A Case Report.

Joji Muramatsu, Kohichi Takada, Shintaro Sugita, Takaaki Tsuchiya, Keisuke Yamamoto, Masaru Takagi, Kazuyuki Murase, Saki Ameda, Yohei Arihara, Koji Miyanishi, Koh-Ichi Sakata, Junji Kato

Internal medicine (Tokyo, Japan) 2021.10 [Domestic journal]

An 18-year-old man presented with sudden vision loss in his left eye. Magnetic resonance imaging revealed a tumor that had invaded the left optic nerve, originating from the left posterior ethmoid sinus. Immunohistochemical analyses identified positive staining for NUT protein in the nuclei of tumor cells. We diagnosed locally advanced NUT carcinoma (NC) and initiated concurrent chemoradiotherapy (CCRT), consisting of chemotherapy with vincristine, doxorubicin, and cyclophosphamide, alternating with ifosphamide and etoposide, plus radiation therapy. The patient achieved a complete response. CCRT can be a useful treatment option for adolescent and young-adult patients with locally advanced unresectable NC.

DOI PubMed

進行食道癌に対するdocetaxel、nedaplatin、5-fluorouracil、放射線併用療法(DNF-R)による根治的化学放射線療法の第I/II相試験-アップデート解析

佐藤昌則, 大沼啓之, 早坂尚貴, 濱口孝太, 村瀬和幸, 高田弘一, 福島悠希, 長谷川智一, 土屋高旭, 染谷正則, 宮西浩嗣, 坂田耕一, 加藤淳二

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 129回・123回 26 - 26 2021.09

血液疾患患者におけるCOVID-19感染症4例の報告(Four cases of COVID-19 patients with hematological malignancy)

小野賢人, 堀口拓人, 下山紗央莉, 藤田千紗, 後藤亜香利, 池田博, 井山諭, 村瀬和幸, 高田弘一, 藤谷好弘, 高橋聡, 黒沼幸治, 小船雅義

日本血液学会学術集会 ( (一社)日本血液学会 ) 83回 OS3 - 4 2021.09

Programmed cell death ligand 1 expression in a case of poorly differentiated lymphocyte‐rich hepatocellular carcinoma

Ginji Omori, Takahiro Osuga, Koji Miyanishi, Kota Hamaguchi, Shingo Tanaka, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Minoru Nagayama, Yasutoshi Kimura, Ichiro Takemasa, Yasuhiro Kikuchi, Toshihiko Torigoe, Junji Kato

Clinical Case Reports ( Wiley ) 9 ( 9 ) 2021.09

DOI

Survival benefit of conversion surgery after intensive chemotherapy for unresectable metastatic gastric cancer: a propensity score-matching analysis

Hiroyuki Ohnuma, Yasushi Sato, Naoki Onoyama, Kota Hamaguchi, Naotaka Hayasaka, Masanori Sato, Kazuyuki Murase, Kohichi Takada, Koji Miyanishi, Takeshi Murakami, Tatsuya Ito, Takayuki Nobuoka, Ichiro Takemasa, Junji Kato

Journal of Cancer Research and Clinical Oncology ( Springer Science and Business Media LLC ) 147 ( 8 ) 2385 - 2396 2021.08

DOI

Eribulin in combination with HER2-targeted antibodies for successful treatment of metastatic salivary duct carcinoma: A report of two cases

Akihito Fujimi, Yasuhiro Nagamachi, Naofumi Yamauchi, Takuji Nishisato, Kazuyuki Murase, Kohichi Takada, Mitsuhiro Tsujiwaki, Shintaro Sugita, Tadashi Hasegawa, Junji Kato

Oral Oncology ( Elsevier BV ) 105287 - 105287 2021.04

DOI

A systemic apolipoprotein A-IV-associated amyloidosis confirmed by proteome analysis.

Taro Murakami, Akira Takasawa, Asako Moriki, Yusuke Igaki, Hiroshi Ikeda, Kazuyuki Murase, Kohichi Takada, Kazufumi Magara, Tomoyuki Aoyama, Yusuke Ono, Daisuke Kyuno, Kumi Takasawa, Masaki Murata, Makoto Osanai

Virchows Archiv : an international journal of pathology 2021.03 [International journal]

Amyloidosis is induced by extracellular deposition of certain proteins. Thirty-six proteins have so far been identified as amyloidogenic proteins in humans. Although it is very important to determine the specific amyloid protein type for the choice of therapy for amyloidosis patient, it might be difficult to identify specific proteins from amyloid-deposited tissue. Apolipoprotein A-IV is known as an amyloid-associated protein, but there have been few reports of apolipoprotein A-IV amyloidosis. Here we report a case of systemic apolipoprotein A-IV-associated amyloidosis that was confirmed by proteome analysis using formalin-fixed paraffin-embedded tissue and an immunohistochemical technique.

DOI PubMed

食道癌診断と治療のup to date 食道腺癌を含めて切除可能進行食道癌に対する三剤併用療法ベースの化学放射線療法は手術療法を代替できるか?:傾向スコアマッチング分析

大沼啓之, 小野山直輝, 濱口孝太, 早坂尚貴, 佐藤昌則, 村瀬和幸, 高田弘一, 宮西浩嗣, 村上武志, 伊東竜哉, 信岡隆幸, 竹政伊知朗, 土屋高旭, 長谷川智一, 堀正和, 染谷正則, 坂田耕一, 加藤淳二

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 128回・122回 35 - 35 2021.03

A case of hypervascular tumors in the liver and pancreas: synchronous hepatocellular carcinoma and pancreatic metastasis from renal cell carcinoma 36 years after nephrectomy

Hajime Nakamura, Shingo Tanaka, Koji Miyanishi, Yutaka Kawano, Takahiro Osuga, Kazuma Ishikawa, Makoto Yoshida, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Hiroshi Yamaguchi, Minoru Nagayama, Yasutoshi Kimura, Ichiro Takemasa, Junji Kato

Clinical Case Reports ( Wiley ) 9 ( 2 ) 932 - 937 2021.02

DOI

Successful mycophenolate mofetil treatment of a patient with severe steroid‐refractory hepatitis evoked by nivolumab plus ipilimumab treatment for relapsed bladder cancer

Ginji Omori, Kohichi Takada, Kazuyuki Murase, Naotaka Hayasaka, Hajime Nakamura, Satoshi Iyama, Hiroyuki Ohnuma, Koji Miyanishi, Fumimasa Fukuta, Toshiaki Tanaka, Naoya Masumori, Junji Kato

Clinical Case Reports ( Wiley ) 9 ( 2 ) 654 - 659 2021.02

DOI

Case series of three patients with hereditary diffuse gastric cancer in a single family: Three case reports and review of literature

Masahiro Hirakawa, Kohichi Takada, Masanori Sato, Chisa Fujita, Naotaka Hayasaka, Takayuki Nobuoka, Shintaro Sugita, Aki Ishikawa, Miyako Mizukami, Hiroyuki Ohnuma, Kazuyuki Murase, Koji Miyanishi, Masayoshi Kobune, Ichiro Takemasa, Tadashi Hasegawa, Akihiro Sakurai, Junji Kato

World Journal of Gastroenterology ( Baishideng Publishing Group Inc. ) 26 ( 42 ) 6689 - 6697 2020.11

DOI

Successful Treatment by Surgery and Lenvatinib of a Patient with Adrenal Metastasis of Papillary Thyroid Cancer

Hajime Nakamura, Kohichi Takada, Kazuyuki Murase, Hiroki Sakamoto, Naotaka Hayasaka, Kazuma Ishikawa, Yuki Ikeda, Makoto Yoshida, Satoshi Iyama, Ko Kobayashi, Tetsuya Shindo, Shintaro Sugita, Koji Miyanishi, Masayoshi Kobune, Naoya Masumori, Junji Kato

Case Reports in Oncological Medicine ( Hindawi Limited ) 2020 1 - 4 2020.11

Papillary thyroid cancer (PTC) is considered an indolent cancer, but some PTC patients do present with distant metastases and treatment strategies for such patients are not well established. Recently, lenvatinib, an inhibitor of multiple tyrosine kinases, has been introduced to treat patients with advanced PTC but carries a risk of serious adverse events such as hemorrhage. Here, we report a PTC patient with a left adrenal metastasis and lenvatinib-induced hemorrhage who underwent successful surgical resection and was subsequently treated with a lower dose of lenvatinib. The patient has now been in a stable state with no adverse events for nearly two years. This case highlights the importance of surgical resection of metastatic PTC and subsequent lenvatinib therapy, even when the tumor is at an advanced stage.

DOI

Pancreatic cancer with leptomeningeal carcinomatosis: case report and literature review

Yuki Ikeda, Makoto Yoshida, Kazuma Ishikawa, Tomohiro Kubo, Kazuyuki Murase, Kohichi Takada, Koji Miyanishi, Junji Kato

International Cancer Conference Journal ( Springer Science and Business Media LLC ) 9 ( 2 ) 96 - 100 2020.04

DOI

切除可能進行食道癌に対する三剤併用療法ベースの化学放射線療法は手術療法を代替できるか? 傾向スコアマッチング分析

大沼啓之, 小野山直輝, 濱口孝太, 早坂尚貴, 佐藤昌則, 村瀬和幸, 高田弘一, 宮西浩嗣, 伊東竜哉, 信岡隆幸, 竹政伊知朗, 長谷川智一, 堀正和, 染谷正則, 坂田耕一, 加藤淳二

日本消化器病学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 126回 50 - 50 2020.03

Blastic plasmacytoid dendritic cell neoplasm(BPDCN)の2例

執行延明, 西田彩華, 菅野莉英, 藤岡茉生, 大橋隆宏, 堀本浩平, 加藤潤史, 肥田時征, 宇原久, 村瀬和幸, 井山諭, 須釜佑介, 前田和男

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 130 ( 3 ) 418 - 418 2020.03

Pulmonary metastasectomy is associated with prolonged survival among patients with bone and soft tissue sarcoma

Junya Shimizu, Makoto Emori, Yasutaka Murahashi, Tomoko Sonoda, Taijiro Mishina, Masahiro Miyajima, Atsushi Watanabe, Shintaro Sugita, Kohichi Takada, Kazuyuki Murase, Tadashi Hasegawa, Toshihiko Yamashita

Molecular and Clinical Oncology ( Spandidos Publications ) 2020.02

DOI

Efficacy of combination therapy with dexmedetomidine for benzodiazepines-induced disinhibition during endoscopic retrograde cholangiopancreatography

Yuki Ikeda, Makoto Yoshida, Kazuma Ishikawa, Tomohiro Kubo, Kazuyuki Murase, Kohichi Takada, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Therapeutic Advances in Gastroenterology ( SAGE Publications ) 13 175628482091182 - 175628482091182 2020.01

Background: Benzodiazepines (BZDs) and analgesics are widely used for conscious sedation during endoscopic ultrasound (EUS) or endoscopic retrograde cholangiopancreatography (ERCP). However, endoscopic procedures are sometimes discontinued because of BZD-induced disinhibitory reactions such as excessive movement. We evaluated the usefulness of dexmedetomidine (DEX) for BZD-induced disinhibition in ERCP. Methods: Between February 2018 and August 2019, 22 patients who underwent EUS or ERCP were enrolled. All patients showed BZD-induced excessive movement at the first examination (BZD group) and received DEX at the second examination (DEX group). The initial DEX dose was 6 μg/kg/h for a 10-min loading, followed by 0.4 μg/kg/h during the procedure. BZDs and analgesics were administered before scope insertion. An additional sedative was administered to achieve a Ramsay sedation scale (RSS) of 4–5. Sedative effect, procedure completion rate, and changes in circulatory and respiratory dynamics were evaluated. Results: Mean RSS scores were significantly higher ( p < 0.001) in the DEX (5.1 ± 0.5) compared with the BZD (4.0 ± 0.5) group. The movement score ( p < 0.001) and number of additional sedatives required ( p < 0.01) were lower in the DEX group. The procedure completion rate was significantly higher in the DEX (95.5%) compared with the BZD group (63.6%; p < 0.05). Significant differences in the frequency of hypotension ( p = 1.00), bradycardia ( p = 0.22), and respiratory depression ( p = 0.68) were not noted between groups. Conclusions: The addition of DEX to BZD therapy yielded better sedative efficacy, lower excessive movement, a reduction in BZDs used, and a higher procedure complete rate. DEX may be used as an alternative method for BZD-induced inhibition during ERCP.

DOI

Management of Multiple Arteriovenous Malformations of the Small Bowel

Masahiro Hirakawa, Rie Ishizuka, Masanori Sato, Naotaka Hayasaka, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Tatsuya Ito, Takayuki Nobuoka, Koji Miyanishi, Masayoshi Kobune, Ichiro Takemasa, Junji Kato

Case Reports in Medicine ( Hindawi Limited ) 2019 1 - 4 2019.12

A 62-year-old Japanese female was referred to our hospital with gastrointestinal bleeding. Although small-bowel bleeding was suspected, no bleeding source was identified by enhanced computed tomography (CT), video capsule endoscopy (VCE), and double-balloon enteroscopy (DBE). Five years later, the patient had recurrent intermittent bloody stools with a significant decrease in hemoglobin levels. Although no active bleeding was observed on antegrade DBE, we detected a pulsatile submucosal uplift accompanied by a small red patch on the top of the uplift in the jejunum. Arteriovenous malformation (AVM) was suspected as the cause of small-bowel bleeding. Multiple-phase CT showed a number of small vascular ectasias during the arterial phase in the jejunum, and we confirmed the presence of multiple AVMs in the jejunum by selective angiography. To identify the location of the lesions and determine the minimal surgical margins, we performed intraoperative selective angiography with indocyanine green (ICG) injection. This technique allowed us to clearly observe the region and perform segmental small-bowel resection with minimal surgical margin. The patient reported that she has had no gastrointestinal bleeding at the two years follow-up visit.

DOI

BH3 profiling discriminates the anti‑apoptotic status of 5‑fluorouracil‑resistant colon cancer cells.

Kazuma Ishikawa, Yutaka Kawano, Yohei Arihara, Tomohiro Kubo, Kohichi Takada, Kazuyuki Murase, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Oncology reports 42 ( 6 ) 2416 - 2425 2019.12 [Refereed] [International journal]

5‑Fluorouracil (5‑FU) is a cytotoxic anticancer drug commonly used for patients with advanced colon cancer. This drug effectively reduces the size of tumors to a certain degree; however, cancer cells can gradually acquire resistance, resulting in disease progression. To identify the mechanism of 5‑FU resistance, we established three 5‑FU‑resistant colon cancer cell lines and analyzed both apoptosis‑related protein expression levels and BH3 profiling. These 5‑FU‑resistant colon cancer cell lines acquired apoptotic resistance to 5‑FU. Although apoptosis‑related protein expression levels were altered in each 5‑FU‑resistant colon cancer cell line variably, BH3 profiling indicated BCLXL dependence in 5‑FU‑resistant HT‑29 cells only. Functional BCLXL inhibition in 5‑FU‑resistant HT‑29 cells not only sensitized the cells to apoptosis but also overcame 5‑FU resistance. The apoptotic BIM protein was preferentially sequestered, thereby resulting in acquired dependence on BCLXL for survival. Additionally, in vivo models showed that BCLXL inhibition controlled tumor progression. These results indicate that BH3 profiling facilitates the identification of the functional role of anti‑apoptotic proteins during drug resistance and has clinical implications for colon cancer in targeting specific proteins such as BCLXL.

DOI PubMed

Exceptionally rapid response to pembrolizumab in a SMARCA4‐deficient thoracic sarcoma overexpressing PD‐L1: A case report

Kohichi Takada, Shintaro Sugita, Kazuyuki Murase, Tomoki Kikuchi, Ginji Oomori, Ryo Ito, Naotaka Hayasaka, Koji Miyanishi, Satoshi Iyama, Hiroshi Ikeda, Masayoshi Kobune, Makoto Emori, Junji Kato, Tadashi Hasegawa

Thoracic Cancer ( Wiley ) 10 ( 12 ) 2312 - 2315 2019.12

DOI

局所進行食道癌に対するDocetaxel/Nedaplatin/5-FU・放射線同時併用療法(DNF-R)の第II相試験アップデート解析

佐藤昌則, 大沼啓之, 早坂尚貴, 村瀬和幸, 高田弘一, 宮西浩嗣, 加藤淳二, 平川昌宏, 佐川保, 堀正和, 染谷正則, 坂田耕一

北海道医学雑誌 ( 北海道医学会 ) 94 ( 2 ) 121 - 121 2019.11

Pneumothorax as an Adverse Event in Patients with Lung Metastasis of Soft Tissue Sarcoma under Eribulin Treatment

Kohichi Takada, Kazuyuki Murase, Hajime Nakamura, Naotaka Hayasaka, Yohei Arihara, Satoshi Iyama, Hiroshi Ikeda, Makoto Emori, Shintaro Sugita, Katsuyuki Nakamura, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Internal Medicine ( Japanese Society of Internal Medicine ) 58 ( 20 ) 3009 - 3012 2019.10

DOI

Six-transmembrane epithelial antigen of the prostate 1 protects against increased oxidative stress via a nuclear erythroid 2-related factor pathway in colorectal cancer

Hajime Nakamura, Kohichi Takada, Yohei Arihara, Naotaka Hayasaka, Kazuyuki Murase, Satoshi Iyama, Masayoshi Kobune, Koji Miyanishi, Junji Kato

Cancer Gene Therapy ( Springer Science and Business Media LLC ) 26 ( 9-10 ) 313 - 322 2019.09

DOI

EPO-R+ myelodysplastic cells with ring sideroblasts produce high erythroferrone levels to reduce hepcidin expression in hepatic cells

Shogo Miura, Masayoshi Kobune, Hiroto Horiguchi, Shohei Kikuchi, Satoshi Iyama, Kazuyuki Murase, Akari Goto, Hiroshi Ikeda, Kohichi Takada, Koji Miyanishi, Junji Kato

Blood Cells, Molecules, and Diseases ( Elsevier BV ) 78 1 - 8 2019.09

DOI

小型混合型肝癌の1例

大須賀崇裕, 宮西浩嗣, 田中信悟, 中村元, 坂本拡基, 大沼啓之, 村瀬和幸, 高田弘一, 小船雅義, 加藤淳二, 永山稔, 木村康利, 竹政伊知朗, 辻脇光洋, 長谷川匡

肝臓 ( (一社)日本肝臓学会 ) 60 ( 8 ) 294 - 301 2019.08

症例は56歳男性。B型肝硬変とアルコール性肝障害で当科通院中。2017年7月のEOB-MRIにて肝S4に多血性腫瘍を認められ入院。採血検査では、肝硬変による肝トランスアミナーゼ上昇、血小板減少を認めたが、腫瘍マーカーは陰性であった。EOB-MRIでは、腫瘍は10mm大で早期相で不均一な高信号、肝細胞相で低信号、拡散強調画像で高信号を呈した。肝細胞癌(HCC)Stage1と診断し、腹腔鏡下肝部分切除術を施行した。術後16ヵ月経過し再発は認めていない。病理学的に腫瘍は高分化型HCC、中分化型HCC、HCCと肝内胆管癌の移行部、高-中分化型肝内胆管癌の4領域で構成される混合型肝癌であった。本症例は小型の段階で、HCCの一部が胆管細胞癌へ脱分化又は形質転換した非常に初期の混合型肝癌と考えられた。(著者抄録)

Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells.

Naotaka Hayasaka, Kohichi Takada, Hajime Nakamura, Yohei Arihara, Yutaka Kawano, Takahiro Osuga, Kazuyuki Murase, Shohei Kikuchi, Satoshi Iyama, Makoto Emori, Shintaro Sugita, Tadashi Hasegawa, Akira Takasawa, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Scientific reports 9 ( 1 ) 5759 - 5759 2019.04 [Refereed] [International journal]

An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients with advanced/metastatic liposarcoma and breast cancer. However, mechanisms of eribulin resistance and/or insensitivity remain largely unknown. In this study, we demonstrated that an increased p-AKT level was associated with eribulin resistance in STS cells. We found a combination of eribulin with the AKT inhibitor, MK-2206, synergistically inhibited STS cell growth in vivo as well as in vitro. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS.

DOI PubMed

リツキシマブが原因と考えられたTEN型薬疹の1例

松井馨之, 澄川靖之, 箕輪智幸, 熊谷綾子, 神谷崇文, 宇原久, 村瀬和幸

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 129 ( 1 ) 45 - 45 2019.01

miR-7977 inhibits the Hippo-YAP signaling pathway in bone marrow mesenchymal stromal cells.

Masahiro Yoshida, Hiroto Horiguchi, Shohei Kikuchi, Satoshi Iyama, Hiroshi Ikeda, Akari Goto, Yutaka Kawano, Kazuyuki Murase, Kohichi Takada, Koji Miyanishi, Junji Kato, Masayoshi Kobune

PloS one 14 ( 3 ) e0213220 2019 [Refereed] [International journal]

We and others have demonstrated that various abnormalities of the bone marrow (BM) mesenchymal stromal cells (MSCs) such as aberrant cytokine expression, abnormal hedgehog signaling, and impaired miRNA biogenesis are observed in patients with acute myeloid leukemia (AML). However, underlying mechanisms to induce the dysfunction of BM MSCs have not yet been clarified. We previously showed that AML cells release abundant exosomal miR-7977, which, in turn, enters BM mesenchymal stromal cells (MSCs). However, the precise function of miR-7977 is not known. In this study, we performed transduction of a miR-7977 mimic into MSCs, compared transcriptomes between control-transduced (n = 3) and miR-7977-transduced MSCs (n = 3), and conducted pathway analysis. The array data revealed that the expression of 0.05% of genes was reduced 2-fold and the expression of 0.01% of genes was increased 2-fold. Interestingly, approximately half of these genes possessed a miR-7977 target site, while the other genes did not, suggesting that miR-7977 regulates the gene expression level directly and indirectly. Gene set enrichment analysis showed that the gene sets of Yes-associated protein 1 (YAP1) _up were significantly enriched (p<0.001, q<0.25), suggesting that miR-7977 modulates the Hippo-YAP signaling pathway. Visualization of pathway and network showed that miR-7977 significantly reduced the expression of Hippo core kinase, STK4. miR-7977 inactivated the Hippo-YAP signaling pathway as proven by GFP-tagged YAP nuclear trans localization and TEAD reporter assay. The miR-7977-transduced MSC cell line, HTS-5, showed elevated saturation density and enhanced entry into the cell cycle. These results suggest that miR-7977 is a critical factor that regulates the Hippo-YAP signaling pathway in BM-MSCs and may be involved in the upregulation of leukemia-supporting stroma growth.

DOI PubMed

Early Lymph Node Metastasis May Predict Poor Prognosis in Soft Tissue Sarcoma.

Makoto Emori, Hiroyuki Tsuchie, Hiroyuki Nagasawa, Tomoko Sonoda, Arihiko Tsukamoto, Junya Shimizu, Yasutaka Murahashi, Emi Mizushima, Kohichi Takada, Kazuyuki Murase, Kotoe Iesato, Keita Igarashi, Tsukasa Hori, Masaki Yamamoto, Shintaro Sugita, Naohisa Miyakoshi, Tadashi Hasegawa, Yoichi Shimada, Toshihiko Yamashita

International journal of surgical oncology 2019 6708474 - 6708474 2019 [International journal]

Background: Lymph node metastasis (LNM) is a relatively rare event in soft tissue sarcoma. An association between the timing of LNM detection and patient prognosis is presently unknown. Patients and Methods: We retrospectively analyzed the clinicopathological features of 33 patients with LNM between 2001 and 2015. Analysis of the timing of LNM diagnosis was grouped according to patients presenting LNM in either <8 months (the median time from primary tumor diagnosis to LNM) or ≥8 months after primary tumor diagnosis. Results: A relationship between the primary tumor size and the timing of the LNM was not significantly found (Rs = 0.0088, p=0.96). Sixteen patients had an LNM detection duration of <8 months, and 17 patients had a duration of ≥8 months. The 5-year survival for patients with an LNM detection duration of <8 months and ≥8 months was 19% and 71%, respectively (p=0.0016). There were 19 patients with pulmonary metastases. Among them, there were 13 patients with a duration of primary tumor diagnosis to LNM of <8 months and 6 with a duration of ≥8 months (p=0.01). Conclusion: Early LNM (<8 months) may predict poor prognosis in soft tissue sarcoma.

DOI PubMed

Trastuzumab-Based Combination Chemotherapy in Patients with Human Epidermal Growth Factor Receptor-2-Positive Metastatic Carcinoma ex Pleomorphic Adenoma

Yohei Arihara, Kazuyuki Murase, Kohichi Takada, Naotaka Hayasaka, Shogo Miura, Koji Miyanishi, Masayoshi Kobune, Makoto Kurose, Yukinori Akiyama, Shintaro Sugita, Junji Kato

Case Reports in Oncology ( S. Karger AG ) 11 ( 3 ) 835 - 841 2018.12

Background: Carcinoma ex pleomorphic adenoma (CXPA) is a rare histologic subtype of lacrimal gland and submandibular gland cancer. Currently, there is no standard treatment for metastatic CXPA, although some case reports have explored the role of targeted agents in chemotherapy. A few histopathologic analyses have shown that some of these tumors overexpress human epidermal growth factor receptor-2 (HER2), suggesting a potential role for HER2-based therapy. We report here two cases of metastatic CXPA that were treated with trastuzumab-based chemotherapy (IRB approved) with rapid and significant responses. Case Report 1: A 66-year-old male was diagnosed as HER2-positive CXPA of the right lacrimal gland with multiple bone and lymph node metastases. Combination chemotherapy with trastuzumab (Tmab) and nanoparticle albumin-bound paclitaxel (nabPTX) was initiated. A rapid response was confirmed, and after seven cycles of treatment, CR(complete response) was achieved. Case Report 2: A 67-year-old female was diagnosed with HER2 positive CXPA of the right submandibular gland. Multiple pulmonary metastatic lesions were detected after surgery, and combination chemotherapy with Tmab and nab-PTX was initiated. A rapid partial response (PR) was confirmed, and she eventually became disease-free. Conclusion: In the absence of definitive clinical trials, which are unlikely to be performed due to the rarity of HER2-positive CXPA, therapeutic information must be obtained from case reports. Some reports, such as this one, have suggested a potential utility of trastuzumab-based chemotherapy.

DOI

低用量IL2はBCL2の発現を誘導することでCD4制御性T細胞のアポトーシスを抑制する(Low-close interleukin-2 induces BCL2 expression and resistance to apoptosis in CD4 regulatory T Cells)

松野鉄平, 村瀬和幸, 高田弘一, 河野豊, 平川昌宏, 宮西浩嗣, 小船雅義, 加藤淳二

札幌医学雑誌 ( 札幌医科大学 ) 87 ( 1-6 ) 49 - 61 2018.12 [Refereed]

制御性T細胞(Treg)は自己免疫寛容や恒常性の維持に重要な役割を果たしている。インターロイキン2(IL-2)はTregの増加、活動、生存に非常に重要である。既報では低用量IL-2はTregの増加に選択的に作用し、自己免疫疾患の臨床症状を改善させると報告されている。IL-2がTregの内因性アポトーシスにどのように作用するのかを調べるために、我々はBH3プロファイリングを用い、ミトコンドリアのアポトーシスプライミングを定量的に測定した。BH3ペプチドパターンではTregのプライミングがTconより多く、それがBCL2に依存していることを示した。実際に、TregではTconよりもBCL2の発現が低かった。IL-2の作用を調べるために、TregとTconに分け、異なった用量のIL-2で培養した。Tregでは低用量のIL-2(10 IU/ml)でプライミングは低下しBCL2発現は増加したが、Tconではプライミングの低下とBCL2発現の増加には高用量のIL-2(>100 IU/ml)が必要であった。また、低用量IL-2はTregにおいてのみアポトーシスへの感受性を減らすことがアポトーシスアッセイによって判明した。ABT-199というBCL2選択的阻害剤はTregとTcon両者のプライミングとアポトーシスを増加させる。IL2はTregにおいてのみこのABT-199の効果を打ち消した。このことからTregにおけるIL2による内因性アポトーシスの阻害がBCL2に依存していることが判明した。(著者抄録)

Secondary malignant giant cell tumor of bone with histone H3.3 mutation: A case series

Makoto Emori, Satoshi Nagoya, Masato Sugawara, Emi Mizushima, Junya Shimizu, Yasutaka Murahashi, Kazuyuki Murase, Kohichi Takada, Shintaro Sugita, Michiaki Takagi, Tadashi Hasegawa, Toshihiko Yamashita

Journal of Orthopaedic Science ( Elsevier BV ) 2018.12

DOI

High expression of nucleoporin 133 mRNA in bone marrow CD138+ cells is a poor prognostic factor in multiple myeloma

Soushi Ibata, Masayoshi Kobune, Shohei Kikuchi, Masahiro Yoshida, Shogo Miura, Hiroto Horiguchi, Kazuyuki Murase, Satoshi Iyama, Kohichi Takada, Koji Miyanishi, Junji Kato

Oncotarget ( Impact Journals LLC ) 9 ( 38 ) 25127 - 25135 2018.05 [Refereed]

Recent advances in plasma cell biology and molecularly-targeted therapy enable us to employ various types of drugs including immunomodulatory drugs, proteasome inhibitors, and immunotherapy. However, the optimal therapeutic strategies to introduce these drugs for heterogeneous patients with multiple myeloma (MM) have not yet been clarified. In the present study, we attempted to identify a new factor indicating poor prognosis in CD138+ myeloma cells using accumulated Gene Expression Omnibus (GEO) datasets from studies of MM and to assess the relationship between gene expression and survival using MAQC-II Project Myeloma (GSE24080). Five GEO datasets (GSE5900, GSE58133, GSE68871, GSE57317 and GSE16791) which were analyzed by the same microarray platform (GLP570) were combined into one MM database including various types of MM. However, we found that gene expression levels were quite heterogeneous. Hence, we focused on the differentially-expressed genes (DEGs) between newlydiagnosed MM and relapsed/refractory MM and found that the expression levels of more than 20 genes changed two-fold or more. Additionally, pathway analysis indicated that six pathways including Hippo signaling were significantly enriched. Then, we applied all DEGs and genes associated with core enrichment for GSE24080 to evaluate their involvement in disease prognosis. We found that nucleoporin 133 (NUP133) is an independent poor prognostic factor by Cox proportional hazard analysis. These results suggested that high expression of NUP133 could be useful when choosing the appropriate MM therapy and may be a new target of MM therapy.

DOI

Clostridium difficile肝膿瘍の1例

松野鉄平, 田中信悟, 宮西浩嗣, 河野豊, 中村元, 坂本拡基, 早坂尚貴, 石川和真, 村瀬和幸, 高田弘一, 高梨訓博, 勝木伸一, 小船雅義, 加藤淳二

肝臓 ( (一社)日本肝臓学会 ) 59 ( 3 ) 180 - 186 2018.03 [Refereed]

症例は68歳、男性。発熱、心窩部痛を主訴に近医を受診し、肝膿瘍、播種性血管内凝固症候群(DIC)、門脈血栓症と診断され当院へ転院となった。前医にてメロペネムが投与されるも改善傾向を認められなかったが、当院入院時の血液培養検査にてClostridium difficile(C.difficile)が検出され、メトロニダゾール内服を開始したところ速やかに改善した。肝膿瘍および便からもC.difficileが検出され、PCR-rebotypingで全て同一菌株と同定された。血液培養検査でC.difficileが検出されたため早期にメトロニダゾールの投与を開始でき、治癒が得られた肝膿瘍症例を経験した。広域抗菌薬に対する反応が悪い肝膿瘍に対しては、原因菌としてC.difficileも念頭に診断・治療を進めることが必要である。(著者抄録)

A case of cisplatin-refractory advanced pure seminoma showing complete remission after treatment with high-dose carboplatin plus etoposide as fourth-line salvage chemotherapy

Kimihito Tachikawa, Naotaka Nishiyama, Takashi Muranaka, Koichi Takada, Kazuyuki Murase, Tsutomu Kouno, Kato Junji, Naoya Masumori

International Cancer Conference Journal ( Springer Science and Business Media LLC ) 7 ( 1 ) 6 - 10 2018.01

DOI

Small molecule CP-31398 induces reactive oxygen species-dependent apoptosis in human multiple myeloma

Yohei Arihara, Kohichi Takada, Yusuke Kamihara, Naotaka Hayasaka, Hajime Nakamura, Kazuyuki Murase, Hiroshi Ikeda, Satoshi Iyama, Tsutomu Sato, Koji Miyanishi, Masayoshi Kobune, Junji Kato

ONCOTARGET ( IMPACT JOURNALS LLC ) 8 ( 39 ) 65889 - 65899 2017.09 [Refereed]

Reactive oxygen species (ROS) are normal byproducts of a wide variety of cellular processes. ROS have dual functional roles in cancer cell pathophysiology. At low to moderate levels, ROS act as signaling transducers to activate cell proliferation, migration, invasion, and angiogenesis. In contrast, high levels of ROS induce cell death. In multiple myeloma (MM), ROS overproduction is the trigger for apoptosis induced by several anticancer compounds, including proteasome inhibitors. However, no drugs for which oxidative stress is the main mechanism of action are currently used for treatment of MM in clinical situations. In this study, we demonstrate that the p53-activating small molecule CP-31398 (CP) effectively inhibits the growth of MM cell lines and primary MM isolates from patients. CP also suppresses the growth of MM xenografts in mice. Mechanistically, CP was found to induce intrinsic apoptosis in MM cells via increasing ROS production. Interestingly, CP-induced apoptosis occurs regardless of the p53 status, suggesting that CP has additional mechanisms of action. Our findings thus indicate that CP could be an attractive candidate for treatment of MM patients harboring p53 abnormalities; this satisfies an unmet clinical need, as such individuals currently have a poor prognosis.

DOI PubMed

[A Case of Chronic Myelogenous Leukemia That Developed Fibrous Pericarditis Owing to Nilotinib Use].

Shogo Miura, Kazuyuki Murase, Akira Sakurada, Kohichi Takada, Satoshi Iyama, Tsutomu Sato, Yasushi Sato, Koji Miyanishi, Masayoshi Kobune, Atsuko Muranaka, Kazutoshi Tachibana, Junji Kato

Gan to kagaku ryoho. Cancer & chemotherapy 44 ( 6 ) 529 - 531 2017.06 [Refereed] [Domestic journal]

A 64-year-old man was diagnosed with chronic-phase chronic myelogenous leukemia(CML)in May 2009. He was treated with imatinib and achieved complete cytogenetic response(CCyR)in 2 months. After 4 months of treatment, he developed interstitial pneumonia and became intolerant to imatinib. He was then switched to nilotinib from October of the same year. In June 2013, he was diagnosed with drug-induced pericarditis resulting from nilotinib use, and thus, nilotinib was discontinued. Subsequently, he was followed up without specific treatment for CML. In January 2014, he was admitted to the Dept. of Cardiovascular, Renal and Metabolic Medicine at our hospital because of heart failure. After examinations of cardiac function, he was diagnosed with constrictive pericarditis. Therefore, pericardiolysis was performed by the Dept. of Cardiovascular Surgery at our hospital. Pathologic findings showed hyaline-like fibrous tissue proliferation in the pericardium, which was diagnosed as fibrous pericarditis induced by nilotinib. We report a case of chronic myelogenous leukemia that developed fibrous pericarditis owing to nilotinib use.

PubMed

肝細胞癌の治療前ステージングにおけるEOB-MRIおよびDiffusion-Weighted Imagingの有用性についての検討

坂本拡基, 宮西浩嗣, 田中信吾, 河野豊, 中村元, 櫻田晃, 石川和真, 佐藤昌則, 菊地尚平, 村瀬和幸, 高田弘一, 加藤淳二

肝臓 ( (一社)日本肝臓学会 ) 58 ( Suppl.1 ) A296 - A296 2017.04 [Refereed]

A typical presentation of primary pulmonary epithelioid sarcoma misdiagnosed as non-small cell lung cancer

Makoto Emori, Mitsuharu Tamakawa, Mitsunori Kaya, Kohichi Takada, Kazuyuki Murase, Chisa Fujita, Sayuri Sato, Ryuji Takahashi, Kanako C. Hatanaka, Shintaro Sugita, Hiroshi Hirano, Toshihiko Yamashita, Tadashi Hasegawa

Pathology International ( Wiley ) 67 ( 4 ) 222 - 224 2017.04

DOI

低分子化合物CP-31398は多発性骨髄腫に対して活性酸素種依存的なアポトーシスを誘導する

在原洋平, 高田弘一, 神原悠輔, 河野豊, 早坂尚貴, 中村元, 菊地尚平, 村瀬和幸, 井山諭, 池田博, 佐藤勉, 宮西浩嗣, 小船雅義, 加藤淳二

International Journal of Myeloma ( 日本骨髄腫学会 ) 7 ( 1 ) 76 - 76 2017.04 [Refereed]

非アルコール性脂肪性肝疾患の組織学的診断時における肝発癌予測因子についての検討

田中信悟, 宮西浩嗣, 坂本拡基, 佐藤昌則, 櫻田晃, 池田裕貴, 石川和真, 河野豊, 村瀬和幸, 高田弘一, 加藤淳二

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 114 ( 臨増総会 ) A311 - A311 2017.03 [Refereed]

Activated p53 with Histone Deacetylase Inhibitor Enhances L-Fucose-Mediated Drug Delivery through Induction of Fucosyltransferase 8 Expression in Hepatocellular Carcinoma Cells

Yutaka Okagawa, Kohichi Takada, Yohei Arihara, Shohei Kikuchi, Takahiro Osuga, Hajime Nakamura, Yusuke Kamihara, Naotaka Hayasaka, Makoto Usami, Kazuyuki Murase, Koji Miyanishi, Masayoshi Kobune, Junji Kato

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 11 ( 12 ) 2016.12 [Refereed]

Background The prognosis of advanced hepatocellular carcinoma (HCC) is dismal, underscoring the need for novel effective treatments. The alpha 1,6-fucosyltransferase (fucosyltransferase 8, FUT8) has been reported to accelerate malignant potential in HCC. Our study aimed to investigate the regulation of FUT8 expression by p53 and develop a novel therapeutic strategy for targeting HCC cells using L-fucose-mediated drug delivery. Methods Binding sites for p53 were searched for within the FUT8 promoter region. FUT8 expression was assessed by immunoblotting. Chromatin immunoprecipitation (ChIP) assays were performed to analyze p53 binding to the FUT8 promoter. The delivery of Cy5.5-encapsulated L-fucose-liposomes (Fuc-Lip-Cy5.5) to a Lens Culinaris agglutinin-reactive fraction of a-fetoprotein (AFP-L3)-expressing HCC cells was analyzed by flow cytometry. The induction of FUT8 by histone deacetylase inhibitor (HDACi) -inducing acetylated -p53 was evaluated by immunoblotting. Flow cytometric analysis was performed to assess whether the activation of p53 by HDACi affected the uptake of Fuc-Lip-Cy5.5 by HCC cells. The cytotoxicity of an L-fucose-bound liposome carrying sorafenib (Fuc-Lip-sorafenib) with HDACi was assessed in vivo and in vitro. Results The knock down of p53 with siRNA led to decreased FUT8 expression. ChIP assays revealed p53 binds to the FUT8 promoter region. Flow cytometric analyses demonstrated the specific uptake of Fuc-Lip-Cy5.5 into AFP-L3-expressing HCC cells in a p53- and FUT8- dependent manner. HDACi upregulated the uptake of Fuc-Lip-Cy5.5 by HCC cells by increasing FUT8 via acetylated -p53. The addition of a HDACi increased apoptosis induced by Fuc-Lip-sorafenib in HCC cells. Conclusions Our findings reveal that FUT8 is a p53 target gene and suggest that p53 activated by HDACi induces Fuc-Lip-sorafenib uptake by HCC cells, highlighting this pathway as a promising therapeutic intervention for HCC.

DOI

A phase II trial of small-dose bortezomib, lenalidomide and dexamethasone (sVRD) as consolidation/maintenance therapy in patients with multiple myeloma

Soushi Ibata, Tsutomu Sato, Hiroyuki Kuroda, Yasuhiro Nagamachi, Satoshi Iyama, Akihito Fujimi, Yusuke Kamihara, Yuichi Konuma, Masahiro Yoshida, Ayumi Tatekoshi, Akari Hashimoto, Hiroto Horiguchi, Kaoru Ono, Kazuyuki Murase, Kohichi Takada, Koji Miyanishi, Masayoshi Kobune, Yasuo Hirayama, Junji Kato

CANCER CHEMOTHERAPY AND PHARMACOLOGY ( SPRINGER ) 78 ( 5 ) 1041 - 1049 2016.11 [Refereed]

Consolidation/maintenance therapy induces deep remission in patients with multiple myeloma (MM); however, the most suitable regimen has been under investigation. The combination therapy with bortezomib, lenalidomide and dexamethasone (VRD) is a powerful regimen for relapsed/refractory as well as newly diagnosed MM as an induction therapy. However, severe adverse events (AEs) may become a problem when VRD is introduced without dose reduction as a consolidation/maintenance therapy. In this single-arm phase II study, we evaluated the efficacy of small-dose VRD regimen (sVRD) in the consolidation/maintenance setting. Sixteen patients who had partial response (PR) or better after any induction therapy were enrolled. Patients received at least six 28-day cycles of subcutaneous bortezomib (1.3 mg/m(2) on days 1 and 15), lenalidomide (10 mg on days 1-21) and dexamethasone (40 mg on days 1, 8, 15 and 22). The overall response rate and the complete response (CR) rate were 100 and 43.8 %, respectively. In particular, one patient with CR and two patients with very good PR at enrollment achieved stringent CR during 6 courses of sVRD. With a median follow-up time of 29.4 months, the median progression-free survival (PFS) and overall survival (OS) were not reached, while the PFS and OS rates at 2.5 years were 66.6 and 77.3 %, respectively. Univariate analysis demonstrated that disease progression as a reason for discontinuation of sVRD had a negative impact on OS. There were no grade 3 or 4 hematologic or nonhematologic AEs. Our sVRD regimen as a consolidation/maintenance therapy was highly effective and well tolerable.

DOI PubMed

The iron chelator deferasirox induces apoptosis by targeting oncogenic Pyk2/β-catenin signaling in human multiple myeloma.

Yusuke Kamihara, Kohichi Takada, Tsutomu Sato, Yutaka Kawano, Kazuyuki Murase, Yohei Arihara, Shohei Kikuchi, Naotaka Hayasaka, Makoto Usami, Satoshi Iyama, Koji Miyanishi, Yasushi Sato, Masayoshi Kobune, Junji Kato

Oncotarget 7 ( 39 ) 64330 - 64341 2016.09 [Refereed] [International journal]

Deregulated iron metabolism underlies the pathogenesis of many human cancers. Recently, low expression of ferroportin, which is the only identified non-heme iron exporter, has been associated with significantly reduced overall survival in multiple myeloma (MM); however, the altered iron metabolism in MM biology remains unclear. In this study we demonstrated, by live cell imaging, that MM cells have increased intracellular iron levels as compared with normal cells. In experiments to test the effect of iron chelation on the growth of MM cells, we found that deferasirox (DFX), an oral iron chelator used to treat iron overload in clinical practice, inhibits MM cell growth both in vivo and in vitro. Mechanistically, DFX was found to induce apoptosis of MM cells via the inhibition of proline-rich tyrosine kinase 2 (Pyk2), which is known to promote tumor growth in MM. Inhibition of Pyk2 is caused by the suppression of reactive oxygen species, and leads to downregulation of the Wnt/β-catenin signaling pathway. Taken together, our findings indicate that high levels of intracellular iron, which might be due to low ferroportin expression, play a role in MM pathophysiology. Therefore, DFX may provide a therapeutic option for MM that is driven by deregulated iron homeostasis and/or Pyk2/Wnt signaling.

DOI PubMed

[Treatment Outcomes of Adult-Onset Ewing Sarcoma: A Single-Center Retrospective Study of Five Cases].

Kazuyuki Murase, Kohichi Takada, Yusuke Kamihara, Makoto Usami, Masahiro Yoshida, Ayumi Tatekoshi, Akari Hashimoto, Yohei Arihara, Naotaka Hayasaka, Shogo Miura, Satoshi Iyama, Tsutomu Sato, Yasushi Sato, Koji Miyanishi, Masayoshi Kobune, Makoto Emori, Mitsunori Kaya, Toshihiko Yamashita, Shintaro Sugita, Tadashi Hasegawa, Junji Kato

Gan to kagaku ryoho. Cancer & chemotherapy 43 ( 8 ) 1015 - 8 2016.08 [Refereed] [Domestic journal]

UNLABELLED: We report the treatment outcomes of 5 cases of adult-onset Ewing sarcoma(ES)managed between 2011 and 2014. We examined prognostic factors including the primary lesion, tumor size, metastatic status, and serum LDH levels. RESULTS: The locations of the primary lesions included the limbs in 1 case and the trunk in 4; the cases in the trunk had a worse prognosis than that in the limbs. Tumor size was greater than 8 cm in only 1 patient, who also displayed evidence of metastases at presentation and high LDH levels. All the patients received chemotherapy consisting of alternating vincristine, doxorubicin, and cyclophosphamide(VDC)and etoposide and ifosfamide(IE). Surgery was selected for the treatment of 4 patients, and radiotherapy was administered to 1 patient for local treatment of the tumor. A median follow-up duration of 31.6 months revealed the 2-year overall survival rate and progression-free survival rate to be 80.0%. CONCLUSIONS: The prognosis of patients with adult-onset ES is poor; however, combined modality therapy, including VDC-IE, was demonstrated to improve the outcome of patients in the present study. Nevertheless, the patient with tumor size exceeding 8 cm, metastasis, and high LDH levels, relapsed 1 year after treatment, as reported previously. Further investigation is required to clarify the factors affecting prognosis in adults, and to develop effective therapies for patients with a poor prognosis.

PubMed

肛門周囲の感覚障害で発症し、前立腺生検にて診断に至った血管内リンパ腫(IVL)の1例

齋藤太郎, 中村祐貴, 鈴木秀一郎, 津田笑子, 林貴士, 齊藤正樹, 久原真, 川又純, 下濱俊, 村瀬和幸, 高田弘一

臨床神経学 ( (一社)日本神経学会 ) 56 ( 6 ) 451 - 451 2016.06

Isoform D of vascular endothelial growth factor in systemic capillary leak syndrome: a case report.

Soushi Ibata, Tsutomu Sato, Kohichi Takada, Ayumi Tatekoshi, Akari Hashimoto, Yusuke Kamihara, Wataru Jomen, Hiroto Horiguchi, Kaoru Ono, Kazuyuki Murase, Satoshi Iyama, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Junji Kato

Journal of medical case reports 10 125 - 125 2016.05 [Refereed] [International journal]

BACKGROUND: Systemic capillary leak syndrome is a rare condition characterized by episodic attacks of hypovolemia due to systemic capillary hyperpermeability, which results in profound hypotension and edema. Although the implication of vascular endothelial growth factor, angiopoietin-2, and C-X-C motif chemokine 10 has been suggested, the pathogenesis of systemic capillary leak syndrome remains unclear. In this report, we describe a case of systemic capillary leak syndrome in which serum isoform D of vascular endothelial growth factor was elevated. To the best of our knowledge, this is the first reported case of systemic capillary leak syndrome in which isoform D of vascular endothelial growth factor is suggested as the plausible biomarker. CASE PRESENTATION: A 41-year-old Japanese man was transferred to our emergency department. He was hypotensive, tachycardic, and edematous over the trunk and all four limbs. He received aggressive intravenous fluid therapy and underwent fasciotomy of the right forearm to prevent muscle necrosis. A diagnosis of systemic capillary leak syndrome was suspected. The presence of serum monoclonal immunoglobulin G and κ light chain supported this diagnosis. Prevention of hypotensive crises was unsuccessfully attempted with theophylline, intravenous immunoglobulin, high-dose dexamethasone, bortezomib, melphalan, and prednisolone; however, the patient's attacks dramatically disappeared after the introduction of thalidomide. The serum of the patient was stored soon after the onset of hypotensive crisis and analyzed to profile possible mediators responsible for the capillary leak. The concentration of vascular endothelial growth factor, angiopoietin-2, and C-X-C motif chemokine 10 were all within normal ranges. Meanwhile, we found that isoform D of vascular endothelial growth factor was elevated, which was normalized after the introduction of thalidomide. CONCLUSIONS: In our patient, isoform D of vascular endothelial growth factor (instead of vascular endothelial growth factor) may have been a causative factor of hypotensive crises, since isoform D contributes to vascular endothelial growth factor receptor-2 signaling, which is the major mediator of the permeability-enhancing effects of vascular endothelial growth factor. We suggest the measurement of isoform D of vascular endothelial growth factor in patients with systemic capillary leak syndrome in whose serum vascular endothelial growth factor is not elevated.

DOI PubMed

Extracellular vesicle miR-7977 is involved in hematopoietic dysfunction of mesenchymal stromal cells via poly(rC) binding protein 1 reduction in myeloid neoplasms

Hiroto Horiguchi, Masayoshi Kobune, Shohei Kikuchi, Masahiro Yoshida, Masaki Murata, Kazuyuki Murase, Satoshi Iyama, Kohichi Takada, Tsutomu Sato, Kaoru Ono, Akari Hashimoto, Ayumi Tatekoshi, Yusuke Kamihara, Yutaka Kawano, Koji Miyanishi, Norimasa Sawada, Junji Kato

HAEMATOLOGICA ( FERRATA STORTI FOUNDATION ) 101 ( 4 ) 437 - 447 2016.04 [Refereed]

The failure of normal hematopoiesis is observed in myeloid neoplasms. However, the precise mechanisms governing the replacement of normal hematopoietic stem cells in their niche by myeloid neoplasm stem cells have not yet been clarified. Primary acute myeloid leukemia and myelodysplastic syndrome cells induced aberrant expression of multiple hematopoietic factors including Jagged-1, stem cell factor and angiopoietin-1 in mesenchymal stem cells even in non-contact conditions, and this abnormality was reverted by extracellular vesicle inhibition. Importantly, the transfer of myeloid neoplasm-derived extracellular vesicles reduced the hematopoietic supportive capacity of mesenchymal stem cells. Analysis of extracellular vesicle microRNA indicated that several species, including miR-7977 from acute myeloid leukemia cells, were higher than those from normal CD34(+) cells. Remarkably, the copy number of miR-7977 in bone marrow interstitial fluid was elevated not only in acute myeloid leukemia, but also in myelodysplastic syndrome, as compared with lymphoma without bone marrow localization. The transfection of the miR-7977 mimic reduced the expression of the posttranscriptional regulator, poly(rC) binding protein 1, in mesenchymal stem cells. Moreover, the miR-7977 mimic induced aberrant reduction of hematopoietic growth factors in mesenchymal stem cells, resulting in decreased hematopoietic-supporting capacity of bone marrow CD34(+) cells. Furthermore, the reduction of hematopoietic growth factors including Jagged-1, stem cell factor and angiopoietin-1 were reverted by target protection of poly(rC) binding protein 1, suggesting that poly(rC) binding protein 1 could be involved in the stabilization of several growth factors. Thus, miR-7977 in extracellular vesicles may be a critical factor that induces failure of normal hematopoiesis via poly(rC) binding protein 1 suppression.

DOI PubMed

Narrow-Band Ultraviolet B Phototherapy Ameliorates Acute Graft-Versus-Host Disease of the Intestine by Expansion of Regulatory T Cells.

Hashimoto A, Sato T, Iyama S, Yoshida M, Ibata S, Tatekoshi A, Kamihara Y, Horiguchi H, Murase K, Kawano Y, Takada K, Miyanishi K, Kobune M, Ichimiya S, Kato J

PloS one 11 ( 3 ) e0152823 2016.03 [Refereed]

DOI PubMed

RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells

Fumito Tamura, Yasushi Sato, Masahiro Hirakawa, Makoto Yoshida, Michihiro Ono, Takahiro Osuga, Yutaka Okagawa, Naoki Uemura, Yohei Arihara, Kazuyuki Murase, Yutaka Kawano, Satoshi Iyama, Kohichi Takada, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Masayoshi Kobune, Rishu Takimoto, Junji Kato

GASTRIC CANCER ( SPRINGER ) 19 ( 1 ) 85 - 97 2016.01 [Refereed]

ST6GalNAc I is a sialyltransferase controlling the expression of sialyl-Tn antigen (STn), which is overexpressed in several epithelial cancers, including gastric cancer, and is highly correlated with cancer metastasis. However, the functional contribution of ST6GalNAc I to development or progression of gastric cancer remains unclear. In this study, we investigated the effects of suppression of ST6GalNAc I on gastric cancer in vitro and in vivo. Gastric cancer cell lines were transfected with ST6GalNAc I siRNA and were examined by cell proliferation, migration, and invasion assays. We also evaluated the effect of ST6GalNAc I siRNA treatment in a peritoneal dissemination mouse model. The differences in mRNA levels of selected signaling molecules were analyzed by polymerase chain reaction (PCR) arrays associated with tumor metastasis in MKN45 cells. The signal transducer and activator of transcription 5b (STAT5b) signaling pathways that reportedly regulate the insulin-like growth factor-1 (IGF-1) were analyzed by Western blot. ST6GalNAc I siRNA inhibited gastric cancer cell growth, migration, and invasion in vitro. Furthermore, intraperitoneal administration of ST6GalNAc I siRNA- liposome significantly inhibited peritoneal dissemination and prolonged the survival of xenograft model mice with peritoneal dissemination of gastric cancer. PCR array confirmed that suppression of ST6GalNAc I caused a significant reduction in expression of IGF-1 mRNA. Decreased IGF-1 expression in MKN45 cells treated with ST6GalNAc I siRNA was accompanied by reduced phosphorylation of STAT5b. ST6GalNAc I may regulate the gene expression of IGF-1 through STAT5b activation in gastric cancer cells and may be a potential target for treatment of metastasizing gastric cancer.

DOI PubMed

[Neurolymphomatosis of the sciatic nerve diagnosed by FDG-PET/CT].

Usami M, Murase K, Takada K, Iijima K, Yoshida M, Tatekoshi A, Hashimoto A, Iyama S, Sato T, Kobune M, Takimoto R, Kaya M, Yamashita T, Morita R, Hasegawa T, Kato J

[Rinsho ketsueki] The Japanese journal of clinical hematology 57 ( 1 ) 52 - 55 2016.01 [Refereed]

DOI PubMed

BAK is a predictive and prognostic biomarker for the therapeutic effect of docetaxel treatment in patients with advanced gastric cancer.

Kubo T, Kawano Y, Himuro N, Sugita S, Sato Y, Ishikawa K, Takada K, Murase K, Miyanishi K, Sato T, Takimoto R, Kobune M, Nobuoka T, Hirata K, Takayama T, Mori M, Hasegawa T, Kato J

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 19 ( 3 ) 827 - 838 2015.10 [Refereed]

DOI PubMed

Effect of duloxetine in Japanese patients with chemotherapy-induced peripheral neuropathy: a pilot randomized trial

Yasuo Hirayama, Kunihiko Ishitani, Yasushi Sato, Satoshi Iyama, Kohichi Takada, Kazuyuki Murase, Hiroyuki Kuroda, Yasuhiro Nagamachi, Yuichi Konuma, Akihito Fujimi, Tamotsu Sagawa, Kaoru Ono, Hiroto Horiguchi, Takeshi Terui, Kazuhiko Koike, Toshiro Kusakabe, Tsutomu Sato, Rishu Takimoto, Masayoshi Kobune, Junji Kato

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY ( SPRINGER JAPAN KK ) 20 ( 5 ) 866 - 871 2015.10 [Refereed]

Chemotherapy-induced peripheral neuropathy (CIPN) is difficult to manage. A phase III trial conducted in the United States demonstrated that duloxetine was effective for CIPN caused by taxane and platinum-based chemotherapy. No randomized trial of duloxetine for CIPN has been conducted in Japan. In this open-label, randomized, crossover study, eligible patients were randomized to Group A or Group B. Group A received duloxetine 20 mg/day orally for the first week and 40 mg/day for the next 3 weeks. Group B received vitamin B12 (VB12) 1.5 mg/day orally for 4 weeks. After a 2- to 4-week washout period, treatment was crossed over for another 4 weeks. The severity of numbness and pain was assessed using a visual analog scale (VAS). Thirty-four patients were enrolled. Obvious decreases in the mean VAS scores for numbness and pain were observed for the periods of duloxetine administration. Significant differences were observed between the duloxetine-first (Group A) and the VB12-first (Group B) groups with respect to numbness (p = 0.03) and pain (p = 0.04) at 4 weeks after administration. Fatigue was observed in six of the 34 participants (17.6 %). Our data suggests that duloxetine has a beneficial effect on CIPN caused by oxaliplatin, paclitaxel, vincristine, or bortezomib in Japanese patients.

DOI PubMed

A dose-escalation study of oxaliplatin/capecitabine/irinotecan (XELOXIRI) and bevacizumab as a first-line therapy for patients with metastatic colorectal cancer

Yasushi Sato, Hiroyuki Ohnuma, Masahiro Hirakawa, Minoru Takahashi, Takahiro Osuga, Yutaka Okagawa, Kazuyuki Murase, Kohichi Takada, Yutaka Kawano, Satoshi Iyama, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Rishu Takimoto, Masayoshi Kobune, Kenji Okita, Toru Mizuguchi, Tomohisa Furuhata, Koichi Hirata, Junji Kato

CANCER CHEMOTHERAPY AND PHARMACOLOGY ( SPRINGER ) 75 ( 3 ) 587 - 594 2015.03 [Refereed]

The aim of this study was to determine the recommended dose (RD) of a triweekly capecitabine, oxaliplatin, irinotecan, and bevacizumab (XELOXIRI/bevacizumab) regimen that was easier to administer than FOLFOXIRI/bevacizumab, using capecitabine instead of 5-fuorouracil (5-FU), in patients with metastatic colorectal cancer (mCRC). Patients received oxaliplatin (100 mg/m(2), day 1), capecitabine (1,700 mg/m(2) per day from day 2 to 15), irinotecan (100, 120, 150 mg/m(2) for dose levels 1, 2, 3, day 1), and bevacizumab (7.5 mg/kg, day 1), repeated every 3 weeks. Dose-limiting toxicities (DLTs) were assessed in the first two cycles to determine the maximum tolerated dose (MTD). Twelve patients received a median of 6.5 cycles of therapy (range 2-12). The DLT was grade 4 neutropenia, observed in one of six patients at dose level 2. The MTD was not reached at dose level 3. Therefore, the RD of irinotecan was defined as 150 mg/m(2). The most common grade a parts per thousand yen3 toxicities were neutropenia (41 %), anemia (17 %), diarrhea (8 %), and febrile neutropenia (8 %). The response rate and median progression-free survival were 83 % and 15 months, respectively. XELOXIRI/bevacizumab is a feasible regimen for patients with mCRC, neutropenia was the DLT, and the RD of irinotecan is 150 mg/m(2). The response rate observed is very promising and warrants further investigation.

DOI PubMed

Increased mitochondrial apoptotic priming of human regulatory T cells after allogeneic hematopoietic stem cell transplantation

Kazuyuki Murase, Haesook T. Kim, O. R. Gregory Bascug, Yutaka Kawano, Jeremy Ryan, Ken-ichi Matsuoka, Matthew S. Davids, John Koreth, Vincent T. Ho, Corey Cutler, Philippe Armand, Edwin P. Alyea, Bruce R. Blazar, Joseph H. Antin, Robert J. Soiffer, Anthony Letai, Jerome Ritz

HAEMATOLOGICA ( FERRATA STORTI FOUNDATION ) 99 ( 9 ) 1499 - 1508 2014.09 [Refereed]

CD4 regulatory T cells play a critical role in establishment of immune tolerance and prevention of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. The recovery and maintenance of regulatory T cells is dependent on homeostatic factors including the generation of naive regulatory T cells from hematopoietic precursor cells, the proliferation and expansion of mature regulatory T cells, and the survival of regulatory T cells in vivo. In this study, quantitation of mitochondrial apoptotic priming was used to compare susceptibility of regulatory T cells, conventional CD4 T cells and CD8 T cells to intrinsic pathway apoptosis in 57 patients after allogeneic hematopoietic stem cell transplantation and 25 healthy donors. In healthy donors, regulatory T cells are more susceptible to mitochondrial priming than conventional T cells. Mitochondrial priming is increased after hematopoietic stem cell transplantation in all T-cell subsets and particularly in patients with chronic graft-versus-host disease. Regulatory T cells express high levels of CD95 and are also more susceptible than conventional T cells to apoptosis through the extrinsic pathway. However, CD95 expression and extrinsic pathway apoptosis is not increased after hematopoietic stem cell transplantation. Decreased expression of BCL2 and increased expression of BIM, a mitochondrial cell death activator protein, in regulatory T cells contributes to increased mitochondrial priming in this T-cell subset but additional factors likely contribute to increased mitochondrial priming following hematopoietic stem cell transplantation.

DOI PubMed

Efficacy of Enteral Supplementation Enriched with Glutamine, Fiber, and Oligosaccharide on Mucosal Injury following Hematopoietic Stem Cell Transplantation.

Iyama S, Sato T, Tatsumi H, Hashimoto A, Tatekoshi A, Kamihara Y, Horiguchi H, Ibata S, Ono K, Murase K, Takada K, Sato Y, Hayashi T, Miyanishi K, Akizuki E, Nobuoka T, Mizugichi T, Takimoto R, Kobune M, Hirata K, Kato J

Case reports in oncology ( 3 ) 7 ( 3 ) 692 - 699 2014.09 [Refereed]

DOI PubMed

Effective Treatment of Metastatic Rhabdomyosarcoma with Pazopanib

Akari Hashimoto, Kohichi Takada, Rishu Takimoto, Hiroto Horiguchi, Tsutomu Sato, Satoshi Iyama, Kazuyuki Murase, Kaoru Ono, Ayumi Tatekoshi, Tsuyoshi Hayashi, Koji Miyanishi, Yasushi Sato, Masayoshi Kobune, Yasuo Hirayama, Hiroshi Kitamura, Katsuya Nakanishi, Naoya Masumori, Tadashi Hasegawa, Junji Kato

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. ) 41 ( 8 ) 1041 - 1044 2014.08 [Refereed]

Pazopanib, an oral tyrosine kinase inhibitor, is the first molecular-Targeted agent approved for the treatment of advanced soft tissue sarcoma (STS). Rhabdomyosarcoma in adults is rare, accounting for less than 3% of all adult STS cases. A 57-year-old woman presented with cervical lymphadenopathy. Computed tomography revealed a heterogeneous mass in the retro-peritoneum, replacing the entire right kidney. On the basis of the above findings, the patient was diagnosed with alveolar rhabdomyosarcoma. She was first treated with 4 courses of vincristine, actinomycin D, and cyclophosphamide (VAC), which resulted in a partial response. Dose reduction and delay occurred owing to hematological toxicity and febrile neutropenia. As second-line chemotherapy, the patient was administered a single daily dose of 800 mg of pazopanib. Because of an episode of hand-foot syndrome and hepatic impairment, the 800-mg daily dose of pazopanib was reduced to a daily dose of 600 mg, which had to be further reduced to a daily dose of 400 mg owing to fatigue and anorexia. The patient maintained a partial response for a total of 4.3 months when treated with pazopanib. Therefore, this drug may be a new treatment option for patients showing metastatic STS after previous chemotherapy.

PubMed

Activated Hepatic Stellate Cells Are Dependent on Self-collagen, Cleaved by Membrane Type 1 Matrix Metalloproteinase for Their Growth

Naoko Kubo Birukawa, Kazuyuki Murase, Yasushi Sato, Akemi Kosaka, Akihiro Yoneda, Hiroki Nishita, Ryosuke Fujita, Miyuki Nishimura, Takafumi Ninomiya, Keiko Kajiwara, Miyono Miyazaki, Yusuke Nakashima, Sigenori Ota, Yuya Murakami, Yasunobu Tanaka, Kenjiro Minomi, Yasuaki Tamura, Yoshiro Niitsu

JOURNAL OF BIOLOGICAL CHEMISTRY ( AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC ) 289 ( 29 ) 20209 - 20221 2014.07 [Refereed]

Stellate cells are distributed throughout organs, where, upon chronic damage, they become activated and proliferate to secrete collagen, which results in organ fibrosis. An intriguing property of hepatic stellate cells (HSCs) is that they undergo apoptosis when collagen is resolved by stopping tissue damage or by treatment, even though the mechanisms are unknown. Here we disclose the fact that HSCs, normal diploid cells, acquired dependence on collagen for their growth during the transition from quiescent to active states. The intramolecular RGD motifs of collagen were exposed by cleavage with their own membrane type 1 matrix metalloproteinase (MT1-MMP). The following evidence supports this conclusion. When rat activated HSCs (aHSCs) were transduced with siRNA against the collagen-specific chaperone gp46 to inhibit collagen secretion, the cells underwent autophagy followed by apoptosis. Concomitantly, the growth of aHSCs was suppressed, whereas that of quiescent HSCs was not. These in vitro results are compatible with the in vivo observation that apoptosis of aHSCs was induced in cirrhotic livers of rats treated with siRNAgp46. siRNA against MT1-MMP and addition of tissue inhibitor of metalloproteinase 2 (TIMP-2), which mainly inhibits MT1-MMP, also significantly suppressed the growth of aHSCs in vitro. The RGD inhibitors echistatin and GRGDS peptide and siRNA against the RGD receptor alpha V beta 1 resulted in the inhibition of aHSCs growth. Transduction of siRNAs against gp46, alpha V beta 1, and MT1-MMP to aHSCs inhibited the survival signal of PI3K/AKT/I kappa B. These results could provide novel antifibrosis strategies.

DOI PubMed

Narrowband ultraviolet B phototherapy ameliorates acute graft-versus-host disease by a mechanism involving in vivo expansion of CD4+CD25+Foxp3+regulatory T cells

Satoshi Iyama, Kazuyuki Murase, Tsutomu Sato, Akari Hashimoto, Ayumi Tatekoshi, Hiroto Horiguchi, Yusuke Kamihara, Kaoru Ono, Shohei Kikuchi, Kohichi Takada, Yutaka Kawano, Tsuyoshi Hayashi, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Satoru Mori, Junji Kato, Toshiharu Yamashita, Junji Kato

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER JAPAN KK ) 99 ( 4 ) 471 - 476 2014.04 [Refereed]

Narrowband ultraviolet B phototherapy (NB-UVB) is a therapeutic alternative for haematopoietic stem cell transplantation-related skin graft-versus-host disease (GVHD). The beneficial effects of this intervention may be induced by direct irradiation of inflammatory cells in the skin; however, the putative involvement of indirect effects on systemic immunity has not been elucidated. To address this issue, 11 acute skin GVHD patients refractory to standard corticosteroid treatment and with no gut/liver involvement were treated with NB-UVB irradiation. The median number of treatments was 10 times, with a mean cumulative exposure of 6.36 J/cm(2). No other immunosuppressive therapy was initiated during irradiation. Eight patients achieved an objective complete response, two had a partial response, and one showed no change. None of the patients experienced progressive skin GVHD or newly diagnosed gut/liver GVHD. NB-UVB was well tolerated, with no patients discontinuing irradiation due to toxicity. We additionally demonstrated by flow cytometry that NB-UVB irradiation induces the increment of the proportion of regulatory T cell (Tregs) in patients' peripheral blood. These results suggest that NB-UVB may exert beneficial effects on steroid-refractory skin GVHD through the expansion of Tregs.

DOI PubMed

Combination chemotherapy of azacitidine and cetuximab for therapy-related acute myeloid leukemia following oxaliplatin for metastatic colorectal cancer

Akari Hashimoto, Kohichi Takada, Hiroto Horiguchi, Tsutomu Sato, Satoshi Iyama, Kazuyuki Murase, Yusuke Kamihara, Kaoru Ono, Ayumi Tatekoshi, Tsuyoshi Hayashi, Koji Miyanishi, Yasushi Sato, Tomohisa Furuhata, Masayoshi Kobune, Rishu Takimoto, Koichi Hirata, Junji Kato

Case Reports in Oncology ( S. Karger AG ) 7 ( 2 ) 316 - 322 2014.03 [Refereed]

Therapy-related leukemia (TRL) has been reported to occur after treatment with alkylating agents and/or topoisomerase II inhibitors. Oxaliplatin (OXP) is used as a key drug for the treatment of colorectal cancer (CRC). Cisplatin and carboplatin have been linked with TRL, but the involvement of OXP is questionable. A 74-year-old male was diagnosed with peritoneal metastasis from CRC in July 2011. The patient received nine cycles of 5-fluorouracil (5-FU), leucovorin (LV), and OXP (mFOLFOX-6 regimen) and three cycles of 5-FU and LV only, resulting in a clinical complete response. However, recurrence of CRC was detected by CT within 3 months after the last course of chemotherapy. In April 2013, laboratory tests showed pancytopenia and 15% blast cells. A bone marrow examination revealed multilineage dysplasia and 20.4% myeloblasts. Cytogenetic analysis indicated a complex karyotype that included chromosome 5 and 7 abnormalities. The patient was diagnosed with TRL and treated with a combination of azacitidine (AZA) and cetuximab (Cmab) for both cancers. AZA might be useful in TRL when a patient needs to be treated simultaneously for more than one primary cancer because of its low toxicity. Moreover, Cmab is an effective therapeutic tool in TRL patients with metastatic CRC with the wild-type K-ras gene.

DOI PubMed

Fucosylated TGF-beta receptors transduces a signal for epithelial-mesenchymal transition in colorectal cancer cells

M. Hirakawa, R. Takimoto, F. Tamura, M. Yoshida, M. Ono, K. Murase, Y. Sato, T. Osuga, T. Sato, S. Iyama, K. Miyanishi, K. Takada, T. Hayashi, M. Kobune, J. Kato

BRITISH JOURNAL OF CANCER ( NATURE PUBLISHING GROUP ) 110 ( 1 ) 156 - 163 2014.01 [Refereed]

Background: Transforming growth factor-beta (TGF-beta) is a major inducer of epithelial-mesenchymal transition (EMT) in different cell types. TGF-beta-mediated EMT is thought to contribute to tumour cell spread and metastasis. Sialyl Lewis antigens synthesised by fucosyltransferase (FUT) 3 and FUT6 are highly expressed in patients with metastatic colorectal cancer (CRC) and are utilised as tumour markers for cancer detection and evaluation of treatment efficacy. However, the role of FUT3 and FUT6 in augmenting the malignant potential of CRC induced by TGF-beta is unclear. Methods: Colorectal cancer cell lines were transfected with siRNAs for FUT3/6 and were examined by cell proliferation, invasion and migration assays. The expression and phosphorylation status of TGF-beta downstream molecules were analysed by western blot. Fucosylation of TGF-beta receptor (T beta R) was examined by lectin blot analysis. Results: Inhibition of FUT3/6 expression by siRNAs suppressed the fucosylation of type I T beta R and phosphorylation of the downstream molecules, thereby inhibiting the invasion and migration of CRC cells by EMT. Conclusion: Fucosyltransferase 3/6 has an essential role in cancer cell adhesion to endothelial cells by upregulation of sialyl Lewis antigens and also by enhancement of cancer cell migration through TGF-beta-mediated EMT.

DOI

[Follicular lymphoma complicated with myelofibrosis and macroglobulinemia at initial presentation].

Kuroda H, Abe T, Jomen W, Yoshida M, Matsuno T, Sato M, Yamada M, Sakurai T, Fujii S, Maeda M, Fujita M, Nagashima K, Murase K, Kato J

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 11 ) 54 2068 - 2073 2013.11 [Refereed]

DOI PubMed

Treatment of pancreatic fibrosis with siRNA against a collagen-specific chaperone in vitamin A-coupled liposomes

Hirotoshi Ishiwatari, Yasushi Sato, Kazuyuki Murase, Akihiro Yoneda, Ryosuke Fujita, Hiroki Nishita, Naoko Kubo Birukawa, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Rishu Takimoto, Masayoshi Kobune, Shigenori Ota, Yasutoshi Kimura, Koichi Hirata, Junji Kato, Yoshiro Niitsu

GUT ( BMJ PUBLISHING GROUP ) 62 ( 9 ) 1328 - 1339 2013.09 [Refereed]

Background and objective Fibrosis associated with chronic pancreatitis is an irreversible lesion that can disrupt pancreatic exocrine and endocrine function. Currently, there are no approved treatments for this disease. We previously showed that siRNA against collagen-specific chaperone protein gp46, encapsulated in vitamin A-coupled liposomes (VA-lip-siRNAgp46), resolved fibrosis in a model of liver cirrhosis. This treatment was investigated for pancreatic fibrosis induced by dibutyltin dichloride (DBTC) and cerulein in rats. Methods Specific uptake of VA-lip-siRNAgp46, conjugated with 6-carboxyfluorescein (FAM) by activated pancreatic stellate cells (aPSCs), was analysed by fluorescence activated cell sorting (FACS). Intracellular distribution of VA-lip-siRNAgp46-FAM was examined by fluorescent microscopy. Suppression of gp46 expression by VA-lip-siRNAgp46 was assessed by immunoblotting. Collagen synthesis in aPSCs was assayed by dye-binding. Specific delivery of VA-lip-siRNAgp46 to aPSCs in DBTC rats was verified following intravenous VA-lip-siRNA-FAM and H-3-VA-lip-siRNAgp46. The effect of VA-lip-siRNA on pancreatic histology in DBTC- and cerulein-treated rats was determined by Azan-Mallory staining and hydroxyproline content. Results FACS analysis revealed specific uptake of VA-lip-siRNAgp46-FAM through the retinol binding protein receptor by aPSCs in vitro. Immunoblotting and collagen assay verified knockdown of gp46 and suppression of collagen secretion, respectively, by aPSCs after transduction of VA-lip-siRNAgp46. Specific delivery of VA-lip-siRNAgp46 to aPSCs in fibrotic areas in DBTC rats was confirmed by fluorescence and radioactivity 24h after the final injection. 10 systemic VA-lip-siRNAgp46 treatments resolved pancreatic fibrosis, and suppressed tissue hydroxyproline levels in DBTC- and cerulein-treated rats. Conclusion These data suggest the therapeutic potential of the present approach for reversing pancreatic fibrosis.

DOI PubMed

Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease.

Ken-ichi Matsuoka, John Koreth, Haesook T Kim, Gregory Bascug, Sean McDonough, Yutaka Kawano, Kazuyuki Murase, Corey Cutler, Vincent T Ho, Edwin P Alyea, Philippe Armand, Bruce R Blazar, Joseph H Antin, Robert J Soiffer, Jerome Ritz

Science translational medicine ( 179 ) 5 ( 179 ) 179ra43 2013.04 [Refereed] [International journal]

CD4(+)Foxp3(+) regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation. We recently reported that daily administration of low-dose interleukin-2 (IL-2) induces selective expansion of functional Tregs and clinical improvement of chronic graft-versus-host disease (GVHD). To define the mechanisms of action of IL-2 therapy, we examined the immunologic effects of this treatment on homeostasis of CD4(+) T cell subsets after transplant. We first demonstrated that chronic GVHD is characterized by constitutive phosphorylation of signal transducer and activator of transcription 5 (Stat5) in conventional CD4(+) T cells (Tcons) associated with elevated amounts of IL-7 and IL-15 and relative functional deficiency of IL-2. IL-2 therapy resulted in the selective increase of Stat5 phosphorylation in Tregs and a decrease of phosphorylated Stat5 in Tcons. Over an 8-week period, IL-2 therapy induced a series of changes in Treg homeostasis, including increased proliferation, increased thymic export, and enhanced resistance to apoptosis. Low-dose IL-2 had minimal effects on Tcons. These findings define the mechanisms whereby low-dose IL-2 therapy restores the homeostasis of CD4(+) T cell subsets and promotes the reestablishment of immune tolerance.

DOI PubMed

Intermittent administration of recombinant human soluble thrombomodulin successfully controlled chronic disseminated intravascular coagulation in a patient with dissecting aortic aneurysm on an outpatient basis

Satoshi Iyama, Tsutomu Sato, Kazuyuki Murase, Yusuke Kamihara, Kaoru Ono, Shohei Kikuchi, Kohichi Takada, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Junji Kato

BLOOD COAGULATION & FIBRINOLYSIS ( LIPPINCOTT WILLIAMS & WILKINS ) 23 ( 6 ) 548 - 550 2012.09 [Refereed]

Chronic disseminated intravascular coagulation (DIC) is a rare but life-threatening complication of dissecting aortic aneurysm. Although anticoagulant therapy may often proves effective for controlling DIC itself, patients would have to be hospitalized for a long period due to continuous infusion therapy. Subcutaneous injection of a highly concentrated preparation of heparin calcium may offer one alternative treatment for DIC; however, daily subcutaneous use of heparin for the treatment of DIC has impaired quality of life (QOL). The other alternative therapy is intravenous administration of recombinant human soluble thrombomodulin (rTM), which includes the active extracellular domain of thrombomodulin. Reportedly, rTM effectively resolves DIC by only 6 consecutive days of administration; however, how frequently rTM should be administered after the resolution of chronic DIC to have good control of it has been unclear. We report herein a case of chronic DIC complicated with dissecting aortic aneurysm, whose resolution of chronic DIC achieved by 6 consecutive days of rTM has been maintained by once a week administration of rTM on an outpatient basis. Blood Coagul Fibrinolysis 23:548-550 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

DOI PubMed

Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms

M. Kobune, S. Iyama, S. Kikuchi, H. Horiguchi, T. Sato, K. Murase, Y. Kawano, K. Takada, K. Ono, Y. Kamihara, T. Hayashi, K. Miyanishi, Y. Sato, R. Takimoto, J. Kato

BLOOD CANCER JOURNAL ( NATURE PUBLISHING GROUP ) 2 2012.09 [Refereed]

Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of the Hh-signaling system in the bone marrow (BM) microenvironment during the development of myeloid neoplasms is unknown. In this study, we assessed the expression of Hh-related genes in primary human CD34(+) cells, CD34(+) blastic cells and BM stromal cells. Both Indian Hh (Ihh) and its signal transducer, smoothened (SMO), were expressed in CD34(+) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)-derived cells. However, Ihh expression was relatively low in BM stromal cells. Remarkably, expression of the intrinsic Hh-signaling inhibitor, human Hh-interacting protein (HHIP) in AML/MDS-derived stromal cells was markedly lower than in healthy donor-derived stromal cells. Moreover, HHIP expression levels in BM stromal cells highly correlated with their supporting activity for SMO+ leukemic cells. Knockdown of HHIP gene in stromal cells increased their supporting activity although control cells marginally supported SMO+ leukemic cell proliferation. The demethylating agent, 5-aza-2'-deoxycytidine rescued HHIP expression via demethylation of HHIP gene and reduced the leukemic cell-supporting activity of AML/MDS-derived stromal cells. This indicates that suppression of stromal HHIP could be associated with the proliferation of AML/MDS cells.

DOI

Improvement of iron-mediated oxidative DNA damage in patients with transfusion-dependent myelodysplastic syndrome by treatment with deferasirox

Shohei Kikuchi, Masayoshi Kobune, Satoshi Iyama, Tsutomu Sato, Kazuyuki Murase, Yutaka Kawano, Kohichi Takada, Kaoru Ono, Yumiko Kaneko, Koji Miyanishi, Yasushi Sato, Tsuyoshi Hayashi, Rishu Takimoto, Junji Kato

FREE RADICAL BIOLOGY AND MEDICINE ( ELSEVIER SCIENCE INC ) 53 ( 4 ) 643 - 648 2012.08 [Refereed]

Myelodysplastic syndrome (MDS) is characterized by dysplastic and ineffective hematopoiesis, peripheral blood cytopenias, and a risk of leukemic transformation. Most MDS patients eventually require red blood cell (RBC) transfusions for anemia and consequently develop iron overload. Excess free iron in cells catalyzes generation of reactive oxygen species that cause oxidative stress, including oxidative DNA, damage. However, it is uncertain how iron-mediated oxidative stress affects the pathophysiology of MDS. This study included MDS patients who visited our university hospital and affiliated hospitals (n=43). Among them, 13 patients received iron chelation therapy when their serum ferritin (SF) level was greater than 1000 ng/mL or they required more than 20 RBC transfusions (or 100 rnL/kg of RBC). We prospectively analyzed 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in peripheral blood mononuclear cells (PBMC) obtained from MDS patients before and after iron chelator, deferasirox, administration. We showed that the 8-OHdG levels in MDS patients were significantly higher than those in healthy volunteers and were positively correlated with SF and chromosomal abnormalities. Importantly, the 8-OHdG levels in PBMC of MDS patients significantly decreased after deferasirox administration, suggesting that iron chelation reduced oxidative DNA damage. Thus, excess iron could contribute to the pathophysiology of MDS and iron chelation therapy could improve the oxidative DNA damage in MDS patients. (C) 2012 Elsevier Inc. All rights reserved.

DOI PubMed

Targeting Anticancer Drug Delivery to Pancreatic Cancer Cells Using a Fucose-Bound Nanoparticle Approach

Makoto Yoshida, Rishu Takimoto, Kazuyuki Murase, Yasushi Sato, Masahiro Hirakawa, Fumito Tamura, Tsutomu Sato, Satoshi Iyama, Takahiro Osuga, Koji Miyanishi, Kohichi Takada, Tsuyoshi Hayashi, Masayoshi Kobune, Junji Kato

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 7 ( 7 ) e39545 2012.07 [Refereed]

Owing to its aggressiveness and the lack of effective therapies, pancreatic ductal adenocarcinoma has a dismal prognosis. New strategies to improve treatment and survival are therefore urgently required. Numerous fucosylated antigens in sera serve as tumor markers for cancer detection and evaluation of treatment efficacy. Increased expression of fucosyltransferases has also been reported for pancreatic cancer. These enzymes accelerate malignant transformation through fucosylation of sialylated precursors, suggesting a crucial requirement for fucose by pancreatic cancer cells. With this in mind, we developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specifically to cancer cells. L-fucose-bound liposomes containing Cy5.5 or Cisplatin were effectively delivered into CA19-9 expressing pancreatic cancer cells. Excess L-fucose decreased the efficiency of Cy5.5 introduction by L-fucose-bound liposomes, suggesting L-fucose-receptor-mediated delivery. Intravenously injected L-fucose-bound liposomes carrying Cisplatin were successfully delivered to pancreatic cancer cells, mediating efficient tumor growth inhibition as well as prolonging survival in mouse xenograft models. This modality represents a new strategy for pancreatic cancer cell-targeting therapy.

DOI PubMed

Prognostic significance of serum ferritin level at diagnosis in myelodysplastic syndrome

Shohei Kikuchi, Masayoshi Kobune, Satoshi Iyama, Tsutomu Sato, Kazuyuki Murase, Yutaka Kawano, Kohichi Takada, Kaoru Ono, Tsuyoshi Hayashi, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Junji Kato

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER TOKYO ) 95 ( 5 ) 527 - 534 2012.05 [Refereed]

Myelodysplastic syndrome (MDS) is characterized by peripheral blood cytopenias and risk of progression to acute myeloid leukemia. Elevated serum ferritin (SF), due to ineffective erythropoiesis and increased iron absorption from the gut, is often observed in non-transfused MDS patients, suggesting involvement of iron overload in its pathogenesis. However, the prognostic value of the baseline SF is unclear. We evaluated baseline SF levels in non-transfused MDS patients. The SF level was significantly higher in the 47 MDS patients in this study than in the healthy controls ( < 0.001). The SF level of higher-risk MDS patients (int-2/high) was significantly higher than that of the lower-risk MDS patients (low/int-1) (467 +/- A 354 vs. 277 +/- A 372 ng/ml, < 0.001). The SF level in MDS patients with chromosomal abnormality was significantly higher than that in patients with normal karyotype. When patients were divided into the low SF group (< 500 ng/ml) and high SF group (a parts per thousand yen500 ng/mL), the survival time was significantly longer in the former group than the latter group (118.8 vs. 10.2 M, = 0.002). Further, leukemia-free survival (LFS) was significantly longer in the low SF group than the high SF group ( = 0.010). Baseline SF level may, therefore, be a prognostic factor for overall survival and LFS in MDS patients.

DOI PubMed

Successful Treatment by Fibrin Glue Sealant for Pneumothorax with Chronic GVHD Resistant to Autologous Blood Patch Pleurodesis

Satoshi Iyama, Tsutomu Sato, Kazuyuki Murase, Shohei Kikuchi, Yusuke Kamihara, Kaoru Ono, Kohichi Takada, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Takuro Obama, Masahiro Miyajima, Atsushi Watanabe, Tetsuya Higami, Yasuo Hirayama, Junji Kato

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE ) 51 ( 15 ) 2011 - 2014 2012 [Refereed]

Pneumothorax associated with chronic graft-versus-host disease (cGVHD) after stem cell transplantation is a rare complication. Autologous blood has been used successfully for pleurodesis, which was less toxic than chemical agents. However, when pneumothorax is resistant to pleurodesis, no other procedure is more effective and conservative. Here, we describe a case of myelodysplastic syndromes complicated with cGVHD-related pneumothorax. His pneumothorax has been resistant to pleurodesis using autologous blood and was treated successfully with fibrin glue sealant. In our limited experience, we believe the best success could be achieved when this method is used to treat persistent pneumothorax with cGVHD.

DOI PubMed

A case of ulcerative colitis accompanied with myelodysplastic syndrome successfully treated by cyclosporine

Sho Takahashi, Yasushi Sato, Tamotsu Sagawa, Shingo Tanaka, Kazuyuki Murase, Kohichi Takada, Satoshi Iyama, Tsutomu Sato, Rishu Takimoto, Masayoshi Kobune, Ganji Kuroiwa, Michiaki Hirayama, Tetsuro Okamoto, Junji Kato

Journal of Japanese Society of Gastroenterology ( 8 ) 108 ( 8 ) 1405 - 1412 2011.08 [Refereed]

A 64-year-old man had been admitted to a previous hospital because of melena and a diagnosis of ulcerative colitis (UC, pancolitis type) had been made. He had received prednisolone and 5-ASA but steroid-induced hyperamylasemia had developed. Prednisolone had been tapered and halted, but it had resulted in UC relapse and thrombocytopenia. Then, he was referred to our hospital due to severe melena with hypovolemic shock. However, he was also positive for CMV antigen. Thus, we attempted to treat him with ganciclovir for CMV and intravenous cyclosporine (CsA) for UC. According to his clinical course, a reduction of CsA blood concentration induced leukocytopenia. Myelodysplastic syndrome (MDS, RAEB-1) was then revealed after bone marrow biopsy. A high blood CsA concentration may cause the improvement of UC and MDS conditions.

DOI PubMed

Iron chelator deferasirox rescued mice from Fas-induced fulminant hepatitis

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

HEPATOLOGY RESEARCH ( WILEY-BLACKWELL ) 41 ( 7 ) 660 - 667 2011.07 [Refereed]

Aim: Fulminant hepatitis is a disease characterized by development of hepatic failure due to severe liver cell injury. Orthotopic liver transplantation is the therapy proven to improve patient survival; however, less burdensome and safer strategies are required. In a previous study, we showed that iron was intimately involved in hepatocyte apoptosis by demonstrating that spontaneous development of fulminant hepatitis in Long-Evans cinnamon rats was prevented by feeding an iron-deficient diet. Recently, a new iron chelator, deferasirox, has become widely available for the treatment of transfusional hemosiderosis. Deferasirox demonstrated good efficacy and improved compliance due to convenient, once-daily p.o. administration. Our aim was to investigate the efficacy of deferasirox as a therapeutic drug against fulminant hepatitis. Methods: Human primary hepatocytes undergoing Fas-stimulated apoptosis were challenged with deferoxamine (DFO) in vitro. In further in vivo experiments, we tested DFO in a mice model of fulminant hepatitis induced by Fas-stimulation. Results: The apoptosis-inducing activity of anti-Fas antibody on human primary hepatocytes was inhibited by the chelation of iron with DFO. DFO suppressed the Fas-induced production of reactive oxygen species (ROS) and the activation of caspase-3, both of which were also suppressed by antioxidant, N-acetyl-L-cystein. In the in vivo experiments, deferasirox effectively reduced hepatic iron concentrations and rescued mice from Fas-induced fulminant hepatitis. Conclusion: These findings indicated that the iron chelation exerted a hepatoprotective effect by scavenging ROS upstream of caspase-3 and that iron chelation with deferasirox is a potential treatment for patients with fulminant hepatitis.

DOI PubMed

Novel missense mutation in the TMPRSS6 gene in a Japanese female with iron-refractory iron deficiency anemia

Tsutomu Sato, Satoshi Iyama, Kazuyuki Murase, Yusuke Kamihara, Kaoru Ono, Shohei Kikuchi, Kohichi Takada, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Junji Kato

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER TOKYO ) 94 ( 1 ) 101 - 103 2011.07 [Refereed]

Iron-refractory iron deficiency anemia (IRIDA) is a rare autosomal-recessive disorder hallmarked by hypochromic microcytic anemia, low transferrin saturation, and unresponsiveness to oral iron with partial recovery after parenteral iron administration. The disease is caused by mutations in TMPRSS6 (transmembrane protease serine 6) that prevent inactivation of membrane-bound hemojuvelin, an activator of hepcidin transcription. To date, 38 cases have been characterized and reported in European countries and the United States. In this paper, we describe the first case of a Japanese female with IRIDA, who carried a novel mutation (K253E) in the CUB (complement factor C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1) domain of the TMPRSS6 gene.

DOI PubMed

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 2011.06 [Refereed]

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 2011.02 [Refereed]

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

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 2010.07 [Refereed]

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 [Refereed]

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

Treatment of Cirrhosis with Vitamin A-Coupled Liposomes Carrying siRNA against Heat Shock Protein

Yoshiro Niitsu, Yasushi Sato, Kazuyuki Murase, Junji Kato

The Liver: Biology and Pathobiology: Fifth Edition ( John Wiley & Sons, Ltd. ) 1121 - 1129 2009.10 [Refereed]

DOI

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 2009.09 [Refereed]

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 2009.08 [Refereed]

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 2009.05 [Refereed]

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

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 2008.09 [Refereed]

[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 ( 9 ) 1623 - 1627 2008.09 [Refereed]

PubMed

Interaction with human stromal cells enhances CXCR4 expression and engraftment of cord blood Lin(-)CD34(-) cells

Masayoshi Kobune, Yutaka Kawano, Sho Takahashi, Kohichi Takada, Kazuyuki Murase, Satosi Iyama, Tsutomu Sato, Rishu Takimoto, Yoshiro Niitsu, Junji Kato

EXPERIMENTAL HEMATOLOGY ( ELSEVIER SCIENCE INC ) 36 ( 9 ) 1121 - 1131 2008.09 [Refereed]

Objective. Transplantation of hematopoietic stem cells (HSCs) is usually accomplished through intravenous injection, a complex process that requires recognition of bone marrow vasculature and migration to a supportive microenvironment. Hence, some populations of HSCs, including cord blood (CB) Lin(-)CD34(-) stem cells, do not engraft well in bone marrow (BM) of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. In this study, we examined the effect of human stromal interactions on the properties of CB Lin(-)CD34(-) cells. Materials and Methods. CD34 and CXCR4 expression on fresh CB Lin(-)CD34(-) cells and CB Lin(-)CD34(-) cells cocultured with human stromal cells were analyzed. Homing activity and engraftment of these cells were assessed using NOD/SCID mice. In an attempt to identify the stromal CXCR4-inducing factor, CB Lin(-)CD34(-) cells were cocultured with a noncontact culture system in the presence of several inhibitors. Result. Coculture with human stromal cells induced expression of CD34 and CXCR4 on CB Lin(-)CD34(-) cells. CXCR4 expression on CB Lin(-)CD34(-) cells was induced even in the noncontact culture condition, suggesting that this CXCR4-inducing factor is soluble. Moreover, CXCR4 induction was inhibited by the soluble Wnt inhibitor DKK1. Furthermore, these cells acquired homing activity and engrafted in the BM of NOD/SCID mice after intravenous injection. Conclusion. These findings maybe useful for understanding the role of stromal cells in homing and engraftment of HSCs. (C) 2008 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

DOI PubMed

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 2008.09 [Refereed]

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

Sato T, Machida T, Takahashi S, Murase K, Kawano Y, Hayashi T, Iyama S, Takada K, Kuribayashi K, Sato Y, Kobune M, Takimoto R, Matsunaga T, Kato J, Niitsu Y

Journal of immunology (Baltimore, Md. : 1950) ( 1 ) 181 ( 1 ) 197 - 207 2008.07 [Refereed]

PubMed

Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone.

Sato Y, Murase K, Kato J, Kobune M, Sato T, Kawano Y, Takimoto R, Takada K, Miyanishi K, Matsunaga T, Takayama T, Niitsu Y

Nature biotechnology ( 4 ) 26 ( 4 ) 431 - 442 2008.04 [Refereed]

DOI PubMed

[An advanced metastatic breast cancer patient successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy].

Sato Y, Takayama T, Sagawa T, Sato T, Okamoto K, Takahashi S, Abe S, Iyama S, Murase K, Kato J, Niitsu Y

Gan to kagaku ryoho. Cancer & chemotherapy ( 3 ) 35 ( 3 ) 471 - 473 2008.03 [Refereed]

PubMed

Successful treatment of chronic myeloproliferative disease-unclassifiable (CMPD-U) with no chromosomal abnormalities by imatinib mesylate

Satoshi Iyama, Takuya Matsunaga, Tsutomu Sato, Kazuyuki Murase, Naoko Araki, Rishu Takimoto, Masayoshi Kobune, Tamotsu Sagawa, Tetsuji Takayama, Yoshiro Niitsu

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE ) 47 ( 8 ) 791 - 794 2008 [Refereed]

We report a chronic myeloproliferative disease-unclassifiable (CMPD-U) patient who achieved hematological remission following imatinib mesylate (imatinib). Chromosomal and molecular analyses demonstrated no genetic abnormalities of c-abl, bcr-abl, c-kit or platelet-derived growth factor receptor (PDGFR) genes from hematopoietic cells. Although there has been one report of CMPD-U patient with chromosomal abnormalities of the PDGFR gene having complete hematologic responses upon treatment with imatinib, there have not been similar reports of patients without chromosomal abnormalities. This is the first case report of a CMPD-U patient with no chromosomal abnormalities who completely responded to treatment with imatinib.

DOI PubMed

Successful treatment of autoimmune pancreatitis complicated with autoimmune thrombocytopenia and interstitial pneumonia by prednisolone

Kazuyuki Murase, Takuya Matsunaga, Tsuyoshi Hayashi, Hirotoshi Ishiwatari, Naoko Araki, Satoshi Iyama, Tsutomu Sato, Masayoshi Kobune, Rishu Takimoto, Koji Miyanishi, Toru Miyazaki, Hisami Ikeda, Junji Kato, Yoshiro Niitsu

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE ) 47 ( 11 ) 1033 - 1038 2008 [Refereed]

DOI PubMed

骨髄腫から産生されるWnt3は、RhoAシグナルを活性化し、VLA6依存性CAM-DRを惹起する

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

日本癌治療学会誌 ( (一社)日本癌治療学会 ) 42 ( 2 ) 482 - 482 2007.09 [Refereed]

Wnt3/RhoA/ROCKシグナル伝達は多発性骨髄腫の接着介在性薬物耐性へと自己分泌性に関与する(Wnt3/RhoA/ROCK signaling is involved in adhesion-mediated drug resistance of multiple myeloma in an autocline manner)

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

日本癌学会総会記事 ( 日本癌学会 ) 66回 334 - 334 2007.08 [Refereed]

A phase I/II study of nedaplatin and 5-fluorouracil with concurrent radiotherapy in patients with esophageal cancer

Yasushi Sato, Tetsuji Takayama, Tamotsu Sagawa, Tetsuro Okamoto, Koji Miyanishi, Tsutomu Sato, Hironobu Araki, Satoshi Iyama, Seiichiro Abe, Kazuyuki Murase, Rishu Takimoto, Hisayasu Nagakura, Masato Hareyama, Junji Kato, Yoshiro Niitsu

CANCER CHEMOTHERAPY AND PHARMACOLOGY ( SPRINGER ) 58 ( 5 ) 570 - 576 2006.11 [Refereed]

Purpose: To determine the recommended dose (RD) of cis-diammine-glycolatoplatinum (nedaplatin) when given concurrently with 5-FU and high dose radiation therapy in the treatment of esophageal cancer. The purpose of the phase II trial is to determine efficacy and further define the side effect profile. Methods: Twenty-six patients with clinical stage I to IVA squamous cell carcinoma of the esophagus were enrolled in a non-surgical treatment comprised of a fixed dose of fluorouracil (400 mg/m(2) administered as continuous intravenous infusion on days 1-5 and days 8-12) plus escalating doses of nedaplatin (40 mg/m(2) in level 1, 50 mg/m(2) in level 2, or 60 mg/m(2) in level 3 on days 1 and 8), repeated twice every 3 weeks with concurrent radiotherapy (60 Gy). Results: Between July 1998 and February 2004, a total of 26 patients entered this trial, all of whom were considered evaluable for toxicity assessment. In phase I of the study, 12 patients were treated in sequential cohorts of three to six patients per dose level. The maximum tolerated dose was reached at level 3 with two grade 4 neutropenia and one grade 4 thrombocytopenia. Thus, the recommended dosing schedule is level 2. Of the 20 patients treated at the RD level 2, including 6 patients of the RD phase I portion, 8 out of 20 patients (40%) had grade 3-4 neutropenia, 5 patients (25.0%) had grade 3-4 thrombocytopenia, 4 patients (20.0%) had grade 3 anemia and 4 patients (20.0%) had grade 3-4 esophagitis. Other toxicities were relatively mild and usually of grade 2 or less. Objective responses were noted in the 26 patients (overall response rate, 88.5%) including 11 (42.3%) complete remissions. The 1- and 3-year survival rates were 65.1 and 37.2%, respectively, with a median survival time of 21.2 months. Conclusions: The combination of nedaplatin and 5-FU with radiation is a feasible regimen that shows promising antitumor activity with an acceptable safety profile in patients with esophageal cancer.

DOI PubMed

Amelioration of murine dextran sulfate sodium-induced colitis by ex vivo extracellular superoxide dismutase gene transfer.

Oku T, Iyama S, Sato T, Sato Y, Tanaka M, Sagawa T, Kuribayashi K, Sumiyosi T, Murase K, Machida T, Okamoto T, Matsunaga T, Takayama T, Takahashi M, Kato J, Hamada H, Niitsu Y

Inflammatory bowel diseases 12 ( 7 ) 630 - 640 2006.07 [Refereed]

DOI PubMed

肝線維化の分子機構と治療肝星細胞のコラーゲン特異シャペロンHSP47を標的とした肝線維化抑制療法

村瀬和幸, 加藤淳二, 佐藤康史, 小船雅義, 瀧本理修, 高田弘一, 河野豊, 佐藤勉, 宮西浩嗣, 荒木啓伸, 新津洋司郎

肝臓 ( (一社)日本肝臓学会 ) 47 ( Suppl.1 ) A38 - A38 2006.04 [Refereed]

Human herpesvirus-6 hepatitis associated with cyclosporine-A encephalitis after bone marrow transplantation for chronic myeloid leukemia

Kageaki Kuribayashi, Takuya Matsunaga, Satoshi Iyama, Koichi Takada, Tsutomu Sato, Kazuyuki Murase, Akihito Fujimi, Rishu Takimoto, Johji Kawanishi, Yoshiro Niitsu

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE ) 45 ( 7 ) 475 - 478 2006 [Refereed]

A 31-year-old man referred to our hospital for treatment of his chronic myeloid leukemia (CML) in the first chronic phase by bone marrow transplantation. We pretreated him with cyclophosphamide and total body irradiation and bone marrow transplantation (BMT) was carried out. On day 31, the engraftment was confirmed and on day 52, acute graft versus host disease (GVHD) was observed. On day 189, he lost consciousness due to cyclosporine A-induced leukoencephalopathy and 375 mg cyclosporine A was changed to 100 mg prednisolone. On day 199, liver dysfunction (AST 410 IU/L, ALT 557 IU/L, gamma GTP 385 IU/L, ALP 363 IU/L, D-Bil 0.3 mg/dl) developed and a liver biopsy was performed. PCR analysis of DNA from the liver biopsy specimen was positive for HHV-6 and immunostaining using anti-HHV-6 and anti-HHV-6b antibodies showed positive staining in the cytosol of hepatocytes. No other viruses were found to induce hepatitis. From these results, he was diagnosed as having HHV-6 hepatitis and it was successfully treated with gancyclovir (GCV) administration.

DOI PubMed

[Essential thrombocythemia associated with incomplete type intestinal Behçet disease during hydroxyurea treatment].

Kobune M, Kato J, Kuribayashi K, Iyama S, Fujimi A, Murase K, Ueno A, Kikuchi S, Satoh T, Okamoto T, Takimoto R, Matsunaga T, Niitsu Y

[Rinsho ketsueki] The Japanese journal of clinical hematology 46 ( 10 ) 1136 - 1140 2005.10 [Refereed]

DOI PubMed

Donor cell derived acute myeloid leukemia after allogeneic cord blood transplantation in a patient with adult T-cell lymphoma

T Matsunaga, K Murase, M Yoshida, A Fujimi, S Iyama, K Kuribayashi, T Sato, K Kogawa, Y Hirayama, S Sakamaki, K Kohda, Y Niitsu

AMERICAN JOURNAL OF HEMATOLOGY ( WILEY-LISS ) 79 ( 4 ) 294 - 298 2005.08 [Refereed]

We report a patient with adult T-cell lymphoma who developed acute myeloid leukemia (AML) after allogeneic cord blood transplantation (CBT). Fluorescence in situ hybridization (FISH) studies and molecular analysis using short tandem repeat (STR) sequences proved the AML to be of donor origin. Although 25 cases of donor cell leukemia (DCL) occurring after allogeneic bone marrow transplantation have previously been reported, there have been no reports of DCL after CBT. This case is the first-reported DCL patient after CBT.

DOI

A Patient with TP53 Germline Mutation Developed Bowen's Disease and Myelodysplastic Syndrome with Myelofibrosis after Chemotherapy against Ovarian Cancer

KURIBAYASHI Kageaki, MATSUNAGA Takuya, SAKAI Toshio, WADA Yuko, TATENO Kumiko, MURASE Kazuyuki, FUJIMI Akihito, TAKIMOTO Rishu, TERUI Takeshi, KATO Junji, SASAKI Aya, SATOH Masaaki, NIITSU Yoshiro

Japanese Journal of Medicine ( The Japanese Society of Internal Medicine ) 44 ( 5 ) 490 - 495 2005.05

Here we report a case of myelodysplastic syndrome (MDS) with myelofibrosis associated with Bowen's disease. A female patient had undergone an operation and chemotherapy for ovarian cancer when she was 65 years old, and she developed MDS at the age of 70 years old. PCR-single strand conformation polymorphism (SSCP) analysis of peripheral blood mononuclear cells, a Bowen's disease lesion, and normal skin showed an abnormal peak in TP53 exon5. Direct sequencing revealed that they all had missense mutation in codon 175 (G to A) of arginine switched to histidine, suggesting a germline mutation of TP53. It was speculated that p53 function was lost by TP53 germline mutation with the loss of a wild type allele induced by the chemotherapy against ovarian cancer, leading to the development of MDS. No therapeutic effects of low dose melphalan or cyclosporine A on MDS were observed, however one month of 30 mg/day prednisolone administration induced a hematological response.

DOI CiNii

Allogeneic bone marrow transplantation in a patient with T-prolymphocytic leukemia with small-intestinal involvement.

Murase K, Matsunaga T, Sato T, Kuribayashi K, Kogawa K, Kawano Y, Okamoto T, Takayama T, Watanabe H, Niitsu Y, Hirayama Y

International journal of clinical oncology 8 ( 6 ) 391 - 394 2003.12 [Refereed]

DOI PubMed

[A case of gastric carcinoma with multiple skin, bone, and bilateral ovary metastasis; effective treatment by chemotherapy].

Mezawa S, Homma H, Doi T, Akiyama T, Murakami K, Kogawa K, Hirata K, Kida M, Murase K, Iyama S

Gan to kagaku ryoho. Cancer & chemotherapy ( 12 ) 30 1973 - 1975 2003.11 [Refereed]

PubMed

Superselective transcatheter embolization for acute lower gastrointestinal hemorrhage after endoscopic mucosal resection: A report of 3 cases

S Mezawa, H Homma, K Murase, T Doi, S Iyama, K Takada, K Hirata, F Mezawa, Y Niitsu

HEPATO-GASTROENTEROLOGY ( H G E UPDATE MEDICAL PUBLISHING S A ) 50 ( 51 ) 735 - 737 2003.05 [Refereed]

One of the most common complications related to endoscopic mucosal resection is hemorrhage; in almost every case, the bleeding is endoscopically managed, but some cases are unresponsive to the treatment. We have encountered three cases of endoscopically uncontrollable lower gastrointestinal hemorrhage after endoscopic mucosal resection in the colon which we successfully treated by urgent superselective transcatheter embolization. In our three cases, massive hemorrhage occurred immediately after endoscopic mucosal resection of a sessile polyp 25-40mm in diameter, two cases in the ascending colon and one in the rectum. Although hemoclip placement was attempted in every case, hemostasis was not achieved. Emergency angiography disclosed massive extravasation of the contrast material in the colon. Hemostasis was achieved immediately after superselective transcatheter arterial embolizations with microcoils, with no observable ischemic complications and without the need of transfusions. In conclusion, superselective transcatheter embolization with microcoils should be considered a safe and efficient treatment option for endoscopically uncontrollable lower gastrointestinal hemorrhage occurring after endoscopic mucosal resection.

リザーバー肝動注用力テーテルの十二指腸球部逸脱の１例

高梨訓博, 高柳典弘, 西堀佳樹, 藤井重之, 堀本正禎, 小野寺義光, 村瀬和幸, 古川孝広, 長岡康裕, 新津洋司郎

日本消化機病學會雜誌. 乙 ( The Japanese Society of Gastroenterology ) 100 ( 5 ) 578 - 582 2003

症例は63歳男性. 平成10年11月直腸癌, 肝転移(S2)に対しMiles手術および肝動脈力ニュレーションを施行した. その後, 外来にて動注化学療法を持続していたところ, 平成12年の上部消化管内視鏡検査で動注用力テーテルの十二指腸球部への逸脱を認めた. その機序としては, カテーテルによる十二指腸壁の外側からの圧排, 穿破が推測された, 今後, 動注症例の増加と予後の改善による経過の長期化にともない, 同様な症例を経験することが多くなると予想され, 報告した.

DOI CiNii

A study of carboplatin-coated tube for the unresectable cholangiocarcinoma

S Mezawa, H Homma, T Sato, T Doi, K Miyanishi, K Takada, T Kukitsu, K Murase, N Yoshizaki, M Takahashi, S Sakamaki, Y Niitsu

HEPATOLOGY ( W B SAUNDERS CO ) 32 ( 5 ) 916 - 923 2000.11 [Refereed]

Most cases of cholangiocarcinoma have reached an unresectable stage by the time they are discovered despite significant progress of diagnostic modalities, Many of these patients with obstructive jaundice are often treated by biliary drainage using stents to relieve the jaundice. However, the stent patency period is as short as 3 to 9 months because of tumor ingrowth or overgrowth, and mean survival is at most 12 months. Therefore, both continuous relief of obstructive jaundice and local control of the tumor are required in the treatment for advanced cholangiocarcinoma. In this investigation, we developed a new percutaneous transhepatic biliary drainage tube coated with carboplatin (carboplatin-coated tube; CCT). CCT continuously released a fixed amount of carboplatin for 4 weeks and showed an antitumor effect on human cholangiocarcinoma cell line HuCC-T1 in vitro, When CCT was embedded in subcutaneous tumor inoculated in nude mice, a significant reduction of tumor size with no apparent damage to normal adjacent tissue was observed. On the basis of these studies, 5 patients with inoperable cholangiocarcinoma were treated with CCT for 4 weeks. Overall efficacy rate of 5 patients with cholangiocarcinoma was 60% (partial response in 3 and no change in 2), No apparent side effect was observed in these patients. Thus, CCT may provide a new treatment modality for this disease. Randomized controlled trials comparing CCT therapy with palliative stenting are required to confirm these results.

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Papers - MURASE Kazuyuki