研究者業績

長嶋 健

ナガシマ タケシ  (Takeshi Nagashima)

基本情報

所属
千葉大学 医学部附属病院 准教授
学位
医学博士(1997年9月 千葉大学)

J-GLOBAL ID
200901003605972184
researchmap会員ID
1000222027

研究キーワード

 1

学歴

 1

論文

 212
  • Hideyuki Yamada, Mamoru Takada, Dhaval Ghone, Muhan Yu, Takeshi Nagashima, Hiroshi Fujimoto, Junta Sakakibara, Yoshie Hasegawa, Shintaro Takao, Akimitsu Yamada, Kazutaka Narui, Takashi Ishikawa, Aussie Suzuki, Masayuki Otsuka
    Scientific reports 14(1) 14146-14146 2024年6月19日  
    Eribulin (ERI), clinically utilized for locally advanced or metastatic breast tumors, has shown potential links to the immune system. Notably, the cGAS-STING pathway, a key component of innate immunity, has gained prominence. Yet, limited reports explore ERI's effects on the cGAS-STING pathway. Additionally, the nuclear presence of cGAS remains poorly understood. This study uniquely delves into ERI's impact on both the cytosolic cGAS-STING pathway and nuclear cGAS. ERI enhances nuclear localization of cGAS, resulting in hyper-activation of the cGAS-STING pathway in triple-negative breast cancer cells. Reduction of cGAS heightened both cell proliferation and ERI sensitivity. In clinical data using ERI in a neo-adjuvant setting, patients with low cGAS cases exhibited reduced likelihood of achieving pathological complete response after ERI treatment. These findings illuminate the potential of cGAS and IFNβ as predictive biomarkers for ERI sensitivity, providing valuable insights for personalized breast cancer treatment strategies.
  • Yoshiki Shinomiya, Yusuke Kouchi, Kiyotaka Onodera, Hiroto Yamamoto, Sakurako Harada-Kagitani, Junta Sakakibara, Takeshi Nagashima, Jun-Ichiro Ikeda, Takashi Kishimoto
    Acta cytologica 2024年1月23日  
    INTRODUCTION: Tall cell carcinoma with reversed polarity (TCCRP) is a rare histologic subtype of breast cancer that was newly categorized in 2020. TCCRP is a relatively novel tumor, and there are no detailed reports about its cellular morphology. We were able to obtain imprint cytological specimens from fresh TCCRP tissue, and we provide our detailed observations. CASE PRESENTATION: The patient was a 73-year-old Japanese female with a 15-mm mass in her right breast. After invasive breast carcinoma was diagnosed based on a core needle biopsy, a lumpectomy was performed. The pathological examination revealed TCCRP, and Sanger sequencing detected IDH2 p.R172M hotspot mutation, which is characteristic of TCCRP. Soon after the surgery, the lumpectomy specimen was sliced before fixation for use in a clinical trial, and imprint cytological materials were obtained from the tumor's cut surface. Cytologically the tumor showed papillary-like cell clusters and isolated cells with moderate cellularity. Neoplastic cell aggregates and clusters with thick vascular cores as the axis or with delicate fibrovascular stroma were observed. Most of the neoplastic cells were cuboidal-to-columnar in shape, with mildly to moderately irregularly shaped blunt nuclei. Some intranuclear cytoplasmic inclusions and nuclear grooves were present, resembling the nuclear findings of papillary thyroid carcinoma. The most characteristic finding was the columnar cell clusters with apically located nuclei, giving the impression of reversed polarity. CONCLUSION: We identified cytological findings in TCCRP, a newly classified rare mammary tumor. Most of the characteristic histological findings were also observed in cytological specimens. Although this study was of imprint cytology, we note that cytology is useful in the preoperative diagnosis of TCCRP.
  • Hideyuki Yamada, Mamoru Takada, Dhaval Ghone, Muhan Yu, Takeshi Nagashima, Hiroshi Fujimoto, Junta Sakakibara, Yoshie Hasegawa, Shintaro Takao, Akimitsu Yamada, Kazutaka Narui, Takashi Ishikawa, Aussie Suzuki, Masayuki Otsuka
    Research square 2023年12月6日  
    Eribulin (ERI), clinically utilized for locally advanced or metastatic breast tumors, has shown potential links to the immune system. Notably, the cGAS-STING pathway, a key component of innate immunity, has gained prominence. Yet, limited reports explore ERI's effects on the cGAS-STING pathway. Additionally, the nuclear presence of cGAS remains poorly understood. This study uniquely delves into ERI's impact on both the cytosolic cGAS-STING pathway and nuclear cGAS. ERI enhances nuclear localization of cGAS, resulting in hyper-activation of the cGAS-STING pathway in triple-negative breast cancer cells. Reduction of cGAS heightened both cell proliferation and ERI sensitivity. In clinical data using ERI in a neo-adjuvant setting, patients with low cGAS cases exhibited reduced likelihood of achieving pathological complete response after ERI treatment. These findings illuminate the potential of cGAS and IFNβ as predictive biomarkers for ERI sensitivity, providing valuable insights for personalized breast cancer treatment strategies.
  • 粕谷 雅晴, 榊原 淳太, 山田 英幸, 山本 寛人, 吉村 悟志, 山崎 美智子, 高田 護, 藤本 浩司, 長嶋 健, 大塚 将之, 岸本 充
    乳腺甲状腺超音波医学 12(4) 131-131 2023年12月  
  • Ryotaro Teranaka, Hiroshi Fujimoto, Takahito Masuda, Masayuki Kuroda, Yasuyuki Aoyagi, Takeshi Nagashima, Mamoru Takada, Junta Sakakibara, Hideyuki Yamada, Hiroto Yamamoto, Yoshitaka Kubota, Masayuki Ohtsuka
    Breast cancer (Tokyo, Japan) 2023年8月23日  
    BACKGROUND: Although targeted treatments against human epidermal growth factor receptor 2 (HER2) have improved survival in patients with metastatic HER2-positive breast cancer, long and repeated treatment is time-consuming and costly for patients. To reduce these burdens, we developed ex vivo gene-transduced adipocytes that secrete anti-HER2 antibodies and evaluated their anti-tumor effects. METHODS: Ceiling culture-derived proliferative adipocytes (ccdPA) secreting anti-HER2 antibody against domain IV receptors: TRA-ccdPA, and domain II receptors: PER-ccdPA, were constructed using a plasmid lentivirus. Delivery of secreted antibody and its specific binding to HER2 breast cancer were evaluated in vitro and in vivo. To optimize antibody production from ccdPA, different conditions of ccdPA implantation were examined. Anti-tumor efficacy was evaluated in HER2-positive-cancer-inoculated nude mice. RESULTS: Anti-HER2 antibody against domain II was identified in supernatants from PER-ccdPAs. The optimal method to achieve the highest concentration of antibody in mouse sera was injecting differentiated ccdPA cells into the mammary fat pad. Antibody in supernatants from PER-ccdPAs bound to the surface of HER2-positive breast cancer cells similar to pertuzumab. Antibodies in mouse sera were delivered to HER2-positive breast cancer tumors and tumor necrosis was observed microscopically. One-time administration of combined TRA-ccdPAs and PER-ccdPAs produced antibody continuously in mouse sera, and anti-tumor effects were maintained for the duration of this study in xenograft models. Furthermore, combination therapy significantly suppressed tumor growth compared with a single administration. CONCLUSION: Ex vivo gene-transduced adipocytes might be useful for cell-based gene therapy. This system may be a platform for various antibody therapies.
  • 佐久間 結, 高田 護, 池田 純一郎, 小舘 明日香, 長嶋 健, 藤本 浩司, 榊原 淳太, 山田 英幸, 山本 寛人, 年光 亜水, 鈴木 正人, 大塚 将之
    日本乳癌学会総会プログラム抄録集 31回 189-189 2023年6月  
  • Junta Sakakibara, Takeshi Nagashima, Hiroshi Fujimoto, Mamoru Takada, Masayuki Ohtsuka
    Journal of medical ultrasonics (2001) 2023年5月25日  
    The ultrasound fusion imaging system is a diagnostic device developed in Japan that utilizes ultrasound and magnetic positioning/navigation. A position sensor with a probe reads spatial location information from a magnetic field generator and by synchronously displaying ultrasound images and magnetic resonance (MR)/computed tomography (CT) images in real time. Lesions that are difficult to observe via ultrasonography alone, such as non-mass enhancement, can be identified. Furthermore, lesions that are difficult to identify with ultrasound alone indicated for MRI-guided biopsy under the National Health Insurance Scheme can be identified using ultrasound fusion technology, thereby enabling tissue biopsy to be performed under ultrasound guidance. Using this ultrasound fusion technology, not only non-mass enhancement but also small lesions that are difficult to identify using ultrasound alone can be detected, thus ensuring that a more accurate preoperative imaging diagnosis is established, and leading to safer, more reassuring examinations and surgical procedures. In this paper, we outline the use of this ultrasound fusion technology and fusion techniques in the treatment of breast cancer.
  • Muhan Yu, Mamoru Takada, Hideyuki Yamada, Hiroshi Fujimoto, Junta Sakakibara, Hiroto Yamamoto, Takeshi Nagashima, Masayuki Ohtsuka
    Cancer medicine 2023年5月10日  
    BACKGROUND: In monarchE and Postoperative Therapy with Endocrine and TS-1 (POTENT) trials, abemaciclib and S-1 have, respectively, shown to be effective as adjuvant therapies for luminal breast cancer (BC), although whether patients who meet the criteria are at high risk of recurrence compared to non-eligible patients is still unknown. Here, we investigated recurrence risk according to the criteria of each trial in Japanese patients. METHODS: We reviewed the records of 992 patients who received surgery at Chiba University Hospital for stage I-III BC from January 2017 to May 2022 and selected 553 analytic cohort patients and retrospectively analyzed the relapse-free survival of the patients as the primary endpoint. High-recurrence risk was defined according to monarchE trial and POTENT trial. RESULTS: The 5-year RFS for monarchE cohort 1 and cohort 2 eligible patients were 77.78% and 89.33%, respectively, which were significantly lower than monarchE non-eligible patients (98.31%; p < 0.0001). However, the 5-year RFS rate for POTENT eligible patients (90.51%) was lower than for POTENT non-eligible patients (98.75%; p = 0.0001); excluding those who met the monarchE criteria, the prognosis of POTENT eligible patients had no significant differences from the prognosis of patients with POTENT non-eligible BC (p = 0.3100). CONCLUSION: MonarchE criteria accurately identify patients who are prone to relapse. Moreover, although POTENT criteria also suggested a reasonable capacity for recurrence prediction, there was no significant difference in recurrence between POTENT non-eligible patients and the patients who were POTENT but not monarchE eligible. This might offer justification for reconsidering the use of S-1 in monarchE non-eligible patients.
  • Shouko Hayama, Rikiya Nakamura, Takayuki Ishige, Takafumi Sangai, Masahiro Sakakibara, Hiroshi Fujimoto, Emi Ishigami, Takahito Masuda, Ayako Nakagawa, Ryotaro Teranaka, Satoshi Ota, Sakae Itoga, Naohito Yamamoto, Takeshi Nagashima, Masayuki Otsuka
    BMC Cancer 23(1) 2023年4月27日  
    Abstract Background There is pressing needs to find the biomarker in the selection of neoadjuvant therapy in postmenopausal luminal breast cancer patients. We examined the hypothesis that PIK3CA mutations and low phosphatase and tensin homolog (PTEN) expression affect the response to neoadjuvant therapy and prognosis in postmenopausal luminal breast cancer patients. Methods Postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, up to stage II, who underwent neoadjuvant chemotherapy (NAC; n = 60) or neoadjuvant endocrine therapy (NAE; n = 55) were selected. PIK3CA exon 9 and exon 20 mutations were screened by high resolution melting analysis and confirmed by Sanger sequence. PTEN expression was evaluated by immunohistochemistry. The relationships among PIK3CA mutations, PTEN expression, clinicopathological features, the pathological effect of neoadjuvant therapy, recurrence-free survival (RFS) and overall survival were analyzed. Results Among 115 patients, PIK3CA mutations and low PTEN expression before treatment were detected in 35 patients (30.4%) and in 28 patients (24.3%), respectively. In the NAC group, tumor with PIK3CA mutations showed significantly poorer response than tumor with PIK3CA wild-type (p = 0.03). On the other hand, in the NAE group, there was no significant difference in pathological therapeutic effect between tumor with PIK3CA mutations and tumor with PIK3CA wild-type (p = 0.54). In the NAC group, the log-rank test showed no difference in RFS between patients with PIK3CA mutations and PIK3CA wild-type (p = 0.43), but patients with low PTEN expression showed significantly worse RFS compared to patients with high PTEN expression (5 year RFS 0.64 vs. 0.87, p = 0.01). In the Cox proportional hazards model for RFS, PTEN expression, progesterone receptor, and pathological therapeutic effect were predictive factors for time to recurrence (All p &lt; 0.05). Conclusions PIK3CA mutations are associated with resistance to NAC but do not affect the response to NAE. Low PTEN expression does not affect response to either NAC or NAE but correlates with shorter RFS in patients who received NAC. These biomarkers will be further evaluated for clinical use to treat postmenopausal luminal breast cancer patients.
  • 三神 功亮, 若井 健, 大塚 亮太, 池原 早苗, 山口 高志, 秋田 新介, 長嶋 健, 三川 信之, 松原 久裕, 池原 譲
    日本病理学会会誌 112(1) 339-339 2023年3月  
  • 三神 功亮, 若井 健, 大塚 亮太, 池原 早苗, 山口 高志, 秋田 新介, 長嶋 健, 三川 信之, 松原 久裕, 池原 譲
    日本病理学会会誌 112(1) 339-339 2023年3月  
  • Mamoru Takada, Taichi Fukushima, Sho Ozawa, Syuma Matsubara, Takeshi Suzuki, Ichiro Fukumoto, Toyoyuki Hanazawa, Takeshi Nagashima, Reiko Uruma, Masayuki Otsuka, Gaku Tanaka
    Scientific reports 12(1) 18230-18230 2022年10月29日  
    Healthcare providers are vulnerable to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) because of their close proximity to patients with coronavirus disease 2019. SARS-CoV-2 is mainly transmitted via direct and indirect contact with respiratory droplets, and its airborne transmission has also been identified. However, evidence for environmental factors is scarce, and evidence-based measures to minimize the risk of infection in clinical settings are insufficient. Using computational fluid dynamics, we simulated exhalation of large and small aerosol particles by patients in an otolaryngology examination room, where medical procedures require the removal of a face mask. The effects of coughing were analyzed, as well as those of humidity as a controllable environmental factor and of a suction device as an effective control method. Our results show that a suction device can minimize aerosol exposure of healthcare workers by efficiently removing both large (11.6-98.2%) and small (39.3-99.9%) aerosol particles. However, for coughing patients, the removal efficiency varies inversely with the particle size, and the humidity notably affects the aerosol behavior, indicating the need for countermeasures against smaller aerosols. Overall, these results highlight the potential and limitation of using a suction device to protect against SARS-CoV-2 and future respiratory infections.
  • 榊原 淳太, 池田 純一郎, 長嶋 健, 藤本 浩司, 高田 護, 大塚 将之
    映像情報Medical 54(6) 31-35 2022年5月  
  • 秋田 新介, 山路 佳久, 竹内 信善, 若井 健, 東 和彦, 池原 早苗, 山口 高志, 中川 綾子, 藤本 浩司, 三階 貴史, 長嶋 健, 三川 信之, 池原 譲
    日本分子腫瘍マーカー研究会誌 37 47-48 2022年  
  • 秋田 新介, 山路 佳久, 竹内 信善, 若井 健, 東 和彦, 池原 早苗, 山口 高志, 中川 綾子, 藤本 浩司, 三階 貴史, 長嶋 健, 三川 信之, 池原 譲
    日本分子腫瘍マーカー研究会プログラム・講演抄録 41回 84-85 2021年9月  
  • 中津川 智子, 藤本 浩司, 楯 真一, 三階 貴文, 坂田 治人, 高田 護, 榊原 淳太, 錦見 恭子, 寺中 亮太郎, 山本 寛人, 宇津野 恵美, 関根 瑞香, 長嶋 健, 松下 一之, 市川 智彦
    日本乳癌学会総会プログラム抄録集 29回 48-48 2021年7月  
  • Mamoru Takada, Gaku Tanaka, Hideyuki Hashimoto, Yasuyuki Hirai, Taichi Fukushima, Takeshi Nagashima, Masayuki Otsuka, Fumio Imazeki
    Breast cancer (Tokyo, Japan) 28(4) 969-976 2021年7月  
    BACKGROUND: The novel coronavirus disease 2019 (COVID-19) undermines the benefits of cancer screening. To date, no study has identified specific infection control methods. We aimed to provide practical methods for COVID-19 risk reduction during breast cancer screening mammography (MMG) by examining an overview of potential contamination routes of aerosols and possible risks for patients and health care providers. METHODS: Computational fluid dynamics (CFD) simulations were conducted for airflow and aerosol dispersion in a 3D virtual model of a mobile MMG laboratory room. This model was constructed based on the actual mobile screening MMG bus 'Cosmos' in the Chiba Foundation for Health Promotion & Disease Prevention. Examiner and patient geometries were obtained by scanning an actual human using a 3D Scanner. Contamination of the room was evaluated by counting the numbers of suspended and deposited aerosols. RESULTS: We applied the CFD simulation model to the exhalation of small or large aerosols from a patient and examiner in the MMG laboratory. Only 14.5% and 54.5% of large and small aerosols, respectively, were discharged out of the room with two doors open. In contrast, the proportion of large and small aerosols discharged out of the room increased to 96.6% and 97.9%, respectively, with the addition of forced gentle wind by the blower fan. This simulation was verified by a mist aerosol experiment conducted in the mobile MMG laboratory. CONCLUSION: Adding forced ventilation to a MMG laboratory with two doors open may enable risk reduction dramatically. This could be applied to other clinical situations.
  • 松下 一之, 宮内 英聡, 石毛 崇之, 西村 基, 川崎 健治, 糸賀 栄, 関根 瑞香, 宇津野 恵美, 滝口 裕一, 稲田 麻里, 長嶋 健, 藤本 浩司, 松原 久裕, 市川 智彦
    日本遺伝カウンセリング学会誌 42(2) 78-78 2021年6月  
  • Manabu Futamura, Mari Oba, Norikazu Masuda, Hiroko Bando, Morihito Okada, Yutaka Yamamoto, Takanori Kin, Toshiaki Saeki, Takeshi Nagashima, Takashi Kuwayama, Uhi Toh, Akira Hirano, Masafumi Inokuchi, Kazuhiko Yamagami, Yutaka Mizuno, Yasuyuki Kojima, Takahiro Nakayama, Hiroyuki Yasojima, Shinji Ohno
    Breast cancer (Tokyo, Japan) 2021年4月3日  
    BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX), a novel taxane formulation, was developed to avoid cremophor/ethanol-associated toxicities including peripheral neuropathy and hypersensitivity. At least 35 phase II studies using combined nab-PTX and anthracycline in neoadjuvant settings are registered in Japan. We analyzed the efficacy and safety of nab-PTX based on patient characteristics in these studies. METHODS: We conducted a meta-analysis using individual patient data (IPD) to investigate the average efficacy of nab-PTX-containing regimens as neoadjuvant chemotherapy for operable breast cancer. IPD were provided by principal investigators who agreed to participate. The primary endpoint was pathological complete response (pCR) rate of each breast cancer subtype. RESULTS: We analyzed the data of 16 studies involving 753 patients. The overall crude frequencies of pCR (ypT0 ypN0, ypT0/is ypN0, and ypT0/is ypNX) were 18.1, 26.0, and 28.6%, respectively. Specifically, the frequencies were 6.7, 10.2, and 13.4% for luminal (n = 343); 40.5, 63.5, and 68.9% for human epidermal growth factor receptor 2 (HER2)-rich, (n = 74); 21.9, 40.6, and 42.7% for luminal/HER2 (n = 96); and 26.3, 31.5, and 32.3% for triple-negative breast cancers (TNBC) (n = 232). The multivariate analyses indicated that HER2 positivity, TNBC, high Ki-67, high nuclear grade, and weekly nab-PTX administration were significantly associated with the pCR. The proportion of hematological toxicities (neutropenia (39.7%) and leukopenia (22.5%)), peripheral sensory neuropathy (9.7%), myalgia (5.7%), and arthralgia (4.7%) was higher than grade 3 adverse events, but most patients recovered. CONCLUSIONS: Nab-PTX is a safe and acceptable chemotherapeutic agent in neoadjuvant settings, particularly for aggressive cancers. UMIN-CTR#: UMIN000028774.
  • 榊原 淳太, 山田 英幸, 山本 寛人, 高田 護, 藤本 浩司, 長嶋 健, 大塚 将之
    乳腺甲状腺超音波医学 10(2) 176-176 2021年4月  
  • 榊原 淳太, 山田 英幸, 山本 寛人, 高田 護, 藤本 浩司, 長嶋 健, 大塚 将之
    乳腺甲状腺超音波医学 10(2) 176-176 2021年4月  
  • Toshinari Yamashita, Hidetoshi Kawaguchi, Norikazu Masuda, Masahiro Kitada, Kazutaka Narui, Masaya Hattori, Tetsuhiro Yoshinami, Nobuki Matsunami, Kazuhiro Yanagihara, Teru Kawasoe, Takeshi Nagashima, Hiroko Bando, Hiroshi Yano, Yoshie Hasegawa, Rikiya Nakamura, Masahiro Kashiwaba, Satoshi Morita, Shinji Ohno, Masakazu Toi
    Investigational new drugs 39(1) 217-225 2021年2月  
    Purpose To date, it is not clear which anticancer agent is useful in combination with trastuzumab and pertuzumab As the first and second selective regimens for advanced or metastatic breast cancer (AMBC), this multicenter, open-label, phase II trial (JBCRG-M03: UMIN000012232) presents a prespecified analysis of eribulin in combination with pertuzumab and trastuzumab. Methods We enrolled 50 patients with no or single prior chemotherapy for HER2-positive AMBC during November 2013-April 2016. All patients received adjuvant or first-line chemotherapy with trastuzumab and a taxane. The treatment comprised eribulin on days 1 and 8 of a 21-day cycle and trastuzumabplus pertuzumab once every 3 weeks, all administered intravenously. While the primary endpoint was the progression-free survival (PFS), secondary endpoints were the response rate and safety. Results Of 50 patients, 49 were eligible for safety analysis, and the full analysis set (FAS) included 46 patients. We treated 8 (16%) and 41 (84%) patients in first- and second-line settings, respectively. While 11 patients (23.9%) had advanced disease, 35 (76.1%) had metastatic disease. The median PFS was 9.2 months for all patients [95% confidence interval (CI): 7.0-11.4]. In the FAS, 44 patients had the measurable lesions and the complete response rate (CR) was 17.4%, and partial response rate (PR) was 43.5%. The grade 3/4 adverse events were neutropenia (5 patients, 10.2%), including febrile neutropenia (2 patients, 4.1%), hypertension (3 patients, 6.1%), and other (1 patient). The average of the left ventricular ejection fraction did not decline markedly. No symptomatic left ventricular systolic dysfunction was observed. Conclusions In patients with HER2-positive AMBC, eribulin, pertuzumab, and trastuzumab combination therapy exhibited substantial antitumor activity with an acceptable safety profile. Hence, we have started a randomized phase III study comparing eribulin and a taxane in combination with pertuzumab and trastuzumab for the treatment of HER2-positive AMBC. Trial registration ID: UMIN-CTR: UMIN000012232.
  • Akane Naruoka, Sumiko Ohnami, Takeshi Nagashima, Masakuni Serizawa, Keiichi Hatakeyama, Keiichi Ohshima, Shumpei Ohnami, Kenichi Urakami, Yasue Horiuchi, Yoshimi Kiyozumi, Hiroyuki Matsubayashi, Masato Abe, Takuma Ohishi, Toru Kameya, Takashi Sugino, Tetsuro Onitsuka, Mitsuhiro Isaka, Yasuhisa Ohde, Teiichi Sugiura, Takaaki Ito, Katsuhiko Uesaka, Yasuto Akiyama, Masatoshi Kusuhara, Ken Yamaguchi
    Biomedical research (Tokyo, Japan) 42(2) 89-94 2021年  
    Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome. This hereditary cancer is caused by germline variants in MEN1. Two patients with MEN1 were identified via whole exome sequencing and gene expression profile analysis, conducted for 5,063 patients with various types of cancers. We obtained multiple tumors from each patient; tumors derived from these two MEN1 patients had a loss of the normal MEN1 allele and frequently chromosomal copy number changes. Thus, we investigated whether structural variants were present in the MEN1 patient genomes. Whole-genome sequencing revealed no catastrophic rearrangements, and the tumor samples had very low somatic variants. The two patients had germline variants in MEN1 and some chromosomal copy number changes including on chromosome 11. The only pathogenic variant detected was the MEN1 germline variant, and chromosomal rearrangements led to tumorigenesis in somatic cells. Furthermore, the MEN1 tumor samples displayed a specific signature characterized by T:A>C:G transition. Studies of multiple tumors obtained from single patients are rare in hereditary cancer syndromes, and our results provide insights that the second hit of the tumor suppressor gene MEN1 may be caused by a gross genome rearrangement, not a small insertion and deletion, nor a change in epigenetic regulation.
  • 吉村 悟志, 藤本 浩司, 長嶋 健, 高田 護, 榊原 淳太, 寺中 亮太郎, 大塚 将之
    日本乳癌学会総会プログラム抄録集 28回 94-94 2020年10月  
  • 藤本 浩司, 長嶋 健, 高田 護, 榊原 淳太, 寺中 亮太郎, 大塚 将之
    日本乳癌学会総会プログラム抄録集 28回 95-95 2020年10月  
  • 中津川 智子, 三階 貴史, 藤本 浩司, 高田 護, 榊原 淳太, 寺中 亮太郎, 坂田 治人, 長嶋 健
    日本乳癌学会総会プログラム抄録集 28回 139-139 2020年10月  
  • 榊原 淳太, 寺中 亮太郎, 高田 護, 藤本 浩司, 長嶋 健, 大塚 将之
    日本乳癌学会総会プログラム抄録集 28回 158-158 2020年10月  
  • 坂本 陽介, 高田 護, 寺中 亮太郎, 榊原 淳太, 藤本 浩司, 三階 貴史, 長嶋 健, 大塚 将之
    日本乳癌学会総会プログラム抄録集 28回 377-377 2020年10月  
  • 長嶋 健, 藤本 浩司, 高田 護, 榊原 淳太, 寺中 亮太郎, 大塚 将之
    日本乳癌学会総会プログラム抄録集 28回 411-411 2020年10月  
  • Shinsuke Akita, Yoshihisa Yamaji, Nobuyoshi Takeuchi, Ken Wakai, Kazuhiko Azuma, Ayako Nakagawa, Hiroshi Fujimoto, Takafumi Sangai, Takeshi Nagashima, Nobuyuki Mitsukawa, Yuzuru Ikehara
    Lymphatic research and biology 18(5) 455-463 2020年10月  
    Background: It is not always possible to detect nonpalpable small lymph nodes (LNs) surrounded by adipose tissue under the wavelength of visible light. A newly developed near-infrared camera with InGaAs element was able to capture photographs using light at >1000-nm wavelength, at which the difference in absorbance between water and lipids is large. This study investigated the ability to detect nonvisible small LNs using light at 1300-nm wavelength. Methods and Results: Following retrieval of LNs through axillary LN dissection from 20 patients with breast cancer, residual specimens were simultaneously photographed using light at 970-, 1070-, 1200-, 1300-, 1450-, and 1600-nm wavelengths. A total of 45 specimens were observed pathologically at the selected portions in which the 1300-nm light was absorbed (high absorbance group [HA group], n = 25) and those in which the 970-nm light was absorbed instead (low absorbance group [LA group], n = 20). All specimens categorized in the HA group detected the LNs, whereas none of those categorized in the LA group detected an LN. The sensitivity and specificity in the identification of an LN were 1.0. The LNs detected using this camera were significantly smaller than those detected by surgeons (3.00 ± 2.93 mm vs. 5.90 ± 3.91 mm, p < 0.01). Discussion: The light at 1300-nm wavelength was absorbed by axillary LNs. This camera detected LNs that were undetectable by surgeons. This novel technology may be applied to lymphatic microsurgery and contribute to the development of a minimally invasive LN dissection method.
  • 高田 護, 長嶋 健, 三階 貴史, 藤本 浩司, 榊原 淳太, 寺中 亮太郎, 大塚 将之
    日本外科学会定期学術集会抄録集 120回 SF-4 2020年8月  
  • 長嶋 健, 三階 貴史, 藤本 浩司, 高田 護, 榊原 淳太, 寺中 亮太郎, 大塚 将之
    日本外科学会定期学術集会抄録集 120回 DP-2 2020年8月  
  • 中津川 智子, 三階 貴文, 楯 真一, 藤本 浩司, 宇津野 恵美, 神津 三佳, 松下 一之, 西村 基, 長嶋 健, 生水 真紀夫, 羽田 明, 野村 文夫, 市川 智彦
    日本遺伝カウンセリング学会誌 41(2) 83-83 2020年6月  
  • Takahito Masuda, Hiroshi Fujimoto, Ryotaro Teranaka, Masayuki Kuroda, Yasuyuki Aoyagi, Takeshi Nagashima, Takafumi Sangai, Mamoru Takada, Ayako Nakagawa, Yoshitaka Kubota, Koutaro Yokote, Masayuki Ohtsuka
    Breast cancer research and treatment 180(3) 625-634 2020年4月  
    PURPOSE: Although recent advances in molecular target therapy have improved the survival of breast cancer patients, high cost and frequent hospital visits result in both societal and individual burden. To reduce these problems, it has been proposed to produce antibodies in vivo. Here, we constructed gene-transduced human ceiling culture-derived proliferative adipocytes secreting anti-HER2 antibody (HER2-ccdPAs) and evaluated their ability to secrete antibody and mediate an anti-tumor effect. METHODS: Plasmid lentivirus was used as a recipient for anti-HER2 antibody cDNA and transduced into human proliferative adipocyte. Secretory antibody expression was evaluated by ELISA and western blot. Specific binding of secretory antibody to HER2 was examined by immunofluorescence analysis. Direct and indirect anti-tumor effects of supernatants from HER2-ccdPAs were evaluated using BT474 (HER2+) and MDA-MB-231 (HER2-) breast cancer cell lines. Additionally, whether adipocyte differentiation affects antibody secretion was investigated using supernatant collected from different cell maturation states. RESULTS: Anti-HER2 antibody was identified in the supernatant from HER2-ccdPAs and its production increased with the differentiation into mature adipocyte. Antibodies in supernatants from HER2-ccdPAs bound to HER2-positive breast cancer cells similar to trastuzumab. Supernatant from HER2-ccdPAs inhibited the proliferation of BT474 but not MDA-MB-231 cells, and downregulated AKT phosphorylation in BT474 cells compared with controls. Supernatants from HER2-ccdPAs also had an indirect anti-tumor effect on BT474 cells through ADCC. Additionally, Single inoculation of HER2-ccdPAs showed an anti-tumor effect in BT474 xenograft model. CONCLUSIONS: HER2-ccdPAs might be useful for cell-based gene therapy. This system could be a platform for various antibody therapies.
  • 榊原 淳太, 寺中 亮太郎, 高田 護, 藤本 浩司, 長嶋 健, 大塚 将之
    乳腺甲状腺超音波医学 9(2) 106-106 2020年3月  
  • Hiroko Masuda, Tsutomu Iwasa, Toru Mukohara, Shinya Tokunaga, Koji Matsumoto, Naoki Niikura, Yasuaki Sagara, Yasuo Miyoshi, Akihiko Shimomura, Masato Takahashi, Takeshi Nagashima, Mihoko Doi, Manabu Futamura, Kenichi Yoshimura, Toshimi Takano, Junji Tsurutani
    CANCER RESEARCH 80(4) 2020年2月  査読有り
  • Toshiaki Iwase, Takafumi Sangai, Hiroshi Fujimoto, Yuji Sawabe, Kazuyuki Matsushita, Kengo Nagashima, Yasunori Sato, Ayako Nakagawa, Takahito Masuda, Takeshi Nagashima, Masayuki Ohtsuka
    Breast cancer research and treatment 179(2) 435-443 2020年1月  査読有り
    PURPOSE: Recent studies suggest that the quality and quantity of visceral adipose tissue (VAT) play significant roles in adipocyte function, and are related to insulin resistance. We tested the hypothesis that high amounts of upper VAT (aVAT) and low-quality VAT worsen treatment outcomes via altered insulin metabolism. METHODS: Cohort 1 included 106 women with breast cancer who were undergoing surgery. Homeostasis model assessment of insulin resistance (HOMA-R), insulin-like growth factor (IGF)-1, and IGF-binding protein 3 (IGFBP3) were measured before the initiation of treatment. aVAT was measured via computed tomography (CT). VAT quality was assessed using CT-determined Hounsfield units (VAT-HU). Associations between the variables investigated and VAT quality and quantity were analyzed. Cohort 2 included 271 patients who underwent chemotherapy. Associations between the variables investigated and survival outcomes after chemotherapy were analyzed via retrospective chart review. RESULTS: In cohort 1, aVAT was significantly correlated with insulin and HOMA-R levels. As body mass index (BMI) class increased, mean IGF-1 increased and mean IGFBP3 decreased, but these trends were not statistically significant. In cohort 2, aVAT was significantly positively correlated with BMI. The patients in the third aVAT tertiles had significantly shorter distant disease-free survival (dDFS) after neoadjuvant chemotherapy setting. In multivariate analysis, aVAT and VAT-HU were significantly associated with shorter dDFS. CONCLUSIONS: High aVAT and low-quality VAT were associated with poor survival outcome, increased insulin levels, and insulin resistance. The present study suggests the importance of evaluating the quality and quantity of VAT when estimating insulin resistance and treatment outcomes.
  • Hiroshi Fujimoto, Nobumitsu Shiina, Takeshi Nagashima, Takafumi Sangai, Junta Sakakibara, Mamoru Takada, Ryotaro Teranaka, Haduki Takishima, Yohei Kawasaki, Masayuki Ohtsuka
    Journal of surgical oncology 121(2) 216-223 2019年12月15日  査読有り
    BACKGROUND AND OBJECTIVES: We investigated the effects of oncoplastic breast-conserving surgery (BCS) using chest wall perforator flaps (CWPFs) on the subsequent expected deformity and evaluated the longevity of flap volume. METHODS: We retrospectively reviewed oncological and cosmetic outcomes of 33 women who had undergone the above procedure. We calculated the percentage of breast volume excised (PBVE) from computed tomography volumetry and compared it between a historical BCS alone and the study (flap) group. We also sequentially evaluated flap volumes by magnetic resonance imaging volumetry. RESULTS: Oncoplastic BCS using 25 lateral flaps and eight inferior flaps, depending on the site of the defect, was performed; mean PBVEs were 31.1% and 19.0%, respectively. No local and two distant recurrences occurred in a median follow-up of 61 months. PBVE was 2.6 times larger in the flap than in the BCS alone group. Over half the patients in the BCS alone group had poor cosmetic results when PBVE exceeded 15%, whereas patients in the flap group achieved good cosmetic results with PBVE >25%. In most patients, 80% of flap volume was maintained 5 years after surgery. CONCLUSIONS: CWPF improves cosmetic outcomes in patients with predicted deformity after BCS alone and maintains its volume for at least 5 years.
  • 榊原 淳太, 大久保 嘉之, 田辺 直人, 森田 泰弘, 長嶋 健, 大塚 将之
    癌と化学療法 46(13) 2170-2172 2019年12月  
    今回、多遺伝子アッセイoncotype DXを用いて、術前内分泌療法中の乳癌局所制御と遠隔再発率の結果に差を認めた症例を経験したので報告する。症例は50歳、女性。右乳房C領域に16×11×11mmの腫瘤を認めた。病理組織学的結果は浸潤性乳癌、ER陽性、PgR陽性、HER2陰性、Ki-67は38%であった。生検材料で算出された再発スコアが4と低リスク群(10年後の遠隔再発率4%と低率、化学療法の上乗せ効果は認めず)であり、術前内分泌療法を開始したが治療開始1ヵ月で26×18×15mmと局所が増大したため、右乳房部分切除術+センチネルリンパ節生検を施行した。低リスク群であっても内分泌療法の効果が腫瘤を形成した局所と血中循環腫瘍細胞のような微小な細胞で違うことが示唆された。(著者抄録)
  • Junta Sakakibara, Yoshiyuki Okubo, Naoto Tanabe, Yasuhiro Morita, Takeshi Nagashima, Masayuki Ohtsuka
    Gan to kagaku ryoho. Cancer & chemotherapy 46(13) 2170-2172 2019年12月  
    We report different treatment effects between local and distant lesions based on oncotype DX in a patient with breast cancer administered neoadjuvant endocrine therapy. The patient was a 50-year-old woman. Ultrasound(US)showed a mass 16×11×11mm in diameter in the C area of her right breast. Histological examination revealed invasive ductal carcinoma positive for estrogen and progesterone receptor and negative for human epidermal growth factor receptor type 2(HER2), and a Ki-67 index of 38%. The recurrence score(RS)calculated from the core needle biopsy was 4(low-risk group)with a predicted 10-year risk of distant recurrence of 4% after 5 years of endocrine therapy. Oncotype DX showed that this patient would not benefit from chemotherapy. We administered neoadjuvant endocrine therapy. However, the tumor size increased to 26×18×15mm 1 month after treatment initiation. Therefore, right breast-conserving surgery and sentinel lymph node biopsy were performed. Histopathologically, the effect of the endocrine therapy was grade 0 and the surgical margins were negative. Even though RS was low in the breast, the effect of endocrine therapy differed between local and distant lesions such as circulating tumor cells.
  • 榊原 淳太, 寺中 亮太郎, 高田 護, 藤本 浩司, 三階 貴史, 長嶋 健, 大塚 将之
    日本臨床外科学会雑誌 80(10) 1923-1923 2019年10月  
  • 赤岡 徹朗, 藤本 浩司, 長嶋 健, 三階 貴史, 榊原 淳太, 高田 護, 寺中 亮太郎, 大塚 将之
    日本臨床外科学会雑誌 80(増刊) 396-396 2019年10月  
  • 藤本 浩司, 長嶋 健, 三階 貴史, 榊原 淳太, 高田 護, 寺中 亮太郎, 大塚 将之
    日本臨床外科学会雑誌 80(増刊) 420-420 2019年10月  
  • Joji Ota, Hajime Yokota, Hazuki Takishima, Akiyo Takada, Ryosuke Irie, Yuka Suzuki, Takeshi Nagashima, Takuro Horikoshi, Koichi Chida, Yoshitada Masuda, Takashi Uno
    European journal of radiology 119 108651-108651 2019年10月  
    PURPOSE: Organ-effective modulation (OEM) is a mechanism to reduce radiation dose to selected organs on computed tomography (CT). The purpose of this study was to measure radiation dose to the breast in Asian patients undergoing chest CT and to clarify the degree of exposure reduction. METHOD: We randomly selected 60 female patients undergoing non-contrast chest CT after breast cancer surgery. To measure radiation dose, an optically stimulated luminescence dosimeter had been attached directly to the gown over the nonoperated breast in 30 patients. Radiologists evaluated the image quality with and without OEM. In order to clarify the characteristics of OEM, the effects of angle and object size were measured using a phantom and an ionization chamber dosimeter. RESULTS: The OEM group received 9.1 ± 1.9 mGy and the non-OEM group received 10.7 ± 2.4 mGy. OEM reduced the exposure by 12.2% (P <  0.01). OEM caused no reduction in diagnostic quality. In the phantom study, the results of the angle effect were 3.2%, 11.2%, 28.7%, 31.3, 25.9%, 14.9% and 6.0% dose reductions at -90, -60, -30, 0, 30, 60 and 90°, respectively. The effect of the subject thickness was 3.7%, 17.5%, 30.2%, 31.7%, and 34.1% at 16, 20, 24, 28 and 32 cm diameters, respectively. CONCLUSIONS: OEM is a useful mechanism for reducing radiation exposure to the breast without affecting diagnostic imaging quality. The reduction rate correlated negatively with body habitus.
  • 荒井 学, 榊原 雅裕, 長島 誠, 大城 崇司, 田中 宏, 吉田 豊, 瓜田 祐, 平沼 綾子, 佐藤 雄, 高木 隆一, 北原 知晃, 川満 健太郎, 門屋 健吾, 肥塚 智, 秋田 新介, 長嶋 健, 岡住 慎一
    日本乳癌学会総会プログラム抄録集 27回 548-548 2019年7月  
  • 梅原 有子, 藤田 和恵, 坂田 治人, 長嶋 健, 田中 知明
    日本乳癌学会総会プログラム抄録集 27回 579-579 2019年7月  
  • 藤本 浩司, 長嶋 健, 三階 貴史, 高田 護, 中川 綾子, 升田 貴仁, 寺中 亮太郎, 大塚 将之
    日本乳癌学会総会プログラム抄録集 27回 272-272 2019年7月  
  • 長嶋 健, 三階 貴史, 藤本 浩司, 高田 護, 升田 貴仁, 中川 綾子, 寺中 亮太郎, 大塚 将之
    日本乳癌学会総会プログラム抄録集 27回 448-448 2019年7月  
  • 中川 綾子, 藤本 浩司, 長嶋 健, 三階 貴史, 高田 護, 升田 貴仁, 寺中 亮太郎, 太田 聡, 松島 惇, 秋田 新介, 大塚 将之
    日本乳癌学会総会プログラム抄録集 27回 454-454 2019年7月  
  • 升田 貴仁, 藤本 浩司, 寺中 亮太郎, 中川 綾子, 高田 護, 三階 貴史, 長嶋 健, 大塚 将之
    日本乳癌学会総会プログラム抄録集 27回 496-496 2019年7月  

MISC

 252

共同研究・競争的資金等の研究課題

 10