mitsuhashiatsushi/published_papers/52858414 Aito Yoshida Shinji Abe Toshihiro Izumi Satoshi Itakura Keichiro Yamada Takuya Wada Takaaki Yamamoto Chiemi Sato Atsushi Mitsuhashi Hirokazu Ogino Seidai Sato Tsutomu Shinohara Masaki Hanibuchi Mika K Kaneko Yukinari Kato Yasuhiko Nishioka Cancer-Specific Antihuman Podoplanin Antibody chLpMab-2f Exerts Antitumor Effects Against Pleural Mesothelioma. Pleural mesothelioma (PM) is a malignancy with a poor prognosis owing to its resistance to chemotherapy. To develop a novel treatment for PM, podoplanin (PDPN), a transmembrane glycoprotein, has attracted significant attention because it is highly expressed in PM and is used for its diagnosis. We previously reported that NZ-12, a human chimeric antihuman PDPN antibody, exhibits antitumor effects against human PM cells through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Additionally, we developed a cancer-specific monoclonal antibody (CasMab) production technology and produced a mouse-human chimeric cancer-specific antihuman PDPN antibody, chLpMab-2, along with an afucosylated version, chLpMab-2f, to enhance ADCC activity. This study aimed to evaluate whether chLpMab-2f exhibits specific antitumor effects against PM in a preclinical model. We demonstrated that chLpMab-2f recognized the surface PDPN of human PM cell lines and human PM patient tissue but did not react with human normal tissues such as lung and kidney tissues. Furthermore, these antibodies exhibited ADCC and CDC activity against PDPN-positive PM cells while showing reduced toxicity toward non-malignant kidney-derived PDPN-positive cells, such as HEK-293FT. Additionally, chLpMab-2f demonstrated stronger ADCC activity through more efficient NK cell activation in comparison to chLpMab-2. Moreover, chLpMab-2f suppressed tumor progression in subcutaneously and intrathoracically transplanted human PM cells in mice. These findings suggest that PDPN-targeting immunotherapy with chLpMab-2f generated by CasMab technology could provide an effective treatment for PM with decreased toxicity toward normal tissues. Cancer science null null 20260120 10.1111/cas.70325 41558821 mitsuhashiatsushi/published_papers/50796637 Atsushi Mitsuhashi Kazuya Koyama Hirokazu Ogino Reona Matsuo Na Thi Nguyen Yohei Yabuki Ryohiko Ozaki Yuki Tsukazaki Yutaka Morita Aito Yoshida Kojin Murakami Seidai Sato Hiroshi Kawano Hiroshi Nokihara Yutaka Inagaki Tsutomu Shinohara Masaki Hanibuchi Hiromitsu Takizawa Yasuhiko Nishioka Clock pathway inhibitor overcomes tumor immune-exclusion via regulation of fibrocyte differentiation. Tumor stroma inhibits lymphocyte infiltration and induces resistance to immune checkpoint inhibitors (ICIs). αSMA+ cancer associated fibroblasts (CAFs) were suggested to form immune-excluded tumors. We previously reported roles of fibrocytes, collagen-expressing monocyte-derived cells, in tumor progression. Considering the aspect of fibrocytes as precursors of CAFs, we focused on fibrocyte differentiation to overcome immune exclusion. In resected lung adenocarcinoma tissues, fibrocytes were abundant in αSMA+ CAF-rich and immune-excluded tumors. Single-cell RNA sequencing revealed that tumor-infiltrating fibrocytes expressed clock genes. The clock pathway inhibitor KL001 suppressed the differentiation of fibrocytes into αSMA+ CAFs in vitro without affecting αSMA expression in fibroblasts. Furthermore, clock pathway inhibitors decreased αSMA+ CAFs and facilitated the infiltration of various immune cells in vivo. In addition, KL001 augmented the efficacy of ICIs by converting immune-excluded tumors into immune-active "hot tumors." Clock genes governing the differentiation of fibrocytes may provide a breakthrough in overcoming immune exclusion. NPJ precision oncology 9 1 274 274 20250805 10.1038/s41698-025-01066-6 40764393 mitsuhashiatsushi/published_papers/50796638 Kaori Nii Hirokazu Ogino Hiroki Bando Yuki Yamamoto Koji Fujita Hiroto Yoneda Nobuhito Naito Atsushi Mitsuhashi Yutaka Morita Yuki Tsukazaki Yohei Yabuki Ryohiko Ozaki Seidai Sato Masaki Hanibuchi Yuishin Izumi Yasuhiko Nishioka Immune checkpoint inhibitor-associated paraneoplastic cerebellar degeneration in a case of extensive-stage small-cell lung cancer with pre-existing anti-SOX1 antibody. Neurological immune-related adverse events can manifest as paraneoplastic neurological syndrome (PNS), especially in patients with small-cell lung cancer (SCLC). We herein report a 73-year-old man with SCLC treated with an immune checkpoint inhibitor (ICI) combined with chemotherapy. Although the chemo-immunotherapy induced a favorable response to SCLC, he later developed acute cerebellar ataxia. He was diagnosed with paraneoplastic cerebellar degeneration associated with anti-Sry-like high mobility group box 1 (SOX1) autoantibody. The antibody was also identified in serum collected at the diagnosis of SCLC and before ICI administration, which retrospectively suggested that the patient was at risk of ICI-induced PNS. J. Med. Invest. 72 : 172-176, February, 2025. The journal of medical investigation : JMI 72 1.2 172 176 20250000 10.2152/jmi.72.172 40268441 mitsuhashiatsushi/published_papers/48788941 Yohei Yabuki Atsushi Mitsuhashi Hirokazu Ogino Aito Yoshida Na Thi Nguyen Hiroto Yoneda Ryohiko Ozaki Yuki Tsukazaki Yutaka Morita Hiroshi Nokihara Seidai Sato Tsutomu Shinohara Masaki Hanibuchi Yasuhiko Nishioka Hypoxia-inducible factor-targeting therapy augmented the sensitivity to programmed death ligand-1 blockade by enhancing interferon-γ-induced chemokines in tumor cells. Immune checkpoint inhibitors (ICIs) targeting programmed death ligand-1 (PD-L1) provide clinical benefits for various advanced malignancies. However, the predictive factors that determine sensitivity to ICIs have not been fully elucidated. We focused on tumor-derived CXCL10/11 as a pivotal factor that determines the response to PD-L1 blockade by regulating T cell accumulation and tumor angiogenesis. We previously reported that CXCL10/11 was upregulated by interferon (IFN)-γ in ICI-sensitive tumor cells but not in ICI-resistant cells, including mouse Lewis lung carcinoma (LLC). In the present study, gene silencing of tumor-derived CXCL10/11 induced resistance to PD-L1 blockade in AB1-HA mesothelioma cell-bearing mice. To identify the mechanisms underlying ICI resistance, we performed a microarray analysis to compare the IFN-γ-inducible genes between ICI-sensitive AB1-HA and ICI-resistant LLC in vitro. A pathway analysis based on microarray data indicated that hypoxia-inducible factor (HIF) 1A is the key signal that inhibits CXCL10/11 expression. We revealed that the HIF1A inhibitors echinomycin (EC) and YC-1 upregulated CXCL10/11 genes induced by IFN-γ in tumor cells in vitro. In addition, combination therapy with PD-L1 blockade and EC demonstrated synergistic antitumor effects in LLC-bearing mice. Combination therapy enhanced tumor infiltration of CD8 T cells and suppressed tumor angiogenesis. The present study suggests that HIF1A signaling in tumor cells dominates ICI resistance via the downregulation of tumor-derived CXCL10/11. International journal of cancer null null 20241217 10.1002/ijc.35301 39686841 mitsuhashiatsushi/published_papers/48568458 Atsushi Mitsuhashi Yasuhiko Nishioka Fibrocytes in tumor microenvironment: Identification of their fraction and novel therapeutic strategy. Fibrocytes were identified as bone marrow-derived myeloid cells that also have fibroblast-like phenotypes, such as ECM production and differentiation to myofibroblasts. Although fibrocytes are known to contribute to various types of tissue fibrosis, their functions in the tumor microenvironment are unclear. We focused on fibrocytes as pivotal regulators of tumor progression. Our previous studies have indicated that fibrocytes induce angiogenesis and cancer stem cell-like phenotypes by secreting various growth factors. In contrast, immune checkpoint inhibitor (ICI)-treated fibrocytes demonstrated antigen-presenting capacity and enhanced antitumor T cell proliferation. Taken together, these findings indicate that fibrocytes have multiple effects on tumor progression. However, the detailed phenotypes of fibrocytes have not been fully elucidated because the isolation of distinct fibrocyte clusters has not been achieved without culturing in ECM-coated conditions or intracellular staining of ECM. The development of single-cell analyses partially resolves these problems. Single-cell RNA sequences in CD45+ immune cells from tumor tissue identified ECM-expressing myeloid-like cells as distinct fibrocyte clusters. In addition, these findings enabled the isolation of tumor-infiltrating fibrocytes as CD45+CD34+ cells. These tumor-infiltrating fibrocytes demonstrated both antigen-presenting ability and differentiation into myofibroblast-like cancer-associated fibroblasts. Considering these functions of fibrocytes in tumor progression, molecular-targeting agents for the migration, activity, and differentiation of fibrocytes are promising therapeutic strategies. Furthermore, identification of specific cell surface markers and master regulators of fibrocytes will advance novel fibrocyte-targeting therapies. In this review, we discuss the multiple roles of tumor-infiltrating fibrocytes and novel cancer therapeutic strategies. Cancer science null null 20241104 10.1111/cas.16385 39492802 mitsuhashiatsushi/published_papers/47371067 Yuki Tsukazaki Hirokazu Ogino Yoshio Okano Soji Kakiuchi Shoko Harada Yuko Toyoda Yugo Matsumura Seiya Ichihara Takeshi Imakura Rikako Matsumoto Ryohiko Ozaki Ei Ogawa Yutaka Morita Atsushi Mitsuhashi Yohei Yabuki Hiroto Yoneda Masaki Hanibuchi Kayoko Hase Eiji Takeuchi Takashi Haku Yasuhiko Nishioka Granulocyte colony-stimulating factor has the potential to attenuate the therapeutic efficacy of chemo-immunotherapy for extensive-stage small-cell lung cancer. BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) has the potential to attenuate the anti-tumor immune responses of T-cells by increasing immune suppressive neutrophils and myeloid-derived suppressor cells. However, the clinical impact of G-CSF on the efficacy of immunotherapy remains unknown. This multi-center retrospective analysis evaluated the impact of G-CSF in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with chemo-immunotherapy. METHODS: We analyzed 65 patients with ES-SCLC who completed four cycles of induction chemo-immunotherapy and evaluated the effects of G-CSF on progression-free survival (PFS), overall survival (OS), and a durable response to immunotherapy (defined as PFS ≥ 12 months). RESULTS: Fifty patients (76.9%) received ≥ 1 dose of G-CSF. The PFS of the patients with G-CSF was poorer than that of the patients without G-CSF (median PFS 8.3 vs. 4.9 months, p = 0.009). The OS of the patients with G-CSF tended to be shorter, but not statistically significant, than that of the patients without G-CSF (median OS 24.3 vs. 16.4 months, p = 0.137). In the multivariate analysis, G-CSF administration was associated with poorer PFS (hazard ratio 2.78, 95% CI 1.36-5.69, p = 0.005) and was identified as a determinant of a durable response (odds ratio 0.18, 95% CI 0.04-0.80, p = 0.024). These results were consistent with other definitions of G-CSF administration (administration of ≥ 1 dose of pegfilgrastim, or either ≥ 5 doses of filgrastim or ≥ 1 dose of pegfilgrastim). CONCLUSIONS: G-CSF has the potential to attenuate the efficacy of immunotherapy; therefore, the indication for G-CSF during chemo-immunotherapy should be carefully considered for ES-SCLC. International journal of clinical oncology null null 20240715 10.1007/s10147-024-02586-0 39009900 mitsuhashiatsushi/published_papers/47371066 Kenya Miyamoto Hirokazu Ogino Takumi Kakimoto Yugo Matsumura Keiko Haji Atsushi Mitsuhashi Yutaka Morita Yuki Tsukazaki Yohei Yabuki Ryohiko Ozaki Hiroto Yoneda Seidai Sato Masaki Hanibuchi Yoshimi Bando Hiroshi Nokihara Yasuhiko Nishioka Transformation of epidermal growth factor receptor mutated lung adenocarcinoma to small-cell carcinoma long after the cessation of tyrosine kinase inhibitor treatment: A case series and literature review. Histological transformation to small-cell lung cancer (SCLC) is a well-known mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and almost all patients receive EGFR-TKIs at the time of transformation. We herein report three cases of EGFR-mutated lung adenocarcinoma that transformed into SCLC long after the cessation of EGFR-TKIs. Rapid tumor progression and elevated SCLC marker levels were observed at the time of transformation. Our case highlights the importance of considering SCLC transformation throughout the clinical course. Careful observation of the tumor behavior and SCLC markers should be performed to avoid diagnostic delays. Respiratory medicine case reports 51 102076 102076 20240000 10.1016/j.rmcr.2024.102076 39027818 mitsuhashiatsushi/published_papers/44455258 Hiroyuki Kozai Hirokazu Ogino Atsushi Mitsuhashi Na Thi Nguyen Yuki Tsukazaki Yohei Yabuki Ryohiko Ozaki Hiroto Yoneda Seidai Sato Masaki Hanibuchi Tsutomu Shinohara Hiroshi Nokihara Yasuhiko Nishioka Potential of fluoropyrimidine to be an immunologically optimal partner of immune checkpoint inhibitors through inducing immunogenic cell death for thoracic malignancies. BACKGROUND: Immune checkpoint inhibitors (ICIs) are a revolutionary paradigm in the treatment of thoracic malignancies and chemoimmunotherapy is a current standard care in this field. Chemotherapeutic agents are known to induce not only direct cytotoxic effects on tumor cells but also immune modulating effects, such as stimulating immunogenic cell death (ICD). Currently, either pemetrexed (PEM) or taxane plus platinum are combined with ICIs for patients with non-small cell lung cancer (NSCLC); however, it is still unknown whether these agents are immunologically optimal partners for ICIs. METHODS: To determine the immunologically optimal chemotherapeutic agent, we first evaluated the ability of several chemotherapeutic agents, including platinum, PEM, taxane, and 5-fluorouracil (5-FU) to induce ICD using several thoracic tumor cell lines in vitro. ICD was evaluated by the cell surface expression of calreticulin (CRT) and adenosine-triphosphate (ATP) secretion. We further performed an antitumor vaccination assay in vivo. RESULTS: 5-FU induced cell surface expression of CRT and ATP secretion most efficiently among the several chemotherapeutic agents. This effect was enhanced when it was combined with platinum. In the antitumor vaccination assay in vivo, we found that vaccination with dying-AB1-HA (a murine malignant mesothelioma cell line) cells treated with 5-FU, but neither PEM nor PTX, reduced the tumor growth of living-AB1-HA cells inoculated 1 week after vaccination by recruiting CD3+ CD8+ T cells into the tumor microenvironment. CONCLUSION: Our findings indicate that fluoropyrimidine can be an immunologically optimal partner of ICIs through the induction of ICD for thoracic malignancies. Thoracic cancer null null 20231226 10.1111/1759-7714.15200 38146645 mitsuhashiatsushi/published_papers/44455257 Hiroto Yoneda Atsushi Mitsuhashi Aito Yoshida Hirokazu Ogino Satoshi Itakura Na Thi Nguyen Hiroshi Nokihara Seidai Sato Tsutomu Shinohara Masaki Hanibuchi Shinji Abe Mika K Kaneko Yukinari Kato Yasuhiko Nishioka Antipodoplanin antibody enhances the antitumor effects of CTLA-4 blockade against malignant mesothelioma by natural killer cells. Combination immunotherapy with multiple immune checkpoint inhibitors (ICIs) has been approved for various types of malignancies, including malignant pleural mesothelioma (MPM). Podoplanin (PDPN), a transmembrane sialomucin-like glycoprotein, has been investigated as a diagnostic marker and therapeutic target for MPM. We previously generated and developed a PDPN-targeting Ab reagent with high Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, the effects of anti-PDPN Abs on various tumor-infiltrating immune cells and their synergistic effects with ICIs have remained unclear. In the present study, we established a novel rat-mouse chimeric anti-mouse PDPN IgG2a mAb (PMab-1-mG2a ) and its core-fucose-deficient Ab (PMab-1-mG2a -f) to address these limitations. We identified the ADCC and CDC activity of PMab-1-mG2a -f against the PDPN-expressing mesothelioma cell line AB1-HA. The antitumor effect of monotherapy with PMab-1-mG2a -f was not sufficient to overcome tumor progression in AB1-HA-bearing immunocompetent mice. However, PMab-1-mG2a -f enhanced the antitumor effects of CTLA-4 blockade. Combination therapy with anti-PDPN Ab and anti-CTLA-4 Ab increased tumor-infiltrating natural killer (NK) cells. The depletion of NK cells inhibited the synergistic effects of PMab-1-mG2a -f and CTLA-4 blockade in vivo. These findings indicated the essential role of NK cells in novel combination immunotherapy targeting PDPN and shed light on the therapeutic strategy in advanced MPM. Cancer science null null 20231226 10.1111/cas.16046 38148492 mitsuhashiatsushi/published_papers/44455259 Yohei Yabuki Masaki Hanibuchi Eiji Takeuchi Takashi Haku Takanori Kanematsu Naoki Nishimura Yuko Toyoda Atsushi Mitsuhashi Kenji Otsuka Seidai Sato Hisatsugu Goto Hiroto Yoneda Hirokazu Ogino Hiroshi Nokihara Shinohara Tsutomu Yasuhiko Nishioka A multicenter, open-label, phase II trial of pemetrexed plus bevacizumab in elderly patients with previously untreated advanced or recurrent nonsquamous non-small cell lung cancer. BACKGROUND: Although the incidence of lung cancer in elderly individuals has been increasing in recent years, the number of clinical trials designed specifically for elderly patients with advanced non-small cell lung cancer (NSCLC) is still limited. To fulfill this unmet medical need, we conducted a phase II study to elucidate the efficacy of pemetrexed (PEM) plus bevacizumab (Bev) combination chemotherapy in elderly patients with nonsquamous NSCLC. METHODS: A total of 29 elderly patients (≥75 years old) with nonsquamous NSCLC were enrolled in this multicenter, open-label, phase II study, and 27 patients were finally analyzed. PEM at 500 mg/m2 on day 1 plus Bev at 15 mg/kg on day 1 were administered triweekly. The primary endpoint was the investigator-assessed objective response rate. RESULTS: The median age at initiating chemotherapy was 80 years old. Almost all patients (92.6%) had adenocarcinoma histology. The median number of cycles administered was 6, and the objective response rate was 40.7%. The median progression-free survival, overall survival and 1-year survival were 8.8 months, 27.2 months and 79%, respectively. The treatment was well-tolerated, and no treatment-related death was observed. CONCLUSION: Combination chemotherapy with PEM plus Bev in elderly patients with previously untreated advanced non-squamous NSCLC exhibited favorable antitumor activity and tolerability, suggesting that a combination of PEM plus Bev might be a promising treatment option for this population. Thoracic cancer 14 32 3232 3239 20231100 10.1111/1759-7714.15115 37718463 mitsuhashiatsushi/published_papers/41646910 Atsushi Mitsuhashi Kazuya Koyama Hirokazu Ogino Tania Afroj Na Thi Nguyen Hiroto Yoneda Kenji Otsuka Masamichi Sugimoto Osamu Kondoh Hiroshi Nokihara Masaki Hanibuchi Hiromitsu Takizawa Tsutomu Shinohara Yasuhiko Nishioka Identification of fibrocyte cluster in tumors reveals the role in antitumor immunity by PD-L1 blockade. Recent clinical trials revealed that immune checkpoint inhibitors and antiangiogenic reagent combination therapy improved the prognosis of various cancers. We investigated the roles of fibrocytes, collagen-producing monocyte-derived cells, in combination immunotherapy. Anti-VEGF (vascular endothelial growth factor) antibody increases tumor-infiltrating fibrocytes and enhances the antitumor effects of anti-PD-L1 (programmed death ligand 1) antibody in vivo. Single-cell RNA sequencing of tumor-infiltrating CD45+ cells identifies a distinct "fibrocyte cluster" from "macrophage clusters" in vivo and in lung adenocarcinoma patients. A sub-clustering analysis reveals a fibrocyte sub-cluster that highly expresses co-stimulatory molecules. CD8+ T cell-costimulatory activity of tumor-infiltrating CD45+CD34+ fibrocytes is enhanced by anti-PD-L1 antibody. Peritumoral implantation of fibrocytes enhances the antitumor effect of PD-L1 blockade in vivo; CD86-/- fibrocytes do not. Tumor-infiltrating fibrocytes acquire myofibroblast-like phenotypes through transforming growth factor β (TGF-β)/small mothers against decapentaplegic (SMAD) signaling. Thus, TGF-βR/SMAD inhibitor enhances the antitumor effects of dual VEGF and PD-L1 blockade by regulating fibrocyte differentiation. Fibrocytes are highlighted as regulators of the response to programmed death 1 (PD-1)/PD-L1 blockade. Cell reports 112162 112162 20230228 10.1016/j.celrep.2023.112162 36870329 mitsuhashiatsushi/published_papers/44455261 Masaki Hanibuch Atsushi Mitsuhashi Atsuro Saijo Tatsuya Kajimoto Seidai Sato Tetsuya Kitagawa Yasuhiko Nishioka A case of atopic cough with aphonia showed a prominent response to a histamine H1 receptor antagonist. A 33-year-old woman admitted to our hospital for further examination of severe non-productive cough lasting for about two months. Her symptom did not ameliorate by treatments including long acting β2 agonists. She had a medical history of drug allergy to non-steroidal anti-inflammatory drugs. At the initial visit, she could not speak at all and communicated with us in writing. Chest auscultation revealed no wheezes, rhonchi and other crackles. Laboratory findings showed a mild eosinophilia with normal total and specific serum immunoglobulin E. The results of an electrocardiogram, a chest X-ray and a chest CT were unremarkable. A fractional exhaled nitric oxide value was within normal limit. Based on these observations, a diagnosis of atopic cough (AC) was suspected, and we started treatment with a histamine H1 receptor antagonist (H1-RA). She had become able to speak again in association with complete disappearance of cough by eight-weeks after treatment initiation, and her symptoms did not recur even after cessation of treatment. By the confirmation of remarkable clinical improvement in response to a H1-RA, a diagnosis of AC was made. To the best of our knowledge, this is the first report of an AC patient who presented severe cough with aphonia. J. Med. Invest. 70 : 281-284, February, 2023. The journal of medical investigation : JMI 70 1.2 281 284 20230000 10.2152/jmi.70.281 37164735 mitsuhashiatsushi/published_papers/44455260 Hiroki Takahashi Hirokazu Ogino Hiroki Bando Atsushi Mitsuhashi Yuki Tsukazaki Yohei Yabuki Ryohiko Ozaki Hiroto Yoneda Seidai Sato Masaki Hanibuchi Yasuhiko Nishioka FoundationOne CDx detected an uncovered variant of epidermal growth factor receptor exon 19 deletion by Oncomine Dx target test in a patient with lung adenocarcinoma. A non-smoker woman with advanced lung adenocarcinoma was referred to us. The Oncomine Dx target test (ODxTT), a next-generation sequencing (NGS)-based hot spots panel test, did not detect any driver mutations, so we treated her with chemo-immunotherapy. After second-line chemotherapy, we performed FoundationOne CDx, a NGS-based comprehensive genomic profiling (CGP) test, and identified a rare variant of epidermal growth factor receptor exon 19 deletion that had not been covered by ODxTT. This case highlights the importance of considering the indication of a CGP test for patients who are likely to harbor driver mutations, even when ODxTT fails to detect any. Respiratory medicine case reports 45 101893 101893 20230000 10.1016/j.rmcr.2023.101893 37485237 mitsuhashiatsushi/published_papers/41646911 Seiya Ichihara Hirokazu Ogino Hiroto Yoneda Keiko Haji Kozo Kagawa Kojin Murakami Masato Mima Yu Aoi Atsushi Mitsuhashi Yuki Tsukazaki Yohei Yabuki Ryohiko Ozaki Seidai Sato Hiroshi Nokihara Yasuhiko Nishioka Immune checkpoint inhibitor-related pneumonitis with atypical radiologic features in a patient with anti-aminoacyl-tRNA synthetase antibody. A man with non-small-cell lung cancer who was negative for anti-nuclear antibodies was admitted for dyspnea after immune checkpoint inhibitor (ICI) administration. Computed tomography (CT) showed complexed radiologic features, including subpleural and basal predominant reticular shadow with cystic structures and peribronchovascular consolidation. Although we treated him with high-dose steroid under a diagnosis of ICI-related pneumonitis, he developed acute exacerbation of pneumonitis with progressive fibrosis and volume loss. A re-evaluation identified anti-aminoacyl-tRNA synthetase antibody in the serum collected before ICI administration. This case highlights the importance of re-evaluating pre-existing autoimmune disorders in patients who develop ICI-related pneumonitis with atypical radiologic features. Respiratory medicine case reports 41 101797 101797 20230000 10.1016/j.rmcr.2022.101797 36583061 mitsuhashiatsushi/published_papers/40799829 Masaki Hanibuchi Atsushi Mitsuhashi Tatsuya Kajimoto Atsuro Saijo Seidai Sato Tetsuya Kitagawa Yasuhiko Nishioka Clinical significance of fractional exhaled nitric oxide and periostin as potential markers to assess therapeutic efficacy in patients with cough variant asthma. BACKGROUND: In Japan, cough variant asthma (CVA) is the most common etiology of chronic cough. Contrary to substantial progress in understanding the roles of various factors in classic asthma, little is known regarding the pathogenesis and development of CVA. Furthermore, few studies have explored valuable biomarkers for evaluating the therapeutic efficacy of patients with CVA. METHODS: We conducted a single-center, prospective study to investigate the clinical significance of various clinical factors as potential "therapeutic" markers for CVA. RESULTS: From December 2019 to September 2020, we enrolled 20 patients with CVA and 10 age-matched healthy control subjects. Fractional exhaled nitric oxide (FeNO) values were significantly higher in patients with CVA than those in healthy controls. All patients with CVA commenced treatment at the initial visit, which markedly alleviated symptoms 12 weeks after treatment. FeNO values and serum periostin levels were significantly decreased following treatment, and altered FeNO values correlated with improved visual analogue scale scores of symptoms. Moreover, changes in both FeNO values and serum periostin levels were significantly correlated with increased values of some pulmonary function tests while also correlating with each other. CONCLUSIONS: Our observations indicate the usefulness of FeNO and periostin as potential "therapeutic" markers for CVA. To the best of our knowledge, this is the first report demonstrating the clinical significance of these factors as potential biomarkers to assess therapeutic efficacy in patients with CVA. Respiratory investigation null null 20221130 10.1016/j.resinv.2022.10.006 36463016 mitsuhashiatsushi/published_papers/40290621 Makoto Tobiume Atsushi Mitsuhashi Atsuro Saijo Hirokazu Ogino Tania Afroj Hirohisa Ogawa Hisatsugu Goto Seidai Sato Akane Abe Keiko Haji Ryohiko Ozaki Hiromitsu Takizawa Yasuhiko Nishioka Analysis of the chemotactic factors for tumor-infiltrating fibrocytes and their prognostic significances in lung cancer. Fibrocytes, which are bone marrow-derived collagen-producing cells, have been reported to be involved in pathogenesis of pulmonary fibrosis. Our previous study reported that tumor-infiltrating fibrocytes play a role in tumor progression and drug resistance in lung cancer. The present study therefore examined chemotactic factors for fibrocytes in tissues of non-small cell lung cancer (NSCLC) and their prognostic significance. Surgically resected tumor tissues were examined for the expression of chemotactic factors, including C-X-C motif chemokine 12 (CXCL12), CCL2, platelet-derived growth factor (PDGF)-AA and PDGF-BB, as well as tumor-infiltrating fibrocytes by immunostaining. The chemotactic ability of fibrocytes in response to each factor was evaluated using a migration assay by counting the migrated cells microscopically, and expression of receptors for chemotactic factors were analyzed by flow cytometry. The expression of CXCL12, but not CCL2, PDGF-AA, or PDGF-BB, was associated with the number of tumor-infiltrating fibrocytes in lung adenocarcinoma (LUAD), but not lung squamous cell carcinoma (LUSQ). In addition, patients with an increased expression of CXCL12 in LUAD but not LUSQ showed a significantly poorer prognosis compared with those with a decreased expression. However, the expression of CCL2, PDGF-AA and PDGF-BB was not correlated with the prognosis of patients with NSCLC. The number of fibrocytes was associated with a poor prognosis in LUAD. Fibrocytes derived from the peripheral blood of healthy subjects as well as patients with lung cancer expressed higher levels of CXCR4 compared with CCR2, PDGF and receptor-α and receptor-β. Overall, these results suggested that targeting tumor-infiltrating fibrocytes via the CXCL12/CXCR4 axis may be a useful strategy for controlling the progression of NSCLC, particularly LUAD. Oncology letters 24 5 417 417 20221100 10.3892/ol.2022.13537 36245829 mitsuhashiatsushi/published_papers/40799830 Na T Nguyen Atsushi Mitsuhashi Hirokazu Ogino Hiroyuki Kozai Hiroto Yoneda Tania Afroj Seidai Sato Hiroshi Nokihara Tsutomu Shinohara Yasuhiko Nishioka S-1 eliminates MDSCs and enhances the efficacy of PD-1 blockade via regulation of tumor-derived Bv8 and S100A8 in thoracic tumor. Myeloid-derived suppressor cells (MDSCs) have been known to play a pivotal role in the induction of immune tolerance, which limits the benefits of immune checkpoint inhibitors (ICIs). Recent studies revealed that several chemotherapeutic agents decreased tumor-infiltrating MDSCs. Therefore, combination therapy with cytotoxic chemotherapeutic agents and ICIs was approved for first-line treatment for lung cancer. However, the impact of chemotherapeutic agents on MDSCs and an optimal partner of ICIs has not been fully investigated in thoracic tumors, including lung cancer and malignant pleural mesothelioma. In the present study, we found that treatment with 5-FU and its oral formulation, S-1, suppressed tumor progression and inhibited the accumulation of MDSCs in thoracic tumor-bearing mice. Tumor-infiltrating T cells and dendritic cells were significantly expanded in S-1-treated mice. 5-FU suppressed the ability of tumor cells to recruit MDSCs, while it did not suppress the survival and differentiation of mouse MDSCs in vitro. We also revealed that 5-FU or S-1 significantly downregulated the expression of tumor-derived Bv8 and S100A8. The knockdown of Bv8 or S100A8 in tumor cells suppressed tumor growth and MDSC recruitment in vivo. Furthermore, in comparison with pemetrexed, administration of S-1 improved the synergistic therapeutic efficacy of anti-PD-1 antibodies with or without carboplatin. Our findings revealed a novel mechanism wherein S-1 primed a favorable tumor microenvironment to provide the rationale for combination therapy with S-1 and ICIs as the optimal therapy for thoracic cancer. Cancer science null null 20221026 10.1111/cas.15620 36285504 mitsuhashiatsushi/published_papers/40290622 Kenji Otsuka Hiroshi Nokihara Atsushi Mitsuhashi Ryohiko Ozaki Yohei Yabuki Hiroto Yoneda Hirokazu Ogino Yasuhiko Nishioka Efficacy and safety of second-line chemotherapy for patients with advanced non-small cell lung cancer complicated by interstitial lung disease. BACKGROUND: Treatment of non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) is limited because of the risk of its acute exacerbation (AE). Furthermore, the efficacy and safety of second-line chemotherapy for these patients is unclear. METHODS: To investigate the efficacy and safety of second-line chemotherapy for NSCLC patients with ILD, we retrospectively reviewed patients who were treated at our institute between April 2010 and December 2018. RESULTS: Thirty-five patients received two or more regimens. Thirty-four patients were male and the median age at the initiation of second-line chemotherapy was 70 years. Almost all patients had a smoking history. Fourteen patients had adenocarcinoma and 15 had squamous cell carcinoma histology. Stages III and IV were observed in 20 and 11 patients, respectively. With respect to the type of ILD, 12 patients had usual interstitial pneumonia (UIP). The overall response rate and disease control rate were 11.4 and 68.6%, respectively. The median progression-free and median overall survival were 4.1 and 6.4 months, respectively. The AE of ILD was observed in eight patients, five of whom died. UIP and low percentage vital capacity were detected as significant risk factors for the AE of ILD. CONCLUSION: Second-line chemotherapy among patients with NSCLC complicated by ILD showed a certain effectiveness, but some patients experienced the AE of ILD, which may lead to death. The risk of the AE of ILD must be considered especially for patients with UIP and low percentage VC. Thoracic cancer null null 20220915 10.1111/1759-7714.14645 36106507 mitsuhashiatsushi/published_papers/40290623 Masaki Hanibuchi Atsuro Saijo Atsushi Mitsuhashi Tatsuya Kajimoto Tetsuya Kitagawa Yasuhiko Nishioka The efficacy of mass screening for chronic obstructive pulmonary disease using screening questionnaires in a medical health check-up population. BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease, highlighting the need for efficient screening strategies to identify patients with COPD. However, there is little evidence regarding the efficacy of mass screening for COPD, and no epidemiological studies on COPD have been conducted in the Shikoku region of Japan. METHODS: In this cross-sectional study, we originally investigated the efficacy of mass screening for COPD among community residents in the aforementioned region using two COPD screening questionnaires. RESULTS: From July 2018 through January 2019, 688 participants were enrolled. COPD was diagnosed using the Global Initiative for the Chronic Obstructive Lung Disease criteria. Twenty-one patients were newly diagnosed with COPD and 19 (90.5%) had early stages COPD. The prevalence of COPD in this study was 3.1%. The COPD Population Screener (COPD-PS) questionnaire and the International Primary Care Airways Guidelines (IPAG) questionnaire had extremely high negative predictive values in discriminating participants with COPD from those without. The scores of both questionnaires were correlated with spirometric tests and with each other. The COPD-PS questionnaire had significantly better specificity and area under the receiver operating characteristic curve value than the IPAG questionnaire. Moreover, only the COPD-PS questionnaire was identified as an independent factor for predicting COPD diagnosis in the multivariate analysis. CONCLUSIONS: Mass screening for COPD using screening questionnaires, particularly the COPD-PS questionnaire, might be useful to identify the early stages of COPD in a medical health check-up population. Respiratory investigation null null 20220831 10.1016/j.resinv.2022.07.005 36057534 mitsuhashiatsushi/published_papers/37206033 Hiroshi Nokihara Hirokazu Ogino Atsushi Mitsuhashi Kensuke Kondo Ei Ogawa Ryohiko Ozaki Yohei Yabuki Hiroto Yoneda Kenji Otsuka Yasuhiko Nishioka Efficacy of osimertinib in epidermal growth factor receptor-mutated non-small-cell lung cancer patients with pleural effusion. BACKGROUND: Osimertinib is a standard first-line treatment for advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Although malignant pleural effusion (PE) is a common clinical problem in NSCLC, information about the efficacy of osimertinib in patients with PE is limited, especially regarding its efficacy in EGFR T790M-negative patients with PE remains unclear. METHODS: We retrospectively reviewed the medical records of patients with NSCLC harboring EGFR mutations who were treated with osimertinib in our institution between May 2016 and December 2020. RESULTS: A total of 63 patients with EGFR mutated NSCLC were treated with osimertinib; 33 (12 with PE) had no EGFR T790M mutation, while 30 (12 with PE) had EGFR T790M mutation. In EGFR T790M-negative NSCLC, the progression-free survival (PFS) of the patients with PE was comparable to that of the patients without PE (median PFS 19.8 vs. 19.8 months, p = 0.693). In EGFR T790M- positive NSCLC, the PFS and overall survival (OS) of the patients with PE were significantly shorter than those of the patients without PE (median PFS 16.8 vs. 8.3 months, p = 0.003; median OS 44.9 vs. 14.2 months, p = 0.007). In the multivariate analysis, the presence of PE was independently associated with shorter PFS and OS in EGFR T790M-positive NSCLC patients, but not EGFR T790M-negative patients. CONCLUSIONS: These data suggest the efficacy of osimertinib may differ between EGFR T790M-positive and -negative NSCLC patients with PE. BMC cancer 22 1 597 597 20220601 10.1186/s12885-022-09701-2 35650550 mitsuhashiatsushi/published_papers/40711746 小山 壱也 三橋 惇志 今倉 健 村上 行人 香川 耕造 佐藤 正大 河野 弘 小川 博久 西岡 安彦 びまん性肺疾患 線維化の病態 シングルセル解析を用いた肺線維症マウスモデルにおけるfibrocyteの検討 (一社)日本呼吸器学会 日本呼吸器学会誌 2186-5884 11 164 164 20220400 mitsuhashiatsushi/published_papers/36517756 Yutaka Morita Atsuro Saijo Hiroshi Nokihara Atsushi Mitsuhashi Hiroto Yoneda Kenji Otsuka Hirokazu Ogino Yoshimi Bando Yasuhiko Nishioka Radiation therapy induces an abscopal effect and upregulates programmed death-ligand 1 expression in a patient with non-small cell lung cancer. Radiation therapy (RT) activates the antigen presentation of dendritic cells and priming of cancer-specific cytotoxic CD8+ T cells, occasionally resulting in a systemic immune response to the tumor outside of the treatment field. The phenomenon of tumor regression at the site distant from irradiated fields is known as the abscopal effect. Several case reports have indicated a potential role of RT in overcoming primary and acquired resistance against immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) and melanoma patients. We herein report an NSCLC patient who developed acquired resistance to an RT-induced abscopal effect and subsequently experienced reactivation of the systemic antitumor immune response by pembrolizumab, an antiprogrammed death 1 antibody. In this case, RT not only induced an abscopal effect but also upregulated the programmed death-ligand 1 expression outside of the irradiated field when the patient developed resistance to the abscopal effect. This case can facilitate our understanding of the mechanism underlying the RT-induced systemic immune response against cancer cells and adaptive resistance mechanism of cancer cells from immune surveillance. These findings highlight the promising results of current clinical trials combining RT and immune checkpoint inhibitors. Ongoing clinical trials will further establish evidence supporting combination therapy with RT and immune checkpoint inhibitors. Thoracic cancer null null 20220122 10.1111/1759-7714.14330 35064748 mitsuhashiatsushi/published_papers/36517757 Masahiro Sako Hiroshi Nokihara Kensuke Kondo Atsushi Mitsuhashi Ryohiko Ozaki Yohei Yabuki Akane Abe Hiroto Yoneda Hirokazu Ogino Kenji Otsuka Hisanori Uehara Yasuhiko Nishioka A case of pulmonary pleomorphic carcinoma with preexisting interstitial pneumonia successfully treated with pembrolizumab. Pulmonary pleomorphic carcinoma is often refractory to chemotherapy and follows an aggressive clinical course. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced lung cancer, and a few cases with pleomorphic carcinoma have been reported to show tumor shrinkage after therapy with ICIs. When treating patients with ICIs, patient selection is essential, and monitoring and management of immune-related adverse events, including pneumonitis, are needed. We herein report a case of pulmonary pleomorphic carcinoma with preexisting interstitial pneumonia treated with pembrolizumab, antiprogrammed cell death 1 antibody. Our report highlights important considerations necessary when treating advanced pleomorphic carcinoma patients complicated with interstitial pneumonia. We also review the literature regarding the use of ICIs in such patients. Thoracic cancer 13 1 129 132 20220100 10.1111/1759-7714.14243 34859591 mitsuhashiatsushi/published_papers/35982689 Hiroto Yoneda Hiroshi Nokihara Atsushi Mitsuhashi Ryohiko Ozaki Yohei Yabuki Hirokazu Ogino Kenji Otsuka Yasuhiko Nishioka Correlation between immune-related adverse events and therapeutic effects of nivolumab in patients with malignant pleural mesothelioma. BACKGROUND: Nivolumab is used for the treatment of malignant pleural mesothelioma (MPM). However, immune-related adverse events (irAEs) occur in patients treated with nivolumab. Several studies have reported the correlation between irAEs and therapeutic effects of immune checkpoint inhibitor, but none have reported the correlation in MPM. Here we report a retrospective study which shows the correlation between irAEs and therapeutic effects of nivolumab in patients with MPM. METHODS: This study included patients treated with nivolumab at Tokushima University Hospital from February 2009 to September 2021. We retrospectively reviewed the medical records to evaluate the several clinical factors, such as the presence or absence of irAEs, their severities, progression-free survival (PFS), overall survival (OS) or objective response to the treatment. RESULTS: Eleven patients received treatment with nivolumab. Objective response rate was 18.2% and the disease control rate was 90.9%. Median PFS was 6.8 months (95% confidence interval, 1.3 to 11.9 months) and median OS was 15.2 months (95% confidence interval, 8.9 to 21.5 months). IrAEs occurred in eight patients (72.7%), and grade ≥ 2 irAEs occurred in six patients (54.5%). PFS and OS were significantly longer in the grade ≥ 2 irAEs group than in grade < 2 irAEs group (median PFS 13.6 vs. 3.8 months, p = 0.0093; median OS not reached vs. 8.6 months, p = 0.0108). CONCLUSIONS: This is the first study to report the correlation between irAEs and therapeutic effects in patients with MPM. Because the presence of irAEs may be associated with a favorable clinical outcome, early detection and appropriate management of irAEs will increase the therapeutic benefits to patients. BMC pulmonary medicine 21 1 373 373 20211115 10.1186/s12890-021-01746-6 34781910 mitsuhashiatsushi/published_papers/34026127 Atsushi Mitsuhashi Kensuke Kondoh Kazuki Horikawa Kazuya Koyama Na Thi Nguyen Tania Afroj Hiroto Yoneda Kenji Otsuka Hirokazu Ogino Hiroshi Nokihara Tsutomu Shinohara Yasuhiko Nishioka PD-1/PD-L1 blockade mediates anti-angiogenic effects by tumor-derived CXCL10/11 as a potential predictive biomarker. Immune checkpoint inhibitor (ICI), PD-1/PD-L1 blockade has been approved for various cancers. However, the underlying anti-tumor mechanisms mediated by ICIs and the predictive biomarkers remain unclear. We report the effects of anti-PD-L1/PD-1 antibody in tumor angiogenesis. In syngeneic mouse models, anti-PD-L1 antibody inhibited tumor angiogenesis and induces netlike hypoxia only in ICI-sensitive cell lines. In tumor tissue and serum of ICI-sensitive cell line-bearing mice, IFN-γ (interferon γ) inducible angiostatic chemokines CXCL10/11 were upregulated by PD-L1 blockade. In vitro, CXCL10/11 gene upregulation by IFN-γ stimulation in tumor cell lines correlated with the sensitivity of PD-L1 blockade. The CXCL10/11 receptor CXCR3-neutralizing antibody or CXCL11-silencing in tumor cells inhibited the anti-angiogenic effect of PD-L1 blockade in vivo. In pretreatment serum of lung carcinoma patients receiving anti-PD-1 antibody, the concentration of CXCL10/11 significantly correlated with the clinical outcome. Our results demonstrate the anti-angiogenic function of PD-1/PD-L1 blockade and identify tumor-derived CXCL10/11 as a potential circulating biomarker of therapeutic sensitivity. Cancer science null null 20211010 10.1111/cas.15161 34628702 mitsuhashiatsushi/published_papers/33716033 Tania Afroj Atsushi Mitsuhashi Hirokazu Ogino Atsuro Saijo Kenji Otsuka Hiroto Yoneda Makoto Tobiume Na Thi Nguyen Hisatsugu Goto Kazuya Koyama Masamichi Sugimoto Osamu Kondoh Hiroshi Nokihara Yasuhiko Nishioka Blockade of PD-1/PD-L1 Pathway Enhances the Antigen-Presenting Capacity of Fibrocytes. Fibrocytes, a distinct population of collagen-producing, monocyte-derived cells, are involved in wound healing as well as fibrotic diseases. Recently, fibrocytes have been revealed to play a role in the tumor microenvironment, particularly under antiangiogenic therapy. In addition, combination cancer immunotherapy with immune checkpoint inhibitor and antiangiogenic agents have been developed for various cancers in the clinical setting, although the immunological background is not clear. In the current study, we aimed to determine the function of fibrocytes in tumor immunity induced by immune checkpoint inhibitor therapy. Human and murine fibrocytes were generated from PBMCs and lungs, respectively. The expression of costimulatory and inhibitory molecules on fibrocytes was examined by flow cytometry. The stimulation of CD8+ T cells by fibrocytes was examined in MLRs with a 3H-thymidine incorporation assay. Fibrocytes expressed CD80low and CD86high as a costimulatory molecule, and expressed PD-L1high, but not PD-L2, as a coinhibitory molecule. Without any stimulation, fibrocytes strongly enhanced the proliferation of CD8+ T cells in mice and humans. Treatment with anti-CD86 and -CD54 Abs inhibited the growth of CD8+ T cells induced by fibrocytes. Anti-PD-L1 Ab further enhanced the proliferation of CD8+ T cells, even in the OVA-specific MLR with OT-1Rag-/- mice. Importantly, fibrocytes derived from PBMCs of patients with lung adenocarcinoma or murine MC38 tumors augmented the proliferation of CD8+ T cells with PD-L1 blockade. These results suggest that fibrocytes infiltrating tumor sites may play a role in the antitumor immunity mediated by CD8+ T cells when the activity is further enhanced by PD-L1/PD-1 blockade. Journal of immunology (Baltimore, Md. : 1950) 206 6 1204 1214 20210315 10.4049/jimmunol.2000909 33504617 mitsuhashiatsushi/published_papers/35982691 Masaki Hanibuchi Atsushi Mitsuhashi Tatsuya Kajimoto Atsuro Saijo Tetsuya Kitagawa A case of chest tightness variant asthma : the usefulness of fractional exhaled nitric oxide as a marker for the diagnosis and clinical improvement. A 50-year-old woman was referred to our hospital for further examination of severe constricting pain at the right-side dominant anterior chest. She had medical history of outgrown childhood asthma and allergies to several animals. Chest auscultation revealed no wheezes, rhonchi and other crackles. Laboratory findings showed an eosinophilia and an elevation of total immunoglobulin E. The results of an electrocardiogram, a chest X-ray and a chest CT were unremarkable. A fractional exhaled nitric oxide value remarkably elevated, but the abnormalities in pulmonary function test were modest. Her chest pain was ameliorated after inhaling procaterol. Based on these findings, a diagnosis of chest tightness variant asthma was formulated, and we started treatment with inhaled corticosteroid / long acting β2 agonist. At two-weeks after treatment, her symptom markedly improved and a fractional exhaled nitric oxide value decreased, which led to a definitive diagnosis of chest tightness variant asthma. A fractional exhaled nitric oxide value further decreased to the normal range in consistent with symptom disappearance at 10-months after treatment, indicating the usefulness of fractional exhaled nitric oxide as a promising marker for the diagnosis and clinical improvement of chest tightness variant asthma. J. Med. Invest. 68 : 389-392, August, 2021. The journal of medical investigation : JMI 68 3.4 389 392 20210000 10.2152/jmi.68.389 34759166 mitsuhashiatsushi/published_papers/35982690 Masaki Hanibuchi Atsuro Saijo Atsushi Mitsuhashi Tatsuya Kajimoto Tetsuya Kitagawa A rare case of invasive thymoma presented a dramatic response to low-dose prednisolone as a single-drug therapy. A 76-year-old woman with a history of angina pectoris, hypertension and dyslipidemia was pointed out an abnormal opacity in the right hilar region on routine chest X-ray. Chest computed tomography showed masses in the anterior mediastinum with the invasion of the adjacent ascending aorta, right brachiocephalic vein and right pleura. Histologic examination led to a diagnosis of Masaoka stage IVa thymoma. Three courses of chemotherapy were given, but further tumor progression was seen. Thereafter, the patient was followed without aggressive treatments. One year after the initial diagnosis, she presented with dyspnea and right chest pain. Chest CT revealed right massive pleural effusion with pleural dissemination and much further progression of existing tumors. For the purpose of symptom palliation, a low dose (5 mg / day) of prednisolone was commenced, which unexpectedly led to marked alleviation of patient's symptoms and dramatic decrease of pleural effusion. To the best of our knowledge, this is the first report of an invasive thymoma responded to low-dose corticosteroid. The present case suggests that corticosteroids, even at low doses, might be potentially effective for invasive thymoma after failure of surgery, chemotherapy and radiotherapy. J. Med. Invest. 68 : 396-399, August, 2021. The journal of medical investigation : JMI 68 3.4 396 399 20210000 10.2152/jmi.68.396 34759168 mitsuhashiatsushi/published_papers/34960461 三橋 惇志 西岡 安彦 【ゲノム医療時代のがん 分子標的薬と診断薬研究「治療」の選択肢を広げる新しい標的，併用療法，横断的・マルチコンパニオン診断薬，リキッドバイオプシー】(第5章)耐性メカニズムとその克服方法 血管新生阻害剤に対する耐性獲得メカニズム (株)羊土社 実験医学 0288-5514 38 15 2603 2608 20200900 mitsuhashiatsushi/published_papers/30156568 Kenji Otsuka Atsushi Mitsuhashi Hisatsugu Goto Masaki Hanibuchi Kazuya Koyama Hirohisa Ogawa Hirokazu Ogino Atsuro Saijo Hiroyuki Kozai Hiroto Yoneda Makoto Tobiume Masatoshi Kishuku Keisuke Ishizawa Yasuhiko Nishioka Anti-PD-1 antibody combined with chemotherapy suppresses the growth of mesothelioma by reducing myeloid-derived suppressor cells. BACKGROUND: The combination of anti-PD-1/PD-L1 antibody with chemotherapy has been approved for the first-line therapy of lung cancer. However, the effects against malignant mesothelioma (MPM) and the immunological mechanisms by which chemotherapy enhances the effect of targeting PD-1/PD-L1 in MPM are poorly understood. MATERIALS AND METHODS: We utilized syngeneic mouse models of MPM and lung cancer and assessed the therapeutic effects of anti-PD-1 antibody and its combination with cisplatin (CDDP) and pemetrexed (PEM). An immunological analysis of tumor-infiltrating cells was performed with immunohistochemistry. RESULTS: We observed significant therapeutic effects of anti-PD-1 antibody against MPM. Although the effect was associated with CD8+ and CD4+ T cells in tumors, the number of Foxp3+ cells was not reduced but rather increased. Consequently, combination with CDDP/PEM significantly enhanced the antitumor effects of anti-PD-1 antibody by decreasing numbers of intratumoral myeloid-derived suppressor cells (MDSCs) and vessels probably through suppression of VEGF expression by CDDP + PEM. CONCLUSIONS: The combination of anti-PD-1 antibody with CDDP + PEM may be a promising therapy for MPM via inhibiting the accumulation of MDSCs and vessels in tumors. Lung cancer (Amsterdam, Netherlands) 146 86 96 20200800 10.1016/j.lungcan.2020.05.023 32526602 mitsuhashiatsushi/published_papers/33716034 Masaki Hanibuchi Atsuro Saijo Atsushi Mitsuhashi Takash Takeji Tetsuya Kitagawa The clinical usefulness of a new hand-held device for fractional exhaled nitric oxide measurement, NIOX VERO®, for diagnosing the etiology of cough. Cough is one of the most common symptoms seen in clinical practice, however the differential diagnosis is often difficult. The utility of fractional exhaled nitric oxide (FeNO) measurement in the differential diagnosis of the etiology of cough has been reported. NIOX VERO® (NOV) is a new hand-held device that will replace NIOX MINO®, but its diagnostic utility has not been fully elucidated in clinical practice. In this study, the performance of NOV for FeNO measurements was determined. We retrospectively analyzed 243 consecutive patients complaining cough. Among 243 patients, final diagnosis was cough variant asthma (CVA) in 74 (30.5%), bronchial asthma (BA) in 48 (19.8%), post-infectious cough (PIC) in 52 (21.4%), atopic chough (AC) in 24 (9.9%), gastroesophageal reflux disease (GERD) in 10 (4.1%), and Others in 35 (14.4%). FeNO values were significantly higher in CVA and BA as compared to PIC, AC, GERD, and Others. In the multivariate analysis, only FeNO value was identified as independent factors to discriminate CVA and non-CVA other than BA. These findings indicated that FeNO measured by using NOV could be used as a diagnostic marker of intractable cough, especially for the differential diagnosis of CVA from non-CVA. J. Med. Invest. 67 : 265-270, August, 2020. The journal of medical investigation : JMI 67 3.4 265 270 20200000 10.2152/jmi.67.265 33148899 mitsuhashiatsushi/published_papers/30156569 Masamitsu Ubukata Atsushi Mitsuhashi Yuki Nishizawa Teruhiro Fujii Masaki Hara Akihito Ohta Kosaku Nitta Anticentromere Antibody-positive Scleroderma Renal Crisis Requiring Dialysis. A 70-year-old man with prior Raynaud's phenomena developed hypertension and renal insufficiency. Raynaud's phenomena, finger skin thickening, interstitial lung disease, and positive anticentromere antibody findings indicated systemic sclerosis (SSc). Based on the presence of SSc, severe hypertension with rapidly progressive renal failure, and proliferative and obliterative arteriolar vasculopathy, scleroderma renal crisis (SRC) was diagnosed. Despite good blood pressure control with antihypertensive drugs, hemodialysis was initiated and could not be withdrawn owing to unimproved renal dysfunction. Although SRC in anticentromere antibody-positive limited cutaneous SSc is extremely rare, some patients may develop SRC, and their renal prognosis may be poor. Internal medicine (Tokyo, Japan) 57 23 3479 3483 20181201 10.2169/internalmedicine.0980-18 30101908 mitsuhashiatsushi/published_papers/13899823 Atsushi Mitsuhashi Yusuke Okuma Yoshitaka Zenke Yukio Hosomi Prognostic effects of osteoclast inhibitors in extensive stage small cell lung cancer patients with bone metastases. Bone metastases (BM) often induce skeletal-related events (SREs) and contribute to poor prognoses in patients with cancer. Osteoclast inhibitors (OIs), such as bisphosphonates (BPs) and denosumab, reportedly prevent SREs and improve quality of life in patients with non-small cell lung cancer and BM, but have not been tested in extensive stage small cell lung cancer (ES-SCLC) patients. From 238 SCLC patient records, the present study reviewed those of 58 BM patients, including 23 who were treated with OIs (OIs group) and 35 who were untreated (untreated group). Patient backgrounds were balanced between groups using propensity score matching, and survival curves were compared using the log-rank test. The median overall survival (OS) times were 8.41 and 12.52 months in untreated and OIs groups, respectively, but these did not differ significantly between groups (log-rank test, P=0.409). The 1-year OS rate was higher in the OIs group (56.1%) when compared with the control group (22.6%). The results indicated that OIs tend to prolong the short term survival of ES-SCLC patients with BM. To the best of our knowledge, this is the first study to examine the prognostic effects of OIs in SCLC patients. The results of the present study may highlight the possibility that OIs improve the prognosis of ES-SCLC patients with BM. Molecular and clinical oncology 2049-9450 9 5 561 565 20181100 10.3892/mco.2018.1710 30345052 mitsuhashiatsushi/published_papers/25698399 Atsuro Saijo Hisatsugu Goto Nakano Mayuri Mitsuhashi Atsushi Yoshinori Aono Masaki Hanibuchi Hirohisa Ogawa Hisanori Uehara Kazuya Kondo Yasuhiko Nishioka Bone marrow-derived fibrocytes promote stem cell-like properties of lung cancer cells. Cancer stem cells (CSCs) represent a minor population that have clonal tumor initiation and self-renewal capacity and are responsible for tumor initiation, metastasis, and therapeutic resistance. CSCs reside in niches, which are composed of diverse types of stromal cells and extracellular matrix components. These stromal cells regulate CSC-like properties by providing secreted factors or by physical contact. Fibrocytes are differentiated from bone marrow-derived CD14 monocytes and have features of both macrophages and fibroblasts. Accumulating evidence has suggested that stromal fibrocytes might promote cancer progression. However, the role of fibrocytes in the CSC niches has not been revealed. We herein report that human fibrocytes enhanced the CSC-like properties of lung cancer cells through secreted factors, including osteopontin, CC-chemokine ligand 18, and plasminogen activator inhibitor-1. The PIK3K/AKT pathway was critical for fibrocytes to mediate the CSC-like functions of lung cancer cells. In human lung cancer specimens, the number of tumor-infiltrated fibrocytes was correlated with high expression of CSC-associated protein in cancer cells. These results suggest that fibrocytes may be a novel cell population that regulates the CSC-like properties of lung cancer cells in the CSC niches. Cancer Letters 1872-7980 421 17 27 20180501 10.1016/j.canlet.2018.02.016 29448000 mitsuhashiatsushi/published_papers/13899825 Atsuro Saijo Hisatsugu Goto Mayuri Nakano Atsushi Mitsuhashi Yoshinori Aono Masaki Hanibuchi Hirohisa Ogawa Hisanori Uehara Kazuya Kondo Yasuhiko Nishioka Bone marrow-derived fibrocytes promote stem cell-like properties of lung cancer cells. Elsevier Ireland Ltd Cancer letters 1872-7980 421 17 27 20180501 10.1016/j.canlet.2018.02.016 29448000 2-s2.0-85042214220 mitsuhashiatsushi/published_papers/13899824 Sho Tabata Masatatsu Yamamoto Hisatsugu Goto Akiyoshi Hirayama Maki Ohishi Takuya Kuramoto Atsushi Mitsuhashi Ryuji Ikeda Misako Haraguchi Kohichi Kawahara Yoshinari Shinsato Kentaro Minami Atsuro Saijo Yuko Toyoda Masaki Hanibuchi Yasuhiko Nishioka Saburo Sone Hiroyasu Esumi Masaru Tomita Tomoyoshi Soga Tatsuhiko Furukawa Shin-Ichi Akiyama Thymidine catabolism promotes NADPH oxidase-derived reactive oxygen species (ROS) signalling in KB and yumoto cells. Thymidine phosphorylase (TP) is a rate-limiting enzyme in the thymidine catabolic pathway. TP is identical to platelet-derived endothelial cell growth factor and contributes to tumour angiogenesis. TP induces the generation of reactive oxygen species (ROS) and enhances the expression of oxidative stress-responsive genes, such as interleukin (IL)-8. However, the mechanism underlying ROS induction by TP remains unclear. In the present study, we demonstrated that TP promotes NADPH oxidase-derived ROS signalling in cancer cells. NADPH oxidase inhibition using apocynin or small interfering RNAs (siRNAs) abrogated the induction of IL-8 and ROS in TP-expressing cancer cells. Meanwhile, thymidine catabolism induced by TP increased the levels of NADPH and intermediates of the pentose phosphate pathway (PPP). Both siRNA knockdown of glucose 6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme in PPP, and a G6PD inhibitor, dihydroepiandrosterone, reduced TP-induced ROS production. siRNA downregulation of 2-deoxy-D-ribose 5-phosphate (DR5P) aldolase, which is needed for DR5P to enter glycolysis, also suppressed the induction of NADPH and IL-8 in TP-expressing cells. These results suggested that TP-mediated thymidine catabolism increases the intracellular NADPH level via the PPP, which enhances the production of ROS by NADPH oxidase and activates its downstream signalling. Scientific reports 8 1 6760 6760 20180430 10.1038/s41598-018-25189-y 29713062 mitsuhashiatsushi/published_papers/13899924 mitsuhashi atsushi 三橋 惇志 Perspective on immune oncology with liquid biopsy, peripheral blood mononuclear cells, and microbiome with non-invasive biomarkers in cancer patients. Clinical and Translational Oncology 20 8 966 974 20180100 mitsuhashiatsushi/published_papers/13899826 Sho Tabata Masatatsu Yamamoto Hisatsugu Goto Akiyoshi Hirayama Maki Ohishi Takuya Kuramoto Atsushi Mitsuhashi Ryuji Ikeda Misako Haraguchi Kohichi Kawahara Yoshinari Shinsato Kentaro Minami Atsuro Saijo Masaki Hanibuchi Yasuhiko Nishioka Saburo Sone Hiroyasu Esumi Masaru Tomita Tomoyoshi Soga Tatsuhiko Furukawa Shin-Ichi Akiyama Thymidine Catabolism as a Metabolic Strategy for Cancer Survival. Cell reports 2211-1247 19 7 1313 1321 20170516 10.1016/j.celrep.2017.04.061 28514652 mitsuhashiatsushi/published_papers/47046097 Hisatsugu Goto Yoshinori Aono Atsushi Mitsuhashi Yasuhiko Nishioka Fibrocytes and chronic inflammation Igaku-Shoin Ltd Respiration and Circulation 0452-3458 64 2 149 155 20160201 2-s2.0-84960481575 mitsuhashiatsushi/published_papers/25613409 Hisatsugu Goto 後東 久嗣 三橋 惇志 Yasuhiko Nishioka 西岡 安彦 線維細胞がかかわる血管新生阻害薬に対する獲得耐性メカニズム Respiratory Molecular Medicine 分子呼吸器病 1342-436X 20 1 111 114 20160000 mitsuhashiatsushi/published_papers/13899828 Atsushi Mitsuhashi Hisatsugu Goto Atsuro Saijo Van The Trung Yoshinori Aono Hirokazu Ogino Takuya Kuramoto Sho Tabata Hisanori Uehara Keisuke Izumi Mitsuteru Yoshida Hiroaki Kobayashi Hidefusa Takahashi Masashi Gotoh Soji Kakiuchi Masaki Hanibuchi Seiji Yano Hiroyasu Yokomise Shoji Sakiyama Yasuhiko Nishioka Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab. Bevacizumab exerts anti-angiogenic effects in cancer patients by inhibiting vascular endothelial growth factor (VEGF). However, its use is still limited due to the development of resistance to the treatment. Such resistance can be regulated by various factors, although the underlying mechanisms remain incompletely understood. Here we show that bone marrow-derived fibrocyte-like cells, defined as alpha-1 type I collagen-positive and CXCR4-positive cells, contribute to the acquired resistance to bevacizumab. In mouse models of malignant pleural mesothelioma and lung cancer, fibrocyte-like cells mediate the resistance to bevacizumab as the main producer of fibroblast growth factor 2. In clinical specimens of lung cancer, the number of fibrocyte-like cells is significantly increased in bevacizumab-treated tumours, and correlates with the number of treatment cycles, as well as CD31-positive vessels. Our results identify fibrocyte-like cells as a promising cell biomarker and a potential therapeutic target to overcome resistance to anti-VEGF therapy. Nature communications 6 8792 8792 20151204 10.1038/ncomms9792 26635184 mitsuhashiatsushi/published_papers/25698386 Yuko Toyoda 豊田 優子 Sho Tabata Jun Kishi 岸 潤 Takuya Kuramoto Atsushi Mitsuhashi Atsuro Saijo 西條 敦郎 Hiroshi Kawano 河野 弘 Hisatsugu Goto 後東 久嗣 Yoshinori Aono 青野 純典 Masaki Hanibuchi 埴淵 昌毅 Hideaki Horikawa Toshihiro Nakajima Tatsuhiko Furukawa Saburo Sone 曽根 三郎 Shin-ichi Akiyama Yasuhiko Nishioka 西岡 安彦 Thymidine Phosphorylase Regulates the Expression of CXCL10 in Rheumatoid Arthritis Fibroblast-like Synoviocytes Thymidine phosphorylase (TP) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) is induced by tumor necrosis factor α (TNFα) and other cytokines that have been reported to be major inflammation mediators in RA. We previously demonstrated that TP plays an important role in angiogenesis and tumor growth, invasion, and metastasis. The aim of this study was to investigate whether the role of TP in the pathogenesis of RA is similar to its role in tumors. In FLS obtained from 2 patients with RA, the expression of TP, interferon-γ (IFNγ)-inducible protein 10 (CXCL10), and other cytokines was measured by quantitative real-time polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assays. Microarray analysis was performed using FLS transfected with TYMP complementary DNA and treated with a TP inhibitor. The expression of TP in FLS was up-regulated by TNFα, interleukin-1β (IL-1β), IL-17, IFNγ, and lipopolysaccharide. Microarray analysis of FLS overexpressing TP identified CXCL10 as a thymidine phosphorylase-related gene. The expression of CXCL10 was induced by TNFα, and this induction was suppressed by TYMP small interfering RNA and TP inhibitor. Furthermore, the combination of TNFα and IFNγ synergistically augmented the expression of TP and CXCL10. TP-induced CXCL10 expression was suppressed by the antioxidant EUK-8. In the synovial tissue of patients with RA, TP levels were significantly correlated with CXCL10 expression. The combination of TNFα and IFNγ strongly induced the expression of thymidine phosphorylase in RA FLS. The induction of thymidine phosphorylase enhanced the expression of CXCL10, which may contribute to the Th1 phenotype and bone destruction observed in RA. Arthritis & Rheumatology 2326-5205 66 3 560 568 20140301 10.1002/art.38263 24574215 mitsuhashiatsushi/published_papers/13899830 Yuko Toyoda Sho Tabata Jun Kishi Takuya Kuramoto Atsushi Mitsuhashi Atsuro Saijo Hiroshi Kawano Hisatsugu Goto Yoshinori Aono Masaki Hanibuchi Hideaki Horikawa Toshihiro Nakajima Tatsuhiko Furukawa Saburo Sone Shin-Ichi Akiyama Yasuhiko Nishioka Thymidine phosphorylase regulates the expression of CXCL10 in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis & rheumatology (Hoboken, N.J.) 2326-5205 66 3 560 8 20140300 10.1002/art.38263 24574215 mitsuhashiatsushi/published_papers/13899829 Hisatsugu Goto Atsushi Mitsuhashi Yasuhiko Nishioka Role of surfactant protein A in non-infectious lung diseases. University of Tokushima The journal of medical investigation : JMI 1349-6867 61 1-2 1 6 20140000 10.2152/jmi.61.1 24705741 2-s2.0-84897946649 mitsuhashiatsushi/published_papers/25892703 Mitsuhashi Atsushi Goto Hisatsugu Kuramoto Takuya Tabata Sho Yukishige Sawaka Hanibuchi Masaki Kakiuchi Soji Saijo Atsuro Aono Yoshinori Uehara Hisanori Yano Seiji Ledford Julie G Sone Saburo Nishioka Yasuhiko SURFACTANT PROTEIN A SUPPRESSES PROGRESSION OF HUMAN LUNG ADENOCARCINOMA IN NUDE MICE VIA MODULATING HOST IMMUNE RESPONSE RESPIROLOGY 1323-7799 18 150 null 20131100 mitsuhashiatsushi/published_papers/13899831 Atsushi Mitsuhashi Hisatsugu Goto Takuya Kuramoto Sho Tabata Sawaka Yukishige Shinji Abe Masaki Hanibuchi Soji Kakiuchi Atsuro Saijo Yoshinori Aono Hisanori Uehara Seiji Yano Julie G Ledford Saburo Sone Yasuhiko Nishioka Surfactant protein A suppresses lung cancer progression by regulating the polarization of tumor-associated macrophages. Surfactant protein A (SP-A) is a large multimeric protein found in the lungs. In addition to its immunoregulatory function in infectious respiratory diseases, SP-A is also used as a marker of lung adenocarcinoma. Despite the finding that SP-A expression levels in cancer cells has a relationship with patient prognosis, the function of SP-A in lung cancer progression is unknown. We investigated the role of SP-A in lung cancer progression by introducing the SP-A gene into human lung adenocarcinoma cell lines. SP-A gene transduction suppressed the progression of tumor in subcutaneous xenograft or lung metastasis mouse models. Immunohistochemical analysis showed that the number of M1 antitumor tumor-associated macrophages (TAMs) was increased and the number of M2 tumor-promoting TAMs was not changed in the tumor tissue produced by SP-A-expressing cells. In addition, natural killer (NK) cells were also increased and activated in the SP-A-expressing tumor. Moreover, SP-A did not inhibit tumor progression in mice depleted of NK cells. Taking into account that SP-A did not directly activate NK cells, these results suggest that SP-A inhibited lung cancer progression by recruiting and activating NK cells via controlling the polarization of TAMs. The American journal of pathology 0002-9440 182 5 1843 53 20130500 10.1016/j.ajpath.2013.01.030 23499372 mitsuhashiatsushi/published_papers/25698411 Atsushi Mitsuhashi Hisatsugu Goto Takuya Kuramoto Sho Tabata Sawaka Yukishige Shinji Abe Masaki Hanibuchi Souji Kakiuchi Atsuro Saijo Yoshinori Aono Hisanori Uehara Seiji Yano G Julie Ledford Saburo Sone Yasuhiko Nishioka Surfactant protein A suppresses lung cancer progression by regulating the polarization of tumor-associated macrophages. Surfactant protein A (SP-A) is a large multimeric protein found in the lungs. In addition to its immunoregulatory function in infectious respiratory diseases, SP-A is also used as a marker of lung adenocarcinoma. Despite the finding that SP-A expression levels in cancer cells has a relationship with patient prognosis, the function of SP-A in lung cancer progression is unknown. We investigated the role of SP-A in lung cancer progression by introducing the SP-A gene into human lung adenocarcinoma cell lines. SP-A gene transduction suppressed the progression of tumor in subcutaneous xenograft or lung metastasis mouse models. Immunohistochemical analysis showed that the number of M1 antitumor tumor-associated macrophages (TAMs) was increased and the number of M2 tumor-promoting TAMs was not changed in the tumor tissue produced by SP-A-expressing cells. In addition, natural killer (NK) cells were also increased and activated in the SP-A-expressing tumor. Moreover, SP-A did not inhibit tumor progression in mice depleted of NK cells. Taking into account that SP-A did not directly activate NK cells, these results suggest that SP-A inhibited lung cancer progression by recruiting and activating NK cells via controlling the polarization of TAMs. The American Journal of Pathology 1525-2191 182 5 1843 1853 20130314 10.1016/j.ajpath.2013.01.030 23499372 mitsuhashiatsushi/published_papers/25698367 Seidai Sato Masaki Hanibuchi Takuya Kuramoto Nodoka Yamamori Hisatsugu Goto Hirohisa Ogawa Atsushi Mitsuhashi Trung The Van Soji Kakiuchi Shin-ichi Akiyama Yasuhiko Nishioka Saburo Sone Macrophage stimulating protein promotes liver metastases of small cell lung cancer cells by affecting the organ microenvironment. The organ microenvironment significantly affects the processes of cancer metastasis. Elucidating the molecular mechanisms of interaction between tumor cells and the organ microenvironment is crucial for the development of effective therapeutic strategies to eradicate cancer metastases. Macrophage stimulating protein (MSP), an activator of macrophages, regulates a pleiotropic array of effects, including proliferation, cellular motility, invasiveness, angiogenesis, and resistance to anoikis. However, the role of MSP in cancer metastasis is still largely unknown. In this study, the action of MSP on the production of metastases was determined in a multiple-organ metastasis model. The murine MSP gene was transfected into two human SCLC cell lines, SBC-5 and H1048, to establish transfectants secreting biologically active MSP. MSP gene transduction did not affect cell proliferation and motility in vitro. Intravenously inoculated MSP transfectants produced significantly larger numbers of liver metastases than parental cells or vector control clones, while there were no significant differences in bone or lung metastases among them. Immunohistochemical analyses of liver metastases revealed that tumor-associated microvessel density and tumor-infiltrating macrophages were significantly increased in lesions produced by MSP transfectants. MSP could stimulate the migration of murine macrophages and endothelial cells in vitro. Consequently, MSP may be one of the major determinants that affects the properties of tumor stroma and that produces a permissive microenvironment to promote cancer metastasis. Clinical & experimental metastasis 1573-7276 30 3 333 44 20130300 10.1007/s10585-012-9540-y 23011677 mitsuhashiatsushi/published_papers/13899832 Seidai Sato Masaki Hanibuchi Takuya Kuramoto Nodoka Yamamori Hisatsugu Goto Hirohisa Ogawa Atsushi Mitsuhashi Trung The Van Soji Kakiuchi Shin-Ichi Akiyama Yasuhiko Nishioka Saburo Sone Macrophage stimulating protein promotes liver metastases of small cell lung cancer cells by affecting the organ microenvironment Clinical and Experimental Metastasis 0262-0898 30 3 333 344 20130300 10.1007/s10585-012-9540-y 23011677 2-s2.0-84875792986 mitsuhashiatsushi/published_papers/24815640 Kuramoto Takuya Goto Hisatsugu Mitsuhashi Atsushi Tabata Sho Ogawa Hirohisa Uehara Hisanori Saijo Atsuro Kakiuchi Soji Maekawa Yoichi Yasutomo Koji Hanibuchi Masaki Akiyama Shin-Ichi Sone Saburo Nishioka Yasuhiko Dll4-Fc, an inhibitor of Dll4-notch signaling, suppresses liver metastasis of small cell lung cancer cells through the downregulation of the NF-κB activity. Notch signaling regulates cell-fate decisions during development and postnatal life. Little is known, however, about the role of Delta-like-4 (Dll4)-Notch signaling between cancer cells, or how this signaling affects cancer metastasis. We, therefore, assessed the roleof Dll4-Notch signaling in cancer metastasis. Wegenerated a solubleDll4 fused to the IgG1constant region (Dll4-Fc) that acts as a blocker of Dll4-Notch signaling and introduced it into human small cell lung cancer (SCLC) cell lines expressing either high levels (SBC-3 and H1048) or low levels (SBC-5) of Dll4. The effects of Dll4-Fc on metastasis of SCLC were evaluated using a mouse model. Although Dll4-Fc had no effect on the liver metastasis of SBC-5, the number of liver metastasis inoculated with SBC-3 and H1048 cells expressing Dll4-Fc was significantly lower than that injected with control cells. To study the molecular mechanisms of the effects of Dll4-Fc on liver metastasis, a PCR array analysis was conducted. Because the expression of NF-κB target genes was affected by Dll4-Fc, we conducted an electrophoretic mobility shift assay and observed that NF-κB activities, both with and without stimulation by TNF-α, w Notch signaling regulates cell-fate decisions during development and postnatal life. Little is known, however, about the role of Delta-like-4 (Dll4)-Notch signaling between cancer cells, or how this signaling affects cancermetastasis. We, therefore, assessed the role of Dll4-Notch signaling in cancer metastasis. We generated a soluble Dll4 fused to the IgG1 constant region (Dll4-Fc) that acts as a blocker of Dll4-Notch signalingand introduceditinto human small cell lung cancer (SCLC) cell lines expressing either high levels (SBC-3 and H1048) or low levels (SBC-5) of Dll4. The effects of Dll4-Fc on metastasis of SCLC were evaluated using a mouse model. Although Dll4-Fc had no effect on the liver metastasis of SBC-5, the number of liver metastasis inoculated with SBC-3 and H1048 cells expressing Dll4-Fc was significantly lower than that injected with control cells. To study the molecular mechanisms of the effects of Dll4-Fc on liver metastasis, a PCR array analysis was conducted. Because the expression of NF-κB target genes was affected by Dll4-Fc, we conducted an electrophoretic mobility shift assay and observed that NF-κB activities, both with and without stimulation by TNF-α, w Molecular cancer therapeutics 1538-8514 11 12 2578 87 20121200 10.1158/1535-7163.MCT-12-0640 22989420 mitsuhashiatsushi/published_papers/13899833 Takuya Kuramoto Kuramoto T Hisatsugu Goto Goto H Atsushi Mitsuhashi Mitsuhashi A Sho Tabata Tabata S Hirohisa Ogawa Ogawa H Hisanori Uehara Uehara H Atsuro Saijo Saijo A Soji Kakiuchi Kakiuchi S Yoichi Maekawa Maekawa Y Koji Yasutomo Yasutomo K Masaki Hanibuchi Hanibuchi M Shin-Ichi Akiyama Akiyama S Saburo Sone Sone S Yasuhiko Nishioka Nishioka Y Dll4-Fc, an inhibitor of Dll4-notch signaling, suppresses liver metastasis of small cell lung cancer cells through the downregulation of the NF-κB activity. Molecular cancer therapeutics 1535-7163 11 12 2578 87 20121200 10.1158/1535-7163.MCT-12-0640 22989420 mitsuhashiatsushi/published_papers/25698426 Trung The Van Masaki Hanibuchi Souji Kakiuchi Seidai Sato Takuya Kuramoto Hisatsugu Goto Atsushi Mitsuhashi Yasuhiko Nishioka Shin-ichi Akiyama Saburo Sone The therapeutic efficacy of S-1 against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice. Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm. S-1 has been developed as a novel oral antineoplastic agent based on the modulation of 5-fluorouracil (5-FU) bioactivity. This study was conducted to investigate the preclinical therapeutic effect of S-1 on MPM. We used three human MPM cell lines, Y-MESO-14, NCI-H290 and MSTO-211H. In vitro proliferation of human MPM cells was determined by MTT assay. Human MPM cells were orthotopically implanted into thoracic cavity of SCID mice. Tumor-bearing mice were treated with S-1 or vehicle. The combination of 5-FU and 5-chloro-2,4-dihydroxypyridine (CDHP) was more effective than 5-FU alone in inhibiting MPM cell proliferation in vitro. This combination was most effective in Y-MESO-14 cells, which co-expressed high protein level of dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP). In vivo data showed that treatment with S-1 significantly reduced thoracic tumors and pleural effusion produced by Y-MESO-14 cells. Moreover, treatment with S-1 prolonged the survival of Y-MESO-14 cell-bearing SCID mice. We demonstrated that S-1 was effective for inhibiting the proliferation of MPM cells, particularly with both DPD and TP expressions, suggesting that S-1 might be therapeutically effective for control of MPM. Cancer Chemotherapy and Pharmacology 1432-0843 68 2 497 504 20110801 10.1007/s00280-010-1503-x 21079960 mitsuhashiatsushi/published_papers/13899834 Trung The Van Masaki Hanibuchi Soji Kakiuchi Seidai Sato Takuya Kuramoto Hisatsugu Goto Atsushi Mitsuhashi Yasuhiko Nishioka Shin-Ichi Akiyama Saburo Sone The therapeutic efficacy of S-1 against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice. Cancer chemotherapy and pharmacology 0344-5704 68 2 497 504 20110800 10.1007/s00280-010-1503-x 21079960 mitsuhashiatsushi/published_papers/13899835 Saburo Sone Takuya Kuramoto Seidai Sato Atsushi Mitsuhashi Souji Kakiuchi Hisatsugu Goto Hiroya Tada Yasuhiko Nishioka [Molecular targeted therapy for cancer]. Recent insights into the molecular mechanism of cancer progression have given rise to specific target-directed therapies, including monoclonal antibodies and small molecular compounds, and the advent of target-specific therapeutics has remarkably improved the outcomes of patients with various malignancies. Recent advance also lead to the identification of prognostic biomarkers as predictive factors in determining response to molecular targeted drugs. Future studies also need to develop biomarkers to further increase the power of patient selection for molecular targeted therapy. Here we review the recent progress in developing new molecular targeted drugs and the resistance to treatments as well as the importance of measuring the QOL by patient-reported outcome, for personalized therapy. Nihon rinsho. Japanese journal of clinical medicine 0047-1852 68 6 997 1006 20100600 20535947 mitsuhashiatsushi/misc/25613321 Hisatsugu Goto 後東 久嗣 三橋 惇志 Yasuhiko Nishioka 西岡 安彦 血管新生阻害薬耐性とfibrocyte Respiratory Molecular Medicine 分子呼吸器病 1342-436X 21 1 4 7 20170301 mitsuhashiatsushi/misc/25613323 Hisatsugu Goto 後東 久嗣 Yoshinori Aono 青野 純典 三橋 惇志 Yasuhiko Nishioka 西岡 安彦 慢性炎症とfibrocyte Respiration & Circulation 呼吸と循環 0452-3458 64 2 149 155 20160215 mitsuhashiatsushi/misc/25892823 荻野 広和 三橋 惇志 後東 久嗣 西條 敦郎 佐藤 正大 坂口 暁 手塚 敏史 倉本 卓哉 田畑 祥 上原 久典 埴淵 昌毅 西岡 安彦 Sphere形成癌幹細胞様分画のヒト肺癌多臓器転移モデルマウスにおける役割についての解析 日本癌学会 日本癌学会総会記事 0546-0476 74 P 3119 20151000 mitsuhashiatsushi/misc/25892730 荻野広和 後東久嗣 三橋惇志 西條敦郎 佐藤正大 柿内聡司 埴淵昌毅 上原久典 西岡安彦 Sphere形成癌幹細胞様分画の肺癌多臓器転移における役割についての解析 日本がん転移学会学術集会・総会プログラム抄録集 24th 68 null 20150000 mitsuhashiatsushi/misc/25892833 後東 久嗣 三橋 惇志 西條 敦郎 柿内 聡司 埴淵 昌毅 上原 久典 矢野 聖二 西岡 安彦 ベバシズマブに対する獲得耐性メカニズムとしての線維細胞(fibrocytes)の役割(The role of fibrocytes in the resistance to bevacizumab in malignant pleural mesothelioma and lung cancer) 日本癌学会 日本癌学会総会記事 0546-0476 73 J 3052 20140900 mitsuhashiatsushi/misc/25892735 後東久嗣 三橋惇志 西條敦郎 倉本卓哉 田畑祥 埴淵昌毅 柿内聡司 青野純典 上原久典 西岡安彦 ベバシズマブに対する獲得耐性メカニズムとしての線維細胞(fibrocytes)の役割 日本がん分子標的治療学会学術集会プログラム・抄録集 18th 67 null 20140529 mitsuhashiatsushi/misc/25698443 Hisatsugu Goto Atsushi Mitsuhashi Yasuhiko Nishioka Role of surfactant protein A in non-infectious lung diseases Surfactant protein A (SP-A) is a large multimeric protein found in the airways and alveoli of the lungs. SP-A is a member of the collectin family of proteins, characterized by NH2-terminal collagen-like regions and COOH-terminal lectin domains. Although other surfactant proteins such as SP-B function to reduce surface tension in the lungs, SP-A as well as SP-D regulates the pulmonary immune response. To date, a number of studies have shown the immunoregulatory function of SP-A, mainly in the field of infectious diseases. By binding to a wide variety of pathogens, SP-A opsonizes and enhances pathogen uptake by phagocytes. In addition to the effect on pathogens, recent studies have shown that SP-A also modulates lung immune system in the area of non-infectious lung diseases. In this review, the potential role of SP-A in the multiple aspects of pulmonary host defense will be discussed, focusing mainly on non-infectious lung diseases such as acute and chronic pulmonary fibrosis and lung cancer. J. Med. Invest. 61: 1-6, February, 2014. The Journal of Medical Investigation : JMI 1349-6867 61 1,2 1 6 20140201 10.2152/jmi.61.1 24705741 mitsuhashiatsushi/misc/25892743 後東久嗣 三橋惇志 倉本卓哉 田畑祥 西條敦郎 柿内聡司 埴淵昌毅 上原久典 西岡安彦 肺癌多臓器転移モデルにおけるsphere形成癌幹細胞様分画の役割 日本がん転移学会学術集会・総会プログラム抄録集 23rd 93 null 20140000 mitsuhashiatsushi/misc/25892739 山子泰斗 後東久嗣 三橋惇志 倉本卓哉 田畑祥 西條敦郎 柿内聡司 埴淵昌毅 小川博久 上原久典 西岡安彦 ヒト小細胞肺癌骨転移に対するRANKL標的治療におけるIGF‐1の関与 日本がん転移学会学術集会・総会プログラム抄録集 23rd 152 null 20140000 mitsuhashiatsushi/misc/28226563 Masaki Hanibuchi Sun-Jin Kim Kenji Otsuka Atsushi Mitsuhashi Hisatsugu Goto Yasuhiko Nishioka Isaiah J. Fidler THERAPEUTIC EFFICACY OF ENDOTHELIN RECEPTOR BLOCKADE ON EXPERIMENTAL BRAIN METASTASES OF HUMAN NON- SMALL CELL LUNG CANCER RESPIROLOGY 1440-1843 18 55 55 20131100 mitsuhashiatsushi/misc/25892747 後東久嗣 三橋惇志 倉本卓哉 田畑祥 西條敦郎 埴淵昌毅 柿内聡司 青野純典 上原久典 曽根三郎 西岡安彦 肺surfactant protein A(SP‐A)の肺癌進展における機能解析 日本がん転移学会学術集会・総会プログラム抄録集 22nd 74 null 20130000 mitsuhashiatsushi/misc/37461333 三橋 惇志 後東 久嗣 倉本 卓哉 柿内 聡司 佐藤 正大 VAN Trung The 西條 敦郎 田畑 祥 小川 博久 上原 久典 秋山 伸一 西岡 安彦 WRIGHT Jo Rae 曽根 三郎 肺サーファクタント蛋白SP-Aの肺がん進展における機能解析 日本肺サーファクタント・界面医学会雑誌 = Journal of Japanese Medical Society for Lung Surfactant and Biological Interface 1882-1812 43 32 32 20121015 mitsuhashiatsushi/misc/37461315 後東 久嗣 三橋 惇志 青野 純典 西岡 安彦 肺の生体防御機構におけるサーファクタント蛋白Aの役割 日本肺サーファクタント・界面医学会雑誌 = Journal of Japanese Medical Society for Lung Surfactant and Biological Interface 1882-1812 43 9 15 20121015 mitsuhashiatsushi/misc/37577714 埴淵 昌毅 阿部 真治 加藤 幸成 金子 美華 木宿 昌俊 川添 和義 黄 俊 三橋 惇志 水口 和生 西岡 安彦 抗ポドプラニン抗体NZ-1の悪性胸膜中皮腫に対する抗体依存性細胞障害活性と抗腫瘍効果 (NPO)日本肺癌学会 肺癌 1348-9992 52 5 769 769 20121000 mitsuhashiatsushi/misc/25892756 倉本卓哉 後東久嗣 三橋惇志 田畑祥 上原久典 西條敦郎 柿内聡司 埴淵昌毅 前川洋一 安友康二 秋山伸一 曽根三郎 西岡安彦 小細胞肺がん転移におけるDll4‐Notchシグナルの臓器特異性に関する検討 日本がん転移学会学術集会・総会プログラム抄録集 21st 84 null 20120000 mitsuhashiatsushi/misc/25892752 三橋惇志 後東久嗣 倉本卓哉 田畑祥 小川博久 上原久典 秋山伸一 WRIGHT Jo Rae 曽根三郎 西岡安彦 肺surfactant protein A(SP‐A)の肺癌進展における機能解析 日本がん転移学会学術集会・総会プログラム抄録集 21st 83 null 20120000 mitsuhashiatsushi/misc/27285577 三橋惇志 後東久嗣 倉本卓哉 柿内聡司 佐藤正大 VAN Trung The 西條敦郎 田畑祥 小川博久 上原久典 秋山伸一 西岡安彦 WRIGHT Jo Rae 曽根三郎 肺サーファクタント蛋白SP‐Aの肺がん進展における機能解析 日本肺サーファクタント・界面医学会学術研究会プログラム・抄録集 47th 20 null 20110000 徳島大学医学部医学科同窓会 青藍会賞 20250700 徳島大学若手研究者学長表彰 20231200 日本癌学会奨励賞 20230900 日本がん分子標的治療学会研究奨励賞 20230600 Cancer Science Young Scientists Award 2022 20221000 第81回日本癌学会学術総会 若手研究者ポスター賞 20221000 第25回日本がん分子標的治療学会学術集会 優秀演題賞 20210500 第24回日本がん分子標的治療学会学術集会 優秀演題賞 20201000 第19回日本がん分子標的治療学会学術集会 優秀演題賞 20150600 18th Annual Congress of the Asian Pacific Society of Respirology, APSR award 2013 20131100 9th International Conference of The Asian Clinical Oncology Society, Young Investigator Award 20100800