Details of a Researcher - TAKADA Kouichi

Papers - TAKADA Kouichi

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Germline <scp>BRCA1</scp>‐Mutated Synchronous and Metachronous Pancreatic Acinar Cell Carcinoma With Long‐Term Survival

Tomohiro Kubo, Yuki Ikeda, Joji Muramatu, Kazuma Ishikawa, Makoto Yoshida, Kazuharu Kukita, Masafumi Imamura, Shintaro Sugita, Akihiro Sakurai, Kohichi Takada

Cancer Reports ( Wiley ) 7 ( 8 ) 2024.08

ABSTRACT Background Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic neoplasm. Recently, molecular analysis revealed that PACC shows a high frequency of the BRCA1/2 mutation and is likely to be considered a cancer associated with hereditary breast and ovarian cancer (HBOC). Hereditary cancers, including HBOC, are characterized by multifocal and/or metachronous tumors. However, no case reports exist of germline BRCA1‐mutated synchronous and metachronous PACC. Case A 58‐year‐old man was diagnosed with synchronous and metachronous PACC at the age of 56 and underwent two surgeries. Ten months after the second surgery, the patient developed multiple liver metastases. Gemcitabine plus nab‐paclitaxel therapy was administered as first‐line chemotherapy. After seven cycles, computed tomography examination revealed progressive disease (PD). Therefore, modified FOLFIRINOX (mFFX) was administered as second‐ line chemotherapy. After 19 cycles of mFFX, comprehensive cancer genomic profiling (CGP) identified a BRCA1 pathogenic variant that was confirmed to be germline origin. Accordingly, we treated the patient with olaparib; however, he was diagnosed with PD after 4 months. He subsequently died 5 years and 9 months after the initial surgery, and 3 years and 10 months after chemotherapy. Based on the genetic data of the patients, his family members received genetic counseling followed by cascade testing. Consequently, the same gBRCA1 pathogenic variant was detected in the son and his surveillance for HBOC‐related cancers was initiated. Conclusion We diagnosed a 58‐year‐old man with a synchronous and metachronous PACC with germline BRCA1 pathogenic variant. Considering that PACC is likely to have BRCA1/2 mutations responsible for HBOC, we need to be aware of the possible presence of multifocal and/or metachronous tumors in patients with PACC. Additionally, patients with PACC should undergo genetic examinations, which would be beneficial in determining treatment strategies and health care for blood relatives.

DOI

LMNA::NTRK1 Fusion-positive Leiomyosarcoma: Discrepancy between DNA-based Comprehensive Genomic Profiling and RNA Sequencing.

Norito Suzuki, Masashi Idogawa, Makoto Emori, Kazuyuki Murase, Yohei Arihara, Hajime Nakamura, Makoto Usami, Tomohiro Kubo, Ichiro Kinoshita, Shintaro Sugita, Takashi Tokino, Tadashi Hasegawa, Akihiro Sakurai, Kohichi Takada

Internal medicine (Tokyo, Japan) 63 ( 15 ) 2215 - 2219 2024.08 [Domestic journal]

A 26-year-old man presented with a tumor in the left soleus muscle. The tumor was diagnosed as a locally advanced leiomyosarcoma. The patient was treated with irradiation followed by wide resection. One year after surgery, the patient presented with multiple lung metastases. Despite aggressive sequential chemotherapy, systemic metastatic tumors continued to develop. To explore therapeutic options for the patient, we performed DNA-based CGP with FoundationOne® CDx (F1). F1 identified an out-of-strand rearrangement of the NOS1AP::NTRK1 gene, which has not been previously reported. In contrast, RNA sequencing revealed an in-frame LMNA::NTRK1 gene, which is an oncogenic fusion gene.

DOI PubMed

Marked Response to Nivolumab by a Patient With <scp>SMARCA4</scp>‐Deficient Undifferentiated Urothelial Carcinoma Showing High <scp>PD</scp>‐<scp>L1</scp> Expression: A Case Report

Yohei Arihara, Ginji Omori, Ko Kobayashi, Shintaro Sugita, Kazuyuki Murase, Tomohiro Kubo, Masashi Idogawa, Tadashi Hasegawa, Kohichi Takada

Cancer Reports ( Wiley ) 7 ( 6 ) 2024.06

ABSTRACT Background SMARCA4 is a component gene of the SWI/SNF (SWItch/Sucrose NonFermentable) chromatin remodeling complex; undifferentiated tumors associated with its functional deletion have been described in several organs. However, no established treatment for these tumors currently exists. Case In this study, we report a case of a SMARCA4‐deficient undifferentiated urothelial carcinoma with high PD‐L1 expression that was effectively treated with nivolumab after early relapse following treatment for non‐invasive bladder cancer. The histological morphology of the rhabdoid‐like undifferentiated tumor of unknown primary led us to suspect a SWI/SNF‐deficient tumor, and subsequent immunostaining led to the diagnosis of a SMARCA4‐deficient undifferentiated tumor. This effort also led to the identification of the developmental origin of this SMARCA4‐deficient undifferentiated tumor as a non‐invasive bladder cancer. We also carried out a detailed immune phenotypic assay on peripheral T cells. In brief, a phenotypic change of CD8+T cells from naive to terminally differentiated effector memory cells was observed. Conclusion Regardless of the organ of cancer origin or cancer type, SWI/SNF‐deficient tumors should be suspected in undifferentiated and dedifferentiated tumors, and immune checkpoint inhibitors may be considered as a promising treatment option for this type of tumor. The pathogenesis of SMARCA4‐deficient anaplastic tumors awaits further elucidation for therapeutic development.

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Crizotinib therapy for congenital embryonal rhabdomyosarcoma associated with an ATIC–ALK gene fusion

Yusuke Akane, Masaki Yamamoto, Akira Takebayashi, Ryo Hamada, Keita Igarashi, Makoto Emori, Shintaro Sugita, Kohichi Takada, Tadashi Hasegawa, Takeshi Tsugawa

Pediatric Blood & Cancer ( Wiley ) 2024.06

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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

Gap junction beta‐4 accelerates cell cycle progression and metastasis through MET–AKT activation in pancreatic cancer

Joji Muramatsu, Yohei Arihara, Makoto Yoshida, Tomohiro Kubo, Hajime Nakamura, Kazuma Ishikawa, Hiromi Fujita, Shintaro Sugita, Takumi Konno, Takashi Kojima, Yutaka Kawano, Masayoshi Kobune, Kohichi Takada

Cancer Science ( Wiley ) 2024.02

Abstract Despite continuing advances in the development of effective new therapies, including immunotherapies, the prognosis of pancreatic cancer remains extremely poor. Gap junction proteins have become attractive targets for potential cancer therapy. However, the role of gap junction beta‐4 (GJB4) protein remains unexplored in pancreatic cancer. Through bioinformatic analyses we discovered pancreatic cancer tissues showed higher levels of GJB4 transcripts compared to normal pancreatic tissues and this had a negative effect on overall survival in patients that had pancreatic cancer. The high expression of nuclear GJB4 was identified as a negative prognostic factor in such patients. Knockdown of GJB4 in cultured pancreatic cancer cells resulted in G₀/G₁ arrest followed by decreased cell proliferation and suppression of metastatic potential. The overexpression of GJB4 accelerated cell proliferation, migration, and invasion in a SUIT‐2 cell line, whereas MET inhibitor canceled the acceleration. GJB4 suppression with siRNA significantly inhibited tumor growth in a mouse xenograft model. Mechanistically, suppression of GJB4 inhibited MET–AKT activities. Such data suggest that targeting the GJB4–MET axis could represent a promising new therapeutic strategy for pancreatic cancer.

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Tissue acquisition for comprehensive genomic profiling of gallbladder cancer using a forward-viewing echoendoscope in a patient who underwent Roux-en-Y reconstruction.

Michihiro Ono, Shutaro Oiwa, Atsushi Uesugi, Seiya Saito, Ryota Yokoyama, Makoto Usami, Tomoyuki Abe, Miri Fujita, Kohichi Takada, Masahiro Maeda

Clinical journal of gastroenterology 2023.10 [Domestic journal]

A 50-year-old man with a history of total gastrectomy, distal pancreatectomy, splenectomy, and Roux-en-Y reconstruction was admitted to our hospital with a gallbladder tumor that had infiltrated the liver and abdominal wall. Because malignant cells were not collected during the percutaneous biopsy, we planned to perform an endoscopic ultrasound-guided fine-needle biopsy with a 22-G Franseen needle using a forward-viewing echoendoscope. Using intermittent manual compression, the forward-viewing echoendoscope reached the duodenum under fluoroscopic guidance. Endoscopic ultrasound-guided fine-needle biopsy was performed using a 22-G needle and 20-mL syringe and yielded a sufficient specimen with a single puncture. Malignant cells were promptly identified during on-site evaluation. The composition of the specimen (> 20% cancer cells and tissue area exceeding 25 mm2) enabled comprehensive genomic profiling. Subsequently, high-tumor mutational burden was diagnosed based on comprehensive genomic profiling, and pembrolizumab was initiated as a second-line therapy. Even in cases involving Roux-en-Y reconstruction, endoscopic ultrasound-guided fine-needle biopsy using a forward-viewing echoendoscope can result in collection of a high-quality specimen.

DOI PubMed

Safety and Efficacy of NY-ESO-1 Antigen-specific T-cell Receptor Gene-Transduced T Lymphocytes in Patients with Synovial Sarcoma: A Phase I/II Clinical Trial.

Akira Kawai, Mikiya Ishihara, Tomoki Nakamura, Shigehisa Kitano, Shintaro Iwata, Kohichi Takada, Makoto Emori, Koji Kato, Makoto Endo, Yoshihiro Matsumoto, Shigeki Kakunaga, Eiichi Sato, Yoshihiro Miyahara, Kunihiko Morino, Shinya Tanaka, Shuichi Takahashi, Fujio Matsuo, Akihiko Matsumine, Shinichi Kageyama, Takafumi Ueda

Clinical cancer research : an official journal of the American Association for Cancer Research 2023.10 [International journal]

PURPOSE: To determine, for patients with advanced or recurrent synovial sarcoma not suitable for surgical resection and resistant to anthracycline, the safety and efficacy of the infusion of autologous T lymphocytes expressing NY-ESO-1 antigen-specific T-cell receptor gene and siRNAs to inhibit the expression of endogenous T-cell receptors (product code: TBI-1301). PATIENTS AND METHODS: Eligible Japanese patients (HLA-A*02:01 or *02:06, NY-ESO-1-positive tumor expression) received cyclophosphamide 750 mg/m2 on days -3 and -2 (induction period) followed by a single dose of 5 x 109 (±30%) TBI-1301 cells as a divided infusion on days 0 and 1 (treatment period). Primary endpoints were safety-related (phase I part) and efficacy-related (objective response rate [ORR] by RECIST v1.1/irRECIST; phase II part). Safety- and efficacy-related secondary endpoints were considered in both phase I/II parts. RESULTS: For the full analysis set (N=8; phase I, n=3; phase II, n=5), the ORR was 50.0% (95%CI: 15.7-84.3) with best overall partial response in 4 of 8 patients according to RECIST v1.1/irRECIST. All patients experienced adverse events and 7 of 8 patients (87.5%) had adverse drug reactions but no deaths were attributed to adverse events. Cytokine release syndrome occurred in 4 of 8 patients (50.0%) but all cases recovered with prespecified treatment. Immune effector cell-associated neurotoxicity syndrome, replication competent retrovirus, and lymphocyte clonality were absent. CONCLUSIONS: Adoptive immunotherapy with TBI-1301 to selectively target NY-ESO-1 positive tumor cells appears to be a promising strategy for the treatment of advanced or recurrent synovial sarcoma with acceptable toxicity.

DOI PubMed

Clinical characterization of patients with gBRCA1/2 mutation-positive unresectable pancreatic cancer: a multicenter prospective study.

Tomohiro Kubo, Joji Muramatsu, Yohei Arihara, Ayako Murota, Kazuma Ishikawa, Makoto Yoshida, Hiroyuki Nagashima, Fumito Tamura, Yuki Ikeda, Makoto Usami, Michihiro Ono, Hajime Nakamura, Daichi Watanabe, Takanori Shibata, Kaoru Kasahara, Akihiro Sakurai, Kohichi Takada

Japanese journal of clinical oncology 2023.10 [Refereed] [International journal]

Authorship： Lead author

BACKGROUND: Accumulating evidence has demonstrated platinum-based chemotherapy followed by maintenance therapy with a poly Adenosine diphosphate (ADP)-ribose polymerase inhibitor (olaparib) show benefits in unresectable pancreatic cancer with a germline (g)BRCA1/2 mutation. Evaluation of the germline BRCA1 and BRCA2 mutation is essential for making decisions on a treatment strategy for patients with unresectable pancreatic cancer. However, the detection rates of germline BRCA1 and BRCA2 mutations and efficacy of maintenance with olaparib remain undetermined, prospectively, in Japan. METHODS & RESULTS: In this prospective analysis, the rate of germline BRCA1 and BRCA2 mutations and efficacy of chemotherapy were analyzed in 136 patients with pancreatic cancer who underwent BRACAnalysis® (85 patients) or FoundationOne® CDx (51 patients) between January 2020 and July 2022. A total of six patients (4.4%) had a germline BRCA1 and BRCA2 mutation. Five patients were treated with modified FOLFIRINOX and one with fluorouracil and oxaliplatin. All patients continued platinum-based chemotherapy for ˃4 months and were subsequently treated with olaparib as a maintenance therapy. The response rate to platinum-based chemotherapy in the germline BRCA1 and BRCA2 mutation-positive group was significantly better than that of the germline BRCA1 and BRCA2 mutation-negative group (66% vs 23%, P = 0.04). All patients harbouring a germline BRCA1 and BRCA2 mutation were able to switch to olaparib. The median progression-free survival using olaparib was 5.7 months (range 3.0-9.2). CONCLUSIONS: The rate of germline BRCA1 and BRCA2 mutations found in patients with unresectable pancreatic cancer was comparable to those of previous studies.An analysis of germline BRCA1 and BRCA2 mutations has benefits for all patients with unresectable pancreatic cancer with regard to decisions on therapeutic strategies in a clinical practice setting.

DOI PubMed

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 ( Springer Science and Business Media LLC ) 2023.09

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Pemphigus vulgaris as an immune-related adverse event in recurrent metastatic esophageal squamous cell carcinoma treated with ipilimumab plus nivolumab: a case report and literature review

Hajime Nakamura, Aika Shionoya, Yohei Arihara, Naotaka Hayasaka, Tomohiro Kubo, Makoto Usami, Shintaro Sugita, Hisashi Uhara, Kohichi Takada

Frontiers in Immunology ( Frontiers Media SA ) 14 2023.09 [Refereed]

Authorship： Last author , Corresponding author

Ipilimumab plus nivolumab therapy is approved for patients with unresectable advanced esophageal squamous cell carcinoma (ESCC). Although a combination of immune checkpoint inhibitors (ICIs), compared to conventional chemotherapy, can improve overall survival in patients with advanced ESCC, this increases the incidence of immune-related adverse events (irAEs). Here, we describe an ESCC case that developed pemphigus vulgaris (PV), an extremely rare cutaneous irAE, during ipilimumab plus nivolumab treatment. The patient achieved a partial response to treatment. The PV was successfully managed after the cessation of ipilimumab and the use of a topical steroid. We should thus re-treat ESCC with nivolumab monotherapy. In the era of ICIs as standard cancer therapeutics, diagnostic criteria for blistering diseases need to be established to properly manage patients with cutaneous irAEs.

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Physical Properties and Cellular Metabolic Characteristics of 3D Spheroids Are Possible Definitive Indices for the Biological Nature of Cancer-Associated Fibroblasts.

Nami Nishikiori, Kohichi Takada, Tatsuya Sato, Sho Miyamoto, Megumi Watanabe, Yui Hirakawa, Shohei Sekiguchi, Masato Furuhashi, Akira Yorozu, Kenichi Takano, Akihiro Miyazaki, Hiromu Suzuki, Hiroshi Ohguro

Cells 12 ( 17 ) 2023.08 [Refereed] [International journal]

The current study's objective was to elucidate some currently unknown biological indicators to evaluate the biological nature of cancer-associated fibroblasts (CAFs). For this purpose, four different CAFs, CAFS1, CAFS2, SCC17F and MO-1000, were established using surgical specimens from oral squamous cell carcinomas (OSCC) with different clinical malignant stages (CAFS1 and CAFS2, T2N0M0, stage II; SCC17F and MO-1000, T4aN2bM0, stage IVA). Fibroblasts unrelated to cancer (non-CAFs) were also prepared and used as controls. Initially, confirmation that these four fibroblasts were indeed CAFs was obtained by their mRNA expression using positive and negative markers for the CAF or fibroblasts. To elucidate possible unknown biological indicators, these fibroblasts were subjected to a cellular metabolic analysis by a Seahorse bioanalyzer, in conjugation with 3D spheroid cultures of the cells and co-cultures with a pancreas ductal carcinoma cell line, MIA PaCa-2. The mitochondrial and glycolytic functions of human orbital fibroblasts (HOF) were nearly identical to those of Graves'-disease-related HOF (GOF). In contrast, the characteristics of the metabolic functions of these four CAFs were different from those of human conjunctival fibroblasts (HconF), a representative non-CAF. It is particularly noteworthy that CAFS1 and CAFS2 showed markedly reduced ratios for the rate of oxygen consumption to the extracellular acidification rate, suggesting that glycolysis was enhanced compared to mitochondrial respiration. Similarly, the physical aspects, their appearance and stiffness, of their 3D spheroids and fibroblasts that were induced effects based on the cellular metabolic functions of MIA PaCa-2 were also different between CAFs and non-CAFs, and their levels for CAFS1 or SCC17F were similar to those for CAFS2 or MO-1000 cells, respectively. The findings reported herein indicate that cellular metabolic functions and the physical characteristics of these types of 3D spheroids may be valuable and useful indicators for estimating potential biological diversity among various CAFs.

DOI PubMed

Establishment and characterization of a novel dedifferentiated chondrosarcoma cell line, SMU-DDCS, harboring an IDH1 mutation

Makoto Emori, Naoya Nakahashi, Akira Takasawa, Kenji Murata, Yasutaka Murahashi, Junya Shimizu, Tomohide Tsukahara, Shintaro Sugita, Kohichi Takada, Tadashi Hasegawa, Makoto Osanai, Kosuke Iba

Human Cell ( Springer Science and Business Media LLC ) 2023.07

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A phase 1 trial of NY-ESO-1-specific TCR-engineered T-cell therapy combined with a lymph node-targeting nanoparticulate peptide vaccine for the treatment of advanced soft tissue sarcoma.

Mikiya Ishihara, Yoshihiro Nishida, Shigehisa Kitano, Akira Kawai, Daisuke Muraoka, Fumiyasu Momose, Naozumi Harada, Yoshihiro Miyahara, Naohiro Seo, Hiroyoshi Hattori, Kohichi Takada, Makoto Emori, Shigeki Kakunaga, Makoto Endo, Yoshihiro Matsumoto, Tetsuro Sasada, Eiichi Sato, Tomomi Yamada, Akihiko Matsumine, Yasuhiro Nagata, Takashi Watanabe, Shinichi Kageyama, Hiroshi Shiku

International journal of cancer 152 ( 12 ) 2554 - 2566 2023.06 [International journal]

The efficacy of immune checkpoint inhibitors is limited in refractory solid tumors. T-cell receptor gene-modified T (TCR-T)-cell therapy has attracted attention as a new immunotherapy for refractory cold tumors. We first investigated the preclinical efficacy and mode of action of TCR-T cells combined with the pullulan nanogel:long peptide antigen (LPA) vaccine in a mouse sarcoma model that is resistant to immune checkpoint inhibition. Without lymphodepletion, the pullulan nanogel:LPA vaccine markedly increased the number of TCR-T cells in the draining lymph node and tumor tissue. This change was associated with enhanced CXCR3 expression in TCR-T cells in the draining lymph node. In the phase 1 trial, autologous New York esophageal squamous cell carcinoma 1 (NY-ESO-1)-specific TCR-T cells were infused twice into HLA-matched patients with NY-ESO-1+ soft tissue sarcoma (STS). The pullulan nanogel:LPA vaccine contains an epitope recognized by TCR-T cells, and it was subcutaneously injected 1 day before and 7 days after the infusion of TCR-T cells. Lymphodepletion was not performed. Three patients with refractory synovial sarcoma (SS) were treated. Two out of the three patients developed cytokine release syndrome (CRS) with low-to-moderate cytokine level elevation. We found obvious tumor shrinkage lasting for more than 2 years by tumor imaging and long-term persistence of TCR-T cells in one patient. In conclusion, NY-ESO-1-specific TCR-T-cell therapy plus vaccination with the pullulan nanogel carrying an LPA containing the NY-ESO-1 epitope without lymphodepletion is feasible and can induce promising long-lasting therapeutic effects in refractory SS (Registration ID: JMA-IIA00346).

DOI PubMed

Assessment for the timing of comprehensive genomic profiling tests in patients with advanced solid cancers.

Kanako Hagio, Junko Kikuchi, Kohichi Takada, Hiroki Tanabe, Minako Sugiyama, Yoshihito Ohhara, Toraji Amano, Satoshi Yuki, Yoshito Komatsu, Takahiro Osawa, Kanako C Hatanaka, Yutaka Hatanaka, Takashi Mitamura, Ichiro Yabe, Yoshihiro Matsuno, Atsushi Manabe, Akihiro Sakurai, Atsushi Ishiguro, Masato Takahashi, Hiroshi Yokouchi, Hirohito Naruse, Yusuke Mizukami, Hirotoshi Dosaka-Akita, Ichiro Kinoshita

Cancer science 2023.05 [International journal]

Comprehensive genomic profiling (CGP) tests have been covered by public insurance in Japan for patients with advanced solid tumors who have completed or are completing standard treatments or do not have them. Therefore, genotype-matched drug candidates are often unapproved or off-label, and improving clinical trial access is critical, involving the appropriate timing of CGP tests. To address this issue, we analyzed the previous treatment data for 441 patients from an observational study on CGP tests discussed by the expert panel at Hokkaido University Hospital between August 2019 and May 2021. The median number of previous treatment lines was two; three or more lines accounted for 49%. Information on genotype-matched therapies was provided to 277 (63%). Genotype-matched clinical trials were ineligible because of an excess number of previous treatment lines or use of specific agents were found in 66 (15%) patients, with the highest proportion in breast and prostate cancers. Many patients met the exclusion criteria of one to two or more treatment lines across cancer types. In addition, previous use of specific agents was a frequent exclusion criterion for breast, prostate, colorectal, and ovarian cancers. The patients with tumor types with a low median number (two or fewer) of previous treatment lines, including most rare cancers, primary unknown cancers, and pancreatic cancers, had significantly fewer ineligible clinical trials. The earlier timing of CGP tests may improve access to genotype-matched clinical trials, with their proportion varying by cancer type. Each relevant society needs to advocate the desirable timing of CGP testing nationwide.

DOI PubMed

Impact of BRAF/MEK inhibitor on BRAF V600E-mutated pilocytic astrocytoma.

Ryo Hamada, Yusuke Akane, Yukinori Akiyama, Kohichi Takada, Masaki Yamamoto

Pediatrics international : official journal of the Japan Pediatric Society 65 ( 1 ) e15653 2023 [International journal]

DOI PubMed

Chimeric antigen receptor T-cell therapy targeting a MAGE A4 peptide and HLA-A*02:01 complex for unresectable advanced or recurrent solid cancer: protocol for a multi-institutional phase 1 clinical trial.

Satoshi Okumura, Mikiya Ishihara, Naomi Kiyota, Kimikazu Yakushijin, Kohichi Takada, Shinichiro Kobayashi, Hiroaki Ikeda, Makoto Endo, Koji Kato, Shigehisa Kitano, Akihiko Matsumine, Yasuhiro Nagata, Shinichi Kageyama, Taizo Shiraishi, Tomomi Yamada, Keizo Horibe, Kazuto Takesako, Hiroshi Miwa, Takashi Watanabe, Yoshihiro Miyahara, Hiroshi Shiku

BMJ open 12 ( 11 ) e065109 2022.11 [International journal]

INTRODUCTION: Adoptive cell transfer of genetically engineered T cells is a promising treatment for malignancies; however, there are few ideal cancer antigens expressed on the cell surface, and the development of chimeric antigen receptor T cells (CAR-T cells) for solid tumour treatment has been slow. CAR-T cells, which recognise major histocompatibility complex and peptide complexes presented on the cell surface, can be used to target not only cell surface antigens but also intracellular antigens. We have developed a CAR-T-cell product that recognises the complex of HLA-A*02:01 and an epitope of the MAGE-A4 antigen equipped with a novel signalling domain of human GITR (investigational product code: MU-MA402C) based on preclinical studies. METHODS AND ANALYSIS: This is a dose-escalation, multi-institutional, phase 1 study to evaluate the tolerability and safety of MU-MA402C for patients with MAGE A4-positive and HLA-A*02:01-positive unresectable advanced or recurrent solid cancer. Two dose cohorts are planned: cohort 1, MU-MA402C 2×108/person; cohort 2, MU-MA402C 2×109/person. Prior to CAR-T-cell infusion, cyclophosphamide (CPA) and fludarabine (FLU) will be administered as preconditioning chemotherapy. Three evaluable subjects per cohort, for a total of 6 subjects (maximum of 12 subjects), will be recruited for this clinical trial. The primary endpoints are safety and tolerability. The severity of each adverse event will be evaluated in accordance with Common Terminology Criteria for Adverse Events V.5.0. The secondary endpoint is efficacy. Antitumour response will be evaluated according to Response Evaluation Criteria in Solid Tumours V.1.1. ETHICS AND DISSEMINATION: This clinical trial will be conducted in accordance with the current version of Good Clinical Practice. The protocol was approved by the Clinical Research Ethics Review Committee of Mie University Hospital (approval number F-2021-017). The trial results will be published in peer-reviewed journals and/or disseminated through international conferences. TRIAL REGISTRATION NUMBER: jRCT2043210077.

DOI PubMed

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 ) 12 ( 1 ) 205 - 211 2022.10 [Refereed]

Authorship： Corresponding author

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Effect of comprehensive cancer genomic profiling on therapeutic strategies and clinical outcomes in patients with advanced biliary tract cancer: A prospective multicenter study

Kohichi Takada, Tomohiro Kubo, Junko Kikuchi, Makoto Yoshida, Ayako Murota, Yohei Arihara, Hajime Nakamura, Hiroyuki Nagashima, Hiroki Tanabe, Shintaro Sugita, Yumi Tanaka, Ayana Miura, Yoshihito Ohhara, Atsushi Ishiguro, Hiroshi Yokouchi, Yasuyuki Kawamoto, Yusuke Mizukami, Hirofumi Ohnishi, Ichiro Kinoshita, Akihiro Sakurai

Frontiers in Oncology ( Frontiers Media SA ) 12 2022.09 [Refereed]

Authorship： Lead author , Corresponding author

Characterization of the genomic landscape of biliary tract cancer (BTC) may lead to applying genotype-matched therapy for patients with this disease. Evidence that comprehensive cancer genomic profiling (CGP) guides genotype-matched therapy to improve clinical outcomes is building. However, the significance of CGP in patients with BTC remains unclarified in clinical practice. Therefore, the purposes of this study were to assess the utility of CGP and identify associations between clinical outcomes and genomic alterations in patients with BTC. In this prospective analysis, detection rates for actionable genomic alterations and access rates for genotype-matched therapy were analyzed in 72 patients with advanced BTC who had undergone commercial CGP. Cox regression analyses assessed relationships between overall survival and genomic alterations detected with CGP. The most common genomic alterations detected were TP53 (41, 56.9%), followed by CDKN2A/B (24, 33.3%/20, 27.8%), and KRAS (20, 27.8%). Actionable genomic alterations were identified in 58.3% (42/72) of patients. Detection rates for FGFR2 fusions, IDH1 mutations, and BRAF V600E were low in this cohort. Eight (11.1%) patients received genotype-matched therapy. For patients with intrahepatic cholangiocarcinoma (ICC), CDKN2A/B loss was associated with shorter overall survival. These real-world data demonstrate that CGP can identify therapeutic options in patients with advanced BTC. CDKN2A/B loss was identified as a poor prognostic factor in patients with ICC. Thus, this study provides a rationale for considering CGP in planning therapeutic strategies for advanced BTC.

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Prognostic usefulness of a modified risk model for solitary fibrous tumor that includes the Ki-67 labeling index.

Shintaro Sugita, Keiko Segawa, Noriaki Kikuchi, Tomoko Takenami, Tomomi Kido, Makoto Emori, Yukinori Akiyama, Kohichi Takada, Shiro Hinotsu, Tadashi Hasegawa

World journal of surgical oncology 20 ( 1 ) 29 - 29 2022.02 [International journal]

BACKGROUND: Predicting the prognosis of patients with solitary fibrous tumor (SFT) is often difficult. The prognostic risk models developed by Demicco et al. are now the standard for evaluating the risk of SFT metastasis in the current World Health Organization classification of soft tissue and bone tumors. METHODS: In this study, we examined the prognostic usefulness of a modified version of the Demicco risk models that replaces the mitotic count with the Ki-67 labeling index. We compared the three-variable and four-variable Demicco risk models with our modified risk models using Kaplan-Meier curves based on data for 43 patients with SFT. RESULTS: We found a significant difference in metastasis-free survival when patients were classified into low-risk and intermediate/high-risk groups using the three-variable (P = 0.022) and four-variable (P = 0.046) Demicco models. There was also a significant difference in metastasis-free survival between the low-risk and intermediate/high-risk groups when the modified three-variable (P = 0.006) and four-variable (P = 0.022) models were used. CONCLUSION: Modified risk models that include the Ki-67 labeling index are effective for prediction of the prognosis in patients with SFT.

DOI PubMed

Complete Response To Eribulin In A Patient With Unresectable Liposarcoma: A Case Report And Implications Of New Biomarkers

Hajime Nakamura, Kohichi Takada, Makoto Emori, Naotaka Hayasaka, Shintaro Sugita

Internal Medicine ( Japanese Society of Internal Medicine ) 2022 [Refereed]

Authorship： Corresponding author

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 ( Japanese Society of Internal Medicine ) 2021.10 [Refereed] [Domestic journal]

Authorship： Corresponding author

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

Reactive oxygen species in cancer: Current findings and future directions

Hajime Nakamura, Kohichi Takada

Cancer Science ( Wiley ) 2021.08 [Refereed] [Invited]

Authorship： Corresponding author

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 [Refereed] [International journal]

PURPOSE: The clinical benefit of conversion surgery (CS) for unresectable gastric cancer (GC), whereby unresectable GC responds to chemotherapy and subsequently receives curative-intent surgery, remains unclear. Here, we aimed to clarify the clinical value of CS. METHODS: In this retrospective cohort study, we analyzed 175 unresectable GC, who received triple combined chemotherapy between 2004 and 2019. We divided patients into two groups: those who underwent CS and those receiving chemotherapy only (CS and C groups, respectively). Propensity score matching was used to minimize confounding bias. RESULTS: Of 175 cases, 61 (34.9%) underwent CS. R0 resection was obtained in 85.2%. After matching, 44 pairs were selected; there were no significant differences in baseline covariants. Group CS had a significantly better median overall survival (OS) (18.8 vs. 46.0 months, p < 0.001), and prolonged progression-free survival (7.4 vs. 25.8 months, p < 0.001). Subgroup analysis of OS showed a favorable trend for CS for almost all subgroups. Multivariate analysis revealed that good ECOG performance status and CS were associated with a longer OS. CONCLUSION: The survival benefit of CS was consistently demonstrated in the univariate and multivariate analysis, even in the matched cohort. Additional large-scale trials are needed for further validation.

DOI PubMed

Six-transmembrane epithelial antigen of the prostate 1 accelerates cell proliferation by targeting c-Myc in liver cancer cells

Kazutaka Iijima, Hajime Nakamura, Kohichi Takada, Naotaka Hayasaka, Tomohiro Kubo, Yui Umeyama, Satoshi Iyama, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Oncology Letters ( Spandidos Publications ) 22 ( 1 ) 546 - 546 2021.05 [Refereed] [International journal]

Authorship： Corresponding author

Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) has emerged as an ideal target in cancer therapeutics. However, the functions of STEAP1 in liver cancer remain unexplored. The current study aimed to characterize the biological roles of STEAP1 in liver cancer. STEAP1 expression was upregulated in tumor tissues, and high STEAP1 expression was associated with poor clinical outcomes in patients with liver cancer, according to several publicly available datasets. STEAP1 silencing using small interfering RNA inhibited cell proliferation and was accompanied by G1 arrest induced by the suppression of cyclin D1 and the promotion of p27. STEAP1 silencing suppressed c-Myc expression, which was identified as a component in STEAP1 signal transduction by mining publicly available datasets and was then confirmed by PCR array. In conclusion, the knockdown of STEAP1 in liver cancer cell lines led to inhibition of cell proliferation involving G1 arrest by suppressing c-Myc. The present study provides a preclinical concept for STEAP1 as a druggable target in liver cancer.

DOI PubMed

Clinical significance of comprehensive genomic profiling tests covered by public insurance in patients with advanced solid cancers in Hokkaido, Japan

Junko Kikuchi, Yoshihito Ohhara, Kohichi Takada, Hiroki Tanabe, Kazuteru Hatanaka, Toraji Amano, Kanako C Hatanaka, Yutaka Hatanaka, Takashi Mitamura, Momoko Kato, Yuka Shibata, Ichiro Yabe, Akira Endoh, Yoshito Komatsu, Yoshihiro Matsuno, Minako Sugiyama, Atsushi Manabe, Akihiro Sakurai, Masato Takahashi, Hirohito Naruse, Yoshihiro Torimoto, Hirotoshi Dosaka-Akita, Ichiro Kinoshita

Japanese Journal of Clinical Oncology ( Oxford University Press (OUP) ) 51 ( 5 ) 753 - 761 2021.04 [Refereed]

Abstract Background Comprehensive cancer genomic profiling has been used recently for patients with advanced solid cancers. Two cancer genomic profiling tests for patients with no standard treatment are covered by Japanese public health insurance since June 2019. Methods We prospectively analyzed data of 189 patients with solid cancers who underwent either of the two-cancer genomic profiling tests at Hokkaido University Hospital and its liaison hospitals and whose results were discussed in molecular tumor board at Hokkaido University Hospital between August 2019 and July 2020. Results All 189 patients had appropriate results. Actionable gene alterations were identified in 93 patients (49%). Frequent mutations included PIK3CA (12%) mutation, BRCA1/2 alteration (7%), ERBB2 amplification (6%) and tumor mutation burden-High (4%). The median turnaround time from sample shipping to acquisition by the expert panel was 26 days. Although 115 patients (61%) were provided with information for genotype-matched therapies, only 21 (11%) received them. Notably, four of eight patients below the age of 20 years were provided information for genotype-matched therapies, and three received them. Their response rates and disease control rates were 29% and 67%, respectively. Most patients who did not undergo the genotype-matched therapies were provided information for only investigational drugs in phases I and II at distant clinical trial sites in central Japan. Twenty-six patients were informed of suspected germline findings, while 11 patients (42%) received genetic counseling. Conclusions The publicly reimbursed cancer genomic profilings may lead to the modest but favorable therapeutic efficacy of genotype-matched therapy for solid cancer patients with no standard therapy. However, poor access to genotype-matched therapy needs to be resolved.

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 [Refereed]

Authorship： Corresponding author

DOI

Response to ‘Is the case really a SMARCA4 ‐deficient thoracic sarcoma?’

Kohichi Takada, Shintaro Sugita, Tadashi Hasegawa

Thoracic Cancer ( Wiley ) 12 ( 1 ) 141 - 141 2021.01 [International journal]

Authorship： Lead author , Corresponding author

DOI PubMed

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 [Refereed] [International journal]

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome often associated with germline mutations in the CDH1 gene. However, the frequency of CDH1 mutations is low in patients with HDGC in East Asian countries. Herein, we report three cases of HDGC harboring a missense CDH1 variant, c.1679C>G, from a single Japanese family. CASE SUMMARY: A 26-year-old female (Case 1) and a 51-year-old male (father of Case 1), who had a strong family history of gastric cancer, were diagnosed with advanced diffuse gastric cancer. After genetic counselling, a 25-year-old younger brother of Case 1 underwent surveillance esophagogastroduodenoscopy that detected small signet ring cell carcinoma foci as multiple pale lesions in the gastric mucosa. Genetic analysis revealed a CDH1 c.1679C>G variant in all three patients. CONCLUSION: It is important for individuals suspected of having HDGC to be actively offered genetics evaluation. This report will contribute to an increased awareness of HDGC.

DOI PubMed

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 [Refereed] [International journal]

Authorship： Corresponding author

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 PubMed

FOXO3a Activation by HDAC Class IIa Inhibition Induces Cell Cycle Arrest in Pancreatic Cancer Cells

Makoto Usami, Shohei Kikuchi, Kohichi Takada, Michihiro Ono, Yusuke Sugama, Yohei Arihara, Naotaka Hayasaka, Hajime Nakamura, Yuuki Ikeda, Masahiro Hirakawa, Makoto Yoshida, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Pancreas ( Ovid Technologies (Wolters Kluwer Health) ) 49 ( 1 ) 135 - 142 2020.01 [Refereed]

DOI

Chemotherapy after progression on nivolumab is essential for responders with genetic alterations of driver gene: Review of two recurrent/metastatic oral squamous cell carcinoma patients.

Kazuhiro Ogi, Junichi Kobayashi, Takafumi Nakagaki, Junya Okamoto, Kazushige Koike, Naoki Hirokawa, Masanori Someya, Hiroki Sakamoto, Kohichi Takada, Takashi Tokino, Yasushi Sasaki, Hiroyoshi Hiratsuka, Akihiro Miyazaki

Oral oncology 104509 - 104509 2019.12 [Refereed] [International journal]

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 ( Hindawi Limited ) 2019 1 - 5 2019.12 [Refereed] [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

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 [Refereed] [International journal]

Authorship： Lead author , Corresponding author

SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a new clinical entity characterized by SMARCA4 inactivation and has a dismal prognosis because of rapid growth. Effective treatments for SMARCA4-DTS have not yet been developed. Most recently, anti-programmed cell death 1 receptor (PD-1) blockade has been effective for SMARCA4-deficient lung cancer and malignant rhabdoid tumor-like tumors. Here, we describe a patient with SMARCA4-DTC who experienced a marked response to the administration of pembrolizumab. A 70-year-old female was referred to our department for treatment of SMARCA4-DTC. Positron emission tomography-computed tomography had revealed a left mediastinal tumor, peritoneal dissemination and multiple cutaneous metastases at diagnosis. Immunohistochemical analyses revealed 60% of tumor cells expressed programmed cell death ligand 1 (PD-L1). The patient was given pembrolizumab as first-line treatment. Pembrolizumab suppressed tumor growth dramatically, with only one dose leading to a partial response. Our case suggests the immunohistochemical analysis of PD-L1 expression be undertaken for patients with SMARCA4-DTS and that pembrolizumab treatment may be a promising strategy for PD-L1-positive SMARCA4-DTS.

DOI PubMed

Treatment outcome of chest wall soft tissue sarcomas: Analysis of prognostic factors

Naoya Nakahashi, Makoto Emori, Hiroyuki Tsuchie, Hiroyuki Nagasawa, Tomoko Sonoda, Kohichi Takada, Masahiro Miyajima, Atsushi Watanabe, Yoichi Shimada, Toshihiko Yamashita

Journal of Surgical Oncology ( Wiley ) 120 ( 7 ) 1235 - 1240 2019.12 [Refereed] [International journal]

BACKGROUND: Primary soft tissue sarcomas (STSs) involving the chest wall are uncommon. The aim of this study was to identify factors that influence the prognosis of patients with primary chest wall STS. METHODS: The records of 38 patients (23 men and 15 women) who were treated at our institutions during 2002 to 2018 were reviewed. The following variables were evaluated as potential prognostic factors: sex, tumor size, chemotherapy, and completeness of surgical margins. Multivariate analysis was conducted to identify predictors of overall survival (OS) and disease-free survival (DFS). RESULTS: Of the 38 included patients, 5 had low-grade tumors and 33 had high-grade tumors. Five patients required chest wall reconstruction including rib resection. Thirty patients (79%) underwent R0 resection. The 5-year OS and DFS rates were 45% and 27%, respectively. Local recurrence developed in 7 patients. Multivariate analysis identified tumor size (hazard ratio [HR]: 4.13; 95% confidence interval [CI]: 1.05-16.24; P = .04) and R1/2 resection (HR: 3.92; 95% CI: 1.12-13.66; P = .03) as predictors of OS. CONCLUSIONS: Prognostic factors for survival included tumor size and completeness of surgical margins. Complete tumor excision is desirable, particularly in cases of early detection.

DOI PubMed

DPP8 is a novel therapeutic target for multiple myeloma

Tsutomu Sato, Ayumi Tatekoshi, Kohichi Takada, Satoshi Iyama, Yusuke Kamihara, Paras Jawaid, Mati Ur Rehman, Kyo Noguchi, Takashi Kondo, Sayaka Kajikawa, Kotaro Arita, Akinori Wada, Jun Murakami, Miho Arai, Ichiro Yasuda, Nam H. Dang, Ryo Hatano, Noriaki Iwao, Kei Ohnuma, Chikao Morimoto

Scientific Reports ( Springer Science and Business Media LLC ) 9 ( 1 ) 2019.12 [Refereed]

AbstractDipeptidyl peptidases (DPPs) are proteolytic enzymes that are ideal therapeutic targets in human diseases. Indeed, DPP4 inhibitors are widely used in clinical practice as anti-diabetic agents. In this paper, we show that DPP4 inhibitors also induced cell death in multiple human myeloma cells. Among five DPP4 inhibitors, only two of them, vildagliptin and saxagliptin, exhibited apparent cytotoxic effects on myeloma cell lines, without any difference in suppression of DPP4 activity. As these two DPP4 inhibitors are known to have off-target effects against DPP8/9, we employed the specific DPP8/9 inhibitor 1G244. 1G244 demonstrated anti-myeloma effects on several cell lines and CD138+ cells from patients as well as in murine xenograft model. Through siRNA silencing approach, we further confirmed that DPP8 but not DPP9 is a key molecule in inducing cell death induced by DPP8/9 inhibition. In fact, the expression of DPP8 in CD38+ cells from myeloma patients was higher than that of healthy volunteers. DPP8/9 inhibition induced apoptosis, as evidenced by activated form of PARP, caspases-3 and was suppressed by the pan-caspase inhibitor Z-VAD-FMK. Taken together, these results indicate that DPP8 is a novel therapeutic target for myeloma treatment.

DOI

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 [Refereed] [Domestic journal]

Authorship： Lead author , Corresponding author

Pneumothorax has been reported as a pazopanib-associated adverse event in patients with lung metastases of soft tissue sarcoma (STS). However, pneumothorax triggered by eribulin treatment has never been reported. We herein report two cases of spontaneous pneumothorax in patients with STS treated with eribulin. Both patients experienced pneumothorax accompanied by sudden dyspnea on day 9 or 10 of eribulin treatment. These two cases suggest that spontaneous pneumothorax may occur as an adverse event of eribulin treatment in such patients. We should therefore be alert for the potential development of pneumothorax during eribulin treatment of patients with STS and lung metastases.

DOI PubMed

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 [Refereed]

Authorship： Lead author

DOI

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]

Authorship： Lead author

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

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]

Authorship： Lead author

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

Ofatumumab combined with chlorambucil for previously untreated chronic lymphocytic leukemia: a phase I/II, open-label study in Japan

Kiyohiko Hatake, Michinori Ogura, Kohichi Takada, Masafumi Taniwaki, Fanghong Zhang, Taizo Fujita, Kiyoshi Ando

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER JAPAN KK ) 106 ( 2 ) 240 - 247 2017.08 [Refereed]

Elderly/comorbid patients with chronic lymphocytic leukemia (CLL) require low-toxicity treatments. Internationally, the standard treatment for such patients is chlorambucil and an anti-CD20 therapy; however, chlorambucil is not approved in Japan. The aim of the present study was to evaluate the safety, efficacy and pharmacokinetics of ofatumumab in combination with chlorambucil in Japanese patients with previously untreated CLL who were inappropriate for fludarabine-based therapy. Ten patients were enrolled and treated in this study, all of whom received at least one dose of the study drugs. The tolerability of the treatment was confirmed initially with three patients. The overall response rate was 50%, as determined by the Independent Review Committee (IRC) with computerized tomography. All patients were alive at follow-up, and only one patient had progressive disease. The most common treatment-related adverse events (AEs) were thrombocytopenia (n = 10), neutropenia (n = 9) and rash (n = 6). One grade 3 serious AE related to the study drug occurred (hypoxia). The results indicate that ofatumumab combined with chlorambucil is an effective treatment for Japanese CLL patients, with a manageable safety profile.

DOI PubMed

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]

Authorship： Lead author

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

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]

Authorship： Lead author

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

A role for peripherally inserted central venous catheters in the prevention of catheter-related blood stream infections in patients with hematological malignancies

Toshiro Sakai, Kyuhei Kohda, Yuichi Konuma, Yasuko Hiraoka, Yukari Ichikawa, Kaoru Ono, Hiroto Horiguchi, Ayumi Tatekoshi, Kouichi Takada, Satoshi Iyama, Junji Kato

International Journal of Hematology ( Springer Science and Business Media LLC ) 100 ( 6 ) 592 - 598 2014.12 [Refereed]

DOI

miR-30-5p Functions as a Tumor Suppressor and Novel Therapeutic Tool by Targeting the Oncogenic Wnt/beta-Catenin/BCL9 Pathway

Jian-Jun Zhao, Jianhong Lin, Di Zhu, Xujun Wang, Daniel Brooks, Ming Chen, Zhang-Bo Chu, Kohichi Takada, Bryan Ciccarelli, Samir Admin, Jianguo Tao, Yu-Tzu Tai, Steven Treon, Geraldine Pinkus, Winston Patrick Kuo, Teru Hideshima, Mary Bouxsein, Nikhil Munshi, Kenneth Anderson, Ruben Carrasco

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 74 ( 6 ) 1801 - 1813 2014.03 [Refereed]

Wnt/beta-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma. In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in multiple myeloma. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between multiple myeloma cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional coactivator of the Wnt signaling pathway known to promote multiple myeloma cell proliferation, survival, migration, drug resistance, and formation of multiple myeloma cancer stem cells. The potential for clinical translation of strategies to re-express miR-30-5p as a therapeutic approach was further encouraged by the capacity of miR-30c and miR-30 mix to reduce tumor burden and metastatic potential in vivo in three murine xenograft models of human multiple myeloma without adversely affecting associated bone disease. Together, our findings offer a preclinical rationale to explore miR-30-5p delivery as an effective therapeutic strategy to eradicate multiple myeloma cells in vivo. (C) 2014 AACR.

DOI PubMed

Successful Treatment with Entecavir for Reactivation of Hepatitis B Virus Following Systemic Chemotherapy in a Hepatitis B Surface Antigen-negative Patient with Colorectal Cancer

Yutaka Okagawa, Kohichi Takada, Hiroyuki Hisai, Yutaka Koshiba, Hironori Wada, Etsu Miyazaki, Yusuke Kanari, Yutaka Kawano, Satoshi Iyama, Tsuyoshi Hayashi, Tsutomu Sato, Yasushi Sato, Koji Miyanishi, Masayoshi Kobune, Rishu Takimoto, Junji Kato

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE ) 53 ( 16 ) 1759 - 1762 2014 [Refereed]

Reactivation of hepatitis B virus (HBV) has recently been reported as a fatal complication in patients undergoing cytotoxic chemotherapy. We herein describe a case of reactivation in a 76-year-old man who had undergone pelvic exenteration for colorectal cancer (CRC). He was treated with a modified FOLFOX6 chemotherapy regimen after the operation. Thirteen months later, his laboratory data showed severe liver dysfunction. His hepatitis B surface antigen (HBsAg) test was positive, and his HBV-DNA level was elevated. We diagnosed the patient with HBV reactivation as his HBsAg test was negative before starting chemotherapy. His liver dysfunction improved after administration of entecavir. This is the first report describing HBV reactivation following chemotherapy for an HBsAg-negative CRC patient.

DOI PubMed

TRIM13 (RFP2) downregulation decreases tumour cell growth in multiple myeloma through inhibition of NF Kappa B pathway and proteasome activity

Moshe E. Gatt, Kohichi Takada, Mala Mani, Mikael Lerner, Marjorie Pick, Teru Hideshima, Daniel E. Carrasco, Alexei Protopopov, Elena Ivanova, Olle Sangfelt, Dan Grander, Bart Barlogie, John D. Shaughnessy, Kenneth C. Anderson, Daniel R. Carrasco

BRITISH JOURNAL OF HAEMATOLOGY ( WILEY ) 162 ( 2 ) 210 - 220 2013.07 [Refereed]

Multiple myeloma (MM) is an incurable neoplasm caused by proliferation of malignant plasma cells in the bone marrow (BM). MM is characterized frequently by a complete or partial deletion of chromosome 13q14, seen in more than 50% of patients at diagnosis. Within this deleted region the tripartite motif containing 13 (TRIM13, also termed RFP2) gene product has been proposed to be a tumour suppressor gene (TSG). Here, we show that low expression levels of TRIM13 in MM are associated with chromosome 13q deletion and poor clinical outcome. We present a functional analysis of TRIM13 using a loss-of-function approach, and demonstrate that TRIM13 downregulation decreases tumour cell survival as well as cell cycle progression and proliferation of MM cells. In addition, we provide evidence for the involvement of TRIM13 downregulation in inhibiting the NF kappa B pathway and the activity of the 20S proteasome. Although this data does not support a role of TRIM13 as a TSG, it substantiates important roles of TRIM13 in MM tumour survival and proliferation, underscoring its potential role as a novel target for therapeutic intervention.

DOI PubMed

Targeted Disruption of the BCL9/beta-Catenin Complex Inhibits Oncogenic Wnt Signaling

Kohichi Takada, Di Zhu, Gregory H. Bird, Kumar Sukhdeo, Jian-Jun Zhao, Mala Mani, Madeleine Lemieux, Daniel E. Carrasco, Jeremy Ryan, David Horst, Mariateresa Fulciniti, Nikhil C. Munshi, Wenqing Xu, Andrew L. Kung, Ramesh A. Shivdasani, Loren D. Walensky, Daniel Ruben Carrasco

SCIENCE TRANSLATIONAL MEDICINE ( AMER ASSOC ADVANCEMENT SCIENCE ) 4 ( 148 ) 148ra117 2012.08 [Refereed]

Authorship： Lead author

Deregulated Wnt/beta-catenin signaling underlies the pathogenesis of a broad range of human cancers, yet the development of targeted therapies to disrupt the resulting aberrant transcription has proved difficult because the pathway comprises large protein interaction surfaces and regulates many homeostatic functions. Therefore, we have directed our efforts toward blocking the interaction of beta-catenin with B cell lymphoma 9 (BCL9), a coactivator for beta-catenin-mediated transcription that is highly expressed in tumors but not in the cells of origin. BCL9 drives beta-catenin signaling through direct binding mediated by its alpha-helical homology domain 2. We developed a stabilized a helix of BCL9 (SAH-BCL9), which we show targets beta-catenin, dissociates native beta-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and exhibits mechanism-based antitumor effects. SAH-BCL9 also suppresses tumor growth, angiogenesis, invasion, and metastasis in mouse xenograft models of Colo320 colorectal carcinoma and INA-6 multiple myeloma. By inhibiting the BCL9-beta-catenin interaction and selectively suppressing oncogenic Wnt transcription, SAH-BCL9 may serve as a prototype therapeutic agent for cancers driven by deregulated Wnt signaling.

DOI PubMed

β-catenin is dynamically stored and cleared in multiple myeloma by the proteasome–aggresome–autophagosome–lysosome pathway

K Sukhdeo, M Mani, T Hideshima, K Takada, V Pena-Cruz, G Mendez, S Ito, K C Anderson, D R Carrasco

Leukemia ( Springer Science and Business Media LLC ) 26 ( 5 ) 1116 - 1119 2012.05 [Refereed]

DOI

BCL9 Promotes Tumor Progression by Conferring Enhanced Proliferative, Metastatic, and Angiogenic Properties to Cancer Cells

Mala Mani, Daniel E. Carrasco, Yunyu Zhang, Kohichi Takada, Moshe E. Gatt, Jin Dutta-Simmons, Hiroshi Ikeda, Felipe Diaz-Griffero, Victor Pena-Cruz, Monica Bertagnolli, Lois L. Myeroff, Sanford D. Markowitz, Kenneth C. Anderson, Daniel R. Carrasco

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 69 ( 19 ) 7577 - 7586 2009.10 [Refereed]

Several components of the Writ signaling cascade have been shown to function either as tumor suppressor proteins or as oncogenes in multiple human cancers, underscoring the relevance of this pathway in oncogenesis and the need for further investigation of Wnt signaling components as potential targets for cancer therapy. Here, using expression profiling analysis as well as in vitro and in vivo functional studies,we show that the Writ pathway component BCL9 is a novel oncogene that is aberrantly expressed in human multiple myeloma as well as colon carcinoma. We show that BCL9 enhances beta-catenin-mediated transcriptional activity regardless of the mutational status of the Writ signaling components and increases cell proliferation, migration, invasion, and the metastatic potential of tumor cells by promoting loss of epithelial and gain of mesenchymal-like phenotype. Most importantly, BCL9 knockdown significantly increased the survival of xenograft mouse models of cancer by reducing tumor load, metastasis, and host angiogenesis through down-regulation of c-Myc, cyclin D1, CD44, and vascular endothelial growth factor expression by tumor cells. Together, these findings suggest that deregulation of BCL9 is an important contributing factor to tumor progression. The pleiotropic roles of BCL9 reported in this study underscore its value as a drug target for therapeutic intervention in several malignancies associated with aberrant Wnt signaling. [Cancer Res 2009;69(19):7577-86]

DOI PubMed

Aurora kinase A is a target of Wnt/beta-catenin involved in multiple myeloma disease progression

Jui Dutta-Simmons, Yunyu Zhang, Gullu Gorgun, Moshe Gatt, Mala Mani, Teru Hideshima, Kohichi Takada, Nicole E. Carlson, Daniel E. Carrasco, Yu-Tzu Tai, Noopur Raje, Anthony G. Letai, Kenneth C. Anderson, Daniel R. Carrasco

BLOOD ( AMER SOC HEMATOLOGY ) 114 ( 13 ) 2699 - 2708 2009.09 [Refereed]

Multiple myeloma (MM) is a cancer of plasma cells with complex molecular characteristics that evolves from monoclonal gammopathy of undetermined significance, a highly prevalent premalignant condition. MM is the second most frequent hematologic cancer in the United States, and it remains incurable, thereby highlighting the need for new therapeutic approaches, particularly those targeting common molecular pathways involved in disease progression and maintenance, shared across different MM subtypes. Here we report that Wnt/beta-catenin is one such pathway. We document the involvement of beta-catenin in cell-cycle regulation, proliferation, and invasion contributing to enhanced proliferative and metastatic properties of MM. The pleiotropic effects of beta-catenin in MM correlate with its transcriptional function, and we demonstrate regulation of a novel target gene, Aurora kinase A, implicating beta-catenin in G2/M regulation. beta-catenin and Aurora kinase A are present in most MM but not in normal plasma cells and are expressed in a pattern that parallels progression from monoclonal gammopathy of undetermined significance to MM. Our data provide evidence for a novel functional link between beta-catenin and Aurora kinase A, underscoring a critical role of these pathways in MM disease progression. (Blood. 2009; 114: 2699-2708)

DOI 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

Efficacy of eribulin monotherapy for bone marrow carcinomatosis of breast cancer in a patient with Werner syndrome.

Akihito Fujimi, Yasuhiro Nagamachi, Naofumi Yamauchi, Riku Hasebe, Naoki Onoyama, Naotaka Hayasaka, Teppei Matsuno, Kazuhiko Koike, Yoshiro Gotoh, Kohji Ihara, Junji Kato, Takuji Nishisato, Kazuyuki Murase, Goro Kutomi, Tokimasa Hida, Hisashi Uhara, Kohichi Takada

Geriatrics & gerontology international 2025.01 [Domestic journal]

DOI PubMed

Establishment and characterization of the novel myxofibrosarcoma cell line, SMU-MFS

Naoya Nakahashi, Makoto Emori, Kohichi Takada, Yasutaka Murahashi, Junya Shimizu, Kazuyuki Murase, Tomohide Tsukahara, Shintaro Sugita, Akira Takasawa, Kousuke Iba, Atsushi Teramoto, Makoto Osanai

Human Cell ( Springer Science and Business Media LLC ) 38 ( 1 ) 2024.12

DOI

Secondary Osteosarcoma After Carbon‐Ion Radiotherapy for Desmoid‐Type Fibromatosis: A Case Report

Mizuki Aketo, Makoto Emori, Kohichi Takada, Kazuyuki Murase, Yohei Arihara, Junya Shimizu, Yasutaka Murahashi, Masahiko Okamoto, Shintaro Sugita, Atsushi Teramoto

Cancer Reports ( Wiley ) 7 ( 11 ) 2024.11

ABSTRACT Background Radiotherapy is considered an alternative treatment for unresectable or pharmacologically resistant desmoid‐type fibromatosis. While it results in relatively good local control, the risk of secondary malignancy remains a concern. Case We present a case of secondary osteosarcoma after carbon‐ion radiation therapy (CIRT). A 31‐year‐old male patient presented with left thigh pain. The tumor was located between the left gluteus maximus and gluteus medius and extended to the vastus lateralis and biceps femoris. It was diagnosed as desmoid‐type fibromatosis after needle biopsy. The patient was treated with several medications, including a cyclooxygenase 2 inhibitor and tamoxifen; however, his left thigh pain did not improve. He was treated with CIRT 1 year after diagnosis (67.2 Gy [relative biological effectiveness] 16fr/4wks). He developed osteosarcoma of the left femur 8 years later. He underwent chemotherapy and tumor excision with disarticulation of the left hip. Pulmonary metastasis was detected 6 and 17 months after the definitive surgery and excised using metastasectomy. However, he died due to the recurrence of multiple pulmonary metastases 29 months after the definitive surgery. Conclusions In this case, we believe that the low radiation dose to the femur may have caused secondary malignancy.

DOI

Application of Single Cell Type-Derived Spheroids Generated by Using a Hanging Drop Culture Technique in Various In Vitro Disease Models: A Narrow Review.

Hiroshi Ohguro, Megumi Watanabe, Tatsuya Sato, Nami Nishikiori, Araya Umetsu, Megumi Higashide, Toshiyuki Yano, Hiromu Suzuki, Akihiro Miyazaki, Kohichi Takada, Hisashi Uhara, Masato Furuhashi, Fumihito Hikage

Cells 13 ( 18 ) 2024.09 [International journal]

Cell culture methods are indispensable strategies for studies in biological sciences and for drug discovery and testing. Most cell cultures have been developed using two-dimensional (2D) culture methods, but three-dimensional (3D) culture techniques enable the establishment of in vitro models that replicate various pathogenic conditions and they provide valuable insights into the pathophysiology of various diseases as well as more precise results in tests for drug efficacy. However, one difficulty in the use of 3D cultures is selection of the appropriate 3D cell culture technique for the study purpose among the various techniques ranging from the simplest single cell type-derived spheroid culture to the more sophisticated organoid cultures. In the simplest single cell type-derived spheroid cultures, there are also various scaffold-assisted methods such as hydrogel-assisted cultures, biofilm-assisted cultures, particle-assisted cultures, and magnet particle-assisted cultures, as well as non-assisted methods, such as static suspension cultures, floating cultures, and hanging drop cultures. Since each method can be differently influenced by various factors such as gravity force, buoyant force, centrifugal force, and magnetic force, in addition to non-physiological scaffolds, each method has its own advantages and disadvantages, and the methods have different suitable applications. We have been focusing on the use of a hanging drop culture method for modeling various non-cancerous and cancerous diseases because this technique is affected only by gravity force and buoyant force and is thus the simplest method among the various single cell type-derived spheroid culture methods. We have found that the biological natures of spheroids generated even by the simplest method of hanging drop cultures are completely different from those of 2D cultured cells. In this review, we focus on the biological aspects of single cell type-derived spheroid culture and its applications in in vitro models for various diseases.

DOI PubMed

切除不能または再発胆道癌に対するゲムシタビン/シスプラチン/S-1(GCS)療法とゲムシタビン/シスプラチン/デュルバルマブ(GCD)療法との比較検討

吉田真誠, 村松丈児, 石川和真, 高田弘一, 村瀬和幸, 大沼啓之, 柾木喜晴, 永島裕之, 宮西浩嗣

胆道 ( (一社)日本胆道学会 ) 38 ( 3 ) 421 - 421 2024.09

Novel method for assessing sinusoidal obstruction syndrome using four‐dimensional computed tomography

Saori Shimoyama‐Ibuki, Satoshi Iyama, Yoshiya Ohashi, Kento Ono, Yusuke Sugama, Chisa Fujita, Akari Goto, Hiroto Horiguchi, Akihito Fujimi, Takeo Tanaka, Kohichi Takada, Koh‐Ichi Sakata, Masayoshi Kobune

eJHaem ( Wiley ) 2024.07

Abstract Introduction To diagnose sinusoidal obstruction syndrome/veno‐occlusive disease (SOS/VOD), transabdominal ultrasonography is usually used to detect hemodynamic changes, but we tried to detect the changes using four‐dimensional computed tomography (4D‐CT). A 42‐year‐old Japanese woman was diagnosed with late‐onset SOS/VOD with transabdominal ultrasonography and was also assessed using 4D‐CT. Method We analyzed the portal vein (PV) contrast effect every 1.5 seconds and plotted the values of the contrast effect. With this graph, we analyzed three hemodynamic parameters. Result We found that these parameters correlated with the patient's status and indicated stasis due to sinusoid constriction. Conclusion 4D‐CT may become a helpful tool to diagnose and follow up with SOS/VOD.

DOI

Modulation of Epithelial-Mesenchymal Transition Is a Possible Underlying Mechanism for Inducing Chemoresistance in MIA PaCa-2 Cells against Gemcitabine and Paclitaxel.

Hajime Nakamura, Megumi Watanabe, Kohichi Takada, Tatsuya Sato, Fumihito Hikage, Araya Umetsu, Joji Muramatsu, Masato Furuhashi, Hiroshi Ohguro

Biomedicines 12 ( 5 ) 2024.05 [International journal]

To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and paclitaxel (PTX) in patients with pancreatic carcinoma, we examined two-dimensional (2D) and three-dimensional (3D) cultures of parent MIA PaCa-2 cells (MIA PaCa-2-PA) and their GEM resistance cell line (MIA PaCa-2-GR) and PTX resistance (MIA PaCa-2-PR). Using these cells, we examined 3D spheroid configurations and cellular metabolism, including mitochondrial and glycolytic functions, with a Seahorse bio-analyzer and RNA sequencing analysis. Compared to the MIA PaCa-2-PA, (1) the formation of the 3D spheroids of MIA PaCa-2-GR or -PR was much slower, and (2) their mitochondrial and glycolytic functions were greatly modulated in MIA PaCa-2-GR or -PR, and such metabolic changes were also different between their 2D and 3D culture conditions. RNA sequencing and bioinformatic analyses of the differentially expressed genes (DEGs) using an ingenuity pathway analysis (IPA) suggested that various modulatory factors related to epithelial -mesenchymal transition (EMT) including STAT3, GLI1, ZNF367, NKX3-2, ZIC2, IFIT2, HEY1 and FBLX, may be the possible upstream regulators and/or causal network master regulators responsible for the acquirement of drug resistance in MIA PaCa-2-GR and -PR. In addition, among the prominently altered DEGs (Log2 fold changes more than 6 or less than -6), FABP5, IQSEC3, and GASK1B were identified as unique genes associated with their antisense RNA or pseudogenes, and among these, FABP5 and GASK1B are known to function as modulators of cancerous EMT. Therefore, the observations reported herein suggest that modulations of cancerous EMT may be key molecular mechanisms that are responsible for inducing chemoresistance against GEM or PTX in MIA PaCa-2 cells.

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

O16-2 Phase I trial of NY-ESO-1 TCR-T cell therapy combined with nanoparticulate vaccine but without lymphodepletion for STS

Mikiya Ishihara, Yoshihiro Nishida, Shigehisa Kitano, Akira Kawai, Naozumi Harada, Yoshihiro Miyahara, Hiroyoshi Hattori, Kohichi Takada, Makoto Emori, Shigeki Kakunaga, Makoto Endo, Yoshihiro Matsumoto, Tetsuro Sasada, Eiichi Sato, Tomomi Yamada, Akihiko Matsumine, Yasuhiro Nagata, Shinichi Kageyama, Hiroshi Shiku

Annals of Oncology ( Elsevier BV ) 34 S1391 - S1391 2023.11

DOI

胆道癌に対して経皮経肝門脈塞栓術施行後に非切除であった症例の検討

村松丈児, 石川和真, 吉田真誠, 大沼啓之, 村瀬和幸, 高田弘一, 柾木喜晴, 齊藤正人, 今村将史, 宮西浩嗣

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 ) 133回・127回 42 - 42 2023.09

術前補助療法施行後の切除可能膵癌における術後早期再発予測因子の解析

齊藤聖也, 吉田真誠, 村松丈児, 石川和真, 柾木喜晴, 木村康利, 今村将史, 久保智洋, 村瀬和幸, 大沼啓之, 高田弘一, 宮西浩嗣, 加藤淳二

膵臓 ( (一社)日本膵臓学会 ) 38 ( 3 ) A446 - A446 2023.07

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

A Case of Atypical Pseudo-Meigs' Syndrome without Pleural Effusion due to Ovarian Metastasis from Sigmoid Colon Cancer

Ginji Omori, Yohei Arihara, Tomoyuki Abe, Kohichi Takada, Norito Suzuki, Ryo Shibuya, Yuki Ikeda, Michiko Yamada, Michihiro Ono, Miri Fujita, Shintaro Sugita, Masahiro Maeda

Internal Medicine ( Japanese Society of Internal Medicine ) 2023

DOI

Hilar/mediastinal and cutaneous drug-induced sarcoidosis-like reaction associated with immune checkpoint inhibitors in metastatic colorectal cancer: a case report.

Tamotsu Sagawa, Yasushi Sato, Hiroyuki Nagashima, Kohichi Takada, Mamoru Takahashi, Masahiro Hirakawa, Kyoko Hamaguchi, Fumito Tamura, Koshi Fujikawa, Koichi Okamoto, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto, Tetsuji Takayama

Frontiers in immunology 14 1203621 - 1203621 2023 [International journal]

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the standard treatment for metastatic colorectal cancer (mCRC) with high microsatellite instability (MSI-H). Among immune-related adverse events (irAEs), drug-induced sarcoidosis-like reactions (DISR) are often difficult to differentiate from cancer progression. MAIN BODY: This is a case of a woman in her mid-60s, with mCRC (RAS wild/BRAF mutant/MSI-H) and abdominal lymph node metastasis, treated with four courses of ipilimumab + nivolumab every 3 weeks, followed by nivolumab every 2 weeks as third-line treatment. After treatment, the original lymph node metastases shrank, but hilar/mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epithelioid granulomas without necrosis, indicating a sarcoidosis-like reaction. Fluorodeoxyglucose-positron emission tomography scan showed abnormal subcutaneous accumulation in bilateral forearms and bilateral knee joints. Biopsy of the cutaneous lesions was also performed, which revealed epithelioid granulomas. As the patient had no symptoms in other organs, no specific therapeutic intervention was administered. After the discontinuation of immunotherapy, the sarcoidosis-like reaction regressed without cancer relapse. CONCLUSIONS: Clinicians should be aware of the possibility of DISR as an irAE during the ICI treatment of mCRC. In suspected cases of DISR following ICI therapy, it is important to differentiate between cancer progression and DISR through histological diagnosis for the subsequent strategy, as radiological and serological findings are not definitive.

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

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

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

Metastatic neuroendocrine carcinoma of right adrenal gland successfully treated with laparoscopic adrenalectomy after multimodal therapy

Yusuke Yamagata, Takashige Abe, Naoya Iwahara, Kohichi Takada, Yasuhiro Hida, Emi Takakuwa, Hiroshi Kikuchi, Ryuji Matsumoto, Takahiro Osawa, Nobuo Shinohara

IJU Case Reports ( Wiley ) 2022.07

DOI

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

Primary cutaneous diffuse large B‐cell lymphoma, leg type, of the face that appeared on pre‐existing T‐cell pseudolymphoma clinically resembling actinic reticuloid

Yuna Hosokawa, Takafumi Kamiya, Shintaro Sugita, Tokimasa Hida, Kohichi Takada, Yasuyuki Sumikawa, Hiroyuki Takahashi, Hisashi Uhara

The Journal of Dermatology ( Wiley ) 2022.03

DOI

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 [Refereed]

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 [Refereed]

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 PubMed

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 [Refereed]

DOI

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 ) e04764 2021.09 [Refereed] [International journal]

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

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 ) 120 105287 - 105287 2021.04 [Refereed] [International journal]

DOI PubMed

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 ( Springer Science and Business Media LLC ) 479 ( 5 ) 1041 - 1046 2021.03 [Refereed] [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

Possible clinical outcomes using early enteral nutrition in individuals with allogeneic hematopoietic stem cell transplantation: A single-center retrospective study

Satoshi Iyama, Hiroomi Tatsumi, Tsukasa Shiraishi, Masahiro Yoshida, Ayumi Tatekoshi, Akihito Endo, Taichiro Ishige, Yuh Shiwa, Soushi Ibata, Akari Goto, Kana Nagashima, Hiroto Horiguchi, Chisa Fujita, Hiroshi Ikeda, Kohichi Takada, Takayuki Nobuoka, Yusuke Kamihara, Shohei Kikuchi, Tsutomu Sato, Hirofumi Ohnishi, Shin-ichi Yokota, Masayoshi Kobune

Nutrition ( Elsevier BV ) 83 111093 - 111093 2021.03 [Refereed]

DOI

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 [Refereed]

DOI

Acanthopanax senticosus Harms extract causes G0/G1 cell cycle arrest and autophagy via inhibition of Rubicon in human liver cancer cells

Yutaka Kawano, Maki Tanaka, Masaki Fujishima, Eri Okumura, Hideo Takekoshi, Kohichi Takada, Osamu Uehara, Yoshihiro Abiko, Hidekatsu Takeda

Oncology Reports ( Spandidos Publications ) 45 ( 3 ) 1193 - 1201 2021.01 [Refereed]

© 2021 Spandidos Publications. All rights reserved. Acanthopanax senticosus (Rupr. et Maxim) Harms (ASH), also known as Siberian ginseng or eleuthero, is a hardy shrub native to China, Korea, Russia and the northern region of Japan. ASH is used for the treatment of several diseases such as heart disease, hypertension, rheumatoid arthritis, allergies, chronic bronchitis, diabetes and cancer. In the present study, the inhibitory effect of the root extract of ASH (ASHE) on HuH-7 and HepG2 liver cancer cells was examined. ASHE suppressed liver cancer cell proliferation by inducing cell cycle arrest at the G0/G1 phase, as well as apoptosis, as indicated by the increased number of Annexin V and 7-AAD-positive cells. Furthermore, the expression of LC3-II, an autophagy marker, in these cells also increased post treatment with ASHE. LC3-II induction was further enhanced by co-treatment with chloroquine. Fluorescence and transmission electron micrographs of ASHE-treated liver cancer cells showed the presence of an increased number of autophagic vesicles. A decreased protein expression level of run domain Beclin-1-interacting and cysteine-rich domain-containing, an autophagy inhibitor, with no change in RUBCN mRNA expression was observed, indicating activation of the autophagosome-lysosome fusion step of autophagy. In conclusion, ASHE exerts cytostatic activity on liver cancer cells via both apoptosis and autophagy, and may serve as a potential therapeutic agent for management of liver cancer and autophagy-related diseases.

DOI

Cardiac Light Chain Deposition Disease Mimicking Immunoglobulin Light Chain Amyloidosis

Arata Osanami, Toshiyuki Yano, Genzou Takemura, Hiroshi Ikeda, Masafumi Inyaku, Yuki Toda, Naoyuki Kamiyama, Hirohito Sugawara, Yufu Gocho, Takefumi Fujito, Nobutaka Nagano, Satoko Takahashi, Atsuko Muranaka, Marenao Tanaka, Norihito Moniwa, Kazuyuki Murase, Kohichi Takada, Hiroyuki Kuroda, Yayoi Ogawa, Tetsuji Miura

Circulation: Cardiovascular Imaging ( Ovid Technologies (Wolters Kluwer Health) ) 13 ( 9 ) e010478 2020.09 [Refereed] [International journal]

DOI PubMed

Two cases of synchronous multicentric invasive ductal carcinomas of the pancreas

Yuki Ikeda, Makoto Yoshida, Kazuma Ishikawa, Kazuyuki Murase, Kohichi Takada, Koji Miyanishi, Ichiro Takemasa, Tadashi Hasegawa, Junji Kato

Gastroenterological Endoscopy ( Japan Gastroenterological Endoscopy Society ) 62 ( 7 ) 785 - 792 2020.07

Case 1: A 64-year-old female with obstructive jaundice, suggesting the presence of pancreatic head tumor, was admitted to our hospital. Enhanced computed tomography (CT) showed a pancreatic head mass, while endoscopic ultrasound (EUS) detected two masses (i.e., pancreatic head and body). Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was performed, and the two masses were identified as adenocarcinoma. The patient underwent subtotal stomach-preserving pancreatoduodenectomy. The pancreatic head and body masses were moderately and well differentiated adenocarcinoma, respectively. Case 2: A 78-year-old female was admitted to our hospital due to suspicion of a pancreatic body tumor. Enhanced CT showed a pancreatic tail mass, while EUS detected two masses (i.e., pancreatic body and tail). EUS-FNA was performed, and the two masses were identified as adenocarcinoma. The patient underwent distal pancreatectomy. Both masses were well differentiated adenocarcinoma, and could be distinguished histologically/ morphologically. The use of preoperative EUS-FNA is necessary to confirm the presence of multiple lesions in patients with initial detection of a pancreatic mass.

DOI

Acquired amegakaryocytic thrombocytopenic purpura possibly induced by anti-PD-1 antibody

Satoshi Iyama, K. Takada, M. Yoshida, D. Takahashi, M. Kobune

Annals of Hematology ( Springer Science and Business Media LLC ) 99 ( 7 ) 1669 - 1670 2020.07

DOI

粘液癌成分を伴った浸潤性膵管癌破裂の1切除例

久保智洋, 村松丈児, 吉田真誠, 木内隆之, 杉田真太朗, 奥田敏徳, 南伸弥, 村瀬和幸, 高田弘一, 宮西浩嗣, 長谷川匡, 加藤淳二

膵臓 ( (一社)日本膵臓学会 ) 35 ( 3 ) A437 - A437 2020.07

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 [Refereed]

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

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 ) 12 ( 5 ) 429 - 434 2020.02 [Refereed] [International journal]

The aim of the present study was to evaluate the survival impact of surgical resection among patients with pulmonary metastases from bone and soft tissue sarcomas. A total of 34 consecutive patients with ≤5 pulmonary metastases from bone and soft tissue sarcomas were retrospectively reviewed. The patients included 19 men and 15 women, with a median age of 64.0 years and a median follow-up of 14.5 months. The oncological outcome was compared between patients who underwent surgical and non-surgical treatment. A total of 22 patients underwent surgery and 12 patients did not undergo surgery. The surgery group had 3- and 5 year overall survival rates of 62 and 53%, respectively. None of the patients in the non-surgery group survived to 3 years. Compared with the non-surgery group, surgery achieved significantly better 3- and 5 year overall survival rates. Pulmonary metastasectomy was associated with significantly improved survival among patients who were aged <64 years (P=0.0155), as well as those who were aged ≥64 years (P=0.0444), which indicated that age was not associated with a difference in survival between the two groups. Therefore, pulmonary metastasectomy may improve the prognosis of patients with pulmonary metastases from bone and soft tissue sarcomas.

DOI PubMed

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 [Refereed]

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 [Refereed]

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 ( Spandidos Publications ) 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

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

Borderline Resectable膵癌に対する治療戦略

吉田真誠, 石川和真, 久保智洋, 伊藤亮, 村瀬和幸, 高田弘一, 宮西浩嗣, 加藤淳二, 本谷雅代, 柾木喜晴, 仲瀬裕志, 木村康利, 永山稔, 今村将史, 竹政伊知朗

日本癌治療学会学術集会抄録集 ( (一社)日本癌治療学会 ) 57回 SY15 - 4 2019.10

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 [Refereed]

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)

Spindle cell rhabdomyosarcoma in a lumbar vertebra with FUS-TFCP2 fusion

Yohei Tagami, Shintaro Sugita, Terufumi Kubo, Noriyuki Iesato, Makoto Emori, Kohichi Takada, Mitsuhiro Tsujiwaki, Keiko Segawa, Taro Sugawara, Tomoki Kikuchi, Tadashi Hasegawa

Pathology - Research and Practice ( Elsevier BV ) 215 ( 8 ) 152399 - 152399 2019.08 [Refereed] [International journal]

A 70-year-old woman developed severe buttock pain that progressed to a walking disturbance. Radiographs and computed tomography scans revealed an osteolytic lesion with osteosclerosis extending from the body to the arch of the fifth lumbar vertebra. Magnetic resonance imaging showed multinodular masses in the fifth lumbar vertebral body extending into the spinous processes and right transverse process. The masses were hypointense to isointense on T1-weighted images and hypointense to hyperintense on T2-weighted images. Histologic examination of biopsy specimens showed destruction of the trabecula of the vertebral bone by a fascicular and solid proliferation of spindle tumor cells and scattered rhabdomyoblasts, in a fibrotic background. The tumor cells were immunoreactive for keratins, vimentin, desmin, MyoD1, myogenin, and anaplastic lymphoma kinase. Fluorescence in situ hybridization detected split signals for FUS and TFCP2 in 80% and 64% of the tumor cells, respectively, suggesting FUS-TFCP2 fusion. Reverse transcription-polymerase chain reaction revealed a FUS-TFCP2 fusion. The final diagnosis was spindle cell rhabdomyosarcoma of a lumbar vertebra with a FUS-TFCP2 fusion. A spindle cell rhabdomyosarcoma with a FUS-TFCP2 fusion in a vertebral bone is rare and should be differentiated from metastatic carcinoma, particularly in the elderly.

DOI PubMed

Gastrointestinal Stromal Tumor in a Patient with Neurofibromatosis Type 1 That Was Successfully Treated with Regorafenib

Akihito Fujimi, Yasuhiro Nagamachi, Naofumi Yamauchi, Fumito Tamura, Tomohiro Kimura, Naoya Miyajima, Hidetoshi Inomata, Takuji Nishisato, Makoto Yoshida, Kohichi Takada, Ko Kobayashi, Junji Kato

Internal Medicine ( Japanese Society of Internal Medicine ) 58 ( 13 ) 1865 - 1870 2019.07 [Refereed]

DOI

Successful Treatment of Hepatocellular Carcinoma with Transcatheter Arterial Chemoembolization followed by Radical Liver Transplantation in a Patient with Severe Liver Damage

Hajime Nakamura, Yutaka Kawano, Koji Miyanishi, Kazuma Ishikawa, Tomohiro Kubo, Shingo Tanaka, Kohichi Takada, Masayoshi Kobune, Kohei Harada, Norio Kawamura, Tsuyoshi Shimamura, Hiromi Kanno-Okada, Junji Kato

Case Reports in Oncology ( S. Karger AG ) 12 ( 1 ) 289 - 296 2019.04 [Refereed]

Introduction: Liver transplantation for hepatocellular carcinoma (HCC) has been established as a curative therapy of underlying liver disease and cancer. However, the role of liver transplantation remains controversial for patients with HCC beyond Milan criteria. Case Presentation: A man in his 50s who was diagnosed as having two foci of HCC and advanced liver cirrhosis was referred to our hospital for further examination and treatment. Both foci of HCC were located in segment 8 of the liver and measured 39 and 9 mm. Endoscopy showed esophageal varices that had a high risk of bleeding. After endoscopic ligation of the esophageal varices, he underwent transcatheter arterial chemoembolization (TACE) for downstaging of the advanced HCCs. No further liver deterioration was observed after TACE, and HCC staging was successfully downstaged to within the Milan criteria. One hundred ten days after TACE, he underwent liver transplantation; at 2.5 years after transplantation, he remains alive without HCC recurrence. Discussion/Conclusion: There are only a few treatment options available for patients with advanced HCC and severe liver damage. Multidisciplinary treatment such as locoregional treatments and prophylaxis of variceal bleeding may result in tumor downstaging, enabling radical liver transplantation without further exacerbation of liver damage.

DOI

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 ( Public Library of Science (PLoS) ) 14 ( 3 ) e0213220 - 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

A case of small combined hepatocellular-cholangiocellular carcinoma

Takahiro Osuga, Koji Miyanishi, Shingo Tanaka, Hajime Nakamura, Hiroki Sakamoto, Hiroyuki Onuma, Kazuyuki Murase, Koichi Takada, Masayoshi Kobune, Junji Kato, Minoru Nagayama, Yasutoshi Kimura, Ichiro Takemasa, Mitsuhiro Tsujiwaki, Tadashi Hasegawa

Acta Hepatologica Japonica ( Japan Society of Hepatology ) 60 ( 8 ) 294 - 301 2019

A 56-year-old man who had been visiting our hospital for type B cirrhosis since 1988 was admitted for the treatment of hepatic tumor that was detected using an EOB-MRI study in July 2017. Blood test showed elevated aminotransferase and thrombocytopenia due to liver cirrhosis however, tumor markers were negative. In CT during angiography, CTAP showed low absorption, and CTHA showed heterogeneously high absorption. We diagnosed the tumor as hepatocellular carcinoma, followed by a laparoscopic partial resection of the liver. In 16 months after surgery, there was no recurrence. As per the pathological findings, the tumor consisted of (1) well-differentiated hepatocellular carcinoma component, (2) moderately-differentiated hepatocellular carcinoma component, (3) transitional portion between hepatocellular carcinoma and intrahepatic cholangiocarcinoma, and (4) intrahepatic cholangiocarcinoma component. Thus, the tumor was diagnosed as classical type combined hepatocellular-cholangiocellular carcinoma as per the WHO classification. It was suggested that dedifferentia-tion and transformation occurred in the untreated small hepatocellular carcinoma.

DOI

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 [Refereed] [International journal]

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 PubMed

Denosumab prevents bone loss in newly diagnosed malignant lymphoma patients undergoing corticosteroid-containing chemotherapy: A prospective, non-randomized study

Ayumi Tatekoshi, Tsutomu Sato, Satoshi Iyama, Kohichi Takada, Kazuyuki Murase, Masahiro Yoshida, Soushi Ibata, Akari Hashimoto, Yusuke Kamihara, Hiroto Horiguchi, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Sapporo Medical journal ( Sapporo Medical University ) 87 ( 1-6 ) 35 - 47 2018.12

Background: Malignant lymphoma patients have a high risk of bone mineral density (BMD) loss caused by corticosteroid-containing chemotherapy. Bisphosphonates have been used to prevent bone loss: however, little is known about effects of denosumab, a fully humanized monoclonal antibody inhibiting osteoclast-mediated bone resorption. Methods: This clinical trial was conducted in newly diagnosed lymphoma patients undergoing corticosteroidcontaining chemotherapy. BMD was evaluated at baseline, and patients with a lumbar spine T-score of < -1 were subcutaneously administered once with 60 mg of denosumab ("Denosumab" group). Patients with a T-score > -1 were allocated to the "No treatment" group. BMD was reevaluated at 24 weeks after enrollment. Bone turnover markers (BTMs) were collected at 0,2, and 24 weeks. Results: Forty-three patients were enrolled (19 in the "Denosumab" group and 24 in the "No treatment" group). Patients in the "No treatment" group had decreased T-scores for the lumbar spine or femoral neck (P < 0.0001 or P = 0.0029, respectively) at 24 weeks after enrollment, whereas both T-scores were stable in the "Denosumab" group. Of the 18 patients in the "Denosumab" group, 12 had a T-score change from baseline (AT-score) of > 0, whereas the remaining six patients had a AT-score < 0. These six patients had severely low T-scores at enrollment. Osteoclastic BTMs were strongly suppressed during the 24 weeks in the "Denosumab" group. The probability of major osteoporotic fracture or hip fracture in the "No treatment?' group increased during the 24 weeks (P = 0.0195 or P = 0.0289, respectively), whereas pretreatment with denosumab prevented increased risks of both types of fractures. Conclusions: Our data suggests that BMD screening at diagnosis of lymphoma should be considered so that the bone health of lymphoma survivors can be improved with denosumab.

DOI

An intronic single nucleotide polymorphism in the MUTYH gene is associated with increased risk for HCV-induced hepatocellular carcinoma.

Akira Sakurada, Koji Miyanishi, Shingo Tanaka, Masanori Sato, Hiroki Sakamoto, Yutaka Kawano, Kohichi Takada, Yusaku Nakabeppu, Masayoshi Kobune, Junji Kato

Free radical biology & medicine 129 88 - 96 2018.12 [Refereed] [International journal]

BACKGROUND & AIMS: The role of base excision repair genes in human hepatocarcinogenesis has not yet been explored. Here, we investigated relationships between variants of these genes and the risk of developing hepatocellular carcinoma (HCC). METHODS: Nineteen tagging SNPs in base excision repair genes (including MUTYH, OGG1 and MTH1) were genotyped using iPLEX assays; one significant SNP was found and confirmed in Japanese patients with chronic hepatitis C (CHC) (n = 38 HCC and 55 controls). The effects of modifying the intronic variants were determined by luciferase assays. MUTYH-null mice were used to examine the involvement of oxidative stress and DNA repair enzymes in hepatocarcinogenesis. RESULTS: Significant associations were found for a single intron SNP (rs3219487) in the MUTYH gene. The risk of developing HCC in patients with A/A or G/A genotypes was higher than in those with the G/G genotype (OR = 9.27, 95% CI = 2.39 -32.1, P = 0.0005). MUTYH mRNA levels in both peripheral mononuclear cells were significantly lower in G/A or A/A genotyped subjects (P = 0.0157 and 0.0108, respectively). We found that -2000 in the MUTYH promoter region is involved in enhanced expression of MUTYH by insertion of a major allele sequence of rs3219487. Liver tumors were observed in MUTYH-null mice after 12 months´ high iron diet, but no tumors developed when dietary anti-oxidant (N-Acetyl-L-cysteine) was also provided. CONCLUSIONS: CHC patients with the rs3219487 adenine allele had a significantly increased risk of developing HCC. MUTYH-null mice with iron-associated oxidative stress were susceptible to development of liver tumors unless prevented by dietary anti-oxidants.

DOI PubMed

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 ) 26 ( 5 ) 926 - 930 2018.12 [Refereed] [Domestic journal]

DOI PubMed

Halo formations around senile hemangiomas in diffuse plane normolipemic xanthomatosis associated with monoclonal gammopathy.

Tokimasa Hida, Hiroki Takahashi, Kohichi Takada, Hisashi Uhara

JAAD case reports 4 ( 10 ) 1034 - 1036 2018.11 [Refereed] [International journal]

DOI PubMed

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 [Refereed]

DOI

Increased Duodenal Iron Absorption through Upregulation of Ferroportin 1 due to the Decrement in Serum Hepcidin in Patients with Chronic Hepatitis C.

Masanori Sato, Koji Miyanishi, Shingo Tanaka, Akira Sakurada, Hiroki Sakamoto, Yutaka Kawano, Kohichi Takada, Masayoshi Kobune, Junji Kato

Canadian journal of gastroenterology & hepatology 2018 2154361 - 2154361 2018 [Refereed] [International journal]

Hepatic iron accumulation is generally increased in the chronic hepatitis C (CHC) liver; however, the precise mechanism of such accumulation remains unclear. We evaluated iron absorption from the gastrointestinal tract of patients with CHC and control participants. We measured the expression of a panel of molecules associated with duodenal iron absorption and serum hepcidin levels to determine the mechanism of iron accumulation in the CHC liver. We enrolled 24 patients with CHC and 9 patients with chronic gastritis without Helicobacter pylori infection or an iron metabolism disorder as control participants. An oral iron absorption test (OIAT) was administered which involved a dosage of 100 mg of sodium ferrous citrate. Serum level of hepcidin-25 was measured by liquid chromatography-tandem mass spectrometry. Ferroportin 1 (FPN) mRNA was measured by RT-PCR and FPN protein was analyzed by western blot. Samples were obtained from duodenum biopsy tissue from each CHC patient and control participant. Caco-2/TC7 cells were incubated in Costar transwells (0.4 μm pores). The OIAT showed significantly greater iron absorption in CHC patients than control participants. Serum hepcidin-25 in the CHC group was significantly lower than in the control group. Compared with control participants, duodenal FPN mRNA expression in CHC patients was significantly upregulated. The FPN mRNA levels and protein levels increased significantly in Caco-2/TC7 cell monolayers cultured in transwells with hepcidin. Lower serum hepcidin-25 levels might upregulate not only FPN protein expression but also mRNA expression in the duodenum and cause iron accumulation in patients with CHC.

DOI PubMed

ART療法中に多発血栓症を併発した悪性リンパ腫患者の一例

池田博, 吉田正宏, 舘越鮎美, 菊地尚平, 村瀬和幸, 高田弘一, 井山諭, 小船雅義, 村上則子, 宮越郁子, 又村了輔, 國本雄介, 加藤淳二

日本エイズ学会誌 ( (一社)日本エイズ学会 ) 19 ( 4 ) 501 - 501 2017.11

A phase II study of modified docetaxel, cisplatin, and S-1 (mDCS) chemotherapy for unresectable advanced gastric cancer.

Naoki Uemura, Shohei Kikuchi, Yasushi Sato, Hiroyuki Ohnuma, Koichi Okamoto, Hiroshi Miyamoto, Masahiro Hirakawa, Tamotsu Sagawa, Koshi Fujikawa, Yasuo Takahashi, Toshinori Okuda, Shinya Minami, Minoru Takahashi, Tetsuro Okamoto, Kohichi Takada, Koji Miyanisi, Tetsuji Takayama, Junji Kato

Cancer chemotherapy and pharmacology ( Springer Science and Business Media LLC ) 80 ( 4 ) 707 - 713 2017.10 [Refereed] [International journal]

PURPOSE: Triplet therapy using docetaxel, cisplatin, and S-1 (DCS) against unresectable gastric cancer as previously reported by us showed high clinical efficacy, with a 87.1% total response rate; however, it also showed a high incidence of grade 3/4 toxicity. With the aim of reducing toxicities, we conducted a phase II study of modified DCS (mDCS), using a reduced dose of docetaxel, and evaluated the clinical efficacy and adverse events of this regimen. METHODS: Patients with unresectable gastric cancer received chemotherapy with S-1 (40 mg/m2 b.i.d) on days 1-14, and docetaxel (50 mg/m2) plus cisplatin (60 mg/m2) on day 8 every 3 weeks. The primary endpoint was the response rate (RR). Overall (OS) and progression-free survival (PFS), and toxicities were also evaluated. RESULTS: Forty-nine patients were enrolled from November 2011 to April 2014, and 43 were eligible. The overall RR was 79.1%, including two cases of a complete response (4.7%), and 32 cases of a partial response (74.4%). Nine cases had stable disease (20.9%) but none showed progressive disease. Of the 43 cases, 15 cases (34.9%) underwent curative conversion surgery. The median PFS was 350 days (95% CI 240-416 days) and median OS was 722 days (95% CI 411 days-not reached). Grade 3/4 neutropenia developed in 79.1%, and febrile neutropenia in 34.9%, of patients. Non-hematological grade 3/4 adverse events were anorexia (25.6%), nausea (4.7%), and diarrhea (9.3%). CONCLUSION: Modified DCS therapy showed high clinical efficacy sufficient enough to attempt conversion therapy against unresectable gastric cancer. Modified DCS showed fewer toxicities, but careful management of these is still essential.

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

Hepatitis C virus reactivation due to antiemetic steroid therapy during treatment of hepatocellular carcinoma

Yutaka Kawano, Koji Miyanishi, Satoshi Takahashi, Tomohiro Kubo, Kazuma Ishikawa, Shintaro Sugita, Kohichi Takada, Masayoshi Kobune, Tadashi Hasegawa, Junji Kato

JOURNAL OF INFECTION AND CHEMOTHERAPY ( ELSEVIER SCIENCE BV ) 23 ( 5-6 ) 323 - 325 2017.05 [Refereed]

Hepatitis C virus (HCV) reactivation is relatively rare compared with hepatitis B reactivation in patients treated with immunosuppressive or anticancer drugs. Here, we present the first case of genotype 2 HCV reactivation due to antiemetic steroid therapy during chemotherapy for hepatocellular carcinoma (HCC), which was verified by not only increased viral load but also pathological exacerbation of liver injury during HCV reactivation. Further chemotherapy for HCC could be continued without steroid therapy. This present case highlights the awareness of HCV reactivation and the management of complex situation. (C) 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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]

A case of intussusceptions at two parts of the ileum caused by an ileus tube

Yutaka Okagawa, Kohichi Takada, Hiroki Sakamoto, Takumi Miura, Shigeki Abeshima, Junji Kato

Journal of Japanese Society of Gastroenterology ( Japanese Society of Gastroenterology ) 114 ( 6 ) 1001 - 1007 2017 [Refereed]

An 87-year-old woman was admitted to our hospital for paralytic ileus, and she was treated using an ileus tube. Although her symptoms improved, abdominal fullness developed again on day 3 after ileus tube insertion. Abdominal computed tomography indicated intussusceptions at the ileum and the terminal part of the ileum therefore, an emergency surgery was performed. During the surgery, antegrade intussusceptions were found in the ileum 60cm from the ileocecal valve and the terminal part of the ileum into the ascending colon. The intussusception of the anal side was resolved by manual reduction, but the oral side needed a partial resection of small bowel because of the presence of necrosis. There were no lesions, such as tumors, at the intussusceptions sites. Therefore, the two intussusceptions were thought to be caused by the ileus tube. We diagnosed a rare case of intussusceptions in the two parts of the ileum as a complication of the placement of an ileus tube.

PubMed

A case of gastric perforation caused by chestnut bezoars

OKAGAWA Yutaka, TAKADA Kohichi, ARIHARA Yohei, KATO Junji

Nippon Shokakibyo Gakkai Zasshi ( The Japanese Society of Gastroenterology ) 114 ( 10 ) 1830 - 1835 2017

A 65-year-old man was admitted under emergency to our hospital because of abdominal pain. His current medication history did not include steroids or nonsteroidal antiinflammatory drugs. He had taken an eradication agent for Helicobacter pylori, and his serum was negative for H. pylori IgG antibody. Abdominal computed tomography indicated gastric perforation;therefore, emergency surgery was performed. Two weeks later, esophagogastroduodenoscopy revealed a gastric ulcer on the lesser curvature of the gastric angle and bezoars. The gastric perforation was thought to be caused by the bezoars. The bezoars were successfully treated with endoscopic therapy using Coca-Cola^®. The bezoars included over 98% tannin, and the patient had frequently consumed chestnuts. We thus diagnosed a rare case of gastric perforation caused by chestnut bezoars.

DOI CiNii

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

Relationship Between Increased Fucosylation and Metastatic Potential in Colorectal Cancer

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

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE ( OXFORD UNIV PRESS INC ) 108 ( 9 ) 2016.09 [Refereed]

Background: Fucose is utilized for the modification of different molecules involved in blood group determination, immunological reactions, and signal transduction pathways. We have recently reported that enhanced activity of the fucosyltransferase 3 and/or 6 promoted TGF-beta-mediated epithelial mesenchymal transition and was associated with increased metastatic potential of colorectal cancer (CRC), suggesting that fucose is required by CRC cells. With this in mind, we examined requirement of L-fucose in CRC cells and developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specific to CRC. Methods: In this study, we first examined the expression of fucosylated proteins in 50cases of CRC by immunochistochemical staining with biotinylated Aleuria aurantia lectin (AAL). Then we carried out an L-fucose uptake assay using three CRC cell lines. Finally, we developed fucose-bound nanoparticles as vehicles for the delivery of an anticancer drug, SN38, and examined tumor growth inhibition in mouse xenograft model (n = 6 mice per group). All statistical tests were two-sided. Results: We found a statistically significant relationship between vascular invasion, clinical stage, and intensity score of AAL staining (P <= .02). L-fucose uptake assay revealed that L-fucose incorporation, as well as fucosylated protein release, was high in cells rich in fucosylated proteins. L-fucose-bound liposomes effectively delivered Cy5.5 into CRC cells. The excess of L-fucose decreased the efficiency of Cy5.5 uptake through L-fucose-bound liposomes, suggesting an L-fucose receptor dependency. Intravenously injected, L-fucose-bound liposomes carrying SN38 were successfully delivered to CRC cells, mediating efficient tumor growth inhibition (relative tumor growth ratio: no treatment group [NT], 8.29 +/- 3.09; SN38-treated group [SN38], 3.53 +/- 1.47; liposome-carrying, SN38-treated group [F0], 3.1 +/- 1.39; L-fucose-bound, liposome-carrying, SN38-treated group [F50], 0.94 +/- 0.89; F50 vs NT, P = .003; F50 vs SN38, P = .02, F50 vs F0, P = .04), as well as prolonging survival of mouse xenograft models (log-rank test, P < .001). Conclusions: Thus, fucose-bound liposomes carrying anticancer drugs provide a new strategy for the treatment of CRC patients.

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

Relationship Between Increased Fucosylation and Metastatic Potential in Colorectal Cancer

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE ( OXFORD UNIV PRESS INC ) 108 ( 8 ) 2016.08 [Refereed]

Background: Fucose is utilized for the modification of different molecules involved in blood group determination, immunological reactions, and signal transduction pathways. We have recently reported that enhanced activity of the fucosyltransferase 3 and/or 6 promoted TGF-beta-mediated epithelial mesenchymal transition and was associated with increased metastatic potential of colorectal cancer (CRC), suggesting that fucose is required by CRC cells. With this in mind, we examined requirement of L-fucose in CRC cells and developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specific to CRC. Methods: In this study, we first examined the expression of fucosylated proteins in 50 cases of CRC by immunochistochemical staining with biotinylated Aleuria aurantia lectin (AAL). Then we carried out an L-fucose uptake assay using three CRC cell lines. Finally, we developed fucose-bound nanoparticles as vehicles for the delivery of an anticancer drug, SN38, and examined tumor growth inhibition in mouse xenograft model (n = 6 mice per group). All statistical tests were two-sided. Results: We found a statistically significant relationship between vascular invasion, clinical stage, and intensity score of AAL staining (P <= .02). L-fucose uptake assay revealed that L-fucose incorporation, as well as fucosylated protein release, was high in cells rich in fucosylated proteins. L-fucose-bound liposomes effectively delivered Cy5.5 into CRC cells. The excess of L-fucose decreased the efficiency of Cy5.5 uptake through L-fucose-bound liposomes, suggesting an L-fucose receptor dependency. Intravenously injected, L-fucose-bound liposomes carrying SN38 were successfully delivered to CRC cells, mediating efficient tumor growth inhibition (relative tumor growth ratio: no treatment group [NT], 8.29 +/- 3.09; SN38-treated group [SN38], 3.53 +/- 1.47; liposome-carrying, SN38-treated group [F0], 3.1 +/- 1.39; L-fucose-bound, liposome-carrying, SN38-treated group [F50], 0.94 +/- 0.89; F50 vs NT, P = .003; F50 vs SN38, P = .02, F50 vs F0, P = .04), as well as prolonging survival of mouse xenograft models (log-rank test, P < .001). Conclusions: Thus, fucose-bound liposomes carrying anticancer drugs provide a new strategy for the treatment of CRC patients.

DOI PubMed

Targeting Notch-1 positive acute leukemia cells by novel fucose-bound liposomes carrying daunorubicin.

Michihiro Ono, Rishu Takimoto, Takahiro Osuga, Yutaka Okagawa, Masahiro Hirakawa, Makoto Yoshida, Yohei Arihara, Naoki Uemura, Naoki Hayasaka, Shogo Miura, Teppei Matsuno, Fumito Tamura, Yasushi Sato, Tsutomu Sato, Satoshi Iyama, Koji Miyanishi, Kohichi Takada, Masayoshi Kobune, Junji Kato

Oncotarget 7 ( 25 ) 38586 - 38597 2016.06 [Refereed] [International journal]

Complete remission by induction therapy in acute myelogenous leukemia (AML) can be achieved due to improvements in supportive and optimized therapy. However, more than 20% of patients will still need to undergo salvage therapy, and most will have a poor prognosis. Determining the specificity of drugs to leukemia cells is important since this will maximize the dose of chemotherapeutic agents that can be administered to AML patients. In turn, this would be expected to lead to reduced drug toxicity and its increased efficacy. We targeted Notch-1 positive AML cells utilizing fucose-bound liposomes, since activation of Notch-1 is required for O-fucosylation. Herein, we report that intravenously injected, L-fucose-bound liposomes containing daunorubicin can be successfully delivered to AML cells that express fucosylated antigens. This resulted in efficient tumor growth inhibition in tumor-bearing mice and decreased proliferation of AML patient-derived leukemia cells. Thus, biological targeting by fucose-bound liposomes that takes advantage of the intrinsic characteristics of AML cells could be a promising new strategy for Notch-1 positive-AML treatment.

DOI 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 ( Public Library of Science (PLoS) ) 11 ( 3 ) e0152823 - 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 J-GLOBAL

Erdheim-Chester Disease Involving the Central Nervous System with the Unique Appearance of a Coated Vertebral Artery

Hime Suzuki, Masahiko Wanibuchi, Katsuya Komatsu, Yukinori Akiyama, Takeshi Mikami, Shintaro Sugita, Tadashi Hasegawa, Mitsunori Kaya, Kohichi Takada, Nobuhiro Mikuni

NMC Case Report Journal ( Japan Neurosurgical Society ) 3 ( 4 ) 125 - 128 2016 [Refereed] [Domestic journal]

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. It is characterized by multiple xanthogranulomatous masses throughout the body, predominantly in the tibia. One of the characteristic radiological findings of the lesions associated with ECD is a "coated artery," which is often observed in the aorta. Although approximately one-fourth of ECD cases involve the central nervous system (CNS), an intracranial-coated artery has only been reported in four cases. We report a case of ECD that involves the CNS and has the unique appearance of a coated vertebral artery (VA). These tumors entirely encase the bilateral VAs without stenosis and are attached to the dura. Cranial magnetic resonance imaging also showed multiple extra-axial tumors in the cavernous sinus, the frontal convexity, and the orbital cavity. Further investigation revealed additional extracranial lesions around the cervical carotid artery, at the bilateral tibia, and at the elbow joint. A biopsy of the cervical and tibial lesions confirmed ECD. Steroid therapy resulted in a month-long improvement of preoperative symptoms. However, the patient's condition gradually progressed and he died of pneumonia 1 year after ECD diagnosis. The encasement of the intracranial artery by the tumor without stenosis and the dural attachment suggest ECD, which requires whole body investigation.

DOI PubMed

集学的治療により救命し得たClostridium perfringens感染症による肝膿瘍の2例

久保智洋, 宮西浩嗣, 河野豊, 桜田晃, 石川和真, 佐藤昌則, 保木寿文, 高田弘一, 佐藤康史, 瀧本理修, 小船雅義, 加藤淳二

肝臓 ( (一社)日本肝臓学会 ) 56 ( Suppl.3 ) A1063 - A1063 2015.11 [Refereed]

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

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 ( Springer Japan ) 19 ( 3 ) 827 - 838 2015.10 [Refereed]

DOI PubMed CiNii

Increased duodenal iron absorption through up-regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis

Toshifumi Hoki, Koji Miyanishi, Shingo Tanaka, Kohichi Takada, Yutaka Kawano, Akira Sakurada, Masanori Sato, Tomohiro Kubo, Tsutomu Sato, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Junji Kato

HEPATOLOGY ( WILEY-BLACKWELL ) 62 ( 3 ) 751 - 761 2015.09 [Refereed]

Increased hepatic iron accumulation is thought to be involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Hepatic iron accumulation, as well as oxidative DNA damage, is significantly increased in NASH livers. However, the precise mechanism of iron accumulation in the NASH liver remains unclear. In this study, 40 cases with a diagnosis of NASH (n=25) or simple steatosis (SS; n=15) by liver biopsy were enrolled. An oral iron absorption test (OIAT) was used, in which 100 mg of sodium ferrous citrate was administered to each individual. The OIAT showed that absorption of iron from the gastrointestinal (GI) tract was increased significantly in NASH patients, compared to SS and control subjects. Iron reduction therapy was effective in patients with NASH, who exhibited iron deposition in the liver and no alanine aminotransferase improvement after other therapies (n=9). Serum hepcidin concentration and messenger RNA (mRNA) levels of divalent metal transporter 1 (DMT1) also were significantly elevated in patients with NASH. OIAT results were correlated with grade of liver iron accumulation and DMT1 mRNA levels. Then, we demonstrated that DMT1 mRNA levels increased significantly in Caco-2/TC7 cell monolayers cultured in transwells with serum from NASH patients. An electrophoresis mobility shift assay showed activation of iron regulatory protein (IRP) in those cells, and IRP1 small interfering RNA clearly inhibited the increase of DMT1 mRNA levels. Conclusion: In spite of elevation of serum hepcidin, iron absorption from the GI tract increased through up-regulation of DMT1 by IRP1 activation by humoral factor(s) in sera of patients with NASH. (Hepatology 2015) Hepatology 2015;62:751-761)

DOI PubMed

A long-term survival case of hepatic epithelioid hemangioendothelioma with lung metastases treated with recombinant interleukin-2

Toshifumi Hoki, Koji Miyanishi, Yutaka Kawano, Shota Yamada, Kohei Harada, Masahiro Hirakawa, Fumito Tamura, Kazuma Ishikawa, Kohichi Takada, Tsutomu Sato, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Tadashi Hasegawa, Junji Kato

Acta Hepatologica Japonica ( Japan Society of Hepatology ) 56 ( 7 ) 356 - 365 2015.07 [Refereed]

A 37-year-old woman was found in a medical checkup to have liver dysfunction. Abdominal CT scan im-ages demonstrated multiple liver tumors. She was referred to our hospital for examination and treatment. Ab-dominal enhanced CT scan images showed irregularly spreading hypovascular tumors located in the surface of both hepatic lobes. Needle liver biopsy revealed many atypical cells with positive staining for factor VIII-related-antigen and CD34. The tumor was diagnosed as an hepatic epithelioid hemangioendothelioma (HEHE). She has received intravenous administration of recombinant interleukin-2 (rIL-2) for six years with a reduction in tumor volume. HEHE is a rare tumor which has low malignant potential, also is often unresectable due to multifocal tumors involving both hepatic lobes at the time of diagnosis. There was no generally accepted therapy except surgical resection and liver transplantation. The long-term survival observed in the present case may indicate the effectiveness of rIL-2 for HEHE.

DOI

Recombinant interleukin-2を投与し6年間経過観察している肺転移を伴う肝類上皮血管内皮腫の1例

保木寿文, 宮西浩嗣, 河野豊, 山田尚太, 原田耕平, 平川昌宏, 田村文人, 石川和真, 高田弘一, 佐藤勉, 佐藤康史, 瀧本理修, 小船雅義, 長谷川匡, 加藤淳二

肝臓 ( (一社)日本肝臓学会 ) 56 ( 7 ) 356 - 365 2015.07 [Refereed]

症例は37歳女性。2009年1月、健診で肝機能障害を指摘され近医を受診し、単純CTにて肝および肺に多発結節病変を認められたため精査加療目的に当科紹介となった。造影CTでは肝被膜下を中心に境界明瞭な低吸収域が多発し癒合している所見を肝両葉に認めた。肝生検で豊富な硝子様の線維性間質内に腫瘍細胞を認め、免疫染色にて第VIII因子関連抗原、CD34陽性であり肝原発の類上皮血管内皮腫(hepatic epithelioid hemangioendothelioma:HEHE)と診断した。同年4月よりrecombinant interleukin-2(rIL-2)の投与を開始し、6年間外来通院にて治療を継続し、病変体積の減少が得られている。HEHEの生物学的悪性度は低いとされるが、既に腫瘍が肝全体を占めるように多発した切除不能例として発見されることが多い。本疾患の長期間の臨床経過を示した報告が少ないことから、本症例について報告する。(著者抄録)

A case of primary testicular diffuse large B-cell lymphoma with a p53 gene point mutation

Makoto Usami, Hiroyuki Kuroda, Saori Shimoyama, Masahiro Yoshida, Michiko Yamada, Tomoyuki Abe, Tamaki Sakurai, Shigeyuki Fujii, Masahiro Maeda, Yosuke Wakabayashi, Kenichi Tsukamoto, Miri Fujita, Yusuke Kanari, Koichi Takada, Junji Kato

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. ) 42 ( 5 ) 613 - 616 2015.05

A 52-year-old man with bilateral swelling in the scrotum was referred to the department of urology in our hospital in January 2013. Pathological examination of the scrotum revealed diffuse large B-cell lymphoma (DLBCL). Immunohistochemical staining revealed p53 overexpression, and polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) revealed a point mutation in exon 7 of the p53 gene. Rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone (R-CHOP) therapy and intrathecal prophylaxis were initiated. After three courses of R-CHOP therapy, high-dose cytarabine was administered, followed by peripheral blood stem cell harvesting. Busulfan, etoposide, and Ara-C (BEA) therapy was then administered, followed by autologous peripheral blood stem cell transplantation (auto-PBSCT). Primary testicular lymphoma (PTL) is a rare, clinically aggressive form of extranodal lymphoma, and there is a high incidence rate of relapse in the central nervous system (CNS). The vast majority of cases are histologically DLBCL. The p53 mutation is an independent marker of poor prognosis in patients with DLBCL treated with R-CHOP therapy. Our patient has been disease free for 17 months after auto-PBSCT with high-dose chemotherapy, which results in a greater level of penetration into the CNS.

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

[Therapy-related myelodysplastic syndrome as a late adverse event of definitive chemoradiotherapy for esophageal and oropharyngeal cancer].

Kamihara Y, Sato Y, Takada K, Okagawa Y, Iyama S, Sato T, Miyanishi K, Takimoto R, Kobune M, Kato J

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 112 ( 9 ) 1664 - 1673 2015 [Refereed]

DOI PubMed

Markers of bone metabolism in multiple myeloma patients switched from zoledronic acid to denosumab.

Tatekoshi A, Sato T, Ibata S, Hashimoto A, Kamihara Y, Horiguchi H, Ono K, Takada K, Iyama S, Takimoto R, Kobune M, Kato J

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 11 ) 55 ( 11 ) 2271 - 2276 2014.11 [Refereed]

To date, intravenous drip infusion of zoledronic acid (ZA) has mainly been used for the treatment and prevention of skeletal-related events (SRE) in patients with multiple myeloma (MM). Recently, denosumab, a fully humanized monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL), has also become available for the same purpose, but little is known about the impact of switching from ZA to denosumab. Herein, we present a retrospective study on bone metabolic markers in 10 MM patients initially treated with ZA and then switched to denosumab. Consequently, the levels of bone resorption markers, tartrate-resistant acid phosphatase 5b (TRACP-5b) and serum type-I collagen crosslinked N-telopeptide (sNTX), significantly decreased after denosumab treatment, while the levels of bone formation markers, osteocalcin (OC) and bone-specific alkaline phosphatase (BAP), showed no apparent changes. No patient developed severe hypocalcemia with denosumab treatment. In one patient not given chemotherapy, the M-protein level increased after switching from ZA to denosumab and plateaued when ZA was restarted. Based on this finding, we anticipate that switching from ZA to denosumab would exert a stronger suppressive effect on osteoclasts, but the anti-myeloma activity of ZA must be taken into consideration.

DOI PubMed CiNii

Anti-erythropoietin receptor antibody-associated pure red cell aplasia accompanied by Coombs-negative autoimmune hemolytic anemia in a patient with T cell/histiocyte-rich large B cell lymphoma.

Fujimi A, Kamihara Y, Kanisawa Y, Hashimoto A, Nakajima C, Hayasaka N, Uemura N, Okuda T, Minami S, Iyama S, Takada K, Sato T, Hara A, Iwata Y, Furuichi K, Wada T, Kato J

International journal of hematology ( Springer Science and Business Media LLC ) 100 ( 5 ) 490 - 493 2014.11 [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

Clinical utility of capsule endoscopy with flexible spectral imaging color enhancement for diagnosis of small bowel lesions.

Sato Y, Sagawa T, Hirakawa M, Ohnuma H, Osuga T, Okagawa Y, Tamura F, Horiguchi H, Takada K, Hayashi T, Sato T, Miyanishi K, Takimoto R, Kobune M, Kato J

Endoscopy international open 2 ( 2 ) E80 - 7 2014.06 [Refereed]

DOI PubMed

Efficacy of enteral supplementation enriched with glutamine, fiber, and oligosaccharide on mucosal injury following hematopoietic stem cell transplantation

Satoshi Iyama, Tsutomu Sato, Hiroomi Tatsumi, Akari Hashimoto, Ayumi Tatekoshi, Yusuke Kamihara, Hiroto Horiguchi, Soushi Ibata, Kaoru Ono, Kazuyuki Murase, Kohichi Takada, Yasushi Sato, Tsuyoshi Hayashi, Koji Miyanishi, Emi Akizuki, Takayuki Nobuoka, Toru Mizugichi, Rishu Takimoto, Masayoshi Kobune, Koichi Hirata, Junji Kato

Case Reports in Oncology ( S. Karger AG ) 7 ( 3 ) 692 - 699 2014.04 [Refereed]

The combination of glutamine, fiber and oligosaccharides (GFO) is thought to be beneficial for alleviating gastrointestinal mucosal damage caused by chemotherapy. A commercial enteral supplementation product (GFO) enriched with these 3 components is available in Japan. We performed a retrospective study to test whether oral GFO decreased the severity of mucosal injury following hematopoietic stem cell transplantation (HSCT). Of 44 HSCT patients, 22 received GFO and 22 did not. Severity of diarrhea/mucositis, overall survival, weight loss, febrile illness/documented infection, intravenous hyperalimentation days/hospital days, engraftment, acute and chronic GVHD, and cumulative incidence of relapse were studied. Sex, age, performance status, diagnosis, disease status, and treatment variables were similar in both groups. There were fewer days of diarrhea grade 3-4 in patients receiving GFO than in those who did not (0.86 vs. 3.27 days) the same was true for days of mucositis grade 3-4 (3.86 vs. 6.00 days). Survival at day 100 was 100% in the GFO group, but only 77.3% for the patients not receiving GFO (p = 0.0091, log-rank test). Weight loss and the number of days of intravenous hyperalimentation were better in the GFO group (p < 0.001 and p = 0.0014, respectively). Although not significant, less gut bacterial translocation with Enterococcus species developed in the GFO group (p = 0.0728) than in the non-GFO group. Other outcomes were not affected. To the best of our knowledge, this is the first comparative clinical study of GFO supplementation to alleviate mucosal injury after allo-HSCT. We conclude that glutamine, fiber and oligosaccharide supplementation is an effective supportive therapy to decrease the severity of mucosal damage in HSCT.

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

Radiation-induced leiomyosarcoma of the prostate after brachytherapy for prostatic adenocarcinoma

Hiroto Horiguchi, Kohichi Takada, Yusuke Kamihara, Soushi Ibata, Satoshi Iyama, Tsutomu Sato, Tsuyoshi Hayashi, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Ko Kobayashi, Yasuo Hirayama, Naoya Masumori, Tadashi Hasegawa, Junji Kato

Case Reports in Oncology ( S. Karger AG ) 7 ( 2 ) 565 - 570 2014.03 [Refereed]

Radiation therapy (RTx) has been employed as a curative therapy for prostatic adenocarcinoma. RTx-induced sarcomas (RISs) are rare, late adverse events, representing less than 0.2% of all irradiated patients. RISs are more aggressive tumors than prostatic adenocarcinomas. Herein, we present a case with RTx-induced prostatic leiomyosarcoma after permanent brachytherapy for prostatic adenocarcinoma. A 69-year-old male presented with dysuria and gross hematuria. Six years previously, he had been diagnosed with localized prostate cancer and was treated by permanent brachytherapy. Urethroscopy showed stenosis by a tumor at the prostate. Transurethral prostatectomy was performed for a diagnosis. Based on pathological findings, the diagnosis was leiomyosarcoma of the prostate. He was treated with three cycles of neoadjuvant chemotherapy (CTx) that consisted of doxorubicin and ifosfamide (AI), followed by a prostatocystectomy with intrapelvic lymphadenectomy. The tumor extended from the prostate and infiltrated the bladder wall and serosa with lymphatic and venous invasion. The surgical margin was negative, and no residual prostatic adenocarcinoma was observed. The proportion of necrotic tumor cells by neoadjuvant CTx was around 50%. Subsequently, adjuvant CTx was offered, but the patient chose a follow-up without CTx. Local recurrence and lung metastasis were detected by computed tomography 3 months after the surgery. He was treated again with AI. However, CTx was not effective and he died 6 months after the operation. In conclusion, an effective treatment strategy for prostatic sarcoma should be developed in the near future, although the clinical feature of prostatic sarcoma remains unclear due to its rare incidence.

DOI PubMed

アデホビル長期投与中にFanconi症候群による低リン血性骨軟化症を発症したB型慢性肝炎の1例

石川和真, 宮西浩嗣, 保木寿文, 田村文人, 河野豊, 高田弘一, 田中信悟, 櫻田晃, 佐藤康史, 佐藤勉, 林毅, 瀧本理修, 小船雅義, 加藤淳二

肝臓 ( (一社)日本肝臓学会 ) 55 ( 3 ) 162 - 169 2014.03 [Refereed]

症例は54歳の男性。2001年より、B型慢性肝炎に対してラミブジンによる治療を受けていたが、経過中にAST、ALTの上昇、HBV DNAの上昇を認められ、2004年よりアデホビルの併用が開始された。2012年7月より両胸郭・股関節痛を自覚したため前医を受診。採血にてALP高値と腎機能障害を認め、徐々に増悪したため精査加療目的に当科紹介となった。精査の結果、近位尿細管障害および腎性低リン血症を認め、骨シンチグラフィでは疼痛部位に一致したテクネシウムの異常集積を認めた。以上よりFanconi症候群および低リン血症性骨軟化症と診断し、原因としてアデホビルが疑われたため、同薬を中止しエンテカビルへ変更したところ、徐々に腎機能障害、骨痛の改善を認めた。アデホビルによるFanconi症候群は少数ながらも近年報告されている。しかし、治療から改善までの詳細な経過を示したものは無いので、本例の経過を報告する。(著者抄録)

A novel strategy inducing autophagic cell death in Burkitt's lymphoma cells with anti-CD19-targeted liposomal rapamycin

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

BLOOD CANCER JOURNAL ( NATURE PUBLISHING GROUP ) 4 2014.02 [Refereed]

Relapsed or refractory Burkitt's lymphoma often has a poor prognosis in spite of intensive chemotherapy that induces apoptotic and/or necrotic death of lymphoma cells. Rapamycin (Rap) brings about autophagy, and could be another treatment. Further, anti-CD19-targeted liposomal delivery may enable Rap to kill lymphoma cells specifically. Rap was encapsulated by anionic liposome and conjugated with anti-CD19 antibody (CD19-GL-Rap) or anti-CD2 antibody (CD2-GL-Rap) as a control. A fluorescent probe Cy5.5 was also liposomized in the same way (CD19 or CD2-GL-Cy5.5) to examine the efficacy of anti-CD19-targeted liposomal delivery into CD19-positive Burkitt's lymphoma cell line, SKW6.4. CD19-GL-Cy5.5 was more effectively uptaken into SKW6.4 cells than CD2-GL-Cy5.5 in vitro. When the cells were inoculated subcutaneously into nonobese diabetic/severe combined immunodeficiency mice, intravenously administered CD19-GL-Cy5.5 made the subcutaneous tumor fluorescent, while CD2-GL-Cy5.5 did not. Further, CD19-GL-Rap had a greater cytocidal effect on not only SKW6.4 cells but also Burkitt's lymphoma cells derived from patients than CD2-GL-Rap in vitro. The specific toxicity of CD19-GL-Rap was cancelled by neutralizing anti-CD19 antibody. The survival period of mice treated with intravenous CD19-GL-Rap was significantly longer than that of mice treated with CD2-GL-Rap after intraperitoneal inoculation of SKW6.4 cells. Anti-CD19-targeted liposomal Rap could be a promising lymphoma cell-specific treatment inducing autophagic cell death.

DOI

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

A case of acquired fanconi's syndrome and hypophosphatemic osteomalacia induced by prolonged adefovir therapy for chronic hepatitis B

Kazuma Ishikawa, Koji Miyanishi, Toshifumi Hoki, Fumito Tamura, Yutaka Kawano, Kohichi Takada, Shingo Tanaka, Akira Sakurada, Yasushi Sato, Tsutomu Sato, Tsuyoshi Hayashi, Risyu Takimoto, Masayoshi Kobune, Junji Kato

Acta Hepatologica Japonica 55 ( 3 ) 162 - 169 2014 [Refereed]

A 54-year-old male with chronic hepatitis B infection was referred to our hospital in October 2012 to exam the cause of chest wall pain, hip joint pain and renal impairment Adefovir dipivoxil (ADV) 10 mg a day had been added to lamivudine (LAM) 100 mg a day in 2004 due to lamivudine resistance. Laboratory data on his first visit to our hospital showed elevated serum creatinine, elevated serum alkaline phosphatase, low serum uric acid and phosphate level. Urinalysis showed proteinuria and glucosuria. Urinary uric acid and Β< inf> 2< /inf> microglobulin were elevated. A whole body bone scintigraphy revealed an abnormal distribution of 99m Tc uptake, with characteristic changes compatible with osteomalacia. From these results, we diagnosed acquired Fanconi's syndrome and osteomalacia in this patient. Concomitant with this diagnosis, we suspected that ADV was the cause of the Fanconi's syndrome, and ADV and LAM were changed to entecavir 1 mg a day. After stop of ADV and treatment with calcitriol, his bone pain improved within a few months His laboratory data have also improved gradually and abnormal 99m Tc uptake has disappeared. Several hypophosphatemic osteomalacia cases induced by ADV have been reported. In previously reported cases, however, a process of recovery in detail was not described. So we report a detail clinical course of patient with osteomalacia associated with Fanconi's syndrome due to ADV therapy. © 2014 The Japan Society of Hepatology.

DOI

[Successful treatment with rituximab in a patient with refractory mixed-type autoimmune hemolytic anemia].

Ono K, Sato T, Iyama S, Tatekoshi A, Hashimoto A, Kamihara Y, Horiguchi H, Kikuchi S, Takada K, Hayashi T, Miyanishi K, Sato Y, Takimoto R, Kobune M, Kato J

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 11 ) 54 2053 - 2055 2013.11 [Refereed]

DOI PubMed

Diagnostic validity of CT gastrography versus gastroscopy for primary lesions in gastric cancer: evaluating the response to chemotherapy, a retrospective analysis.

Sho Takahashi, Michiaki Hirayama, Ganji Kuroiwa, Yutaka Kawano, Kohichi Takada, Tsutomu Sato, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Junji Kato

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association ( 4 ) 16 ( 4 ) 543 - 8 2013.10 [Refereed] [Domestic journal]

BACKGROUND: This retrospective study was carried out to compare computed tomographic (CT) gastrography and conventional optical gastroscopy (GS) in order to evaluate the effectiveness of chemotherapy in primary gastric lesions. METHODS: Patients with unresectable advanced and unresected early gastric cancer who had primary lesions and had received chemotherapy were enrolled. For primary lesions, CT gastrography and endoscopic assessment were done after chemotherapy, based on the Japanese Classification of Gastric Carcinoma (JCGC) criteria, 13th edition, and the Response Evaluation Criteria in Solid Tumors (RECIST). For metastatic solid lesions including lymph nodes, CT assessment was done based on the RECIST criteria. RESULTS: Data from 23 patients were analyzed. With median follow-up of 9.4 months (range 2-23 months), 58 examinations were assessed by GS and CT gastrography. Setting optical endoscopic results as the gold standard, the accuracy of CT gastrography for primary gastric lesions was 77.6 % (45 of 58) (weighted κ = 0.72; P < 0.01) according to the JCGC 13th edition criteria and 90.0 % (52 of 58) (weighted κ = 0.75; P < 0.01) according to the RECIST. When all results were divided into two groups [the non-progressive disease (non-PD) group and PD group], accuracy was 93.1 % (52 of 58) (κ = 0.81; P < 0.01), sensitivity was 100 %, and specificity was 75.0 % (12 of 16). In addition, the predictability of PD was 100 % (12 of 12). The four cases of failure in specification were the following: a case of gastric remnant cancer, a case with insufficient distension of the stomach, a healed case with stenosis and scarring, and a case in which the wrong position had been selected for the examination. The average period until PD was 9.9 months (range 5-18 months), and the concordance period between GS and CT gastrography was 7.2 months in both non-PD and PD cases. CONCLUSIONS: There was good concordance between the evaluations of GS and CT gastrography. CT gastrography exhibited favorable results in accuracy as well as 100 % PD predictability, which implied the possibility of using CT gastrography as a substitute for endoscopic assessments at post-chemotherapy assessments.

DOI PubMed

A case of idiopathic encapsulating peritoneal sclerosis with intractable ileus successfully treated by surgery and steroid therapy.

Ikeda Y, Sato Y, Kamihara Y, Hirakawa M, Onuma H, Takada K, Hayashi T, Sato T, Miyanishi K, Takimoto R, Kohune M, Nobuoka T, Noguchi H, Oi M, Honma H, Hirata K, Hasegawa T, Kato J

Clinical journal of gastroenterology ( Springer Science and Business Media LLC ) 6 ( 4 ) 295 - 298 2013.08 [Refereed]

DOI PubMed

ASH、NASHの最前線アルコール性肝障害および非アルコール性脂肪肝炎からの発癌における酸化ストレスの関与についての検討

田中信悟, 宮西浩嗣, 河野豊, 保木寿文, 久保智洋, 高田弘一, 林毅, 佐藤勉, 佐藤康史, 小船雅義, 瀧本理修, 加藤淳二

肝臓 ( (一社)日本肝臓学会 ) 54 ( Suppl.1 ) A70 - A70 2013.04 [Refereed]

A phase II study of neoadjuvant combination chemotherapy with docetaxel, cisplatin, and S-1 for locally advanced resectable gastric cancer: nucleotide excision repair (NER) as potential chemoresistance marker

Masahiro Hirakawa, Yasushi Sato, Hiroyuki Ohnuma, Tetsuji Takayama, Tamotsu Sagawa, Takayuki Nobuoka, Keisuke Harada, Hiroshi Miyamoto, Yasuhiro Sato, Yasuo Takahashi, Shinich Katsuki, Michiaki Hirayama, Minoru Takahashi, Michihiro Ono, Masahiro Maeda, Kohichi Takada, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Rishu Takimoto, Masayoshi Kobune, Koichi Hirata, Junji Kato

CANCER CHEMOTHERAPY AND PHARMACOLOGY ( SPRINGER ) 71 ( 3 ) 789 - 797 2013.03 [Refereed]

The combination of docetaxel, cisplatin, and S-1 (DCS) chemotherapy is expected to be a promising regimen for advanced gastric cancer. This study was performed to evaluate the efficacy and safety of neoadjuvant DCS chemotherapy for locally advanced resectable gastric cancer. Patients with locally advanced gastric cancer received 2 courses of preoperative chemotherapy with S-1 (40 mg/m(2) b.i.d.) on days 1-14 and docetaxel (60 mg/m(2)) plus cisplatin (60 mg/m(2)) on day 8 every 3 weeks, followed by standard curative surgery within 4-8 weeks. The primary endpoint was R0 resectability. Expression of damage DNA binding protein complex subunit 2 (DDB2)/excision repair cross-complementing 1 (ERCC1) in the pretreated tumor tissues was examined by immunohistochemistry. A total of 43 patients received neoadjuvant chemotherapy. The response rate was 74.4 %, and disease control ratio was 100 %. Grade 4 neutropenia developed in 53.5 % of patients and febrile neutropenia in 16.3 %. Non-hematological grade 3/4 adverse events were anorexia (23.3 %), nausea (14.0 %), and diarrhea (23.3 %), but these were generally transient and manageable. The proportion of R0 resections in the 43 eligible patients was 90.7 %, and a pathological response was found in 65.9 % of patients. There were no treatment-related deaths and no major surgical complications. The accuracy of the combination of DDB2 and ERCC1 expression for predicting chemoresistance was 82.5 %. Preoperative treatment with DCS combination for locally advanced gastric cancer demonstrated a sufficient R0 resection rate and a good pathological response with manageable toxicities. The DDB2/ERCC1-high phenotype, as determined by immunohistochemistry, may be useful predictor of resistance to DCS chemotherapy.

DOI PubMed

急性胆嚢炎を合併した巨大肝細胞癌(stage IVA)に対して集学的治療により治癒が得られた1例

河野豊, 宮西浩嗣, 田村文人, 堀口拓人, 田中信悟, 高田弘一, 林毅, 佐藤勉, 佐藤康史, 瀧本理修, 小船雅義, 加藤淳二

肝臓 ( (一社)日本肝臓学会 ) 53 ( Suppl.3 ) A962 - A962 2012.10 [Refereed]

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

What I do, study, and think as an information professional (32) : What I expect from information professionals

YAMADA Koji

Journal of Information Processing and Management ( Japan Science and Technology Agency ) 54 ( 10 ) 674 - 675 2012

DOI CiNii

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

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

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

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

非アルコール性脂肪性肝炎における鉄吸収亢進機序と除鉄療法の有用性の検討

宮西浩嗣, 河野豊, 小船雅義, 高田弘一, 永島裕之, 佐藤康史, 瀧本理修, 加藤淳二

アルコールと医学生物学 ( (株)響文社 ) 29 142 - 146 2010.04 [Refereed]

肝生検を施行し、組織学的に診断された非アルコール性脂肪性肝炎(NASH)患者22例を対象に、鉄吸収調節因子であるペプシジン、ヘモジュベリンと十二指腸鉄吸収関連分子の発現量の測定ならびにin vitroにおいてNASH患者血清が十二指腸鉄吸収関連分子発現に及ぼす影響を解析し、NASHにおける鉄吸収亢進機序を検討した。また、1年以上除鉄療法を継続したNASH患者の鉄代謝とアディポサイトカイン値を追跡し除鉄療法の有用性を検討した。コントロール群として用いたRNAは鉄代謝マーカーに異常がない転移性肝癌5例と肝エキノコッカス症1例の外科的に切除された肝臓の非病変部より抽出した。NASH患者では健常人に比較して血清ペプシジン濃度は有意に増加していた。NASH患者の肝臓におけるペプシジン、ヘモジュベリンRNA発現はコントロール群のそれと比較して有意に増加していた。両者には正の相関が認められた。NASH患者十二指腸ではDMT1、Dcyt b、HephaestinのRNA発現がコントロール群と比較して有意に増加していた。ferroportin-1のRNA発現量は有意差が認められなかった。NASH患者血清でCaco-2細胞を培養したところ、ferroportin-1、Dcyt bとHephaestinのRNA発現がコントロール血清で培養したものと差がなかったが、DMT1のRNA発現は有意に増加していた。NASH患者の除鉄療法を施行し、1年以上の経過を観察したところ、肝細胞障害程度の改善、血清フェリチン値低下、アディポネクチンの増加が認められた。

[Cholangiocarcinoma with bile duct adenoma and hamartoma-like lesion in the bile duct].

Sho Takahashi, Kohichi Takada, Yutaka Kawano, Koji Miyanishi, Hirotoshi Ishiwatari, Tsuyoshi Hayashi, Tamotsu Sagawa, Tsutomu Sato, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Ganji Kuroiwa, Michiaki Hirayama, Hirotoshi Tobioka, Kouichi Hirata, Mutsuko Omatsu, Tadashi Hasegawa, Junji Kato

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology ( 3 ) 107 ( 3 ) 461 - 9 2010.03 [Refereed] [Domestic journal]

A 76-year-old man presented with fever of unknown origin. Diagnostic imaging showed a liver tumor measuring 3cm in maximum dimension. The tumor was subsequently resected, and histopathology showed a moderately differentiated adenocarcinoma. This showed a number of bile ductules with variable amounts of stroma, well circumscribed but not encapsulated, so the lesion was diagnosed as a cholangiocarcinoma. Within the tumor there was also a cholangiolocarcinoma-like lesion. In addition, cystically dilated ductules resembling bile duct hamartoma and bile duct adenoma adjacent to the tumor were found, but with no area of transition among them. In the Glisson's capsule around the tumor, there was also a bile duct hamartoma.

DOI PubMed

進行膵癌に対する動注化学療法の効果の検討

宮西浩嗣, 河野豊, 高田弘一, 林毅, 石渡裕俊, 吉田真誠, 菊地尚平, 永島裕之, 加藤淳二

IVR: Interventional Radiology ( (一社)日本インターベンショナルラジオロジー学会 ) 24 ( 4 ) 406 - 406 2009.10 [Refereed]

Suppressive effect of sulindac on branch duct-intraductal papillary mucinous neoplasms.

Tsuyoshi Hayashi, Hirotoshi Ishiwatari, Hideyuki Ihara, Yutaka Kawano, Koichi Takada, Koji Miyanishi, Masayoshi Kobune, Rishu Takimoto, Tomoko Sonoda, Tetsuji Takayama, Junji Kato, Yoshiro Niitsu

Journal of gastroenterology ( SPRINGER TOKYO ) 44 ( 9 ) 964 - 75 2009 [Refereed] [Domestic journal]

BACKGROUND: When considering surgery for branch duct-intraductal papillary mucinous neoplasms (BD-IPMNs) with suspected malignancy, it should be recognized that these lesions are frequently multifocal and are usually found in elderly patients with potential comorbidities that could affect the outcome of surgery. Clinical trials of chemoprevention have been conducted for a wide variety of malignancies. METHODS: Twenty-two BD-IPMN patients participated in the trial at our institution from June 2004 to January 2007. Ten of the 22 patients who rejected surgical therapy although their lesions or clinical symptoms met the criteria for surgical resection of the International Association of Pancreatology guidelines were assigned to the treatment group. Sulindac (150 mg twice daily) and omeprazole (20 mg once daily) were administered to these patients for 18 months. The remaining 12 patients comprised the control group. Branch duct diameter and mural nodule heights were monitored by either magnetic resonance cholangiopancreatography (MRCP) or computed tomography (CT) and by endoscopic ultrasonography (EUS). RESULTS: Both branch duct diameter and mural nodule height of BD-IPMNs in the treatment group were significantly reduced, while those in the control group were unchanged. Immunohistochemical staining for cyclooxygenase-1 and -2 was negative in hyperplasia, adenoma and carcinoma portions of resected pancreatic specimens but was clearly positive for glutathione-S-transferase pi (GST-pi), suggesting that GST-pi is a putative target molecule for sulindac. CONCLUSIONS: Although a larger scale randomized controlled study is needed in future, the present results suggest the promise of chemoprevention of carcinoma derived from BD-IPMNs by sulindac.

DOI PubMed

[Effective CDDP arterial infusion with DSM for liver metastasis of malignant melanoma complicating DIC due to intratumoral hemorrhage--a case report].

Kohichi Takada, Junji Kato, Yutaka Kawano, Sho Takahashi, Tsuyoshi Hayashi, Hirotoshi Ishiwatari, Koji Miyanishi, Rishu Takimoto, Masayoshi Kobune, Tamotsu Sagawa, Tsutomu Sato, Yasushi Sato, Toshiharu Yamashita, Hiroshi Natori, Yoshiro Niitsu

Gan to kagaku ryoho. Cancer & chemotherapy ( 10 ) 35 ( 10 ) 1803 - 5 2008.10 [Refereed] [Domestic journal]

A 65-year-old male, who had been diagnosed with melanoma of stage IIB and treated by chemotherapy since 2003 at the Dermatology Department, was referred to our department for liver metastasis of melanoma that had become resistant to chemotherapeutic agents. In 2006, he started receiving hepatic arterial infusion of CDDP. He was admitted to the hospital on an emergency basis for general fatigue the next May. Blood tests revealed anemia and thrombocytopenia. Contrast CT showed aggravation of liver metastasis. Contrast ultrasonography revealed nodular contrast enhancement at the margin of the tumor. On the basis of image findings and blood test results, DIC due to intratumoral hemorrhage was diagnosed. CDDP arterial infusion with DSM resulted in improved DIC, and he was able to be discharged. Taken together, attention has to be paid to the potential for emergency complications of DIC due to liver metastasis of melanoma with intratumoral hemorrhage. Moreover, it was shown that arterial infusion with DSM was effective for liver metastasis of melanoma.

PubMed

腫瘍内出血によりDICが惹起された悪性黒色腫多発肝転移にDSM併用CDDP動注化学療法が有効であった1例

高田弘一, 加藤淳二, 河野豊, 高橋祥, 林毅, 石渡裕俊, 宮西浩嗣, 瀧本理修, 小船雅義, 佐川保, 佐藤勉, 佐藤康史, 山下利春, 名取博, 新津洋司郎

癌と化学療法 ( (株)癌と化学療法社 ) 35 ( 10 ) 1803 - 1805 2008.10 [Refereed]

症例は65歳、男性。2003年よりメラノーマstage IIBと診断され、当院皮膚科にて化学療法を施行されてきたが肝転移の制御が困難となり、当科へ紹介された。2006年よりCDDPを用いた肝動注化学療法を開始したが、2007年5月全身倦怠感および貧血、血小板減少のため緊急入院となった。造影CTで肝転移は増大していた。造影超音波では腫瘍辺縁部に結節状の造影所見を認めた。以上より腫瘍内出血によるDICと診断した。出血の原因と考えられる病変は多血性であったため、肝転移に対する治療としてDSM併用CDDP動注化学療法を施行した。同治療によりDICが改善した。メラノーマ肝転移は、経過中に腫瘍内出血を来しDICを発症する可能性があり注意を要する。また、メラノーマ肝転移に対してDSM併用動注化学療法が有効である可能性が示唆された。(著者抄録)

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

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

Case report of a focal nodular hyperplasia-like nodule present in cirrhotic liver

Sho Takahashi, Koji Miyanishi, Kohichi Takada, Yutaka Kawano, Tamotsu Sagawa, Yasushi Sato, Rishu Takimoto, Tetsuji Takayama, Junji Kato, Mutsuko Omatsu, Tadashi Hasegawa, Masamichi Kojiro, Yoshiro Niitsu

HEPATOLOGY RESEARCH ( BLACKWELL PUBLISHING ) 38 ( 5 ) 521 - 528 2008.05 [Refereed]

An 81-year-old female was referred to Sapporo Medical University Hospital because of a nodular lesion 20 mm in diameter found in the liver S8 during follow-up for type C liver cirrhosis. Abdominal ultrasonography showed a capsule-like structure, and contrast computed tomography revealed hypervascularity at the early phase and inner pooling of the contrast medium with ring enhancement at the late phase. Magnetic resonance T2-weighted imaging (T2WI) demonstrated a hyperintensity nodule with further hyperintensity signals in some parts of the nodule, and the signal pattern differed from that of typical fibrosis. SPIO-magnetic resonance imaging showed partial hypointensity signals by T2WI, which indicated the presence of Kupffer cells. Angiography did not show a spoke-wheel pattern. The results by imaging modalities indicated that the nodule was atypical for hepatocellular carcinoma (HCC) and focal nodular hyperplasia (FNH), and liver nodule biopsy was performed for histological diagnosis. Compared with the background liver, the nodule revealed high cellular density, cellular dysplasia at the periphery, a pseudo-crypt structure and irregular hepatic cord arrangement in some parts of the nodule. Among them, there was immature fibrous tissue containing arterioles with muscular hypertrophy. There has been no report of well-differentiated HCC with a central scar, and this case was presumed to be an FNH-like nodule with dysplasia physically associated with cirrhotic tissue.

DOI PubMed

A phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for unresectable advanced pancreatic cancer after vascular supply distribution via superselective embolization

Koji Miyanishi, Hirotoshi Ishiwatari, Tsuyoshi Hayashi, Minoru Takahashi, Yutaka Kawano, Kohichi Takada, Hideyuki Ihara, Toshinori Okuda, Kunihiro Takanashi, Sho Takahashi, Yasushi Sato, Takuya Matsunaga, Hisato Homma, Junji Kato, Yoshiro Niitsu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY ( OXFORD UNIV PRESS ) 38 ( 4 ) 268 - 274 2008.04 [Refereed]

Background: We previously reported that arterial infusion chemotherapy improved the response rate and survival of the patients with pancreatic cancer at advanced stages in an open trial. We conducted a Phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for advanced pancreatic cancer after vascular supply distribution via super-selective embolization. Methods: Patients were treated after arterial embolization for hemodynamic change to restrict the blood flow into the pancreas (mainly to the great pancreatic artery and the caudal pancreatic artery). Arterial infusion chemotherapy consisted of gemcitabine in doses that were increased from 600 to 1000 mg/m(2) in subsequent cohorts on Day 1 plus continuous infusion of 5-fluorouracil 300 mg/m(2)/day on Days 1-5 every 2 weeks. Result: Twelve patients were enrolled. The maximum tolerated dose of gemcitabine was determined to be Level 3 (1000 mg/m(2)). Only very mild hematological and non-hematological toxicities were noted. The overall response rate was 33.3%. The median survival time was 22.7 (95% CI; 9.5-24.5) months and the 1- and 2-year overall survival rates were 83.3 and 25.0%, respectively. Conclusion: Arterial infusion chemotherapy using 1000 mg/m(2) gemcitabine on Day 1 and 300 mg/m(2)/day 5-fluorouracil on Days 1-5 every 2 weeks warrants a Phase II study.

DOI PubMed

非アルコール性脂肪性肝疾患の病態と治療非アルコール性脂肪性肝炎における肝内鉄過剰蓄積機序の解析

高田弘一, 加藤淳二, 河野豊, 高橋祥, 小船雅義, 瀧本理修, 宮西浩嗣, 佐藤康史, 佐藤勉, 高山哲治, 新津洋司郎

肝臓 ( (一社)日本肝臓学会 ) 49 ( Suppl.1 ) A32 - A32 2008.04 [Refereed]

Adenoviral vector-mediated transfer of the Indian hedgehog gene modulates lymphomyelopoiesis in vivo

Masayoshi Kobune, Junii Kato, Yutaka Kawano, Katsunori Sasaki, Hiroaki Uchida, Kohichi Takada, Sho Takahashi, Rishu Takimoto, Yoshiro Niitsu

STEM CELLS ( WILEY ) 26 ( 2 ) 534 - 542 2008.02 [Refereed]

Indian hedgehog (Ihh) plays an essential role in angiogenesis, hematogenesis, and epiphysis formation during embryogenesis. In the present study, we injected an adenoviral vector (Adv) carrying the mock-control (Adv-control) or Ihh (Adv-Ihh) gene into severe combined immunodeficiency (SCID) or BALB/c mice to evaluate the effects of Ihh on the regulation of postnatal hematopoiesis in vivo. After the i.v. injection of Adv-Ihh, the expression of vector-derived Ihh mRNA was detected in the liver. Four weeks after administration of Adv-Ihh to SCID mice, we observed an increase in the number of c-Kit+ cells and clonogenic cells per 10(5) mononuclear cells in the bone marrow compared with Advcontrol-administered mice. Moreover, after administration of Adv-Ihh to BALB/c mice, the number of splenic B220+IgM(low)-CD23(int)CD2(int) B lymphocytes and CD4+ T lymphocytes was strongly increased. Furthermore, the number of thymic double-negative (DN)2, DN3, CD8+ immature single-positive, and CD4+/CD8- cells was significantly elevated relative to the number in mice that received the control Adv vector. Our results suggest that enhanced signaling by Ihh can modulate the proliferation and differentiation of splenic B lymphocytes and thymic T lymphocytes during bone marrow hematopoiesis in vivo. Thus, modulation of the hedgehog signaling pathway may provide a therapeutic strategy to stimulate lymphomyelopoiesis in vivo.

DOI PubMed

腫瘍内出血により急速に増大した悪性黒色腫肝転移の1例

高田弘一, 高山哲治, 河野豊, 高橋祥, 高橋究, 山口正人, 早坂享子, 林毅, 石渡裕俊, 宮西浩嗣, 加藤淳二, 名取博, 山下利春, 新津洋司郎

超音波医学 ( (公社)日本超音波医学会 ) 35 ( 1 ) 73 - 73 2008.01 [Refereed]

胆管過誤腫と胆管細胞腺腫を内在した胆管細胞癌の1例

高橋祥, 高田弘一, 宮西浩嗣, 河野豊, 石渡裕俊, 林毅, 加藤淳二, 新津洋司郎, 水口徹, 尾松睦子, 長谷川匡

肝臓 ( (一社)日本肝臓学会 ) 48 ( Suppl3 ) A577 - A577 2007.11 [Refereed]

腫瘍内出血により血小板減少を来たした悪性黒色腫多発肝転移にDSM併用CDDP動注化学療法が有効であった1例

高田弘一, 加藤淳二, 河野豊, 高橋祥, 林毅, 石渡裕俊, 宮西浩嗣, 山下利春, 新津洋司郎

肝臓 ( (一社)日本肝臓学会 ) 48 ( Suppl3 ) A632 - A632 2007.11 [Refereed]

全身MRIが診断に有用であった肝細胞癌坐骨転移の症例

河野豊, 宮西浩嗣, 高田弘一, 高橋祥, 加藤淳二, 新津洋司郎

肝臓 ( (一社)日本肝臓学会 ) 48 ( Suppl3 ) A612 - A612 2007.11 [Refereed]

Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C

Junji Kato, Koji Miyanishi, Masayoshi Kobune, Tokiko Nakamura, Kohichi Takada, Rishu Takimoto, Yutaka Kawano, Sho Takahashi, Minoru Takahashi, Yasushi Sato, Tetsuji Takayama, Yoshiro Niitsu

JOURNAL OF GASTROENTEROLOGY ( SPRINGER TOKYO ) 42 ( 10 ) 830 - 836 2007.10 [Refereed]

Background. We have previously demonstrated that in patients with chronic hepatitis C (CHC), iron depletion improves serum alanine aminotransferase (ALT) levels as well as hepatic oxidative DNA damage. However, it has not been determined whether continuation of iron depletion therapy for CHC favorably influences its progression to hepatocellular carcinoma (HCC). Methods. We conducted a cohort study on biopsy-proven CHC patients with moderate or severe liver fibrosis who failed to respond to previous interferon (IFN) therapy or had conditions for which IFN is contradicted. Patients were divided into two groups: subjects in group A (n = 35) underwent weekly phlebotomy (200 g) until they reached a state of mild iron deficiency, followed by monthly maintenance phlebotomy for 44-144 months (median, 107 months), and they were advised to consume a low-iron diet (5-7 mg iron/day); group B (n = 40) comprised CHC patients who declined to receive iron depletion therapy. Results. In group A, during the maintenance phase, serum ALT levels decreased to less than 60 IU/l in all patients and normalized (< 40 IU/l) in 24 patients (69%), whereas in group B no spontaneous decrease in serum ALT occurred. Hepatocarcinogenesis rates in groups A and B were 5.7% and 17.5% at the end of the fifth year, and 8.6% and 39% in the tenth year, respectively. Multivariate analysis revealed that iron depletion therapy significantly lowered the risk of HCC (odds ratio, 0.57) compared with that of untreated patients (P = 0.0337). Conclusions. Long-term iron depletion for CHC patients is a promising modality for lowering the risk of progression to HCC.

DOI PubMed

[Reactivation of hepatitis B virus due to rituximab plus CHOP after preemptive lamivudine administration in a patient with diffuse large B-cell lymphoma].

Kaoru Ono, Satoshi Iyama, Takuya Matsunaga, Tsutomu Sato, Yasushi Sato, Toshinori Okuda, Kohichi Takada, Yutaka Kawano, Tsuyoshi Hayashi, Koji Miyanishi, Tamotsu Sagawa, Masayoshi Kobune, Rishu Takimoto, Junji Kato, Yoshiro Niitsu

Gan to kagaku ryoho. Cancer & chemotherapy ( 9 ) 34 ( 9 ) 1509 - 12 2007.09 [Refereed] [Domestic journal]

A 59-year-old woman received eight cycles of R-CHOP for diffuse large B-cell lymphoma from July, 2004. Pretreatment HBV serological tests were positive, however, the transaminases were within normal limits, and she remained asymptomatic. Lamivudine (LAM) was administered orally from the start of R-CHOP. HBV-DNA levels gradually decreased and were not detected until December, 2004. LAM was administered until 3 months after the end of chemotherapy, with the entire treatment lasting less than 1 year. Two months after the cessation of treatment, she was re-admitted for general malaise. A liver function test revealed severe abnormalities, and HBVDNA levels were increased. Clinically, she was experiencing acute hepatitis due to HBV reactivation. She was then treated with LAM and interferon-beta immediately. Her HBV-DNA levels soon decreased, and liver function improved.

PubMed

【NASH 最新の知見】NASHの成因と病態 NASHにおける鉄代謝異常

高田弘一, 加藤淳二, 河野豊, 新津洋司郎

臨床消化器内科 ( (株)日本メディカルセンター ) 22 ( 11 ) 1467 - 1472 2007.09 [Refereed]

NASH(非アルコール性脂肪性肝炎)の発症・進展には酸化ストレスの関与が示唆されている.この酸化ストレス増加の原因の一つとして,肝への鉄過剰蓄積が関与している可能性が示唆されている.本稿では,最近わかってきたNASHにおける鉄代謝異常に関して概説した.NASHにおいては肝臓に鉄が過剰に蓄積し,血清フェリチン値やトランスフェリン飽和度が上昇していることから,鉄がNASHの病態を修飾していると考えられる.また,肝内鉄過剰の原因として消化管からの鉄吸収が亢進していることが推測された.その機序は,十二指腸粘膜でのDMTI,DcytbおよびHephaestinの発現が上昇していることによると考えられた.NASHに対する除鉄療法(瀉血+低鉄栄養療法)は,血清ALT値およびIV型コラーゲン値を改善させ,かつ組織学的改善も得られ,有効な治療である.(著者抄録)

非アルコール性脂肪性肝炎における鉄代謝異常の分子機構解析

高田弘一, 加藤淳二, 河野豊, 高橋祥, 小船雅義, 瀧本理修, 宮西浩嗣, 新津洋司郎

アルコールと医学生物学 ( (株)響文社 ) 27 160 - 163 2007.09 [Refereed]

非アルコール性脂肪性肝炎(NASH)患者の消化管からの鉄吸収動態を評価するとともに、十二指腸における鉄吸収関連分子および肝由来の鉄代謝調節ホルモンであるHepcidin mRNA発現量を測定し、肝に鉄が蓄積する機序について解析した。肝生検を施行し、組織学的に診断したNASH患者13例を対象とした。鉄代謝の評価指標として血清鉄、%トランスフェリン飽和度、血清フェリチン濃度を測定した。NASH患者は鉄過剰状態にあると考えられた。NASH患者ではクエン酸第一鉄100mgを経口摂取後、健常人に比較して有意に上昇した。鉄吸収試験の結果から、NASH患者では消化管からの鉄吸収が亢進していることが明らかとなった。コントロール群に比較してNASH患者ではHepcidin mRNA発現量が有意に上昇した。

[A case of resection of synchronous multiple liver metastases from colorectal cancer after hepatic infusion chemotherapy and systemic chemotherapy].

Tamotsu Sagawa, Yasushi Sato, Tetsuji Takayama, Masahiro Hirakawa, Seiichiro Abe, Satoshi Iyama, Koji Miyanishi, Yutaka Kawano, Kohichi Takada, Tokiko Nakamura, Junji Kato, Yoshiro Niitsu

Gan to kagaku ryoho. Cancer & chemotherapy ( 9 ) 34 ( 9 ) 1481 - 4 2007.09 [Refereed] [Domestic journal]

A 70-year-old man was admitted for tranverse colon cancer with multiple liver metastases. Hepatic arterial infusion chemotherapy and systemic chemotherapy (FOLFOX 4) were conducted postoperatively. Thirteen months after the first surgery, liver metastases became resectable and hepatectomy was performed. Though multiple liver metastases were unresectable at the time of the first examination, hepatectomy was possible followed by hepatic arterial infusion chemotherapy and systemic chemotherapy.

PubMed

当科におけるPSE施行症例の検討

高橋祥, 宮西浩嗣, 河野豊, 高田弘一, 庵原秀之, 石渡裕俊, 林毅, 加藤淳二, 新津洋司郎

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 104 ( 臨増大会 ) A689 - A689 2007.09 [Refereed]

肝動注療法および全身化学療法にて切除可能となった大腸癌肝転移の1例

佐川保, 佐藤康史, 高山哲治, 平川昌宏, 阿部清一郎, 井山諭, 宮西浩嗣, 河野豊, 高田弘一, 中村とき子, 加藤淳二, 新津洋司郎

癌と化学療法 ( (株)癌と化学療法社 ) 34 ( 9 ) 1481 - 1484 2007.09 [Refereed]

症例は70歳、男性。横行結腸癌、多発性肝転移と診断した。原発巣による狭窄症状があったことより、横行結腸切除術を施行。肝転移に対しては肝動注、全身化学療法FOLFOX4を施行した。肝転移は縮小し単発となったので13ヵ月後に手術可能となり、肝切除術を施行した。肝動注、全身化学療法により切除可能となった横行結腸癌、多発性肝転移症例を経験したので報告する。(著者抄録)

[A case of intraductal papillary mucinous neoplasm with internal pancreatic fistula causing left ureteral obstruction].

Sho Takahashi, Hisato Homma, Takehide Akiyama, Shinichi Mesawa, Kenichiro Hirata, Katsuhisa Kogawa, Kunihiro Takanashi, Hirotoshi Ishiwatari, Yutaka Kawano, Tsuyoshi Hayashi, Kohichi Takada, Koji Miyanishi, Junji Kato, Yoshiro Niitsu

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology ( 8 ) 104 ( 8 ) 1236 - 44 2007.08 [Refereed] [Domestic journal]

A 75-year-old man had been admitted to another hospital because of left abdominal pain, and was given a diagnosis of left hydronephrosis and acute pancreatitis. After a JJ stent insertion and medication, he was transferred to our hospital for further examinations. US and EUS revealed a chronic pancreatitis-like pattern and multicystic lesion in the pancreas head and body. At that time enhanced CT findings showed an extrapancreatic low density area to be inflammatory change, extending from the pancreas body to the left crus of the diaphragm and posteriorly the spreading from the left crus of the diaphragm via the left urinary duct into the left iliopsoas muscle, in which MRI revealed partial high intensity. ERCP and MRCP showed focal irregular narrowing of the pancreatic duct of unknown cause, and we decided that an internal pancreatic fistula due to pancreatitis had induced left ureteral obstruction, caused by a protein plug or alcohol. Follow-up 6 months later showed that extrapancreatic spreading of the low density area had markedly regressed without any change in the ureteral obstruction.

DOI PubMed

Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism

Masayoshi Kobune, Hiroki Chiba, Junji Kato, Kazunori Kato, Kiminori Nakamura, Yutaka Kawano, Kohichi Takada, Rishu Takimoto, Tetsuji Takayama, Hirofumi Hamada, Yoshiro Niitsu

MOLECULAR CANCER THERAPEUTICS ( AMER ASSOC CANCER RESEARCH ) 6 ( 6 ) 1774 - 1784 2007.06 [Refereed]

Adhesion of myeloma cells to bone marrow stromal cells is now considered to play a critical role in chemoresistance. However, little is known about the molecular mechanism governing cell adhesion-mediated drug resistance (CAM-DR) of myeloma cells. In this study, we focused our interests on the implication of the Wnt signal in CAM-DR. We first screened the expression of Wnt family in myeloma cell lines and found that Wnt3 was overexpressed in all the myeloma cells examined. KMS-5 and ARH77, which highly expressed Wnt3 protein, tightly adhered to human bone marrow stromal cells, and accumulation of (3-catenin and GTP-bounded RhoA was observed in these myeloma cell lines. Conversely, RPM18226 and MM1S, which modestly expressed Wnt3 protein, rather weakly adhered to human bone marrow stromal. We then examined the relevance of Wnt3 expression to adhesive property to stromal cells and to CAM-DR of myeloma cells. KMS-5 and ARH-77 exhibited apparent CAM-DR against doxorubicin. This CAM-DR was significantly reduced by anti-integrin (it antibody, antiintegrin as antibody and a Wnt-receptor competitor, secreted Frizzled-related protein-1, and Rho kinase inhibitor Y27632, but not by the specific inhibitor of canonical signaling (Dickkopf-1), indicating that Wnt-mediated CAMDR that is dependent on integrin alpha(6)/beta(1) (VLA-6)-mediated attachment to stromal cells is induced by the Wnt/RhoA/Rho kinase pathway signal. This CAM-DR was also significantly reduced by Wnt3 small interfering RNA transfer to KMS-5. These results indicate that Wnt3 contributes to VLA-6-mediated CAM-DR via the Wnt/RhoA/ROCK pathway of myeloma cells in an autocrine manner. Thus, the Wnt3 signaling pathway could be a promising molecular target to overcome CAM-DR of myeloma cells.

DOI PubMed

Iron/IRP-1-dependent regulation of mRNA expression for transferrin receptor, DMT1 and ferritin during human erythroid differentiation

Junji Kato, Masayoshi Kobune, Shunichi Ohkubo, Koshi Fujikawa, Maki Tanaka, Rishu Takimoto, Kohichi Takada, Daisuke Takahari, Yutaka Kawano, Yutaka Kohgo, Yoshiro Niitsu

EXPERIMENTAL HEMATOLOGY ( ELSEVIER SCIENCE INC ) 35 ( 6 ) 879 - 887 2007.06 [Refereed]

Objective. We investigated iron regulatory protein (IRP)-dependent expression of transferrin receptor (TfR), divalent metal transpoter-1 (DMT1) and ferritin during erythroid differentiation system using an in vitro three-phase liquid culture. Method. Peripheral blood hematopoietic progenitor cells were cultured with interleukin-3 and stem cell factor (SCF) for 7 days (first phase), subsequently with SCF, erythropoietin (EPO) and insulin-like growth factor-I (IGF-I) for 5 days (second phase), and finally with EPO and IGF-I for 3 days (third phase). Cells were subjected to colony assay, flow-cytometric analysis, mRNA assessment, electrophoretic mobility shift assay (EMSA), immunoblotting, and immunoprecipitation. Results. In the second/third phases, erythroid cells serially differentiated. Expression of TfR and DMT1 mRNA, which have iron-responsive elements (IREs) at 3'-UTR, reached a maximum on second phase, and thereafter decreased, while expression of ferritin mRNA, which has an IRE at the 5'-UTR, decreased reciprocally on second phase. IRP in the cytosol after precipitation of polysome decreased on second phase, suggesting that IRP bound to IREs of these mRNAs in the polysome. When cells were incubated with (FeCl3)-Fe-59, Fe-59-bound IRP-1 immunoprecipitated with anti-IRP-1 antibodies was detected on first phase and third phase, but was not detected on second phase. Conclusion. These results suggest that IRP-1/IRE interactions, which are supposedly induced after sensing a decrease of the intracellular non-Heme iron levels, play a crucial role on the posttranscriptional regulation of TfR, DMT1, and ferritin mRNAs during differentiation of normal human erythropoietic cells. (c) 2007 International Society for Experimental Hematology. Published by Elsevier Inc.

DOI PubMed

C型慢性肝炎および非アルコール性脂肪性肝炎における鉄吸収関連分子の解析

高田弘一, 加藤淳二, 河野豊, 高橋祥, 小船雅義, 瀧本理修, 宮西浩嗣, 新津洋司郎

肝臓 ( (一社)日本肝臓学会 ) 48 ( Suppl.1 ) A31 - A31 2007.04 [Refereed]

C型肝炎からの肝発癌における酸化的DNA損傷修復系遺伝子群の検討

宮西浩嗣, 加藤淳二, 小船雅義, 河野豊, 高橋祥, 高田弘一, 石渡裕俊, 林毅, 佐藤康史, 新津洋司郎

肝臓 ( (一社)日本肝臓学会 ) 48 ( Suppl.1 ) A68 - A68 2007.04 [Refereed]

[A case of primary carcinoma of the cystic duct with limy bile].

Sho Takahashi, Hisato Homma, Takehide Akiyama, Shinichi Mesawa, Kazuhiko Koike, Kenichiro Hirata, Katsuhisa Kogawa, Yutaka Kawano, Kohichi Takada, Tsutomu Sato, Yoshiro Niitsu

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology ( 3 ) 104 ( 3 ) 394 - 400 2007.03 [Refereed] [Domestic journal]

A 78-year-old man had been admitted to a previous hospital because of epigastralgia and a diagnosis of cholecystolithiasis had been made. He had been transferred to our institution for further examination. CT scan and US revealed chronic cholecystitis and gallstone, however, ERC revealed severe obstruction of the cystic duct and EUS revealed dilation of that duct and a solitary mass there. Carcinoma of the cystic duct was diagnosed, and we performed cholecystectomy and resection of the extrahepatic duct with two-field lymphadenectomy. The pathological specimen showed a round flat elevated mass localized in the cystic duct. Histopathologically, the diagnosis was well differentiated tubular adenocarcinoma of the cystic duct with limy bile and tiny gallstone.

DOI PubMed

Hepatitis C virus core protein promotes proliferation of human hepatoma cells through enhancement of transforming growth factor alpha expression via activation of nuclear factor-kappa B

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

GUT ( B M J PUBLISHING GROUP ) 55 ( 12 ) 1801 - 1808 2006.12 [Refereed]

Background: Hepatitis C virus (HCV) infection is a major cause of human hepatocellular carcinoma (HCC). The precise mechanism of hepatocarcinogenesis in humans by HCV is currently unclear. It was recently shown, however, that transgenic mice with the HCV core gene often develop HCC, suggesting tumorigenic activity of the HCV core protein. Further, the HCV core protein expressed in HepG2 cells transfected with the core gene was shown to stimulate proliferation of transfectants through activation of nuclear factor-kappa B (NF-kappa B). The downstream target molecule(s) of NF-kappa B activated by the HCV core protein to evoke cell proliferation is not yet identified. Transforming growth factor (TGF)alpha, which is often overexpressed in various tumour tissues such as HCC, has been shown to stimulate hepatocyte proliferation through activation of the mitogen-activated protein kinase or extracellular signal-related protein kinase (MAPK/ERK) cascade. Aims: To explore the possibility that TGF alpha might be a target molecule for NF-kB activated by the HCV core, and that TGFa participates in the growth promotion of the core transfectants in an autocrine manner, activating the MAPK/ERK pathway. Methods: A HCV core expression vector was transfected into human hepatoma Huh-7, HepG2 and Hep3B cells. NF-kappa B activity was examined by an electrophoretic mobility shift assay. TGFa transcription was assessed by a luciferase reporter assay. TGF alpha protein was determined by immunoblot and ELISA. MAPK/ERK activity was examined by an in vitro kinase assay. Cell proliferation was assessed by a water-soluble tetrazolium salt-1 assay. Results: In the HCV core transfectants, NF-kappa B bound to the kappa B site in the TGFa proximal promoter region, resulting in an increase in TGF alpha transcription. Immunoblot as well as ELISA showed increased TGF alpha expression in the HCV core transfectants. SN50, a specific inhibitory peptide for NF-kappa B, cancelled HCV core-induced TGF alpha expression. HCV core protein increased cell proliferation as well as ERK activity of the HCV core transfectants as compared with the mock transfectants. The growth-promoting activity and activation of ERK by the HCV core protein were negated by treatment with anti-TGF alpha antibodies. Conclusions: These results suggest that the HCV core protein promotes proliferation of human hepatoma cells by activation of the MAPK/ERK pathway through up regulation of TGF alpha transcription via activation of NF-kappa B. Our finding provides a new insight into the mechanism of hepatocarcinogenesis by HCV infection.

DOI

多血性胆管細胞癌の2例

高田弘一, 高橋究, 高山哲治, 山口正人, 早坂亨子, 太田由紀子, 鎌形千夏, 高橋祥, 河野豊, 石渡裕俊, 加藤淳二, 名取博, 新津洋司郎, 水口徹, 桂巻正, 尾松睦子, 長谷川匡

超音波医学 ( (公社)日本超音波医学会 ) 33 ( 6 ) 699 - 700 2006.11 [Refereed]

硬変肝に発生しFNH様の画像所見を呈した多血性結節の1例

高橋祥, 宮西浩嗣, 河野豊, 高田弘一, 庵原秀之, 石渡裕俊, 林毅, 佐藤康史, 加藤淳二, 新津洋司郎, 尾松睦子, 長谷川匡

肝臓 ( (一社)日本肝臓学会 ) 47 ( Suppl.3 ) 614 - 614 2006.11 [Refereed]

アルコール性および非アルコール性脂肪性肝炎における鉄代謝異常の解析および酸化的DNA障害の検討

高田弘一, 加藤淳二, 河野豊, 高橋祥, 奥田敏徳, 小船雅義, 瀧本理修, 宮西浩嗣, 新津洋司郎

アルコールと医学生物学 ( (株)響文社 ) 26 91 - 95 2006.09 [Refereed]

アルコール性脂肪性肝炎(ASH)および非アルコール性脂肪性肝炎(NASH)患者の鉄吸収動態や肝への鉄沈着の程度、さらに酸化的DNA傷害について解析した。肝生検を施行し、組織学的に診断したASH 5例、NASH 23例を対象とした。ASHおよびNASHでは正常人に比べ血清フェリチンおよび%トランスフェリン飽和度が高値であった。肝への鉄沈着はASHおよびNASH両者で確認し、NASHの症例において肝への鉄沈着が高い傾向を認めた。8-OH-dGレベルもASHおよびNASHで増加し、ASHと比較してNASHの方が有意に増加した。除鉄療法により、血清フェリチンおよびHbは有意に低下し、ALTも低下した。IV型コラーゲンも低下した。除鉄療法を48週間施行した後、肝生検を行い組織学的にも治療効果判定を行った。Necro-Inflammationの改善が得られたが、Fibrosisの改善は得られなかった。

酸化ストレスと肝疾患 C型慢性肝炎おける鉄代謝異常の発生機序の検討

宮西浩嗣, 加藤淳二, 河野豊, 小船雅義, 高田弘一, 藤川幸司, 奥田敏徳, 石渡裕俊, 林毅, 佐藤康史, 新津洋司郎

肝臓 ( (一社)日本肝臓学会 ) 47 ( Suppl.1 ) A45 - A45 2006.04 [Refereed]

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]

高度進行肝細胞癌に対する5-FUとCDDPを用いた肝動注化学療法の成績

奥田敏徳, 宮西浩嗣, 高田弘一, 河野豊, 石渡裕俊, 林毅, 佐藤康史, 高橋稔, 加藤淳二, 新津洋司郎

肝臓 ( (一社)日本肝臓学会 ) 47 ( Suppl.1 ) A184 - A184 2006.04 [Refereed]

StageIV膵癌に対するGemcitabineを中心とした多剤併用動注化学療法の治療成績

石渡裕俊, 林毅, 宮西浩嗣, 奥田敏徳, 河野豊, 高田弘一, 新津洋司郎

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 103 ( 臨増総会 ) A193 - A193 2006.03 [Refereed]

Ex vivo expansion of G-CSF-mobilized peripheral blood CD133(+) progenitor cells on coculture with human stromal cells

Y Kawano, M Kobune, H Chiba, K Nakamura, R Takimoto, K Takada, Y Ito, J Kato, H Hamada, Y Niitsu

EXPERIMENTAL HEMATOLOGY ( ELSEVIER SCIENCE INC ) 34 ( 2 ) 150 - 158 2006.02 [Refereed]

Objective. The pentaspan molecule CD133 has been shown to be a marker of more primitive hematopoietic progenitors in mobilized peripheral blood (PB). Our objective was to assess the efficacy of PB CD133(+) cells in our coculture system using human telomerized stromal (HTS) cells. Methods. Five thousand PB CD133(+) cells or conventional cord blood (CB) CD34(+) cells were expanded with or without HTS cells in the presence or absence of stem cell factor, thrombopoietin, and Flk-2/Flt-3 ligand. Results. The coculture was significantly superior in expanding PB clonogenic cells as compared with the stroma-free culture (CFU-C, 2 +/- 0 vs 111 +/- 15-fold of initial cell number p < 0.01), and the fold increase of PB clonogenic cells was comparable to that for CB cells after two weeks of coculture (BFU-E, 54 +/- 3 vs 56 +/- 4-fold; CFU-GM, 156 +/- 26 vs 83 +/- 9-fold; CFU-Mix, 30 +/- 11 vs 80 +/- 36-fold). However, proliferation of CFU-Mk from PB on coculture with HTS cells was modest as compared with stroma-free culture. Concomitantly, multiple hematopoietic cells transmigrated below the stromal layer and formed cobblestone areas (CAs). The production of hematopoietic progenitor cells from CAs after coculture with PB was significantly lower than that seen in cells cocultured with CB for four weeks (CFU-Mix, 0 +/- 0 vs 9 +/- 5-fold on day 28, p < 0.01), although a similar number of CAs derived from PB and CB were observed. Conclusion. PB CD133(+) cells proliferated efficiently above the stromal layer, while the characteristics of PB CD133(+) cells underneath the human stromal layer were likely to be maintained, even after long-term hematopoietic-stromal interaction. (C) 2006 International Society for Experimental Hematology. Published by Elsevier Inc.

DOI PubMed

Stage IV膵癌に対する動注化学療法の治療成績

林毅, 石渡裕俊, 奥田敏徳, 河野豊, 高田弘一, 宮西浩嗣, 加藤淳二, 新津洋司郎

日本内科学会雑誌 ( (一社)日本内科学会 ) 95 ( Suppl. ) 128 - 128 2006.02 [Refereed]

Human Herpesvirus-6 Hepatitis Associated with Cyclosporine-A Encephalitis after Bone Marrow Transplantation for Chronic Myeloid Leukemia

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

Japanese Journal of Medicine ( The Japanese Society of Internal Medicine ) 45 ( 7 ) 475 - 478 2006

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, γGTP 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 CiNii

NASHにおける鉄代謝異常の解析と除鉄療法の有用性の検討

高田弘一, 加藤淳二, 宮西浩嗣, 奥田敏徳, 河野豊, 高梨訓博, 石渡裕俊, 新津洋司郎, 池田健

肝臓 ( (一社)日本肝臓学会 ) 46 ( Suppl.1 ) A45 - A45 2005.05 [Refereed]

A case of signet ring cell carcinoma of the stomach discovered by abdominal wall metastasis

Kunihiro Takanashi, Yoshimitsu Onodera, Shigeyuki Fujii, Yoshiki Nishibori, Norihiro Takayanagi, Shinya Minami, Takahiro Kogawa, Hiroyuki Nagashima, Seiichiro Abe, Yasuhiro Nagaoka, Masayoshi Horimoto, Kohichi Takada, Yasushi Sato, Yoshiro Niitsu

Japanese Journal of Gastroenterology ( 4 ) 102 ( 4 ) 459 - 465 2005.04 [Refereed]

PubMed

Augmentation of antitumor effects of p53 gene therapy by combination with HDAC inhibitor

R Takimoto, J Kato, T Terui, K Takada, G Kuroiwa, J Wu, H Ohnuma, D Takahari, M Kobune, Y Sato, T Takayama, T Matsunaga, Y Niitsu

CANCER BIOLOGY & THERAPY ( LANDES BIOSCIENCE ) 4 ( 4 ) 421 - 428 2005.04 [Refereed]

We have previously shown that the HDAC inhibitors (HDACl) activate the p53 molecule through acetylation of 320 and 373 lysine residues, upregulate PIG3 and NOXA and induce apoptosis in cancer cells expressing wild and pseudo-wild type p53 genes (Terui T, et al. Cancer Res 2003; 63:8948-54). It has also been reported that expression of the Coxackie adenovirus receptor and subsequent transfection efficiency of the adenovirus in cancer cells were enhanced by HDACl treatment. In this study, we extended these observations to explore the combination effect of adenoviral vector carrying wild type p53 (Ad-p53) gene therapy with a HDACl, sodium butyrate (SIB), on xenografted human gastric cancer cells (KATO-III) and hepatocellular carcinoma cells (HuH7) in nude mice. We first confirmed an increased expression of Coxackie adenovirus receptors with an associated increment of transgene (X-gal) expression by SB treatment in KATO-III cells. We then injected Ad-p53 into subcutaneous tumors of KATO-III and HuH7 combined with intraperitoneal administration of SB and found a significantly higher growth suppressive effect than single treatments of each. Even a complete regression of tumors was observed in three of five mice treated with this combination while with single treatment no tumor regression was observed. Tumors treated with the combination showed higher numbers of TUNEL positive cells than those treated with a single modality. Moreover, necrotic changes were more evident in tumors treated with the combination than separately, a compatible finding to the observation that vascularity revealed by CD34 staining was poorer in tumors treated with the combination than those treated with p53 gene or SB alone. This was further supported by the finding that BAI-1 (brain specific angiogenesis inihibitor-1), an inhibitor of vascularization, was induced by SB treatment in KATO-III and HuH7 cells transfected with Ad-p53. Thus SB was shown to be an efficient potentiator of p53 gene therapy for cancer.

PubMed

[A case of metastatic liver tumor from colorectal carcinoma--continued arterial infusion chemotherapy through a microcatheter located in replaced right hepatic artery].

Takanashi K, Takahashi M, Miyanishi K, Hayashi T, Takada K, Oku T, Ishiwatari H, Kogawa T, Takayama T, Kato J, Niitsu Y

Gan to kagaku ryoho. Cancer & chemotherapy ( 9 ) 31 1415 - 1417 2004.09 [Refereed]

PubMed

Interleukin-11 as an osteoprotegerin-inducing factor in culture medium of blastic cells from a patient with acute megakaryocytic leukemia complicated with osteosclerosis

T Sato, T Matsunaga, M Kida, K Morii, T Machida, Y Kawano, K Nakamura, K Kuribayashi, K Takada, S Iyama, Y Sato, T Takayama, M Takahashi, J Kato, M Chokki, Y Niitsu

AMERICAN JOURNAL OF HEMATOLOGY ( WILEY-LISS ) 77 ( 1 ) 62 - 66 2004.09 [Refereed]

We came across a rare case of acute megalkaryocytic leukemia, the clinical course of which was relatively chronic and nonaggressive. This case was complicated with generalized severe osteosclerosis (OS). The medium in which blastic cells from the patient were cultured showed a strong activity to enhance the expression of an osteosclerotic cytokine, osteoprotegerin (OPG), as revealed by real-time quantitative RT-PCR and Western blot analysis. The OPG-inducing activity of the culture medium was neutralized by the anti-interieukin-11 (IL-11) antibody. These results indicate that IL-11 produced by the blasts was a causative factor of the OS observed in this patient. (C) 2004 Wiley-Liss, Inc.

DOI PubMed

A comparative randomized trial of intermittent intrahepatic arterial carboplatin- versus doxorubicin-lipiodol emulsion in advanced hepatocellular carcinoma (stage IV)

H Homma, S Mezawa, T Doi, K Miyanishi, K Takada, T Kukitsu, T Oku, E Masuko, S Nojiri, Y Niitsu

HEPATO-GASTROENTEROLOGY ( H G E UPDATE MEDICAL PUBLISHING S A ) 51 ( 58 ) 1135 - 1139 2004.07 [Refereed]

Background/Aims: The study was performed to investigate the anti-tumor effect, survival rate, and toxicity of intermittent intrahepatic infusion chemotherapy with carboplatin suspended in lipiodol. Methodology: We conducted a randomized controlled study containing either doxorubicin or carboplatin in 65 patients with advanced hepatocellular carcinoma. Results: The results observed in the carboplatin- and doxorubicin-lipiodol groups included: response rates, 29.0 and 20.6% respectively, 1-year survival rates of, 60.4% and 40.4%, respectively, and the difference achieved statistical significance (p=0.025). The median survival of 31 patients who received carboplatin emulsified with lipiodol was 16.9 months, 34 patients who received doxorubicin was 12.1 months. The difference achieved statistical significance. Conclusions: Compared with doxorubicin, carboplatin caused neither cardiotoxicity nor nephrotoxicity, and side effects of nausea and vomiting were less severe. Therefore, carboplatin is effective and preferable for repeated intrahepatic arterial administration to treat advanced hepatocellular carcinoma over a relatively long period.

PubMed

Fas-mediated apoptosome formation is dependent on reactive oxygen species derived from mitochondrial permeability transition in Jurkat cells

T Sato, T Machida, S Takahashi, S Iyama, Y Sato, K Kuribayashi, K Takada, T Oku, Y Kawano, T Okamoto, R Takimoto, T Matsunaga, T Takayama, M Takahashi, J Kato, Y Niitsu

JOURNAL OF IMMUNOLOGY ( AMER ASSOC IMMUNOLOGISTS ) 173 ( 1 ) 285 - 296 2004.07 [Refereed]

Generation of reactive oxygen species (ROS) and activation of caspase cascade are both indispensable in Fas-mediated apoptotic signaling. Although ROS was presumed to affect the activity of the caspase cascade on the basis of findings that antioxidants inhibited the activation of caspases and that the stimulation of ROS by itself activated caspases, the mechanism by which these cellular events are integrated in Fas signaling is presently unclear. In this study, using human T cell leukemia Jurkat cells as well as an in vitro reconstitution system, we demonstrate that ROS are required for the formation of apoptosome. We first showed that ROS derived from mitochondrial permeability transition positively regulated the apoptotic events downstream of mitochondrial permeability transition. Then, we revealed that apoptosome formation in Fas-stimulated Jurkat cells was clearly inhibited by N-acetyl-L-cysteine and manganese superoxide dismutase by using both the immunoprecipitation and size-exclusion chromatography methods. To confirm these in vivo findings, we next used an in vitro reconstitution system in which in vitro-translated apoptotic protease-activating factor 1 (Apaf-1), procaspase-9, and cytochrome c purified from human placenta were activated by dATP to form apoptosome; the formation of apoptosome was markedly inhibited by reducing reagents such as DTT or reduced glutathione (GSH), whereas hydrogen peroxide prevented this inhibition. We also found that apoptosome formation was substantially impaired by GSH-pretreated Apaf-1, but not GSH-pretreated procaspase-9 or GSH-pretreated cytochrome c. Collectively, these results suggest that ROS plays an essential role in apoptosome formation by oxidizing Apaf-1 and the subsequent activation of caspase-9 and -3.

PubMed

[A case of cholangiocellular carcinoma complicated with intratumoral hemorrhagic necrosis].

Kohichi Takada, Shoichi Horita, Takashi Meguro, Yoshiyuki Inoue, Hideaki Nakamura, Masumi Maruya, Takashi Kato, Takayuki Morita, Kazuro Nagashima, Yutaka Kawano, Yoshiro Niitsu

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology ( 6 ) 101 ( 6 ) 616 - 21 2004.06 [Refereed] [Domestic journal]

PubMed

A case of Gardner syndrome with a mutation at codon 1556 of APC: a suggested case of genotype-phenotype correlation in dental abnormality

T Oku, T Takayama, Y Sato, Y Sato, K Takada, T Hayashi, M Takahashi, M Kuroda, J Kato, Y Niitsu

EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY ( LIPPINCOTT WILLIAMS & WILKINS ) 16 ( 1 ) 101 - 105 2004.01 [Refereed]

A 25-year-old man with suspected Gardner syndrome was introduced to our hospital by a dentist who, during examination of the patient, had found dental dysplasias and multiple osteomas of the jaw. Radiographs, endoscopy and biopsies revealed adenomatous polyposis of the colon. Genetic analysis of peripheral lymphocytes revealed a one-base deletion at codon 1556 in exon 15 of APC, which caused a frame shift and a premature stop at codon 1564. The pedigree analysis demonstrated five patients in his family who presented with dental abnormality and osteomas in addition to adenomatous polyposis of the colon. Although the relationship between the location of APC mutations and dental abnormalities remains controversial, this case supports the hypothesis that a mutation at around codon 1556 of APC is closely associated with dental abnormality and osteomas. (C) 2004 Lippincott Williams Wilkins.

DOI PubMed

Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors

T Terui, K Murakami, R Takimoto, M Takahashi, K Takada, T Murakami, S Minami, T Matsunaga, T Takayama, J Kato, Y Niitsu

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 63 ( 24 ) 8948 - 8954 2003.12 [Refereed]

Two controversial issues regarding p53 are whether it is involved in apoptosis induction of tumor cells by a histone deacetylase (HDAQ inhibitor and, given that p53 is indeed involved, which genes of acetylated p53 targets are responsible for giving rise to apoptotic death. We, in the present study, first confirmed that some substantial extent of apoptotic cell death was seen when p53-deficient cells (KATO-III) were transfected with wild-type p53 and treated with sodium butyrate (SB) or trichostatin A. By Western blotting, using specific antibodies, we then demonstrated that residues 320, 373, and 382 lysines of p53 were acetylated in KATO-III cells transfected with wild-type p53 (KATO-III/p53) treated with a HDAC inhibitor. However, as revealed by terminal deoxynucleotidyl transferase-mediated nick end labeling staining, only those KATO-III cells transfected with K320R p53 or K373R p53 became insensitive to the HDAC inhibitor, suggesting that these two residues of p53 may be essential for HDAC inhibitor-induced apoptosis, whereas others such as K382R p53 may not. Furthermore, reverse transcription-PCR demonstrated that among various p53-related proapoptotic genes, expression of PIG3 and NOXA were clearly enhanced by SB treatment in KATO-III/p53 cells but not in KATO-III/K320R or KATO-III/K373R cells. Finally, we revealed that apoptosis could be evoked by SB even in cells where p53 mutations occur at residues other than 320 lysine or 373 lysine (TMK-1 and HSC-39 cells) and that this apoptosis was significantly, although not totally, suppressed by the anti-p53 antisense. It was, therefore, concluded that acetylation of the p53 molecule at residues 320 and 373, giving rise to up-regulation of PIG3 and NOXA, is one of the mechanisms for induction of apoptosis by HDAC inhibitors in cancer cells.

A resectable case of hepatocellular carcinoma complicated with hepatic alveolar echinococcosis

Takashi Kato, Yasuo Seino, Kohichi Takada, Masumi Maruya, Shunichi Okubo, Hideaki Nakamura, Yoshiyuki Inoue, Takashi Meguro, Shoichi Horita, Taro Oshikiri, Hideyuki Yamada, Yuji Miyasaka, Miyoshi Fujita, Takayuki Morita, Tatsuya Yoshida, Kanako Chikai

Japanese Journal of Gastroenterology ( 5 ) 100 ( 5 ) 587 - 592 2003.05 [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.

PubMed

An autopsy case of hepatocellular carcinoma with a solitary mediastinal lymph node metastasis

Kohichi Takada, Shoichi Horita, Takashi Meguro, Yoshiyuki Inoue, Takayuki Gouda, Hideaki Nakamura, Masumi Maruya, Tomoki Fujita, Shoko Arai, Yuuji Miyasaka, Miyoshi Fujita, Takayuki Morita, Yusuke Ishida, Kazuro Nagashima, Yoshiro Niitsu

Japanese Journal of Gastroenterology ( 2 ) 100 ( 2 ) 177 - 184 2003.02 [Refereed]

PubMed

[A case of successful management of refractory ascites by transjugular intrahepatic portosystemic shunting (TIPS) in Budd-Chiari syndrome associated with alcoholic liver fibrosis].

Sho Takahashi, Minoru Takahashi, Kohichi Takada, Yutaka Kawano, Seiya Hagiwara, Takehide Akiyama, Tsutomu Sato, Tadashi Doi, Koji Miyanishi, Yasushi Sato, Junji Kato, Yoshiro Niitsu, Hisato Homma, Hiroshi Neda

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology ( 9 ) 99 ( 9 ) 1085 - 91 2002.09 [Refereed] [Domestic journal]

PubMed

Normalization of elevated hepatic 8-hydroxy-2 '-deoxyguanosine levels in chronic hepatitis C patients by phlebotomy and low iron diet

J Kato, M Kobune, T Nakamura, G Kuroiwa, K Takada, R Takimoto, Y Sato, K Fujikawa, M Takahashi, T Takayama, T Ikeda, Y Niitsu

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 61 ( 24 ) 8697 - 8702 2001.12 [Refereed]

Accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in DNA, which may result from the continuous reactive oxygen species (ROS) generation associated with chronic inflammation, has been reported in various human preneoplastic lesions and in cancerous tissues. However, no direct causative relationship between the 8-OHdG formation and carcinogenesis has been thus far demonstrated in humans. Directly proving the causality requires showing that depletion of 8-OHdG levels in tissue by interfering with ROS generation results in a reduction in cancer. Chronic hepatitis C virus (HCV) infection is associated with a high risk of hepatocellular carcinoma (HCC). Several studies on patients with chronic HCV have shown that hepatic iron overload is attributable to liver injury, and that iron depletion improved serum aminotransferase levels. Excess iron is known to generate ROS within cells, which causes mutagenic lesions, such as 8-OHdG. In this study, therefore, we have evaluated whether therapeutic iron reduction (phlebotomy and low iron diet) with a long-term follow-up (6 years) would decrease the hepatic 8-OHdG levels and the risk of HCC development in patients with chronic HCV. Patients (34) enrolled were those who had undergone standard IFN therapy but had no sustained response. Quantitative immunohistochemistry using the KS-400 image analyzing system and electrochemical detection was used for 8-OHdG detection. With this treatment, elevated hepatic 8-OHdG levels in patients with chronic hepatitis C (8.3 +/- 4.6/10(5) dG) significantly decreased to almost normal levels (2.2 +/- 0.9/10(5) dG; P < 0.001) with concomitant improvement of hepatitis severity, including fibrosis, whereas HCV titers were unaffected. None of these patients developed HCC. Thus, long-term iron reduction therapy in patients with chronic hepatitis C may potentially lower the risk of progression to HCC.

A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload

J Kato, K Fujikawa, M Kanda, N Fukuda, K Sasaki, T Takayama, M Kobune, K Takada, R Takimoto, H Hamada, T Ikeda, Y Niitsu

AMERICAN JOURNAL OF HUMAN GENETICS ( UNIV CHICAGO PRESS ) 69 ( 1 ) 191 - 197 2001.07 [Refereed]

Ferritin, which is composed of H and L subunits, plays an important role in iron storage and in the control of intracellular iron distribution. Synthesis of both ferritin subunits is controlled by a common cytosolic protein, iron regulatory protein (IRP), which binds to the iron-responsive element (IRE) in the 5'-UTR of the H- and L-ferritin mRNAs. In the present study, we have identified a single point mutation (A49U) in the IRE motif of H- ferritin mRNA, in four of seven members of a Japanese family affected by dominantly inherited iron overload. Gel-shift mobility assay and Scatchard-plot analysis revealed that a mutated IRE probe had a higher binding affinity to IRP than did the wild-type probe. When mutated H subunit was overexpressed in COS-1 cells, suppression of H- subunit synthesis and of the increment of radiolabeled iron uptake were observed. These data suggest that the A49U mutation in the IRE of H-subunit is responsible for tissue iron deposition and is a novel cause of hereditary iron overload, most likely related to impairment of the ferroxidase activity generated by H subunit.

Effect of transjugular intrahepatic portosystemic shunt formation on portal hypertensive gastropathy and gastric circulation

S Mezawa, H Homma, H Ohta, E Masuko, T Doi, K Miyanishi, K Takada, T Kukitsu, T Sato, Y Niitsu

AMERICAN JOURNAL OF GASTROENTEROLOGY ( ELSEVIER SCIENCE INC ) 96 ( 4 ) 1155 - 1159 2001.04 [Refereed]

OBJECTIVES: The aim of this study was to investigate the effect of a transjugular intrahepatic portosystemic shunt (TIPS) on portal hypertensive gastropathy (PHG) and gastric hemodynamics. METHODS: A total of 16 patients with cirrhosis and portal hypertensive gastropathy were prospectively studied. Of these, 12 patients underwent TIPS for esophageal varices and four for refractory ascites. Gastric mucosal blood flow (GMBF) was assessed by laser Doppler flowmeter, and total blood flow (TBF) in submucosa and mucosa by near-infrared endoscopy. Portal venous pressure was obtained by a transducer during the TIPS procedure. The severity of portal hypertensive gastropathy was classified as none, mild, or severe. The examinations were performed before and 2 wk after the procedure. RESULTS: TIPS significantly reduced portal venous pressure. PHG improved in all four patients with severe PHG and in five of 12 patients with mild PHG after treatment. Gastric mucosal blood flow increased from 49.0 to 55.6 ml/min/100 g after TIPS. In contrast, TBF decreased from 0.35/s to 0.27/s after treatment. Liver function tests showed no significant changes before and after the procedure. CONCLUSIONS: It is considered that TIPS may have a beneficial effect on PHG at least for a short time. The mechanism by which PHG improves may be closely related to the improvement of the injured gastric perfusion in cirrhotic patients with PHG. (Am J Gastroenterol 2001:96: 1155-1159. (C) 2001 by Am. Coll. of Gastroenterology).

A case of successful management of portosystemic shunt with autosomal dominant polycystic kidney disease by balloon-occluded retrograde transvenous obliteration and partial splenic embolization

K Takada, H Homma, M Takahashi, S Mezawa, K Miyanishi, T Sumiyoshi, T Doi, T Kukitsu, J Kato, Y Niitsu

EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY ( LIPPINCOTT WILLIAMS & WILKINS ) 13 ( 1 ) 75 - 78 2001.01 [Refereed]

describe a patient with autosomal dominant polycystic kidney disease who was successfully managed for severe abdominal distension, impaired liver function and a portosystemic shunt by interventional therapies, The patient's intra-hepatic portal vein was compressed and narrowed by multiple liver cysts, which resulted in a decrease of the portal blood flow and portal hypertension due to a huge gastro-renal shunt. These haemodynamic changes were assumed to contribute to insufficient protein synthesis in the liver, Therefore, we first repeatedly performed minocycline hydrochloride instillations to treat the multiple liver cysts, Then, we conducted a partial splenic embolization to prevent elevation of the portal vein pressure prior to balloon-occluded retrograde transvenous obliteration which was performed to increase the portal blood flow. The portal blood flow markedly increased, and protein synthesis in the liver also recovered and the clinical symptoms improved. The patient has been monitored for more than two years up to the present and her liver function parameters have remained within the normal range, Renal insufficiency is known to be a major prognostic factor in autosomal dominant polycystic kidney disease, In some cases, however, liver involvement with multiple cysts may result in a fatal outcome, In such cases, interventional therapies, as provided to this patient, should be considered. Eur J Gastroenterol Hepatol 13:75-78 (C) 2001 Lippincott Williams & Wilkins.

Re: Spontaneous rupture of renal metastasis of hepatocellular carcinoma: management by emergency transcatheter arterial embolization.

Mezawa S, Homma H, Doi T, Takada K, Kukitsu T, Kinebuchi M, Matsuura A, Sato N, Mezawa F, Miyanishi K, Niitsu Y

CardioVascular and Interventional Radiology. 24 ( 2 ) 143 - 144 2001 [Refereed]

DOI

Implantation of a dual chambers port for hepatic and splenic arterial infusion chemotherapy in advanced pancreatic carcinoma with multiple liver metastasis

T. Kukitsu, H. Homma, S. Iyama, T. Doi, M. Kida, S. Mezawa, K. Murase, K. Takada, K. Miyanishi, Y. Niitsu

Gan to kagaku ryoho. Cancer & chemotherapy 28 ( 11 ) 1562 - 1564 2001

PubMed

Hepatic and splenic arterial infusion chemotherapy after transcatheter peripancreatic arterial embolization for patients with inoperable adenocarcinoma of the pancreas

H. Homma, T. Kukitsu, S. Mezawa, T. Doi, M. Kida, K. Miyanishi, K. Takada, K. Murase, S. Iyama, Y. Niitsu

Gan to kagaku ryoho. Cancer & chemotherapy 28 ( 11 ) 1558 - 1561 2001

Thirty-one patients with advanced pancreatic carcinoma and liver metastases were treated by hepatic and splenic arterial infusion chemotherapy after transcatheter peripancreatic arterial embolization. The response rate for these 31 patients was 61.3%, with a mean survival period of 17.8 +/- 3.2 months and a 50% survival period of 12 months. By site of the primary tumor, the response rate for pancreatic head and body carcinoma was 81%, with a mean survival period of 21.6 +/- 4.0 months and a 50% survival period of 17 months, whereas the response rate for pancreatic caudal carcinoma was 20%, with a mean survival period of 6.1 +/- 0.5 months and a 50% survival period of 6 months. We believe that the current chemotherapy is an effective treatment for advanced pancreatic cancer with liver metastases.

PubMed

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.

A novel arterial infusion chemotherapy for the treatment of patients with advanced pancreatic carcinoma after vascular supply distribution via superselective embolization

H Homma, T Doi, S Mezawa, K Takada, T Kukitsu, T Oku, T Akiyama, T Kusakabe, K Miyanishi, Y Niitsu

CANCER ( WILEY-LISS ) 89 ( 2 ) 303 - 313 2000.07 [Refereed]

BACKGROUND. Patients with American Joint Committee on Cancer Stage TV advanced pancreatic carcinoma have been treated by systemic chemotherapy, intraarterial chemotherapy, radiation therapy, and multidisciplinary treatment using a combination of these. However, the outcome has not always been satisfactory. In the current study the authors describe the method and results of a new chemotherapy for advanced pancreatic carcinoma. METHODS. To restrict the blood flow into the pancreas (mainly to the great pancreatic artery and the caudal pancreatic artery), the peripancreatic blood vessels were embolized superselectively with microcoils. In 31 patients with advanced pancreatic carcinoma, the catheter tip for the arterial infusion chemotherapy was placed in the splenic artery just proximal to the branching of the great pancreatic artery when the treatment was given for primary tumors, and in the common hepatic artery when the treatment was given for a metastatic liver lesion. The other end of the catheter was connected to an implanted injection port embedded in the femoral region, and 5-fluorouracil and cisplatin were administered by continuous arterial infusion. RESULTS. Of the 31 patients with advanced pancreatic carcinoma, 23 (74%) underwent hemodynamic change and arterial infusion chemotherapy, with a response rate of 73.9% (complete response rate of 8.7% and a partial response rate of65.2%) and a mean survival period of 18.26 +/- 10.06 months. The I-year, 2-year, and 3-year survival rates were 90.9%, 42.8%, and 18.3%, respectively, with a mean survival period of 19.0 months. Of these 23 patients, the 16 patients with liver metastases had a response rate of 68.8% and a mean survival period of 16.25 +/- 8.35 months, whereas the 7 patients without liver metastases had a response rate of 87.5% and a mean survival period of 22.86 +/- 12.69 months. CONCLUSIONS. In patients with Stage IV advanced pancreatic carcinoma, arterial infusion chemotherapy after hemodynamic change was found to be effective against both primary tumors and metastatic liver lesions. The authors believe that the treatment presented in the current study should be attempted, even in patients with advanced pancreatic carcinoma, as long as the blood vessels for vascular supply distribution exist. (C) 2000 American Cancer Society.

Suppressive effect of ethanol on the expression of hepatic asialoglycoprotein receptors augmented by interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha

J Kato, Y Mogi, Y Kohgo, R Takimoto, M Kobune, H Hisai, T Nakamura, K Takada, Y Niitsu

JOURNAL OF GASTROENTEROLOGY ( SPRINGER VERLAG ) 33 ( 6 ) 855 - 859 1998.12 [Refereed]

Blood levels of inflammatory-related cytokines, including interleukin (IL)-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha, are elevated in patients with alcoholic liver diseases. We investigated the effects of these cytokines and ethanol on the expression of hepatic asialoglycoprotein receptors (AGPRs) in a human hepatoblastoma cell line, HepG2. An [I-125]-asialo-orosomucoid binding assay showed significant increases in surface AGPR numbers in HepG2 cells by treatment with IL-1 beta, IL-6, and TNF-alpha, to levels which were approximately 130% of the values in untreated control cells. However, the enhanced AGPR numbers induced by treatment with these cytokines were markedly suppressed, to 70%-80% of the number in the untreated cells, by treatment with ethanol. Immunological detection of AGPR with a specific antibody demonstrated that the modulation of surface AGPR numbers was correlated with the cellular expression levels of AGPR. These results suggest that, although IL-1 beta, IL-6, and TNF-alpha stimulate the synthesis of hepatic AGPR, ethanol suppresses the expression of AGPR augmented by these cytokines. This leads to an increase in serum asialo-orosomucoid levels caused by the disordered catabolism mediated by AGPR in patients with alcoholic liver diseasde.

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