Updated on 2024/10/22

Information

 

写真a

 
MORODOMI YOSUKE
 
Organization
Faculty of Pharmaceutical Sciences Academic Researcher
Title
Academic Researcher
Contact information
メールアドレス
Tel
0926426337

Degree

  • Doctor of Medicine

Papers

  • Murine Nuclear Tyrosyl-tRNA Synthetase Deficiency Leads to Fat Storage Deficiency and Hearing Loss. International journal

    Julia A Jones, Jiadong Zhou, Jianjie Dong, Salvador Huitron-Resendiz, Ely Boussaty, Eduardo Chavez, Na Wei, Calin Dan Dumitru, Yosuke Morodomi, Taisuke Kanaji, Allen F Ryan, Rick Friedman, Tong Zhou, Sachiko Kanaji, Matthew Wortham, Simon Schenk, Amanda J Roberts, Xiang-Lei Yang

    The Journal of biological chemistry   300 ( 10 )   107756 - 107756   2024.10   ISSN:00219258 eISSN:1083-351X

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Journal of Biological Chemistry  

    Aminoacyl-tRNA synthetases (aaRS) are fundamental to the translation machinery with emerging roles in transcriptional regulation. Previous cellular studies have demonstrated tyrosyl-tRNA synthetase (YARS1 or TyrRS) as a stress response protein through its cytosol-nucleus translocation to maintain cellular homeostasis. Here, we established a mouse model with a disrupted TyrRS nuclear localization signal, revealing its systemic impact on metabolism. Nuclear TyrRS deficiency (YarsΔNLS) led to reduced lean mass, reflecting a mild developmental defect, and reduced fat mass, possibly due to increased energy expenditure. Consistently, YarsΔNLS mice exhibit improved insulin sensitivity and reduced insulin levels, yet maintain normoglycemia, indicative of enhanced insulin action. Notably, YarsΔNLS mice also develop progressive hearing loss. These findings underscore the crucial function of nuclear TyrRS in the maintenance of fat storage and hearing and suggest that aaRSs' regulatory roles can affect metabolic pathways and tissue-specific health. This work broadens our understanding of how protein synthesis interconnects metabolic regulation to ensure energy efficiency.

    DOI: 10.1016/j.jbc.2024.107756

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  • Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response". International journal

    Julia A Jones, Na Wei, Haissi Cui, Yi Shi, Guangsen Fu, Navin Rauniyar, Ryan Shapiro, Yosuke Morodomi, Nadine Berenst, Calin Dan Dumitru, Sachiko Kanaji, John R Yates 3rd, Taisuke Kanaji, Xiang-Lei Yang

    Cell reports   42 ( 6 )   112632 - 112632   2023.6

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    Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation while selectively activating transcription factor ATF4 to aid cell survival and recovery. However, this integrated stress response is acute and cannot resolve lasting stress. Here, we report that tyrosyl-tRNA synthetase (TyrRS), a member of the aminoacyl-tRNA synthetase family that responds to diverse stress conditions through cytosol-nucleus translocation to activate stress-response genes, also inhibits global translation. However, it occurs at a later stage than eIF2α/ATF4 and mammalian target of rapamycin (mTOR) responses. Excluding TyrRS from the nucleus over-activates translation and increases apoptosis in cells under prolonged oxidative stress. Nuclear TyrRS transcriptionally represses translation genes by recruiting TRIM28 and/or NuRD complex. We propose that TyrRS, possibly along with other family members, can sense a variety of stress signals through intrinsic properties of this enzyme and strategically located nuclear localization signal and integrate them by nucleus translocation to effect protective responses against chronic stress.

    DOI: 10.1016/j.celrep.2023.112632

  • 第5土曜特集 mRNAワクチンやゲノム編集で注目が集まる遺伝子治療 遺伝子治療技術を用いた疾患治療 肺癌に対する免疫細胞治療

    諸富 洋介, 原田 結, 米満 吉和

    医学のあゆみ   285 ( 5 )   440 - 445   2023.4   ISSN:00392359

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    Publisher:医歯薬出版  

    DOI: 10.32118/ayu28505440

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  • Inflammatory platelet production stimulated by tyrosyl-tRNA synthetase mimicking viral infection. International journal

    Yosuke Morodomi, Sachiko Kanaji, Brian M Sullivan, Alessandro Zarpellon, Jennifer N Orje, Eric Won, Ryan Shapiro, Xiang-Lei Yang, Wolfram Ruf, Paul Schimmel, Zaverio M Ruggeri, Taisuke Kanaji

    Proceedings of the National Academy of Sciences of the United States of America   119 ( 48 )   e2212659119   2022.11

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    Platelets play a role not only in hemostasis and thrombosis, but also in inflammation and innate immunity. We previously reported that an activated form of tyrosyl-tRNA synthetase (YRSACT) has an extratranslational activity that enhances megakaryopoiesis and platelet production in mice. Here, we report that YRSACT mimics inflammatory stress inducing a unique megakaryocyte (MK) population with stem cell (Sca1) and myeloid (F4/80) markers through a mechanism dependent on Toll-like receptor (TLR) activation and type I interferon (IFN-I) signaling. This mimicry of inflammatory stress by YRSACT was studied in mice infected by lymphocytic choriomeningitis virus (LCMV). Using Sca1/EGFP transgenic mice, we demonstrated that IFN-I induced by YRSACT or LCMV infection suppressed normal hematopoiesis while activating an alternative pathway of thrombopoiesis. Platelets of inflammatory origin (Sca1/EGFP+) were a relevant proportion of those circulating during recovery from thrombocytopenia. Analysis of these "inflammatory" MKs and platelets suggested their origin in myeloid/MK-biased hematopoietic stem cells (HSCs) that bypassed the classical MK-erythroid progenitor (MEP) pathway to replenish platelets and promote recovery from thrombocytopenia. Notably, inflammatory platelets displayed enhanced agonist-induced activation and procoagulant activities. Moreover, myeloid/MK-biased progenitors and MKs were mobilized from the bone marrow, as evidenced by their presence in the lung microvasculature within fibrin-containing microthrombi. Our results define the function of YRSACT in platelet generation and contribute to elucidate platelet alterations in number and function during viral infection.

    DOI: 10.1073/pnas.2212659119

  • Circulating immune cells with megakaryocyte signature in response to COVID-19 mRNA vaccination. International journal

    Taisuke Kanaji, Yosuke Morodomi, Sachiko Kanaji

    Thrombosis research   220   1 - 4   2022.10

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    DOI: 10.1016/j.thromres.2022.10.003

  • Mechanistic perspectives on anti-aminoacyl-tRNA synthetase syndrome. International journal

    Sachiko Kanaji, Wenqian Chen, Yosuke Morodomi, Ryan Shapiro, Taisuke Kanaji, Xiang-Lei Yang

    Trends in biochemical sciences   2022.10

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    Antisynthetase syndrome (ASSD) is an autoimmune disease characterized by circulating autoantibodies against one of eight aminoacyl-tRNA synthetases (aaRSs). Although these autoantibodies are believed to play critical roles in ASSD pathogenesis, the nature of their roles remains unclear. Here we describe ASSD pathogenesis and discuss ASSD-linked aaRSs - from the WHEP domain that may impart immunogenicity to the role of tRNA in eliciting the innate immune response and the secretion of aaRSs from cells. Through these explorations, we propose that ASSD pathogenesis involves the tissue-specific secretion of aaRSs and that extracellular tRNAs or tRNA fragments and their ability to engage Toll-like receptor signaling may be important disease factors.

    DOI: 10.1016/j.tibs.2022.09.011

  • The impact of aberrant von Willebrand factor-GPIbα interaction on megakaryopoiesis and platelets in humanized type 2B von Willebrand disease model mouse. International journal

    Sachiko Kanaji, Yosuke Morodomi, Hartmut Weiler, Alessandro Zarpellon, Robert R Montgomery, Zaverio M Ruggeri, Taisuke Kanaji

    Haematologica   107 ( 9 )   2133 - 2143   2022.9

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    Type 2B von Willebrand disease (VWD) is caused by gain-of-function mutations in von Willebrand factor (VWF). Increased VWF affinity for GPIba results in loss of high molecular weight multimers and enhanced platelet clearance, both contributing to the bleeding phenotype. Severity of the symptoms vary among type 2B VWD patients, with some developing thrombocytopenia only under stress conditions. Efforts have been made to study underlying pathophysiology for platelet abnormalities, but animal studies have been limited because of species specificity in the VWF-GPIba interaction. Here, we generated a severe form of type 2B VWD (p.V1316M) knockin mice in the context of human VWF exon 28 (encoding A1 and A2 domains) and crossed them with human GPIba transgenic strain. Heterozygous mutant mice recapitulated the phenotype of type 2B VWD in autosomal dominant manner and presented severe macrothrombocytopenia. Of note, platelets remaining in the circulation had extracytoplasmic GPIba shed-off from the cell surface. Reciprocal bone marrow transplantation determined mutant VWF produced from endothelial cells as the major cause of the platelet phenotype in type 2B VWD mice. Moreover, altered megakaryocyte maturation in the bone marrow and enhanced extramedullary megakaryopoiesis in the spleen were observed. Interestingly, injection of anti-VWF A1 blocking antibody (NMC-4) not only ameliorated platelet count and GPIba expression, but also reversed MK ploidy shift. In conclusion, we present a type 2B VWD mouse model with humanized VWF-GPIba interaction which demonstrated direct influence of aberrant VWF-GPIba binding on megakaryocytes.

    DOI: 10.3324/haematol.2021.280561

  • Detection of anti-GPIbα autoantibodies in a case of immune thrombocytopenia following COVID-19 vaccination. International journal

    Takayuki Nakamura, Yosuke Morodomi, Sachiko Kanaji, Takashi Okamura, Koji Nagafuji, Taisuke Kanaji

    Thrombosis research   209   80 - 83   2022.1

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    DOI: 10.1016/j.thromres.2021.11.030

  • Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear Staphylococcus aureus bacteremia. International journal

    Josh Sun, Satoshi Uchiyama, Joshua Olson, Yosuke Morodomi, Ingrid Cornax, Nao Ando, Yohei Kohno, May M T Kyaw, Bernice Aguilar, Nina M Haste, Sachiko Kanaji, Taisuke Kanaji, Warren E Rose, George Sakoulas, Jamey D Marth, Victor Nizet

    Science translational medicine   13 ( 586 )   2021.3

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    Staphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20 to 30%) despite modern supportive care. In a human bacteremia cohort, we found that development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta), a commonly prescribed P2Y12 receptor inhibitor used after myocardial infarction, blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thereby providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu) provided similar therapeutic benefit. Thus, a "toxin-platelet-AMR" regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof of concept for repurposing two commonly prescribed drugs as adjunctive therapies to improve patient outcomes.

    DOI: 10.1126/scitranslmed.abd6737

  • Extracellular tyrosyl-tRNA synthetase cleaved by plasma proteinases and stored in platelet α-granules: Potential role in monocyte activation. International journal

    Eric Won, Yosuke Morodomi, Sachiko Kanaji, Ryan Shapiro, My-Nuong Vo, Jennifer N Orje, Courtney D Thornburg, Xiang-Lei Yang, Zaverio M Ruggeri, Paul Schimmel, Taisuke Kanaji

    Research and practice in thrombosis and haemostasis   4 ( 7 )   1167 - 1177   2020.10

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    BACKGROUND: Tyrosyl-tRNA synthetase (YRS) belongs to the family of enzymes that catalyzes the tRNA aminoacylation reaction for protein synthesis, and it has been recently shown to exert noncanonical functions. Although database results indicate extremely low levels of YRS mRNA in platelets, YRS protein is abundantly present. The source of YRS in platelets, as well as the physiological role of platelet-stored YRS, remains largely unknown. OBJECTIVES: To clarify how YRS accumulates in platelets and determine the potential role of platelet-stored YRS. METHODS: Recombinant YRS proteins with epitope tags were prepared and tested in vitro for proteolytic cleavage in human plasma. Fluorescent-labeled YRS was examined for uptake by platelets, as demonstrated by western blotting and confocal microscopy analysis. Using RAW-Dual reporter cells, Toll-like receptor and type I interferon activation pathways were analyzed after treatment with YRS. RESULTS: Full-length YRS was cleaved by both elastase and matrix metalloproteinases in the plasma. The cleaved, N-terminal YRS fragment corresponds to the endogenous YRS detected in platelet lysate by western blotting. Both full-length and cleaved forms of YRS were taken up by platelets in vitro and stored in the α-granules. The N-terminal YRS fragment generated by proteolytic cleavage had monocyte activation comparable to that of the constitutive-active mutant YRS (YRSY341A) previously reported. CONCLUSION: Platelets take up both full-length YRS and the active form of cleaved YRS fragment from the plasma. The cleaved, N-terminal YRS fragment stored in α-granules may have potential to activate monocytes.

    DOI: 10.1002/rth2.12429

  • LINE-1 Hypomethylation Is Associated With Malignant Traits and Cell Proliferation in Lung Adenocarcinoma. International journal

    Hirokazu Kitahara, Tatsuro Okamoto, Shinichiro Shimamatsu, Mikihiro Kohno, Yosuke Morodomi, Tetsuzo Tagawa, Hiroyuki Kitao, Shinji Okano, Yoshinao Oda, Yoshihiko Maehara, Masaki Mori

    Anticancer research   40 ( 10 )   5659 - 5666   2020.10

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    BACKGROUND/AIM: Long interspersed nuclear element-1 (LINE-1) methylation status is a marker for global DNA methylation. However, the relationship between LINE-1 methylation and the biology of lung adenocarcinoma remains unclear. Here, we aimed to examine the role of LINE-1 in lung cancer. MATERIALS AND METHODS: LINE-1 methylation levels were quantified by bisulfite pyrosequencing of resected tumor specimens from 162 patients with lung adenocarcinoma. The relationships of LINE-1 methylation with clinicopathological factors, gene mutations, and Ki-67 immunoreactivity were investigated. RESULTS: LINE-1 hypomethylation was associated with tumor invasion and advanced stage. TP53 mutations were more frequently detected in the LINE-1 hypomethylation group than in the hypermethylation group. LINE-1 hypomethylation was associated with poor recurrence-free survival, high maximum standardized uptake value in positron-emission tomography, and high Ki-67 expression in tumors. CONCLUSION: LINE-1 hypomethylation was associated with high-grade malignancy and poor prognosis in lung adenocarcinoma, but was not related to driver mutations.

    DOI: 10.21873/anticanres.14579

  • Mechanisms of anti-GPIbα antibody-induced thrombocytopenia in mice. International journal

    Yosuke Morodomi, Sachiko Kanaji, Eric Won, Zaverio M Ruggeri, Taisuke Kanaji

    Blood   135 ( 25 )   2292 - 2301   2020.6

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    Immune thrombocytopenia (ITP) is an acquired bleeding disorder characterized by antibody-mediated platelet destruction. Different mechanisms have been suggested to explain accelerated platelet clearance and impaired thrombopoiesis, but the pathophysiology of ITP has yet to be fully delineated. In this study, we tested 2 mouse models of immune-mediated thrombocytopenia using the rat anti-mouse GPIbα monoclonal antibody 5A7, generated in our laboratory. After a single IV administration of high-dose (2 mg/kg) 5A7, opsonized platelets were rapidly cleared from the circulation into the spleen and liver; this was associated with rapid upregulation of thrombopoietin (TPO) messenger RNA. In contrast, subcutaneous administration of low-dose 5A7 (0.08-0.16 mg/kg) every 3 days gradually lowered the platelet count; in this case, opsonized platelets were observed only in the spleen, and TPO levels remained unaltered. Interestingly, in both models, the 5A7 antibody was found on the surface of, as well as internalized to, bone marrow megakaryocytes. Consequently, platelets generated in the chronic phase of repeated subcutaneous 5A7 administration model showed reduced GPIbα membrane expression on their surface. Our findings indicate that evaluation of platelet surface GPIbα relative to platelet size may be a useful marker to support the diagnosis of anti-GPIbα antibody-induced ITP.

    DOI: 10.1182/blood.2019003770

  • Modified application of Kawamoto's film method for super-resolution imaging of megakaryocytes in undecalcified bone marrow. International journal

    Yosuke Morodomi, Sachiko Kanaji, Eric Won, Tadafumi Kawamoto, Taisuke Kanaji

    Research and practice in thrombosis and haemostasis   4 ( 1 )   86 - 91   2020.1

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    BACKGROUND: Super-resolution microscopy has enabled high-resolution imaging of the actin cytoskeleton in megakaryocytes and platelets. These technologies have extended our knowledge of thrombopoiesis and platelet spreading using megakaryocytes and platelets cultured in vitro on matrix proteins. However, for better understanding of megakaryocytopoiesis and platelet production, high-resolution imaging of cells in an in vivo bone marrow microenvironment is required. Development of Kawamoto's film method greatly advanced the techniques of thin cryosectioning of hard tissues such as undecalcified bones. One obstacle that remains is the spherical aberration that occurs due to the difference in the refractive index for the light path, limiting the usage of Kawamoto's film method to lower magnification observation. OBJECTIVES: To overcome the weakness of the conventional Kawamoto's film method for higher magnification observation of undecalcified bone marrow. METHODS: We have modified the original method with a very simple method: flipping the film at the step of mounting the sections on the glass. RESULTS AND CONCLUSIONS: This new method successfully led to the adjustment of the refractive index and enabled super-resolution imaging of megakaryocytes in undecalcified mouse femurs. Our modified method will expand the application of Kawamoto's film method and enable precise analysis of megakaryocytopoiesis and platelet production in the bone marrow microenvironment under pathophysiological conditions.

    DOI: 10.1002/rth2.12276

  • TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding. International journal

    Tine Wyseure, Tingyi Yang, Jenny Y Zhou, Esther J Cooke, Bettina Wanko, Merissa Olmer, Ruchi Agashe, Yosuke Morodomi, Niels Behrendt, Martin Lotz, John Morser, Annette von Drygalski, Laurent O Mosnier

    JCI insight   4 ( 19 )   2019.10

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    Excessive vascular remodeling is characteristic of hemophilic arthropathy (HA) and may contribute to joint bleeding and the progression of HA. Mechanisms for pathological vascular remodeling after hemophilic joint bleeding are unknown. In hemophilia, activation of thrombin-activatable fibrinolysis inhibitor (TAFI) is impaired, which contributes to joint bleeding and may also underlie the aberrant vascular remodeling. Here, hemophilia A (factor VIII-deficient; FVIII-deficient) mice or TAFI-deficient mice with transient (antibody-induced) hemophilia A were used to determine the role of FVIII and TAFI in vascular remodeling after joint bleeding. Excessive vascular remodeling and vessel enlargement persisted in FVIII-deficient and TAFI-deficient mice, but not in transient hemophilia WT mice, after similar joint bleeding. TAFI-overexpression in FVIII-deficient mice prevented abnormal vessel enlargement and vascular leakage. Age-related vascular changes were observed with FVIII or TAFI deficiency and correlated positively with bleeding severity after injury, supporting increased vascularity as a major contributor to joint bleeding. Antibody-mediated inhibition of uPA also prevented abnormal vascular remodeling, suggesting that TAFI's protective effects include inhibition of uPA-mediated plasminogen activation. In conclusion, the functional TAFI deficiency in hemophilia drives maladaptive vascular remodeling in the joints after bleeding. These mechanistic insights allow targeted development of potentially new strategies to normalize vascularity and control rebleeding in HA.

    DOI: 10.1172/jci.insight.128379

  • Humanized GPIbα-von Willebrand factor interaction in the mouse. International journal

    Sachiko Kanaji, Jennifer N Orje, Taisuke Kanaji, Yuichi Kamikubo, Yosuke Morodomi, Yunfeng Chen, Alessandro Zarpellon, Jerome Eberhardt, Stefano Forli, Scot A Fahs, Rashmi Sood, Sandra L Haberichter, Robert R Montgomery, Zaverio M Ruggeri

    Blood advances   2 ( 19 )   2522 - 2532   2018.10

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    The interaction of platelet glycoprotein Ibα (GPIbα) with von Willebrand factor (VWF) initiates hemostasis after vascular injury and also contributes to pathological thrombosis. GPIbα binding to the VWF A1 domain (VWFA1) is a target for antithrombotic intervention, but attempts to develop pharmacologic inhibitors have been hindered by the lack of animal models because of the species specificity of the interaction. To address this problem, we generated a knockin mouse with Vwf exon 28-encoding domains A1 and A2 replaced by the human homolog (VWFh28). VWFh28 mice (M1HA) were crossbred with a transgenic mouse strain expressing human GPIbα on platelets (mGPIbαnull;hGPIbαTg; H1MA) to generate a new strain (H1HA) with humanized GPIbα-VWFA1 binding. Plasma VWF levels in the latter 3 strains were similar to those of wild-type mice (M1MA). Compared with the strains that had homospecific GPIbα-VWF pairing (M1MA and H1HA), M1HA mice of those with heterospecific pairing had a markedly greater prolongation of tail bleeding time and attenuation of thrombogenesis after injury to the carotid artery than H1MA mice. Measurements of GPIbα-VWFA1 binding affinity by surface plasmon resonance agreed with the extent of observed functional defects. Ristocetin-induced platelet aggregation was similar in H1HA mouse and human platelet-rich plasma, and it was comparably inhibited by monoclonal antibody NMC-4, which is known to block human GPIbα-VWFA1 binding, which also inhibited FeCl3-induced mouse carotid artery thrombosis. Thus, the H1HA mouse strain is a fully humanized model of platelet GPIbα-VWFA1 binding that provides mechanistic and pharmacologic information relevant to human hemostatic and thrombotic disorders.

    DOI: 10.1182/bloodadvances.2018023507

  • miR-3148 Is a Novel Onco-microRNA that Potentiates Tumor Growth In Vivo. International journal

    Takaki Akamine, Yosuke Morodomi, Yui Harada, Koji Teraishi, Tetsuzo Tagawa, Tatsuro Okamoto, Yoshihiko Maehara, Yoshikazu Yonemitsu

    Anticancer research   38 ( 10 )   5693 - 5701   2018.10

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    BACKGROUND/AIM: Alterations of microRNA expression in three-dimensional spheroids were examined to identify novel microRNAs that might be associated with tumorigenesis. MATERIALS AND METHODS: Using microRNA microarray analysis, we screened for microRNAs that were dramatically up-regulated inside three-dimensional spheroids in genetically-modified HCT116 human colon cancer cells expressing Copepoda Green Fluorescent Protein under hypoxia. RESULTS: miR-3148 was identified as a possible candidate onco-microRNA. A growth advantage of HCT116 cells stably expressing miR-3148 (HCT116-miR3148) was observed compared to parental cells in vivo, but not in vitro. Additionally, no change in growth under hypoxic or starvation conditions was seen in these cells cultured two-dimensionally; however, HCT116-miR3148 cells maintained as three-dimensional spheroids were highly resistant to hypoxic conditions. HCT116-miR3148 cells were more sensitive to mitogen-activated protein kinase (MAPK) kinase inhibitors and extracellular signal-regulated kinase (ERK) inhibitors. CONCLUSION: MiR-3148 may be a novel onco-microRNA that protects cancer cells from serious stress conditions through the MAPK/ERK pathway, especially in vivo.

    DOI: 10.21873/anticanres.12906

  • Tyrosyl-tRNA synthetase stimulates thrombopoietin-independent hematopoiesis accelerating recovery from thrombocytopenia. International journal

    Taisuke Kanaji, My-Nuong Vo, Sachiko Kanaji, Alessandro Zarpellon, Ryan Shapiro, Yosuke Morodomi, Akinori Yuzuriha, Koji Eto, Rajesh Belani, Minh-Ha Do, Xiang-Lei Yang, Zaverio M Ruggeri, Paul Schimmel

    Proceedings of the National Academy of Sciences of the United States of America   115 ( 35 )   E8228-E8235   2018.8

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    New mechanisms behind blood cell formation continue to be uncovered, with therapeutic approaches for hematological diseases being of great interest. Here we report an enzyme in protein synthesis, known for cell-based activities beyond translation, is a factor inducing megakaryocyte-biased hematopoiesis, most likely under stress conditions. We show an activated form of tyrosyl-tRNA synthetase (YRSACT), prepared either by rationally designed mutagenesis or alternative splicing, induces expansion of a previously unrecognized high-ploidy Sca-1+ megakaryocyte population capable of accelerating platelet replenishment after depletion. Moreover, YRSACT targets monocytic cells to induce secretion of transacting cytokines that enhance megakaryocyte expansion stimulating the Toll-like receptor/MyD88 pathway. Platelet replenishment by YRSACT is independent of thrombopoietin (TPO), as evidenced by expansion of the megakaryocytes from induced pluripotent stem cell-derived hematopoietic stem cells from a patient deficient in TPO signaling. We suggest megakaryocyte-biased hematopoiesis induced by YRSACT offers new approaches for treating thrombocytopenia, boosting yields from cell-culture production of platelet concentrates for transfusion, and bridging therapy for hematopoietic stem cell transplantation.

    DOI: 10.1073/pnas.1807000115

  • Correlation between CXCR4/CXCR7/CXCL12 chemokine axis expression and prognosis in lymph-node-positive lung cancer patients. International journal

    Masakazu Katsura, Fumihiro Shoji, Tatsuro Okamoto, Shinichiro Shimamatsu, Fumihiko Hirai, Gouji Toyokawa, Yosuke Morodomi, Tetsuzo Tagawa, Yoshinao Oda, Yoshihiko Maehara

    Cancer science   109 ( 1 )   154 - 165   2018.1

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    The CXCR4/CXCR7/CXCL12 chemokine axis plays important roles in the migration of tumor cells during cancer development by modulating site-specific distant metastasis including to regional lymph nodes. We investigated the correlation of these chemokine expressions to prognosis in lymph-node-positive non-small-cell lung cancer (NSCLC) patients. A total of 140 surgically resected specimens of primary site (PS) and metastatic lymph nodes (MLN) of NSCLC involving hilar and/or mediastinal lymph nodes (N1-2) were collected. CXCR4, CXCR7 and CXCL12 expressions were evaluated. Cox regression analysis was performed to determine whether these chemokines were independent prognostic factors in N1-2 NSCLC. High expression of CXCR4 in PS and CXCL12 in MLN was associated with poor overall survival (OS) (P = .025 and .033, respectively). Significant correlations between CXCR4 expression in PS and CXCL12 expression in MLN were observed (P = .040). There was significant difference in OS between 2 groups according to expressions of CXCR4 in PS and CXCL12 in MLN (P = .0033). Expression of CXCL12 in MLN was identified as an independent prognostic factor (HR 1.79, 95&#37; CI 1.08-3.04, P = .023). CXCL12 in MLN was mainly expressed by tumor cells compared with stromal cells (56&#37; vs 25&#37;, respectively, P < .0001). CXCR4/CXCL12 may play roles in tumor progression in MLN and is associated with poor prognosis of lymph-node-positive NSCLC patients.

    DOI: 10.1111/cas.13422

  • Monitoring trifluridine incorporation in the peripheral blood mononuclear cells of colorectal cancer patients under trifluridine/tipiracil medication. International journal

    Ryota Nakanishi, Hiroyuki Kitao, Mamoru Kiniwa, Yosuke Morodomi, Makoto Iimori, Junji Kurashige, Masahiko Sugiyama, Yuichiro Nakashima, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara

    Scientific reports   7 ( 1 )   16969 - 16969   2017.12

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    Trifluridine/tipiracil (TFTD, TAS-102) is an orally administrated anti-cancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC). Trifluridine (FTD) is an active cytotoxic component of TFTD and mediates the anticancer effect via its incorporation into DNA. However, it has not been examined whether FTD is incorporated into the tissues of patients who received TFTD medication. By detecting FTD incorporation into DNA by a specific antibody, we successfully detected FTD in the bone marrow and spleen cells isolated from FTD-challenged mice as well as human peripheral blood mononuclear cells (PBMCs) activated with phytohemagglutinin-P and exposed to FTD in vitro. FTD was also detected in PBMCs isolated from mCRC patients who had administrated TFTD medication. Intriguingly, weekly evaluation of PBMCs from mCRC patients revealed the percentage of FTD-positive PBMCs increased and decreased in parallel with the administration and cessation of TFTD medication, respectively. To our knowledge, this is the first report to detect an active cytotoxic component of a chemotherapeutic drug in clinical specimens using a specific antibody. This technique may enable us to predict the clinical benefits or the adverse effects of TFTD in mCRC patients.

    DOI: 10.1038/s41598-017-17282-5

  • Reply to "EGFR Mutation in Patients with Lung Adenosquamous Cell Carcinoma". International journal

    Yosuke Morodomi, Tatsuro Okamoto, Yoshihiko Maehara

    Annals of surgical oncology   24 ( Suppl 3 )   676 - 676   2017.12

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    DOI: 10.1245/s10434-017-6181-z

  • Clinical Significance of DNA Damage Response Factors and Chromosomal Instability in Primary Lung Adenocarcinoma. International journal

    Tatsuro Okamoto, Mikihiro Kohno, Kensaku Ito, Kazuki Takada, Masakazu Katsura, Yosuke Morodomi, Gouji Toyokawa, Fumihiro Shoji, Yoshihiko Maehara

    Anticancer research   37 ( 4 )   1729 - 1735   2017.4

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    AIM: The purpose of this study was to investigate the biological role of DNA damage-response genes and chromosomal instability in primary lung adenocarcinoma. MATERIALS AND METHODS: We investigated 60 surgically-resected lung adenocarcinomas. Levels of checkpoint kinase 2 gene (CHEK2) and breast cancer type 1 susceptibility protein gene (BRCA1) mRNA expression were evaluated by polymerase chain reaction (PCR). Epidermal growth factor receptor (EGFR) mutations (exon 19 deletion and exon 21 mutation) were detected by the PCR clamp method. Mutations in Kirsten rat sarcoma viral oncogene homolog gene (KRAS) and TP53 were examined by direct sequencing. Expression levels of p27 and p16 proteins were assessed by immunohistochemistry. Chromosomal aberrations (CA) were examined in 20 samples with single-nucleotide polymorphism-comparative genomic hybridization. RESULTS: CHEK2 mRNA levels were significantly increased in tumor tissues compared to normal tissues (p=0.0123, paired t-test), whereas BRCA mRNA levels were not increased. TP53 mutation positivity and BRCA1 mRNA expression were positively associated with CHEK2 mRNA expression status (p=0.022 and p=0.0008). High CHEK2 mRNA expression was associated with poor recurrence-free survival (p=0.028). CHEK2 mRNA levels were higher in samples with a high CA frequency than in those with a low CA frequency (averages: 0.326 vs. 0.185; p=0.0129). CONCLUSION: The CHEK2 mRNA expression level was found elevated in lung adenocarcinoma and was related to a poor prognostic outcome. The CHEK2 pathway may be important for the proliferation of lung adenocarcinoma, especially in tumors with chromosomal instability.

  • Underlying Problems in Surgical Treatment of cT1-2N1 Non-Small Cell Lung Cancer. International journal

    Tatsuro Okamoto, Tetsuzo Tagawa, Yosuke Morodomi, Shinichiro Shimamatsu, Hirokazu Kitahara, Yoshihiko Maehara

    The Thoracic and cardiovascular surgeon   65 ( 2 )   130 - 135   2017.3

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    Background Obtaining an accurate preoperative diagnosis of N1 in non-small cell lung cancer (NSCLC) is a major difficulty. The aim of this retrospective study was to evaluate the pathological and long-term outcomes of NSCLC patients clinically staged with N1 disease, to aid in the search for better treatment strategies. Materials and Methods We retrospectively reviewed the clinical records of 1,180 consecutive patients with NSCLC who underwent surgery for curative intent from 1991 to 2011 in our department. Data on 96 (8.1&#37;) patients who had cT1-2N1 disease and underwent lobectomy or more extensive surgery were available. Results Only 32&#37; of patients (n = 31) were confirmed to have pathological N1 disease, and 34 and 33&#37; of patients were proven to have pN0 and pN2 disease, respectively. Female gender, ≤ 30 pack-year tobacco smoking history, adenocarcinoma, and left-sided disease were significantly associated with pathological upstaging (χ2 test). Multivariate analysis using logistic regression revealed left-sided disease to be independently associated with upstaging (relative risk 4.00, p = 0.015). Left-sided disease was more likely to be underestimated by clinical N staging than right-sided disease (χ2 test, p = 0.0001). Univariate and multivariate survival analyses demonstrated that left-sided disease was an independent prognostic factor associated with poor outcomes (Cox proportional hazards regression: hazard ratio 2.27, p = 0.037). Conclusion The diagnostic accuracy of clinical N1 status was poor. Left-sided disease appeared to be understaged by the preoperative assessment of N status, and therefore, patients who might benefit from preoperative induction treatment would not receive it.

    DOI: 10.1055/s-0035-1558648

  • Clinical Evaluation and Outcomes of Digital Chest Drainage after Lung Resection.

    Fumihiro Shoji, Shinkichi Takamori, Takaki Akamine, Gouji Toyokawa, Yosuke Morodomi, Tatsuro Okamoto, Yoshihiko Maehara

    Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia   22 ( 6 )   354 - 358   2016.12

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    BACKGROUND: Analog chest drainage systems (ACS) are generally used to monitor postoperative alveolar air leakage (PAL) after lung resection. An electronic digital chest drainage system (DCS) has recently been developed that reportedly has several advantages over the traditional ACS. Here, we report a single institution's experience of PAL management with the DCS. We also sought to establish whether DCS had superior clinical benefits and outcomes compared with ACS. METHODS: We enrolled 112 consecutive patients who underwent lung resection and were subsequently managed with DCS. We compared PAL rate, duration of chest drainage, and the incidence of complications with a group of 121 consecutive patients previously managed with ACS after lung resection, using propensity score matching. RESULTS: Mean maximum and minimum PAL rates during DCS chest drainage were 48.9 ml/min (range: 2.0-868.6 ml/min) and 0.1 ml/min (0.0-1.2 ml/min), respectively. Mean PAL rate at DCS removal was 1.3 ml/min (0.0-10.0 ml/min). After propensity score matching, mean duration of chest drainage was significantly shorter with DCS than ACS (2.7 days, range: 1-9 days, compared with 3.7 days, range: 1-21 days, respectively; P = 0.031). CONCLUSIONS: Managing PAL with DCS after pulmonary resection appears to reduce the duration of chest drainage.

    DOI: 10.5761/atcs.oa.16-00179

  • Prognostic Significance of Expression of the Epithelial-Mesenchymal Transition-Related Factor Brachyury in Intrathoracic Lymphatic Spread of Non-Small Cell Lung Cancer. International journal

    Shinichiro Shimamatsu, Tatsuro Okamoto, Akira Haro, Hirokazu Kitahara, Mikihiro Kohno, Yosuke Morodomi, Tetsuzo Tagawa, Shinji Okano, Yoshinao Oda, Yoshihiko Maehara

    Annals of surgical oncology   23 ( Suppl 5 )   1012 - 1020   2016.12

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    BACKGROUND: Brachyury is a transcriptional regulator that plays important roles in epithelial mesenchymal transition (EMT) during development and has been reported to be essential for mesoderm formation in the early human embryo. We investigated Brachyury protein expression in hilar and mediastinal metastatic lymph nodes of non-small cell lung cancer patients and the prognostic significance of Brachyury expression at metastatic sites. METHODS: Expression of Brachyury in 115 surgically resected primary lung cancer and corresponding metastatic lymph node samples was evaluated by immunohistochemical staining. The relationships between Brachyury protein expression and the patient's clinicopathological factors and prognosis were analyzed. RESULTS: Brachyury expression in metastatic lymph nodes was significantly higher than that in the primary tumor (p = 0.012). Patients with high Brachyury expression in the metastatic lymph nodes had significantly poor prognoses (p = 0.0236) compared with patients with low expression. In addition, patients with larger differences in Brachyury expression between metastatic lymph nodes and the primary tumor had significantly poorer prognoses compared with patients with smaller differences (p = 0.0146). The Brachyury protein expression level in metastatic lymph nodes was significantly associated with the protein expression levels of other EMT-related factors (E-cadherin [inverse association], p = 0.0265; Slug, p = 0.029; and interleukin-8, p = 0.0135). CONCLUSIONS: High expression of Brachyury protein in metastatic carcinoma cells in the intrathoracic lymph nodes was associated with poor prognosis of lung cancer patients. Increased Brachyury expression during the metastatic process may confer further potential for invasion and metastasis of cancer cells.

  • A novel method of using bioabsorbable materials for the surgical repair of flail chest. International journal

    Yosuke Morodomi, Tatsuro Okamoto, Tetsuzo Tagawa, Fumihiro Shoji, Masakazu Katsura, Takatoshi Fujishita, Tetsuhiro Fujiyoshi, Tomohiko Akahoshi, Mitsuhiro Yasuda, Yoshihiko Maehara

    The journal of trauma and acute care surgery   81 ( 5 )   984 - 987   2016.11

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  • Clinical implications of sarcopenia in patients undergoing complete resection for early non-small cell lung cancer. International journal

    Yuzo Suzuki, Tatsuro Okamoto, Takatoshi Fujishita, Masakazu Katsura, Takaki Akamine, Shinkichi Takamori, Yosuke Morodomi, Tetsuzo Tagawa, Fumihiro Shoji, Yoshihiko Maehara

    Lung cancer (Amsterdam, Netherlands)   101   92 - 97   2016.11

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    OBJECTIVES: Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength. We aimed to investigate sarcopenia in patients with stage I non-small cell lung cancer (NSCLC) who underwent complete resection, and the relationship of sarcopenia with clinicopathological factors. METHODS: All consecutive patients who underwent lung resection between January 2005 and December 2008 were enrolled in this retrospective study. Eligible patients were assigned to one of 2 groups according to the presence or absence of sarcopenia, as assessed by the sum of cross-sectional areas of skeletal muscles in the region of the third lumbar vertebra (L3) on preoperative computed tomography (CT). RESULTS: Sixteen of 52 male (30.8&#37;) and 22 of 38 female (57.9&#37;) patients were identified with sarcopenia (p=0.01). Patients with sarcopenia were more likely to have a low body mass index (BMI) (p<0.0001). Kaplan-Meier analysis showed that patients with sarcopenia had a significantly worse outcome than patients without sarcopenia (5-year-survival: 72.8&#37; vs 85.8&#37;, respectively, p=0.028). Multivariate analysis found that sarcopenia was a significant independent prognostic factor (hazard ratio: 7.09, p=0.0008). CONCLUSIONS: Sarcopenia identified on a cross-sectional CT image of the L3 level was associated with poor outcome with completely resected early-stage NSCLC.

    DOI: 10.1016/j.lungcan.2016.08.007

  • Clinical Significance of PD-L1 Protein Expression in Surgically Resected Primary Lung Adenocarcinoma. International journal

    Kazuki Takada, Tatsuro Okamoto, Fumihiro Shoji, Mototsugu Shimokawa, Takaki Akamine, Shinkichi Takamori, Masakazu Katsura, Yuzo Suzuki, Takatoshi Fujishita, Gouji Toyokawa, Yosuke Morodomi, Shinji Okano, Yoshinao Oda, Yoshihiko Maehara

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   11 ( 11 )   1879 - 1890   2016.11

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    INTRODUCTION: The clinicopathological features of carcinomas expressing programmed death ligand 1 (PD-L1) and their associations with common driver mutations, such as mutations in the EGFR gene, in lung adenocarcinoma are not clearly understood. Here, we examined PD-L1 protein expression in surgically resected primary lung adenocarcinoma and the association of PD-L1 protein expression with clinicopathological features, EGFR mutation status, and patient outcomes. METHODS: The expression of PD-L1 protein in 417 surgically resected primary lung adenocarcinomas was evaluated by immunohistochemical analysis. The cutoff value for defining PD-L1 positivity was determined according to the histogram of proportions of PD-L1-positive cancer cells. RESULTS: Samples from 85 patients (20.4&#37;) and 144 patients (34.5&#37;) were positive for PD-L1 protein expression according to 5&#37; and 1&#37; PD-L1 cutoff values, respectively. Fisher's exact tests showed that PD-L1 positivity was significantly associated with male sex, smoking, higher tumor grade, advanced T status, advanced N status, advanced stage, the presence of pleural and vessel invasions, micropapillary or solid predominant histological subtypes, and wild-type EGFR. Univariate and multivariate survival analyses revealed that patients with PD-L1 positivity had poorer prognoses than those without PD-L1 protein expression at the 1&#37; cutoff value (disease-free survival p < 0.0001, overall survival p < 0.0001). CONCLUSIONS: PD-L1 protein expression was significantly higher in smoking-associated adenocarcinoma and in EGFR mutation-negative adenocarcinoma. PD-L1 protein expression was associated with poor survival in patients with lung adenocarcinoma. The PD-L1/programmed cell death 1 pathway may contribute to the progression of smoking-associated tumors in lung adenocarcinoma.

    DOI: 10.1016/j.jtho.2016.06.006

  • Predictive impact for postoperative recurrence using the preoperative prognostic nutritional index in pathological stage I non-small cell lung cancer. International journal

    Fumihiro Shoji, Yosuke Morodomi, Takaki Akamine, Shinkichi Takamori, Masakazu Katsura, Kazuki Takada, Yuzo Suzuki, Takatoshi Fujishita, Tatsuro Okamoto, Yoshihiko Maehara

    Lung cancer (Amsterdam, Netherlands)   98   15 - 21   2016.8

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    BACKGROUND: The most effective treatment for early-stage non-small cell lung cancer (NSCLC) is surgical resection. Nevertheless, up to 20&#37; of patients, even those with stage I NSCLC, relapse after surgery and die. The prognostic nutritional index (PNI) is used to assess immunonutritional conditions or is a predictor of postoperative recurrence in patients with digestive malignancies. However, the usefulness of the PNI for lung cancer is still unknown. We retrospectively analyzed clinicopathological features of stage I NSCLC patients to identify predictors of recurrence and to investigate effects of preoperative PNI levels. METHODS: We selected 141 consecutive stage I NSCLC patients who were treated from August 2005 to August 2010. We measured their preoperative PNI levels in uni- and multivariate Cox regression analyses of recurrence-free survival. RESULTS: A low PNI was significantly associated with sex (P=0.0117), preoperative serum carcino embryonic antigen levels (P=0.0228), and postoperative recurrence (P<0.0001). In multivariate analysis, PNI (RR: 9.243; 95&#37; CI: 3.662-25.823; P<0.0001), pleural invasion (RR: 8.664; 95&#37; CI: 2.510-38.056; P=0.0005), and intratumoral blood vessel invasion (RR: 3.151; 95&#37; CI: 1.259-7.681; P=0.0152) were independent prognostic factors. The low-PNI group had a significantly shorter recurrence-free survival than the high-PNI group, regardless of pathological T factors (T1a, P=0.0422; T1b, P<0.0001; T2a, P=0.0098). CONCLUSIONS: The preoperative PNI level is a simple and novel predictor of recurrence in stage I NSCLC patients, and might help identify patients who will need multimodality therapy such as induction or adjuvant therapy.

    DOI: 10.1016/j.lungcan.2016.05.010

  • Case of a Cardiopulmonary Arrest Due to Postoperative Subglottic Stenosis Developed on the Second Day after Lung Surgery.

    Tomonari Shimagaki, Tatsuro Okamoto, Yosuke Morodomi, Fumihiro Shoji, Takaki Akamine, Shinkichi Takamori, Masakazu Katsura, Kazuki Takada, Yuzo Suzuki, Takatoshi Fujishita, Kengo Hayamizu, Kentaro Tokuda, Mitsuhiro Yasuda, Yoshihiko Maehara

    Fukuoka igaku zasshi = Hukuoka acta medica   107 ( 7 )   136 - 40   2016.7

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    We experienced a case of the cardiopulmonary arrest due to subglottic stenosis developed on the
    second day after lung cancer surgery. Case : A 73-year-old female who was diagnosed with primary
    lung cancer was referred to our department for surgery. The second day after left lung
    segmentectomy, she showed respiratory discomfort symptoms and exhibited hoarseness and stridor,
    which were revealed as the subglottic stenosis by bronchoscopy. During the emergency airway
    management, she went into cardiopulmonary arrest. We performed cardiopulmonary resuscitation
    and simultaneous urgent tracheotomy.

  • Nanomedicines Eradicating Cancer Stem-like Cells in Vivo by pH-Triggered Intracellular Cooperative Action of Loaded Drugs. International journal

    Hiroaki Kinoh, Yutaka Miura, Tsukasa Chida, Xueying Liu, Kazue Mizuno, Shigeto Fukushima, Yosuke Morodomi, Nobuhiro Nishiyama, Horacio Cabral, Kazunori Kataoka

    ACS nano   10 ( 6 )   5643 - 55   2016.6

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    Nanomedicines capable of control over drug functions have potential for developing resilient therapies, even against tumors harboring recalcitrant cancer stem cells (CSCs). By coordinating drug interactions within the confined inner compartment of core-shell nanomedicines, we conceived multicomponent nanomedicines directed to achieve synchronized and synergistic drug cooperation within tumor cells as a strategy for enhancing efficacy, overcoming drug resistance, and eradicating CSCs. The approach was validated by using polymeric micellar nanomedicines co-incorporating the pan-kinase inhibitor staurosporine (STS), which was identified as the most potent CSC inhibitor from a panel of signaling-pathway inhibitors, and the cytotoxic agent epirubicin (Epi), through rationally contriving the affinity between the drugs. The micelles released both drugs simultaneously, triggered by acidic endosomal pH, attaining concurrent intracellular delivery, with STS working as a companion for Epi, down-regulating efflux transporters and resistance mechanisms induced by Epi. These features prompted the nanomedicines to eradicate orthotopic xenografts of Epi-resistant mesothelioma bearing a CSC subpopulation.

    DOI: 10.1021/acsnano.6b00900

  • Prognostic Impact of EGFR Driver Mutations on Postoperative Disease Recurrence in Lung Adenocarcinoma. International journal

    Tatsuro Okamoto, Hirokazu Kitahara, Shinichiro Shimamatsu, Masakazu Katsura, Kazuki Takada, Takatoshi Fujishita, Yuzo Suzuki, Yosuke Morodomi, Tetsuzo Tagawa, Yoshihiko Maehara

    Anticancer research   36 ( 6 )   3057 - 63   2016.6

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    AIM: The purpose of this study was to investigate the prognostic significance of epidermal growth factor receptor (EGFR) sensitizing mutations in patients with lung adenocarcinoma who underwent complete surgical resection. PATIENTS AND METHODS: We retrospectively reviewed the clinical records of 164 patients with lung adenocarcinoma who underwent surgery from 2003 to 2010. Seventy-four patients harbored EGFR mutations; two with exon 18 mutations, 27 with exon 19 mutations, and 45 with exon 21 mutations. RESULTS: There were more female patients and more never-/light smokers among patients with EGFR mutations than among patients without EGFR mutations. Patients with EGFR mutations had a trend for better disease-free survival and overall survival compared to patients without EGFR mutations (p=0.068 and p=0.049, respectively). Patients with exon 21 mutations had significantly better disease-free survival than patients with exon 19 mutations (p=0.027). CONCLUSION: Adenocarcinomas harboring EGFR exon 21 mutation were less malignant than adenocarcinomas harboring exon 19 mutation.

  • The antibodies against 5-bromo-2'-deoxyuridine specifically recognize trifluridine incorporated into DNA. International journal

    Hiroyuki Kitao, Yosuke Morodomi, Shinichiro Niimi, Mamoru Kiniwa, Kazuhiko Shigeno, Kazuaki Matsuoka, Yuki Kataoka, Makoto Iimori, Eriko Tokunaga, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara

    Scientific reports   6   25286 - 25286   2016.5

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    Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102 (also named TFTD), which consists of FTD and a thymidine phosphorylase inhibitor. FTD is supposed to exert its cytotoxicity via massive misincorporation into DNA, but the underlying mechanism of FTD incorporation into DNA and its correlation with cytotoxicity are not fully understood. The present study shows that several antibodies against 5-bromo-2'-deoxyuridine (BrdU) specifically cross-react with FTD, either anchored to bovine serum albumin or incorporated into DNA. These antibodies are useful for several biological applications, such as fluorescence-activated cell sorting, fluorescent immunostaining and immunogold detection for electron microscopy. These techniques confirmed that FTD is mainly incorporated in the nucleus during S phase in a concentration-dependent manner. In addition, FTD was also detected by immunohistochemical staining in paraffin-embedded HCT-116 xenograft tumors after intraperitoneal administration of FTD. Intriguingly, FTD was hardly detected in surrounding matrices, which consisted of fibroblasts with marginal expression of the nucleoside transporter genes SLC29A1 and SLC29A2. Thus, applications using anti-BrdU antibodies will provide powerful tools to unveil the underlying mechanism of FTD action and to predict or evaluate the efficacy and adverse effects of TAS-102 clinically.

    DOI: 10.1038/srep25286

  • PD-L1 Is Upregulated by Simultaneous Amplification of the PD-L1 and JAK2 Genes in Non-Small Cell Lung Cancer. International journal

    Seiichi Ikeda, Tatsuro Okamoto, Shinji Okano, Yuichiro Umemoto, Tetsuzo Tagawa, Yosuke Morodomi, Mikihiro Kohno, Shinichiro Shimamatsu, Hirokazu Kitahara, Yuzo Suzuki, Takatoshi Fujishita, Yoshihiko Maehara

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   11 ( 1 )   62 - 71   2016.1

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    OBJECTIVES: The programmed death ligand 1(PD-L1)/programmed cell death protein 1 (PD-1) pathway is one of the most important checkpoint pathways for mediating tumor-induced immune suppression through T-cell exhaustion. Recently, targeted therapies using monoclonal antibodies against components of this pathway have been shown to reduce tumor burden in patients with non-small cell lung cancer (NSCLC). However, the prognostic significance of PD-L1 expression is controversial and the precise mechanisms of PD-L1 gene activation in lung cancer have yet to be clarified. METHODS: We investigated copy number alterations (CNAs) in the PD-L1 gene by real-time PCR in 94 surgically resected lung cancer samples to find possible associations between PD-L1 CNA and lung cancer biology. Janus kinase 2 gene (JAK2) CNA and its influence on the PD-L1/PD-1 pathway were also assessed. RESULTS: Five samples were shown to have PD-L1 gene amplification, whereas 89 samples did not. The patients with PD-L1 amplification had worse prognoses than did those without PD-L1 amplification. Genetic amplification of the PD-L1 gene was correlated with JAK2 gene amplification. The lung cancer cell line HCC4006 was found to harbor both JAK2 and PD-L1 amplification. Flow cytometry analyses revealed the level of PD-L1 protein expression to be higher in HCC4006 cells than in other NSCLC cell lines. Expression of the PD-L1 protein was significantly reduced by the JAK2 inhibitor TG-101348 and the signal transducer and activator of transcription 3 (STAT-3) inhibitor BP-1-102, but not by the STAT1 inhibitor fludarabine. CONCLUSIONS: Our data suggest that expression of PD-L1 protein is upregulated by the simultaneous amplification of the PD-L1 and JAK2 genes through JAK-STAT signaling in NCSLC.

    DOI: 10.1016/j.jtho.2015.09.010

  • Peritoneal Dissemination Requires an Sp1-Dependent CXCR4/CXCL12 Signaling Axis and Extracellular Matrix-Directed Spheroid Formation. International journal

    Yuta Kasagi, Yui Harada, Yosuke Morodomi, Toshiki Iwai, Satoru Saito, Kumi Yoshida, Eiji Oki, Hiroshi Saeki, Kippei Ohgaki, Masahiko Sugiyama, Mitsuho Onimaru, Yoshihiko Maehara, Yoshikazu Yonemitsu

    Cancer research   76 ( 2 )   347 - 57   2016.1

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    Peritonitis carcinomatosa is an advanced and intractable state of gastrointestinal and ovarian cancer, where mechanistic elucidation might enable the development of more effective therapies. Peritoneal dissemination of this type of malignancy has been generally thought to initiate from "milky spots" of primitive lymphoid tissues in the peritoneal cavity. In this study, we offer evidence challenging this idea, based on the finding that tumor implantation and directional dissemination was not required for the presence of milky spots, but rather SCF/CXCL12-expressing niche-like cells located at the border regions of perivascular adipose tissue. Interestingly, we found that peritoneal cavity lavage fluid, which specifically contains peritoneal collagen type IV and plasma fibronectin, dramatically facilitated spheroid formation of murine and human colon cancer cells. Spheroid formation strongly induced the expression of CXCR4 in an Sp1-dependent manner to promote niche-directed metastasis. Notably, disrupting sphere formation or inhibiting Sp1 activity was sufficient to suppress tumor dissemination and potentiated chemosensitivity to 5-fluorouracil. Our findings illuminate mechanisms of peritoneal cancer dissemination and highlight the Sp1/CXCR4/CXCL12 signaling axis as a rational target for the development of therapeutics to manage this intractable form of malignancy.

    DOI: 10.1158/0008-5472.CAN-15-1563

  • Clinical role of a new prognostic score using platelet-to-lymphocyte ratio in patients with malignant pleural mesothelioma undergoing extrapleural pneumonectomy. International journal

    Tetsuzo Tagawa, Masaki Anraku, Yosuke Morodomi, Tomoyoshi Takenaka, Tatsuro Okamoto, Mitsuhiro Takenoyama, Yukito Ichinose, Yoshihiko Maehara, B C John Cho, Ronald Feld, Ming-Sound Tsao, Natasha Leighl, Andrea Bezjak, Shaf Keshavjee, Marc de Perrot

    Journal of thoracic disease   7 ( 11 )   1898 - 906   2015.11

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    BACKGROUND: To investigate the prognostic value of platelet-to-lymphocyte ratio (PLR) and create a new prognostic score in patients with malignant pleural mesothelioma (MPM) undergoing extrapleural pneumonectomy (EPP). METHODS: Of 85 patients who underwent EPP for MPM over 10 years at Toronto General Hospital, 65 patients whose blood test results before initial therapy were available were retrospectively analyzed as a training cohort to identify and develop a prognostic score. Receiver operating characteristic (ROC) analysis was performed to examine cutoff values of hematologic parameters for survival. The prognostic score was externally validated in a cohort of 32 patients who underwent EPP for MPM over 13 years at two institutes in Japan. RESULTS: In the training cohort, multivariate analysis confirmed sex (P=0.0053) and PLR (P=0.049) as independent predictors of overall survival. The prognostic score was established using sex and PLR. The score was defined as follows: female:male =0:1 point; PLR <215:>215=0:1 point. The patients were classified into three risk groups according to the sum of the points: risk 0 (0 point), 1 (1 point), and 2 (2 points). Median survival time of the patients in the training cohort according to the risk groups were not reached, 32.0 and 19.4 months for risk 0 (n=6), 1 (n=36) and 2 (n=23), respectively (P=0.0006). In the validation cohort, median survival time was not reached, 45.9 and 14.5 months for risk 0 (n=4), 1 (n=18) and 2 (n=10), respectively (P=0.0002). CONCLUSIONS: The new prognostic score using PLR is simple and useful for predicting the prognosis of patients with MPM undergoing EPP. Further study should be done to examine the role of this scoring system to optimize treatment strategy.

    DOI: 10.3978/j.issn.2072-1439.2015.11.15

  • Clinical Significance of Detecting Somatic Gene Mutations in Surgically Resected Adenosquamous Cell Carcinoma of the Lung in Japanese Patients. International journal

    Yosuke Morodomi, Tatsuro Okamoto, Mitsuhiro Takenoyama, Kazuki Takada, Masakazu Katsura, Yuzo Suzuki, Takatoshi Fujishita, Hirokazu Kitahara, Shinichiro Shimamatsu, Mikihiro Kohno, Tetsuzo Tagawa, Shinji Okano, Kenichi Taguchi, Yukito Ichinose, Yoshihiko Maehara

    Annals of surgical oncology   22 ( 8 )   2593 - 8   2015.8

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    BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) inhibitors are effective and useful agents for treating patients who harbor EGFR-TKI-sensitive mutations or EML4-ALK rearrangement. Therefore, the importance of determining the presence of these somatic mutations when treating lung adenocarcinomas is widely accepted. However, genetic mutations are rarely evaluated in patients with adenosquamous cell carcinoma of the lung, a relatively infrequent histologic type of lung cancer, because of limited knowledge and the unclear value of assessing these oncogenic mutations in these patients. Therefore, we investigated the clinical implications of somatic mutations in surgically resected adenosquamous cell carcinoma of the lung in Japanese patients. METHODS: We retrospectively analyzed 32 patients with adenosquamous cell carcinoma of the lung who underwent surgical resection at two institutes in Japan. EGFR mutations and EML4-ALK rearrangement were assessed in all of the patients. RESULTS: Overall, 7 (21.9 &#37;) of 32 patients had EGFR mutations: three patients had an exon 19 deletion and 4 had an exon 21, L858R mutation. There were no T790 M mutations. The median relapse-free survival was 766 days and the median overall survival was 1,152 days in the total cohort. Relapse-free survival and overall survival were not significantly different between patients with or without EGFR mutations. CONCLUSIONS: Detecting EGFR mutations in patients with adenosquamous cell carcinoma is clinically important, especially in patients with disease recurrence because EGFR-TKIs may be effective in this histologic type of lung cancer.

    DOI: 10.1245/s10434-014-4218-0

  • Liver transplantation followed by pulmonary resection complicated with end-stage liver cirrhosis: a case report. International journal

    Daisuke Taniguchi, Norifumi Harimoto, Kazuki Takeishi, Shinji Itoh, Yoichi Yamashita, Toru Ikegami, Tomoharu Yoshizumi, Hirofumi Kawanaka, Ken Shirabe, Yosuke Morodomi, Tetsuzo Tagawa, Tatsuro Okamoto, Yoshihiko Maehara

    Anticancer research   35 ( 6 )   3411 - 4   2015.6

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    BACKGROUND: With the recent popularization of living-donor liver transplantation (LDLT), it has become important to provide treatment for comorbidities in recipients. We report the case of a patient who was successfully treated with LDLT, followed by left upper lobectomy for lung cancer concomitant with decompensated liver cirrhosis. CASE REPORT: A 67-year-old female was admitted for treatment for severe liver cirrhosis. The lung cancer was identified preoperatively using computed tomography. We initially performed LDLT to improve liver function and coagulopathy; the patient was discharged postoperatively on day 39 without complication. Three months after LDLT, we performed a left upper lobectomy. RESULTS: The patient's postoperative course was uneventful and she was discharged after 11 days. CONCLUSION: We conclude that an aggressive and appropriate surgical strategy, including LDLT, is an effective curative treatment in patients with controllable malignancy, concomitant with severe liver dysfunction.

  • 下部消化管 腹膜播種の薬剤耐性出現の分子メカニズムと新規治療戦略

    笠木 勇太, 原田 結, 諸富 洋介, 堤 亮介, 西村 章, 中司 悠, 工藤 健介, 堤 智崇, 田尻 裕匡, 由茅 隆文, 田中 仁寛, 財津 瑛子, 津田 康雄, 中島 雄一郎, 安藤 幸滋, 今村 裕, 大垣 吉平, 佐伯 浩司, 沖 英次, 米満 吉和, 前原 喜彦

    日本外科学会定期学術集会抄録集   115回   YIA - 2   2015.4

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  • Associations between driver gene mutations and cytotoxic chemosensitivity in patients with non-small cell lung cancer. International journal

    Yosuke Morodomi, Tatsuro Okamoto, Mikihiro Kohno, Masakazu Katsura, Kazuki Takada, Yuzo Suzuki, Takatoshi Fujishita, Hirokazu Kitahara, Shinichiro Shimamatsu, Tsukihisa Yoshida, Tetsuzo Tagawa, Shinji Okano, Yoshihiko Maehara

    Anticancer research   35 ( 3 )   1791 - 6   2015.3

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    BACKGROUND/AIM: Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) gene mutations or echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement often have a better prognosis when they are treated with specific inhibitors than when treated with cytotoxic agents. However, the associations between gene mutations and cytotoxic chemosensitivity are still unclear. The objective of the present study was to identify which clinicopathological factors, including genetic mutations, influence chemosensitivity, determined using the succinate dehydrogenase inhibition (SDI) test in patients with NSCLC. MATERIALS AND METHODS: The chemosensitivity of tumor tissues from 96 patients with NSCLC who underwent surgical resection was evaluated using the SDI test. RESULTS: In patients with adenocarcinoma, tumors with EGFR gene mutations were significantly more sensitive to 5-fluorouracil (5-FU) than tumors without EGFR gene mutations (p<0.0149). CONCLUSION: Our data suggest that patients with adenocarcinoma harboring EGFR gene mutations may be susceptible to 5-FU.

  • Impact of the epidermal growth factor receptor mutation status on the post-recurrence survival of patients with surgically resected non-small-cell lung cancer. International journal

    Tomoyoshi Takenaka, Mitsuhiro Takenoyama, Masafumi Yamaguchi, Ryo Toyozawa, Eiko Inamasu, Miyako Kojo, Gouji Toyokawa, Tsukihisa Yoshida, Yoshimasa Shiraishi, Yosuke Morodomi, Fumihiko Hirai, Kenichi Taguchi, Mototsugu Shimokawa, Takashi Seto, Yukito Ichinose

    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery   47 ( 3 )   550 - 5   2015.3

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    OBJECTIVES: The impact of epidermal growth factor receptor (EGFR) status and the use of EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy have not been well discussed only in recurrent non-small-cell lung cancer (NSCLC). The purpose of this study was to identify the prognostic factors associated with post-recurrence survival after surgical resection of NSCLC in terms of the EGFR mutation status and the use of EGFR-TKI therapy. METHODS: From 2000 through 2011, 1237 consecutive patients with NSCLC underwent pulmonary resection at our institution. Of these patients, 280 experienced postoperative recurrence by the end of 2012. We reviewed the cases of recurrence and analysed the predictors and length of post-recurrence survival. RESULTS: The median post-recurrence survival time and the 5-year survival rate of all patients were 25 months and 20.8&#37;, respectively. A multivariate analysis identified the Eastern Cooperative Oncology Group (ECOG) performance status (PS), brain metastasis, number of sites of recurrence and EGFR mutation status to be independent prognostic factors for post-recurrence survival. Among all cases, the median post-recurrence survival time according to the use of EGFR-TKI therapy was as follows: 49 months in the EGFR mutation-positive patients treated with EGFR-TKI therapy, 20 months in the EGFR wild or unknown cases treated with EGFR-TKI therapy and 17 months in the patients not treated with EGFR-TKI therapy. As to EGFR mutation-positive cases, the patients treated with EGFR-TKIs exhibited significantly longer post-recurrence survival time than the patients treated without EGFR-TKIs (49 vs 12 months). CONCLUSIONS: It is essential for recurrent NSCLC patients to be examined for the EGFR mutation status. Patients with a positive EGFR mutation status receive significant benefits from EGFR-TKI therapy.

    DOI: 10.1093/ejcts/ezu227

  • 肺腺癌の発癌・進展におけるProgrammed Death of Ligand 1発現の意義 Reviewed

    高田 和樹, 岡野 慎士, 寺石 紘司, 桂 正和, 鈴木 雄三, 藤下 卓才, 北原 大和, 島松 晋一郎, 諸富 洋介, 田川 哲三, 岡本 龍郎, 小田 義直, 前原 喜彦

    肺癌   54 ( 5 )   525 - 525   2014.10

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  • 非小細胞肺癌におけるPD-L1およびJAK2遺伝子増幅とPD-L1発現への関与 Reviewed

    岡本 龍郎, 池田 誠一, 岡野 慎士, 梅本 雄一郎, 田川 哲三, 諸富 洋介, 島松 晋一郎, 北原 大和, 鈴木 雄三, 藤下 卓才, 桂 正和, 高田 和樹, 前原 喜彦

    肺癌   54 ( 5 )   440 - 440   2014.10

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  • Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy.

    Gouji Toyokawa, Mitsuhiro Takenoyama, Fumihiko Hirai, Ryo Toyozawa, Eiko Inamasu, Miyako Kojo, Yosuke Morodomi, Yoshimasa Shiraishi, Tomoyoshi Takenaka, Masafumi Yamaguchi, Mototsugu Shimokawa, Takashi Seto, Yukito Ichinose

    International journal of clinical oncology   19 ( 4 )   601 - 6   2014.8

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    BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that responds poorly to chemotherapy. Although treatment with pemetrexed in combination with cisplatin serves as first-line chemotherapy for MPM, the optimal second-line and beyond therapy has not yet been fully examined. METHODS: Between March 2008 and October 2011, 17 consecutive Japanese patients pretreated with at least one regimen of platinum plus pemetrexed chemotherapy received gemcitabine and vinorelbine. Responses, survival time, and toxicity were retrospectively evaluated. RESULTS: Response [partial response (PR) + complete response (CR)] and disease control [stable disease (SD) + PR + CR] rates were 18 and 82 &#37;, respectively. The median progression-free survival (PFS) after combination chemotherapy was 6.0 months, whereas the median overall survival (OS) was 11.2 months. Grade 3 or 4 neutropenia and anemia were observed in 41 and 29 &#37; of patients, respectively, and one patient experienced febrile neutropenia. Grade 3 or 4 nonhematologic toxicities included constipation (6 &#37;) and phlebitis (6 &#37;). CONCLUSION: Combination chemotherapy using gemcitabine with vinorelbine was shown to have moderate activity in Japanese MPM patients pretreated with platinum plus pemetrexed chemotherapy. A further multicenter phase II trial is warranted to confirm the efficacy and safety of this combination treatment.

    DOI: 10.1007/s10147-013-0619-5

  • The prognostic impact of the amount of tobacco smoking in non-small cell lung cancer--differences between adenocarcinoma and squamous cell carcinoma. International journal

    Tatsuro Okamoto, Yuzo Suzuki, Takatoshi Fujishita, Hirokazu Kitahara, Shinichiro Shimamatsu, Mikihiro Kohno, Yosuke Morodomi, Daigo Kawano, Yoshihiko Maehara

    Lung cancer (Amsterdam, Netherlands)   85 ( 2 )   125 - 30   2014.8

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    BACKGROUNDS: The purpose of this study was to investigate the relationship between the level of tobacco smoking and the clinicopathological features of non-small cell lung cancer (NSCLC) patients, individually for adenocarcinoma (Ad) and squamous cell carcinoma (Sq). PATIENTS AND METHODS: We retrospectively reviewed the clinical records of 1825 consecutive lung cancer patients who underwent surgery in our department. Among these, the data sets of 750 Ad patients and 364 Sq patients who received lobectomy or more extensive resection were available. RESULTS: In Ad patients, those who had never smoked (never-smokers) (n=309) were more likely to be female, to have less advanced stage tumors, and to have a significantly better prognosis than those who had ever smoked (ever-smokers) (n=441) (5-year OS: never-smokers, 67.9&#37;; ever-smokers, 53.7&#37;, p<0.0001). In Sq patients, the never-smokers (n=15) were more likely to be female than the ever-smokers (n=349). Among ever-smokers, the light-smokers (PY≤30; n=56) were associated with more female patients, more advanced stage tumors, and significantly worse prognoses than were the heavy smokers (PY>30; n=292) (p=0.0003). The multivariate survival analysis showed that light smoking was related to a worse prognosis compared with heavy smoking (HR=2.06, 95&#37; CI 1.43-2.98, p=0.0001). CONCLUSIONS: The never-smokers had a significantly better prognosis than ever-smokers among Ad patients, whereas the light-smokers had a significantly worse prognosis than heavy smokers among Sq patients. There may be factors other than tobacco carcinogens that influence the development of Sq in never and/or light smokers.

    DOI: 10.1016/j.lungcan.2014.06.006

  • Non-small cell lung cancer patients with EML4-ALK fusion gene are insensitive to cytotoxic chemotherapy. International journal

    Yosuke Morodomi, Mitsuhiro Takenoyama, Eiko Inamasu, Ryo Toyozawa, Miyako Kojo, Gouji Toyokawa, Yoshimasa Shiraishi, Tomoyoshi Takenaka, Fumihiko Hirai, Masafumi Yamaguchi, Kenichi Taguchi, Takashi Seto, Kenji Sugio, Yukito Ichinose

    Anticancer research   34 ( 7 )   3825 - 30   2014.7

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    BACKGROUND: Although patients with the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase gene (EML4-ALK) re-arrangement and epidermal growth factor gene EGFR mutations have proven sensitive to specific inhibitors, there is currently no consensus regarding the sensitivity of non-small cell lung cancer (NSCLC) patients with such mutations to cytotoxic chemotherapy. PATIENTS AND METHODS: The responses to first-line cytotoxic chemotherapy were retrospectively compared between advanced or postoperative recurrent patients with non-squamous NSCLC who harbor the EML4-ALK fusion gene (ALK+), EGFR mutation (EGFR+), or neither abnormality (wild-type). RESULTS: Data for 22 ALK+, 30 EGFR+, and 60 wild-type patients were analyzed. The ALK+ group had a significantly lower response rate than the other two groups. Progression-free survival was significantly shorter in the ALK+ cohort compared to the EGFR+ (p<0.001) and wild-type cohorts (p=0.0121). CONCLUSION: NSCLC patients with the EML4-ALK fusion gene might be relatively insensitivite to cytotoxic chemotherapy.

  • Application of continuous negative pressure irrigation and negative pressure fixation to treat a bronchopleural fistula with thoracic empyema. International journal

    Yosuke Morodomi, Mitsuhiro Takenoyama, Masafumi Yamaguchi, Eiko Inamasu, Tsukihisa Yoshida, Daigo Kawano, Tatsuro Okamoto, Yojiro Inoue, Yoshihiko Maehara, Yukito Ichinose

    Journal of the American College of Surgeons   218 ( 5 )   e87-90   2014.5

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    DOI: 10.1016/j.jamcollsurg.2013.12.053

  • Successful resection of a giant mediastinal non-seminomatous germ cell tumor showing fluorodeoxyglucose accumulation after neoadjuvant chemotherapy: report of a case.

    Kazuki Takada, Yosuke Morodomi, Tatsuro Okamoto, Yuzo Suzuki, Takatoshi Fujishita, Hirokazu Kitahara, Shinichiro Shimamatsu, Mikihiro Kohno, Daigo Kawano, Noriko Hidaka, Yoichi Nakanishi, Yoshihiko Maehara

    Fukuoka igaku zasshi = Hukuoka acta medica   105 ( 5 )   117 - 23   2014.5

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    A 32-year-old man presented with a mediastinal non-seminomatous germ cell tumor showing fluorodeoxyglucose (FDG) accumulation (maximum standardized uptake value = 22.21) and extremely elevated blood alpha-fetoprotein (AFP) level (9203.0 ng/ml). The patient underwent 4 cycles of neoadjuvant chemotherapy (cisplatin, bleomycin, and etoposide), which normalized the AFP level and reduced the tumor size, allowing complete resection without a support of extracorporeal circulation. Despite preoperative positron emission tomography revealing increased FDG uptake in the residual tumor (maximum standardized uptake value = 3.59), the pathologic evaluation revealed that no viable germ cell tumor cells remained. We believe FDG uptake should not be used as a criterion for surgical resection after neoadjuvant chemotherapy. It is appropriate to resect the residual tumor regardless of FDG uptake after induction chemotherapy if a tumor is resectable and the AFP level normalizes.

  • A rare case of a bronchial anomaly running in the hilar region from the right lower lobe to the middle lobe.

    Takatoshi Fujishita, Tatsuro Okamoto, Yuzo Suzuki, Hirokazu Kitahara, Shinichiro Shimamatsu, Mikihiro Kohno, Yosuke Morodomi, Daigo Kawano, Yoshio Matsuo, Hiroshi Honda, Yoshihiko Maehara

    Fukuoka igaku zasshi = Hukuoka acta medica   105 ( 4 )   100 - 4   2014.4

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    A 77-year-old male was referred to our department due to lung cancer (cT3N0M0) of the right lower lobe. During right lower lobectomy, a thin duct structure was recognized in the hilar region between the middle and lower lobes that was identified to be a supernumerary bronchus upon a review of the preoperative chest CT images. Although bronchial anomalies are rare, it is important to carefully view preoperative images for any such anomalies in order to more safely perform surgery.

  • [Case of pulmonary inflammatory pseudotumor with cysts].

    Masakazu Katsura, Hirokazu Kitahara, Yosuke Morodomi, Daigo Kawano, Takaomi Koga, Toshiya Furuta, Tatsuro Okamoto, Yoshinao Oda, Yoshihiko Maehara

    Fukuoka igaku zasshi = Hukuoka acta medica   105 ( 3 )   74 - 8   2014.3

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    We herein report a case involving a 58-year-old female patient with multiple cystic lesions in the right lobe of the lung. The lesions were revealed on chest computed tomography in 2002 and followed up. Transbronchial lung biopsy showed no malignancy in June 2013. The lesions gradually increased in size and thickness and were associated with fluid-filled cysts. We performed a right lower lobectomy in November 2013. Pathological examination revealed inflammatory pseudotumor. Such a case of inflammatory pseudotumor presenting as a pulmonary cyst has not been previously described. Intractable infection and inflammation are regarded as common causes of inflammatory pseudotumor. This condition should be considered in patients with a medical history consistent with infectious disease and a pulmonary cyst found on chest computed tomography.

  • 肺腺癌の発癌・進展におけるProgrammed Death of Ligand 1(PD-L1)発現意義の免疫病理学的検討 Reviewed

    岡本 龍郎, 池田 誠一, 梅本 雄一郎, 岡野 慎士, 川野 大悟, 諸富 洋介, 河野 幹寛, 島松 晋一郎, 北原 大和, 鈴木 雄三, 藤下 卓才, 小田 義直, 前原 喜彦

    日本外科学会雑誌   115 ( 臨増2 )   436 - 436   2014.3

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  • 肺腺癌の発癌・進展におけるProgrammed Death of Ligand 1(PD-L1)発現意義の免疫病理学的検討 Reviewed

    岡野 慎士, 岡本 龍郎, 池田 誠一, 梅本 雄一郎, 川野 大悟, 諸富 洋介, 河野 幹寛, 島松 晋一郎, 北原 大和, 鈴木 雄三, 藤下 卓才, 小田 義直, 居石 克夫, 前原 喜彦

    日本病理学会会誌   103 ( 1 )   203 - 203   2014.3

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  • Dramatic response to crizotinib in an ALK-positive adenocarcinoma patient with disseminated intravascular coagulation. International journal

    Gouji Toyokawa, Mitsuhiro Takenoyama, Sawori Watanabe, Ryo Toyozawa, Eiko Inamasu, Miyako Kojo, Yoshimasa Shiraishi, Yosuke Morodomi, Tomoyoshi Takenaka, Fumihiko Hirai, Masafumi Yamaguchi, Kenichi Taguchi, Takashi Seto, Yukito Ichinose

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   8 ( 11 )   e96-8   2013.11

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    DOI: 10.1097/JTO.0b013e3182a008ed

  • Amrubicin as second-line and beyond treatment for platinum-refractory advanced thymic carcinoma. International journal

    Fumihiko Hirai, Takashi Seto, Takeharu Yamanaka, Ryo Toyozawa, Eiko Inamasu, Miyako Kojo, Gouji Toyokawa, Yosuke Morodomi, Yoshimasa Shiraishi, Tomoyoshi Takenaka, Masafumi Yamaguchi, Mitsuhiro Takenoyama, Yukito Ichinose

    Japanese journal of clinical oncology   43 ( 10 )   1018 - 22   2013.10

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    OBJECTIVE: Thymic carcinoma is a rare mediastinal neoplasm, and the prognosis of patients with advanced thymic carcinoma is poor. No standard chemotherapeutic regimen has yet been established for the disease. This is the first report to evaluate the role of amrubicin, a novel anthracycline anticancer drug, in second-line and beyond treatment for patients with platinum-refractory advanced thymic carcinoma. METHODS: This study was a review of thymic carcinoma patients who had received amrubicin monotherapy between June 2003 and December 2011 for the progression of disease previously treated with platinum-based chemotherapy. Amrubicin was administered at 35 or 40 mg/m(2) for three consecutive days every 3 weeks, until progression. RESULTS: Nine patients with recurrent thymic carcinoma were registered. Their median age was 61 years (range 45-72), and the patients included five males and four females. All nine patients had Masaoka's Stage IVb disease. There were three squamous cell carcinomas, one adenocarcinoma, one small-cell carcinoma and two other histological types. The mean number of chemotherapy cycles was five (range 2-13). Grade 3 or higher toxicities included mainly neutropenia (55.5&#37;), anemia (25.0&#37;) and febrile neutropenia (11.1&#37;). No treatment-related deaths were observed. The response rate was 44.4&#37; (95&#37; confidence interval: 19-73). The median progression-free survival after the amrubicin monotherapy was 4.9 months, while the median overall survival was 6.4 months. CONCLUSIONS: Single-agent amrubicin was found to be potentially useful as second-line and beyond chemotherapy for patients with advanced thymic carcinoma. Further multi-institutional prospective studies are warranted.

    DOI: 10.1093/jjco/hyt106

  • [Case of adenocarcinoma in situ accompanied by an intrapulmonary lymph node with a sarcoid-like reaction].

    Daigo Kawano, Tatsuro Okamoto, Yosuke Morodomi, Mikihiro Kono, Shinichiro Shimamatsu, Hirokazu Kitahara, Junji Kawasaki, Mitsuhiro Miyazaki, Motoyuki Yamagata, Takashi Sonoda

    Fukuoka igaku zasshi = Hukuoka acta medica   104 ( 10 )   394 - 6   2013.10

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    A 65-year-old male underwent a chest CT scan, which revealed an 8 mm nodule on the wall of a bulla in the left lower lobe of the lung, and was thus suspected to be lung cancer. Pulmonary wedge resection of the left lower lobe by means of video-assisted thoracoscopic surgery was thus performed. A specimen of the lung revealed the presence of intrapulmonary lymph node on the wall of a bulla. The histopathological findings of the resected lung specimen showed non-caseating granulomas in the lymph node, and adenocarcinoma in situ. We concluded that the sarcoid-like reaction observed in the intrapulmonary lymph node was therefore related to the adenocarcinoma in situ.

  • An extremely rare case of small-cell lung cancer harboring variant 2 of the EML4-ALK fusion gene. International journal

    Gouji Toyokawa, Mitsuhiro Takenoyama, Kenichi Taguchi, Ryo Toyozawa, Eiko Inamasu, Miyako Kojo, Yoshimasa Shiraishi, Yosuke Morodomi, Tomoyoshi Takenaka, Fumihiko Hirai, Masafumi Yamaguchi, Takashi Seto, Mototsugu Shimokawa, Yukito Ichinose

    Lung cancer (Amsterdam, Netherlands)   81 ( 3 )   487 - 490   2013.9

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    Anaplastic lymphoma kinase (ALK) fuses echinoderm microtubule-associated protein-like 4 (EML4) to acquire a transforming activity in lung adenocarcinomas. However, the presence of an EML4-ALK fusion gene in other lung cancer histologies is an extremely rare phenomenon. A 43-year-old female was referred to our department due to dyspnea on effort and left back pain. Computed tomography (CT) showed a large mass in the upper lobe of the left lung and a massive left pleural effusion, while a CT-guided needle biopsy confirmed a diagnosis of small-cell lung cancer (SCLC). Surprisingly, the tumor was genetically considered to harbor the EML4-ALK fusion gene (variant 2). Although the patient underwent two regimens of cytotoxic chemotherapy for SCLC, she died approximately seven months after the administration of first-line chemotherapy. Our analysis of 30 consecutive patients with SCLC for EML4-ALK revealed that two patients, including the current patient and a patient we previously reported, harbored the EML4-ALK fusion gene.

    DOI: 10.1016/j.lungcan.2013.05.022

  • The first case of lung carcinosarcoma harboring in-frame deletions at exon19 in the EGFR gene. International journal

    Gouji Toyokawa, Mitsuhiro Takenoyama, Kenichi Taguchi, Katsumi Arakaki, Eiko Inamasu, Ryo Toyozawa, Miyako Kojo, Yoshimasa Shiraishi, Yosuke Morodomi, Tomoyoshi Takenaka, Fumihiko Hirai, Masafumi Yamaguchi, Takashi Seto, Alvaro Leone, Paolo Graziano, Yukito Ichinose

    Lung cancer (Amsterdam, Netherlands)   81 ( 3 )   491 - 494   2013.9

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    Mutations of the epidermal growth factor receptor (EGFR) gene play a critical role in carcinogenesis of lung cancer, particularly adenocarcinoma. However, to the best of our knowledge, no mutations of the EGFR in patients with lung carcinosarcoma have been identified. We herein report the case of a 61-year-old female referred for a detailed examination of a left pulmonary mass shadow. Although bronchoscopy was performed, it failed to lead to a diagnosis, and video-assisted thoracoscopic surgery was therefore carried out to diagnose the tumor. The pathology revealed biphasic features consisting of both adenocarcinoma and chondrosarcoma. Intriguingly, both the adenocarcinoma and chondrosarcoma components were proven to harbor an exon19 deletion in the EGFR gene. Although carcinosarcoma is a rare malignancy of the lungs, genetic analyses of oncogenic drivers, such as the EGFR gene, should be conducted.

    DOI: 10.1016/j.lungcan.2013.06.013

  • Ex vivo generation of highly purified and activated natural killer cells from human peripheral blood. International journal

    Satoru Saito, Yui Harada, Yosuke Morodomi, Mitsuho Onimaru, Kumi Yoshida, Ryoichi Kyuragi, Hisahiro Matsubara, Yoshikazu Yonemitsu

    Human gene therapy methods   24 ( 4 )   241 - 52   2013.8

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    Adoptive immunotherapy using natural killer (NK) cells has been a promising treatment for intractable malignancies; however, there remain a number of difficulties with respect to the shortage and limited anticancer potency of the effector cells. We here established a simple feeder-free method to generate purified (>90&#37;) and highly activated NK cells from human peripheral blood-derived mononuclear cells (PBMCs). Among the several parameters, we found that CD3 depletion, high-dose interleukin (IL)-2, and use of a specific culture medium were sufficient to obtain highly purified, expanded (∼200-fold) and activated CD3(-)/CD56(+) NK cells from PBMCs, which we designated zenithal-NK (Z-NK) cells. Almost all Z-NK cells expressed the lymphocyte-activated marker CD69 and showed dramatically high expression of activation receptors (i.e., NKG2D), interferon-γ, perforin, and granzyme B. Importantly, only 2 hours of reaction at an effector/target ratio of 1:1 was sufficient to kill almost all K562 cells, and the antitumor activity was also replicated in tumor-bearing mice in vivo. Cytolysis was specific for various tumor cells, but not for normal cells, irrespective of MHC class I expression. These findings strongly indicate that Z-NK cells are purified, expanded, and near-fully activated human NK cells and warrant further investigation in a clinical setting.

    DOI: 10.1089/hgtb.2012.183

  • Recurrence of thymic neuroendocrine carcinoma 24 years after total excision: A case report. International journal

    Gouji Toyokawa, Kenichi Taguchi, Miyako Kojo, Ryo Toyozawa, Eiko Inamasu, Yosuke Morodomi, Yoshimasa Shiraishi, Tomoyoshi Takenaka, Fumihiko Hirai, Masafumi Yamaguchi, Takashi Seto, Mitsuhiro Takenoyama, Yukito Ichinose

    Oncology letters   6 ( 1 )   147 - 149   2013.7

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    A 77-year-old male presented with chest pain in March 2012. The individual had undergone surgery for an anterior mediastinal tumor 24 years earlier and the pathological diagnosis was that of a thymoma. The patient underwent a medical check-up every 6 months for the next 20 years. However, ∼3 years following the final check-up, sudden chest pain was reported and the patient was referred again. Computed axial tomography revealed a mediastinal mass adjacent to the left lung, pericardium and sternum. There was no apparent invasion to the adjacent structures. The patient underwent surgical resection following a diagnosis of recurrent thymoma. A posterolateral thoracotomy was performed under video-assisted thoracoscopy. Severe adhesions were observed around the tumor, which appeared to invade the left lung and pericardium, but not the chest wall. The tumor was extirpated in combination with partial resection of the left lung and pericardium. The pathological diagnosis of the tumor was of a well-differentiated neuroendocrine carcinoma (NEC) of the thymus. The specimen that was excised 24 years earlier was re-examined by a pathologist and was reported to exhibit the same histology. Primary NECs of the thymus are rare among anterior mediastinal tumors and the 5-year survival rate is ∼30&#37;. The present case study reports a case of a thymic NEC and describes the pathological and clinical features.

  • First case of combined small-cell lung cancer with adenocarcinoma harboring EML4-ALK fusion and an exon 19 EGFR mutation in each histological component. International journal

    Gouji Toyokawa, Kenichi Taguchi, Taro Ohba, Yosuke Morodomi, Tomoyoshi Takenaka, Fumihiko Hirai, Masafumi Yamaguchi, Takashi Seto, Mitsuhiro Takenoyama, Kenji Sugio, Yukito Ichinose

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   7 ( 12 )   e39-e41   2012.12

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    DOI: 10.1097/JTO.0b013e3182762bcb

  • Prediction of true-negative lymph node metastasis in clinical IA non-small cell lung cancer by measuring standardized uptake values on positron emission tomography.

    Tomoyoshi Takenaka, Tokujiro Yano, Yosuke Morodomi, Kensaku Ito, Naoko Miura, Daigo Kawano, Fumihiro Shoji, Shingo Baba, Koichiro Abe, Hiroshi Honda, Yoshihiko Maehara

    Surgery today   42 ( 10 )   934 - 9   2012.10

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    PURPOSE: We developed a method for predicting true-negative lymph node metastases in clinical IA non-small lung cancer (NSCLC) by the combined evaluation of computed tomography (CT), 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) findings and the maximum standardized uptake value (SUVmax) of primary tumors. METHODS: The subjects of this study were 94 patients with clinical stage IA NSCLC who underwent both preoperative CT and FDG-PET. We analyzed the relationship between the SUVmax of primary tumors and various clinicopathological factors to find the best method available for assessing true-negative lymph node metastasis. RESULTS: The pathological stages were IA (n = 80), IB (n = 4), IIA (n = 5), IIIA (n = 4), and IV (n = 1). Pathologic lymph node metastasis was recognized in nine patients and the SUVmax of these tumors ranged from 3.3 to 20.3. A SUVmax of 3.0 was defined as the cut-off point and patients were dichotomized according to this point. Tumors with SUVmax of 3.0 or less were associated with a significantly lower incidence of pleural and vascular invasion and were characterized by the degree of differentiation. CONCLUSION: The SUVmax of primary tumors reflects the grade of malignancy; therefore, the combined evaluation of FDG-PET/CT findings with the SUVmax of primary tumors may help predict lymph node metastasis negativity.

    DOI: 10.1007/s00595-012-0277-7

  • BioKnife, a uPA activity-dependent oncolytic Sendai virus, eliminates pleural spread of malignant mesothelioma via simultaneous stimulation of uPA expression. International journal

    Yosuke Morodomi, Tokujiro Yano, Hiroaki Kinoh, Yui Harada, Satoru Saito, Ryoichi Kyuragi, Kumi Yoshida, Mitsuho Onimaru, Fumihiro Shoji, Tsukihisa Yoshida, Kensaku Ito, Yasunori Shikada, Riichiroh Maruyama, Mamoru Hasegawa, Yoshihiko Maehara, Yoshikazu Yonemitsu

    Molecular therapy : the journal of the American Society of Gene Therapy   20 ( 4 )   769 - 77   2012.4

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    Malignant pleural mesothelioma (MPM) is highly intractable and readily spreads throughout the surface of the pleural cavity, and these cells have been shown to express urokinase-type plasminogen activator receptor (uPAR). We here examined the potential of our new and powerful recombinant Sendai virus (rSeV), which shows uPAR-specific cell-to-cell fusion activity (rSeV/dMFct14 (uPA2), named "BioKnife"), for tumor cell killing in two independent orthotopic xenograft models of human. Multicycle treatment using BioKnife resulted in the efficient rescue of these models, in association with tumor-specific fusion and apoptosis. Such an effect was also seen on both MSTO-211H and H226 cells in vitro; however, we confirmed that the latter expressed uPAR but not uPA. Of interest, infection with BioKnife strongly facilitated the uPA release from H226 cells, and this effect was completely abolished by use of either pyrrolidine dithiocarbamate (PDTC) or BioKnife expressing the C-terminus-deleted dominant negative inhibitor for retinoic acid-inducible gene-I (RIG-IC), indicating that BioKnife-dependent expression of uPA was mediated by the RIG-I/nuclear factor-κB (NF-κB) axis, detecting RNA viral genome replication. Therefore, these results suggest a proof of concept that the tumor cell-killing mechanism via BioKnife may have significant potential to treat patients with MPM that is characterized by frequent uPAR expression in a clinical setting.

    DOI: 10.1038/mt.2011.305

  • Serum antioxidant capacity and oxidative injury to pulmonary DNA in never-smokers with primary lung cancer. International journal

    Kensaku Ito, Tokujiro Yano, Yosuke Morodomi, Tsukihisa Yoshida, Mikihiro Kohno, Akira Haro, Yasunori Shikada, Tatsuro Okamoto, Riichiroh Maruyama, Yoshihiko Maehara

    Anticancer research   32 ( 3 )   1063 - 7   2012.3

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    BACKGROUND/AIM: Recently, in spite of the decrease in smoking in developed nations, the prevalence of primary lung cancer has been increasing in never-smokers. In the present study, we examined the status of oxidative stress and attempted to clarify the influence of oxidative stress in non-smoking patients with lung cancer. PATIENTS AND METHODS: Sixty-one lung cancer patients who underwent a surgical resection, including 27 never-smokers and 34 ever-smokers with a history of more than 20 pack-years, were included. In addition, 18 surgical patients with benign lung diseases treated during the same period were also included as non-malignant controls. Using blood samples, both serum oxidative stress (OS) and anti-oxidant capacity (AOC) were examined with the derivatives of reactive oxygen metabolites (D-Roms) test and the biological antioxidant power (BAP) test, respectively. To assess the oxidative damage of the DNA in lung tissues, the non-lesion site tissues of the lung were immunohistochemically examined for the accumulation of thymidine glycol (TG). RESULTS: There was no significant relationship between the serum OS level and various clinicopathological factors including the patient age, sex, body mass index, pathologic stage, and smoking status. On the other hand, the mean level of AOC was significantly lower in never-smokers than in ever-smokers. Although the mean TG-positive rate in ever-smokers was significantly higher than that in never-smokers, the mean TG-positive rate of the latter was significantly higher than that of patients with benign diseases. CONCLUSION: The present study first demonstrated the low AOC in never-smokers with NSCLC, which may be a factor contributing to excessive oxidative DNA damage in the lung tissues.

  • Pericardial fat pad tissue produces angiogenic factors for healing the bronchial stump. International journal

    Fumihiro Shoji, Tokujiro Yano, Naoko Miura, Yosuke Morodomi, Tsukihisa Yoshida, Mitsuho Onimaru, Yoshihiko Maehara

    Interactive cardiovascular and thoracic surgery   13 ( 3 )   271 - 5   2011.9

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    Maintaining blood flow in and supplying various anti-inflammatory or angiogenic cytokines to the bronchial stump are very important factors involved in its healing. Pericardial fat pad tissue samples surgically obtained from 20 patients were assessed, and their angiogenic ability was investigated. The messenger RNA level of all angiogenic cytokines, including vascular endothelial growth factor, fibroblast growth factor-2 (FGF-2), platelet-derived growth factor-A (PDGF-A), angiopoietin-1 (Ang-1), Ang-2 and hepatocyte growth factor (HGF) were detected in the pericardial fat pad tissue. The protein levels of all cytokines except PDGF-A increased with time from day one to day seven after primary culture of the pericardial fat pad tissue. In particular, both HGF and Ang-2 protein levels on day seven were significantly higher than those on day one (P=0.0475 and P=0.0417, respectively). On the other hand, the protein level of FGF-2 decreased in time and was significantly lower on day seven than on day one (P=0.0296). The present study demonstrated the angiogenic ability of the pericardial fat pad. These results suggest that reinforcement of the bronchial stump by the pericardial fat pad is a worthwhile and justified procedure, and may prevent bronchopleural fistula after pulmonary resections.

    DOI: 10.1510/icvts.2011.274480

  • Assessing a clinical pathway to improve the quality of care in pulmonary resections.

    Fumihiro Shoji, Tokujiro Yano, Akira Haro, Tsukihisa Yoshida, Kensaku Ito, Yosuke Morodomi, Yoshifumi Wakata, Yoshihiko Maehara

    Surgery today   41 ( 6 )   787 - 90   2011.6

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    PURPOSE: To evaluate the efficacy of the current clinical pathway for pulmonary resections. METHODS: This study examined variances from expected clinical pathway outcomes for pulmonary resections performed between 2005 and 2009. Data on a total of 383 patients were retrospectively analyzed. RESULTS: The median length of hospital stay (LOS) using the clinical pathway was 12 days (range: 1-188 days); the mean LOS was 15.5 days. The cost per day with use of the clinical pathway was 102 726 yen. Poor control of pain from intercostal neuralgia was the most frequently observed variance from expected outcomes. It affected 119 of 168 electronic clinical pathway patients (70.8&#37;). The clinical pathway was terminated in 3.9&#37; of patients (15/383) due to serious or life-threatening complications. CONCLUSIONS: This study showed the single institutional experience of the clinical pathway for pulmonary resections. These findings indicate a need to revise certain aspects of the pathway, based on data from our analysis of variances.

    DOI: 10.1007/s00595-010-4483-x

  • The influence of intracellular epidermal growth factor receptor (EGFR) signal activation on the outcome of EGFR tyrosine kinase inhibitor treatment for pulmonary adenocarcinoma.

    Daigo Kawano, Tokujiro Yano, Fumihiro Shoji, Kensaku Ito, Yosuke Morodomi, Akira Haro, Naoko Miura, Tomoyoshi Takenaka, Ichiro Yoshino, Yoshihiko Maehara

    Surgery today   41 ( 6 )   818 - 23   2011.6

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    PURPOSE: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, exhibit up to a 70&#37; response rate against non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the EGFR gene (EGFR). The mechanism of intrinsic resistance of EGFR mutation-positive NSCLC against EGFR-TKIs is not known. The current study assesses the relationship between the molecular expression of EGFR signals and the response to gefitinib treatment in patients with pulmonary adenocarcinoma to elucidate the mechanism of intrinsic resistance to gefitinib. METHODS: The present study included 30 patients with pulmonary adenocarcinoma who were treated with gefitinib for a postoperative recurrence. The correlation between the response to gefitinib treatment and various clinical and molecular features was evaluated. RESULTS: EGFR mutations were detected in 20 (66.7&#37;) of the 30 patients. The response to gefitinib treatment was a complete response in 1 case, partial response in 12 cases, stable disease in 4 cases, and progressive disease in 13 cases. Both univariate and multivariate analyses showed the presence of an EGFR mutation, and the expression of phospho-EGFR (p-EGFR) significantly correlated with a better response to gefitinib treatment. Ten of the 16 p-EGFR positive patients were disease controlled, but all 4 p-EGFR negative patients were intrinsically resistant to EGFR-TKIs (P = 0.025). Other factors including sex, smoking status, serum carcinoembryonic antigen and cytokeratin-19 fragment levels, EGFR, Met proto-oncogene, phospho-Met, and hepatocyte growth factor expression were not associated with the response to gefitinib treatment. CONCLUSION: These results suggest that, even if EGFR mutations were observed, a p-EGFR negative state might be a cause of intrinsic resistance to EGFR-TKIs.

    DOI: 10.1007/s00595-011-4514-2

  • Antagonism of VEGF by genetically engineered dendritic cells is essential to induce antitumor immunity against malignant ascites. International journal

    Masahiko Sugiyama, Yoshihiro Kakeji, Shunichi Tsujitani, Yui Harada, Mitsuho Onimaru, Kumi Yoshida, Sakura Tanaka, Yasunori Emi, Masaru Morita, Yosuke Morodomi, Mamoru Hasegawa, Yoshihiko Maehara, Yoshikazu Yonemitsu

    Molecular cancer therapeutics   10 ( 3 )   540 - 9   2011.3

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    Malignant ascitis (MA) is a highly intractable and immunotherapy-resistant state of advanced gastrointestinal and ovarian cancers. Using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A/vascular permeability factor and its decoy receptor, soluble fms-like tryrosine kinase receptor-1 (sFLT-1), was a major cause of MA resistance to dendritic cell (DC)-based immunotherapy. We found that the ratio of VEGF-A/sFLT-1 was increased not only in murine but also in human MA, and F-gene-deleted recombinant Sendai virus (rSeV/dF)-mediated secretion of human sFLT-1 by DCs augmented not only the activity of DCs themselves, but also dramatically improved the survival of tumor-bearing animals associated with enhanced CTL activity and its infiltration to peritoneal tumors. These findings were not seen in immunodeficient mice, indicating that a VEGF-A/sFLT-1 imbalance is critical for determining the antitumor immune response by DC-vaccination therapy against MA.

    DOI: 10.1158/1535-7163.MCT-10-0479

  • Effectiveness of erlotinib against recurrent pulmonary adenocarcinoma unresponsive to gefitinib: report of a case.

    Fumihiro Shoji, Daigo Kawano, Kensaku Ito, Yosuke Morodomi, Tokujiro Yano, Yoshihiko Maehara

    Surgery today   41 ( 2 )   255 - 7   2011.2

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    We report a case of recurrent pulmonary adenocarcinoma, found 2 years after resection, which responded extremely well to erlotinib, after gefitinib treatment had failed to evoke any response. This case report provides useful information for thoracic oncologists and shows that we should consider giving erlotinib after gefitinib for recurrent pulmonary adenocarcinoma, even if the gefitinib treatment is ineffective.

    DOI: 10.1007/s00595-009-4259-3

  • Prognostic impact of local treatment against postoperative oligometastases in non-small cell lung cancer. International journal

    Tokujiro Yano, Akira Haro, Tsukihisa Yoshida, Yosuke Morodomi, Kensaku Ito, Yasunori Shikada, Fumihiro Shoji, Riichiroh Maruyama, Yoshihiko Maehara

    Journal of surgical oncology   102 ( 7 )   852 - 5   2010.12

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    OBJECTIVES: In this study, we investigated prognostic factors associated with survival after distantly metastatic recurrence in surgically resected non-small cell lung cancer (NSCLC), and clarified the influence of local treatment on the prognosis for oligometastatic recurrence. METHODS: From 1994 through 2004, 418 consecutive patients with NSCLC underwent complete resection; 138 experienced a postoperative recurrence by December 2005. Of those, we reviewed 93 patients with only distant metastases for clinicopathological information, treatment modality, and survival. RESULTS: For the 93 patients with distant metastasis alone, the 2- and 5-year survival rates after recurrence were 43.9&#37; and 38.7&#37;, respectively. Of those patients, 44 first received local treatment, including radiotherapy in 31 and a surgical resection in 13. Their recurrent disease (oligometastases) was limited with the potential to be controlled with local treatment. The targeted metastatic organs were brain in 14 patients, bone in 14, lungs in 12, and other organs in 4. Significant prognostic factors for postrecurrence survival included adenocarcinoma histology, long disease-free interval (DFI) (1 year or longer), and the performance of local treatment for oligometastases. CONCLUSION: Local therapy such as radiotherapy and surgery, might be considered first-line treatment in patients with postoperative oligometastatic recurrence, especially those with a DFI ≥ 1 year.

    DOI: 10.1002/jso.21750

  • Urokinase-targeted fusion by oncolytic Sendai virus eradicates orthotopic glioblastomas by pronounced synergy with interferon-β gene. International journal

    Yuzo Hasegawa, Hiroaki Kinoh, Yasuo Iwadate, Mitsuho Onimaru, Yasuji Ueda, Yui Harada, Satoru Saito, Aki Furuya, Takashi Saegusa, Yosuke Morodomi, Mamoru Hasegawa, Shigeyoshi Saito, Ichio Aoki, Naokatsu Saeki, Yoshikazu Yonemitsu

    Molecular therapy : the journal of the American Society of Gene Therapy   18 ( 10 )   1778 - 86   2010.10

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    Glioblastoma multiforme (GM), the most frequent primary malignant brain tumor, is highly invasive due to the expression of proteases, including urokinase-type plasminogen activator (uPA). Here, we show the potential of our new and powerful recombinant Sendai virus (rSeV) showing uPA-specific cell-to-cell fusion activity [rSeV/dMFct14 (uPA2), named "BioKnife"] for GM treatment, an effect that was synergistically enhanced by arming BioKnife with the interferon-β (IFN-β) gene. BioKnife killed human GM cell lines efficiently in a uPA-dependent fashion, and this killing was prevented by PA inhibitor-1. Rat gliosarcoma 9L cells expressing both uPA and its functional receptor uPAR (9L-L/R) exhibited high uPA activity on the cellular surface and were highly susceptible to BioKnife. Although parent 9L cells (9L-P) were resistant to BioKnife and to BioKnife expressing IFN-β (BioKnife-IFNβ), cell-cell fusion of 9L-L/R strongly facilitated the expression of IFN-β, and in turn, IFN-β significantly accelerated the fusion activity of BioKnife. A similar synergy was seen in a rat orthotopic brain GM model with 9L-L/R in vivo; therefore, these results suggest that BioKnife-IFNβ may have significant potential to improve the survival of GM patients in a clinical setting.

    DOI: 10.1038/mt.2010.138

  • Results of a surgical resection of pulmonary metastasis from malignant head and neck tumor. International journal

    Akira Haro, Tokujiro Yano, Tsukihisa Yoshida, Kensaku Ito, Yosuke Morodomi, Fumihiro Shoji, Torahiko Nakashima, Yoshihiko Maehara

    Interactive cardiovascular and thoracic surgery   10 ( 5 )   700 - 3   2010.5

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    There have been only a few reports about a surgical resection of pulmonary metastasis from malignant head and neck tumor. Here we investigate the survival after a pulmonary metastasectomy, and discuss the prognostic factors. We retrospectively reviewed 25 patients who underwent a pulmonary metastasectomy from malignant head and neck tumor at Kyushu University Hospital from 1981 through 2008. We assessed the five year overall survival by the Kaplan-Meier method and the log-rank (Mantel-Cox) test using the Stat View software program. The three- or five-year overall survival after a metastasectomy was 53.3&#37; and 50.0&#37;, respectively. We investigated the clinico-pathological prognostic factors including gender, age, histology, disease free interval, number or size of pulmonary metastatic tumors, and the operative procedure. Both age (older than 60 years) (P=0.0189) and pulmonary metastases from squamous cell carcinomas in either oral cavity or pharyngeal region (P=0.0002) were identified to be adverse prognostic factors. To obtain a long survival, a positive surgical resection is considered to be an effective and standard treatment for pulmonary metastasis from malignant head and neck tumor. It is also necessary, however, to elucidate fully the primary site and histology of such pulmonary metastasis.

    DOI: 10.1510/icvts.2009.219766

  • Prognostic significance of intratumoral blood vessel invasion in pathologic stage IA non-small cell lung cancer. International journal

    Fumihiro Shoji, Akira Haro, Tsukihisa Yoshida, Kensaku Ito, Yosuke Morodomi, Tokujiro Yano, Yoshihiko Maehara

    The Annals of thoracic surgery   89 ( 3 )   864 - 9   2010.3

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    BACKGROUND: The 5-year survival rate of pathologic stage IA non-small cell lung cancer (NSCLC) is excellent; however, up to 10&#37; of patients with pathologic stage IA NSCLC still relapse postoperatively and die. This study retrospectively analyzed the clinicopathologic features of patients with pathologic stage IA NSCLC to identify the prognostic factors and investigate the effect of a combination of intratumoral vessel invasion and tumor size. METHODS: From December 1991 to December 2003, 217 consecutive patients with stage IA NSCLC were selected, and disease-free survival (DFS) was analyzed. RESULTS: Intratumoral blood vessel invasion (BVI) was identified as an independent poor prognostic factor (p = 0.0006). The relative risk for patients with BVI was 4.599 times higher than that for patients without BVI (95&#37; confidence interval, 1.913 to 11.056). According to the new T N M system, the difference in DFS between the patients with and without BVI was statistically significant, not only in tumors exceeding 2 cm (T1b with BVI vs T1b without BVI, p = 0.0020) but also in tumors smaller than 2 cm (T1a with BVI vs T1a without BVI, p < 0.0001). The survival curve of T1b patients without BVI was similar to that of T1a patients without BVI (p = 0.0892). Distant recurrence was frequently observed in both T1a and T1b patients with BVI. CONCLUSIONS: BVI is an independent poor prognostic factor in patients with pathologic stage IA NSCLC. These T1a and T1b patients with BVI both might benefit from adjuvant chemotherapy.

    DOI: 10.1016/j.athoracsur.2009.09.047

  • Synovial sarcoma of the chest wall.

    Daigo Kawano, Ichiro Yoshino, Fumihiro Shoji, Yosuke Morodomi, Tokujiro Yano, Yoshihiko Maehara

    General thoracic and cardiovascular surgery   58 ( 2 )   95 - 7   2010.2

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    We here report a rare case of synovial sarcoma of the chest wall. A 71-year-old Japanese woman noticed a left anterior chest wall mass after twice having had surgery for lung cancer. An aspiration biopsy diagnosed synovial sarcoma. She then underwent a surgical resection. Pathology examination revealed a biphasic-type synovial sarcoma. When the prepared RNA from the tumor was subjected to a polymerase chain reaction, SYT-SSX1 fusion gene transcripts were demonstrated. Patients with the SYT-SSX1 fusion gene have a worse clinical outcome than patients with SYT-SSX2-positive tumors. After a second surgery, performed in 1 year later, there was no evidence of recurrence for 30 months; however, careful observation may be required.

    DOI: 10.1007/s11748-009-0480-7

  • Verification of the newly proposed T category (seventh edition of the tumor, node, and metastasis classification) from a clinicopathological viewpoint in non-small cell lung cancer-special reference to tumor size. International journal

    Tokujiro Yano, Yosuke Morodomi, Kensaku Ito, Tsukihisa Yoshida, Akira Haro, Fumihiro Shoji, Takaomi Koga, Yoshihiko Maehara

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   5 ( 1 )   45 - 8   2010.1

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    INTRODUCTION: This study first verified the T classification, which is the major point of the revision regarding the seventh Tumor, Node, and Metastasis classification, from a viewpoint of the clinicopathological findings at the primary tumor site in non-small cell lung cancer. METHODS: The medical records of 1393 patients with non-small cell lung cancer who underwent a complete resection at this hospital from 1974 to 2003 were thoroughly reviewed for pathologic findings and survival. RESULTS: According to greatest dimension of the primary tumors, the 5-year postoperative survival was 77.8&#37; for T1a (< or =2 cm), 63.3&#37; for T1b (< or =3 cm), 46.4&#37; for T2a (< or =5 cm), 38.8&#37; for T2b (<7 cm), and 21.4&#37; for T3 (>7 cm). The differences among those new T categories were all statistically significant. The incidence of lymphatic permeation within the primary tumor was 17.2&#37; for T1b and 29.8&#37; for T2a (T1b versus T2a, p < 0.05). The incidence of vascular invasion within the primary tumor was 24.9&#37; for T1b, 35.3&#37; for T2a, and 54.2&#37; for T2b (T1b versus T2a and T2a versus T2b, p < 0.05). On the other hand, the incidence of pleural invasion of the primary tumor was 18.1&#37; for T1a, 29.4&#37; for T1b, 49.3&#37; for T2a, 47.3&#37; for T2b, and 87.5&#37; for T3 (T1a versus T1b, T1b versus T2a, T2b versus T3, p < 0.05). Significant differences were observed among the newly revised T subsets in at least one incidence of lymphatic, vascular, or pleural invasion. CONCLUSION: The new T classification, which is based mainly on the tumor size, is therefore considered to be appropriate for the pathologic findings of the primary tumor.

    DOI: 10.1097/JTO.0b013e3181c0996c

  • Clinicopathological significance of Sip1-associated epithelial mesenchymal transition in non-small cell lung cancer progression. International journal

    Naoko Miura, Tokujiro Yano, Fumihiro Shoji, Daigo Kawano, Tomoyoshi Takenaka, Kensaku Ito, Yosuke Morodomi, Ichiro Yoshino, Yoshihiko Maehara

    Anticancer research   29 ( 10 )   4099 - 106   2009.10

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    BACKGROUND: Epithelial-mesenchymal transition (EMT) is a key event in cancer progression. The expression of EMT-related factors in non-small cell lung cancer (NSCLC) and their impact on clinicopathological variables was examined. PATIENTS AND METHODS: A total of 137 NSCLC patients who underwent surgical resections were investigated. The expression of Twist, Snail, smad-interacting protein 1 (Sip1), E-cadherin, N-cadherin, vimentin and beta-catenin was detected by immunohistochemical analyses. RESULTS: The expression of Sip1 was associated with the reduced expression of E-cadherin (p=0.04) and the positive expression of N-cadherin (p=0.04). There was no association between the expression of Twist nor Snail and the epithelial or mesenchymal markers. The expression of Sip1 correlated with advanced T status (p=0.01), tumor diameter (p=0.01) and advanced stage (p=0.01). Furthermore, the expression of Sip1 was associated with poor postoperative overall survival (p=0.02). CONCLUSION: The expression of Sip1 is significantly associated with tumor growth and poor prognoses in NSCLC and EMT might be activated via Sip1 expression and result in accelerated tumor growth and poor survival in NSCLC.

  • [Treatment of malignant pleural mesothelioma--present status and future view].

    Tokujiro Yano, Yosuke Morodomi, Kensaku Ito, Naoko Miura, Tomoyoshi Takenaka, Daigo Kawano, Fumihiro Shoji, Yoshihiko Maehara

    Fukuoka igaku zasshi = Hukuoka acta medica   99 ( 4 )   74 - 9   2008.4

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  • 【mRNAワクチンやゲノム編集で注目が集まる遺伝子治療】遺伝子治療技術を用いた疾患治療 肺癌に対する免疫細胞治療

    諸富 洋介, 原田 結, 米満 吉和

    医学のあゆみ   2023.4

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    肺癌は悪性度の高い疾患であり,わが国を含め世界各国の死因の上位を占めている.しかし,急速な科学技術の発展とともに分子標的薬などが開発され,治療法が一変してきている.そのなかでも,免疫チェックポイント阻害薬(ICI)が肺癌などの固形腫瘍にも有効であることが証明されて以来,悪性腫瘍も免疫の力によって制御できる可能性があることがわかってきた.本稿では,肺癌に対する免疫療法の現状を述べるとともに,特に近年注目を集めているナチュラルキラー細胞(NK細胞)を用いた細胞治療について概説する.(著者抄録)

  • 腹膜播種の全容解明 Sp1によるCXCR4/CXCL12シグナル活性化と細胞外マトリクスを介したスフェア形成

    原田 結, 笠木 勇太, 諸富 洋介, 米満 吉和

    日本癌学会総会記事   2016.10

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  • 有瘻性膿胸に対する持続洗浄を併用した閉鎖式陰圧療法

    諸富 洋介, 岡本 龍郎, 山口 正史, 井上 要二郎, 高田 和樹, 桂 正和, 鈴木 雄三, 藤下 卓才, 北原 大和, 田川 哲三, 竹之山 光広, 一瀬 幸人, 前原 喜彦

    日本呼吸器外科学会雑誌   2015.4

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  • 栄養・感染症・緩和 悪性胸水に対するドレナージおよび胸膜癒着術の原発巣別検討

    諸富 洋介, 岡本 龍郎, 高田 和樹, 桂 正和, 鈴木 雄三, 藤下 卓才, 北原 大和, 島松 晋一郎, 田川 哲三, 徳永 えり子, 沖 英次, 調 憲, 前原 喜彦

    日本外科学会定期学術集会抄録集   2015.4

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  • 悪性胸膜中皮腫における線溶系分子の発現と臨床病理学的因子に関する検討

    諸富 洋介, 岡本 龍郎, 高田 和樹, 桂 正和, 鈴木 雄三, 藤下 卓才, 北原 大和, 島松 晋一郎, 田川 哲三, 岡野 慎士, 田口 健一, 竹之山 光広, 一瀬 幸人, 前原 喜彦

    肺癌   2014.10

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  • 腹膜播種の分子細胞メカニズムの解明(Molecular and Cellular Mechanism of Directed Tumor Dissemination in the Peritoneal Cavity)

    原田 結, 笠木 勇太, 諸富 洋介, 米満 吉和

    日本癌学会総会記事   2014.9

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  • 腹膜播種治療モデルにおける癌細胞sphere形成抑制の意義(Sphere formation abolishment decreases peritoneal dissemination in murine model)

    笠木 勇太, 原田 結, 諸富 洋介, 中島 雄一郎, 安藤 幸滋, 今村 裕, 大垣 吉平, 佐伯 浩司, 沖 英次, 米満 吉和, 森田 勝, 藤 也寸志, 前原 喜彦

    日本癌学会総会記事   2014.9

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  • ゲフィチニブで増悪後にエルロチニブへ交替した症例の検討 術後再発症例における特徴

    諸富 洋介, 岡本 龍郎, 鈴木 雄三, 藤下 卓才, 北原 大和, 島松 晋一郎, 河野 幹寛, 川野 大悟, 前原 喜彦

    日本癌治療学会誌   2014.6

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  • 肺腺扁平上皮癌におけるドライバー遺伝子異常と臨床病理学的因子の検討

    諸富 洋介, 岡本 龍郎, 鈴木 雄三, 藤下 卓才, 北原 大和, 島松 晋一郎, 河野 幹寛, 川野 大悟, 田口 健一, 竹之山 光広, 一瀬 幸人, 前原 喜彦

    日本呼吸器外科学会雑誌   2014.4

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    Language:Japanese  

  • 肺癌の個別化医療時代における外科医の役割 Driver mutationを有する非小細胞肺癌における抗悪性腫瘍薬感受性の特徴

    諸富 洋介, 岡本 龍郎, 吉田 月久, 河野 幹寛, 鈴木 雄三, 藤下 卓才, 北原 大和, 島松 晋一郎, 川野 大悟, 前原 喜彦

    日本外科学会雑誌   2014.3

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  • 癌細胞sphere形成プロセスと腹膜播種のメカニズム(Elucidation of the process of cancer cell sphere formation and peritoneal dissemination)

    笠木 勇太, 原田 結, 諸富 洋介, 安藤 幸滋, 井田 智, 木村 和恵, 沖 英次, 森田 勝, 楠本 哲也, 米満 吉和, 前原 喜彦

    日本癌学会総会記事   2013.10

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  • 腹膜播種がん幹細胞様細胞が足場とするニッシェ様細胞の同定とその標的化(Identification of mesenteric hematopoiesis where is the metastatic niche of tumor dissemination)

    原田 結, 諸富 洋介, 米満 吉和

    日本癌学会総会記事   2013.10

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  • 肺腺扁平上皮癌切除症例の検討

    諸富 洋介, 豊澤 亮, 稲益 英子, 古城 都, 豊川 剛二, 白石 祥理, 竹中 朋祐, 平井 文彦, 山口 正史, 瀬戸 貴司, 竹之山 光広, 一瀬 幸人

    日本呼吸器外科学会雑誌   2013.4

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  • 呼吸器外科領域における基礎研究と治療への展開 腫瘍融解型センダイウイルスベクターを用いた悪性胸膜中皮腫に対する革新的遺伝子治療

    諸富 洋介, 原田 結, 齊藤 智, 竹之山 光広, 一瀬 幸人, 岡本 龍郎, 井上 誠, 長谷川 護, 前原 喜彦, 米満 吉和

    日本外科学会雑誌   2013.3

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  • EML4-ALK融合遺伝子陽性症例での一次化学療法の治療効果

    諸富 洋介, 杉尾 賢二, 豊澤 亮, 稲益 英子, 古城 都, 豊川 剛二, 白石 祥理, 竹中 朋祐, 平井 文彦, 山口 正史, 瀬戸 貴司, 一瀬 幸人

    肺癌   2012.10

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  • 腹膜播種の治療戦略 終末期癌性腹膜炎患者に対する胃瘻造設の有用性

    諸富 洋介, 池田 陽一

    日本外科系連合学会誌   2012.5

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  • Imbalance in VEGF-A/sFLT-1 Enables Malignant Ascites to Resist Dendritic Cell-based Immunotherapy

    M. Sugiyama, Y. Yonemitsu, Y. Kakeji, H. Saeki, E. Oki, Y. Emi, M. Morita, Y. Morodomi, M. Hasegawa, Y. Maehara

    EUROPEAN JOURNAL OF CANCER   2011.9

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  • In vivo imaging可能なマウス同所性胸膜中皮腫移植モデルの確立

    諸富 洋介, 米満 吉和, 矢野 篤次郎, 吉田 月久, 伊藤 謙作, 波呂 祥, 亀山 敏文, 鹿田 康紀, 丸山 理一郎, 前原 喜彦

    日本外科学会雑誌   2011.5

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  • ウロキナーゼ選択性腫瘍融解型センダイウイルスベクターを用いた悪性胸膜中皮腫に対する革新的遺伝子治療

    諸富 洋介, 米満 吉和, 矢野 篤次郎, 喜納 宏昭, 庄司 文裕, 吉田 久美, 上田 泰次, 井上 誠, 長谷川 誠, 前原 喜彦

    日本外科学会雑誌   2010.3

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  • 多発性内臓動脈瘤に対する1手術例

    諸富 洋介, 伊東 啓行, 井口 博之, 内山 秀昭, 米満 吉和, 前原 喜彦

    日本血管外科学会雑誌   2010.2

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    内臓動脈瘤は比較的まれな疾患と考えられているが、画像診断の進歩とともに無症候性の動脈瘤の発見例が増加しつつある。今回検診にて偶然発見された多発性内臓動脈瘤の1例を報告する。症例は73歳女性、検診にて胃十二指腸動脈、固有肝動脈、左肝動脈に各々径3.5cm、1.1cm、0.9cm大の動脈瘤を指摘された。一期的にこれらの動脈瘤を切除し、固有肝動脈は再建した。病理診断は非特異的な動脈瘤の所見であり、炎症や感染の関与は明らかではなかった。(著者抄録)

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Research Projects

  • 血小板をベクターとして用いる癌に対する革新的ドラッグデリバリーシステムの開発

    Grant number:23H02769  2023 - 2025

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant type:Scientific research funding

  • 血小板をベクターとして用いる癌に対する革新的ドラッグデリバリーシステムの開発

    Grant number:23H02769  2023 - 2025

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • がん幹細胞化に関与するSphere形成メカニズムを標的とした革新的治療開発

    Grant number:15H05792  2015 - 2019

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant type:Scientific research funding

  • 肺扁平上皮癌における喫煙量別比較に基づいた新たなドライバー遺伝子変異の同定

    Grant number:15K10263  2015 - 2017

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant type:Scientific research funding

  • 悪性胸膜中皮腫の微小環境の特性を標的とした新規治療法の開発

    Grant number:25861255  2013 - 2015

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant type:Scientific research funding

Travel Abroad

  • 2015.11 - 2022.7

    Staying countory name 1:United States   Staying institution name 1:Scripps Research Institute