Updated on 2021/12/14

写真a

 
TOYOOKA Shinichi
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
External link

Degree

  • 医学博士 ( 岡山大学 )

Research Areas

  • Life Science / Respiratory surgery

 

Papers

  • Oncogenic potential of human pluripotent stem cell-derived lung organoids with HER2 overexpression. International journal

    Akihiro Miura, Daisuke Yamada, Masahiro Nakamura, Shuta Tomida, Dai Shimizu, Yan Jiang, Tomoka Takao, Hiromasa Yamamoto, Ken Suzawa, Kazuhiko Shien, Masaomi Yamane, Masakiyo Sakaguchi, Shinichi Toyooka, Takeshi Takarada

    International journal of cancer   149 ( 8 )   1593 - 1604   2021.10

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    Lung adenocarcinoma (LUAD) is the most common types among lung cancers generally arising from terminal airway and understanding of multistep carcinogenesis is crucial to develop novel therapeutic strategy for LUAD. Here we used human induced pluripotent stem cells (hiPSCs) to establish iHER2-hiPSCs in which doxycycline induced the expression of the oncoprotein human epidermal growth factor receptor 2 (HER2)/ERBB2. Lung progenitors that differentiated from iHER2-hiPSCs, which expressed NKX2-1/TTF-1 known as a lung lineage maker, were cocultured with human fetal fibroblast and formed human lung organoids (HLOs) comprising alveolar type 2-like cells. HLOs that overexpressed HER2 transformed to tumor-like structures similar to atypical adenomatous hyperplasia, which is known for lung precancerous lesion and upregulated the activities of oncogenic signaling cascades such as RAS/RAF/MAPK and PI3K/AKT/mTOR. The degree of morphological irregularity and proliferation capacity were significantly higher in HLOs from iHER2-hiPSCs. Moreover, the transcriptome profile of the HLOs shifted from a normal lung tissue-like state to one characteristic of clinical LUAD with HER2 amplification. Our results suggest that hiPSC-derived HLOs may serve as a model to recapitulate the early tumorigenesis of LUAD and would provide new insights into the molecular basis of tumor initiation and progression.

    DOI: 10.1002/ijc.33713

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  • Protective effects of anti-HMGB1 monoclonal antibody on lung ischemia reperfusion injury in mice

    Kentaro Nakata, Mikio Okazaki, Dai Shimizu, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Daiki Ousaka, Toshiaki Ohara, Akihiro Matsukawa, Masahiro Nishibori, Shinichi Toyooka

    Biochemical and Biophysical Research Communications   573   164 - 170   2021.10

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    Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.bbrc.2021.08.015

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  • Lung transplantation for idiopathic multicentric Castleman disease: potential efficacy and tolerability of a humanized anti-interleukin-6 receptor monoclonal antibody. International journal

    Yasuaki Tomioka, Shinji Otani, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

    Surgical case reports   7 ( 1 )   209 - 209   2021.9

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    BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disease caused by the overrepresentation of interleukin-6 (IL-6). Tocilizumab (TCZ) is a humanized monoclonal antibody that binds to the IL-6 receptor and is approved for the treatment of iMCD. The efficacy and tolerability of TCZ in patients with iMCD undergoing lung transplantation (LTx) remain unknown. CASE PRESENTATION: We present the case of a 48-year-old iMCD patient with end-stage lung disease (ESLD) who was successfully treated with cadaveric single-LTx. Intravenous TCZ was used to stabilize the iMCD patient every 2 weeks, except for withdrawal immediately after LTx. At 32 month post-transplant, the patient remained asymptomatic without evidence of rejection, development of de novo donor-specific antibody (DSA), and recurrent iMCD in the native lung. CONCLUSIONS: Single-LTx can be a feasible treatment option for ESLD caused by iMCD. TCZ can be used safely and may be beneficial in recipients with iMCD, and TCZ in combination with usual immunosuppression can be helpful in stabilizing iMCD patients pre- and post-LTx.

    DOI: 10.1186/s40792-021-01297-2

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  • Pulmonary lymphatic involvement in metastatic uterine sarcomas: imaging and pathological appearance. International journal

    Takahiro Kitayama, Takashi Tanaka, Takao Hiraki, Shinichi Toyooka, Hiroyuki Yanai, Susumu Kanazawa

    Radiology case reports   16 ( 9 )   2460 - 2462   2021.9

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    Pulmonary lymphatic involvement of sarcomas is an extremely rare form of metastases. We report the computed tomography (CT) features of pathologically confirmed pulmonary lymphatic involvement from metastatic uterine sarcomas. The CT illustrated smooth or nodular thickenings of the interlobular septa and bronchovascular bundle. Moreover, ground-glass opacity along the interlobular septa was also detected. These findings suggest that lymphatic involvement has diagnostic value for detecting this rare form of metastatic sarcomas. We also discuss possible differential diagnoses in this case and review previous cases reporting pulmonary lymphatic involvement in metastatic sarcomas. To the best of our knowledge, this is the first report describing pulmonary lymphatic involvement in metastatic uterine sarcomas. Pulmonary lymphatic spread of sarcomas is a rare form of metastatic sarcomas, but it should be considered when these findings suggesting lymphatic involvement are detected on CT.

    DOI: 10.1016/j.radcr.2021.05.076

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  • Sarcopenia is related to poor prognosis in patients after trimodality therapy for locally advanced non-small cell lung cancer.

    Kuniaki Katsui, Takeshi Ogata, Kenta Watanabe, Kotaro Yoshio, Masahiro Kuroda, Masaomi Yamane, Takao Hiraki, Katsuyuki Kiura, Shinichi Toyooka, Susumu Kanazawa

    International journal of clinical oncology   26 ( 8 )   1450 - 1460   2021.8

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    BACKGROUND: The association between sarcopenia and prognosis in patients with locally advanced non-small cell lung cancer (NSCLC) undergoing trimodality therapy, consisting of preoperative concurrent chemoradiotherapy and surgery, has not been reported. Therefore, we aimed to investigate the association of sarcopenia and fat mass with prognosis after trimodality therapy. METHODS: To assess sarcopenia, the psoas muscle mass was measured. Using computed tomography data, including third lumbar vertebra level images, psoas muscle mass and visceral and subcutaneous fat mass were measured. Additionally, body mass indices, and visceral/subcutaneous fat ratio, obtained by dividing the visceral fat index by the subcutaneous fat index, were calculated. We investigated the relationship between these parameters and overall survival. RESULTS: Ninety-nine eligible patients were included. In the univariate analysis, age, clinical stage, tumor location, psoas muscle index, and visceral/subcutaneous fat ratio were significant prognostic factors for overall survival (P = 0.008, P = 0.04, P = 0.04, P = 0.02, and P = 0.02, respectively). In the multivariate analysis, age and psoas muscle index were significant prognostic factors for overall survival (P = 0.01 and P = 0.03, respectively). The 5-year overall survival rates for the high and low psoas muscle index groups were 79.6% [95% confidence interval (CI), 67.1-94.5%] and 66.2% (95% CI, 54.1-81.1%), respectively; whereas, the 10-year overall survival rates were 61.9% (95% CI, 42.0-91.4%) and 25.3% (95% CI, 8.6-74.2%), respectively. CONCLUSION: Sarcopenia was related to poor overall survival in patients with locally advanced NSCLC undergoing trimodality therapy. Assessment of body composition prior to treatment may provide important information for formulating rational therapeutic strategies.

    DOI: 10.1007/s10147-021-01927-7

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  • Robot-assisted thoracoscopic lobectomy for severe incomplete interlober fissure. International journal

    Mikio Okazaki, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

    Journal of surgical case reports   2021 ( 8 )   rjab336   2021.8

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    An incomplete interlobar fissure makes thoracoscopic lobectomy difficult and is predictive of morbidity after thoracoscopic lobectomy. This report demonstrates the robot-assisted thoracoscopic (RATS) lobectomy technique for patients with severe incomplete interlobar fissures. A fissureless approach was chosen for pulmonary resection. Near-infrared fluorescence imaging with intravenous indocyanine green (ICG) was used to detect the interlobar line after transection of the bronchus, pulmonary artery and vein. Interlobar fissure was identified and divided by robotic staplers. This combined technique using ICG and fissureless lobectomy made RATS lobectomy safe for patients with severe incomplete interlobar fissures.

    DOI: 10.1093/jscr/rjab336

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  • Emphysematous changes and lower levels of plasma irisin are associated with bronchiolitis obliterans syndrome after bilateral living-donor lobar lung transplantation.

    Toshio Shiotani, Seiichiro Sugimoto, Haruchika Yamamoto, Kentaroh Miyoshi, Shinji Otani, Ken Suzawa, Hiromasa Yamamoto, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka

    Surgery today   2021.7

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    PURPOSE: Decreased irisin levels may be associated with the development of emphysema. Similarly, emphysematous changes may develop in patients with chronic lung allograft dysfunction (CLAD) after living-donor lobar lung transplantation (LDLLT). We investigated the severity of emphysematous changes and the relationship between irisin levels and CLAD after bilateral LDLLT and cadaveric lung transplantation (CLT). METHODS: The subjects of this retrospective study were 59 recipients of bilateral LDLLT (n = 31) or CLT (n = 28), divided into a non-CLAD group (n = 41), a LDLLT-CLAD group (n = 11), and a CLT-CLAD group (n = 7). We compared the severity of emphysematous changes, the skeletal muscle mass, and the plasma irisin levels among the groups. RESULTS: The emphysematous changes were significantly more severe in the LDLLT-CLAD and CLT-CLAD groups (p = 0.046 and 0.036), especially in patients with bronchiolitis obliterans syndrome (BOS), than in the non-CLAD group. Although the skeletal muscle mass was similar in all the groups, the plasma irisin levels were significantly lower in the LDLLT-CLAD group (p = 0.022), especially in the patients with BOS after LDLLT, than in the non-CLAD group. CONCLUSION: Emphysematous changes and lower levels of plasma irisin were associated with CLAD, especially in patients with BOS, after bilateral LDLLT.

    DOI: 10.1007/s00595-021-02339-w

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  • Publisher Correction: Sarcopenia is associated with poor prognosis after chemoradiotherapy in patients with stage III non-small-cell lung cancer: a retrospective analysis. International journal

    Kuniaki Katsui, Takeshi Ogata, Soichi Sugiyama, Kotaro Yoshio, Masahiro Kuroda, Takao Hiraki, Katsuyuki Kiura, Yoshinobu Maeda, Shinichi Toyooka, Susumu Kanazawa

    Scientific reports   11 ( 1 )   14586 - 14586   2021.7

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  • Appropriate use of cancer comprehensive genome profiling assay using circulating tumor DNA

    Kuniko Sunami, Hideaki Bando, Yasushi Yatabe, Yoichi Naito, Hideaki Takahashi, Katsuya Tsuchihara, Shinichi Toyooka, Koshi Mimori, Shinji Kohsaka, Hiroyuki Uetake, Ichiro Kinoshita, Keigo Komine, Masayuki Takeda, Tetsu Hayashida, Kenji Tamura, Kazuto Nishio, Noboru Yamamoto

    Cancer Science   2021.7

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    Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1111/cas.15022

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    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.15022

  • Lung transplantation for bronchiectasis due to hyper-immunoglobulin E syndrome. International journal

    Dai Shimizu, Shinji Otani, Seiichiro Sugimoto, Haruchika Yamamoto, Yasuaki Tomioka, Toshio Shiotani, Kentaroh Miyoshi, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka

    The Annals of thoracic surgery   2021.7

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    Hyper-immunoglobulin E syndrome (HIES) is one of the primary immunodeficiencies characterized by recurrent staphylococcal skin and lung infections that result in lung destruction and critically diminished pulmonary function. Despite the lack of definitive treatment, there have been no reports of successful lung transplantation (LTx) for HIES patients. We report the case of a 42-year-old female HIES patient with progressive bronchiectasis whose pulmonary infection was controlled prior to transplantation and subsequent LTx was uneventful. LTx may be feasible in HIES if the patient is immunologically stable preoperatively, and peri-operative infections, especially Aspergillus infections, are well-controlled.

    DOI: 10.1016/j.athoracsur.2021.05.088

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  • Chronic Lung Injury After Trimodality Therapy for Locally Advanced Non-Small Cell Lung Cancer. International journal

    Junichi Soh, Seiichiro Sugimoto, Kei Namba, Akihiro Miura, Toshio Shiotani, Haruchika Yamamoto, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Kuniaki Katsui, Masaomi Yamane, Katsuyuki Kiura, Susumu Kanazawa, Shinichi Toyooka

    The Annals of thoracic surgery   112 ( 1 )   279 - 288   2021.7

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    BACKGROUND: Trimodality therapy is a treatment option for patients with locally advanced non-small cell lung cancer (LA-NSCLC). Thoracic radiation has both early (radiation pneumonitis) and late (chronic lung injury [CLI]) adverse effects on the lung. While CLI is expected to result in various problems in long-term survivors, these manifestations have not been precisely investigated. METHODS: We enrolled 112 LA-NSCLC patients who had received induction chemoradiotherapy followed by surgery, and then undergone follow-up computed tomography (CT) every 6 months for greater than 1 year. All chest CT images were reviewed to evaluate any injury of the pulmonary parenchyma. RESULTS: CLI at 1 year after surgery and its progression were observed in 94 (84%) and 38 (34%) patients, respectively. Progressive lung fibrosis as the first manifestation of CLI progression was most frequent after right middle and lower lobectomy. Cavity formation was the subsequent manifestation after progressive lung fibrosis , and chronic infection was the final stage of CLI. The cumulative rate of chronic infection was 76.4% at 10 years in patients with cavity formation. Ten patients with chronic infection included 7 cases of pulmonary aspergillosis and 2 cases of cavity infections with methicillin-resistant Staphylococcus aureus or Stenotrophomonas maltophilia. Among them, 4 patients required surgical interventions including completion pneumonectomy or fenestration. CONCLUSIONS: CLI is a common incidence after trimodality therapy for LA-NSCLC. CLI frequently results in cavity formation, which is a precursor of highly refractory chronic infections requiring surgical intervention. Appropriate management needs to be established for CLI developing after trimodality therapy.

    DOI: 10.1016/j.athoracsur.2020.07.068

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  • "Hybrid Lung Transplantation" Combining Living Donor and Cadaveric Lung Transplants: Report of 2 Cases. International journal

    Takeshi Kurosaki, Takahiro Oto, Shinji Otani, Kentaroh Miyoshi, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

    Transplantation proceedings   2021.6

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    We present 2 cases of "hybrid lung transplant," which included sequentially implanting a living lobar graft to 1 side and a cadaveric graft to the other side. This procedure was approved by the institutional review board at Okayama University Hospital. The 2 recipients were diagnosed with severe idiopathic pulmonary fibrosis, and living donor lobar lung transplant was considered; however, 2 appropriate donors were not available. Therefore, we accepted extended criteria donor lungs with a partial pressure of oxygen/fraction of inspired oxygen ratio of <251 mm Hg. However, 1 of the 2 patients developed grade 2 primary graft dysfunction. The living donor lobar lung had a low volume but was in good condition, which contributed to the patient's recovery after primary graft dysfunction during the perioperative period. The other patient's status of bronchiolitis obliterans syndrome had gradually progressed to grade 3, and only the living donor lung was functioning at that time. However, both patients are alive 5.5 and 4.2 years after lung transplant, respectively. Hybrid lung transplantation may increase patients' chances of receiving transplants because patients are not likely to survive while waiting for ideal donor lungs to become available.

    DOI: 10.1016/j.transproceed.2021.04.019

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  • Sarcopenia is associated with poor prognosis after chemoradiotherapy in patients with stage III non-small-cell lung cancer: a retrospective analysis. International journal

    Kuniaki Katsui, Takeshi Ogata, Soichi Sugiyama, Kotaro Yoshio, Masahiro Kuroda, Takao Hiraki, Katsuyuki Kiura, Yoshinobu Maeda, Shinichi Toyooka, Susumu Kanazawa

    Scientific reports   11 ( 1 )   11882 - 11882   2021.6

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    We intended to investigate whether muscle and adipose masses were associated with prognosis among patients with stage III non-small-cell lung cancer (NSCLC) who were undergoing chemoradiotherapy (CCRT). We retrospectively explored data of patients with stage III NSCLC who underwent definitive CCRT (≥ 60 Gy) between January 2004 and March 2018 at our hospital. We examined the relationship of overall survival (OS) with body mass index (BMI), skeletal muscle index (SMI), psoas muscle index (PMI), visceral adipose tissue index (VAI), subcutaneous adipose tissue index (SAI), and visceral-to-subcutaneous adipose tissue area ratio (VSR) using log-rank tests for the univariate analysis and Cox proportional hazard models for the multivariate analysis. Overall, 16, 32, and 12 patients had stage IIIA, IIIB, and IIIC NSCLC, respectively. The total radiotherapy dose ranged from 60 Gy/30 fractions to 66 Gy/33 fractions. In the univariate analysis, the performance status (PS), BMI, and SMI were associated with OS, whereas the PMI, VAI, SAI, and VSR were not. In the multivariate analysis, the PS and SMI were associated with OS. The hazard ratios and 95% confidence intervals were 2.91 and 1.28-6.64 for PS, and 2.36 and 1.15-4.85 for SMI, respectively. The 1, 3, and 5-year OS rates were 92.1%, 59.6%, and 51.0% in patients with high SMI, and 63.6%, 53.8%, and 17.9% in patients with low SMI, respectively. The SMI correlated with prognosis in our study population, whereas adipose mass did not. Therefore, sarcopenia should be considered while predicting the OS in such patients.

    DOI: 10.1038/s41598-021-91449-z

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  • Clinical Outcome of Palliative Concurrent Chemoradiotherapy with Cisplatin/Docetaxel for Stage III Non-small Cell Lung Cancer.

    Kuniaki Katsui, Takeshi Ogata, Kenta Watanabe, Kotaro Yoshio, Masahiro Kuroda, Takao Hiraki, Katsuyuki Kiura, Yoshinobu Maeda, Shinichi Toyooka, Susumu Kanazawa

    Acta medica Okayama   75 ( 3 )   269 - 277   2021.6

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    Palliative concurrent chemoradiotherapy (CCRT) is often administered to patients with stage III non-small cell lung cancer (NSCLC). We investigated the clinical outcomes of patients receiving palliative CCRT for NSCLC. Data of patients with NSCLC who underwent palliative CCRT (n=16), preoperative CCRT plus surgery (n=97), or definitive CCRT (n=48) were evaluated. In all groups, the concurrent chemotherapy regimens consisted of cisplatin and docetaxel. Rates of local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS), overall survival (OS), and prognosis were compared. The 2-year rates of LC, DMFS, PFS, and OS in 16 patients who underwent palliative CCRT were 44.4%, 12.5%, 12.5%, and 18.8%, respectively. Univariate analysis showed that palliative CCRT was associated with poor LC (p<0.001), DMFS (p<0.001), PFS (p<0.001), and OS (p<0.001) outcomes in patients who completed CCRT as a preoperative treatment and poor LC (p=0.01), DMFS (p=0.003), PFS (p=0.04), and OS (p=0.004) outcomes in patients who were considered for definitive CCRT. Although there were some long-term survivors, the clinical outcomes of palliative CCRT were significantly inferior to those of the ideal treatments. Therefore, careful determination of the appropriate treatment indications and further studies are warranted.

    DOI: 10.18926/AMO/62218

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  • Robot-assisted intrathoracic procedure for dumbbell tumour in the prone position

    Mikio Okazaki, Tomoyuki Takigawa, Ken Suzawa, Shinichi Toyooka

    Interactive CardioVascular and Thoracic Surgery   2021.5

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    Publishing type:Research paper (scientific journal)   Publisher:Oxford University Press (OUP)  

    <title>Abstract</title>
    A 24-year-old man presented with a dumbbell-shaped right posterior mediastinal mass. The patient was placed in the prone position following general anaesthesia and intubation. After laminectomy and dissection of the dorsal part of the tumour using a posterior approach were performed, the tumour was completely resected using a robotic approach in the thoracic cavity without repositioning. This is the first report of robotic resection for posterior mediastinal tumour in the prone position as well as a novel combined posterior approach and robotic resection for dumbbell tumours.

    DOI: 10.1093/icvts/ivab117

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  • Circulating anti-human leukocyte antigen IgM antibodies as a potential early predictor of allograft rejection and a negative clinical outcome after lung transplantation.

    Kazuaki Miyahara, Kentaroh Miyoshi, Takeshi Kurosaki, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

    Surgery today   2021.5

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    PURPOSE: Anti-human leukocyte antigen (HLA) immunoglobulin (Ig) M production stimulated by an alloantigen is sensitive, making IgM a novel potential marker of allorejection after organ transplantation. This study examined the relationship between the serum levels of anti-HLA IgM early after clinical lung transplantation (LTx) and the post-transplant outcomes. METHODS: Thirty-one consecutive patients who underwent deceased LTx were included. Immunoreactivity against HLA was retrospectively analyzed by measuring the anti-HLA IgM levels in the serum sampled for the first 14 days after LTx. The flow panel reactive antibody technique was used. The ratio of the anti-class I IgM level at each day to baseline was obtained, and the peak IgM level was determined for each case. The correlation between the peak IgM level and subsequent development of acute rejection (AR), chronic lung allograft dysfunction (CLAD), and survival outcomes were examined. RESULTS: The peak IgM level was a significant risk factor for AR within 90 days in univariate and multivariate analyses. In the long term, the patients with positive IgM (peak level > 1.8) tended to have a poorer CLAD-free and overall survival than those with negative IgM. CONCLUSION: Elevation of anti-HLA IgM levels early after LTx may be correlated with a higher incidence of rejection and negative clinical outcomes.

    DOI: 10.1007/s00595-021-02293-7

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  • Randomized phase II study of daily and alternate-day administration of S-1 for adjuvant chemotherapy in completely-resected stage I non-small cell lung cancer: results of the Setouchi Lung Cancer Group Study 1301. International journal

    Norihito Okumura, Junichi Soh, Hiroyuki Suzuki, Masao Nakata, Toshiya Fujiwara, Hiroshige Nakamura, Makoto Sonobe, Takuji Fujinaga, Kazuhiko Kataoka, Kenichi Gemba, Masafumi Kataoka, Katsuyuki Hotta, Hiroshige Yoshioka, Keitaro Matsuo, Junichi Sakamoto, Hiroshi Date, Shinichi Toyooka

    BMC cancer   21 ( 1 )   506 - 506   2021.5

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    BACKGROUND: The aim of this multicenter, randomized phase II study was to analyze the feasibility and safety of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological stage I (tumor diameter > 2 cm) non-small cell lung cancer (NSCLC). METHODS: Patients were randomly assigned to receive adjuvant chemotherapy for 1 year comprising either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Group A) or a 2-week oral administration of S-1 (80 mg/m2/day) followed by 1 week of rest (Group B). The primary endpoint was feasibility, which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more. RESULTS: Ninety-three patients were enrolled of whom 90 patients received S-1 treatment. Median follow-up was 66.9 months. The treatment completion rate based on an RDI of 70% or more for 6 months was 84.4% (95%CI; 70.5-93.5%) in group A and 64.4% (95%CI; 48.8-78.1%) in group B. There were no grade 4 adverse events in either group. Moderate or severe adverse events (grade 2 or grade 3) were significantly more frequent in group B (67%) compared with group A (29%, P = 0.001). The 5-year relapse-free survival rate was 87.0 and 80.9% for group A and B, respectively (P = 0.451). The 5-year overall survival rate for all patients (n = 93) was 100 and 89.4% for group A and B, respectively (P = 0.136). CONCLUSION: Alternate-day oral administration of S-1 for 1 year as adjuvant chemotherapy was demonstrated to be feasible with low toxicity in completely resected stage I (tumor diameter > 2 cm) NSCLC. TRIAL REGISTRATION: Trial registration number: UMIN000011994 . Date of registration: 10/8/2013.

    DOI: 10.1186/s12885-021-08232-6

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  • Best practices for the extraction of genomic DNA from formalin-fixed paraffin-embedded tumor tissue for cancer genomic profiling tests. International journal

    Hirofumi Inoue, Shuta Tomida, Shigeru Horiguchi, Hironari Kato, Hiromi Matsuoka, Etsuko Sanehira, Masashi Matsuoka, Hiroyuki Yanai, Akira Hirasawa, Shinichi Toyooka

    Pathology international   71 ( 5 )   360 - 364   2021.5

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    Recently, two cancer genomic profiling tests have been approved in Japan and implemented in routine clinical practice: the FDA-approved FoundationOne CDx test, and the OncoGuide NCC Oncopanel test. The quality and quantity of DNA significantly affects the sequencing results; therefore, preparing a sufficient amount of high-quality DNA for clinical cancer genomic profiling tests is important. We examined the best practices for the extraction of cancer genomic DNA from formalin-fixed paraffin-embedded (FFPE) tumor tissues of pancreatic, lung and colon cancer specimens. We found that the quality of cancer genomic DNA extracted from 10-μm-thick FFPE samples improved significantly, compared with that from 4-μm-thick FFPE samples, suggesting that 10-μm-thick FFPE samples are preferable for clinical cancer genomic profiling tests. For convenience, we created a quick reference table for calculating the required number of FFPE slides.

    DOI: 10.1111/pin.13086

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  • RATS? VATS? Uniportal VATS?〜あなたならどのアプローチを選ぶ?〜 肥満症例や不全分葉症例から見たRATSの有用性

    岡崎 幹生, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    日本呼吸器外科学会雑誌   35 ( 3 )   PD3 - 3   2021.5

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    Language:Japanese   Publisher:(NPO)日本呼吸器外科学会  

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  • 肺移植患者の周術期におけるClostridioides difficile感染症の検討

    坂田 龍平, 大谷 真二, 石上 恵美, 石原 恵, 土生 智大, 岩田 一馬, 久保 友次郎, 松田 直樹, 清水 大, 松原 慧, 富岡 泰章, 山本 治慎, 塩谷 俊雄, 三好 健太郎, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    日本呼吸器外科学会雑誌   35 ( 3 )   O18 - 4   2021.5

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  • 肺移植における最適な術前予後予測スコアリング法 9つの術前予後予測スコアリング法の検証から

    山本 治慎, 杉本 誠一郎, 富岡 泰章, 塩谷 俊雄, 清水 大, 松原 慧, 三好 健太郎, 大谷 真二, 岡崎 幹生, 山根 正修, 豊岡 伸一

    日本呼吸器外科学会雑誌   35 ( 3 )   O18 - 5   2021.5

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  • N2肺癌に対する術前導入化学放射線療法後手術症例における好中球/リンパ球比の検討

    山本 寛斉, 津高 慎平, 富岡 泰章, 塩谷 俊雄, 諏澤 憲, 三好 健太郎, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    日本呼吸器外科学会雑誌   35 ( 3 )   O8 - 1   2021.5

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  • 肺移植後移植片慢性機能不全におけるGoddard scoreの検討

    塩谷 俊雄, 杉本 誠一郎, 山本 治慎, 富岡 泰章, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 山根 正修, 豊岡 伸一

    日本呼吸器外科学会雑誌   35 ( 3 )   O18 - 3   2021.5

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  • 肺がん治療発展を目指した呼吸器外科医の役割 家族性肺がんの経験

    諏澤 憲, 山本 寛斉, 三好 健太郎, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    日本呼吸器外科学会雑誌   35 ( 3 )   MO10 - 3   2021.5

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  • ロボット支援手術第2世代術者のラーニングカーブ

    大谷 真二, 岡崎 幹生, 坂田 龍平, 松田 直樹, 岩田 一馬, 高津 史明, 諏澤 憲, 三好 健太郎, 山本 寛斉, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    日本呼吸器外科学会雑誌   35 ( 3 )   MO58 - 1   2021.5

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  • UNCX遺伝子多型と肺移植後の腎機能障害との関係

    富岡 泰章, 杉本 誠一郎, 山本 治慎, 清水 大, 松原 慧, 塩谷 俊雄, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 山根 正修, 豊岡 伸一

    日本呼吸器外科学会雑誌   35 ( 3 )   RO17 - 2   2021.5

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  • Vessel sealerを常時用いたRATS手技

    岡崎 幹生, 諏澤 憲, 大谷 真二, 三好 健太郎, 山本 寛斉, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    日本呼吸器外科学会雑誌   35 ( 3 )   RV5 - 1   2021.5

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  • N2肺癌に対する免疫チェックポイント阻害剤を用いた周術期治療の可能性 WJOG12119L試験

    濱田 顕, 宗 淳一, 大泉 弘幸, 坪井 正博, 堀之内 秀仁, 吉野 一郎, 棚橋 雅幸, 豊岡 伸一, 岡田 守人, 横見瀬 裕保, 山下 素弘, 光冨 徹哉

    日本呼吸器外科学会雑誌   35 ( 3 )   S - 5   2021.5

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  • 肺移植における予後改善に向けての取組 生体肺移植と脳死肺移植の違いに着目した慢性移植肺機能不全(CLAD)の早期診断を目指した取り組み

    杉本 誠一郎, 塩谷 俊雄, 山本 治慎, 富岡 泰章, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 山根 正修, 豊岡 伸一

    日本呼吸器外科学会雑誌   35 ( 3 )   PD2 - 4   2021.5

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  • Phase II Study of Neoadjuvant Concurrent Chemo-immuno-radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage IIIA-B (Discrete N2) Non-small-cell Lung Cancer: SQUAT trial (WJOG 12119L). International journal

    Akira Hamada, Junichi Soh, Akito Hata, Kiyoshi Nakamatsu, Mototsugu Shimokawa, Yasushi Yatabe, Hiroyuki Oizumi, Masahiro Tsuboi, Hidehito Horinouchi, Ichiro Yoshino, Masayuki Tanahashi, Shinichi Toyooka, Morihito Okada, Hiroyasu Yokomise, Motohiro Yamashita, Yasumasa Nishimura, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Tetsuya Mitsudomi

    Clinical lung cancer   2021.4

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    INTRODUCTION: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069). PATIENTS AND METHODS: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m2] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%. CONCLUSION: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.

    DOI: 10.1016/j.cllc.2021.04.006

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  • Clinical features and prognostic impact of coexisting autoimmune disease other than myasthenia gravis in resected thymomas: analysis of a Japanese multi-institutional retrospective database. International journal

    Tomoyuki Hishida, Hisao Asamura, Kazuo Yoshida, Masahiro Tsuboi, Kohei Yokoi, Shinichi Toyooka, Akihide Matsumura, Tetsuzo Tagawa, Meinoshin Okumura

    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery   59 ( 3 )   641 - 649   2021.4

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    OBJECTIVES: The purpose of this study was to clarify the prevalence, clinical features and survival of patients with thymoma and non-myasthenia gravis autoimmune disease (NMAD) using a nationwide cohort. METHODS: The Japanese Association for Research on the Thymus nationwide database, which includes data from 32 institutions, was examined to clarify the prevalence and characteristics of NMAD associated with thymomas and elucidate the prognostic impact of NMAD for thymoma patients. RESULTS: Among the 2423 patients with thymomas who were surgically treated between 1991 and 2010, 114 (4.7%) were identified with NMAD. The most frequently observed NMAD was pure red cell aplasia (PRCA) in 44 (1.8%), followed by hypogammaglobulinaemia (0.5%) and rheumatic arthritis (0.5%). Twenty-eight percent of patients with NMAD had concomitant myasthenia gravis. The presence of NMAD was not an independent prognostic factor for overall survival (OS) irrespective of the type of NMAD [PRCA+: hazard ratio (HR) 1.99, 95% confidence interval 0.74-4.47; PRCA- NMAD: HR 1.28, 0.30-3.56]; however, there were more cases with advanced age and disease of the thymoma amongst PRCA+ patients and these showed a worse OS than patients with PRCA- NMAD (P < 0.001), who had an OS similar to those without NMAD (P = 0.489). The 10-year OS rates in PRCA+, PRCA- NMAD and NMAD- groups were 45.5%, 97.4% and 89.5%, respectively. The main causes of death in PRCA+ patients were the progression of thymoma and other diseases including pneumonia. CONCLUSIONS: Although the presence of NMAD itself did not significantly affect survival after surgery for thymoma, the type of NMAD was associated with different clinical features and prognosis. The NMAD+ thymomas should be separately categorized according to the presence or absence of PRCA.

    DOI: 10.1093/ejcts/ezaa362

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  • Long-term clinical follow-up after lung transplantation in patient with scoliosis: a case report.

    Haruchika Yamamoto, Shinji Otani, Kentaroh Miyoshi, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

    General thoracic and cardiovascular surgery   69 ( 4 )   752 - 755   2021.4

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    Severe scoliosis causes anatomical distortion of structures in the chest, which raises concerns about donor-recipient size-mismatch in lung transplantation (LT), so that severe scoliosis is considered as an absolute contraindication for LT. Also, postoperative right-side bronchial stenosis is one of the common complications in LT recipients with severe scoliosis. To date, the long-term outcomes in severe scoliosis patients with bronchial stenosis after LT have not been reported. A 14-year-old female patient with scoliosis and interstitial pneumonia underwent bilateral cadaveric LT. Although she developed bronchial stenosis post-LT, necessitating bronchoscopic intervention on three occasions, her lung function and perfusion recovered to the levels recorded prior to development of the obstruction, with the good condition maintained for more than 5 years after the LT. Therefore, while patients with severe scoliosis are at an elevated risk of postoperative transient bronchial stenosis, scoliosis should not always be considered as a contraindication to LT.

    DOI: 10.1007/s11748-020-01539-4

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  • Effectiveness of scheduled intravenous acetaminophen in the postoperative pain management of video-assisted thoracic surgery.

    Yoshinobu Shikatani, Junichi Soh, Kazuhiko Shien, Takeshi Kurosaki, Shinji Ohtani, Hiromasa Yamamoto, Arata Taniguchi, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Hiroshi Morimatsu, Shinichi Toyooka

    Surgery today   51 ( 4 )   589 - 594   2021.4

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    PURPOSE: The scheduled administration of intravenous acetaminophen (scheduled-IV-AcA) is one of the more effective multimodal analgesic approaches for postoperative pain in abdominal/orthopedic surgeries. However, there is little evidence concerning scheduled-IV-AcA after general thoracic surgery, especially when limited to video-assisted thoracoscopic surgery (VATS). We investigated the efficacy of scheduled-IV-AcA administration in patients after undergoing VATS. METHODS: Ninety-nine patients who underwent VATS lobectomy or segmentectomy via an 8-cm access window and 1 camera port were retrospectively reviewed by categorizing them into groups either with scheduled-IV-AcA (Group AcA: n = 29) or without it (Group non-AcA: n = 70). Group AcA received 1 g of IV-AcA every 6 h from the end of the operation until the end of POD2. Postoperative pain was measured using a numeric rating scale (NRS) three times per day until discharge. RESULTS: NRS scores were significantly lower in Group AcA with motion (on POD1 to the first point of POD2) than in Group non-AcA. Group non-AcA was also more likely to use additional analgesics than Group AcA (39% vs. 17%, p = 0.058). CONCLUSIONS: Scheduled-IV-AcA administration is a safe and effective multimodal analgesic approach in patients undergoing VATS pulmonary resection via an 8-cm access window.

    DOI: 10.1007/s00595-020-02127-y

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  • 当院における小児肺移植の成績

    大谷 真二, 富岡 泰章, 松原 慧, 清水 大, 山本 治慎, 塩谷 俊雄, 諏澤 憲, 三好 健太郎, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    日本外科学会定期学術集会抄録集   121回   PS - 8   2021.4

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  • A PET/CT volumetric parameter predicts prognosis of non-small cell lung cancer treated using preoperative chemoradiotherapy and surgery: A retrospective case series study. International journal

    Kuniaki Katsui, Takeshi Ogata, Akihiro Tada, Kenta Watanabe, Kotaro Yoshio, Masahiro Kuroda, Katsuyuki Kiura, Takao Hiraki, Shinichi Toyooka, Susumu Kanazawa

    Molecular and clinical oncology   14 ( 4 )   73 - 73   2021.4

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    The purpose of the present study was to clarify whether positron emission tomography/computed tomography (PET/CT) volumetric parameters were prognostic predictors of non-small cell lung cancer (NSCLC) treatment in patients who had undergone preoperative concurrent chemoradiotherapy (CCRT) and surgery. In the present study, retrospectively surveyed the data of patients with NSCLC who underwent preoperative CCRT and surgery at Okayama University Hospital (Okayama, Japan) between April 2006 and March 2018. The maximum standardized uptake value (SUVmax) and volumetric parameters, including metabolic tumor volume (MTV) and total lesion glycolysis (TLG), were calculated using PET/CT and the percentage decrease (Δ) in each parameter value post-CCRT. The SUVmax threshold for defining MTV was set at 2.5. Furthermore, the association between survival and PET parameter values was analyzed. A total of 52 patients were included in the present study. The median follow-up period was 50.65 months. In univariate analysis, ΔTLG was identified to be a significant predictor of progression-free survival (PFS; P=0.03). The 5-year PFS rates were 48.6 and 76.6% for patients with low ΔTLG and high ΔTLG, respectively. High ΔTLG was indicative of a higher overall survival rate (P=0.08). The present results suggest that ΔTLG calculated using PET/CT is a prognostic predictor of NSCLC treated using preoperative CCRT and surgery, and may help physicians determine treatment strategies.

    DOI: 10.3892/mco.2021.2235

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  • Role of surgery in a novel multimodal therapeutic approach to complete cure of advanced lung cancer: current and future perspectives.

    Masaomi Yamane, Shinichi Toyooka

    Surgery today   2021.3

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    Non-small cell lung cancer (NSCLC) is considered potentially curable by multimodal therapy in a subset of patients, including those with locally advanced (LA) disease or nodal spread, who would otherwise have a poor prognosis. Guidelines recommend perioperative chemotherapy with platinum-based regimens, with or without radiotherapy, as the standard treatment modality for high-risk resectable LA-NSCLC. Although the classical regimens of adjuvant chemotherapy have been platinum-based doublet or oral agents such as tegafur/uracil, some molecular targeted therapeutic agents and immune checkpoint inhibitors have been developed recently with an expected favorable effect. Recent trials of perioperative therapy using these agents have demonstrated favourable anticancer efficacy for LA-NSCLC with an acceptable adverse events profile. The ideal timing of perioperative therapy administration, before or after surgery, is still controversial. Because some speculation and concepts have arisen from basic research, several trials are ongoing to clarify the efficacy of newly developed agents in the adjuvant or neoadjuvant setting. This review discusses the role of surgery in the new era and analyzes when and which optimal perioperative multimodal therapy, including chemotherapy, radiotherapy, molecular-targeted therapy, and immunotherapy, should be administered for resectable or potentially resectable NSCLC to provide possible complete cure.

    DOI: 10.1007/s00595-021-02228-2

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  • Lung transplantation for Kartagener syndrome: technical aspects and morphological adaptation of the transplanted lungs.

    Haruchika Yamamoto, Seiichiro Sugimoto, Kentaroh Miyoshi, Shinji Otani, Masaomi Yamane, Shinichi Toyooka

    General thoracic and cardiovascular surgery   69 ( 3 )   588 - 592   2021.3

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    While technical considerations in lung transplantation for Kartagener syndrome have been discussed, little information is available about the postoperative morphological changes of the grafted lungs. Herein, we discuss both the technical aspects and postoperative morphological adaptation of the grafted lungs in a case of Kartagener syndrome. A 46-year-old male patient with Kartagener syndrome underwent bilateral cadaveric lung transplantation. The right arterial anastomosis for transplantation of the size-matched grafts required technical elaboration. After the transplantation, we found a free space in the cardiac notch of the left lung and partial collapse of the lower lobe of the right lung due to dextrocardia. Follow-up computed tomography performed on day 42 after the transplantation demonstrated resolution of the atelectasis and morphological adaptation of the grafts into the recipient's chest cavity with dextrocardia. Considering such early morphological adaptation of size-matched grafts, lobar reduction could be avoided in lung transplantation for Kartagener syndrome.

    DOI: 10.1007/s11748-020-01509-w

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  • Relationships of physical and breast cancer phenotypes with three single-nucleotide polymorphisms (rs2046210, rs3757318, and rs3803662) associated with breast cancer risk in Japanese women.

    Kengo Kawada, Naruto Taira, Taeko Mizoo, Yoko Suzuki, Yukiko Kajiwara, Minami Hatono, Takahiro Tsukioki, Mariko Kochi, Yuko Abe, Keiko Nishiyama, Takayuki Iwamoto, Hirokuni Ikeda, Tadahiko Shien, Hiroyoshi Doihara, Setsuko Ishihara, Hiroshi Kawai, Kensuke Kawasaki, Yoichi Ishibe, Yutaka Ogasawara, Shinichi Toyooka

    Breast cancer (Tokyo, Japan)   28 ( 2 )   478 - 487   2021.3

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    BACKGROUND: Recent genome-wide association studies have shown that many single-nucleotide polymorphisms (SNPs) are associated with breast cancer risk. However, it is often unclear how these SNPs are related to breast cancer. Analysis of associations between SNPs and phenotypes may be important for determining mechanisms of action, including carcinogenesis. METHODS: In previous case-control studies, we found three SNPs (rs2046210, rs3757318, and rs3573318) associated with breast cancer risk in Japanese women. Among these SNPs, two (rs2046210 and rs3757318) are located at 6q25.1, in proximity to the estrogen receptor 1 gene (ESR1). Using data from these studies, we examined associations between factors related to breast cancer risk, such as height, weight, and breast density, and the three SNPs in cases and controls. We also investigated whether the SNPs correlated with breast cancer features, such as estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor type-2 (HER2) status, and clinical stage. RESULTS: There was a significant difference in mean height between risk and non-risk allele carriers for rs2046210 (156.0 ± 5.8 vs. 154.3 ± 5.5 cm, p = 0.002), and rs3757318 (155.8 ± 5.7 vs. 154.7 ± 5.6 cm, p = 0.035) in cases, but no significant associations between height and these SNPs in controls. There was also a significant difference in breast density between risk and non-risk allele carriers for rs2046210 (p = 0.040) and rs3757318 (p = 0.044) in cases. rs2046210 and rs3757318 risk allele carriers tended to have higher breast density in all subjects and in controls. In cases, rs3757318 risk allele carriers were also significantly more likely to be ER-negative compared to non-risk allele carriers (ER-positive rate: 77% vs. 84%, p = 0.036). CONCLUSIONS: SNPs rs2046210 and rs3757318, which are associated with breast cancer risk in Japanese women, were significantly associated with height and high breast density, and this association was particularly strong in those with breast cancer. These findings suggest that SNPs in the ESR1 gene region affect phenotypes such as height and breast density.

    DOI: 10.1007/s12282-020-01185-x

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  • 脳死肺移植後、タクロリムス濃度調整に難渋した、クローン病合併レシピエントの1例

    松原 慧, 大谷 真二, 金 聖暎, 今井 祥子, 開原 裕子, 長谷川 祐子, 清水 大, 富岡 泰章, 山本 治慎, 塩谷 俊雄, 三好 健太郎, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    移植   55 ( 4 )   508 - 508   2021.3

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  • 脳死片肺移植を施行した多中心性キャッスルマン病の1例

    富岡 泰章, 大谷 真二, 松原 慧, 清水 大, 山本 治慎, 塩谷 俊雄, 三好 健太郎, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    移植   55 ( 4 )   506 - 506   2021.3

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  • 高IgE症候群による気管支拡張症に対して両側脳死肺移植を施行した1例

    清水 大, 大谷 真二, 富岡 泰章, 松原 慧, 塩谷 俊雄, 山本 治慎, 三好 健太郎, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    移植   55 ( 4 )   507 - 507   2021.3

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  • 反転肺移植術の可能性 当院で経験した3症例

    山本 治慎, 大谷 真二, 日笠 友起子, 黒崎 毅史, 三好 健太郎, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一, 小林 求, 大藤 剛宏

    移植   55 ( 4 )   453 - 453   2021.3

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  • 小児に対するABO血液型不一致の両側脳死肺移植の経験

    塩谷 俊雄, 杉本 誠一郎, 松原 慧, 富岡 泰章, 清水 大, 山本 治慎, 三好 健太郎, 大谷 真二, 岡崎 幹生, 山根 正修, 大藤 剛宏, 豊岡 伸一

    移植   55 ( 4 )   491 - 491   2021.3

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  • 肺移植手術手技を応用した自家肺移植

    塩谷 俊雄, 大谷 真二, 青景 圭樹, 黒崎 毅史, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一, 坪井 正博, 大藤 剛宏

    移植   55 ( 4 )   451 - 451   2021.3

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  • Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Locally Advanced Non-small-cell Lung Cancer Treated with Trimodality Therapy. International journal

    Shimpei Tsudaka, Hiromasa Yamamoto, Hiroki Sato, Kuniaki Katsui, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Katsuyuki Kiura, Susumu Kanazawa, Shinichi Toyooka

    Annals of surgical oncology   2021.2

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    PURPOSE: Current evidence suggests that the neutrophil-to-lymphocyte ratio (NLR) is a prognostic factor in several types of cancer. In this study, we aimed to evaluate the prognostic impact of clinicopathological factors, including postoperative NLR, in patients with locally advanced non-small-cell lung cancer (LA-NSCLC) who underwent surgery after chemoradiotherapy (CRT) with or without postoperative adjuvant chemotherapy. METHODS: The medical records of LA-NSCLC patients treated with trimodality therapy at our institution between June 1999 and May 2019 were reviewed. The association between several clinicopathological factors and overall survival (OS) was analyzed. RESULTS: A total of 168 patients were included in this study. Regarding the prognosis, the 5-year OS rate was 68.1%, and the 2-year recurrence-free survival rate was 66.1% in the entire population. In multivariate analysis, we identified that high postoperative NLR, not pretreatment or preoperative NLR, was one of the independent factors for unfavorable OS (NLR high vs NLR low; hazard ratio = 2.45, 95% confidence interval: 1.53-3.94, p < 0.001). In addition, among patients with high postoperative NLR, patients who received postoperative adjuvant chemotherapy showed significantly better 5-year OS compared with those who did not (p = 0.016). On the other hand, postoperative adjuvant chemotherapy had no impact on the prognosis in patients with low NLR (p = 0.19). CONCLUSIONS: Our results suggest that high postoperative NLR was not only an independent unfavorable prognostic factor in patients with LA-NSCLC who were treated with trimodality therapy, but also a promising indicator for postoperative treatment in this population.

    DOI: 10.1245/s10434-021-09690-9

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  • Lung stereotactic body radiation therapy for elderly patients aged ≥ 80 years with pathologically proven early-stage non-small cell lung cancer: a retrospective cohort study. International journal

    Kenta Watanabe, Kuniaki Katsui, Soichiro Sugiyama, Kotaro Yoshio, Masahiro Kuroda, Takao Hiraki, Katsuyuki Kiura, Yoshinobu Maeda, Shinichi Toyooka, Susumu Kanazawa

    Radiation oncology (London, England)   16 ( 1 )   39 - 39   2021.2

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    BACKGROUND: Stereotactic body radiation therapy (SBRT) is an established therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC). Many elderly patients are medically inoperable owing to comorbidities. Therefore, SBRT may be a useful therapy for elderly patients. However, the application of SBRT for patients aged ≥ 80 years has not been completely elucidated. Therefore, this study aimed to assess the clinical utility of SBRT for elderly patients aged ≥ 80 years with pathologically proven early-stage NSCLC. METHODS: We retrospectively evaluated the data of patients aged ≥ 80 years with pathologically proven primary NSCLC who underwent SBRT at our institution between January 2009 and March 2020. Treatment outcomes and toxicities were analyzed. We used the Kaplan-Meier method to estimate survival curves and the log-rank test to compare the survival curves. We performed univariate and multivariate Cox regression analyses. p-values < 0.05 were regarded significant. RESULTS: Sixty-four patients (65 lesions) were included, and the median follow-up period was 38.7 (range 3.5-95.7) months. The median age was 82.9 (range 80.0-94.8) years. Sixteen patients were medically operable, and 48 patients were medically inoperable. The prescribed dose of SBRT was either 48 Gy in four fractions or 60 Gy in 10 fractions. The median survival time was 60.0 months (95% confidence interval, 43.5-71.1). The 1-, 3-, and 5-year local control, cancer-specific survival, progression-free survival, and overall survival rates were 98.4%, 98.4%, 81.0%, and 88.9%; 90.1%, 93.7%, 58.9%, and 68.3%; and 87.4%, 83.5%, 38.2%, and 47.5%, respectively. Multivariate analysis revealed that inoperability and solid nodules were the predictors of poor overall survival after SBRT in elderly patients. Two patients (3.1%) had grade 3 radiation pneumonitis, and one patient (1.6%) had grade 5 radiation pneumonitis. CONCLUSIONS: SBRT was feasible in patients aged ≥ 80 years with NSCLC. It achieved good local control with minimal toxicity. SBRT may be beneficial in elderly patients with early-stage NSCLC.

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  • Preoperative Cumulative Smoking Dose on Lung Cancer Surgery in a Japanese Nationwide Database. International journal

    Yugo Tanaka, Hiroyuki Yamamoto, Masami Sato, Shinichi Toyooka, Morihito Okada, Shunsuke Endo, Yukio Sato, Kenji Suzuki, Yoshimasa Maniwa, Eriko Fukuchi, Hiroaki Miyata, Masayuki Chida

    The Annals of thoracic surgery   2021.2

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    BACKGROUND: Smoking is a known risk factor for postoperative mortality and morbidity. However, the significance of cumulative smoking dose in preoperative risk assessment has not been established. We examined the influence of preoperative cumulative smoking dose on surgical outcomes after lobectomy for primary lung cancer. METHODS: A total of 80,989 patients with primary lung cancer undergoing lobectomy from 2014 to 2016 were enrolled. Preoperative cumulative smoking dose was categorized by pack-years (PY): nonsmokers, PY = 0; light smokers, 0 < PY < 10; moderate smokers, 10 ≤ PY < 30; and heavy smokers, 30 ≤ PY. The risk of short-term outcomes was assessed according to PY by multivariable analysis adjusted for other covariates. RESULTS: Postoperative 30-day mortality, as well as pulmonary, cardiovascular, and infectious complications, increased with preoperative PY. Multivariable analysis revealed that the odds ratios (ORs) for postoperative mortality compared with nonsmokers were 1.76 for light smokers (P = .044), 1.60 for moderate smokers (P = .026), and 1.73 for heavy smokers (P = .003). The ORs for pulmonary complications compared with nonsmokers were 1.20 for light smokers (P = .022), 1.40 for moderate smokers (P < .001), and 1.72 for heavy smokers (P < .001). Heavy smokers had a significantly increased risk of postoperative cardiovascular (OR, 1.26; P = .002) and infectious (OR, 1.39; P = .007) complications compared with nonsmokers. CONCLUSIONS: The risk of mortality and morbidity after lung resection could be predicted according to preoperative cumulative smoking dose. These findings contribute to the development of strategies in perioperative management of lung resection patients.

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  • The prognostic nutritional index is correlated negatively with the lung allocation score and predicts survival after both cadaveric and living-donor lobar lung transplantation.

    Haruchika Yamamoto, Seiichiro Sugimoto, Junichi Soh, Toshio Shiotani, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka

    Surgery today   2021.2

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    PURPOSE: The prognostic nutritional index (PNI), calculated based on the serum albumin levels and the total lymphocyte count, has been identified as a predictor of clinical outcomes in various fields of surgery. In this study, we investigated the relationship between the PNI and the lung allocation score (LAS) as well as the impact of the PNI on the outcomes of both cadaveric lung transplantation (CLT) and living-donor lobar lung transplantation (LDLLT). METHODS: We reviewed retrospective data for 127 recipients of lung transplantation (LT), including 71 recipients of CLT and 56 recipients of LDLLT. RESULTS: The PNI was correlated significantly and negatively with the LAS (r = - 0.40, P = 0.0000037). Multivariate analysis revealed that age (P = 0.00093), BMI (P = 0.00087), and PNI (P = 0.0046) were independent prognostic factors of a worse outcome after LT. In a subgroup analysis, survival after both CLT (P = 0.015) and LDLLT (P = 0.041) was significantly worse in the low PNI group than in the high PNI group. CONCLUSION: Preoperative nutritional evaluations using the PNI can assist with the assessment of disease severity in LT recipients and may predict survival after both CLT and LDLLT.

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  • The prognostic impact of sarcopenia on elderly patients undergoing pulmonary resection for non-small cell lung cancer.

    Akihiro Miura, Hiromasa Yamamoto, Hiroki Sato, Yasuaki Tomioka, Toshio Shiotani, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

    Surgery today   2021.2

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    PURPOSE: The number of elderly patients who undergo surgery is increasing, even though they are at a high risk due to a decreased physical strength. Furthermore, sarcopenia is generally associated with a poor prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: This study included NSCLC patients  ≥ 65 years old who underwent pulmonary resection in our hospital between 2012 and 2015. Sarcopenia was assessed using the psoas muscle mass index based on computed tomography at the level of the third lumbar vertebra. We elucidated the impact of sarcopenia on short- and long-term outcomes after surgery. RESULTS: We enrolled 259 patients, including 179 with sarcopenia. Patients with sarcopenia before surgery tended to have postoperative complications (p = 0.0521), although they did not show a poor prognosis. In patients with sarcopenia, a multivariate analysis revealed that postoperative complications and the progression of sarcopenia 1 year after surgery were significant risk factors for a poor prognosis (p = 0.0169 and 0.00370, respectively). CONCLUSIONS: The progression of sarcopenia after surgery is associated with a poor prognosis in elderly NSCLC patients with sarcopenia. A strategy to prevent postoperative progressive sarcopenia may be necessary for improving the clinical outcome of this population.

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  • Lung Laceration Caused by Short Hookwire Placement Before Video-Assisted Thoracoscopic Surgery. International journal

    Kazuaki Munetomo, Yusuke Matsui, Toshihiro Iguchi, Takao Hiraki, Hiromasa Yamamoto, Shinichi Toyooka, Susumu Kanazawa

    Cardiovascular and interventional radiology   44 ( 2 )   339 - 341   2021.2

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  • Long-term Follow-up of Living-Donor Kidney Transplantation after Cadaveric Lung Transplantation.

    Toshio Shiotani, Seiichiro Sugimoto, Kota Araki, Yasuaki Tomioka, Kentaroh Miyoshi, Shinji Otani, Masaomi Yamane, Shinichi Toyooka

    Acta medica Okayama   75 ( 1 )   87 - 89   2021.2

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    Although chronic kidney disease (CKD) commonly develops after lung transplantation (LT), living-donor kid-ney transplantation (LDKT) for CKD after LT is known to provide favorable outcomes. We describe the long-term follow-up findings of a patient who underwent LDKT after bilateral cadaveric LT. A 37-year-old male underwent LDKT for CKD 18 years after receiving bilateral cadaveric LT. He developed chronic lung allograft dysfunction (CLAD) 20 years after the LT; however, at 26 years after the initial LT, he is still alive with no pro-gression of CLAD or CKD. KT could be a viable option for CKD even after LT in Japan.

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  • Successful Bronchoscopic Treatment for Postoperative Bronchopleural Fistula Using N-butyl-2-cyanoacrylate (NBCA): Report of a Post-completion Pneumonectomy Case with a History of Induction Chemoradiotherapy Followed by Bilobectomy for Advanced Lung Cancer.

    Toshio Shiotani, Hiromasa Yamamoto, Riko Katsube, Yasuaki Tomioka, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Junichi Soh, Masaomi Yamane, Shinichi Toyooka

    Acta medica Okayama   75 ( 1 )   91 - 94   2021.2

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    Bronchopleural fistula (BPF) is a severe complication following lung resection. We present the case of a patient with a history of advanced lung cancer, who had undergone induction chemoradiotherapy followed by right middle and lower lobectomy, and who developed BPF after completion right pneumonectomy. Although we had covered the bronchial stump with an omental pedicled flap, BPF was found on postoperative day 19. We covered the fistula with n-butyl-2-cyanoacrylate (NBCA) using bronchoscopy. Although we had to repeat the NBCA treatment, we ultimately cured the patient's BPF and no recurrence was observed up to 15.2 months after surgery.

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  • Volumetric PET Parameters Predict Prognosis after Definitive Chemoradiotherapy with Cisplatin/Docetaxel for Stage III Non-Small Cell Lung Cancer.

    Kuniaki Katsui, Takeshi Ogata, Akihiro Tada, Soichi Sugiyama, Kotaro Yoshio, Masahiro Kuroda, Katsuyuki Kiura, Yoshinobu Maeda, Shinichi Toyooka, Takao Hiraki, Susumu Kanazawa

    Acta medica Okayama   75 ( 1 )   15 - 23   2021.2

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    The aim of this study was to investigate whether volumetric positron emission tomography (PET) parameters are prognostic predictors in stage III non-small cell lung cancer patients receiving definitive concurrent chemo-radiotherapy (CCRT) with cisplatin/docetaxel. Cases involving definitive CCRT were reviewed retrospectively, and the maximum standardized uptake value, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated. The relationships between these PET parameters and prognosis were analyzed. MTV and TLG were significant predictors of distant metastasis-free survival (DMFS) (p = 0.0003 and 0.0005, respectively) and progression-free survival (PFS) (p = 0.001 and 0.0007, respectively). The three-year DMFS rates in patients with low and high MTV were 13.3% and 64.6%, respectively, and the corresponding values in those with low and high TLG were 13.3% and 65.2%, respectively. The three-year PFS rates in patients with low and high MTV were 13.3% and 57.8%, respectively, and the corresponding values in patients with low and high TLG were 13.3% and 57.8%, respectively. However, MTV and TLG were not predictors of local control or overall sur-vival. We demonstrated that volumetric PET parameters were predictors of patients receiving definitive CCRT. Our findings contradict the findings of previous reports and warrant further research to validate them.

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  • Staged surgery for empyema and lung gangrene caused by pseudoaneurysm after radiofrequency ablation. International journal

    Kentaro Nakata, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

    Interactive cardiovascular and thoracic surgery   2021.1

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    Lung gangrene is a potentially fatal disease, and primary or staged surgery, depending on the patient's condition, is reported to be useful. We describe successful management, by staged surgery, of a rare case of empyema and lung gangrene complicating lung radiofrequency ablation. The patient, who was a diabetic with colorectal pulmonary metastases, underwent embolization of a pulmonary artery pseudoaneurysm in the right basal segment that developed after lung radiofrequency ablation. He subsequently developed lung gangrene caused by lung ischaemia, and empyema, necessitating pleural decortication followed by open-window thoracostomy. Subsequently, right basal segmentectomy was performed, with thoracostoma closure. Staged surgery might be beneficial for high-risk patients with empyema and lung gangrene caused by lung ischaemia.

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  • Effect of isoflavones on breast cancer cell development and their impact on breast cancer treatments. International journal

    Minami Hatono, Hirokuni Ikeda, Yoko Suzuki, Yukiko Kajiwara, Kengo Kawada, Takahiro Tsukioki, Mariko Kochi, Ken Suzawa, Takayuki Iwamoto, Hiromasa Yamamoto, Tadahiko Shien, Masaomi Yamane, Naruto Taira, Hiroyoshi Doihara, Shinichi Toyooka

    Breast cancer research and treatment   185 ( 2 )   307 - 316   2021.1

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    PURPOSE: Epidemiological studies have suggested that intake of soy isoflavones is associated with a reduced risk of development of breast cancer and an improved prognosis in patients with breast cancer. In addition, basic research has demonstrated the antitumor effects of these compounds on breast cancer cell lines. However, the detailed effects of the intake of equol, which is one of the metabolites of the soy isoflavones, are yet to be clarified on the risk of development and recurrence of breast cancer and its interactions with drugs used for treating breast cancer. This study aimed to determine the antitumor effects of equol and investigate the impact of adding equol to therapeutic agents for breast cancer using breast cancer cell lines. METHODS: We examined the antitumor effect of equol on breast cancer cell lines using MTS assay. We also studied the combined effect of equol and the existing hormonal or chemotherapeutic agents using combination index. We evaluated the expressions of the related proteins by Western blot analysis and correlated the findings with the antitumor effect. RESULTS: Equol showed bi-phasic protumor and antitumor effects; at a low concentration, it promoted the tumor growth in hormone receptor-positive cell lines, whereas antitumor effects were generally observed when an excessive amount of dose unexpected in the blood and the tissue was administered. When used with tamoxifen, equol might have some antagonistic effect, although it depends on equol concentration and the type of cancer cells. CONCLUSIONS: We confirmed that equol has dual action, specifically a tumor growth-promoting effect and an antitumor effect. Although the results suggested that equol might exert an antagonistic effect against tamoxifen depending on the concentration, equol did not exert an antagonistic effect on other therapeutic agents.

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  • The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis. International journal

    Kota Araki, Rie Kinoshita, Nahoko Tomonobu, Yuma Gohara, Shuta Tomida, Yuta Takahashi, Satoru Senoo, Akihiko Taniguchi, Junko Itano, Ken-Ichi Yamamoto, Hitoshi Murata, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Kouichi Ichimura, Masahiro Nishibori, Nobuaki Miyahara, Shinichi Toyooka, Masakiyo Sakaguchi

    Journal of molecular medicine (Berlin, Germany)   99 ( 1 )   131 - 145   2021.1

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    In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

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  • 外科系新専門医制度のあるべきグランドデザイン 地域枠医師に対する外科専門研修のあり方 充実した地域医療の実現を目指して

    黒田 新士, 吉田 龍一, 池田 宏国, 岡崎 幹生, 大澤 晋, 小谷 恭弘, 山根 正修, 杉本 誠一郎, 菊地 覚次, 安井 和也, 野田 卓男, 笠原 真悟, 豊岡 伸一, 土井原 博義, 藤原 俊義

    日本外科学会雑誌   122 ( 1 )   83 - 85   2021.1

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  • 希望と安心をもたらす医療安全管理 無過失補償制度の可能性も含めて 外科領域の医療安全は手術室でのノンテクニカルスキル

    山根 正修, 豊岡 伸一

    日本外科学会雑誌   122 ( 1 )   111 - 113   2021.1

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  • Prognostic nutrition index affects the prognosis of patients undergoing trimodality therapy for locally advanced non-small cell lung cancer.

    Junichi Soh, Ken Suzawa, Kazuhiko Shien, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Kuniaki Katsui, Masaomi Yamane, Katsuyuki Kiura, Susumu Kanazawa, Shinichi Toyooka

    Surgery today   50 ( 12 )   1610 - 1618   2020.12

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    PURPOSE: Trimodality therapy, comprised of induction chemoradiotherapy (iCRT) followed by surgery, is a highly invasive treatment option for locally advanced non-small cell lung cancers (LA-NSCLCs; defined as a heterogenous disease). We conducted this study to investigate the prognostic nutritional index (PNI) of LA-NSCLC patients undergoing trimodality therapy, which has not been studied in detail before. METHODS: The subjects of this retrospective study were 127 patients who underwent trimodality therapy between 1999 and 2016. We measured the PNI at three points: before iCRT (pre-iCRT), before the operation, and after the operation. RESULTS: PNIs decreased significantly as treatment progressed. Patients with clinical T3/4 (cT3/4) disease had a significantly lower PNI than those with cT1/2 disease, but the extent of lymph-node metastasis did not affect the PNI at any point. Using the cut-off values of receiver-operating curve analyses, multivariable analyses revealed that a high PNI pre-iCRT correlated significantly with a better survival of LA-NSCLC patients, especially those with cT3/4 disease (hazard ratio 3.84; 95% confidential interval 1.34-12.5, P = 0.012). CONCLUSIONS: Measuring the PNI before trimodality therapy is important for predicting the clinical outcome of patients with LA-NSCLC, with differing predictive ability according to the disease extent. Perioperative intensive nutritional intervention must be considered for patients who undergo trimodality therapy for LA-NSCLC.

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  • Multiplex gene-panel testing for lung cancer patients. International journal

    Yasushi Yatabe, Kuniko Sunami, Koichi Goto, Kazuto Nishio, Naoko Aragane, Sadakatsu Ikeda, Akira Inoue, Ichiro Kinoshita, Hideharu Kimura, Tomohiro Sakamoto, Miyako Satouchi, Junichi Shimizu, Koji Tsuta, Shinichi Toyooka, Kazumi Nishino, Yutaka Hatanaka, Shingo Matsumoto, Masashi Mikubo, Tomoyuki Yokose, Hirotoshi Dosaka-Akita

    Pathology international   70 ( 12 )   921 - 931   2020.12

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    The year 2019 was considered to be the first year of cancer genome medicine in Japan, with three gene-panel tests using next-generation sequencing (NGS) techniques being introduced into clinical practice. Among the three tests, the Oncomine CDx Target test was approved under the category of regular molecular testing for lung cancer, which meant that this test could be used to select patients for molecularly targeted drugs. Conversely, the other two tests, NCC OncoPanel and FoundationOne CDx, were assigned to be used under the National Cancer Genome Medicine Network, and implementation was restricted to patients for whom standard treatment was completed or expected to be completed. These NGS tests can detect a series of genetic alterations in individual tumors, which further promotes the development of therapeutic agents and elucidates molecular pathways. The NGS tests require appropriate tissue size and tumor cell content, which can be accessed only by pathologists. In this report, we review the current reimbursement schema in our national healthcare policy and the requirements of the specimens for NGS testing based on the recently published 'Guidance of Gene-panel Testing Using Next-Generation Sequencers for Lung Cancer', by the Japanese Society of Lung Cancer.

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  • Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction. International journal

    Kazuya Nishii, Kadoaki Ohashi, Tomoki Tamura, Kiichiro Ninomiya, Takehiro Matsubara, Satoru Senoo, Hirohisa Kano, Hiromi Watanabe, Naohiro Oda, Go Makimoto, Hisao Higo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Hiromasa Yamamoto, Shuta Tomida, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

    Oncology letters   20 ( 6 )   393 - 393   2020.12

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    The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

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  • Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction

    Kazuya Nishii, Kadoaki Ohashi, Tomoki Tamura, Kiichiro Ninomiya, Takehiro Matsubara, Satoru Senoo, Hirohisa Kano, Hiromi Watanabe, Naohiro Oda, Go Makimoto, Hisao Higo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Hiromasa Yamamoto, Shuta Tomida, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

    ONCOLOGY LETTERS   20 ( 6 )   2020.12

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    The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube (TM) method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

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  • Clinical features and outcomes of patients with stage I multiple primary lung cancers. International journal

    Yasushi Shintani, Jiro Okami, Hiroyuki Ito, Takashi Ohtsuka, Shinichi Toyooka, Takeshi Mori, Shun-Ichi Watanabe, Hisao Asamura, Masayuki Chida, Hiroshi Date, Shunsuke Endo, Takeshi Nagayasu, Ryoichi Nakanishi, Etsuo Miyaoka, Meinoshin Okumura, Ichiro Yoshino

    Cancer science   2020.11

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    The number of patients with multiple primary lung cancers (MPLC) is rising. We studied the clinical features and factors related to outcomes of MPLC patients, using the database of surgically resected lung cancer (LC) cases compiled by the Japanese Joint Committee of Lung Cancer Registry. From the 18,978 registered cases, 9,689 patients with clinical stage I non-small cell lung cancer who achieved complete resection were extracted. Tumors were defined as synchronous MPLC when multiple LC was simultaneously resected or treatment was performed within 2 years after the initial surgery, while metachronous MPLC was defined as second LC treated more than 2 years after the initial surgery. Of these cases, 579 (6.0%) were synchronous MPLC and 477 (5.0%) metachronous MPLC, with 51 overlapping cases. Whereas female, non-smoker, low consolidation tumor ratio (CTR), and adenocarcinoma were significantly more frequent in the synchronous MPLC group, patients with metachronous MPLC had higher frequencies of males, smokers, chronic obstructive pulmonary disease (COPD), and non-adenocarcinoma. There was no significant difference for survival rate between patients with and without synchronous or metachronous MPLC. Age, gender, CTR for second LC, and histological combination of primary and second LC were prognostic indicators for both types of MPLC, while logistic regression analysis showed that female, history of malignant disease other than LC, and COPD were risk factors for MPLC incidence. The present findings may have major implications regarding MPLC diagnosis and identification of independent prognosticators, and provide valuable information for postoperative management of patients with MPLC.

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  • A Simple Prognostic Benefit Scoring System for Sarcoma Patients with Pulmonary Metastases: Sarcoma Lung Metastasis Score

    Haruchika Yamamoto, Hiromasa Yamamoto, Junichi Soh, Etsuji Suzuki, Kei Namba, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Takashi Yorifuji, Katsuhito Takahashi, Shinichi Toyooka

    Annals of Surgical Oncology   2020.11

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    DOI: 10.1245/s10434-020-09272-1

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  • Impact of the preoperative body mass index on the postoperative outcomes in patients with completely resected non-small cell lung cancer: A retrospective analysis of 16,503 cases in a Japanese Lung Cancer Registry Study. International journal

    Koichi Fukumoto, Shoichi Mori, Yasushi Shintani, Jiro Okami, Hiroyuki Ito, Takashi Ohtsuka, Shinichi Toyooka, Takeshi Mori, Shun-Ichi Watanabe, Hisao Asamura, Masayuki Chida, Hiroshi Date, Shunsuke Endo, Takeshi Nagayasu, Ryoichi Nakanishi, Etsuo Miyaoka, Meinoshin Okumura, Ichiro Yoshino

    Lung cancer (Amsterdam, Netherlands)   149   120 - 129   2020.11

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    OBJECTIVES: The aim of this study was to evaluate the impact of the preoperative body mass index (BMI) on the postoperative outcomes in patients with completely resected non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The data of patients with NSCLC in whom R0 resection was achieved were extracted from the database of NSCLC samples accumulated by the Japanese Joint Committee of Lung Cancer Registry in the year 2010, and the surgical outcomes including postoperative morbidity, mortality and the prognosis, were evaluated. RESULTS: Among 18,978 registered lung cancer cases, 16,509 patients (9996 men and 6513 women) were extracted. The median of age was 69 years old, and the histologic types included adenocarcinoma (n = 12,029), squamous cell carcinoma (n = 3286), large-cell carcinoma (n = 488) and others. The patients were divided into three groups according to their BMI: normal (BMI 18.5 to <25), underweight (BMI < 18.5) and overweight (BMI ≥ 25). Multivariate logistic regression analyses of factors associated with postoperative morbidity and mortality showed no significant differences among the three groups. In comparison to the normal group, the overall survival (OS) of the underweight group was significantly worse (p < 0.001) while that of the overweight group was marginally better (p = 0.075). A multivariate analysis of factors associated with OS showed that in addition to the age, sex and clinical stage, the preoperative BMI (underweight group vs. normal group: hazard ratio [HR] 1.417 [95% confidence interval {CI}: 1.278-1.572, p < 0.001], overweight group vs. normal group: HR 0.883 [95% CI: 0.806-0.967, p = 0.007]) was an independent prognostic factor. A multivariate analysis for the disease-free survival (DFS) also showed the preoperative BMI to be an independent significant prognostic factor. CONCLUSIONS: The preoperative BMI is an independent prognostic factor in patients with completely resected NSCLC. A low preoperative BMI was associated with significantly poor survival in Japan.

    DOI: 10.1016/j.lungcan.2020.09.011

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  • Continuing surgical education of non-technical skills. International journal

    Masaomi Yamane, Seiichiro Sugimoto, Etsuji Suzuki, Keiju Aokage, Mikio Okazaki, Junichi Soh, Makio Hayama, Yuji Hirami, Takashi Yorifuji, Shinichi Toyooka

    Annals of medicine and surgery (2012)   58   177 - 186   2020.10

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    Background: The non-technical skills for surgeons (NOTSS) system was developed as a tool to assess surgical skills for patient safety during surgery. This study aimed to develop a NOTSS-based training system for surgical trainees to acquire non-technical skills using a chest surgery scenario in a wet lab. Materials and methods: Trainees were categorized into three subgroups according to the years of experience as follows: Level A: 6 years or more; Level B: 3-5 years; and Level C: 1-2 years. Three stages of surgical procedure were designed: 1. chest wall resection and right upper lobe lobectomy, 2. right middle lobe sleeve lobectomy, and 3. right lower lobe lobectomy. One instructor was assigned to each operation table, who evaluated each participant's NOTSS scores consisting of 16 elements. Results: When comparing average NOTSS score of all the three procedures, significant differences were observed between Level A, B, and C trainees. As an example of varying elements by procedure, Level A trainees demonstrated differences in Situation Awareness, and a significant difference was observed in Level C trainees regarding the elements of Decision Making. On the contrary, no significant difference was observed among Level B trainees. In the comparison between first-time and experienced participants, a significant improvement was observed in some elements in Level B and C trainees. Conclusion: This study highlights the usefulness and feasibility of the NOTSS scoring system for surgeons with different experiences and the effectiveness of providing feedback to trainees during intraoperative handoffs in a wet lab.

    DOI: 10.1016/j.amsu.2020.07.062

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  • Chemoradiation therapy for non-small cell lung cancer exacerbates thoracic aortic calcification determined by computed tomography.

    Takashi Miki, Shunsaku Miyauchi, Toru Miyoshi, Masashi Yoshida, Keishi Ichikawa, Junichi Soh, Kazufumi Nakamura, Katsuyuki Kiura, Susumu Kanazawa, Shinichi Toyooka, Hiroshi Ito

    Heart and vessels   35 ( 10 )   1401 - 1408   2020.10

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    Preoperative chemoradiation therapy (CRT) has been considered as an effective treatment for non-small cell lung cancer. However, there is concern that CRT progresses atherosclerosis in cancer survivors. This study sought to determine if preoperative CRT exacerbated thoracic aortic calcification (TAC) detected by computed tomography (CT) in patients with lung cancer. Among 473 patients who underwent surgery for lung cancer at Okayama University Hospital between 2011 and 2015, 34 patients undergoing preoperative CRT and surgery (CRT group) and 33 matched patients undergoing initial surgery (non-CRT group) were analyzed and compared. The volume of TAC between the 2nd and 12th thoracic vertebrae was quantitatively measured by CT at baseline and 1-year follow-up. Patients in the CRT group (62 ± 7 years old, 74% male) received cisplatin chemotherapy with docetaxel or vinorelbine and radiation therapy (mean 47.3 ± 4.0 Gy). The percent change in TAC volume was significantly greater in the CRT compared with the non-CRT group (58.7%, 95% confidence interval [CI] 41.7-75.7% vs. 27.2%, 95% CI 9.9-44.4%; p = 0.01). Multivariate logistic regression analysis identified CRT as an independent factor associated with greater TAC progression (> the median value) (odds ratio 3.63, 95% CI 1.19-11.08; p = 0.02). In conclusion, preoperative CRT for lung cancer exacerbates TAC. Follow-up of such patients should thus include careful longitudinal assessment for cardiovascular disease.

    DOI: 10.1007/s00380-020-01611-2

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  • A Giant Thymic Cyst Accompanied by Acute Mediastinitis.

    Akihiro Miura, Kazuhiko Shien, Tomohiro Toji, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Junichi Soh, Masaomi Yamane, Shinichi Toyooka

    Acta medica Okayama   74 ( 5 )   431 - 433   2020.10

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    We encountered a rare case of thymic cyst accompanied by mediastinitis. A 39-year-old Japanese male presented with fever and chest pain. The chest CT revealed a mass composed of a lobular cystic lesion with inflammation, suggesting the onset of mediastinitis. A definitive histological diagnosis was not obtained, and we performed a thymectomy. Pathologically, the thymic cyst was accompanied by multiple cavities, mimicking thymic cysts, caused by the inflammatory abscess. The surrounding adipose tissue showed inflammatory cell infiltrations with chronic fibrosis. These findings indicate that clinicians should be aware that thymic cysts may cause severe mediastinitis.

    DOI: 10.18926/AMO/60804

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  • 肺移植待機患者の予後予測におけるPrognostic Nutrition Index(PNI)の有用性

    松原 慧, 大谷 真二, 清水 大, 富岡 泰章, 山本 治慎, 塩谷 俊雄, 三好 健太郎, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    移植   55 ( 総会臨時 )   353 - 353   2020.10

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  • 当院の肺移植後リンパ増殖性疾患7例の検討 治療後のCLAD発症と日和見感染症による死亡をどう防ぐか

    清水 大, 大谷 真二, 富岡 泰章, 松原 慧, 塩谷 俊雄, 山本 治慎, 三好 健太郎, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    移植   55 ( 総会臨時 )   246 - 246   2020.10

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  • 当院における高齢者レシピエント症例の検討

    富岡 泰章, 大谷 真二, 清水 大, 松原 慧, 山本 治慎, 塩谷 俊雄, 三好 健太郎, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    移植   55 ( 総会臨時 )   253 - 253   2020.10

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  • 肺移植におけるLiquid biopsy ドナー由来血中遊離DNAとマイクロRNA

    杉本 誠一郎, 塩谷 俊雄, 富岡 泰章, 石上 恵美, 石原 恵, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 山根 正修, 豊岡 伸一

    移植   55 ( 総会臨時 )   242 - 242   2020.10

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  • ハイリスク症例をいかに手術に繋げるか? 導入放射線化学療法後の局所進行非小細胞肺癌に対する手術後に反回神経麻痺を発症した症例の検討

    杉本 誠一郎, 諏澤 憲, 富岡 泰章, 塩谷 俊雄, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 山根 正修, 豊岡 伸一

    肺癌   60 ( 6 )   492 - 492   2020.10

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  • 左上顎洞腫瘤を契機に発見された左心室内への浸潤を伴う肺神経内分泌癌(小細胞癌)の集学的治療の一例

    平生 敦子, 加藤 有加, 西 達也, 岡崎 幹生, 二宮 貴一朗, 二宮 崇, 久保 寿夫, 頼 冠名, 市原 英基, 大橋 圭明, 山根 正修, 堀田 勝幸, 田端 雅弘, 豊岡 伸一, 前田 嘉信, 木浦 勝行

    肺癌   60 ( 6 )   683 - 683   2020.10

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  • 集学的治療が行われた局所進行肺癌患者における末梢血好中球/リンパ球比(NLR)の予後的意義について

    津高 慎平, 山本 寛斉, 諏澤 憲, 三好 健太郎, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    肺癌   60 ( 6 )   658 - 658   2020.10

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  • 最新低侵襲手術におけるリンパ節郭清手技:単孔式VATS vs ロボット支援手術 RATSにおけるリンパ節郭清手技

    岡崎 幹生, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    肺癌   60 ( 6 )   464 - 464   2020.10

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  • 高分化腺癌-いつ切るの? すりガラス成分を有する小型肺癌に対する治療の至適介入時期

    諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    肺癌   60 ( 6 )   484 - 484   2020.10

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  • 希少がん診断と治療 悪性軟部腫瘍の免疫ゲノムプロファイリング LOHはT・Bリンパ球浸潤と生存に相関する

    高橋 克仁, 宮地 康僚, 樋口 肇, 菰原 義弘, 相田 真一, 山本 寛斉, 諏澤 憲, 高橋 侑子, 豊岡 伸一, 楢原 啓之, 四元 淳子, 大山 優, 矢嶋 淳, 大野 烈士, 寺岡 慧

    日本癌治療学会学術集会抄録集   58回   WS29 - 1   2020.10

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  • 非小細胞肺癌手術症例と末梢血リンパ球/単球比とその継時的変化の関連の検討

    富岡 泰章, 山本 寛斉, 塩谷 俊雄, 諏澤 憲, 三好 健太郎, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    肺癌   60 ( 6 )   587 - 587   2020.10

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  • 間質性肺炎合併肺癌:To treat, or not to treat? 間質性肺炎合併肺癌に対する外科的治療

    山本 寛斉, 松原 慧, 富岡 泰章, 塩谷 俊雄, 諏澤 憲, 三好 健太郎, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 豊岡 伸一

    肺癌   60 ( 6 )   481 - 481   2020.10

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  • Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer. Reviewed International journal

    Kosuke Ochi, Ken Suzawa, Shuta Tomida, Kazuhiko Shien, Jui Takano, Shunsaku Miyauchi, Tatsuaki Takeda, Akihiro Miura, Kota Araki, Kentaro Nakata, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Tadahiko Shien, Masaomi Yamane, Kazuo Azuma, Yoshiharu Okamoto, Shinichi Toyooka

    Biochemical and biophysical research communications   529 ( 3 )   760 - 765   2020.8

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    BACKGROUND: The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. MATERIALS AND METHODS: A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. RESULTS: TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. CONCLUSION: Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance.

    DOI: 10.1016/j.bbrc.2020.06.077

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  • A phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with solid cancers harboring human epidermal growth factor receptor 2 amplification (JUPITER trial). International journal

    Kenta Takahashi, Eri Ishibashi, Toshio Kubo, Yohei Harada, Hideyuki Hayashi, Masayuki Kano, Yasushi Shimizu, Hidekazu Shirota, Yukiko Mori, Manabu Muto, Chikashi Ishioka, Hirotoshi Dosaka-Akita, Hisahiro Matsubara, Hiroshi Nishihara, Naoko Sueoka-Aragane, Shinichi Toyooka, Akihiro Hirakawa, Ukihide Tateishi, Satoshi Miyake, Sadakatsu Ikeda

    Medicine   99 ( 32 )   e21457   2020.8

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    INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. It is too difficult to conduct a conventional randomized, controlled trial in a rare fraction. Therefore, we have designed a organ-agnostic basket study, which covers a variety of solid cancers harboring HER2 amplification, in 1 study protocol. METHODS/DESIGN: This trial is a multicenter, single-arm, basket phase 2 study in Japan. Patients with solid cancers harboring HER2 amplification that have progressed with standard treatment, or rare cancers for which there is no standard treatment, will be eligible. Target cancers include bile duct, urothelial, uterine, ovarian, and other solid cancers where HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. A total of 38 patients will be treated with combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unmanageable toxicity, death, or patient refusal. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, and duration of response. DISCUSSION: The aim of this trial is to evaluate the safety and efficacy of combination therapy with trastuzumab and pertuzumab in patients with locally advanced or metastatic, solid cancers harboring HER2 amplification. Instead of focusing on 1 organ type, our trial design uses a basket study focusing on HER2 amplification, regardless of the site or origin of the cancer. The results of our study will advance clinical and scientific knowledge concerning the treatment of locally advanced, rare solid cancers harboring HER2 amplification, using the combination of trastuzumab and pertuzumab. TRIAL REGISTRATION: This trial was registered in Japan Registry of Clinical Trials (jCRT) on February 25, 2019, as jRCT2031180150.

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  • The neutrophil-to-lymphocyte ratio as a novel independent prognostic factor for multiple metastatic lung tumors from various sarcomas. Reviewed

    Hiromasa Yamamoto, Kei Namba, Haruchika Yamamoto, Tomohiro Toji, Junichi Soh, Kazuhiko Shien, Ken Suzawa, Takeshi Kurosaki, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Katsuhito Takahashi, Toshiyuki Kunisada, Takahiro Oto, Shinichi Toyooka

    Surgery today   2020.8

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    PURPOSE: Sarcomas are among the most refractory malignant tumors and often recur as pulmonary metastasis. Although the presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with the prognosis of several malignancies, the relationship between the NLR and sarcoma with pulmonary metastasis is unclear. We investigated the impact of the NLR in patients who underwent surgical resection for metastatic lung tumors from various sarcomas. METHODS: The subjects of this retrospective study were 158 patients with metastatic lung tumors from various sarcomas, who underwent initial pulmonary metastasectomy between 2006 and 2015. We examined the clinicopathological variables, including the NLR and the characteristics of surgical procedures. Survival was estimated by the Kaplan-Meier method and prognostic factors were evaluated by multivariate analysis. RESULTS: Multivariate analysis revealed significantly better survival of the group with an NLR < 2.26 immediately before the most recent pulmonary metastasectomy, in addition to such factors as the largest resected lesion being < 22 mm, a disease-free interval of > 2 years, and 3 or more pulmonary metastasectomies. CONCLUSION: The NLR immediately before the most recent pulmonary metastasectomy is a novel independent prognostic factor, which may be helpful when considering repeated pulmonary metastasectomy.

    DOI: 10.1007/s00595-020-02093-5

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  • Fibrosis or Necrosis in Resected Lymph Node Indicate Metastasis Before Chemoradiotherapy in Lung Cancer Patients. Reviewed International journal

    Yuta Takahashi, Junichi Soh, Kazuhiko Shien, Hiromasa Yamamoto, Masaomi Yamane, Katsuyuki Kiura, Susumu Kanazawa, Hiroyuki Yanai, Shinichi Toyooka

    Anticancer research   40 ( 8 )   4419 - 4423   2020.8

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    BACKGROUND/AIM: The histological features of lymph nodes (LNs) treated by chemoradiotherapy (CRT) in non-small cell lung cancer (NSCLC) have not been well studied. The purpose of this study was to evaluate the histological findings of LNs affected by CRT. PATIENTS AND METHODS: Among 107 clinically N2 NSCLC patients who underwent induction CRT followed by surgery from 1999 to 2017, 24 patients who received pathological evaluation of mediastinal LN before CRT were enrolled in this study. Postoperatively, we histologically reviewed all resected LNs (n=117) of the station evaluated before CRT. RESULTS: Fibrosis and/or necrosis were observed in all investigated LN stations. Histological observation of fibrosis and/or necrosis in the resected LNs after CRT indicated the presence of LN metastasis before CRT. CONCLUSION: The metastatic LNs that responded to CRT showed specific histological features, which enabled us to know the accurate clinical stage of the patient even though cancer cells were not found in the post-treated LNs.

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  • ウェットラボでのノンテクニカルスキル評価システムの有用性の検討

    山根 正修, 杉本 誠一郎, 岡崎 幹生, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   RO28 - 2   2020.8

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  • 肉腫多発肺転移に対する肺切除術

    山本 寛斉, 諏澤 憲, 三好 健太郎, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   O44 - 7   2020.8

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  • 気胸を合併し、発見された肺原発血管肉腫の1切除例

    毛利 謙吾, 岡崎 幹生, 塩谷 俊雄, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   SP4 - 3   2020.8

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  • 肺移植から学ぶ呼吸器外科学 肺移植から学ぶゲノム医療

    杉本 誠一郎, 塩谷 俊雄, 山本 治慎, 田中 真, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   S - 7   2020.8

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  • ロボット支援下肺葉切除術時の肺動脈損傷に対する対応

    岡崎 幹生, 諏澤 憲, 塩谷 俊雄, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   V1 - 1   2020.8

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  • 臨床的N0・病理学的リンパ節転移陽性肺がんに対する肺切除の現状

    諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   O3 - 1   2020.8

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  • 肺移植の問題点と改善策 高度無気肺を合併したドナー肺による移植成績

    塩谷 俊雄, 杉本 誠一郎, 山本 治慎, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   PD1 - 3   2020.8

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  • 右下肺静脈・左心房経由で左心室まで浸潤した小細胞肺癌に対する緊急手術の1例

    岡崎 幹生, 諏澤 憲, 塩谷 俊雄, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   RV3 - 1   2020.8

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  • 右下肺静脈・左心房経由で左心室まで浸潤した小細胞肺癌に対する緊急手術の1例

    岡崎 幹生, 諏澤 憲, 塩谷 俊雄, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   RV3 - 1   2020.8

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  • ロボット支援下肺葉切除術時の肺動脈損傷に対する対応

    岡崎 幹生, 諏澤 憲, 塩谷 俊雄, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   V1 - 1   2020.8

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  • ウェットラボでのノンテクニカルスキル評価システムの有用性の検討

    山根 正修, 杉本 誠一郎, 岡崎 幹生, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   RO28 - 2   2020.8

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  • 地域枠医師に対する外科専門研修のあり方 充実した地域医療の実現を目指して

    黒田 新士, 吉田 龍一, 池田 宏国, 岡崎 幹生, 大澤 晋, 小谷 恭弘, 山根 正修, 杉本 誠一郎, 菊地 覚次, 安井 和也, 野田 卓男, 笠原 真悟, 豊岡 伸一, 土井原 博義, 藤原 俊義

    日本外科学会定期学術集会抄録集   120回   SP - 4   2020.8

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  • 肺移植から学ぶ呼吸器外科学 肺移植から学ぶゲノム医療

    杉本 誠一郎, 塩谷 俊雄, 山本 治慎, 田中 真, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   S - 7   2020.8

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  • 肺移植の問題点と改善策 高度無気肺を合併したドナー肺による移植成績

    塩谷 俊雄, 杉本 誠一郎, 山本 治慎, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   PD1 - 3   2020.8

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  • 気胸を合併し、発見された肺原発血管肉腫の1切除例

    毛利 謙吾, 岡崎 幹生, 塩谷 俊雄, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   SP4 - 3   2020.8

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  • 抗HMGB1抗体による肺虚血再灌流障害の抑制

    中田 憲太郎, 岡崎 幹生, 清水 大, 宮内 俊作, 荒木 恒太, 三浦 章博, 塩谷 俊雄, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛弘, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   O47 - 4   2020.8

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  • 自然気胸後の器質化期膿胸に対する醸膿胸膜切除術 明瞭な臓側胸膜外層の同定に基づいた剥離

    清水 大, 三好 健太郎, 松原 慧, 山本 治慎, 諏澤 憲, 大谷 真二, 山本 寛斎, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   MO59 - 10   2020.8

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  • 臨床的N0・病理学的リンパ節転移陽性肺がんに対する肺切除の現状

    諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   O3 - 1   2020.8

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  • 抗HMGB1抗体による肺虚血再灌流障害の抑制

    中田 憲太郎, 岡崎 幹生, 清水 大, 宮内 俊作, 荒木 恒太, 三浦 章博, 塩谷 俊雄, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛弘, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   O47 - 4   2020.8

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  • 進化する外科マネージメントセンター それぞれの夢を実現するためのキャリアパス支援システム

    菊地 覚次, 黒田 新士, 吉田 龍一, 香川 俊輔, 山根 正修, 小谷 恭弘, 笠原 真悟, 豊岡 伸一, 藤原 俊義

    日本外科学会定期学術集会抄録集   120回   SP - 8   2020.8

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  • 外科系新専門医制度の発展・継続を加速する広域指導者養成プログラムの開発・運用

    山根 正修, 万代 康弘, 伊野 英男, 豊岡 伸一

    日本外科学会定期学術集会抄録集   120回   SSF - 2   2020.8

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  • 自然気胸後の器質化期膿胸に対する醸膿胸膜切除術 明瞭な臓側胸膜外層の同定に基づいた剥離

    清水 大, 三好 健太郎, 松原 慧, 山本 治慎, 諏澤 憲, 大谷 真二, 山本 寛斎, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   MO59 - 10   2020.8

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  • 肉腫多発肺転移に対する肺切除術

    山本 寛斉, 諏澤 憲, 三好 健太郎, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   34 ( 3 )   O44 - 7   2020.8

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  • Survival Outcomes of Treatment with Radiofrequency Ablation, Stereotactic Body Radiotherapy, or Sublobar Resection for Patients with Clinical Stage I Non-Small-Cell Lung Cancer: A Single-Center Evaluation. Reviewed International journal

    Toshihiro Iguchi, Takao Hiraki, Yusuke Matsui, Toshiharu Mitsuhashi, Norihisa Katayama, Kuniaki Katsui, Junichi Soh, Jun Sakurai, Hideo Gobara, Shinichi Toyooka, Susumu Kanazawa

    Journal of vascular and interventional radiology : JVIR   31 ( 7 )   1044 - 1051   2020.7

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    PURPOSE: To retrospectively compare the outcomes of radiofrequency (RF) ablation, stereotactic body radiotherapy (SBRT), and sublobar resection (SLR) in patients with stage I non-small-cell lung cancer (NSCLC) at a single center. MATERIALS AND METHODS: Overall, 289 patients (38 RF ablation, 58 SBRT, and 193 SLR) were included. Kaplan-Meier curves were generated, multiple propensity score was estimated using a multinomial logistic regression model, and relationships between treatments and outcomes were assessed using a Cox proportional hazard model. Hazard ratios (HRs) for death from any cause and disease progression or death from any cause were examined by a crude model, an inverse probability of treatment weighting (IPTW) model, and an IPTW model adjusted for missing variables. RESULTS: The 5-year overall and progression-free survival rates were 58.9% and 39.9%, respectively, for RF ablation; 42.0% and 34.9%, respectively, for SBRT; and 85.5% and 75.9%, respectively, for SLR. Significantly longer survival time and lower HR were observed for SLR than other treatments. However, after statistical adjustment, these relationships were not significant except for reduced HR of disease progression or death from any cause of SLR compared to RF ablation in the IPTW model. The median hospital stays for RF ablation, SBRT, and SLR were 6.5, 6, and 16 days, respectively. Adverse events of grade 3 or higher occurred only in 11 SLR cases. CONCLUSIONS: SLR achieved the longest survival. However, after statistical adjustment, there were no significant outcome differences among RF ablation, SBRT, and SLR, except for 1 model. RF ablation or SBRT may be alternative treatments for selected patients with early-stage NSCLC.

    DOI: 10.1016/j.jvir.2019.11.035

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  • Influences of preoperative metformin on immunological factors in early breast cancer. International journal

    Takahiro Tsukioki, Tadahiko Shien, Takehiro Tanaka, Yoko Suzuki, Yukiko Kajihara, Minami Hatono, Kengo Kawada, Mariko Kochi, Takayuki Iwamoto, Hirokuni Ikeda, Naruto Taira, Hiroyoshi Doihara, Shinichi Toyooka

    Cancer chemotherapy and pharmacology   86 ( 1 )   55 - 63   2020.7

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    PURPOSE: Metformin has been suggested to possibly reduce cancer risk. However, the mechanism underlying the positive effects of metformin on cancer treatment remains unclear. We conducted a prospective study to evaluate the effects of preoperative metformin in patients with early breast cancer. METHOD: We evaluated the effects on immunological factors (TILs, CD4 + , CD8 + , PD-L1, IFNγ and IL-2) by comparing core needle biopsies (CNB) obtained before metformin treatment with surgical specimens. Seventeen patients were enrolled in this prospective study from January to December 2016. We also analyzed 59 patients undergoing surgery during the same period to reveal the correlation of immune factors between CNB and surgical specimen. RESULT: There was a moderate correlation between CNB and surgical specimens on TILs and CD8 + lymphocyte. (TILs Rs = 0.63, CD4 + Rs = 0.224, CD8 + Rs = 0.42) In the metformin group, TILs increases were confirmed in five (29%) patients, while a decrease was confirmed in two (12%). The expressions of CD4 + and CD8 + by TILs were increased in 41% and 18% of surgical specimens, respectively. However, TILs number (p = 0.0554), CD4+ (p = 0.0613) and CD8 + (p = 0.0646) expressions did not significantly increased. Furthermore, IFNγ expression appeared to be increased in response to metformin (p = 0.08). CONCLUSION: Preoperative metformin tends to increase TILs, as well as the numbers of CD4 and CD8 positive lymphocytes, and IFNγ levels. Metformin might improve immune function and have a possibility of chemo-sensitivity and thereby increase the effectiveness of immunotherapy, based on the results of this preliminary study.

    DOI: 10.1007/s00280-020-04092-2

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  • Radiation pneumonitis after definitive concurrent chemoradiotherapy with cisplatin/docetaxel for non-small cell lung cancer: Analysis of dose-volume parameters. International journal

    Kuniaki Katsui, Takeshi Ogata, Kenta Watanabe, Norihisa Katayama, Masahiro Kuroda, Katsuyuki Kiura, Takao Hiraki, Yoshinobu Maeda, Shinichi Toyooka, Susumu Kanazawa

    Cancer medicine   9 ( 13 )   4540 - 4549   2020.7

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    BACKGROUND: Radiation pneumonitis (RP) is a major pulmonary adverse event of chest radiotherapy. The PACIFIC trial that identified durvalumab as an effective subsequent-line therapy after concurrent chemoradiotherapy (CCRT) found that patients with grade 2 or higher RP may have to be excluded from treatment under certain criteria. The purpose of this study was to investigate the relationship between grade ≥2 RP and the parameters of dose-volume histograms after CCRT with cisplatin/docetaxel for stage III non-small cell lung cancer and conduct a subset analysis of severe RP that can lead to the permanent discontinuation of treatment per the PACIFIC trial criteria to help determine treatment strategy. METHODS: We calculated the percentage of the lung volume received at least 5 Gy (V5) and 20 Gy (V20), the mean lung dose (MLD), and the lung volume spared from a 5 Gy dose (VS5) to the total lung volume. Factors affecting the incidence of grade ≥2 RP were identified; severe RP was defined as grade ≥3 as well as grade 2 RP that required ≥10 mg prednisolone for at least 12 weeks. RESULTS: This study included 45 patients. On univariate analysis, all parameters and total lung volume were found to be significant predictors of grade ≥2 RP (P = .001, .003, .03, .004, and .02, respectively). On multivariate analysis, V20 was a significant predictive factor of grade ≥2 RP (P = .007). Severe RP developed in 6 of 37 patients (16.2%) whose V20 values were 35% or lower. On univariate analysis, only V20 was a significant predictor of severe RP in these patients (P = .01). CONCLUSIONS: The best approach to reduce the rate of grade ≥2 RP is to maintain the V5, V20, MLD, and VS5 as low as possible during radiotherapy planning in patients receiving definitive CCRT with cisplatin/docetaxel.

    DOI: 10.1002/cam4.3093

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  • Lung perfusion scintigraphy to detect chronic lung allograft dysfunction after living-donor lobar lung transplantation. Reviewed International journal

    Haruchika Yamamoto, Seiichiro Sugimoto, Takeshi Kurosaki, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Masaomi Yamane, Takahiro Oto, Shinichi Toyooka

    Scientific reports   10 ( 1 )   10595 - 10595   2020.6

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    Because chronic lung allograft dysfunction (CLAD) develops predominantly on one side after bilateral living-donor lobar lung transplantation (LDLLT), lung perfusion scintigraphy (Q-scinti) was expected to show a perfusion shift to the contralateral unaffected lung with the development of CLAD. Our study examined the potential usefulness of Q-scinti in the diagnosis of CLAD after bilateral LDLLT. We conducted a single-center retrospective cohort study of 58 recipients of bilateral LDLLT. The unilateral shift values on Q-scinti were calculated and compared between the CLAD group (N = 27) and the non-CLAD group (N = 31) from 5 years before to 5 years after the diagnosis of CLAD. The unilateral shift values in Q-scinti were significantly higher in the CLAD group than in the non-CLAD group from 5 years before the diagnosis of CLAD to 5 years after the diagnosis (P < 0.05). The unilateral shift values in Q-scinti were significantly correlated with the percent baseline values of the forced expiratory volume in 1 s (P = 0.0037), the total lung capacity (P = 0.0028), and the forced vital capacity (P = 0.00024) at the diagnosis of CLAD. In patients developing unilateral CLAD after bilateral LDLLT, Q-scinti showed a unilateral perfusion shift to the contralateral unaffected lung. Thus, Q-scinti appears to have the potential to predict unilateral CLAD after bilateral LDLLT.

    DOI: 10.1038/s41598-020-67433-4

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  • Clinical impacts of EGFR mutation status: analysis of 5,780 surgically resected lung cancer cases. Reviewed International journal

    Kenichi Suda, Tetsuya Mitsudomi, Yasushi Shintani, Jiro Okami, Hiroyuki Ito, Takashi Ohtsuka, Shinichi Toyooka, Takeshi Mori, Shun-Ichi Watanabe, Hisao Asamura, Masayuki Chida, Hiroshi Date, Shunsuke Endo, Takeshi Nagayasu, Ryoichi Nakanishi, Etsuo Miyaoka, Meinoshin Okumura, Ichiro Yoshino

    The Annals of thoracic surgery   2020.6

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    BACKGROUND: To elucidate the clinical, pathologic, and prognostic impacts of EGFR mutation and mutation subtypes in early-stage lung cancer, we conducted a retrospective analysis of the Japanese Joint Committee of Lung Cancer Registry database (a nationwide database for surgically-resected lung cancer patients; n = 18,973). METHODS: Of 13,951 patients classified as non-squamous non-small cell lung cancer in the database, 5,780 patients (41.0%) had been tested for EGFR mutation and were included in this study. RESULTS: EGFR mutation was detected in 2,410 patients (41.7%), and presence of EGFR mutation was significantly correlated with clinicopathological factors such as the presence of ground-glass opacity (P < 0.001) and better prognosis. Analysis of initial recurrence sites identified significantly higher frequencies of brain and adrenal gland metastases in patients with and without EGFR mutation, respectively. Of 2,410 patients with EGFR mutations, 983 (40.8%) had exon 19 deletion (Exon 19 Del), 1,170 (48.5%) had L858R mutation, and 257 (10.7%) had other EGFR mutations. Higher smoking rate was found in patients with other EGFR mutations (p = 0.02). In the comparison of Exon 19 Del and L858R, we found that Exon 19 Del correlated with younger age (P < 0.001), higher rate of pure solid tumors (P < 0.001), advanced pathological stage (trend P = 0.0004), and poorer recurrence-free survival (P = 0.001). CONCLUSIONS: In addition to clinicopathological and prognostic impacts of EGFR mutation status, tumors with Exon 19 Del have a more aggressive phenotype and poorer prognosis than those with L858R in early-stage lung cancers.

    DOI: 10.1016/j.athoracsur.2020.05.041

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  • MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by ROS1 Fusions. International journal

    Hiroki Sato, Adam J Schoenfeld, Evan Siau, Yue Christine Lu, Huichun Tai, Ken Suzawa, Daisuke Kubota, Allan J W Lui, Besnik Qeriqi, Marissa Mattar, Michael Offin, Masakiyo Sakaguchi, Shinichi Toyooka, Alexander Drilon, Neal X Rosen, Mark G Kris, David Solit, Elisa De Stanchina, Monika A Davare, Gregory J Riely, Marc Ladanyi, Romel Somwar

    Clinical cancer research : an official journal of the American Association for Cancer Research   26 ( 12 )   2932 - 2945   2020.6

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    PURPOSE: ROS1 tyrosine kinase inhibitors (TKI) provide significant benefit in lung adenocarcinoma patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes. EXPERIMENTAL DESIGN: ROS1 fusions were expressed in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) patients treated with ROS1 TKIs, and genetic alterations hypothesized to confer AR were modeled in these cell lines. RESULTS: Eight of the 75 patients with a ROS1 fusion had a concurrent MAPK pathway alteration and this correlated with shorter overall survival. In addition, the induction of ROS1 fusions stimulated activation of MEK/ERK signaling with minimal effects on AKT signaling, suggesting the importance of the MAPK pathway in driving ROS1 fusion-positive cancers. Of 8 patients, 2 patients harbored novel in-frame deletions in MEK1 (MEK1delE41_L54) and MEKK1 (MEKK1delH907_C916) that were acquired after ROS1 TKIs, and 2 patients harbored NF1 loss-of-function mutations. Expression of MEK1del or MEKK1del, and knockdown of NF1 in ROS1 fusion-positive cells activated MEK/ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 and MEK inhibited growth of cells expressing both ROS1 fusion and MEK1del. CONCLUSIONS: We demonstrate that downstream activation of the MAPK pathway can mediate of innate acquired resistance to ROS1 TKIs and that patients harboring ROS1 fusion and concurrent downstream MAPK pathway alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations.

    DOI: 10.1158/1078-0432.CCR-19-3321

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  • Prognostic value of OCT4A and SPP1C transcript variant co-expression in early-stage lung adenocarcinoma. International journal

    Seijiro Koshimune, Mitsuko Kosaka, Nobuhiko Mizuno, Hiromasa Yamamoto, Tomoyuki Miyamoto, Kohta Ebisui, Shinichi Toyooka, Aiji Ohtsuka

    BMC cancer   20 ( 1 )   521 - 521   2020.6

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    BACKGROUND: Octamer-binding transcription factor 4A (OCT4A) is essential for cell pluripotency and reprogramming both in humans and mice. To date, however, the function of human OCT4 in somatic and/or tumour tissues is largely unknown. METHODS: RT-PCR was used to identify full-length splice forms of OCT4 transcripts in normal and cancer cells. A FLAG-tagged OCT4 genomic transgene was used to identify OCT4-positive cancer cells. A potential role for OCT4 in somatic cancer cells was examined by cell ablation of OCT4-positive cells using promoter-driven diphtheria toxin A. OCT4 and secreted phosphoprotein 1 (SPP1) transcripts in early-stage lung adenocarcinoma tumours were analysed and compared with pathohistological features. RESULTS: The results show that, unlike in murine cells, OCT4A and OCT4B variants are transcribed in both human cancer cells and in adult tissues such as lung, kidney, uterus, breast, and eye. We found that OCT4A and SPP1C are co-expressed in highly aggressive human breast, endometrial, and lung adenocarcinoma cell lines, but not in mesothelial tumour cell lines. Ablation of OCT4-positive cells in lung adenocarcinoma cells significantly decreased cell migration and SPP1C mRNA levels. The OCT4A/SPP1C axis was found in primary, early-stage, lung adenocarcinoma tumours. CONCLUSIONS: Co-expression of OCT4 and SPP1 may correlate with cancer aggressiveness, and the OCT4A/SPP1C axis may help identify early-stage high-risk patients with lung adenocarcinoma. Contrary to the case in mice, our data strongly suggest a critical role for OCT4A and SPP1C in the development and progression of human epithelial cancers.

    DOI: 10.1186/s12885-020-06969-0

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  • 気管支断端瘻閉鎖後の治癒経過から考える治療方針

    山本 治慎, 三好 健太郎, 松原 慧, 塩谷 俊雄, 諏澤 憲, 大谷 真二, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本臨床外科学会雑誌   81 ( 6 )   1206 - 1206   2020.6

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  • Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer. Reviewed International journal

    Hirotsugu Kenmotsu, Nobuyuki Yamamoto, Takeharu Yamanaka, Katsuo Yoshiya, Toshiaki Takahashi, Tsuyoshi Ueno, Koichi Goto, Haruko Daga, Norihiko Ikeda, Kenji Sugio, Takashi Seto, Shinichi Toyooka, Hiroshi Date, Tetsuya Mitsudomi, Isamu Okamoto, Kohei Yokoi, Hideo Saka, Hiroaki Okamoto, Yuichi Takiguchi, Masahiro Tsuboi

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology   JCO1902674   2020.5

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    PURPOSE: To evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant chemotherapy in patients with pathologic stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We performed a randomized, open-label, phase III study at 50 institutions within 7 clinical study groups in Japan. Patients with completely resected pathologic stage II-IIIA (TNM 7th edition) nonsquamous NSCLC were randomly assigned to receive either pemetrexed (500 mg/m2, day 1) plus cisplatin (75 mg/m2, day 1) or vinorelbine (25 mg/m2, days 1 and 8) plus cisplatin (80 mg/m2, day 1) with stratification by sex, age, pathologic stage, EGFR mutation, and institution. These treatments were planned to be given every 3 weeks for 4 cycles. The primary end point was recurrence-free survival in the modified intent-to-treat population, excluding ineligible patients. RESULT: Between March 2012 and August 2016, 804 patients were enrolled (402 assigned to vinorelbine plus cisplatin and 402 assigned to pemetrexed plus cisplatin). Of 784 eligible patients, 410 (52%) had stage IIIA disease and 192 (24%) had EGFR-sensitive mutations. At a median follow-up of 45.2 months, median recurrence-free survival was 37.3 months for vinorelbine plus cisplatin and 38.9 months for pemetrexed plus cisplatin, with a hazard ratio of 0.98 (95% CI, 0.81 to 1.20; 1-sided P = .474). Grade 3-4 toxicities reported more frequently for vinorelbine plus cisplatin than for pemetrexed plus cisplatin were febrile neutropenia (11.6% v 0.3%, respectively), neutropenia (81.1% v 22.7%, respectively), and anemia (9.3% v 2.8%, respectively). One treatment-related death occurred in each arm. CONCLUSION: Although this study failed to show the superiority of pemetrexed plus cisplatin for patients with resected nonsquamous NSCLC, this regimen showed a better tolerability as adjuvant chemotherapy.

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  • Antitumor Effects of Pan-RAF Inhibitor LY3009120 Against Lung Cancer Cells Harboring Oncogenic BRAF Mutation. Reviewed International journal

    Shunsaku Miyauchi, Kazuhiko Shien, Tatsuaki Takeda, Kota Araki, Kentaro Nakata, Akihiro Miura, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Ken Suzawa, Hiromasa Yamamoto, Mikio Okazaki, Junichi Soh, Shuta Tomida, Masaomi Yamane, Masakiyo Sakaguchi, Shinichi Toyooka

    Anticancer research   40 ( 5 )   2667 - 2673   2020.5

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    BACKGROUND/AIM: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation. MATERIALS AND METHODS: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments. RESULTS: LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation. CONCLUSION: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.

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  • チームアプローチで実現するゲノム医療と薬剤師の役割 ゲノム医療におけるデータサイエンティストの役割と育成

    冨田 秀太, 森田 瑞樹, 山下 範之, 平沢 晃, 豊岡 伸一

    薬学雑誌   140 ( 5 )   657 - 661   2020.5

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    次世代シークエンサーを用いた遺伝子パネル検査とそのデータ解析はゲノム医療の根幹であるにもかかわらず、その担い手であるデータサイエンティストが極端に不足している。基本的なデータ解析の流れを理解し、解析結果の解釈ができる人材育成が喫緊の課題である。遺伝子パネル検査の流れを概説するとともに、遺伝子変異量(TMB)の概念と遺伝子パネル検査におけるTMBの算出方法について解説した。

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  • チームアプローチで実現するゲノム医療と薬剤師の役割 ゲノム医療におけるデータサイエンティストの役割と育成

    冨田 秀太, 森田 瑞樹, 山下 範之, 平沢 晃, 豊岡 伸一

    薬学雑誌   140 ( 5 )   657 - 661   2020.5

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    次世代シークエンサーを用いた遺伝子パネル検査とそのデータ解析はゲノム医療の根幹であるにもかかわらず、その担い手であるデータサイエンティストが極端に不足している。基本的なデータ解析の流れを理解し、解析結果の解釈ができる人材育成が喫緊の課題である。遺伝子パネル検査の流れを概説するとともに、遺伝子変異量(TMB)の概念と遺伝子パネル検査におけるTMBの算出方法について解説した。

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  • Association between Histological Types and Enhancement of Dynamic CT for Primary Lung Cancer.

    Shogo Fukuma, Takayoshi Shinya, Junichi Soh, Ryuichiro Fukuhara, Nanako Ogawa, Fumiyo Higaki, Takehiro Tanaka, Eiki Ichihara, Takao Hiraki, Shinichi Toyooka, Susumu Kanazawa

    Acta medica Okayama   74 ( 2 )   129 - 135   2020.4

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    The aim of this study was to explore enhancement patterns of different types of primary lung cancers on 2-phase dynamic computed tomography (CT). This study included 217 primary lung cancer patients (141 adenocarcinomas [ADs], 48 squamous cell carcinomas [SCCs], 20 small cell lung carcinomas [SCLCs], and 8 others) who were examined using a 2-phase dynamic scan. Regions of interest were identified and mean enhancement values were calculated. After excluding the 20 SCLCs because these lesions had different clinical stages from the other cancer types, the mean attenuation values and subtractions between phases were compared between types of non-small cell lung carcinomas (NSCLCs) using the Kruskal-Wallis test. Late phase attenuation and attenuation of the late minus unenhanced phase (LMU) of SCCs were significantly higher than those of ADs (p<0.05). To differentiate SCC and AD in the late phase, a threshold of 80.21 Hounsfield units (HU) gave 52.9% accuracy. In LMU, a threshold of 52.16 HU gave 59.3% accuracy. Dynamic lung CT has the potential to aid in differentiating among NSCLC types.

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  • Computed tomography fluoroscopy-guided cutting needle biopsy of pulmonary nodules ≤8 mm: A retrospective study including 117 nodules. International journal

    Yanqing Zhao, Yusuke Matsui, Takao Hiraki, Toshihiro Iguchi, Koji Tomita, Mayu Uka, Hideo Gobara, Shinichi Toyooka, Susumu Kanazawa

    European journal of radiology   125   108903 - 108903   2020.4

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    PURPOSE: To evaluate the diagnostic yield and safety of computed tomography (CT) fluoroscopy-guided cutting needle biopsy (CNB) for pulmonary nodules ≤ 8 mm. METHOD: Data of CT fluoroscopy-guided CNB for pulmonary nodules ≤ 8 mm performed in a single institution were retrospectively analyzed. One hundred and seventeen biopsy procedures for 117 pulmonary nodules (mean size, 7.4 mm) in 114 patients were included in the study. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall diagnostic accuracy were calculated. Univariate analyses were performed to elucidate the risk factors for diagnostic failure (i.e., non-diagnostic, false-positive, or false-negative results). Complications were graded per the Clavien-Dindo Classification. RESULTS: One (0.9 %) non-diagnostic biopsy result was found. The diagnostic accuracy was 95.7 % (112/117). The sensitivity and specificity were 95.8 % (91/95) and 95.5 % (21/22), respectively. PPV and NPV were 98.9 % (91/92) and 87.5 % (21/24), respectively. Univariate analyses showed that nodules in the lower lobes (p = 0.006) and prone biopsy position (p = 0.021) were the significant risk factors for diagnostic failure. The incidence of pneumothorax requiring chest tube placement (Grade IIIa) was 6.8 % (8/117). No Grade IIIb or higher complications were observed. CONCLUSION: CT fluoroscopy-guided CNB for pulmonary nodules ≤ 8 mm showed a high diagnostic yield without severe complications.

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  • Prognostic Nutritional Index Negatively Correlates with Lung Allocation Score and Predicts Survival after Both Cadaveric and Living-Donor Lobar Lung Transplantation

    H. Yamamoto, S. Sugimoto, T. Shiotani, K. Miyoshi, S. Otani, M. Okazaki, M. Yamane, T. Oto, S. Toyooka

    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation   39 ( 4 )   S311   2020.4

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    Copyright © 2020. Published by Elsevier Inc. PURPOSE: The preoperative nutritional status affects the clinical outcome of surgery. To predict the clinical outcome, a prognostic nutritional index (PNI) calculated using serum albumin levels (ALB) and total lymphocyte count (TLC) has been shown to be valuable in various fields of surgery. In this study, we investigated the relationship between PNI and lung allocation score (LAS) as well as the impact of PNI on outcomes of lung transplantation (LT), including cadaveric lung transplantation (CLT) and living-donor lobar lung transplantation (LDLLT). METHODS: Between June 2003 and August 2016, a total of 127 patients underwent LT at Okayama University Hospital, including 71 recipients of CLT and 56 recipients of LDLLT. The PNI was calculated by the following equation: PNI = (10 × ALB(g/dl)+(0.005 × TLC(/mm3)). The overall survival was evaluated by univariate analysis (the log rank test) and multivariate analysis (the Cox proportional hazard regression model) using preoperative factors, including sex, age, BMI, diagnosis, oxygen concentration, mechanical ventilation, tracheostomy, ECMO support, use of glucocorticoids, serum creatinine level, diabetes mellitus, LAS, and PNI. RESULTS: PNI was significantly negatively correlated with LAS (r=-0.3, P=0.00062) (Fig. 1A). The univariate analysis revealed that the overall survival was significantly worse in the patients with age>28 (P=0.047), BMI<24.2 (P=0.0098), LAS>58.04 (P=0.000072), PNI<46.35 (P=0.018) (Fig. 1B). The multivariate analysis demonstrated that age (P=0.00093), BMI (P=0.0024), and PNI (P=0.0047) were independent prognostic factors of worse outcome. In the subgroup analysis, low PNI is a significant prognostic factor of worse survival after CLT (P=0.015) (Fig. 1C) and LDLLT (P=0.041) (Fig. 1D). CONCLUSION: Preoperative nutritional evaluation using PNI could contribute to the assessment of LT recipient's severity and predict survival after both CLT and LDLLT.

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  • Evaluation of Therapeutic Target Gene Expression Based on Residual Cancer Burden Classification After Neoadjuvant Chemotherapy for HER2-Negative Breast Cancer. International journal

    Yuko Takahashi, Takayuki Iwamoto, Yoko Suzuki, Yukiko Kajiwara, Minami Hatono, Takahiro Tsukioki, Kengo Kawada, Mariko Kochi, Hirokuni Ikeda, Tadahiko Shien, Naruto Taira, Junji Matsuoka, Hiroyoshi Doihara, Shinichi Toyooka

    Clinical breast cancer   20 ( 2 )   117 - 124   2020.4

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    INTRODUCTION: Patients with residual disease usually have a poor prognosis after neoadjuvant chemotherapy for breast cancer. The aim of this study was to explore therapeutic targets and potential additional adjuvant treatments for patients with residual disease after standard neoadjuvant chemotherapy. PATIENTS AND METHODS: We retrieved publicly available complementary DNA microarray data from 399 human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer samples from patients who underwent standard neoadjuvant chemotherapy. We analyzed the messenger RNA (mRNA) expression levels of key breast cancer markers and therapeutic target genes according to residual cancer burden (RCB) classification: RCB-0/I, RCB-II, and RCB-III. RESULTS: Among hormone receptor-positive samples, there were more luminal A tumors by PAM50 (Prediction Analysis of Microarray 50 [Prosigna], aka Prosigna Breast Cancer Prognostic Gene Signature Assay) in RCB-III than in RCB-0/I and RCB-II (P < .01). The mRNA expressions of ESR1 and PGR were significantly higher, and that of MKI67 was lower in RCB-II and RCB-III than in RCB-0/I. The mRNA expression of cyclin D1 was up-regulated in RCB-III and that of CDKN2A was down-regulated in RCB-III (P = .027 and < .01). Among triple-negative (TN) samples, RCB-III had higher clinical stage and more lymph node-positive samples than RCB-0/1 and RCB-II (P < .01). In both subtypes, VEGF-C expression was significantly higher in RCB-III than in RCB-0/I and RCB-II. CONCLUSION: In hormone receptor-positive breast cancer, biological features such as luminal A were associated with RCB; this trend was not observed in TN breast cancer. Further, some targeted therapies should be tested as new strategies after standard neoadjuvant chemotherapy in future clinical trials.

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  • Plasma micro-RNA Levels are Associated with the Development of Chronic Lung Allograft Dysfunction after Bilateral Living-Donor and Cadaveric Lung Transplantation

    T. Shiotani, S. Sugimoto, H. Yamamoto, D. Shimizu, K. Miyoshi, S. Otani, M. Okazaki, M. Yamane, T. Oto, S. Toyooka

    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation   39 ( 4 )   S194   2020.4

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    Copyright © 2020. Published by Elsevier Inc. PURPOSE: Micro-RNAs (miRNAs) regulate genes by selectively silencing their target messenger RNAs. Recently, serum levels of miRNA related to pulmonary fibrosis (miR-21 and miR-155), have been shown to be associated with the development of chronic lung allograft dysfunction (CLAD) after cadaveric lung transplantation (CLT). We investigated the relationship between miRNAs levels and CLAD after bilateral living-donor lobar lung transplantation (LDLLT) and CLT. METHODS: Blood samples were collected from a total of 70 patients who underwent bilateral LDLLT (n=39) and bilateral CLT (n=31), including patients with CLAD (the CLAD group, n=25) and those without CLAD (the non-CLAD group, n=45). Plasma miRNA levels (miR-21 and miR-155) were quantified using real-time PCR and compared between the two groups. The relationship between miRNA levels and the results of pulmonary function tests at the onset of CLAD was assessed. Appropriate cut-off values of miRNA levels were set for the diagnosis of CLAD. RESULTS: The median follow-up period was 3074 (1071-7523) days. Plasma miRNA levels of the CLAD group were significantly higher than those of the non-CLAD group (miR-21, P<0.001; miR-155, P=0.013) (Fig. 1). In the CLAD group, miRNA levels after LDLLT were comparable to those after CLT. Moreover, miRNA levels were significantly negatively correlated with the baseline values of forced expiratory volume in 1 second (FEV1) (miR-21, P<0.001; miR-155, P=0.039) and those of total lung cavity (TLC) (miR-21, P<0.001; miR-155, P=0.0012) (Fig. 2). An ROC analysis of the performance of miR-21 level as a marker of CLAD yielded an AUC of 0.94 at a threshold level of 6.51. Patients with miR-21 level≥6.51 showed significantly better CLAD-free survival than those with miR-21 level<6.51 (P<0.001) (Fig. 3). CONCLUSION: Plasma miRNA levels are associated with the development of CLAD after bilateral LDLLT and CLT, and might be a potential biomarker for the diagnosis of CLAD.

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  • CTガイド下生検では診断困難であった肺門部結節影

    松原 慧, 大谷 真二, 高津 史明, 富岡 泰章, 津高 慎平, 山本 治慎, 塩谷 俊雄, 難波 圭, 諏澤 憲, 三好 健太郎, 山本 寛斉, 岡崎 幹雄, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    岡山医学会雑誌   132 ( 1 )   46 - 46   2020.4

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  • Pulmonary resection in a prone position for lung cancer invading the spine. Reviewed

    Shunsaku Miyauchi, Junichi Soh, Kazuhiko Shien, Masato Tanaka, Hiromasa Yamamoto, Toshifumi Ozaki, Shinichi Toyooka

    General thoracic and cardiovascular surgery   68 ( 3 )   298 - 301   2020.3

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    The prone position is usually not selected for pulmonary resection. The intraoperative body position is an important issue in surgery for non-small cell lung cancer invading the spine because the standard intraoperative body position for a vertebrectomy is a prone position, while that for a pulmonary resection is a lateral decubitus position. Intraoperative changes in body position can cause several complications. Using an O-arm with a navigation system, a partial vertebrectomy was completed with the patient in a prone position thanks to the recognition of accurate surgical margins in the vertebral body; then, without changing the patient's body position, a lobectomy with systemic lymph node dissection was performed via a posterior approach. Especially for procedures requiring a wide resection of the chest wall, a prone position can be selected for a lobectomy with systemic lymph node dissection via a posterior approach without any significant difficulties.

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  • Influence of breast density on breast cancer risk: a case control study in Japanese women.

    Keiko Nishiyama, Naruto Taira, Taeko Mizoo, Mariko Kochi, Hirokuni Ikeda, Takayuki Iwamoto, Tadahiko Shien, Hiroyoshi Doihara, Setuko Ishihara, Hiroshi Kawai, Kensuke Kawasaki, Yoichi Ishibe, Yutaka Ogasawara, Shinichi Toyooka

    Breast cancer (Tokyo, Japan)   27 ( 2 )   277 - 283   2020.3

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    BACKGROUND: Mammography is the standard examination for breast cancer screening of woman aged ≥ 40 years. High breast density on mammography indicates that mammary gland parenchyma occupy a high percentage of the breast. The objective of this study was to investigate factors associated with breast density and the risk of high breast density for breast cancer. METHODS: A multicenter case-control study was performed in 530 patients and 1043 controls. Breast density was classified as C1-C4 using the Breast Imaging Reporting and Data System (BI-RADS). Clinical factors were obtained from questionnaires or medical records, and the influence of each factor (breast density, menopausal status, body mass index (BMI), parity, presence or absence of breastfeeding history, age at menarche, age at first birth, and familial history of breast cancer) on breast cancer risk in all patients was calculated as an age-adjusted odds ratio (OR). Multivariate logistic regression analyses were then performed in all patients and in pre- and postmenopausal and BMI-stratified groups using factors with a significant age-adjusted OR as adjustment factors. RESULTS: Age-adjusted ORs for breast cancer were significant for breast density, BMI, parity, and breast feeding, but not for age at menarche, age at first birth, or family history of breast cancer. In multivariate analysis, there was a significant correlation between breast density and breast cancer in postmenopausal women (OR for C1 vs. C2 1.90 [95% CI 1.34-2.70]; C1 vs. C4 2.85 [95% CI 1.10-7.16]). This correlation was also significant in patients in the third BMI quartile (22.3-24.5 kg/m2) (OR for C1 vs. C4 8.76 [95% CI 2.38-42.47]); and fourth BMI quartile (>24.5 kg/m2) (OR for C1 vs. C2 1.92 [95% CI 1.17-3.15]; C1 vs. C4 11.89 [95% CI 1.56-245.17]). CONCLUSION: Breast density on mammography is a risk factor for breast cancer after adjustment for other risk factors. This risk is particularly high in postmenopausal women and those with a high BMI.

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  • Embolization using hydrogel-coated coils for pulmonary arteriovenous malformations. Reviewed International journal

    T Iguchi, T Hiraki, Y Matsui, H Fujiwara, J Sakurai, K Baba, S Toyooka, H Gobara, S Kanazawa

    Diagnostic and interventional imaging   101 ( 3 )   129 - 135   2020.3

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    PURPOSE: To prospectively evaluate the efficacy and safety of embolization using hydrogel-coated coils for the treatment of pulmonary arteriovenous malformations (PAVMs). MATERIALS AND METHODS: The outcomes of 21 PAVMs in 19 patients (3 men and 16 women; mean age, 58.8±15.2 [SD] years; age range 14-78 years) treated by venous sac embolization (VSE) with additional feeding artery embolization were prospectively evaluated. For VSE, using one or more 0.018-inch hydrogel-coated coils was mandatory. Recanalization and/or reperfusion were evaluated by pulmonary arteriography 1 year after embolization. RESULTS: The mean feeding artery and venous sac sizes were 4.0mm and 8.5mm, respectively. Embolization was successfully completed in 20/21 PAVMs, yielding a technical success rate of 95%. The feeding artery was also embolized in 17/20 successful PAVMs (85%). A technical failure occurred in one PAVM, where embolization was abandoned because of migration of one bare coil to the left ventricle. The mean numbers of hydrogel-coated coils and bare platinum detachable coils used for VSE were 3.3±2.1 (SD) (range, 1-8) and 4.4±3.9 (SD) (range, 1-17), respectively. The mean percentages of hydrogel-coated coils in number, length, and estimated volume were 42.9%, 33.3%, and 72.7% respectively. One patient with one PAVM was lost to follow-up after 3 months. Neither recanalization nor reperfusion was noted in the remaining 19 PAVMs (success rate, 19/19 [100%]). One grade 4 (coil migration) adverse event occurred, and it was treated without any sequelae. CONCLUSION: VSE using hydrogel-coated coils with additional feeding artery embolization is a safe and effective treatment for PAVM.

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  • Right single lung transplantation using an inverted left donor lung: interposition of pericardial conduit for pulmonary venous anastomosis - a case report. Reviewed International journal

    Haruchika Yamamoto, Kentaroh Miyoshi, Shinji Otani, Takeshi Kurosaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka, Motomu Kobayashi, Takahiro Oto

    BMC pulmonary medicine   20 ( 1 )   46 - 46   2020.2

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    BACKGROUND: Lung transplantation (LTx) is still limited by the shortage of suitable donor lungs. Developing flexible surgical procedures can help to increase the chances of LTx by unfolding recipient-to-donor matching options based on the pre-existing organ allocation concept. We report a case in which a successful left-to-right inverted LTx was completed using the interposition of a pericardial conduit for pulmonary venous anastomosis. CASE PRESENTATION: A left lung graft was offered to a 59-year-old male who had idiopathic pulmonary fibrosis with predominant damage in the right lung. He had been prescribed bed rest with constant oxygen inhalation through an oxymizer pendant and had been on the waiting list for 20 months. Considering the condition of the patient (LAS 34.3) and the scarcity of domestic organ offers, the patient was highly likely to be incapable of tolerating any additional waiting time for another donor organ if he was unable to accept the presently reported offer of a left lung. Eventually, we decided to transplant the left donor lung into the right thorax of the recipient. Because of the anterior-posterior position gap of the hilar structures, the cuff lengths of the pulmonary veins had to be adjusted. The patient did not develop any anastomotic complications after the transplantation. CONCLUSIONS: A left-to-right inverted LTx is technically feasible using an autologous pericardial conduit for pulmonary venous anastomosis in selected cases. This technique provides the potential benefit of resolving challenging situations in which surgeons must deal with a patient's urgency and the logistical limitations of organ allocation.

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  • A Surgical Instructor Training Course for the Next Generation. Reviewed

    Masaomi Yamane, Yasuhiro Mandai, Hideo Ino, Akihiro Matsukawa, Shinichi Toyooka

    Acta medica Okayama   74 ( 1 )   73 - 76   2020.2

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    In 2016, Gunma University Hospital's Medical Accident Investigation Committee released a report reiterating the necessity of medical education and the need for surgeons to master non-technical skills. We designed a 17-h training course for surgical instructors, designed to teach participants how to sufficiently educate surgeon trainees and encourage their professional identity formation. A post-training survey showed that participants improved their awareness, and their behavioral changes led to favorable team performances. We then began offering a 3-h workshop focusing on the participants' experiences. We propose that the training course using participant narratives is required and effective to establish surgeons' self-reflection and professional identity as surgeons.

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  • 肺内Solitary fibrous tumorの1例

    三道 幹大, 正岡 佳久, 岡本 聡一郎, 小河 七子, 福原 隆一郎, 田中 高志, 稲井 良太, 松井 裕輔, 新家 崇義, 金澤 右, 田中 健大, 大谷 真二, 豊岡 伸一

    Japanese Journal of Radiology   38 ( Suppl. )   72 - 72   2020.2

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  • DV200 index for assessing RNA integrity in next-generation sequencing Reviewed International journal

    Takehiro Matsubara, Junichi Soh, Mizuki Morita, Takahiro Uwabo, Shuta Tomida, Toshiyoshi Fujiwara, Susumu Kanazawa, Shinichi Toyooka, Akira Hirasawa

    BioMed Research International   2020   9349132   2020.2

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    DOI: 10.1155/2020/9349132

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  • Pulmonary aspergillosis as a late complication after surgery for locally advanced non-small cell lung cancer treated with induction chemoradiotherapy. Reviewed

    Seiichiro Sugimoto, Junichi Soh, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Masaomi Yamane, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Shinichi Toyooka

    Surgery today   2020.1

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    PURPOSE: Some long-term survivors after surgery for locally advanced non-small cell lung cancer (NSCLC) treated with induction chemoradiotherapy (trimodality treatment) develop chronic pulmonary aspergillosis (CPA). The aim of our study was to assess the characteristics and outcomes of CPA that develops after trimodality treatment. METHODS: We retrospectively reviewed the data of 187 NSCLC patients who underwent trimodality treatment between 1999 and 2018. RESULTS: Six male ever-smoker patients developed CPA. All 6 patients had undergone extended resection for NSCLC and had a history of either adjuvant chemotherapy (n = 3) or radiation pneumonitis (n = 4). Among the 4 patients with CPA localized in a single lung, 3 patients were treated surgically (completion pneumonectomy or cavernostomy) and 1 patient was treated with antifungal therapy alone. Both treatments led to the improved control of CPA. In contrast, patients with CPA in both lungs were not candidates for surgery, and died of CPA. The survival rates after trimodality treatment in the CPA group and the group without CPA were comparable (10-year survival rate, 50.0% vs. 57.6%, P = 0.59). CONCLUSION: The early diagnosis of CPA localized in a single lung after NSCLC surgery is critical to improving control and survival in patients with CPA.

    DOI: 10.1007/s00595-020-01960-5

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  • [Training Medical Staff with Basic Skills for Data Science in Genomic Medicine].

    Shuta Tomida, Mizuki Morita, Noriyuki Yamashita, Akira Hirasawa, Shinichi Toyooka

    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan   140 ( 5 )   657 - 661   2020

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    The development of specialized training programs for medical personnel, particularly nurses, clinical laboratory technicians, and pharmacists, is considered critical for the promotion of genomic medicine throughout Japan. Specifically, medical personnel skilled at analyzing and understanding high-throughput genomic data are in high demand. In this symposium, we will introduce the basic knowledge and skills necessary for processing genomic data.

    DOI: 10.1248/yakushi.19-00217-2

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  • Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. International journal

    H Yoshioka, M Shimokawa, T Seto, S Morita, Y Yatabe, I Okamoto, J Tsurutani, M Satouchi, T Hirashima, S Atagi, K Shibata, H Saito, S Toyooka, N Yamamoto, K Nakagawa, T Mitsudomi

    Annals of oncology : official journal of the European Society for Medical Oncology   30 ( 12 )   1978 - 1984   2019.12

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    BACKGROUND: Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data. PATIENTS AND METHODS: Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan-Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model. RESULTS: OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 [95% confidence interval (CI): 0.883-1.775, P = 0.2070]. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312-0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively. CONCLUSION: G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.

    DOI: 10.1093/annonc/mdz399

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  • YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers. Reviewed

    Takeda T, Yamamoto H, Suzawa K, Tomida S, Miyauchi S, Araki K, Nakata K, Miura A, Namba K, Shien K, Soh J, Shien T, Kitamura Y, Sendo T, Toyooka S

    Cancer science   2019.12

  • Airway bacteria of the recipient but not the donor are relevant to post-lung transplant pneumonia. Reviewed

    Konishi Y, Miyoshi K, Kurosaki T, Otani S, Sugimoto S, Yamane M, Oto T, Toyooka S

    General thoracic and cardiovascular surgery   2019.12

  • Negative impact of recipient SPRED2 deficiency on transplanted lung in a mouse model. Reviewed

    Hashimoto K, Yamane M, Sugimoto S, Hirano Y, Kurosaki T, Otani S, Miyoshi K, Ohara T, Okazaki M, Yoshimura T, Oto T, Matsukawa A, Toyooka S

    Transplant immunology   57   101242   2019.12

  • N2非小細胞肺癌に対する外科治療

    杉本 誠一郎, 豊岡 伸一

    肺癌   59 ( 7 )   1129 - 1133   2019.12

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    N2陽性の非小細胞肺癌では、局所の制御を目的とした放射線治療や手術と、遠隔転移の制御を目的とした化学療法を組み合わせた集学的治療が行われてきた。N2非小細胞肺癌に対する導入療法後手術の有用性が示唆されていたが、第III相試験では、根治的化学放射線療法と比較した導入療法後手術の優越性は証明されていないのが現状である。しかし、切除可能なN2非小細胞肺癌で、特に肺葉切除術が可能な場合には、導入化学放射線療法後の手術の有用性が示唆されており、治療の選択肢として考慮すべきである。また、最近では新しい治療薬として免疫チェックポイント阻害剤が登場し、切除不能III期非小細胞肺癌に対して、化学放射線療法との逐次併用による有用性が示され、治療の選択肢が増えている。本稿では、N2非小細胞肺癌に対する導入療法後手術の臨床試験を概説し、当院における導入放射線化学療法後手術の周術期管理や手術の工夫を述べるとともに、今後の展望について述べる。(著者抄録)

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01244&link_issn=&doc_id=20200109370001&doc_link_id=130007775582&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130007775582&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

  • Dose-volume parameters predict radiation pneumonitis after induction chemoradiotherapy followed by surgery for non-small cell lung cancer: a retrospective analysis. International journal

    Kuniaki Katsui, Takeshi Ogata, Kenta Watanabe, Norihisa Katayama, Junichi Soh, Masahiro Kuroda, Katsuyuki Kiura, Yoshinobu Maeda, Shinichi Toyooka, Susumu Kanazawa

    BMC cancer   19 ( 1 )   1144 - 1144   2019.11

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    BACKGROUND: The relationship between lung dose-volume histogram (DVH) parameters and radiation pneumonitis (RP) associated with induction concurrent chemoradiotherapy (CCRT) followed by surgery in patients with non-small cell lung cancer (NSCLC) is unclear, particularly when concerning irradiation of the whole lung prior to resection. We performed this study to identify factors associated with grade ≥ 2 RP in such patients. METHODS: Patients who received induction CCRT (chemotherapy: cisplatin and docetaxel; radiotherapy: 46 Gy/23 fractions) between May 2003 and May 2017 were reviewed. The mean lung dose (MLD) and the percentage of the lung volume that received ≥5 Gy (V5) and ≥ 20 Gy (V20) were calculated. Factors associated with the development of grade ≥ 2 RP were analyzed. RESULTS: One hundred and eight patients were included in this study, 34 (31.5%) of whom experienced grade ≥ 2 RP. A V20 ≥ 21%, an MLD ≥10 Gy, and a lower lobe tumor location were significant predictors of grade ≥ 2 RP on univariate analysis (p = 0.007, 0.002, and 0.004, respectively). Moreover, an MLD ≥10 Gy and lower lobe location were significant predictors of grade ≥ 2 RP on multivariate analysis (p = 0.026 and 0.0043, respectively). The cumulative incidence rates of grade ≥ 2 RP at 6 months were 15.7 and 45.6% in patients with MLDs < 10 Gy and ≥ 10 Gy, respectively, and were 23.5 and 55.6% in patients with upper/middle lobe- vs. lower lobe-located tumors, respectively. CONCLUSIONS: MLD and lower lobe location were predictors of grade ≥ 2 RP in patients who received induction CCRT. It is necessary to reduce the MLD to the greatest extent possible to prevent the occurrence of this adverse event.

    DOI: 10.1186/s12885-019-6359-9

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  • Impact of pathological stage and histological subtype on clinical outcome of adjuvant chemotherapy of paclitaxel plus carboplatin versus oral uracil-tegafur for non-small cell lung cancer: subanalysis of SLCG0401 trial.

    Junichi Soh, Shinichi Toyooka, Norihito Okumura, Hiroshige Nakamura, Masao Nakata, Motohiro Yamashita, Junichi Sakamoto, Motoi Aoe, Katsuyuki Hotta, Satoshi Morita, Hiroshi Date

    International journal of clinical oncology   24 ( 11 )   1367 - 1376   2019.11

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    BACKGROUND: Pathological stage (pStage) and histological subtype are strong determinants of the treatment strategy for non-small cell lung cancer (NSCLC). Setouchi Lung Cancer study Group (SLCG) recently reported the results of a multicenter trial (SLCG0401) indicating that paclitaxel plus carboplatin (CBDCA/PTX) as adjuvant chemotherapy does not yield better survival than uracil-tegafur (UFT) in NSCLC patients with pStage IB-IIIA disease, while stratified analyses considering the pStage and histological subtype have not been performed. METHODS: We reanalyzed the overall survival (OS) and relapse-free survival (RFS) in 402 patients who had been randomly assigned to receive CBDCA/PTX or UFT by multivariate analysis with adjustments for the pStage and histological subtype. RESULTS: There were no significant differences in the OS or RFS between the two treatment settings either in the entire cohort (n = 402) and in some of subsets: pStage IB (n = 228), pStage II (n = 117), adenocarcinoma (AD, n = 265), and squamous cell carcinoma (SQ, n = 101). In pStage IIIA patients (n = 57), CBDCA/PTX yielded superior RFS to UFT [hazard ratio (HR) 0.44; P = 0.016]. Among the patients with non-AD and non-SQ histology (n = 36), UFT yielded both superior OS and RFS to CBDCA/PTX (HRs 0.16 and 0.23; P = 0.046 and 0.011, respectively). CONCLUSIONS: There are subsets of patients in which one or the other between UFT and CBDCA/PTX is significantly more effective. Selection of adjuvant therapy for NSCLC patients needs to be made taking into consideration the pStage and histological subtype.

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  • Favorable survival even with high disease-specific complication rates in lymphangioleiomyomatosis after lung transplantation - long-term follow-up of a Japanese center. Reviewed

    Kurosaki T, Otani S, Miyoshi K, Okazaki M, Sugimoto S, Suno M, Yamane M, Kobayashi M, Oto T, Toyooka S

    The clinical respiratory journal   2019.11

  • 臨床的疑問より発した研究-Reverse translational research High tumor mutation burdenのALK陽性肺癌におけるアレクチニブ早期耐性について

    槇本 剛, 大橋 圭明, 冨田 秀太, 二宮 貴一朗, 久保 寿夫, 頼 冠名, 市原 英基, 堀田 勝幸, 田端 雅弘, 豊岡 伸一, 木浦 勝行

    肺癌   59 ( 6 )   571 - 571   2019.11

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  • Warm retrograde perfusion can remove more fat from lung grafts with fat embolism in a porcine model. Reviewed

    Irie M, Otani S, Kurosaki T, Tanaka S, Ohki T, Miyoshi K, Sugimoto S, Yamane M, Oto T, Toyooka S

    General thoracic and cardiovascular surgery   2019.11

  • c-I期非小細胞肺癌における予後因子としてのスリガラス様陰影 第7次全国肺癌登録

    朝倉 啓介, 新谷 康, 岡見 次郎, 奥村 明之進, 伊藤 宏之, 大塚 崇, 豊岡 伸一, 森 毅, 渡辺 俊一, 伊達 洋至, 横井 香平, 淺村 尚生, 永安 武, 宮岡 悦良, 吉野 一郎, 肺癌登録合同委員会

    肺癌   59 ( 6 )   696 - 696   2019.11

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  • Bリンパ球過形成を伴う小結節性胸腺腫瘍の1切除例

    上山 廉起, 岡崎 幹生, 塩谷 俊雄, 諏澤 憲, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   59 ( 6 )   923 - 923   2019.11

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  • 肺癌との鑑別が困難であった肺結節性リンパ過形成の1例

    富岡 泰章, 山本 寛斉, 松原 慧, 山本 治慎, 塩谷 俊雄, 難波 圭, 諏澤 憲, 三好 健太郎, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   59 ( 6 )   878 - 878   2019.11

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  • サルベージ治療・オリゴ再発に対する局所治療戦略 術前化学放射線療法後手術を行った局所進行肺癌術後再発症例の臨床経過

    諏澤 憲, 枝園 和彦, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   59 ( 6 )   586 - 586   2019.11

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  • 腹臥位による後方アプローチ併用ロボット支援下ダンベル型神経鞘腫摘出術

    岡崎 幹生, 諏澤 憲, 塩谷 俊雄, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   59 ( 6 )   745 - 745   2019.11

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  • 定型カルチノイドを伴うびまん性特発性肺神経内分泌過形成の1例

    富岡 泰章, 山本 寛斉, 松原 慧, 山本 治慎, 塩谷 俊雄, 難波 圭, 諏澤 憲, 三好 健太郎, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   59 ( 6 )   878 - 878   2019.11

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  • 肉腫多発肺転移に対する肺切除術

    山本 寛斉, 諏澤 憲, 三好 健太郎, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   59 ( 6 )   684 - 684   2019.11

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  • 頭頸部癌治療歴を有する非小細胞肺がん患者に対する手術症例の検討

    高津 史明, 諏澤 憲, 枝園 和彦, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   59 ( 6 )   711 - 711   2019.11

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  • 完全切除II-IIIA期の非扁平上皮非小細胞肺癌に対するPEM/CDDPとVNR/CDDPを比較する第III相試験(JIPANG)

    駄賀 晴子, 釼持 広知, 山本 信之, 山中 竹春, 岡本 勇, 光冨 徹哉, 瀬戸 貴司, 杉尾 賢二, 豊岡 伸一, 伊達 洋至, 坂 英雄, 横井 香平, 岡本 浩明, 滝口 裕一, 坪井 正博, JIPANG運営委員会

    肺癌   59 ( 6 )   594 - 594   2019.11

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  • 非小細胞肺癌II/IIIA期における術後CBDCA+S-1とS-1維持の忍容性試験SLCG1001 長期予後と分子マーカーの解析

    吉岡 弘鎮, 尾瀬 功, 奥村 典仁, 園部 誠, 中村 廣繁, 岡部 和倫, 片岡 正文, 山下 素弘, 中田 昌男, 片岡 和彦, 山下 芳典, 沖田 千佳, 能登原 憲司, 宗 淳一, 堀田 勝幸, 松尾 恵太郎, 坂本 純一, 山本 寛斉, 豊岡 伸一, 伊達 洋至

    肺癌   59 ( 6 )   747 - 747   2019.11

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  • 人生100年時代の肺がん治療 外科医の立場から

    宗 淳一, 富沢 健二, 武本 智樹, 小原 秀太, 藤野 智大, 古賀 教将, 西野 将矢, 濱田 顕, 千葉 眞人, 須田 健一, 杉本 誠一郎, 豊岡 伸一, 光冨 徹哉

    肺癌   59 ( 6 )   853 - 853   2019.11

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  • 肺門部浸潤肺癌手術例の検討 多施設共同データ結果

    山下 素弘, 豊岡 伸一, 伊達 洋至, 奥村 仁典, 中村 宏繁, 岡部 和倫, 牧 祐歩, 宗 淳一

    肺癌   59 ( 6 )   742 - 742   2019.11

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  • SPECT/CTを用いて切除範囲を評価した左肺底動脈大動脈起始症の1例

    山本 諒, 杉本 誠一郎, 中田 憲太郎, 塩谷 俊雄, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 山根 正修, 大藤 剛宏, 豊岡 伸一, 末澤 孝徳

    肺癌   59 ( 5 )   509 - 509   2019.10

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  • 新規臨床試験最新情報 完全切除非扁平上皮非小細胞肺癌に対する術後補助化学療法第III相試験 JIPANG試験

    上野 剛, 釼持 広知, 山本 信之, 山中 竹春, 杉尾 賢二, 瀬戸 貴司, 豊岡 伸一, 伊達 洋至, 光冨 徹哉, 岡本 勇, 横井 香平, 坂 英雄, 岡本 浩明, 滝口 裕一, 坪井 正博

    日本癌治療学会学術集会抄録集   57回   SSY14 - 2   2019.10

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  • Correction to: Risk assessments for broncho-pleural fistula and respiratory failure after lung cancer surgery by National Clinical Database Japan. Reviewed

    Endo S, Ikeda N, Kondo T, Nakajima J, Kondo H, Shimada Y, Sato M, Toyooka S, Okada Y, Sato Y, Yoshino I, Okada M, Okumura M, Chida M, Fukuchi E, Miyata H

    General thoracic and cardiovascular surgery   67 ( 10 )   904 - 906   2019.10

  • バイオバンクでの長期保存生体試料の品質管理標準化のための予備的検討

    山本 英喜, 松原 岳大, 森田 瑞樹, 冨田 秀太, 豊岡 伸一, 平沢 晃

    臨床病理   67 ( 補冊 )   283 - 283   2019.10

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  • 非小細胞肺癌におけるモネンシン併用療法によるEMT関連薬剤耐性の克服(Overcoming EMT-mediated drug resistance with Monensin-based combined therapy in non-small cell lung cancer)

    大智 宏祐, 諏澤 憲, 冨田 秀太, 荒木 恒太, 宮内 俊策, 三浦 章博, 武田 達明, 難波 圭, 枝園 和彦, 山本 寛斉, 岡崎 幹生, 枝園 忠彦, 豊岡 伸一

    日本癌学会総会記事   78回   P - 1139   2019.9

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  • ドナー胸腔内所見により再斡旋によるレシピエント変更後に肺移植を行った1例

    松原 慧, 大谷 真二, 山本 治慎, 塩谷 俊雄, 難波 圭, 二萬 英斗, 諏澤 憲, 三好 健太郎, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    移植   54 ( 総会臨時 )   315 - 315   2019.9

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  • ネラチニブ耐性乳がんにおけるYES1の重要性(The importance of YES1 in neratinib-resistant breast cancer)

    武田 達明, 山本 寛斉, 諏澤 憲, 北村 佳久, 千堂 年昭, 豊岡 伸一

    日本癌学会総会記事   78回   P - 3157   2019.9

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  • 肺移植後移植片慢性機能不全の予防と治療-本邦における肺移植開始後20年での現状- 肺移植後移植片慢性機能不全(CLAD)における血中micro-RNA発現量の検討 Reviewed

    塩谷 俊雄, 杉本 誠一郎, 松原 慧, 山本 治慎, 二萬 英斗, 三好 健太郎, 大谷 真二, 岡崎 幹生, 山根 正修, 大藤 剛宏, 豊岡 伸一

    移植   54 ( 総会臨時 )   189 - 189   2019.9

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  • 生体・脳死肺移植における予後予測因子としてのPrognostic Nutrition Index(PNI)の有用性 Reviewed

    山本 治慎, 杉本 誠一郎, 塩谷 俊雄, 三好 健太郎, 大谷 真二, 岡崎 幹生, 山根 正修, 大藤 剛宏, 豊岡 伸一

    移植   54 ( 総会臨時 )   215 - 215   2019.9

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  • ハイリスク症例に対する肺移植 高度の胸膜癒着を認めたレシピエントに対する肺移植 Reviewed

    杉本 誠一郎, 塩谷 俊雄, 山本 治慎, 大河 知世, 三好 健太郎, 大谷 真二, 岡崎 幹生, 山根 正修, 大藤 剛宏, 豊岡 伸一

    移植   54 ( 総会臨時 )   174 - 174   2019.9

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  • 妊婦に合併した縦隔成熟奇形腫に対して手術を行った1例

    宮内 俊策, 枝園 和彦, 宗 淳一, 山本 寛斉, 山根 正修, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 6 )   624 - 628   2019.9

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    縦隔成熟奇形腫は無症状で検診発見されることが多いが、時に急速に増大することがある。今回我々は、妊婦に合併し急速に増大したため妊娠中に手術を施行した症例を経験した。症例は27歳、女性。検診で胸部異常陰影を指摘され当科受診となった。初診時、患者は妊娠10週の妊婦であった。胸部X線写真で右上肺野中枢側に8cm大の腫瘤影、単純MRIで前縦隔に10cm大の多房性嚢胞性病変を認め、成熟奇形腫が疑われた。右前胸部痛が出現しており、腫瘍の急速な増大が考えられ手術の方針とした。手術は妊娠15週に胸骨正中切開で縦隔腫瘍摘出術、右肺上葉・心膜合併部分切除術を施行した。腫瘍は成熟奇形腫の診断で未熟成分や悪性所見は認めなかった。術後経過は良好で、妊娠40週で正常分娩に至った。妊娠と急速増大との因果関係は不明であるが、本症例のような場合でも術前検査や手術時期・方法に注意すれば妊娠中でも安全に手術が行えると考える。(著者抄録)

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  • Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts. Reviewed International journal

    Yosuke Mitsui, Nahoko Tomonobu, Masami Watanabe, Rie Kinoshita, I Wayan Sumardika, Chen Youyi, Hitoshi Murata, Ken-Ichi Yamamoto, Takuya Sadahira, Acosta Gonzalez Herik Rodrigo, Hitoshi Takamatsu, Kota Araki, Akira Yamauchi, Masahiro Yamamura, Hideyo Fujiwara, Yusuke Inoue, Junichiro Futami, Ken Saito, Hidekazu Iioka, Eisaku Kondo, Masahiro Nishibori, Shinichi Toyooka, Yasuhiko Yamamoto, Yasutomo Nasu, Masakiyo Sakaguchi

    Oncology research   27 ( 8 )   945 - 956   2019.8

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    S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11-RAGE-TPL2-COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

    DOI: 10.3727/096504019X15555408784978

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  • Acquired resistance mechanisms to afatinib in HER2-amplified gastric cancer cells. Reviewed International journal

    Takahiro Yoshioka, Kazuhiko Shien, Tatsuaki Takeda, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Hidejiro Torigoe, Hiroki Sato, Shuta Tomida, Hiromasa Yamamoto, Junichi Soh, Toshiyoshi Fujiwara, Shinichi Toyooka

    Cancer science   110 ( 8 )   2549 - 2557   2019.8

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    Cancer treatment, especially that for breast and lung cancer, has entered a new era and continues to evolve, with the development of genome analysis technology and the advent of molecular targeted drugs including tyrosine kinase inhibitors. Nevertheless, acquired drug resistance to molecular targeted drugs is unavoidable, creating a clinically challenging problem. We recently reported the antitumor effect of a pan-HER inhibitor, afatinib, against human epidermal growth factor receptor 2 (HER2)-amplified gastric cancer cells. The purpose of the present study was to identify the mechanisms of acquired afatinib resistance and to investigate the treatment strategies for HER2-amplified gastric cancer cells. Two afatinib-resistant gastric cancer cell lines were established from 2 HER2-amplified cell lines, N87 and SNU216. Subsequently, we investigated the molecular profiles of resistant cells. The activation of the HER2 pathway was downregulated in N87-derived resistant cells, whereas it was upregulated in SNU216-derived resistant cells. In the N87-derived cell line, both MET and AXL were activated, and combination treatment with afatinib and cabozantinib, a multikinase inhibitor that inhibits MET and AXL, suppressed the cell growth of cells with acquired resistance both in vitro and in vivo. In the SNU216-derived cell line, YES1, which is a member of the Src family, was remarkably activated, and dasatinib, a Src inhibitor, exerted a strong antitumor effect in these cells. In conclusion, we identified MET and AXL activation in addition to YES1 activation as novel mechanisms of afatinib resistance in HER2-driven gastric cancer. Our results also indicated that treatment strategies targeting individual mechanisms of resistance are key to overcoming such resistance.

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  • Impact of chronic lung allograft dysfunction, especially restrictive allograft syndrome, on the survival after living-donor lobar lung transplantation compared with cadaveric lung transplantation in adults: a single-center experience. Reviewed

    Seiichiro Sugimoto, Haruchika Yamamoto, Takeshi Kurosaki, Shinji Otani, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka, Takahiro Oto

    Surgery today   49 ( 8 )   686 - 693   2019.8

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    PURPOSE: The differences in chronic lung allograft dysfunction (CLAD) between living-donor lobar lung transplantation (LDLLT) and cadaveric lung transplantation (CLT) remain unclear. We conducted this study to compare the impact of CLAD on the outcomes after LDLLT vs. CLT. METHODS: We conducted a retrospective review of the data of 97 recipients of bilateral lung transplantation, including 51 recipients of LDLLT and 46 recipients of CLT. RESULTS: The CLAD-free survival and overall survival after LDLLT were similar to those after CLT. CLAD and restrictive allograft syndrome (RAS), but not bronchiolitis obliterans syndrome (BOS), developed significantly later after LDLLT than after CLT (p = 0.015 and p = 0.035). Consequently, patients with CLAD and RAS, but not those with BOS, after LDLLT had a significantly better overall survival than those after CLT (p = 0.037 and p = 0.0006). Furthermore, after the diagnosis of CLAD, the survival of patients with RAS after LDLLT tended to be better than that after CLT (p = 0.083). CONCLUSION: CLAD, especially RAS, appears to develop later after LDLLT than after CLT and seems to have a lower impact on the overall survival after LDLLT than that after CLT.

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  • 災害ボランティア活動に参加した喘息患者の血痰精査中に発見された右胸部異常陰影の一例

    鹿谷 芳伸, 黒崎 毅史, 大谷 真二, 中田 憲太郎, 難波 圭, 諏澤 憲, 枝園 和彦, 久保 寿夫, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 宗 淳一, 山根 正修, 大藤 剛宏, 豊岡 伸一

    岡山医学会雑誌   131 ( 2 )   113 - 113   2019.8

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  • IB〜IIIA期肺癌切除例に対するCBDCA/PTXとUFTによる術後補助療法のランダム化比較試験(SLCG0401試験)の病期・組織型別のサブ解析

    宗 淳一, 豊岡 伸一, 奥村 典仁, 中村 廣繁, 中田 昌男, 山下 素弘, 青江 基, 堀田 勝幸, 吉岡 弘鎮, 伊達 洋至, 森田 智視

    肺癌   59 ( 4 )   425 - 425   2019.8

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  • Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis. Reviewed International journal

    Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    International journal of cancer   145 ( 2 )   569 - 575   2019.7

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    The metastatic dissemination of cancer cells to remote areas of the body is the most problematic aspect in cancer patients. Among cancers, melanomas are notoriously difficult to treat due to their significantly high metastatic potential even during early stages. Hence, the establishment of advanced therapeutic approaches to regulate metastasis is required to overcome the melanoma disease. An accumulating mass of evidence has indicated a critical role of extracellular S100A8/A9 in melanoma distant metastasis. Lung S100A8/A9 is induced by melanoma cells from distant organs and it attracts these cells to its enriched lung environment since melanoma cells possess several receptors that sense the S100A8/A9 ligand. We hence aimed to develop a neutralizing antibody against S100A8/A9 that would efficiently block melanoma lung metastasis. Our protocol provided us with one prominent antibody, Ab45 that efficiently suppressed not only S100A8/A9-mediated melanoma mobility but also lung tropic melanoma metastasis in a mouse model. This prompted us to make chimeric Ab45, a chimera antibody consisting of mouse Ab45-Fab and human IgG2-Fc. Chimeric Ab45 also showed significant inhibition of the lung metastasis of melanoma. From these results, we have high hopes that the newly produced antibody will become a potential biological tool to block melanoma metastasis in future clinical settings.

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  • Tumour size determines both recurrence-free survival and disease-specific survival after surgical treatment for thymoma. Reviewed International journal

    Meinoshin Okumura, Ichiro Yoshino, Motoki Yano, Shun-Ichi Watanabe, Masahiro Tsuboi, Kazuo Yoshida, Hiroshi Date, Kohei Yokoi, Jun Nakajima, Shin-Ichi Toyooka, Hisao Asamura, Etsuo Miyaoka

    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery   56 ( 1 )   174 - 181   2019.7

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    OBJECTIVES: The tumour, node and the metastasis (TNM) staging system for thymic epithelial tumours was adopted by the Union for International Cancer Control (UICC) in 2016. Although the T factor is defined by the invasive nature of a thymoma, tumour size is not considered. The aim of this study was to examine the clinical importance of tumour size using a nationwide retrospective database of cases treated from 1991 to 2010 compiled by the Japanese Association for Research of the Thymus. METHODS: Tumour size was evaluated by the maximum diameter shown by computed tomography imaging prior to resection. Tumour size was available for 2083 thymoma patients undergoing upfront surgical treatment. The tumour size ranged from 0.6 to 19.4 cm (mean 5.1 cm, median 4.9 cm). Harrell's C-index was adopted to determine the cut-off value of the tumour size in 0.5-cm increments. RESULTS: The highest C-index value (0.7760) was obtained in terms of recurrence-free survival after the complete resection when the cut-off value was set at 5.0 cm. The 10-year recurrence-free survival rate was 93.8% in patients with a tumour ≤5.0 cm and 84.3% in patients with a tumour >5.0 cm (P < 0.0001). The highest C-index value (0.8885) in terms of disease-specific survival was obtained when the cut-off value was set at 8.0 cm. The 10-year disease-specific survival rate was 98.8% in patients with a tumour <8.0 cm and 90.1% in those with a tumour ≥8.0 cm (P < 0.0001). The Cox's proportional hazard model analysis showed that the tumour size and the TNM-based pathological stage were independent factors to determine both recurrence-free survival and disease-specific survival. CONCLUSIONS: Tumour size is an important prognostic factor and should be considered when determining the treatment strategy for thymoma patients.

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  • Clinical outcome of patients with recurrent non-small cell lung cancer after trimodality therapy. Reviewed

    Ken Suzawa, Junichi Soh, Yuta Takahashi, Hiroki Sato, Kazuhiko Shien, Hiromasa Yamamoto, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

    Surgery today   49 ( 7 )   601 - 609   2019.7

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    PURPOSES: The purpose of this study was to review the clinical course of patients with recurrence after induction chemoradiotherapy followed by surgery (trimodality therapy) for locally advanced non-small cell lung cancer (LA-NSCLC) and to identify the factors associated with favorable clinical outcome after recurrence. METHODS: We analyzed the records of 140 patients with LA-NSCLC who were treated with trimodality therapy between 1999 and 2014. RESULTS: Recurrence developed after trimodality therapy in 48 patients. A yp-N positive status was associated with a high risk of recurrence (HR, 2.05; P = 0.048). Of the 45 of these patients able to be assessed retrospectively, 18 had oligometastatic recurrence and 20 underwent local treatment with curative intent. Local treatment was most frequently given to patients with oligometastatic recurrence (P < 0.001). The median post-recurrence survival (PRS) was 41.4 months, and the 2-year PRS rate was 62%. Patients who received local treatment showed better PRS (P = 0.009). The presence of liver metastasis (P = 0.008), bone metastasis (P = 0.041), or dissemination (P < 0.0001) were associated with worse PRS. CONCLUSION: The survival of patients who received aggressive local treatment for postoperative recurrence after trimodality therapy for LA-NSCLC was better than that of patients who did not.

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  • Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness. Reviewed International journal

    Youyi Chen, I Wayan Sumardika, Nahoko Tomonobu, Rie Kinoshita, Yusuke Inoue, Hidekazu Iioka, Yosuke Mitsui, Ken Saito, I Made Winarsa Ruma, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Junichiro Futami, Miyoko Kubo, Endy Widya Putranto, Takashi Murakami, Ming Liu, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    Neoplasia (New York, N.Y.)   21 ( 7 )   627 - 640   2019.7

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    Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes.

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  • Prolonged warm ischemia exacerbated acute rejection after lung transplantation from donation after cardiac death in a mouse. Reviewed

    Hirano Y, Sugimoto S, Yamamoto S, Okada M, Otani S, Ohara T, Yamane M, Matsukawa A, Oto T, Toyooka S

    General thoracic and cardiovascular surgery   2019.7

  • Melanoma cell adhesion molecule is the driving force behind the dissemination of melanoma upon S100A8/A9 binding in the original skin lesion. Reviewed International journal

    Youyi Chen, I Wayan Sumardika, Nahoko Tomonobu, I Made Winarsa Ruma, Rie Kinoshita, Eisaku Kondo, Yusuke Inoue, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Ming Liu, Junichiro Futami, Kaori Sasai, Hiroshi Katayama, Miyoko Kubo, Endy Widya Putranto, Toshihiko Hibino, Bei Sun, Masahiro Nishibori, Shinichi Toyooka, Masakiyo Sakaguchi

    Cancer letters   452   178 - 190   2019.6

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    Since metastasis accounts for the majority of cancer-associated deaths, studies on the mechanisms of metastasis are needed to establish innovative strategies for cancer treatment. We previously reported that melanoma cell adhesion molecule (MCAM) functions as a critical receptor for S100A8/A9, and binding of S100A8/A9 to MCAM results in the migration of melanoma cells to lung tissue. However, the critical role of MCAM in the original melanoma skin lesion is still not clear. In this study, we aimed to determine the importance of the S100A8/A9-MCAM axis in melanoma dissemination in a skin lesion as a critical early step for metastasis. Mechanistic studies revealed the downstream signaling of MCAM that signaled the induction of metastasis. S100A8/A9-MCAM binding activates mitogen-activated protein kinase kinase kinase 8 (MAP3K8), also termed TPL2, leading to strong activation of the transcription factor ETV4 and subsequent induction of matrix metalloproteinase-25 (MMP25), and finally to induction of melanoma lung tropic metastasis. Collectively, our results demonstrate a crucial role of the S100A8/A9-MCAM signaling axis in metastatic onset of melanoma cells and indicate that strategies targeting the identified pathway may be useful for the establishment of innovative anti-cancer therapies.

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  • Extracellular S100A11 Plays a Critical Role in Spread of the Fibroblast Population in Pancreatic Cancers. Reviewed International journal

    Hitoshi Takamatsu, Ken-Ichi Yamamoto, Nahoko Tomonobu, Hitoshi Murata, Yusuke Inoue, Akira Yamauchi, I Wayan Sumardika, Youyi Chen, Rie Kinoshita, Masahiro Yamamura, Hideyo Fujiwara, Yosuke Mitsui, Kota Araki, Junichiro Futami, Ken Saito, Hidekazu Iioka, I Made Winarsa Ruma, Endy Widya Putranto, Masahiro Nishibori, Eisaku Kondo, Yasuhiko Yamamoto, Shinichi Toyooka, Masakiyo Sakaguchi

    Oncology research   27 ( 6 )   713 - 727   2019.6

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    The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE+ expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11-RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE-MyD88-mTOR-p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.

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  • exSSSRs (extracellular S100 soil sensor receptors)-Fc fusion proteins work as prominent decoys to S100A8/A9-induced lung tropic cancer metastasis. Reviewed International journal

    Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    International journal of cancer   144 ( 12 )   3138 - 3145   2019.6

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    Within the "seed and soil" theory of organ tropic cancer metastasis is a growing compilation of evidence that S100A8/A9 functions as a soil signal that attracts cancer cells to certain organs, which prove beneficial to their growth. S100A8/A9-sensing receptors including Toll-like receptor 4 (TLR4), advanced glycation end products (RAGE), and also important receptors we recently succeeded in identifying (EMMPRIN, NPTNβ, MCAM, and ALCAM) have the potential to become promising therapeutic targets. In our study, we prepared extracellular regions of these novel molecules and fused them to human IgG2-Fc to extend half-life expectancy, and we evaluated the anti-metastatic effects of the purified decoy proteins on metastatic cancer cells. The purified proteins markedly suppressed S100A8/A9-mediated lung tropic cancer metastasis. We hence expect that our novel biologics may become a prominent medicine to prevent cancer metastasis in clinical settings through cutting the linkage between "seed and soil".

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  • Droplet digital PCR as a novel system for the detection of microRNA‑34b/c methylation in circulating DNA in malignant pleural mesothelioma. Reviewed International journal

    Hiroki Sato, Junichi Soh, Keisuke Aoe, Nobukazu Fujimoto, Shin Tanaka, Kei Namba, Hidejiro Torigoe, Kazuhiko Shien, Hiromasa Yamamoto, Shuta Tomida, Hiroyuki Tao, Kazunori Okabe, Takumi Kishimoto, Shinichi Toyooka

    International journal of oncology   54 ( 6 )   2139 - 2148   2019.6

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    Malignant pleural mesothelioma (MPM) is a rare malignancy arising from the pleura that is difficult to diagnose, contributing to its dismal prognosis. Previously, we reported that the degree of microRNA (miR)‑34b/c methylation in circulating DNA is associated with the development of MPM. Herein, we present a newly developed droplet digital PCR (ddPCR)‑based assay for the detection of miR‑34b/c methylation in circulating DNA in patients with MPM. We originally prepared two probes within a short amplicon of 60 bp, designing one from the positive strand and the other from the complementary strand. The two probes functioned cooperatively, and our established assay detected DNA methylation accurately in the preliminary validation. We subsequently verified this assay using clinical samples. Serum samples from 35 cases of MPM, 29 cases of pleural plaque and 10 healthy volunteers were collected from 3 different institutions and used in this study. We divided the samples into 2 groups (group A, n=33; group B, n=41). A receiver‑operating characteristic curve analysis using the samples in group A determined the optimal cut‑off value for the diagnosis of MPM, with a sensitivity of 76.9% and a specificity of 90%. On the other hand, the use of the same criterion yielded a sensitivity of 59.1% and a specificity of 100% in group B, and corresponding values of 65.7 and 94.9% for the entire cohort, indicating a moderate sensitivity and a high specificity. In addition, when the analysis was focused on stage II or more advanced MPM, the sensitivity improved to 81.8%, suggesting the possibility that the methylated allele frequency in MPM may be associated with the stage of disease progression. On the whole, the findings of this study indicate that miR‑34b/c methylation in circulating DNA is a promising biomarker for the prediction of disease progression in patients with MPM.

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  • Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression. Reviewed International journal

    I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Rie Kinoshita, I Made Winarsa Ruma, Hiroki Sato, Eisaku Kondo, Yusuke Inoue, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Junichiro Futami, Endy Widya Putranto, Toshihiko Hibino, Masahiro Nishibori, Shinichi Toyooka, Masakiyo Sakaguchi

    Molecular carcinogenesis   58 ( 6 )   980 - 995   2019.6

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    Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin-β (NPTNβ), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTNβ showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTNβ as an S100A8/A9 receptor in lung cancer. Our results showed that NPTNβ has strong ability to induce cancer-related cellular events, including anchorage-independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTNβ mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage-independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9-NPTNβ axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS-NFIA/NFIB-SPDEF, in linking to the aggressive development of lung cancers.

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  • SOCS3 overexpression in T cells ameliorates chronic airway obstruction in a murine heterotopic tracheal transplantation model. Reviewed

    Kumi Mesaki, Masaomi Yamane, Seiichiro Sugimoto, Masayoshi Fujisawa, Teizo Yoshimura, Takeshi Kurosaki, Shinji Otani, Shinichiro Miyoshi, Takahiro Oto, Akihiro Matsukawa, Shinichi Toyooka

    Surgery today   49 ( 5 )   443 - 450   2019.5

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    PURPOSE: Suppressor of cytokine signaling-3 (SOCS3) is a negative feedback inhibitor of cytokine signaling with T-cell-mediated immunosuppressive effects on obliterative bronchiolitis (OB). In this study, we aimed to investigate the impact of T-cell-specific overexpression of SOCS3 using a murine heterotopic tracheal transplantation (HTT) model. METHODS: Tracheal allografts from BALB/c mice were subcutaneously transplanted into wild-type C57BL/6J (B6; WT) mice and SOCS3 transgenic B6 (SOCS3TG) mice. Tracheal allografts were analyzed by immunohistochemistry and quantitative polymerase chain reaction assays at days 7 and 21. RESULTS: At day 21, allografts in SOCS3TG mice showed significant amelioration of airway obstruction and epithelial loss compared with allografts in WT mice. The intragraft expression of IFN-γ and CXCL10 was suppressed, while that of IL-4 was enhanced in SOCS3TG mice at day 7. The T-bet levels were lower in SOCS3TG allografts than in WT allografts at day 7. CONCLUSION: We revealed that the overexpression of SOCS3 in T cells effectively ameliorates OB development in a murine HTT model by inhibiting the Th1 phenotype in the early phase. Our results suggest that the regulation of the T-cell response, through the modulation of SOCS expression, has potential as a new therapeutic strategy for chronic lung allograft dysfunction.

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  • A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cancers Harboring HER2 Aberration in Japan (HER2-CS STUDY). Reviewed

    Ninomiya K, Hata T, Yoshioka H, Ohashi K, Bessho A, Hosokawa S, Ishikawa N, Yamasaki M, Shibayama T, Aoe K, Kozuki T, Harita S, Ueda Y, Murakami T, Fujimoto N, Yanai H, Toyooka S, Takata M, Hotta K, Kiura K, HER2-CS Network

    Chest   2019.5

  • Ganetespib in Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-resistant Non-small Cell Lung Cancer. Reviewed International journal

    Eisuke Kurihara, Kazuhiko Shien, Hidejiro Torigoe, Tatsuaki Takeda, Yuta Takahashi, Yusuke Ogoshi, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Mikio Okazaki, Tadahiko Shien, Shuta Tomida, Shinichi Toyooka

    Anticancer research   39 ( 4 )   1767 - 1775   2019.4

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    BACKGROUND: The 90-kDa heat-shock protein (HSP90) is a chaperone protein expressed at high levels in cancer cells and is involved in the folding or stabilization of several client proteins, including epidermal growth factor receptor (EGFR). Ganetespib is a second-generation HSP90 inhibitor with a potent antitumor effect against various cancer types. MATERIALS AND METHODS: This study examined the antitumor effect of ganetespib in EGFR-mutant non-small cell lung cancer (NSCLC) cells and experimentally established EGFR-tyrosine kinase inhibitor (TKI)-resistant cells harboring various resistance mechanisms, including EGFR T790M mutation, met proto-oncogene amplification, and epithelial-mesenchymal transition. RESULTS: Ganetespib showed a potent antitumor effect at low concentrations, suppressing EGFR-related downstream pathway molecules and inducing cleavage of poly ADP-ribose polymerase in all examined EGFR-TKI-resistant cell lines in vitro. Ganetespib also inhibited in vivo tumor growth in resistant cells harboring EGFR T790M. CONCLUSION: Ganetespib might be a promising therapeutic option for the treatment of patients with EGFR-TKI-resistant NSCLC.

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  • EGFR-TKI耐性NSCLCに対するHSP90阻害剤ganetespibの有用性の検討

    栗原 英祐, 枝園 和彦, 鳥越 英次郎, 武田 達明, 荒木 恒太, 宮内 俊策, 三浦 章博, 高橋 優太, 諏澤 憲, 山本 寛斉, 宗 淳一, 冨田 秀太, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 3 )   O17 - 4   2019.4

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  • 第7次事業2010年肺癌外科切除18972例の報告

    岡見 次郎, 新谷 康, 奥村 明之進, 伊藤 宏之, 大塚 崇, 豊岡 伸一, 森 毅, 渡辺 俊一, 中西 良一, 永安 武, 伊達 洋至, 淺村 尚生, 遠藤 俊輔, 千田 雅之, 横井 香平, 宮岡 悦良, 吉野 一郎, 肺癌登録合同委員会

    日本呼吸器外科学会雑誌   33 ( 3 )   np10 - np10   2019.4

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  • IB-IIIA期肺癌切除例に対する術後補助療法第三相試験(SLCG0401) 病期・組織型別のサブ解析

    宗 淳一, 豊岡 伸一, 奥村 典仁, 中村 廣繁, 中田 昌男, 山下 素弘, 青江 基, 伊達 洋至

    日本呼吸器外科学会雑誌   33 ( 3 )   RO21 - 2   2019.4

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  • Risk assessments for broncho-pleural fistula and respiratory failure after lung cancer surgery by National Clinical Database Japan. Reviewed

    Shunsuke Endo, Norihiko Ikeda, Takashi Kondo, Jun Nakajima, Haruhiko Kondo, Yoshihisa Shimada, Masami Sato, Shinichi Toyooka, Yoshinori Okada, Yukio Sato, Ichiro Yoshino, Morihito Okada, Meinoshin Okumura, Masayuki Chida, Eriko Fukuchi, Hiroaki Miyata

    General thoracic and cardiovascular surgery   67 ( 3 )   297 - 305   2019.3

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    BACKGROUND: Broncho-pleural fistula (BPF) and respiratory failure (RF) are life-threatening complications after lung cancer surgery and can result in long-term hospitalization and decreased quality of life. Risk assessments for BPF and RF in addition to mortality and major morbidities are indispensable in surgical decision-making and perioperative care. METHODS: The characteristics and operative data of 80,095 patients who had undergone lung cancer surgery were derived from the 2014 and 2015 National Clinical Database (NCD) of Japan datasets. After excluding 1501 patients, risk models were developed from these data and validated by another dataset for 42,352 patients derived from the 2016 NCD dataset. Receiver operating characteristic curves were generated for postoperative BPF and RF development. The concordance-index was used to assess the discriminatory ability and validity of the model. RESULTS: BPF and RF occurred in 259 (0.3%) and 420 patients (0.5%), respectively, in the model development dataset and in 129 (0.3%) and 198 patients (0.5%), respectively, in the model validation dataset. Characteristic variables including types of surgery and comorbidities were identified as risk factors for BPF and RF, respectively. The concordance indexes of assessments for BPF and RF were 0.847 (p < 0.001) and 0.848 (p < 0.001), respectively, for the development dataset and 0.850 (p < 0.001) and 0.844 (p < 0.001), respectively, for the validation dataset. CONCLUSIONS: These models are satisfactory for predicting BPF and RF after lung cancer surgery in Japan and could guide preoperative assessment and optimal measures for preventing BPF and RF.

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  • Anti-tumor effect of neratinib against lung cancer cells harboring HER2 oncogene alterations. Reviewed International journal

    Yusuke Ogoshi, Kazuhiko Shien, Takahiro Yoshioka, Hidejiro Torigoe, Hiroki Sato, Masakiyo Sakaguchi, Shuta Tomida, Kei Namba, Eisuke Kurihara, Yuta Takahashi, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka

    Oncology letters   17 ( 3 )   2729 - 2736   2019.3

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    Human epidermal growth factor receptor 2 (HER2) is a member of the ErbB family of receptor tyrosine kinases. Numerous studies have reported the amplification and overexpression of HER2 in several types of cancer, including non-small cell lung cancer (NSCLC). However, the benefits of HER2-targeted therapy have not been fully established. In the present study, the anti-tumor effect of neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), against NSCLC cells harboring HER2 alterations was investigated. The sensitivity of normal bronchial epithelial cells (BEAS-2B) ectopically overexpressing wild-type or mutant HER2 to neratinib was assessed. Furthermore, the anti-tumor activity of neratinib in several NSCLC cell lines harboring HER2 alterations was determined in vitro and in vivo, and the association between their genetic alterations and sensitivity to neratinib treatment was investigated. BEAS-2B cells ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, G660D and S310F) exhibited constitutive autophosphorylation of HER2, as determined by western blotting. While these BEAS-2B cells were sensitive to neratinib, they were insensitive to erlotinib, a first-generation epidermal growth factor receptor-TKI. Neratinib also exerted anti-proliferative effects on HER2-altered (H2170, Calu-3 and H1781) NSCLC cell lines. Neratinib was also demonstrated to exert strong tumor growth inhibitory activity in mouse xenograft models using HER2-altered lung cancer cells. The results of the present study strongly suggest that neratinib has potential as a promising therapeutic option for the treatment of HER2-altered NSCLC.

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  • Feasibility of lung transplantation from donors mechanically ventilated for prolonged periods. Reviewed

    Seiichiro Sugimoto, Takeshi Kurosaki, Shinji Otani, Shin Tanaka, Yukiko Hikasa, Masaomi Yamane, Shinichi Toyooka, Motomu Kobayashi, Takahiro Oto

    Surgery today   49 ( 3 )   254 - 260   2019.3

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    PURPOSE: When patients are mechanically ventilated for more than 5 days, they are usually declined as donors for lung transplantation (LTx); thus, the long-term outcomes of LTx from such donors remain unclear. We investigated the feasibility of LTx from donors that had been mechanically ventilated for prolonged periods. METHODS: The subjects of this retrospective comparative investigation were 31 recipients of LTx from donors who had been mechanically ventilated for < 5 days (short-term group) and 50 recipients of LTx from donors who had been mechanically ventilated for ≥ 5 days (long-term group). RESULTS: The median duration of donor mechanical ventilation was 3 days in the short-term group and 8.5 days in the long-term group. However, other than the difference in the duration of donor ventilation, there were no significant differences in the clinical characteristics of the donors or recipients between the groups. The overall survival rate after LTx was comparable between the long-term group and short-term group (5-year survival rate, 66.6% vs. 75.2%). CONCLUSION: The potential inclusion of donors who have been on mechanical ventilation for more than 5 days could be a feasible strategy to alleviate donor organ shortage.

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  • Lung transplant candidates with idiopathic pulmonary fibrosis and long-term pirfenidone therapy: Treatment feasibility influences waitlist survival. Reviewed International journal

    Shin Tanaka, Kentaroh Miyoshi, Hisao Higo, Takeshi Kurosaki, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Katsuyuki Kiura, Shinichi Toyooka, Takahiro Oto

    Respiratory investigation   57 ( 2 )   165 - 171   2019.3

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    BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronically progressive lung disease with exceptionally poor prognosis. While lung transplantation (LTx) is considered the last-resort therapeutic option, dismal waitlist mortality still hampers the salvage of patients with IPF. Pirfenidone, originally designed for IPF treatment, has increasingly been utilized. This study aimed to evaluate whether Pirfenidone could influence outcomes of patients with IPF on the Japanese LTx waitlist. METHODS: This retrospective single-center cohort study included 25 consecutive patients with IPF who were registered as LTx candidates at our institution between July 1999 and August 2016. Patients with a history of pretransplant Pirfenidone therapy (Pirfenidone group) were compared with those with no history (non-Pirfenidone group). RESULTS: In total, 6 (24%) patients received Pirfenidone as pretransplant therapy for 45.2 (range, 18.6-66.8) months. During the treatment period, the Pirfenidone group achieved a significant reduction in the decline rate of the forced vital capacity (-6.2% vs. -0.3%, p = 0.04) and a lower lung allocation score (31 vs. 41, p = 0.013) compared with the non-Pirfenidone group. The Pirfenidone group exhibited 100% waitlist survival three years after registration that was comparable to other indications, and 66% of the patients were still alive at the time of organ availability. No patient in the Pirfenidone group developed Pirfenidone-related surgical complications postoperatively. CONCLUSIONS: Patients with IPF successfully managed with long-term Pirfenidone therapy achieved favorable outcomes after LTx registration, comparable to other patients with LTx indications. The tolerability to antifibrotic therapy can be a predictor of waitlist survival.

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  • A single-nucleotide polymorphism in a gene modulating glucocorticoid sensitivity is associated with the decline in total lung capacity after lung transplantation. Reviewed

    Haruchika Yamamoto, Seiichiro Sugimoto, Shin Tanaka, Takeshi Kurosaki, Shinji Otani, Masaomi Yamane, Naruto Taira, Takahiro Oto, Shinichi Toyooka

    Surgery today   49 ( 3 )   268 - 274   2019.3

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    PURPOSE: Glucocorticoids are used to prevent chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). Our study was aimed at assessing the association between the glucocorticoid-induced transcript 1 gene (GLCCI1) variant, which modulates glucocorticoid sensitivity, and the postoperative lung function and development of CLAD after LT. METHODS: A total of 71 recipients of LT were genotyped for the GLCCI1 variant (rs37972) and divided into three groups: the homozygous mutant allele (TT) group, the heterozygous mutant allele (CT) group, and the wild-type allele (CC) group. The results of pulmonary function tests were compared with the postoperative baseline values. RESULTS: The total lung capacity (TLC) in the TT group was significantly lower than that in the CC group at 3 years after LT (P = 0.029). In the recipients of cadaveric LT, the TLC and forced expiratory volume in 1 s in the TT group were significantly lower than those in the CC groups, resulting in a significant worse CLAD-free survival at 3 years after LT (P = 0.016). CONCLUSION: The GLCCI1 variant was associated with a significant decrease of the TLC at 3 years after LT and the development of CLAD at 3 years, especially in patients undergoing cadaveric LT.

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  • チームアプローチで実現するゲノム医療と薬剤師の役割 ゲノム医療におけるデータサイエンティストの役割と育成

    冨田 秀太, 森田 瑞樹, 山下 範之, 平沢 晃, 豊岡 伸一

    日本薬学会年会要旨集   139年会 ( 1 )   264 - 264   2019.3

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  • 肺癌患者に対する化学放射線療法は大動脈石灰化を増悪させる(Chemoradiation Therapy to Patients with Lung Cancer Exacerbates Aortic Calcification)

    三木 崇史, 三好 亨, 市川 啓之, 宮内 俊策, 宗 淳一, 豊岡 伸一, 中村 一文, 森田 宏, 伊藤 浩

    日本循環器学会学術集会抄録集   83回   OJ33 - 4   2019.3

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  • Application of amplicon-based targeted sequencing with the molecular barcoding system to detect uncommon minor EGFR mutations in patients with treatment-naïve lung adenocarcinoma. Reviewed International journal

    Kei Namba, Shuta Tomida, Takehiro Matsubara, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Takahiro Yoshioka, Tatsuaki Takeda, Hidejiro Torigoe, Hiroki Sato, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichi Toyooka

    BMC cancer   19 ( 1 )   175 - 175   2019.2

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    BACKGROUND: In lung cancer, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor sensitizing mutations co-existing with rare minor EGFR mutations are known as compound mutations. These minor EGFR mutations can lead to acquired resistance after EGFR tyrosine kinase inhibitor treatment, so determining the mutation status of patients is important. However, using amplicon-based targeted deep sequencing based on next-generation sequencing to characterize mutations is prone to sequencing error. We therefore assessed the benefit of incorporating molecular barcoding with high-throughput sequencing to investigate genomic heterogeneity in treatment-naïve patients who have undergone resection of their non-small cell lung cancer (NSCLC) EGFR mutations. METHODS: We performed amplicon-based targeted sequencing with the molecular barcoding system (MBS) to detect major common EGFR mutations and uncommon minor mutations at a 0.5% allele frequency in fresh-frozen lung cancer samples. RESULTS: Profiles of the common mutations of EGFR identified by MBS corresponded with the results of clinical testing in 63 (98.4%) out of 64 cases. Uncommon mutations of EGFR were detected in seven cases (10.9%). Among the three types of major EGFR mutations, patients with the G719X mutation had a significantly higher incidence of compound mutations than those with the L858R mutation or exon 19 deletion (p = 0.0052). This was validated in an independent cohort from the Cancer Genome Atlas dataset (p = 0.018). CONCLUSIONS: Our findings demonstrate the feasibility of using the MBS to establish an accurate NSCLC patient genotype. This work will help understand the molecular basis of EGFR compound mutations in NSCLC, and could aid the development of new treatment modalities.

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  • Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in EGFR-Mutant Non-Small Cell Lung Cancer Cells. Reviewed International journal

    Kei Namba, Kazuhiko Shien, Yuta Takahashi, Hidejiro Torigoe, Hiroki Sato, Takahiro Yoshioka, Tatsuaki Takeda, Eisuke Kurihara, Yusuke Ogoshi, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Shinichi Toyooka

    Molecular cancer research : MCR   17 ( 2 )   499 - 507   2019.2

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    Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistant cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multigene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. IMPLICATIONS: Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance.

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  • Demographics, Safety and Quality, and Prognostic Information in Both the Seventh and Eighth Editions of the TNM Classification in 18,973 Surgical Cases of the Japanese Joint Committee of Lung Cancer Registry Database in 2010. Reviewed International journal

    Okami J, Shintani Y, Okumura M, Ito H, Ohtsuka T, Toyooka S, Mori T, Watanabe SI, Date H, Yokoi K, Asamura H, Nagayasu T, Miyaoka E, Yoshino I, Japanese Join, Committee of Lung, Cancer Registry

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   14 ( 2 )   212 - 222   2019.2

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    INTRODUCTION: The Japanese Joint Committee of Lung Cancer Registry performed the fourth nationwide registry study of surgical cases. Demographics, safety and quality, prognostic information, and correlations between the seventh and the eighth editions of the TNM classification were investigated. The principal results were compared with those of previous Japanese Joint Committee of Lung Cancer Registry studies. METHODS: The clinicopathologic profiles, staging, and prognosis of patients who had an operation for primary lung cancer in 2010 were retrospectively collected in 2016 and analyzed. RESULTS: The cohort consisted of 18,973 patients from 297 hospitals (11,771 males, mean age 68.3 years). Tumor smaller than 2.0 cm was seen in 39.0% of patients, and limited resection was performed in 22.7%. The 30- and 90-day mortality rates were 0.43 and 1.26%, respectively. The overall and disease-free survival rates at 5 years were 74.7 and 67.8%, respectively. The respective 5-year survival rates by pathological stage in the seventh edition in the present study (2010) and in the previous study (2004) were 88.9% and 86.8% for stage IA, 76.7% and 73.9% for stage IB, 64.1% and 61.6% for stage IIA, 56.1% and 49.8% for stage IIB, 47.9% and 40.9% for stage IIIA, 30.2% and 27.8% for stage IIIB, and 36.1% and 27.9% for stage IV. The 5-year survival rates by clinical stage in the eighth edition in the present study were 97.0% for stage 0, 91.6% for stage IA1, 81.4% for stage IA2, 74.8% for stage IA3, 71.5% for stage IB, 60.2% for stage IIA, 58.1% for stage IIB, 50.6% for stage IIIA, 40.5% for stage IIIB, 37.5% for stage IIIC, and 36.0% for IVA/B. With restaging, the overall survival rates of clinical stage IA and IB in the seventh edition were stratified into stages 0 to IA3 and stages IA1 to IIA in the eighth edition, respectively. CONCLUSIONS: This study demonstrates improved surgical results for lung cancer in Japan. The TNM revision for the eighth edition was supported by the assessment of stage migration from the previous edition and the prognostic stratification.

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  • NEUROPLASTIN-β MEDIATES S100A8/A9-INDUCED LUNG CANCER DISSEMINATIVE PROGRESSION Reviewed

    Sumardika IW, Chen Y, Tomonobu N, Kinoshita R, Ruma IMW, Sato H, Kondo E, Inoue Y, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Putranto EW, Hibino T, Nishibori M, Toyooka S, Sakaguchi M

    Molecular Carcinogenesis   2019.2

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    Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin-β (NPTNβ), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTNβ showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTNβ as an S100A8/A9 receptor in lung cancer. Our results showed that NPTNβ has strong ability to induce cancer-related cellular events, including anchorage-independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTNβ mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage-independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9-NPTNβ axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS-NFIA/NFIB-SPDEF, in linking to the aggressive development of lung cancers. This article is protected by copyright.

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  • Detection of lung cancer cells using a terahertz chemical microscope

    Kosuke Sato, Masahiro Iida, Hirofumi Inoue, Toshihiko Kiwa, Shinichi Toyooka, Keiji Tsukada

    Optics InfoBase Conference Papers   Part F146-JSAP 2019   2019

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    © 2019 OSA - The Optical Society. All rights reserved. We have developed the TCM to evaluate the ration of cancer cells to normal cells for realizing the cancer genome therapy. The THz amplitude radiated from the sensing plate increased by increasing the cell population of lung cell carcinoma.

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  • Long-term spontaneous remission with active surveillance in IgG4-related pleuritis: A case report and literature review. Reviewed

    Makimoto G, Ohashi K, Taniguchi K, Soh J, Taniguchi A, Miyahara N, Toyooka S, Yoshino T, Maeda Y, Kiura K

    Respiratory medicine case reports   28   100938   2019

  • SPRED2 deficiency may lead to lung ischemia-reperfusion injury via ERK1/2 signaling pathway activation. Reviewed

    Masanori Okada, Masaomi Yamane, Sumiharu Yamamoto, Shinji Otani, Kentaroh Miyoshi, Seiichiro Sugimoto, Akihiro Matsukawa, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi

    Surgery today   48 ( 12 )   1089 - 1095   2018.12

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    PURPOSE: Inflammatory changes during lung ischemia-reperfusion injury (IRI) are related to the activation of the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. Sprouty-related EVH1 (enabled/vasodilator-stimulated phosphoprotein homology 1)-domain-containing proteins (SPREDs) are known inhibitors of ERK1/2 signaling. The role of SPRED2 in lung IRI was examined in a left hilar clamp mouse model. METHODS: C57BL/6 wild-type (WT) and Spred2-/- mice were used in the left hilar clamp model. Experimental groups underwent 30 min of left hilar clamping followed by 1 h of reperfusion. U0126, an ERK1/2 inhibitor, was administered to Spred2-/- mice with reperfused lungs. RESULTS: The partial pressures of oxygen of the Spred2-/- mice after reperfusion were significantly worse than those of WT mice (p < 0.01). Spred2-/- mice displayed more severe injuries than WT mice with increased neutrophil infiltration observed by a histological evaluation and flow cytometry (p < 0.001). This severe inflammation was inhibited by U0126. In addition, the rate of ERK1 activation was significantly higher in the lungs of Spred2-/- mice after reperfusion than in WT mice according to a Western blot analysis (p < 0.05). CONCLUSION: The activation of the ERK1/2 signaling pathway influences the severity of lung IRI, causing inflammation with neutrophil infiltration. SPRED2 may be a promising target for the suppression of lung IRI.

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  • Comparative mutational evaluation of multiple lung cancers by multiplex oncogene mutation analysis. Reviewed International journal

    Yuta Takahashi, Kazuhiko Shien, Shuta Tomida, Shinsuke Oda, Takehiro Matsubara, Hiroki Sato, Ken Suzawa, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Takahiro Yoshioka, Hidejiro Torigoe, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka

    Cancer science   109 ( 11 )   3634 - 3642   2018.11

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    In patients presenting with synchronous or metachronous multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). The present study was aimed at investigating the mutational profiles of synchronous/metachronous MLC and to compare the classification of paired tumors by multiplex gene mutation analysis with the histopathological evaluation. We carried out targeted sequencing of 20 lung cancer-related oncogenes using next-generation sequencing (NGS) in 82 tumors from 37 MLC patients who underwent surgical resection at our department. The patients were diagnosed as MP or IM cases based on the Martini and Melamed criteria, histopathological and gene mutational evaluations. Matching mutations between paired tumors was observed in 20 (54%) patients, who were diagnosed as IM cases by mutational evaluation. Patients who could not be clearly diagnosed by histopathological evaluation were classified as equivocal cases. Among the histopathological IM cases (n = 7), six (86%) were confirmed as IM cases also by mutational evaluation, and most of the paired tumors of these cases (n = 5) harbored multiple matching mutations. Among the histopathological MP cases (n = 17), mutational evaluation yielded a discordant diagnosis in eight (47%) cases. Of these, the paired tumors of four cases harbored multiple matching mutations, suggesting that the mutational diagnosis might be more suitable in these patients. Our findings suggest that multiplex mutational analysis could be a useful complementary tool for distinguishing between MP and IM in addition to histopathological evaluation.

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  • Study Protocol: Phase-Ib Trial of Nivolumab Combined With Metformin for Refractory/Recurrent Solid Tumors. Reviewed

    Kubo T, Ninomiya T, Hotta K, Kozuki T, Toyooka S, Okada H, Fujiwara T, Udono H, Kiura K

    Clinical lung cancer   19 ( 6 )   e861 - e864   2018.11

  • Donor-derived cell-free DNA is associated with acute rejection and decreased oxygenation in primary graft dysfunction after living donor-lobar lung transplantation. Reviewed International journal

    Shin Tanaka, Seiichiro Sugimoto, Takeshi Kurosaki, Kentaroh Miyoshi, Shinji Otani, Ken Suzawa, Shinsuke Hashida, Masaomi Yamane, Takahiro Oto, Shinichi Toyooka

    Scientific reports   8 ( 1 )   15366 - 15366   2018.10

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    Donor-derived cell-free DNA (dd-cf-DNA) has been shown to be an informative biomarker of rejection after lung transplantation (LT) from deceased donors. However, in living-donor lobar LT, because small grafts from blood relatives are implanted with short ischemic times, the detection of dd-cf-DNA might be challenging. Our study was aimed at examining the role of dd-cf-DNA measurement in the diagnosis of primary graft dysfunction and acute rejection early after living-donor lobar LT. Immediately after LT, marked increase of the plasma dd-cf-DNA levels was noted, with the levels subsequently reaching a plateau with the resolution of primary graft dysfunction. Increased plasma levels of dd-cf-DNA were significantly correlated with decreased oxygenation immediately (p = 0.022) and at 72 hours (p = 0.046) after LT. Significantly higher plasma dd-cf-DNA levels were observed in patients with acute rejection (median, 12.0%) than in those with infection (median, 4.2%) (p = 0.028) or in a stable condition (median, 1.1%) (p = 0.001). Thus, measurement of the plasma levels of dd-cf-DNA might be useful to monitor the severity of primary graft dysfunction, and plasma dd-cf-DNA could be a potential biomarker for the diagnosis of acute rejection after LT.

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  • Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer. Reviewed International journal

    Hiroki Sato, Hiromasa Yamamoto, Masakiyo Sakaguchi, Kazuhiko Shien, Shuta Tomida, Tadahiko Shien, Hirokuni Ikeda, Minami Hatono, Hidejiro Torigoe, Kei Namba, Takahiro Yoshioka, Eisuke Kurihara, Yusuke Ogoshi, Yuta Takahashi, Junichi Soh, Shinichi Toyooka

    Cancer science   109 ( 10 )   3183 - 3196   2018.10

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    Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non-small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide-3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR-TKI-resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single-agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal-epithelial transition factor amplification, induction of epithelial-to-mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long-term treatment with the combination therapy induced the conversion from EMT to mesenchymal-to-epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR-TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR-TKIs.

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  • Dose-Volume Parameters Predict Radiation Pneumonitis after Surgery with Induction Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer. Reviewed

    Ogata T, Katsui K, Yoshio K, Ihara H, Katayama N, Soh J, Kuroda M, Kiura K, Maeda Y, Toyooka S, Kanazawa S

    Acta medica Okayama   72 ( 5 )   507 - 513   2018.10

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    To clarify the relationship between dose-volume histogram (DVH) parameters and radiation pneumonitis (RP) after surgery in cases of non-small cell lung cancer (NSCLC) treated with induction concurrent chemoradiotherapy (CCRT). Patients with NSCLC treated with induction CCRT (chemotherapy: cisplatin and docetaxel; radiotherapy: 2.0 Gy fractions once daily for a total of 46 Gy) before surgery were reviewed. We calculated the percentage of lung volume receiving at least 20 Gy (V20) and the mean lung dose (MLD) for the total lung volume and the lung remaining after resection. Factors affecting the incidence of RP at grade 2 or higher (≥ G2 RP) were analyzed. Eighteen of 49 patients (37%) experienced ≥G2 RP. The V20 and MLD for the lung remaining after resection (V20r and MLDr) were significant predictors according to the multivariate analysis (p=0.007 and 0.041, respectively). The incidence of ≥G2 RP was 8% in patients with V20r<10%, and 13% in patients with MLDr<5.6 Gy, respectively. The optimal approach to reduce the rate of postoperative RP in patients with induction CCRT for NSCLC is to keep the V20r below 10% and/or the MLDr below 5.6 Gy in the radiotherapy planning.

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  • Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions. Reviewed

    Kato Y, Ninomiya K, Ohashi K, Tomida S, Makimoto G, Watanabe H, Kudo K, Matsumoto S, Umemura S, Goto K, Ichihara E, Ninomiya T, Kubo T, Sato A, Hotta K, Tabata M, Toyooka S, Maeda Y, Kiura K

    Cancer science   109 ( 10 )   3149 - 3158   2018.10

  • Low-risk donor lungs optimize the post-lung transplant outcome for high lung allocation score patients. Reviewed

    Takeshi Kurosaki, Kentaroh Miyoshi, Shinji Otani, Kentaro Imanishi, Seiichiro Sugimoto, Masaomi Yamane, Motomu Kobayashi, Shinichi Toyooka, Takahiro Oto

    Surgery today   48 ( 10 )   928 - 935   2018.10

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    PURPOSE: The lung allocation score (LAS) has been generally recognized as a contributor to the overall survival in lung transplant candidates. However, donor-related risks have never been taken into consideration in previous research that validated the LAS. This study aimed to determine whether or not the role of the LAS as a predictor of the posttransplant outcome is influenced by the quality of the donor lungs. METHODS: We retrospectively reviewed 108 patients who underwent lung transplantation at Okayama University Hospital since 1998. The cohort was divided into two groups based on the lung donor score (DS; ≤ 4/> 4). Correlations between the LAS and posttransplant outcomes were investigated in both groups. RESULTS: In the high-DS group, an elevated LAS was strongly associated with posttransplant PaO2/FiO2 (p = 0.018). However, in the low-DS group, no correlation was found between them. There was no significant difference in the long-term survival according to the LAS in the low-DS group. The LAS effectively predicted the posttransplant outcome only when lungs with DS > 4 were transplanted; the LAS was not reliable if high-quality lungs were transplanted. CONCLUSION: Lung transplantation can be feasible and provides a survival benefit even for high-LAS patients if lungs from a low-risk donor are transplanted.

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  • EMT化を示すAlectinib耐性後の患者由来新規ALK肺癌細胞株の樹立とその耐性化の克服

    槇本 剛, 大橋 圭明, 佐藤 晃子, 渡邉 洋美, 二宮 貴一朗, 二宮 崇, 頼 冠名, 久保 寿夫, 市原 英基, 片山 英樹, 堀田 勝幸, 田端 雅弘, 豊岡 伸一, 前田 嘉信, 木浦 勝行

    肺癌   58 ( 6 )   599 - 599   2018.10

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  • 非小細胞肺癌完全切除例に対する術後補助化学療法におけるERCC1の効果予測因子としての意義

    中田 昌男, 最相 晋輔, 宗 淳一, 奥村 典仁, 中村 廣繁, 山下 素弘, 多田 弘人, 森田 智視, 豊岡 伸一, 伊達 洋至, 瀬戸内肺癌研究会

    肺癌   58 ( 6 )   516 - 516   2018.10

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  • 肺癌におけるPrecision Medicineの現状と今後の展開 肺癌のゲノム異常と治療の課題

    豊岡 伸一, 枝園 和彦, 山本 寛斉, 宗 淳一, 冨田 秀太

    日本癌治療学会学術集会抄録集   56回   PD3 - 2   2018.10

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  • デジタルPCR法による呼気濃縮液を用いたEGFR遺伝子診断法の検討

    西井 和也, 大橋 圭明, 田村 朋季, 妹尾 賢, 狩野 裕久, 渡邉 洋美, 小田 尚廣, 槇本 剛, 肥後 寿夫, 二宮 貴一朗, 加藤 有加, 南 大輔, 二宮 崇, 久保 寿夫, 堀田 勝幸, 田端 雅弘, 冨田 秀太, 豊岡 伸一, 前田 嘉信, 木浦 勝行

    肺癌   58 ( 6 )   597 - 597   2018.10

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  • Myoepithelioma occurring in the posterior mediastinum harboring EWSR1 rearrangement: a case report. Reviewed International journal

    Tomohiro Habu, Junichi Soh, Tomohiro Toji, Kazuhiko Shien, Eito Niman, Kei Namba, Hiroki Sato, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

    Japanese journal of clinical oncology   48 ( 9 )   851 - 854   2018.9

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    Myoepithelioma is a rare neoplasm usually occurring in the salivary glands or the mammary glands but also, more rarely, in the thoracic cavity. The diagnosis of myoepithelioma is based on the presence of histological and immunohistochemical characteristics of myoepithelioma, but in unusual locations, the diagnosis is challenging. For such cases, cytogenetic approaches have been developed as helpful tools for the diagnosis. We report a surgical case of 51-year-old woman with myoepithelioma occurring in the posterior mediastinum that harbored the Ewing sarcoma breakpoint region1 (EWSR1) gene rearrangement. To the best of our knowledge, this is the first report of a myoepithelioma occurring in the posterior mediastinum. In this case, the patient underwent the thoracoscopic surgery for a diagnostic tumorectomy and was diagnosed as myoepithelioma based on the following immunohistological findings. Considering the unusual location, we additionally performed a cytogenetic analysis to confirm the presence of the EWSR1 gene rearrangement, which is a genetic characteristic of myoepithelioma.

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  • Airway complications have a greater impact on the outcomes of living-donor lobar lung transplantation recipients than cadaveric lung transplantation recipients. Reviewed

    Seiichiro Sugimoto, Masaomi Yamane, Shinji Otani, Takeshi Kurosaki, Shuji Okahara, Yukiko Hikasa, Shinichi Toyooka, Motomu Kobayashi, Takahiro Oto

    Surgery today   48 ( 9 )   848 - 855   2018.9

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    PURPOSE: Airway complications (ACs) after living-donor lobar lung transplantation (LDLLT) could have different features from those after cadaveric lung transplantation (CLT). We conducted this study to compare the characteristics of ACs after LDLLT vs. those after CLT and investigate their impact on outcomes. METHODS: We reviewed, retrospectively, data on 163 recipients of lung transplantation, including 83 recipients of LDLLT and 80 recipients of CLT. RESULTS: The incidence of ACs did not differ between LDLLT and CLT. The initial type of AC after LDLLT was limited to stenosis in all eight patients, whereas that after CLT consisted of stenosis in three patients and necrosis in ten patients (p = 0.0034). ACs after LDLLT necessitated significantly earlier initiation of treatment than those after CLT (p = 0.032). The overall survival rate of LDLLT recipients with an AC was significantly lower than that of those without an AC (p = 0.030), whereas the overall survival rate was comparable between CLT recipients with and those without ACs (p = 0.25). CONCLUSION: ACs after LDLLT, limited to bronchial stenosis, require significantly earlier treatment and have a greater adverse impact on survival than ACs after CLT.

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  • HER増幅胃癌におけるアファチニブ耐性機序(Acquired resistant mechanism to afatinib in HER2 amplified gastric cancer cells)

    吉岡 貴裕, 枝園 和彦, 難波 圭, 冨田 秀太, 山本 寛斉, 宗 淳一, 藤原 俊義, 豊岡 伸一

    日本癌学会総会記事   77回   1449 - 1449   2018.9

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  • EGFR変異陽性肺癌におけるLRIG1の抗腫瘍効果(Tumor-suppressive effect of LRIG1 in non-small cell lung cancer harboring mutant EGFR)

    鳥越 英次郎, 山本 寛斉, 阪口 政清, 難波 圭, 佐藤 博紀, 枝園 和彦, 諏澤 憲, 宗 淳一, 冨田 秀太, 佃 和憲, 三好 新一郎, 豊岡 伸一

    日本癌学会総会記事   77回   940 - 940   2018.9

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  • Inherited lung cancer syndromes targeting never smokers. Reviewed

    Yamamoto H, Yatabe Y, Toyooka S

    Translational lung cancer research   7 ( 4 )   498 - 504   2018.8

  • 病理病期IB〜IIIA期非小細胞肺癌完全切除症例に対する術後補助化学療法 無作為化比較第3相試験(SLCG0401)

    井上 啓爾, 福田 実, 竹之内 光広, 一瀬 幸人, 高森 信三, 奥村 典仁, 松尾 恵太郎, 宗 淳一, 豊岡 伸一, 伊達 洋至

    肺癌   58 ( 4 )   303 - 303   2018.8

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  • Embigin Promotes Prostate Cancer Progression by S100A4-Dependent and-Independent Mechanisms. Reviewed International journal

    I Made Winarsa Ruma, Rie Kinoshita, Nahoko Tomonobu, Yusuke Inoue, Eisaku Kondo, Akira Yamauchi, Hiroki Sato, I Wayan Sumardika, Youyi Chen, Ken-Ichi Yamamoto, Hitoshi Murata, Shinichi Toyooka, Masahiro Nishibori, Masakiyo Sakaguchi

    Cancers   10 ( 7 )   2018.7

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    Embigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is involved in prostate and mammary gland development. As embigin's roles in cancer remain elusive, we studied its biological functions and interaction with extracellular S100A4 in prostate cancer progression. We found by a pull-down assay that embigin is a novel receptor for S100A4, which is one of the vital cancer microenvironment milleu. Binding of extracellular S100A4 to embigin mediates prostate cancer progression by inhibition of AMPK activity, activation of NF-κB, MMP9 and mTORC1 signaling, and inhibition of autophagy, which increase prostate cancer cell motility. We also found that embigin promotes prostate cancer growth, spheroid- and colony-forming ability, and survival upon chemotherapy independently of S100A4. An in vivo growth mouse model confirmed the importance of embigin and its cytoplasmic tail in mediating prostate tumor growth. Moreover, embigin and p21WAF1 can be used to predict survival of prostate cancer patients. Our results demonstrated for the first time that the S100A4-embigin/AMPK/mTORC1/p21WAF1 and NF-κB/MMP9 axis is a vital oncogenic molecular cascade for prostate cancer progression. We proposed that embigin and p21WAF1 could be used as prognostic biomarkers and a strategy to inhibit S100A4-embigin binding could be a therapeutic approach for prostate cancer patients.

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  • 悪性胸膜中皮腫に対するREIC/Dkk-3遺伝子治療

    山本 寛斉, 諏澤 憲, 枝園 和彦, 宗 淳一, 黒崎 毅史, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本がん免疫学会総会プログラム・抄録集   22回   146 - 146   2018.7

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  • 膵がん進展に導く膵がん細胞 間質線維芽細胞クロストークを介在する分泌性S100A11 受容体RAGE連携の役割

    光井 洋介, 山本 健一, Sumardika I Wayan, 木下 理恵, 村田 等, 二見 淳一郎, 高松 仁, 山本 靖彦, 西堀 正洋, 豊岡 伸一, 渡部 昌実, 那須 保友, 阪口 政清

    日本がん免疫学会総会プログラム・抄録集   22回   156 - 156   2018.7

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  • 腫瘍浸潤リンパ球(TIL)を含んだ腫瘍解離細胞(DTC)の保存

    渡邊 元嗣, 高橋 優太, 冨田 秀太, 宗 淳一, 松原 岳大, 難波 圭, 佐藤 博紀, 森田 瑞樹, 枝園 和彦, 山本 寛斉, 鵜殿 平一郎, 豊岡 伸一

    日本がん免疫学会総会プログラム・抄録集   22回   161 - 161   2018.7

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  • 分泌性S100A11-受容体RAGEシグナルに着眼した膵がん間質増大のメカニズムの解明

    山本 健一, 高松 仁, 光井 洋介, 木下 理恵, 村田 等, 二見 淳一郎, 山本 靖彦, 西堀 正洋, 豊岡 伸一, 阪口 政清

    日本がん免疫学会総会プログラム・抄録集   22回   117 - 117   2018.7

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  • Is Surgery after Chemoradiotherapy Feasible in Lung Cancer Patients with Superior Vena Cava Invasion? Reviewed

    Sato H, Soh J, Hotta K, Katsui K, Kanazawa S, Kiura K, Toyooka S

    Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia   24 ( 3 )   131 - 138   2018.6

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    PURPOSE: The purpose of this study is to explore the possibility of surgery after chemoradiotherapy (CRT) for locally advanced-non-small-cell lung cancer (LA-NSCLC) with superior vena cava (SVC) resection in terms of prognosis and early and late postoperative course. METHODS: The medical records of NSCLC patients who underwent surgery after CRT at our institution between January 2001 and March 2016 were reviewed. We evaluated the feasibility of surgery with SVC resection after CRT. RESULTS: A total of 8 LA-NSCLC patients were enrolled in this study. The SVC management included a graft replacement in two patients, pericardial patch repair in two, and direct suture closure in four. A complete resection was achieved in seven of the eight patients (87.5%). Postoperative early and late complication rate (Clavien-Dindo classification ≥ grade III) was 25%. All the complications were manageable, and no treatment-related deaths occurred in this series. Although seven out of eight patients showed good patency of reconstructed SVC, one patient exhibited the SVC occlusion during long-term follow-up period. Regarding the prognosis, the 5-year overall survival (OS) rate was 60.0%, and the 2-year recurrence-free survival (RFS) rate was 75.0%. CONCLUSION: Our results suggest that surgery with SVC resection after CRT is a feasible procedure in terms of clinical outcomes and postoperative course.

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  • Tumor-suppressive effect of LRIG1, a negative regulator of ErbB, in non-small cell lung cancer harboring mutant EGFR. Reviewed International journal

    Hidejiro Torigoe, Hiromasa Yamamoto, Masakiyo Sakaguchi, Chen Youyi, Kei Namba, Hiroki Sato, Kazuhiko Shien, Junichi Soh, Ken Suzawa, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    Carcinogenesis   39 ( 5 )   719 - 727   2018.5

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    Epidermal growth factor receptor (EGFR) is a member of the ErbB (HER) family that is known to play important roles in the pathogenesis of various human cancers. Mutations of the EGFR gene are commonly found as oncogenic driver mutations and have been targeted for treatment of non-small cell lung cancer (NSCLC). Leucine-rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell-surface protein that is known as a negative regulator of the ErbB (HER) family. In this study, we first confirmed that the expression levels of LRIG1 were much lower in NSCLC than in non-malignant cells or tissues. Next, we focused on the effect of LRIG1 in NSCLC. For this purpose, we established clones stably overexpressing LRIG1, using EGFR-mutant (HCC827, HCC4011 and NCI-H1975) and wild-type (A549) cells. Transfection of LRIG1 was associated with a decrease in the expression and phosphorylation levels of EGFR in the HCC827, HCC4011 and NCI-H1975 cells. It was also associated with strong suppression of the cell proliferative, invasive, migratory and tumorigenic potential of the HCC827 cells. On the other hand, no such effects were observed in the A549 cells. In addition, LRIG1 also downregulated the expression and phosphorylation levels of other tyrosine kinase receptors, such as HER2, HER3, MET and IGF-1R, and prevented the epithelial-to-mesenchymal transition induced by TGF-β in the HCC827 cells. These findings suggest that LRIG1 exerts important tumor-suppressive effects in EGFR-mutant NSCLC and has the potential to become a novel therapeutic target for EGFR-mutant NSCLC.

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  • Preoperative short hookwire placement for small pulmonary lesions: evaluation of technical success and risk factors for initial placement failure Reviewed

    Toshihiro Iguchi, Takao Hiraki, Yusuke Matsui, Hiroyasu Fujiwara, Yoshihisa Masaoka, Takashi Tanaka, Takuya Sato, Hideo Gobara, Shinichi Toyooka, Susumu Kanazawa

    European Radiology   28 ( 5 )   2194 - 2202   2018.5

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    Objectives: To retrospectively evaluate the technical success of computed tomography fluoroscopy-guided short hookwire placement before video-assisted thoracoscopic surgery and to identify the risk factors for initial placement failure. Methods: In total, 401 short hookwire placements for 401 lesions (mean diameter 9.3 mm) were reviewed. Technical success was defined as correct positioning of the hookwire. Possible risk factors for initial placement failure (i.e., requirement for placement of an additional hookwire or to abort the attempt) were evaluated using logistic regression analysis for all procedures, and for procedures performed via the conventional route separately. Results: Of the 401 initial placements, 383 were successful and 18 failed. Short hookwires were finally placed for 399 of 401 lesions (99.5%). Univariate logistic regression analyses revealed that in all 401 procedures only the transfissural approach was a significant independent predictor of initial placement failure (odds ratio, OR, 15.326
    95% confidence interval, CI, 5.429–43.267
    p &lt
    0.001) and for the 374 procedures performed via the conventional route only lesion size was a significant independent predictor of failure (OR 0.793, 95% CI 0.631–0.996
    p = 0.046). Conclusions: The technical success of preoperative short hookwire placement was extremely high. The transfissural approach was a predictor initial placement failure for all procedures and small lesion size was a predictor of initial placement failure for procedures performed via the conventional route. Key points: • Technical success of preoperative short hookwire placement was extremely high. • The transfissural approach was a significant independent predictor of initial placement failure for all procedures. • Small lesion size was a significant independent predictor of initial placement failure for procedures performed via the conventional route.

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  • Therapeutic strategies for afatinib-resistant lung cancer harboring HER2 alterations Reviewed

    Hidejiro Torigoe, Kazuhiko Shien, Tatsuaki Takeda, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Masakiyo Sakaguchi, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    Cancer Science   109 ( 5 )   1493 - 1502   2018.5

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    Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small-cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan-HER inhibitor afatinib could be a useful therapeutic agent as HER2-targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib-resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib-resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial-to-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. The afatinib-resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC-like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations.

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  • A Multicenter Randomized Controlled Study of Paclitaxel plus Carboplatin versus Oral Uracil-Tegafur as the Adjuvant Chemotherapy in Resected Non-Small Cell Lung Cancer. Reviewed International journal

    Shinichi Toyooka, Norihito Okumura, Hiroshige Nakamura, Masao Nakata, Motohiro Yamashita, Hirohito Tada, Shinsuke Kajiwara, Naoki Watanabe, Morihito Okada, Junichi Sakamoto, Motoi Aoe, Junichi Soh, Shinichiro Miyoshi, Katsuyuki Hotta, Keitaro Matsuo, Hiroshi Date

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   13 ( 5 )   699 - 706   2018.5

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    INTRODUCTION: We conducted a randomized controlled study to compare the survival benefit of paclitaxel plus carboplatin and oral uracil-tegafur (UFT) as adjuvant chemotherapy in resected NSCLC. METHODS: In an open-label multicenter trial, patients with pathological stage IB to IIIA NSCLC were randomized into a group receiving paclitaxel (175 mg/m2) plus carboplatin (area under the curve 5) every 3 weeks for four cycles (arm A) or a group receiving orally administered UFT (250 mg/m2) daily for 2 years (arm B). The primary and secondary end points were overall survival and relapse-free survival and toxicity, respectively. RESULTS: Between November 2004 and November 2010, 402 patients from 40 institutions were included (201 in each arm). The median follow-up period was 6.5 years. The 5-year overall survival rate was 70% (95% confidential interval [CI]: 63-76] in arm A versus 73% (95% CI: 66-78) in arm B (hazard ratio = 0.92, 95% CI: 0.55-1.41, p = 0.69). There was no significant difference in the 5-year relapse-free survival rate between arms A and B (56% versus 57% [hazard ratio = 0.92, 95% CI: 0.63-1.34, p = 0.50]). Toxicities were well tolerated and there was no treatment-related death. Toxicities of any grade or grade 4 were significantly more frequent in the paclitaxel plus carboplatin group (95.7% and 22.1%, respectively) than in the UFT group (76.5% and 1.0%, respectively [p < 0.0001 in both]). CONCLUSIONS: As adjuvant chemotherapy, paclitaxel plus carboplatin was no better than UFT in terms of survival among patients with stage IB to IIIA NSCLC tumors who underwent complete resection (UMIN000000810).

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  • β-1,3-Galactosyl-O-Glycosyl-Glycoprotein β-1,6-N-Acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. Reviewed International journal

    I Wayan Sumardika, Chen Youyi, Eisaku Kondo, Yusuke Inoue, I Made Winarsa Ruma, Hitoshi Murata, Rie Kinoshita, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiroki Sato, Akira Yamauchi, Junichiro Futami, Endy Widya Putranto, Toshihiko Hibino, Shinichi Toyooka, Masahiro Nishibori, Masakiyo Sakaguchi

    Oncology research   26 ( 3 )   431 - 444   2018.4

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    We previously identified novel S100A8/A9 receptors, extracellular matrix metalloproteinase inducer (EMMPRIN), melanoma cell adhesion molecule (MCAM), activated leukocyte cell adhesion molecule (ALCAM), and neuroplastin (NPTN) β, that are critically involved in S100A8/A9-mediated cancer metastasis and inflammation when expressed at high levels. However, little is known about the presence of any cancer-specific mechanism(s) that modifies these receptors, further inducing upregulation at protein levels without any transcriptional regulation. Expression levels of glycosyltransferase-encoding genes were examined by a PCR-based profiling array followed by confirmation with quantitative real-time PCR. Cell migration and invasion were assessed using a Boyden chamber. Western blotting was used to examine the protein level, and the RNA level was examined by Northern blotting. Immunohistochemistry was used to examine the expression pattern of β-1,3-galactosyl-O-glycosyl-glycoprotein β-1,6-N-acetylglucosaminyltransferase 3 (GCNT3) and MCAM in melanoma tissue. We found that GCNT3 is overexpressed in highly metastatic melanomas. Silencing and functional inhibition of GCNT3 greatly suppressed migration and invasion of melanoma cells, resulting in the loss of S100A8/A9 responsiveness. Among the novel S100A8/A9 receptors, GCNT3 favorably glycosylates the MCAM receptor, extending its half-life and leading to further elevation of S100A8/A9-mediated cellular motility in melanoma cells. GCNT3 expression is positively correlated to MCAM expression in patients with high-grade melanomas. Collectively, our results showed that GCNT3 is an upstream regulator of MCAM protein and indicate the possibility of a potential molecular target in melanoma therapeutics through abrogation of the S100A8/A9-MCAM axis.

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  • Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer Reviewed

    Takahiro Yoshioka, Kazuhiko Shien, Kei Namba, Hidejiro Torigoe, Hiroki Sato, Shuta Tomida, Hiromasa Yamamoto, Hiroaki Asano, Junichi Soh, Kazunori Tsukuda, Takeshi Nagasaka, Toshiyoshi Fujiwara, Shinichi Toyooka

    Cancer Science   109 ( 4 )   1166 - 1176   2018.4

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    Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti-human epidermal growth factor receptor 2 (HER2) drugs have been developed, trastuzumab is still the only anti-HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2-positive gastric cancer. First, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan-HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an antitumor effect in most of the HER2-amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene that inhibits the activation of insulin-like growth factor-1 receptor (IGF-1R), were less sensitive to pan-HER inhibitors. A combination therapy consisting of pan-HER inhibitors and an IGF-1R inhibitor, picropodophyllin, showed a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER2 amplification and three cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER2-amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF-1R-targeting therapy can overcome drug insensitiveness in HER2-amplified gastric cancer.

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  • What factors determine the survival of patients with an acute exacerbation of interstitial lung disease after lung cancer resection? Reviewed

    Masahiro Miyajima, Atsushi Watanabe, Toshihiko Sato, Satoshi Teramukai, Masahito Ebina, Kazuma Kishi, Yukihiko Sugiyama, Haruhiko Kondo, Satoru Kobayashi, Yutaka Takahashi, Hiroyuki Ito, Ryoji Yamamoto, Shigeki Sawada, Hideki Fujimori, Kazunori Okabe, Jun Arikura, Yasushi Shintani, Hiroshige Nakamura, Shinichi Toyooka, Tohru Hasumi, Takehiro Watanabe, Yoshinobu Hata, Hisashi Iwata, Minoru Aoki, Kazuhito Funai, Shuhei Inoue, Osamu Kawashima, Tomohiko Iida, Hiroshi Date

    Surgery today   48 ( 4 )   404 - 415   2018.4

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    PURPOSES: Acute exacerbation of interstitial pneumonia (AEIP) is a leading cause of death after lung cancer resection in patients with interstitial lung disease. METHODS: We retrospectively analyzed 1763 patients with non-small cell lung cancer with a clinical diagnosis of interstitial lung disease (ILD) who underwent lung cancer resection between 2000 and 2009 at 61 hospitals in Japan. AEIP occurred in 164 of 1763 (9.3%) patients with a mortality rate of 43.9% (72/164). Univariate and multivariate analyses were carried out to identify possible risk factors of fatal AEIP. We then analyzed the 164 patients who developed postoperative AEIP and identified the preoperative and postoperative risk factors. RESULTS: A multivariate regression analysis identified that the sex, percent vital capacity, neoadjuvant radiation, preoperative history of AEIP, preoperative use of steroids, usual interstitial pneumonia pattern on CT, and surgical procedures were independent preoperative risk factors for death due to AEIP. ILD patients with emphysema somehow showed a lower risk of fatal AEIP than those without emphysema in this study. CONCLUSIONS: This study revealed eight risk factors for fatal AEIP.

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  • [Induction Chemoradiotherapy for Locally Advanced Non-small Cell Lung Cancer]. Reviewed

    Miura A, Soh J, Shien K, Yamamoto H, Toyooka S

    Kyobu geka. The Japanese journal of thoracic surgery   71 ( 4 )   270 - 277   2018.4

  • IV期肺癌における呼吸器外科の役割は拡大しているか? 手術を契機に診断した胸膜播種・悪性胸水を伴うIVA期肺癌は切除非適応か? 多施設共同後方視的解析

    藤原 俊哉, 松浦 求樹, 宗 淳一, 枝園 和彦, 山本 寛斉, 牧 佑歩, 上野 剛, 杉本 龍士郎, 岡崎 幹生, 田尾 裕之, 葉山 牧夫, 片岡 正文, 佐野 由文, 岡部 和倫, 山下 素弘, 川真田 修, 片岡 和彦, 森山 重治, 豊岡 伸一, 岡山大学呼吸器外科研究会

    日本呼吸器外科学会雑誌   32 ( 3 )   PD3 - 1   2018.4

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  • 【肺癌の集学的治療の現況】局所進行肺癌における集学的治療 局所進行非小細胞肺癌に対する術前導入化学放射線療法後手術

    三浦 章博, 宗 淳一, 枝園 和彦, 山本 寛斉, 豊岡 伸一

    胸部外科   71 ( 4 )   270 - 277   2018.4

  • Second primary cancer in survivors of locally advanced non-small cell lung cancer treated with concurrent chemoradiation followed by surgery Reviewed

    Go Makimoto, Toshio Kubo, Isao Oze, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Junichi Soh, Shinichi Toyooka, Kuniaki Katsui, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

    Japanese Journal of Clinical Oncology   48 ( 3 )   287 - 290   2018.3

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    The standard treatment for patients with locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT), but surgical resection following induction CRT can extend overall survival in a select population. However, patients who survive longer are at risk of developing a second primary cancer (SPC). This is the first report to determine the incidence of SPC in survivors with LA-NSCLC after trimodal therapy. Between October 1997 and October 2013, 112 Stage III NSCLC patients underwent trimodal therapy in our hospital. The 5-year overall survival rate was 71.8%. SPC developed in 10 of the 112 patients 0.60-15.0 (median 5.49) years after initiating CRT. The observed incidence of SPC was 1.8 per 100 patient-years. Although trimodal therapy can prolong patient survival, the estimated incidence of SPC does not increase. A large prospective study with a longer follow-up time is required to determine the effects of trimodal therapy, including the development of SPC.

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  • Therapeutic Potential of Afatinib for Cancers with ERBB2 (HER2) Transmembrane Domain Mutations G660D and V659E Reviewed

    Hiromasa Yamamoto, Shinichi Toyooka, Takashi Ninomiya, Shigemi Matsumoto, Masashi Kanai, Shuta Tomida, Katsuyuki Kiura, Manabu Muto, Ken Suzawa, Patrice Desmeules, Mark G. Kris, Bob T. Li, Marc Ladanyi

    Oncologist   23 ( 2 )   150 - 154   2018.2

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    We previously reported on a family with hereditary lung cancer, in which a germline mutation in the transmembrane domain (G660D) of avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2
    human epidermal growth factor receptor 2 [HER2]) seemed to be responsible for the cancer predisposition. Although few data are available on treatment, anti-ERBB2 therapeutic agents may be effective for ERBB2-mutant cancers. The familial lung cancer patient in one of the authors’ institutes developed bone metastasis with enlarging lung tumors and was treated with the ERBB2 inhibitor afatinib. We also encountered a patient with ampullary adenocarcinoma with ERBB2 G660D and S310F comutations in another institute of the authors’, revealed by comprehensive genomic profiling. This patient was then treated with afatinib and also achieved transitory response. We also searched for ERBB2 transmembrane mutations in various types of cancers in PubMed, The Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) database. Besides our two cases, two patients with V659E mutations were found via PubMed. Three potential patients were found in TCGA. In addition, MSK-IMPACT allowed identification of three additional urothelial carcinomas with G660D mutations and two lung adenocarcinomas with V659E mutations. Our experience suggests that establishing a database of integrated information regarding the clinical genome and therapeutic outcome of patients with recurrent but less common mutations is essential to implement precision oncology. Key Points: Rare but targetable mutations such as avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2
    human epidermal growth factor receptor 2 [HER2]) transmembrane domain (TMD) mutations can be detected by comprehensive genomic profiling. Afatinib may be effective for patients with cancer with ERBB2 (HER2) TMD mutations. In order to implement precision oncology, it is important to establish a database of integrated information regarding the clinical genomes and therapeutic outcomes of patients with recurrent but less common mutations.

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  • A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non–Small Cell Lung Cancer Reviewed

    Katsuyuki Hotta, Keisuke Aoe, Toshiyuki Kozuki, Kadoaki Ohashi, Kiichiro Ninomiya, Eiki Ichihara, Toshio Kubo, Takashi Ninomiya, Kenichi Chikamori, Daijiro Harada, Naoyuki Nogami, Taizo Hirata, Shiro Hinotsu, Shinichi Toyooka, Katsuyuki Kiura

    Journal of Thoracic Oncology   13 ( 2 )   273 - 279   2018.2

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    Trastuzumab emtansine (T-DM1), an anti–erb-b2 receptor tyrosine kinase 2 (HER2) antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a phase II trial of T-DM1 monotherapy in relapsed NSCLC with documented HER2 positivity (an immunohistochemistry [IHC] score of 3+, both an IHC score of 2+ and fluorescence in situ hybridization positivity, or exon 20 mutation). This study was terminated early because of limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: median age, 67 years
    male sex, 47%
    performance status of 0 to 1, 80%
    HER2 status IHC 3+, 33%
    HER status IHC 2+/fluorescence in situ hybridization–positive, 20%
    and exon 20 mutation, 47%. The median number of delivered cycles was 3 (range 1–11). One patient achieved a partial response with an objective response rate of 6.7% (90% confidence interval: 0.2–32.0). With a median follow-up time of 9.2 months, the median progression-free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3 or 4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment-related deaths. T-DM1 had a limited efficacy for HER2-positive NSCLC in our cohort. Applying the concept of precision medicine to tumors appears challenging
    thus, additional molecular approaches are warranted.

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  • Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma Reviewed

    Hiroki Sato, Masakiyo Sakaguchi, Hiromasa Yamamoto, Shuta Tomida, Keisuke Aoe, Kazuhiko Shien, Takahiro Yoshioka, Kei Namba, Hidejiro Torigoe, Junichi Soh, Kazunori Tsukuda, Hiroyuki Tao, Kazunori Okabe, Shinichiro Miyoshi, Harvey I. Pass, Shinichi Toyooka

    Oncogenesis   7 ( 1 )   11   2018.1

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    Malignant pleural mesothelioma (MPM) is an aggressive tumor with an unfavorable prognosis. The standard therapeutic approaches are limited to surgery, chemotherapy, and radiotherapy. Because the consequent clinical outcome is often unsatisfactory, a different approach in MPM treatment is required. S100A11, a Ca2+-binding small protein with two EF-hands, is frequently upregulated in various human cancers. Interestingly, it has been found that intracellular and extracellular S100A11 have different functions in cell viability. In this study, we focused on the impact of extracellular S100A11 in MPM and explored the therapeutic potential of an S100A11-targeting strategy. We examined the secretion level of S100A11 in various kinds of cell lines by enzyme-linked immunosorbent assay. Among them, six out of seven MPM cell lines actively secreted S100A11, whereas normal mesothelial cell lines did not secrete it. To investigate the role of secreted S100A11 in MPM, we inhibited its function by neutralizing S100A11 with an anti-S100A11 antibody. Interestingly, the antibody significantly inhibited the proliferation of S100A11-secreting MPM cells in vitro and in vivo. Microarray analysis revealed that several pathways including genes involved in cell proliferation were negatively enriched in the antibody-treated cell lines. In addition, we examined the secretion level of S100A11 in various types of pleural effusions. We found that the secretion of S100A11 was significantly higher in MPM pleural effusions, compared to others, suggesting the possibility for the use of S100A11 as a biomarker. In conclusion, our results indicate that extracellular S100A11 plays important roles in MPM and may be a therapeutic target in S100A11-secreting MPM.

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  • Development of novel biologics for cancer metastasis via prevention of extracellular S100A8/A9 function Reviewed

    Kinoshita Rie, Yamauchi Akira, Shien Kazuhiko, Tomida Shuta, Toyooka Shinichi, Kondo Eisaku, Sakaguchi Masakiyo

    CANCER SCIENCE   109   1017   2018.1

  • Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension. Reviewed International journal

    Kazufumi Nakamura, Masakiyo Sakaguchi, Hiromi Matsubara, Satoshi Akagi, Toshihiro Sarashina, Kentaro Ejiri, Kaoru Akazawa, Megumi Kondo, Koji Nakagawa, Masashi Yoshida, Toru Miyoshi, Takeshi Ogo, Takahiro Oto, Shinichi Toyooka, Yuichiro Higashimoto, Kei Fukami, Hiroshi Ito

    PloS one   13 ( 9 )   e0203046   2018

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    BACKGROUND: Pulmonary vascular remodeling of pulmonary arterial hypertension (PAH) is characterized by an inappropriate increase of vascular cells. The receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of hyperproliferative diseases. RAGE is also implicated in the etiology of PAH and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in patients with PAH. METHODS AND RESULTS: PASMCs were obtained from 12 patients with PAH including 9 patients with idiopathic PAH (IPAH) and 3 patients with heritable PAH (HPAH) (2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining revealed that RAGE and S100A8 and A9, ligands of RAGE, were overexpressed in IPAH and HPAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE in IPAH and HPAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by 3H-thymidine incorporation. This result indicates overgrowth characterized by continued growth under a condition of no growth stimulation in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under a condition of no growth stimulation in IPAH and HPAH-PASMCs (P<0.0001). Furthermore, AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH and HPAH-PASMCs (P<0.0001). CONCLUSIONS: RAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH.

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  • Short hookwire placement under imaging guidance before thoracic surgery: A review Reviewed

    T. Iguchi, T. Hiraki, Y. Matsui, H. Fujiwara, Y. Masaoka, M. Uka, H. Gobara, S. Toyooka, S. Kanazawa

    Diagnostic and Interventional Imaging   2018

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    During video-assisted thoracic surgery (VATS), localization is sometimes needed to detect a target lesion that is too small and/or too far from the pleura. In 1995, Kanazawa et al. developed short hookwire and suture system. Since then, this system has been placed often for selected targets before VATS in Japan. This short hookwire and suture system is a representative preoperative localization method and the placement procedure is well-established. Its placement success rates are very high (range: 97.6%–99.6%), and dislodgement of this short hookwire rarely occurs with an incidence of 0.4%–2.5%. The most common complication of short hookwire placement is pneumothorax (incidence: 32.1%–68.1%), followed by pulmonary hemorrhage (incidence: 8.9%–41.6%). Complications are frequent
    however, most complications are minor and asymptomatic.

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  • Model of lung cancer surgery risk derived from a Japanese nationwide web-based database of 78 594 patients during 2014-2015 Reviewed

    Shunsuke Endo, Norihiko Ikeda, Takashi Kondo, Jun Nakajima, Haruhiko Kondo, Kohei Yokoi, Masayuki Chida, Masami Sato, Shinichi Toyooka, Koichi Yoshida, Yoshinori Okada, Yukio Sato, Morihito Okada, Meinoshin Okumura, Koji Chihara, Eriko Fukuchi, Hiroaki Miyata

    EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY   52 ( 6 )   1182 - 1189   2017.12

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    OBJECTIVES: Using data obtained from a Japanese nationwide annual database with web-based data entry, we developed a risk model of mortality and morbidity after lung cancer surgery.
    METHODS: The characteristics and operative and postoperative data from 80 095 patients who underwent lung cancer surgery were entered into the annual National Clinical Database of Japan data sets for 2014 and 2015. After excluding 1501 patients, the development data set for risk models included 38 277 patients entering in 2014 and the validation data set included 40 317 patients entering in 2015. Receiver-operating characteristic curves were generated for the outcomes of mortality and composite mortality/major morbidity. The concordance index was used to assess the discriminatory ability and validity of the model.
    RESULTS: The 30-day mortality and overall mortality rates, including in-hospital deaths, were 0.4% and 0.8%, respectively, in 2014, and 0.4% and 0.8%, respectively, in 2015. The rate of major morbidity was 5.6% in 2014 and 5.6% in 2015. Several risk factors were significantly associated with mortality, namely, male sex, performance status, comorbidities of interstitial pneumonia and liver cirrhosis, haemodialysis and the surgical procedure pneumonectomy. The concordance index for mortality and composite mortality/major morbidity was 0.854 (P &lt; 0.001) and 0.718 (P &lt; 0.001), respectively, for the development data set and 0.849 (P &lt; 0.001) and 0.723 (P &lt; 0.001), respectively, for the validation data set.
    CONCLUSIONS: This model was satisfactory for predicting surgical outcomes after pulmonary resection for lung cancer in Japan and will aid preoperative assessment and improve clinical outcomes for lung cancer surgery.

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  • 胸膜外肺全摘術と放射線療法で、術後13年無再発生存中の悪性胸膜中皮腫の1例

    岡部 和倫, 山本 寛斉, 宗 淳一, 豊岡 伸一

    肺癌   57 ( 7 )   895 - 895   2017.12

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  • Restrictive ventilatory impairment is associated with poor outcome in patients with cT1aN0M0 peripheral squamous cell carcinoma of the lung Reviewed

    Hiroyuki Tao, Junichi Soh, Hiromasa Yamamoto, Toshiya Fujiwara, Tsuyoshi Ueno, Makio Hayama, Mikio Okazaki, Ryujiro Sugimoto, Motohiro Yamashita, Yoshifumi Sano, Kazunori Okabe, Motoki Matsuura, Kazuhiko Kataoka, Shigeharu Moriyama, Shinichi Toyooka, Shinichiro Miyoshi

    JOURNAL OF THORACIC DISEASE   9 ( 11 )   4325 - 4335   2017.11

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    Background: Patients with squamous cell carcinoma (SqCC) of the lung sometimes have a comorbid pulmonary disease such as pulmonary emphysema or an interstitial lung disease (ILD), both of which negatively affect patient outcome. The aim of this study was to determine the outcome of patients in a multicenter database who underwent surgery for cT1aN0M0 peripheral SqCC lung cancer.
    Methods: The medical records of a total of 228 eligible patients from seven institutions were reviewed to evaluate the impact of concomitant impaired pulmonary function and other clinicopathological factors on overall survival (OS) and relapse-free survival (RFS).
    Results: Six patients with positive or unclear tumor margins were excluded. Of the 222 remaining study patients, 42 (18.9%) and 97 (43.7%) patients were found to have coexisting restrictive or obstructive ventilatory impairment, respectively. Over a median follow-up period of 30.6 months, the 5-year OS and RFS were 69.0% and 62.6%, respectively. By multivariate analysis, ILDs identified on high-resolution computed tomography (HRCT), pulmonary function test results indicating a restrictive ventilatory impairment, and wedge resection were found to be independent risk factors for poor OS. An increased level of serum squamous cell carcinoma antigen (SCC-Ag) (&gt; 1.5 ng/mL) and the same risk factors for poor OS were independent risk factors for recurrence. Among patients who underwent anatomical lung resection (lobectomy and segmentectomy, n=173), a restrictive ventilatory impairment was an independent risk factor for poor OS, and increased serum SCC-Ag level, ILDs on HRCT, and restrictive ventilatory impairment were independent risk factors for poor RFS by multivariate analysis. Factors such as visceral pleural invasion, and lymphatic or vascular invasion were not significantly associated with outcome.
    Conclusions: A restrictive ventilatory impairment negatively affects the outcome of patients with cT1aN0M0 peripheral SqCC lung cancer.

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  • Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer Reviewed

    Haiyang Chen, Kazuhiko Shien, Ken Suzawa, Kazunori Tsukuda, Shuta Tomida, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Kei Namba, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Shinichiro Miyoshi, Shinichi Toyooka

    ONCOLOGY LETTERS   14 ( 4 )   4349 - 4354   2017.10

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    Docetaxel is a third-generation chemotherapeutic drug that is widely used in the treatment of patients with non-small cell lung cancer (NSCLC). However, the majority of patients with NSCLC eventually acquire resistance to the treatment. In the present study, the mechanism of acquired resistance to docetaxel treatment in lung cancer cells was investigated. The three NSCLC cell lines, H1299 with wild-type epidermal growth factor receptor (EGFR), EGFR-mutant HCC4006 and HCC827, and experimentally established docetaxel-resistant (DR) cells, H1299-DR, HCC827-DR, and HCC4006-DR were used with stepwise increases in concentrations of docetaxel. It was demonstrated that the established cell lines showed resistance to docetaxel and EGFR-tyrosine kinase inhibitors (TKIs). Molecular analysis revealed that all of the resistant cell lines highly expressed ATP binding cassette subfamily B member 1 (ABCB1), which is also known as P-glycoprotein or MDR1. Furthermore, HCC827-DR and HCC4006-DR cells exhibited a cancer stem cell-like marker and epithelial-to-mesenchymal transition features, respectively. Elacridar (GF120918), a third-generation inhibitor of ABCB1, was able to overcome resistance to docetaxel. Additionally, knockdown of ABCB1 using small interfering RNA (si)-ABCB1 recovered sensitivity to docetaxel. However, elacridar and si-ABCB1 could not recover sensitivity to EGFR-TKIs in established resistant cells. The results of the present study revealed that docetaxelresis-tant NSCLC cells also acquired cross-resistance to EGFR-TKI therapy through mechanisms other than ABCB1, that ABCB1 serves an important role in acquired resistance to docetaxel in lung cancer, and that combination therapy with elacridar can overcome ABCB1-mediated docetaxel resistance.

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  • Postoperative pyoderma gangrenosum exacerbated by granulocyte-colony stimulating factor after lung cancer surgery Reviewed

    Haruchika Yamamoto, Seiichiro Sugimoto, Shinji Otani, Shinichi Toyooka

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   47 ( 10 )   991 - 992   2017.10

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  • JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer Reviewed

    Kazuhiko Shien, Vassiliki A. Papadimitrakopoulou, Dennis Ruder, Carmen Behrens, Li Shen, Neda Kalhor, Juhee Song, J. Jack Lee, Jing Wang, Ximing Tang, Roy S. Herbst, Shinichi Toyooka, Luc Girard, John D. Minna, Jonathan M. Kurie, Ignacio I. Wistuba, Julie G. Izzo

    MOLECULAR CANCER THERAPEUTICS   16 ( 10 )   2234 - 2245   2017.10

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    Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non-small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine IL6 and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAF). We also analyzed the prognostic significance of these molecule expressions in clinical NSCLC samples. In NSCLC cells with acquired resistance to targeted drugs, we observed activation of the IL6-cytokine pathway and STAT3 along with epithelial-to-mesenchymal transition (EMT) features. In particular, IL6 family cytokine oncostatin-M (OSM) induced a switch to the EMT phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3-dependent manner. The crosstalk between NSCLC cells and CAFs also preferentially activated the OSM/STAT3 pathway via a paracrine mechanism and decreased sensitivity to targeted drugs. The selective JAK1 inhibitor filgotinib effectively suppressed STAT3 activation and OSMR expression, and cotargeting inhibition of the oncogenic pathway and JAK1 reversed resistance to targeted drugs. In the analysis of clinical samples, OSMR gene expression appeared to be associated with worse prognosis in patients with surgically resected lung adenocarcinoma. Our data suggest that the OSMRs/JAK1/STAT3 axis contributes to resistance to targeted drugs in oncogene-driven NSCLC cells, implying that this pathway could be a therapeutic target. (C) 2017 AACR.

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  • Effects of Cold Ischemia on RNA Stability and Quality of Lung Tissues Based on Standard PREanalytical Code Categorization Reviewed

    Takehiro Matsubara, Shuta Tomida, Junichi Soh, Takahiro Uwabo, Yoshiko Mori, Mizuki Morita, Yasutomo Nasu, Susumu Kanazawa, Shinichi Toyooka

    BIOPRESERVATION AND BIOBANKING   15 ( 5 )   484 - 486   2017.10

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  • 臨床試験から視た肺癌手術 瀬戸内肺癌研究会13年の活動

    宗 淳一, 奥村 典仁, 山下 芳典, 片岡 和彦, 佐野 由文, 片岡 正文, 岡部 和倫, 山下 素弘, 青江 基, 中田 昌男, 根津 賢司, 中村 廣繁, 三好 新一郎, 豊岡 伸一, 伊達 洋至

    日本臨床外科学会雑誌   78 ( 増刊 )   333 - 333   2017.10

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  • Estimation of age-related DNA degradation from formalin-fixed and paraffin-embedded tissue according to the extraction methods Reviewed

    Mototsugu Watanabe, Shinsuke Hashida, Hiromasa Yamamoto, Takehiro Matsubara, Tomoaki Ohtsuka, Ken Suzawa, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichi Toyooka, Shinichiro Miyoshi

    EXPERIMENTAL AND THERAPEUTIC MEDICINE   14 ( 3 )   2683 - 2688   2017.9

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    Techniques for the extraction and use of nucleic acids from formalin-fixed and paraffin-embedded (FFPE) tissues, preserved over long time periods in libraries, have been developed. However, DNA extracted from FFPE tissues is generally damaged, and long-term storage may affect DNA quality. Therefore, it is important to elucidate the effect of long-term storage on FFPE tissues and evaluate the techniques used to extract DNA from them. In the present study, the yield, purity, and integrity of DNA in FFPE tissue samples was evaluated. Two DNA extraction techniques were used: A silica-binding DNA collection method using QIAamp DNA FFPE Tissue kit (QIA) and a total tissue DNA collection method using a WaxFree DNA extraction kit (WAX). A total of 25 FFPE tissues from lung adenocarcinomas were studied, which had been surgically resected and fixed at Okayama University Hospital prior to examination and subsequent storage at room temperature for 0.5, 3, 6, 9 and 12 years. Extracted DNA was quantified using ultraviolet absorbance, fluorescent dye, and quantitative polymerase chain reaction (qPCR). The quality of the DNA was defined by the absorbance ratio of 260 to 280 nm (A260/280) and Q-score, which is the quantitative value of qPCR product size ratio. The results demonstrated that the yield of total DNA extracted using WAX was significantly greater than when QIA was used (P&lt;0.01); however, DNA extracted using WAX included more contaminants and was significantly more fragmented compared with DNA extracted using QIA (P&lt;0.01). Aging had no significant effect on absolute DNA yield or DNA purity, although it did significantly contribute to increased DNA degradation for both QIA and WAX extraction (QIA P=0.02, WAX P=0.03; 0.5 years vs. 3 years, QIA P&lt;0.01, WAX P=0.03; 9 years vs. 12 years). Both extraction methods are viable depending on whether high yield or high quality of extracted DNA is required. However, due to the increased degradation with age, storage time limits the available DNA in FFPE tissues regardless of the extraction method.

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  • Induction chemoradiotherapy using docetaxel and cisplatin with definitive-dose radiation followed by surgery for locally advanced non-small cell lung cancer Reviewed

    Hidejiro Torigoe, Junichi Soh, Shuta Tomida, Kei Namba, Hiroki Sato, Kuniaki Katsui, Katsuyuki Hotta, Kazuhiko Shien, Hiromasa Yamamoto, Masaomi Yamane, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC DISEASE   9 ( 9 )   3076 - 3086   2017.9

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    Background: Induction chemoradiotherapy (CRT) followed by surgery is a therapeutic option for locally advanced non-small cell lung cancer (LA-NSCLC). Typically, around 40-50 Gy of radiation is applied as the induction-dose; however, a definitive-dose (DD) of radiation (60 Gy or higher) is occasionally applied to increase local control. We investigated the impact of induction CRT with DD radiation in LA-NSCLC patients treated with a single regimen of docetaxel and cisplatin.
    Methods: We reviewed 110 patients with LA-NSCLC who underwent induction CRT followed by surgery using a single regimen (docetaxel and cisplatin) between January 1999 and December 2014 at our hospital. The clinical outcomes of a DD group (60 Gy or higher, n= 11) and a non-DD group (less than 60 Gy, n= 99) were investigated using a propensity score (PS)-matched analysis.
    Results: An advanced clinical stage was significantly more common in the DD group than in the nonDD group (P= 0.033). Before and after the PS-matching based on seven factors including clinical stage, there was no significant difference in the rates of postoperative (PO) complication, mortality, 5-year overall survival (OS), or 5-year recurrence-free survival (RFS) between the two groups. After the PS-matching, the pathological complete response (CR) rate was significantly higher in the DD group than in the non-DD group [50% (n= 5/10) vs. 0% (n= 0/10), P= 0.033].
    Conclusions: Induction CRT followed by surgery using docetaxel and cisplatin with DD radiation can be performed safely and is associated with a higher pathological CR rate than that attained using non-DD radiation in LA-NSCLC patients.

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  • Advantage of Induction Chemoradiotherapy for Lung Cancer in Securing Cancer-Free Bronchial Margin Reviewed

    Hiroki Sato, Shinichi Toyooka, Junichi Soh, Katsuyuki Hotta, Kuniaki Katsui, Kazuhiko Shien, Hiromasa Yamamoto, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi

    ANNALS OF THORACIC SURGERY   104 ( 3 )   971 - 978   2017.9

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    Background. Bronchoplasty is a useful procedure for preserving pulmonary function. For this procedure, it is critical to secure the negative surgical margin for avoiding local recurrence. In this study, we examined the status of the surgical bronchial margin as well as the clinical outcomes in bronchoplasty with or without induction chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC).
    Methods. The medical records of NSCLC patients who underwent bronchoplasty at our institution between January 1999 and September 2014 were reviewed. We compared the clinical outcomes of bronchoplasty with or without induction CRT.
    Results. A total of 58 NSCLC patients were included in this study. Among these, 38 patients underwent primary surgical procedure with bronchoplasty and 20 patients underwent bronchoplasty after induction CRT. Intraoperative pathologic diagnosis for the surgical margin of the bronchus revealed that the patients in the primary surgical procedure group had a significantly higher rate of positive surgical margin than the induction CRT group (p = 0.023), requiring an additional bronchial resection to secure the negative margin. After additional resection of positive bronchial stumps, no significant difference was found in the rate of positive margin with postoperative histologic diagnosis between the two groups. In addition, no significant differences in the postoperative complication rate and overall and recurrence-free survivals were observed between the two groups.
    Conclusions. Our results suggest that induction CRT before surgical procedure may help ensure the intraoperative negative surgical margin of the bronchus. Our study also indicates that bronchoplasty after induction CRT is feasible in comparison with bronchoplasty in primary surgical procedure. (C) 2017 by The Society of Thoracic Surgeons

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  • 第3世代EGFR-TKI Osimertinib耐性肺癌細胞株における獲得耐性機構の解明

    難波 圭, 枝園 和彦, 吉岡 貴裕, 鳥越 英次郎, 佐藤 博紀, 山本 寛斉, 宗 淳一, 浅野 博昭, 佃 和憲, 豊岡 伸一

    肺癌   57 ( 5 )   440 - 440   2017.9

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  • 分子標的薬への耐性機構の解明 肺がんにおける分子標的薬耐性メカニズムの解明

    枝園 和彦, 佐藤 博紀, 鳥越 英次郎, 難波 圭, 吉岡 貴裕, 山本 寛斉, 宗 淳一, 豊岡 伸一

    肺癌   57 ( 5 )   377 - 377   2017.9

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  • 抗HER2療法耐性におけるYes1の重要性

    武田 達明, 山本 寛斉, 諏澤 憲, 冨田 秀太, 難波 圭, 渡邉 元嗣, 枝園 和彦, 宗 淳一, 佃 和憲, 豊岡 伸一

    日本癌学会総会記事   76回   P - 3366   2017.9

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  • 肺がん新治療の展望 HER2異常肺癌に対する治療戦略

    豊岡 伸一, 諏澤 憲, 二宮 崇, 山本 寛斉, 枝園 和彦, 宗 淳一, 冨田 秀太, 木浦 勝行

    日本癌学会総会記事   76回   SST6 - 3   2017.9

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  • 分子バーコード技術を用いた低頻度多重変異の同定

    難波 圭, 冨田 秀太, 枝園 和彦, 山本 寛斉, 宗 淳一, 佃 和憲, 豊岡 伸一

    日本癌学会総会記事   76回   P - 3052   2017.9

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  • HER2陽性胃癌に対するアファチニブ・ネラチニブの抗腫瘍効果

    吉岡 貴裕, 枝園 和彦, 高橋 優太, 栗原 英祐, 難波 圭, 鳥越 英次郎, 佐藤 博紀, 山本 寛斉, 宗 淳一, 浅野 博昭, 佃 憲徳, 藤原 俊義, 豊岡 伸一

    日本癌学会総会記事   76回   P - 2336   2017.9

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  • HER2遺伝子異常肺癌に対するマルチキナーゼ阻害剤Afatinb耐性獲得機序の解明

    鳥越 英次郎, 枝園 和彦, 吉岡 貴裕, 難波 圭, 佐藤 博紀, 山本 寛斉, 宗 淳一, 浅野 博昭, 冨田 秀太, 佃 和憲, 豊岡 伸一

    肺癌   57 ( 5 )   441 - 441   2017.9

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  • Radiofrequency ablation of pulmonary tumors near the diaphragm Reviewed

    T. Iguchi, T. Hiraki, H. Gobara, H. Fujiwara, J. Sakurai, Y. Matsui, T. Mitsuhashi, S. Toyooka, S. Kanazawa

    DIAGNOSTIC AND INTERVENTIONAL IMAGING   98 ( 7-8 )   535 - 541   2017.7

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    Purpose: To retrospectively evaluate the feasibility, safety, and efficacy of radiofrequency ablation (RFA) of lung tumors located near the diaphragm.
    Materials and methods: A total of 26 patients (15 men, 11 women; mean age, 61.5 years +/- 13.0 [SD]) with a total of 29 lung tumors near the diaphragm (i.e., distance &lt; 10 mm) were included. Mean tumor diameter was 11.0 mm +/- 5.3 (SD) (range, 2-23 mm). Efficacy of RFA, number of adverse events and number of adverse events with a grade &gt;= 3, based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, were compared between patients with lung tumors near the diaphragm and a control group of patients with more distally located lung tumors (i.e., distance &gt;= 10 mm).
    Results: RFA was technically feasible for all tumors near the diaphragm. Four grade 3 adverse events (1 pneumothorax requiring pleurodesis and 3 phrenic nerve injuries) were observed. No grade &gt;= 4 adverse events were reported. The median follow-up period for tumors near the diaphragm was 18.3 months. Local progression was observed 3.3 months after RFA in 1 tumor. The technique efficacy rates were 96.2% at 1 year and 96.2% at 2 years and were not different, from those observed in control subjects (186 tumors; P = 0.839). Shoulder pain (P &lt; 0.001) and grade 1 pleural effusion (P &lt; 0.001) were more frequently observed in patients with lung tumor near the diaphragm. The rates of grade &gt;= 3 adverse events did not significantly differ between tumors near the diaphragm (4/26 sessions) and the controls (7/133 sessions) (P = 0.083).
    Conclusion: RFA is a feasible and effective therapeutic option for lung tumors located near the diaphragm. However, it conveys a higher rate of shoulder pain and asymptomatic pleural effusion by comparison with more distant lung tumors. (C) 2017 Editions francaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

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  • Erratum to “Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer” [Lung Cancer 76 (1) (2012) 32–38](S0169500211005150)(10.1016/j.lungcan.2011.10.002) Reviewed

    Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Hiromasa Yamamoto, Yuho Maki, Takayuki Muraoka, Kazuhiko Shien, Masashi Furukawa, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Keisuke Aoe, Shinichiro Miyoshi

    Lung Cancer   76 ( 1 )   32 - 38   2017.6

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    Small-cell lung cancer (SCLC) is an aggressive tumor with a dismal prognosis among primary lung cancers. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family is comprised of tumor-suppressive miRNAs, and its reduced expression by methylation has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the alteration and tumor-suppressive impact of miR-34s in SCLC. The methylation of miR-34a and miR-34b/c was observed in 4 (36%) and 7 (64%) of 11 SCLC cell lines, respectively. Among the 27 SCLC clinical specimens, miR-34a and miR-34b/c were methylated in 4 (15%) and 18 (67%), respectively. In contrast, 13 (28%) miR-34a methylated cases and 12 (26%) miR-34b/c methylated cases were found in 47 NSCLC primary tumors. The frequency of miR-34b/c methylation was significantly higher in SCLC than in NSCLC (p&lt
    . 0.001). The expressions of miR-34s were reduced in methylated cell lines and tumors and restored after 5-aza-2'-deoxycytidine treatment, indicating that methylation was responsible for the reduced expression of miR-34s. Because the frequency of methylation was higher in miR-34b/c, we focused on miR-34b/c for a functional analysis. We examined the effect of miR-34b/c introduction on cell proliferation, migration and invasion. The transfection of miR-34b/c to two SCLC cell lines (H1048 and SBC5) resulted in the significant inhibition of cell growth, migration, and invasion, compared with control transfectants. Our results indicate that the aberrant methylation of miR-34b/c plays an important role in the pathogenesis of SCLC, implying that miR-34b/c may be a useful therapeutic target for SCLC. © 2011 Elsevier Ireland Ltd.

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  • Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer (vol 76, pg 32, 2012) Reviewed

    Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Hiromasa Yamamoto, Yuho Maki, Takayuki Muraoka, Kazuhiko Shien, Masashi Furukawa, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Keisuke Aoe, Shinichiro Miyoshi

    LUNG CANCER   108   254 - 255   2017.6

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  • Optimal method for quantitative detection of plasma EGFR T790M mutation using droplet digital PCR system Reviewed

    Ken Suzawa, Hiromasa Yamamoto, Kadoaki Ohashi, Shinsuke Hashida, Shuta Tomida, Toshio Kubo, Yuho Maki, Junichi Soh, Kazunori Tsukuda, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

    ONCOLOGY REPORTS   37 ( 5 )   3100 - 3106   2017.5

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    Though patients with EGFR mutations are initially responsive to EGFR-tyrosine kinase inhibitors (TKIs), most tumors ultimately acquire resistance to EGFR-TKIs. The most frequently reported mechanism is EGFR T790M mutation. In this study, using a droplet digital PCR (ddPCR) system, we assessed optimal conditions for a mutation detection assay for EGFR T790M obtained from circulating cell-free DNA (cfDNA) in plasma. The advantages of locked nucleic acids (LNA) probe, short amplicon size, and blocking oligo using peptide nucleic acids (PNA) were assessed using control DNAs from cell lines to improve the sensitivity of mutation detection. T790M alleles were then analyzed using ddPCR in 59 plasma samples from 24 NSCLC patients with EGFR mutations, and compared to the T790M status which were determined thorough re-biopsies. The assessment of the optimal assay method revealed that the assay using the short amplicon can efficiently detect more fragmented-DNA. The LNA probe and PNA clamp contributed better separation between positive and negative droplets. This PNA-LNA-ddPCR clamp method can detect mutant alleles in the sample with a mutant allele content of 0.01%. In clinical plasma samples, T790M alleles were detected via ddPCR with a sensitivity of 42.8% and specificity of 97.3%. We established a highly-sensitive detection assay for the T790M allele using the PNA-LNA-ddPCR clamp method. ddPCR is a promising method for detecting non-invasive T790M mutation.

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  • Is tumor location an independent prognostic factor in locally advanced non-small cell lung cancer treated with trimodality therapy? Reviewed

    Kazuhiko Shien, Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Shinichiro Miyoshi

    JOURNAL OF THORACIC DISEASE   9 ( 5 )   E489 - E491   2017.5

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  • Early postoperative complications after middle lobe-preserving surgery for secondary lung cancer Reviewed

    Yuho Maki, Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Shinichiro Miyoshi

    SURGERY TODAY   47 ( 5 )   601 - 605   2017.5

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    Purpose Preservation of the middle lobe during lung surgery is traditionally avoided, because its presence in the hemithoracic cavity is considered a cause of complications. We report a series of lung cancer patients who underwent a secondary pulmonary resection with the preservation of the middle lobe to explore the complications and feasibility of these procedures.
    Methods We reviewed the clinical courses of six patients who underwent surgery for metachronous lung cancers. Five patients underwent right upper lobectomy, including one sleeve lobectomy, after having undergone prior right lower lobectomy. The remaining patient underwent a right lower lobectomy after having undergone a prior right upper lobectomy.
    Results There were no treatment-related deaths. One patient was readmitted for surgery to treat delayed air leakage progressing to pyothorax. One patient was treated for persistent air leakage. Two patients required intermittent drainage of pulmonary effusion, because of middle lobe atelectasis. The postoperative forced vital capacity and forced expiratory volume in 1 s were greater than the values predicted post-pneumonectomy in four evaluable patients.
    Conclusions While postoperative complications after middle lobe-preserving surgery are manageable, their high incidence should be considered when performing this surgery.

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  • Diagnostic Value of Dual-time-point F-18 FDG PET/CT and Chest CT for the Prediction of Thymic Epithelial Neoplasms Reviewed

    Takayoshi Shinya, Takashi Tanaka, Junichi Soh, Toshi Matsushita, Shuhei Sato, Shinichi Toyooka, Tadashi Yoshino, Shinichiro Miyoshi, Susumu Kanazawa

    ACTA MEDICA OKAYAMA   71 ( 2 )   105 - 112   2017.4

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    We retrospectively assessed the dual-time-point (DTP) F-18 FDG PET/CT findings of thymic epithelial neoplasms (TENs) and investigated the diagnostic capacity of PET/CT compared to that of CT for predicting carcinoma. We calculated the ratio of the standardized uptake value of the tumor and that of the aortic arch (T/M ratio) for both the 90-min early scan and the 2-h delayed scan in 56 TEN patients. We used a multivariate logistic regression (MLR) analysis to estimate the CT features of carcinoma. We compared the diagnostic capacities of PET/CT and chest CT using receiver operating characteristic (ROC) analyses. The ROC curve revealed that the appropriate cut-off T/M ratio value for the highest accuracy was 2.39 with 75.0% accuracy. The area under the curve (AUC) was 0.855. The statistical analyses for DTP scans of 35 TEN patients demonstrated 74.3% accuracy and 0.838 AUC for the early scan versus 82.9% and 0.825 for the delayed scan. The MLR analysis indicated that mediastinal fat infiltration was a predictor of carcinoma. The ROC curve obtained for the model yielded an AUC of 0.853. Delayed scanning could improve the diagnostic capacity for carcinoma. The T/M ratio and mediastinal fat infiltration are predictive of carcinoma with moderate diagnostic accuracy.

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  • Feasibility of adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 for completely resected non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 1001 Reviewed

    Norihito Okumura, Makoto Sonobe, Kazunori Okabe, Hiroshige Nakamura, Masafumi Kataoka, Motohiro Yamashita, Masao Nakata, Kazuhiko Kataoka, Yoshinori Yamashita, Junichi Soh, Hiroshige Yoshioka, Katsuyuki Hotta, Keitaro Matsuo, Junichi Sakamoto, Shinichi Toyooka, Hiroshi Date

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   22 ( 2 )   274 - 282   2017.4

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    This multicenter study evaluated the feasibility of novel adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent, long-term maintenance with S-1 in patients with completely resected stage II-IIIA non-small-cell lung cancer (NSCLC).
    Patients received four cycles of S-1 (80 mg/m(2)/day for 2 weeks, followed by 2 weeks rest) plus carboplatin (area under the curve 5, day 1) followed by S-1 (80 mg/m(2)/day for 2 weeks, followed by a 1-week rest). Patients unable to continue S-1 plus carboplatin because of severe toxicity converted to single-agent S-1 maintenance. The duration of adjuvant chemotherapy was 10 months in both situations. The primary endpoint was feasibility, defined as the proportion of patients who completed four cycles of S-1 plus carboplatin and single-agent S-1 maintenance for 10 months. The treatment completion rate was determined; treatment was considered feasible if the lower 90% confidence interval (CI) was 50%.
    Eighty-nine patients were enrolled, of whom 87 were eligible and assessable. Seventy-eight patients (89.7%) completed four cycles of S-1 plus carboplatin and 55 (63.2%) completed the following S-1 maintenance therapy for a total of 10 months. The treatment completion rate was 63.2% (90% CI, 54.4-71.2%), indicating feasibility. There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (13.8%), thrombocytopenia (11.5%), and anorexia (4.6%). The 2-year relapse-free survival rate was 59.8%.
    We concluded that adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 is feasible and tolerable in patients with completely resected NSCLC.
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  • Lung Cancer Panelを用いた多発小型肺癌のマルチプレックス遺伝子変異解析

    枝園 和彦, 冨田 秀太, 佐藤 博紀, 高橋 優太, 諏澤 憲, 山本 寛斉, 宗 淳一, 三好 新一郎, 豊岡 伸一

    日本呼吸器外科学会雑誌   31 ( 3 )   RO16 - 4   2017.4

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  • Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer (vol 12, e0171356, 2017) Reviewed

    T. Takeda, H. Yamamoto, H. Kanzaki, K. Suzawa, T. Yoshioka, S. Tomida

    PLOS ONE   12 ( 3 )   e0171356   2017.3

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  • Radiofrequency ablation of pulmonary metastases from sarcoma: single-center retrospective evaluation of 46 patients Reviewed

    Takuya Sato, Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Jun Sakurai, Yusuke Matsui, Toshiharu Mitsuhashi, Junichi Soh, Shinichi Toyooka, Susumu Kanazawa

    JAPANESE JOURNAL OF RADIOLOGY   35 ( 2 )   61 - 67   2017.2

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    This retrospective, single-center study evaluated radiofrequency (RF) ablation for pulmonary metastases of sarcoma.
    Forty-six patients with sarcoma (144 pulmonary metastases) underwent 88 RF ablation sessions. Data regarding local tumor progression, efficacy, procedural adverse events (AEs; National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0), overall survival (OS), and OS-associated prognostic factors were retrospectively evaluated using univariate analyses.
    Local progression occurred in 22 of 144 tumors (15.3%). Primary and secondary efficacy rates were 83.5 and 90.0% at 1 year and 76.3 and 81.4% at 2 years, respectively. Seventy-three grade 1 AEs, 33 grade 2 AEs, and no grade &gt;= 3 AEs were observed. Twenty-eight patients (60.9%) remained alive and 18 died, yielding 1-, 2-, and 3-year OS rates of 80.6, 70.1, and 47.1% (median survival time, 31.7 months). Univariate analysis revealed extrapulmonary metastasis (P = 0.005), noncurative RF ablation (P = 0.009), and a post-RF ablation disease-free interval of &lt;= 12 months (P = 0.015) as significant negative prognostic factors.
    RF ablation is safe, offers good local control, and may be a viable treatment option for pulmonary metastasis of sarcoma.

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  • Feasibility of Pulmonary Resection for Lung Cancer in Patients With Coronary Artery Disease or Atrial Fibrillation. Reviewed International journal

    Yoshitaka Kitamura, Kenji Suzuki, Satoshi Teramukai, Makoto Sonobe, Shinichi Toyooka, Yoshihisa Nakagawa, Hiroyasu Yokomise, Hiroshi Date

    The Annals of thoracic surgery   103 ( 2 )   432 - 440   2017.2

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    BACKGROUND: The aim of this study was to clarify the outcomes of lung resection for lung cancer in patients with cardiac disease, especially coronary artery disease, in a large-scale multi-institutional cohort. METHODS: We retrospectively analyzed the data on 1,254 patients who underwent major lung resection for lung cancer and had been diagnosed with coronary stenosis, atrial fibrillation, or both, in 58 institutions in Japan between January 2009 and December 2011. The primary outcome was 90-day postoperative mortality or in-hospital death. RESULTS: Among the 1,254 patients, 902 (71.9%) and 452 patients (36.0%) were preoperatively diagnosed with coronary stenosis and atrial fibrillation, respectively, and 951 patients (75.8%) received antiplatelet therapy. Among the patients with coronary stents (n = 532; 42.4%), 204 (16.3%) received drug-eluting stents. The 90-mortality or in-hospital death rate was 2.6% (n = 32), including stent thrombosis (n = 1), thromboembolic events without stent thrombosis (n = 2), and bleeding events (n = 2). In the multivariate analyses, blood transfusion, history of cerebrovascular disease, amount of bleeding, and history of congestive heart failure were associated with a higher independent risk of 90-day mortality or in-hospital death (odds ratio, 9.400, 3.574, 2.827, and 2.945, respectively). Preoperative discontinuation of antiplatelet therapy was not associated with an independent risk of 90-day mortality or in-hospital death on univariate analysis. CONCLUSIONS: Major lung resection for lung cancer in patients with coronary artery disease is feasible. Our study suggests that discontinuation of antiplatelet therapy may not increase postoperative complications in patients with coronary artery disease.

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  • Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer Reviewed

    Tatsuaki Takeda, Hiromasa Yamamoto, Hirotaka Kanzaki, Ken Suzawa, Takahiro Yoshioka, Shuta Tomida, Xiaojiang Cui, Ramachandran Murali, Kei Namba, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Kazuhiko Shien, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yoshihisa Kitamura, Shinichiro Miyoshi, Toshiaki Sendo, Shinichi Toyooka

    PLOS ONE   12 ( 2 )   2017.2

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    Background
    Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15-23% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumabresistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474. Lapatinib is also a molecular-targeted drug for HER2-positive breast cancer, which acquired the resistance to trastuzumab. Acquired resistance to lapatinib is also an issue to be conquered.
    Methods
    We established trastuzumab/lapatinib-dual resistant cell line (named as BT-474-RL2) by additionally treating BT-474-R with lapatinib. We analyzed the mechanisms of resistance to trastuzumab and lapatinib. Besides, we analyzed the effect of the detected resistance mechanism in HER2-positive breast cancer patients.
    Results
    Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R and BT-474-RL2. Silencing of Yes1 by siRNA induced both BT-474-R and BT-474-RL2 to restore the sensitivity to trastuzumab and lapatinib. Pharmaceutical inhibition of Yes1 by the Src inhibitor dasatinib was also effective to restore the sensitivity to trastuzumab and lapatinib in the two resistant cell lines. Combination treatment with dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, the combination treatments induced G1-phase cell-cycle arrest and apoptosis. Consistent with cell line data, high expression of Yes1 mRNA was correlated with worse prognosis in patients with HER2-positive breast cancer.
    Conclusion
    Yes1 plays an important role in acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancer. Our data suggest that pharmacological inhibition of Yes1 may be an effective strategy to overcome resistance to trastuzumab and lapatinib.

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  • Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies Reviewed

    Ken Suzawa, Kazuhiko Shien, Huang Peng, Masakiyo Sakaguchi, Masami Watanabe, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Shuta Tomida, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Hiromi Kumon, Shinichiro Miyoshi, Shinichi Toyooka

    ANTICANCER RESEARCH   37 ( 1 )   301 - 307   2017.1

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    Background: Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and its overexpression by adenovirus vector (Ad-REIC) exhibits a remarkable therapeutic effect on various human cancer types through a mechanism triggered by endoplasmic reticulum stress. Materials and Methods: We examined the direct anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma cell lines in vitro, and the distant bystander effect using immunocompetent mouse allograft models with bilateral flank tumors. Results: Ad-REIC treatment showed antitumor effect in many lung cancer and malignant mesothelioma cell lines in vitro. In an in vivo model, Ad-REIC treatment inhibited the growth not only of directly treated tumors but also of distant untreated tumors. By immunohistochemical analysis, infiltration of T-cells and natural killer (NK) cells and expression of the major histocompatibility complex (MHC) class I molecules were observed in bilateral tumors. Conclusion: Ad-REIC treatment not only had a direct antitumor effect but also an indirect bystander effect through stimulation of the immune system.

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  • Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features Reviewed

    Hiroki Sato, Kazuhiko Shien, Shuta Tomida, Kazuhiro Okayasu, Ken Suzawa, Shinsuke Hashida, Hidejiro Torigoe, Mototsugu Watanabe, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    SCIENTIFIC REPORTS   7   40847   2017.1

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    MicroRNA (miR)-200 family members (miR-200s) are frequently silenced in advanced cancer and have been implicated in the process of epithelial-to-mesenchymal transition (EMT). We previously reported that miR-200s were silenced through promoter methylation in acquired EGFR-tyrosine kinase inhibitor (TKI) resistant non-small cell lung cancer (NSCLC) cells harboring EMT features. In this study, we examined the functional role of miR-200s in NSCLC cells and investigated a novel approach to overcoming acquired EGFR-TKI resistance. In the analysis of NSCLC cell lines, each of the miR-200s expression-silenced cell lines showed promoter methylation. Significant correlations between miR-200c silencing and several oncogenic pathway alterations, including EMT-changes and LIN28B overexpression, were observed in the database analysis. In addition, EGFR-wild type cell lines had lower miR-200s expression levels than EGFR-mutant cell lines. The introduction of miR-200c using pre-miR-200c caused LIN28B suppression in cells with acquired EGFR-TKI resistance that harbored EMT features. Interestingly, both the introduction of miR-200c and the knockdown of LIN28B produced an antitumor effect in acquired EGFR-TKI resistance cells, whereas these manipulations were not effective in parental cells. The miR-200c/LIN28B axis plays an important role in cells with acquired resistance to EGFR-TKI that harbor EMT features and might be a useful therapeutic target for overcoming resistance.

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  • Trastuzumab Emtansine in HER2+Recurrent Metastatic Non-Small-Cell Lung Cancer: Study Protocol Reviewed

    Kadoaki Ohashi, Katsuyuki Hotta, Taizo Hirata, Keisuke Aoe, Toshiyuki Kozuki, Kiichiro Ninomiya, Hiroe Kayatani, Hiroyuki Yanai, Shinichi Toyooka, Shiro Hinotsu, Minoru Takata, Katsuyuki Kiura

    CLINICAL LUNG CANCER   18 ( 1 )   92 - 95   2017.1

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    The treatment outcome has been unsatisfactory for patients with non small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patientg with HER2+ lung cancers. The major eligibility criteria are as follows: age &gt;= 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer. (C) 2016 Elsevier Inc. All rights reserved.

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  • Unique circulating microRNAs in relation to EGFR mutation status in Japanese smoker male with lung adenocarcinoma Reviewed

    Sachio Ito, Yoshihiro Kamoto, Akiko Sakai, Kaori Sasai, Tatsuro Hayashi, Shinichi Toyooka, Hiroshi Katayama

    Oncotarget   8 ( 70 )   114685 - 114697   2017

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    The incidence of lung adenocarcinoma has been increasing recently in smokers. The molecular target therapy has been developed for lung adenocarcinoma patients harboring EGFR gene mutation. However, the treatment modalities for patients without mutation are currently limited. Thus, analysis of EGFR gene mutation status at early stage is important strategy to classify the patients for improving treatments and prognosis efficiently. This study aimed to identify microRNA (miRNA) signature in relation to mutation status in EGFR gene in early stage of lung adenocarcinoma male patients with smoking history. MiRNA profiles were assessed by microarray in paired plasma and tissue pooled from 10 EGFR wild type (EGFR-wt) and 10 EGFR mutated (EGFR-mut) patients. Expressions of selected miRNAs were verified further by real-time qRT-PCR in 83 plasma samples consisting of 55 EGFR-wt patients and 28 EGFR-mut patients and their correlation with clinicopathological parameters and EGFR gene mutation status were evaluated. We found that seven miRNAs (miR-16-5p, miR-23a-3p, miR-103a-3p, miR122-5p, miR-223-3p, miR-346 and miR-451a) were differentially expressed in stage I and stage I+II. Especially, miR-23a-3p was only miRNA shown higher expression in EGFR-wt patients than EGFR-mut patients. Thus, our findings could be useful non-invasive biomarkers to differentiate mutation status in EGFR gene in smoker lung adenocarcinoma male patients.

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  • Reconstruction of Anterior Chest Wall with Polypropylene Mesh: Two Primary Sternal Chondrosarcoma Cases Reviewed

    Shinichi Kawana, Hiromasa Yamamoto, Yuho Maki, Seiichiro Sugimoto, Shinichi Toyooka, Shinichiro Miyoshi

    ACTA MEDICA OKAYAMA   71 ( 3 )   259 - 262   2017

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    Primary sternal chondrosarcoma is a rare malignant tumor that is refractory to chemotherapy and radiation. Effective therapy is radical resection of the tumor. We present two patients with primary sternal chondrosarcoma who underwent a radical resection of the lower half of the sternum and bilateral ribs, followed by reconstruction with 2 sheets of polypropylene mesh layered orthogonally. The patients have maintained almost the same pulmonary function as preoperative values, with stability of the chest wall. Although there are various ways to reconstruct the anterior chest wall, reconstruction with polypropylene mesh layered orthogonally is an easy-to-use and sufficient method.

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  • ß-1,3-galactosyl-O-glycosyl-glycoprotein ß-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. Reviewed

    Sumardika IW, Youyi C, Kondo E, Inoue Y, Ruma IMW, Murata H, Kinoshita R, Yamamoto KI, Tomida S, Shien K, Satoh H, Yamauchi A, Futami J, Putranto EW, Hibino T, Toyooka S, Nishibori M, Sakaguchi M

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  • Role of surgery in N2 NSCLC: pros Reviewed

    Kazuhiko Shien, Shinichi Toyooka

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   46 ( 12 )   1168 - 1173   2016.12

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    The optimal management of clinical N2 Stage IIIA non-small cell lung cancer is still controversial. For a cure of locally advanced IIIA/N2 non-small cell lung cancer, the control of both local regions and possible distant micrometastases is crucial. Chemotherapy is generally expected to prevent distant recurrence. For local tumor control, radiotherapy or surgery has been adopted singly or in combination. If a complete resection can be safely performed, surgery remains the strongest modality for 'eradicating' local disease. Many retrospective studies have reported a possible survival benefit of induction treatment followed by surgery in selected patients with IIIA/N2 non-small cell lung cancer; however, randomized Phase III trials have failed to demonstrate the superiority of induction treatment followed by surgery over chemoradiotherapy, mainly because of the heterogeneity of the N2 status. IIIA/N2 non-small cell lung cancer consists of a heterogeneous group of disease ranging from microscopically single station to radiologically bulky ipsilateral multi-station mediastinal lymph node involvement. A recent definition proposed by the American College of Chest Physicians classified non-small cell lung cancer based on the N2 status, such as discrete or infiltrative type, and recommendations were made according to this N2 status, with definitive chemoradiotherapy recommended for infiltrative clinical N2 and definitive chemoradiotherapy or induction treatment followed by surgery recommended for other cases. Thus, the introduction of a multimodality treatment strategy seems to be necessary for the improved prognosis of non-small cell lung cancer patients with IIIA/N2 disease. In this review, we discuss the role of surgery and the optimal surgical management for patients with IIIA/N2 non-small cell lung cancer.

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  • Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway Reviewed

    Tomoaki Ohtsuka, Masakiyo Sakaguchi, Hiromasa Yamamoto, Shuta Tomida, Katsuyoshi Takata, Kazuhiko Shien, Shinsuke Hashida, Tomoko Miyata-Takata, Mototsugu Watanabe, Ken Suzawa, Junichi Soh, Chen Youyi, Hiroki Sato, Kei Namba, Hidejiro Torigoe, Kazunori Tsukuda, Tadashi Yoshino, Shinichiro Miyoshi, Shinichi Toyooka

    SCIENTIFIC REPORTS   6   39557   2016.12

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    HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers. Because HER2 can be a therapeutic target in HER2-driven malignancies, it is important to understand the molecular mechanisms of HER2 activation. In the current study, we identified that cytokeratin 19 (KRT19) binds to HER2 at the inside face of plasma membrane. HER2 and KRT19, which were concurrently introduced to a human embryonic kidney 293 T cells, revealed an association with each other and resulted in phosphorylation of HER2 with the subsequent activation of a downstream Erk-associated pathway. A binding assay revealed that both the NH2-terminal head domain of KRT19 and the COOH-terminal domain of HER2 were essential for their binding. To investigate the impact of the interaction between HER2 and KRT19 in lung cancer, we examined their expressions and localizations in lung cancers. We found that KRT19 was highly expressed in HER2-positive lung cancer cells, and KRT19 and HER2 were co-localized at the cell membrane. In conclusion, we found that KRT19 intracellularly binds to HER2, playing a critical role in HER2 activation.

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  • Usefulness of Thoracoscopic Debridement for Chronic Empyema after an Extrapleural Pneumonectomy Reviewed

    Hidejiro Torigoe, Shinichi Toyooka, Hiromasa Yamamoto, Junichi Soh, Shinichiro Miyoshi

    ACTA MEDICA OKAYAMA   70 ( 6 )   507 - 510   2016.12

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    We present the case of a 65-year-old Japanese man diagnosed with chronic empyema (without a bronchopleural fistula) that occurred 7 months after he underwent an extrapleural pneumonectomy for right malignant pleural mesothelioma (MPM). Following thoracic drainage and irrigation for 1 month, we performed surgery by a thoracoscopic approach, in light of his general condition. We performed debridement and removal of the Gore-Tex polytetralluoroethylene (PTFE) patch that had been used for the reconstruction of the diaphragm and the pericardium. The empyema had not relapsed when he died from recurrence of the MPM at 4 months after the thoracoscopic surgery. This patient's case suggests that thoracoscopic debridement and patch removal can be a therapeutic option for not only early-stage (exudative or fibrinopurulent) empyema but also late-stage (organized and chronic) empyema without a bronchopleural fistula, particularly for patients in poor general condition.

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  • Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells. Reviewed International journal

    Satomi Saho, Hiroki Satoh, Eisaku Kondo, Yusuke Inoue, Akira Yamauchi, Hitoshi Murata, Rie Kinoshita, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, I Wayan Sumardika, Chen Youyi, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Yoshihiko Sakaguchi, Ken Saito, Hidekazu Iioka, Nam-Ho Huh, Shinichi Toyooka, Masakiyo Sakaguchi

    Cancer microenvironment : official journal of the International Cancer Microenvironment Society   9 ( 2-3 )   93 - 105   2016.12

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    S100A11, a small Ca2+ binding protein, acts extracellularly as a mediator of cancer progression. That raises the question of how a protein that lacks the classical secretory signal is able to be secreted outside cells without being damaged. Some insights into this question have been obtained, and there has been accumulating evidence indicating a pivotal role of a non-classical vesicle-mediated pathway using lysosomes or peroxisomes for the protein secretion. To obtain a more precise insight into the secretory mechanism of S100A11, we first screened representative cancer cells exhibiting significantly active secretion of S100A11. From the results of profiling, we turned our attention to aggressive cancer mesothelioma cells. In mesothelioma cells, we found that abundant dimeric S100A11 was produced selectively in the peroxisome after transportation of monomeric S100A11 through an interaction with PEX14, a peroxisome membrane protein, resulting in peroxisomal secretion of dimerized S100A11. In an extracellular environment in vitro, dimerized S100A11 promoted mesothelial cell invasion indirectly with the help of fibroblast cells. Overall, the results indicate that the peroxisome functions as an essential vesicle for the production of dimerized S100A11 and the subsequent secretion of the protein from mesothelioma cells and that peroxisome-mediated secretion of dimerized S100A11 might play a critical role in mesothelioma progression in a tumor microenvironment.

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  • NSCLCにおける分子バーコードシークエンス分析による複数の低頻度変異の検出(Detection of multiple low-frequency mutations by molecular-barcode sequencing in NSCLC)

    難波 圭, 冨田 秀太, 枝園 和彦, 鳥越 英次郎, 佐藤 博紀, 山本 寛斉, 宗 淳一, 佃 和憲, 三好 新一郎, 豊岡 伸一

    肺癌   56 ( 6 )   639 - 639   2016.11

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  • 腸型肺腺癌の1切除例

    清水 大, 三好 健太郎, 目崎 久美, 枝園 和彦, 杉本 誠一郎, 山本 寛斉, 宗 淳一, 豊岡 伸一, 大藤 剛宏, 三好 新一郎

    肺癌   56 ( 6 )   682 - 682   2016.11

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  • Development of an annually updated Japanese national clinical database for chest surgery in 2014 Reviewed

    Shunsuke Endo, Norihiko Ikeda, Takashi Kondo, Jun Nakajima, Haruhiko Kondo, Kohei Yokoi, Masayuki Chida, Masami Sato, Shinichi Toyooka, Koichi Yoshida, Yoshinori Okada, Yukio Sato, Meinoshin Okumura, Munetaka Masuda, Koji Chihara, Hiroaki Miyata

    General Thoracic and Cardiovascular Surgery   64 ( 10 )   569 - 576   2016.10

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    Objectives: A national clinical database (NCD) adopted an “Internet-based collection” in 2011. An NCD specializing in chest surgery was launched based on the NCD system in 2014. The system was linked to the board certification as the second level in the hierarchy of the specialty of chest surgery and accreditation of educational institutions for chest surgery. Here, we report the status of the NCD for chest surgery in 2014 and clarified its registration rate and its accuracy. Methods: Chest surgeries undertaken in Japan since January 1st, 2014 until the end of the same year were registered through an Internet-based system until April 8th, 2015. The registration rate was compared with the annual survey conducted by the Japanese Association for Thoracic Surgery (JATS) from 2011 to 2014. The rate of accurate inputting was measured by an Internet-based audit in reference to 563 anonymous operative notes of patients presented by 106 chest surgeons at the time of renewal for board certification for chest surgery. Results: A total of 88,112 chest-surgical procedures were registered from 1000 chest surgery units (CSUs). Distribution of procedures by thoracic disease was almost identical to that of the annual survey conducted by JATS. However, the NCD had 4260 more registered procedures compared with the annual survey. The Internet-based audit showed that inter-rater agreement between Internet-based data and operative notes in any item was &gt
    94 %. Conclusions: The NCD system can sustainably provide important and up-to-date information relating to preoperative status, oncology, and best practice for chest surgery in Japan.

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  • 悪性胸膜中皮腫におけるS100A11の働き

    佐藤 博紀, 山本 寛斉, 難波 圭, 鳥越 英次郎, 下田 篤志, 吉岡 貴裕, 枝園 和彦, 宗 淳一, 豊岡 伸一

    日本癌学会総会記事   75回   J - 1061   2016.10

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  • Long-Term Survival after Radiofrequency Ablation of Lung Oligometastases from Five Types of Primary Lesions: A Retrospective Evaluation Reviewed

    Kenichi Omae, Takao Hiraki, Hideo Gobara, Toshihiro Iguchi, Hiroyasu Fujiwara, Yusuke Matsui, Shinichi Toyooka, Takeshi Nagasaka, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   27 ( 9 )   1362 - 1370   2016.9

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    Purpose: To conduct a retrospective evaluation of long-term survival after radiofrequency (RF) ablation for lung oligometastases from 5 types of primary lesions.
    Materials and Methods: The study population consisted of 123 patients with lung oligometastases from colorectal cancer (CRC), non small-cell lung cancer, hepatocellular carcinoma, esophageal cancer, and renal-cell carcinoma treated with RF ablation. Lung oligometastases were defined as 1-5 Metastases confined to the lung while the primary cancer and other metastases were eradicated. Overall survival (OS) and recurrence-free survival (RFS) were estimated for-the overall study population and for patients with each type of primary lesion. The OS and RFS rates were compared with those of the patients with any of the other four primary lesion types. Finally, various variables were analyzed to determine what factors influenced OS and RFS.
    Results: The Median follow-up was 45.7 months; and the 5-year-OS and RFS rates for all 123 patients Were 62% and 25%, respectively, The OS :time for patients with metastases from. CRC was significantly longer (P = .042); it was significantly shorter (P = .022) in patients with metastases from esophageal cancer. Longer disease-free interval was significantly (P = .015) associated with better OS. There was no variable significantly associated with OS and RFS on multivariate analyses.
    Conclusions: Data from this single-center study appear promising in terms of long-term survival after RF ablation of lung oligometastases from 5 primary lesions.

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  • The Feasibility of Median Sternotomy With or Without Thoracotomy for Locally Advanced Non-Small Cell Lung Cancer Treated With Induction Chemoradiotherapy Reviewed

    Hiroki Sato, Shinichi Toyooka, Junichi Soh, Katsuyuki Hotta, Kuniaki Katsui, Hiromasa Yamamoto, Seiichiro Sugimoto, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi

    ANNALS OF THORACIC SURGERY   102 ( 3 )   985 - 992   2016.9

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    Background. This study aimed to compare the morbidity and mortality of a median sternotomy approach and a lateral thoracotomy and to investigate the feasibility of a median sternotomy for locally advanced non-small cell lung cancer (NSCLC) after induction chemoradiotherapy.
    Methods. The medical records of patients with locally advanced NSCLC who underwent induction chemoradiotherapy followed by surgery at our institution between January 1999 and September 2014 were reviewed. We compared the morbidity and mortality of a median sternotomy approach and a lateral thoracotomy.
    Results. A total of 102 NSCLC patients were the subjects of this study. Among them, 31 patients underwent surgery with a median sternotomy approach and 71 patients underwent surgery with a lateral thoracotomy. Patients in the median sternotomy group had a significantly higher rate of postoperative arrhythmia than those in the lateral thoracotomy group (p = 0.0028). However, all the complications were manageable, and no treatment-related deaths occurred in the median sternotomy group. Regarding the prognosis, the 5-year overall survival rate was 72.7%, and the 2-year recurrence-free survival rate was 66.5% in the entire population. No significant differences in overall survival or recurrence-free survival were observed between the 2 approaches.
    Conclusions. Whereas the lateral thoracotomy approach is a standard procedure, our experience suggests that a median sternotomy approach for locally advanced NSCLC after induction chemoradiotherapy is a feasible procedure and can be a surgical option. (C) 2016 by The Society of Thoracic Surgeons

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  • Study about the Efficacy of Metformin to Immune Function in Cancer Patients Reviewed

    Mototsugu Watanabe, Hiromasa Yamamoto, Shingo Eikawa, Kazuhiko Shien, Tadahiko Shien, Junichi Soh, Katsuyuki Hotta, Jun Wada, Shiro Hinotsu, Toshiyoshi Fujiwara, Katsuyuki Kiura, Hiroyoshi Doihara, Shinichiro Miyoshi, Heiichiro Udono, Shinichi Toyooka

    ACTA MEDICA OKAYAMA   70 ( 4 )   327 - 330   2016.8

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    A study to evaluate the effect of metformin on the immune system was commenced in July 2014. Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and previous studies have reported that metformin has an anti-tumor effect. The aim of this study is to evaluate the efficacy of metformin on the immune system in human cancer patients in vivo. The primary outcome parameter will be the rate change in the population of CD8(+) T cells, which produce multiple cytokines.

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  • Randomized feasibility study of S-1 for adjuvant chemotherapy in completely resected Stage IA non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 0701 Reviewed

    Junichi Soh, Norihito Okumura, Masao Nakata, Hiroshige Nakamura, Minoru Fukuda, Masafumi Kataoka, Shinsuke Kajiwara, Yoshifumi Sano, Motoi Aoe, Kazuhiko Kataoka, Katsuyuki Hotta, Keitaro Matsuo, Shinichi Toyooka, Hiroshi Date

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   46 ( 8 )   741 - 747   2016.8

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    Objective: The aim of this multicenter study was to determine the appropriate administration schedule for S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological-Stage IA ( tumor diameter, 2-3 cm) non-small-cell lung cancer.
    Methods: Patients were randomly assigned to receive adjuvant chemotherapy consisting of either the 4-week oral administration of S-1 ( 80-120 mg/body/day) followed by a 2-week rest ( Group A), or the 2-week oral administration of S-1 ( 80-120mg/body/day) followed by a 1-week rest ( Group B). The duration of adjuvant chemotherapy was 1 year in both arms. The primary endpoint was compliance, namely drug discontinuation-free survival, which was calculated using the Kaplan-Meier method with log-rank test.
    Results: Eighty patients were enrolled in this study, and 76 patients actually received S-1 treatment. The drug discontinuation-free survival rates at 1 year were 49.1% in Group A and 52.7% in Group B ( P = 0.373). The means of the relative dose intensities were 55.3% in Group A and 64.6% in Group B ( P = 0.237). There were no treatment-related deaths. Patients with grade 3/ 4 toxicities were significantly more frequent in Group A ( 40.5%) than in Group B ( 15.4%, P = 0.021). The 2-year relapse-free survival rates were 97.5% in Group A and 92.5% in Group B, and the 2-year overall survival rates were 100% in both groups.
    Conclusions: The feasibility showed no significant difference between the two groups among patients with completely resected Stage IA ( tumor diameter, 2-3 cm) non-small-cell lung cancer.

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  • 胸腔鏡下拡大胸腺摘除術を施行した重症筋無力症の1例

    尾山 貴徳, 野田 卓男, 納所 洋, 谷本 光隆, 牧 佑歩, 宗 淳一, 豊岡 伸一, 三好 新一郎, 柴田 敬, 井上 拓志, 吉永 治美

    日本小児科学会雑誌   120 ( 7 )   1142 - 1142   2016.7

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  • Yesl is the key molecule for the resistance to trastuzumab in breast cancer, and dasatinib overcomes the resistance Reviewed

    Yamamoto Hiromasa, Takeda Tatsuaki, Kanzaki Hirotaka, Suzawa Ken, Namba Kei, Sato Hiroki, Torigoe Hidejiro, Watanabe Mototsugu, Maki Yuho, Soh Junichi, Asano Hiroaki, Tsukuda Kazunori, Miyoshi Shinichiro, Kitamura Yoshihisa, Sendo Toshiaki, Toyooka Shinichi

    CANCER RESEARCH   76   2016.7

  • The proliferative effects of asbestos-exposed peripheral blood mononuclear cells on mesothelial cells. Reviewed International journal

    Yuho Maki, Yasumitsu Nishimura, Shinichi Toyooka, Junichi Soh, Kazunori Tsukuda, Kazuhiko Shien, Masashi Furukawa, Takayuki Muraoka, Tsuyoshi Ueno, Norimitsu Tanaka, Hiromasa Yamamoto, Hiroaki Asano, Megumi Maeda, Naoko Kumagai-Takei, Suni Lee, Hidenori Matsuzaki, Takemi Otsuki, Shinichiro Miyoshi

    Oncology letters   11 ( 5 )   3308 - 3316   2016.5

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    Malignant mesothelioma (MM) is thought to arise from the direct effect of asbestos on mesothelial cells. However, MM takes a long time to develop following exposure to asbestos, which suggests that the effects of asbestos are complex. The present study examined the effects of asbestos exposure on the cell growth of MeT-5A human mesothelial cells via cytokines produced by immune cells. Peripheral blood mononuclear cells (PBMCs) were stimulated with antibodies against cluster of differentiation (CD)3 and CD28 upon exposure to the asbestos chrysotile A (CA) or crocidolite (CR); the growth of MeT-5A cells in media supplemented with PBMC culture supernatants was subsequently examined. MeT-5A cells exhibited an increase in proliferation when grown in supernatant from the 7-day PBMC culture exposed to CA or CR. Analysis of cytokine production demonstrated increased levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1α, IL-1β, IL-3, IL-5, IL-13 and IL-17A in supernatants. Individual administration of these cytokines, excluding G-CSF and GM-CSF, led to an increase in cell growth of MeT-5A, whereas this effect was not observed following the combined administration of these cytokines. The results indicate that cytokines secreted by immune cells upon exposure to asbestos cause an increase in the growth activity of mesothelial cells, suggesting that alterations in the production of cytokines by immune cells may contribute to tumorigenesis in individuals exposed to asbestos.

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  • 非小細胞肺癌術後補助化学療法におけるS-1+CBDCA併用療法とS-1維持療法の多施設共同認容性試験

    中村 廣繁, 奥村 典仁, 園部 誠, 岡部 和倫, 片岡 正文, 山下 素弘, 中田 昌男, 片岡 和彦, 山下 芳典, 宗 淳一, 吉岡 弘鎮, 堀田 勝幸, 松尾 恵太郎, 坂本 純一, 豊岡 伸一, 三好 新一郎, 伊達 洋至

    日本呼吸器外科学会雑誌   30 ( 3 )   RO9 - 4   2016.4

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  • 小型肺癌に対する外科治療戦略 肺野末梢型cT1aN0M0扁平上皮癌の予後因子

    田尾 裕之, 宗 淳一, 藤原 俊哉, 葉山 牧夫, 岡崎 幹生, 杉本 龍士郎, 上野 剛, 岡部 和倫, 山下 素弘, 佐野 由文, 片岡 和彦, 松浦 求樹, 森山 重治, 豊岡 伸一, 三好 新一郎

    日本外科学会定期学術集会抄録集   116回   SY - 6   2016.4

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  • Genetic alterations in lung adenocarcinoma with a micropapillary component. Reviewed International journal

    Masashi Furukawa, Shinichi Toyooka, Kouichi Ichimura, Hiromasa Yamamoto, Junichi Soh, Shinsuke Hashida, Mamoru Ouchida, Kazuhiko Shien, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

    Molecular and clinical oncology   4 ( 2 )   195 - 200   2016.2

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    Pulmonary adenocarcinoma (PA) with a micropapillary component (PA-MPC) is known as an aggressive subtype of PA. The molecular profiles of PA-MPC have not been well characterized. the pathological reports of patients who underwent surgical resection for lung cancer between April, 2004 and May, 2012 were reviewed. Of the 674 patients diagnosed with PA, 28 were found to have MPC. A total of 138 resected PAs without MPC were selected in the same period to serve as age-, gender- and smoking status-matched controls to the PA-MPC group. Mutational status was determined by the following two methods: SNaPshot assay based on multiplex polymerase chain reaction (PCR), primer extension and capillary electrophoresis that was designed to assess 38 somatic mutations in 8 genes [AKT1, BRAF, endothelial growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), mitogen-activated protein kinase kinase 1, neuroblastoma RAS viral oncogene homolog, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA) and phosphatase and tensin homolog]; and a PCR-based sizing assay that assesses EGFR exon 19 (deletions), EGFR exon 20 (insertions) and human epidermal growth factor receptor 2 exon 20 (insertions). echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene (EML4-ALK) was screened by ALK immunohistochemistry and confirmed using the reverse transcription PCR assay and the break-apart fluorescence in situ hybridization assay. Regarding genetic alterations, 13 (46.4%) of the 28 PA-MPCs harbored mutually exclusive mutations: 9 (32.1%) EGFR mutations, 1 (3.6%) KRAS mutation and 3 (10.7%) EML4-ALK fusion genes. PAs without MPC harbored 42 (30.4%) EGFR mutations, 17 (12.3%) KRAS mutations, 3 (2.2%) EML4-ALK fusion genes and 1 (0.7%) PIK3CA mutation. EML4-ALK fusion genes appeared to occur significantly more frequently in PA-MPCs compared with PAs without MPC (P=0.027). Although the sample size was small, our study suggests that the molecular pathogenesis of PA-MPC may be different from that of other adenocarcinomas.

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  • Induction S-1+Concurrent Radiotherapy Followed by Surgical Resection of Locally Advanced Non-small-cell Lung Cancer in an Elderly Patient Reviewed

    Hidejiro Torigoe, Shinichi Toyooka, Kuniaki Katsui, Junichi Soh, Yuho Maki, Katsuyuki Kiura, Shinichiro Miyoshi

    ACTA MEDICA OKAYAMA   70 ( 1 )   63 - 65   2016.2

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    We present the case of a 77 year-old Japanese man diagnosed with lung squamous cell carcinoma with mediastinal lymph node metastasis. He was treated with induction chemoradiotherapy for T1bN2M0 stage IIIA disease. Considering his age, we selected S-1 as the chemotherapeutic drug. Observing an objective response with no severe adverse events, we performed a left upper lobectomy with sleeve resection of the pulmonary artery. No residual tumor cells were found in the resected specimens, and no critical complication was observed in the clinical course. This case suggests that induction chemoradiotherapy using S-1 combined with concurrent radiation followed by surgery can he a therapeutic option for elderly patients with locally advanced non-small-cell lung cancer.

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  • 放射線化学療法後に外科手術を行った局所進行非小細胞肺癌症例の長期フォローアップ解析

    槇本 剛, 久保 寿夫, 南 大輔, 大橋 圭明, 堀田 勝幸, 田端 雅弘, 豊岡 伸一, 勝井 邦彰, 谷本 光音, 木浦 勝行

    日本内科学会雑誌   105 ( Suppl. )   192 - 192   2016.2

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  • Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations Reviewed

    Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Mizuki Morita, Hiromasa Yamamoto, Shuta Tomida, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

    Cancer Science   107 ( 1 )   45 - 52   2016.1

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    Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations. In this study, we demonstrated the antitumor effect of afatinib, as a HER2-targeted therapy, in lung cancers harboring HER2 alterations in vitro and in vivo. Our results strongly suggest that afatinib is a promising therapeutic option for NSCLC patients with HER2-amplification or mutations.

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  • Radiofrequency Ablation of Lung Tumors Using a Multitined Expandable Electrode: Impact of the Electrode Array Diameter on Local Tumor Progression Reviewed

    Hiroki Ihara, Hideo Gobara, Takao Hiraki, Toshiharu Mitsuhashi, Toshihiro Iguchi, Hiroyasu Fujiwara, Yusuke Matsui, Junichi Soh, Shinichi Toyooka, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   27 ( 1 )   87 - 95   2016.1

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    Purpose: To retrospectively investigate the impact of the electrode array diameter on local tumor progression after lung radiofrequency ablation.
    Materials and Methods: This study included 651 lung tumors treated using multitined expandable electrodes and followed for 6 months. The mean long-axis tumor diameter was 12 mm +/- 7 (range, 2-42 mm). The difference between electrode array diameter and tumor diameter (DAT) was used to investigate the impact of the electrode array diameter. All tumors were classified into 2 groups according to various variables including DAT (&gt;= 10 mm or &lt; 10 mm). The primary technique efficacy rates were calculated using Kaplan-Meier analysis and compared between the 2 groups of each variable using the log-rank test. In addition, crude and multivariate multilevel survival analyses were performed by sequentially including DAT and the other variables in 5 models.
    Results: The median DAT for 651 tumors was 12 mm (range, 15 to 24 mm). The technique efficacy rate was significantly lower in the &lt; 10 mm DAT group than in the &gt;= 10 nun group (P &lt; .001). In the crude and multivariate multilevel survival analyses, &lt; 10 mm DAT was a significant risk factor for local progression in all models except model 5 (P = .067). In the &gt;= 10 mm group, the technique efficacy rates were riot significantly different-between the 2 &gt;= 10 min DAT subgroups (ICY to &lt; 15 mm DAT vs &gt;= 15 mm DAT).
    Conclusions: DAT is an important risk factor for local progression. We recommend an electrode that is &gt;= 10 mm larger than the tumor diameter.

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    researchmap

  • Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma Reviewed

    Ken Suzawa, Hiromasa Yamamoto, Tomoyuki Murakami, Hideki Katayama, Masashi Furukawa, Kazuhiko Shien, Shinsuke Hashida, Kazunori Okabe, Keisuke Aoe, Junichi Soh, Hiroaki Asan, Kazunori Tsukuda, Yusuke Mimura, Shinichi Toyooka, Shinichiro Miyoshi

    ONCOLOGY LETTERS   11 ( 1 )   705 - 712   2016.1

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    Malignant pleural mesothelioma (MPM) is an aggressive disease that is resistant to conventional therapies. Cell lines are useful models for studying the biological characteristics of tumors; therefore, the establishment of MPM cell lines is valuable for exploring novel therapeutic strategies for MPM. In the present study, 4 MPM cell lines (YUMC8, YUMC44, YUMC63, and YUMC64) were established, which consisted of 2 epithelioid and 2 sarcomatoid mesothelioma histological subtypes, from Japanese patients with MPM. The DNA methylation status, mutations, copy number gains, protein expression of representative genes, and the sensitivity to several drugs were examined in these 4 cell lines. Methylation of P16 was demonstrated in 3/4 cell lines, in which the protein expression of p16 was lost. Methylation of RASSF1A was observed in 3/4 cell lines. Copy number gains of EGFR, HER2 or MET were not detected in the 4 cell lines. Mutations in various genes, including EGFR, KRAS,HER2,BRAF, and PIK3CA, which are frequently detected in non-small cell lung cancer, were not detected in the 4 cell lines. microRNA-34b/c is a direct transcriptional target of p53 and is often silenced in MPM by promoter methylation. In the present study, miR-34b/c was heavily methylated in 2/4 established MPM cell lines. For cell adhesion molecules, E-cadherin expression was detected in the 2 epithelioid MPM cell lines, whereas N-cadherin expression was detected in all 4 established cell lines by western blotting. Vimentin was strongly expressed in the 2 sarcomatoid MPM cell lines. None of the established MPM cell lines demonstrated significant responses to the drugs tested, including NVP-AUY922, 17-DMAG, Trichostatin A, and Vorinostat. Although novel molecular findings were not observed in the current characterization of these MPM cell lines, these lines will be useful for future extensive analyses of the biological behavior of MPM and the development of novel therapeutic strategies.

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  • [Cross-sectoral Approach of a Perioperative Management Center for General Thoracic Surgery]. Reviewed

    Shimoda A, Soh J, Ashiba T, Murata N, Fukuda T, Kobayashi M, Torigoe H, Maki Y, Sugimoto S, Yamane M, Toyooka S, Oto T, Miyoshi S

    Kyobu geka. The Japanese journal of thoracic surgery   69 ( 1 )   20 - 24   2016.1

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  • Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations Reviewed

    Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Mizuki Morita, Hiromasa Yamamoto, Shuta Tomida, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

    CANCER SCIENCE   107 ( 1 )   45 - 52   2016.1

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    Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G(1) arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations.

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  • Low frequency of drug-resistant virus did not affect the therapeutic efficacy in daclatasvir plus asunaprevir therapy in patients with chronic HCV genotype-1 infection Reviewed

    Hideaki Kinugasa, Fusao Ikeda, Kouichi Takaguchi, Chizuru Mori, Takehiro Matsubara, Hidenori Shiraha, Akinobu Takaki, Yoshiaki Iwasaki, Shinichi Toyooka, Kazuhide Yamamoto

    ANTIVIRAL THERAPY   21 ( 1 )   37 - 44   2016

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    Background: The efficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance-associated virus (RAV) and therapeutic outcomes have not been well-understood.
    Methods: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non-structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR-invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy.
    Results: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3%) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88% frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12%) for three of four patients.
    Conclusions: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically significant RAVs for ASV plus DCV therapy.

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  • 肺類上皮血管内皮腫の1例

    田中 晶平, 小田 尚廣, 佐藤 晃子, 宮原 信明, 狩野 裕久, 中西 将元, 秦 雄介, 槇本 剛, 久保 寿夫, 大橋 圭明, 二宮 崇, 堀田 勝幸, 金廣 有彦, 田端 雅弘, 谷本 光音, 木浦 勝行, 牧 佑歩, 宗 淳一, 豊岡 伸一, 三好 新一郎

    肺癌   55 ( 7 )   1127 - 1127   2015.12

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  • Fever after lung radiofrequency ablation: Prospective evaluation of its incidence and associated factors Reviewed

    Yoshihisa Masaoka, Takao Hiraki, Hideo Gobara, Toshihiro Iguchi, Hiroyasu Fujiwara, Yusuke Matsui, Shinichi Toyooka, Junichi Soh, Katsuyuki Kiura, Susumu Kanazawa

    EUROPEAN JOURNAL OF RADIOLOGY   84 ( 11 )   2202 - 2209   2015.11

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    Purpose: To prospectively investigate the incidence of post-lung radiofrequency (RF) ablation fever as well as its associated factors, according to the grade of fever.
    Materials and Methods: A total of 56 patients who underwent 67 lung RF sessions were analyzed. Postablation fever (&gt;= 37.0 degrees C) was graded according to the common toxicity criteria of adverse events v. 4.0. Fever &gt;= 37.0 degrees C and &lt;38.0 C was defined as grade 0 fever. The 67 RF sessions were divided into two groups according to the presence of post-ablation fever, and the factors associated with fever were determined using univariate and multivariate analyses. Subsequently, the RF sessions accompanied by post-ablation fever were further divided into two groups according to the grade of fever (grade 0 vs. grade &gt;= 1), and the factors associated with the grade of fever were determined.
    Results: Grade 0, 1, and 2 fever accompanied 36 (54%), 11(16%), and 2 (3%) sessions, respectively. Post-ablation fever was significantly associated with larger ablated parenchymal volume (P=0.001) and development of pulmonary infiltration (P=0.004). Additionally, development of pulmonary infiltration (P=0.048) was also significantly and independently associated with higher grade of fever in the multivariate analysis.
    Conclusions: The incidences of grade 0, 1, and 2 post-ablation fever were 54%, 16%, and 3%, respectively. Larger ablated parenchymal volume and development of pulmonary infiltration were found to be associated with the development of post-ablation fever, with the latter being an independent factor associated with higher grade of fever. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

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  • DNA copy number gains in malignant pleural mesothelioma Reviewed

    Masashi Furukawa, Shinichi Toyooka, Tatsuro Hayashi, Hiromasa Yamamoto, Nobukazu Fujimoto, Junichi Soh, Shinsuke Hashida, Kazuhiko Shien, Hiroaki Asano, Keisuke Aoe, Kazunori Okabe, Harvey I. Pass, Kazunori Tsukuda, Takumi Kishimoto, Shinichiro Miyoshi

    Oncology Letters   10 ( 5 )   3274 - 3278   2015.11

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    Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with an extremely poor prognosis. The incidence of MPM is increasing as a result of widespread exposure to asbestos. The molecular pathogenesis of MPM remains unclear. The present study analyzed the frequency of various genomic copy number gains (CNGs) in MPM using reverse transcription-quantitative polymerase chain reaction. A total of 83 primary MPMs and 53 primary lung adenocarcinomas were analyzed to compare the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2. In MPM, the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2 were detected in 12 (14.5%), 8 (9.6%), 5 (6.0%), 4 (4.8%) and 1 (1.2%) of the samples, respectively. In lung adenocarcinomas, the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2 were detected in 21 (39.6%), 12 (22.6%), 5 (9.4%), 10 (18.9%) and 0 (0.0%) of the samples, respectively. The CNGs of EGFR, KRAS and FGFR1 were significantly less frequent in the MPMs compared with the lung adenocarcinomas (P=0.0018, 0.048 and 0.018, respectively). Overall, the MPMs exhibited these CNGs less frequently compared with the lung adenocarcinomas (P=0.0002). The differences in CNGs between the two tumor types suggested that they are genetically different.

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  • Predicting pleural invasion using HRCT and F-18-FDG PET/CT in lung adenocarcinoma with pleural contact Reviewed

    Takashi Tanaka, Takayoshi Shinya, Shuhei Sato, Toshiharu Mitsuhashi, Koichi Ichimura, Junichi Soh, Shinichi Toyooka, Mitsumasa Kaji, Shinichiro Miyoshi, Susumu Kanazawa

    ANNALS OF NUCLEAR MEDICINE   29 ( 9 )   757 - 765   2015.11

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    To evaluate the relevance of high-resolution computed tomography (HRCT) findings and fluorine-18-fluorodeoxyglucose (F-18-FDG) uptake for risk stratification of visceral pleural invasion by lung adenocarcinoma.
    The HRCT findings and F-18-FDG uptake for lung adenocarcinomas with pleural contact on CT were retrospectively analyzed in 208 consecutive patients (94 females and 114 males; median age, 69.0 years) between January 2009 and December 2013, with institutional review board approval. The HRCT findings and maximum standardized uptake value (SUVmax) were recorded for each patient. Multivariate logistic regression was used for statistical analysis, and subgroup analysis stratified for whole tumor size a parts per thousand currency sign3 cm was also performed.
    Multivariate analysis showed that SUVmax [odds ratio (OR) 1.09, 95 % confidence interval (CI) 1.02-1.16, P = 0.014] and obtuse angle (OR 4.14, 95 % CI 1.97-8.74, P &lt; 0.001) were significant independent predictors for visceral pleural invasion. Receiver operating characteristic (ROC) analysis showed that, compared with the multivariate models [area under the curve (Az) 0.819-0.829], SUVmax alone (Az 0.815) was useful in predicting visceral pleural invasion. In the subgroup analysis, multivariate analysis showed that SUVmax (OR 1.29, 95 % CI 1.12-1.50, P = 0.001) and contact length with the pleura (OR 1.13, 95 % CI 1.05-1.22, P = 0.001) were significant independent predictors for visceral pleural invasion. ROC analysis showed that SUVmax alone (Az 0.844) showed similar diagnostic performance to the multivariate models (Az 0.845-0.857).
    SUVmax alone and multivariate models including SUVmax are useful for the prediction of visceral pleural invasion by lung adenocarcinoma.

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  • [SIGNIFICANCE OF NONCODING RNA IN SURGERY: NONCODING RNA IN LUNG CANCER]. Reviewed

    Yamamoto H, Toyooka S, Maki Y, Soh J, Miyoshi S

    Nihon Geka Gakkai zasshi   116 ( 6 )   374 - 377   2015.11

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  • 【ノンコーディングRNAの外科領域における意義】肺癌における意義

    山本 寛斉, 豊岡 伸一, 牧 佑歩, 宗 淳一, 三好 新一郎

    日本外科学会雑誌   116 ( 6 )   374 - 377   2015.11

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    ノンコーディングRNA(non-coding RNA,ncRNA)はタンパク質へ翻訳されずに機能するRNAの総称であるが,近年ノンコーディングRNAの癌における異常が報告されている.特にマイクロRNA(micro-RNA,miRNA)と長鎖ノンコーディングRNA(longnon-coding RNA,lncRNA)はバイオマーカーとしての可能性が示唆されており,肺癌においてもmiRNA-21(miR-21),miR-34,miR-200などのmiRNAやMALAT1,HOTAIR,BANCRなどのlncRNAの発現異常が報告されている.そのため,ncRNAは肺癌の早期診断・予後予測・化学療法や放射線療法の感受性判定に使用されるバイオマーカーや,新規の治療標的として臨床応用することが期待されている.外科医の肺癌治療における役割は,確かな外科手技を手術適応のある肺癌患者に提供することであるが,肺癌治療成績の向上に更に大きく貢献するためには,より鋭敏なスクリーニングテストを用いて肺癌根治手術症例を増やすこと,肺癌手術症例において再発リスクの高い患者を漏らさず濃厚に観察することで再発症例を早期に確実に検出することが必要である.血液検体や肺癌切除検体においてncRNAの解析を行い,新たなバイオマーカーを探究することは一つの方法である.外科医は臨床検体へのアプローチが容易であることから,検体提供のみならず主体的な立場で研究を進めることが望まれる.(著者抄録)

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  • Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib Reviewed

    Shinsuke Hashida, Hiromasa Yamamoto, Kazuhiko Shien, Yuichiro Miyoshi, Tomoaki Ohtsuka, Ken Suzawa, Mototsugu Watanabe, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    CANCER SCIENCE   106 ( 10 )   1377 - 1384   2015.10

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    Afatinib is an irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that is known to be effective against the EGFR T790M variant, which accounts for half of the mechanisms of acquired resistance to reversible EGFR-TKIs. However, acquired resistance to afatinib was also observed in clinical use. Thus, elucidating and overcoming the mechanisms of resistance are important issues in the treatment of non-small cell lung cancer. In this study, we established various afatinib-resistant cell lines and investigated the resistance mechanisms. EGFR T790M mutations were not detected using direct sequencing in established resistant cells. Several afatinib-resistant cell lines displayed MET amplification, and these cells were sensitive to the combination of afatinib plus crizotinib. As a further investigation, a cell line that acquired resistance to afatinib plus crizotinib, HCC827-ACR, was established from one of the MET amplified-cell lines. Several afatinib-resistant cell lines including HCC827-ACR displayed epithelial-to-mesenchymal transition (EMT) features and epigenetic silencing of miR-200c, which is a suppresser of EMT. In addition, these cell lines also exhibited overexpression of ALDH1A1 and ABCB1, which are putative stem cell markers, and resistance to docetaxel. In conclusion, we established afatinib-resistant cells and found that MET amplification, EMT, and stem cell-like features are observed in cells with acquired resistance to EGFR-TKIs. This finding may provide clues to overcoming resistance to EGFR-TKIs.

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  • Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model Reviewed

    Daisuke Minami, Nagio Takigawa, Yuka Kato, Kenichiro Kudo, Hideko Isozaki, Shinsuke Hashida, Daijiro Harada, Nobuaki Ochi, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Takehiro Tanaka, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Mitsune Tanimoto, Katsuyuki Kiura

    CANCER SCIENCE   106 ( 10 )   1296 - 1302   2015.10

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    Malignant mesothelioma is an aggressive and therapy-resistant neoplasm arising from mesothelial cells. Evidence suggests that the major pathology associated with asbestos-induced mesothelioma is local iron overload. In the present study, we induced iron-induced mesothelioma in rats based on previous reports. Ten Wistar rats were given ferric saccharate and nitrilotriacetate i.p. for 5 days a week. Five of the ten rats exhibited widespread mesotheliomas in the peritoneum and tunica vaginalis. The tumor cells showed positive immunostaining for calretinin, wilms tumor-1, podoplanin and the oxidative DNA marker 8-hydroxy-2-deoxyguanosine. In three of the five rats with mesothelioma, array-based comparative genomic hybridization analysis identified a common chromosomal deletion mapped to the chromosomal 4q31 locus, which encompasses the TBXAS1 gene. Downregulation of the TBXAS1 gene was confirmed using quantitative PCR. TBXAS1 gene expression was also reduced in three of four human malignant pleural mesothelioma cell lines compared with normal bronchial epithelial cells. Immunohistochemistry revealed that TBXAS1 expression was weakly positive and positive in five and three out of eight human malignant mesothelioma samples, respectively. In conclusion, TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. The relationship between iron overload and TBXAS1 downregulation should be pursued further.

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  • ドセタキセル耐性非小細胞肺癌細胞はEGFR-TKIにも交差耐性を示す

    Chen Haiyang, 諏澤 憲, 橋田 真輔, 大塚 智明, 渡邉 元嗣, 牧 祐歩, 山本 寛斉, 宗 淳一, 佃 和憲, 三好 新一郎, 豊岡 伸一

    日本癌学会総会記事   74回   E - 1177   2015.10

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  • トランスレーショナルリサーチ 基礎から臨床応用へ EGFRチロシンキナーゼ阻害剤に対する獲得耐性の機序

    豊岡 伸一, 諏澤 憲, 冨田 秀太, 牧 佑歩, 山本 寛斉, 宗 淳一, 三好 新一郎

    肺癌   55 ( 5 )   359 - 359   2015.10

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  • REIC/Dkk-3遺伝子治療の胸部悪性腫瘍に対する免疫刺激を介する抗腫瘍効果

    諏澤 憲, 枝園 和彦, 阪口 政清, 渡部 昌実, 橋田 真輔, 宗 淳一, 山本 寛斉, 牧 祐歩, 佃 和憲, 那須 保友, 公文 裕巳, 三好 新一郎, 豊岡 伸一

    日本癌学会総会記事   74回   J - 1224   2015.10

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  • 鉄誘発ラット悪性中皮腫モデルにおけるTBXAS1遺伝子発現の抑制

    南 大輔, 瀧川 奈義夫, 工藤 健一郎, 加藤 有加, 磯崎 英子, 原田 大二郎, 越智 宣明, 二宮 崇, 久保 寿夫, 大橋 圭明, 堀田 勝幸, 田端 雅弘, 豊岡 伸一, 谷本 光音, 木浦 勝行

    肺癌   55 ( 5 )   502 - 502   2015.10

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  • 集学的治療 非小細胞肺癌術後補助化学療法におけるS-1+CBDCA併用療法とS-1維持療法の多施設共同認容性試験 SLCG1001

    岡部 和倫, 田尾 裕之, 宗 淳一, 豊岡 伸一, 奥村 典仁, 山下 素弘, 中田 昌男, 片岡 正文, 片岡 和彦, 中村 廣繁, 山下 芳典, 園部 誠, 吉岡 弘鎮, 堀田 勝幸, 坂本 純一, 三好 新一郎, 伊達 洋至

    肺癌   55 ( 5 )   388 - 388   2015.10

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  • 集学的治療 病理病期IA期非小細胞肺癌完全切除例に対するティーエスワン単剤による術後化学療法の無作為化忍容性試験

    中田 昌男, 宗 淳一, 奥村 典仁, 中村 廣繁, 福田 実, 片岡 正文, 梶原 伸介, 青江 基, 片岡 和彦, 堀田 勝幸, 松尾 恵太郎, 豊岡 伸一, 伊達 洋至

    肺癌   55 ( 5 )   388 - 388   2015.10

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  • T790M変異を含むEGFR遺伝子変異を有する非小細胞肺癌細胞株に対するTAE226の抗腫瘍効果

    山本 寛斉, 阪口 政清, 宗 淳一, 佃 和憲, 木浦 勝行, 猶本 良夫, 三好 新一郎, 豊岡 伸一

    日本癌学会総会記事   74回   P - 2193   2015.10

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  • 鉄誘発ラット悪性中皮腫モデルにおけるTBXAS1遺伝子発現の抑制

    南 大輔, 瀧川 奈義夫, 加藤 有加, 工藤 健一郎, 磯崎 英子, 二宮 崇, 久保 寿夫, 大橋 圭明, 堀田 勝幸, 豊岡 伸一, 谷本 光音, 木浦 勝行

    日本癌学会総会記事   74回   P - 1040   2015.10

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  • Extended sleeve lobectomy after induction chemoradiotherapy for non-small cell lung cancer Reviewed

    Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Masaomi Yamane, Shigeru Hattori, Kazuhiko Shien, Kentaroh Miyoshi, Seiichiro Sugimoto, Takahiro Oto, Shinichiro Miyoshi

    SURGERY TODAY   45 ( 9 )   1121 - 1126   2015.9

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    Extended sleeve lobectomy is a challenging surgery. While induction chemoradiotherapy (ChRT) followed by surgery is one of the therapeutic strategies used for locally advanced non-small cell lung cancer (NSCLC), ChRT can impair the anastomotic healing potential. We herein present our experience with cases who underwent an extended sleeve lobectomy after induction ChRT.
    The medical records of patients who underwent a surgery for NSCLC after ChRT were reviewed.
    Between December 2007 and January 2013, nine patients underwent an extended sleeve lobectomy; the left lingular division and lower lobe in four patients, the right upper lobe and trachea in one patient, the carina and trachea in one patient, the right middle and lower lobes in one patient, the right upper and middle lobes and carina in one patient and the right upper lobe and superior segment of the lower lobe in one patient. While no postoperative 90-day deaths occurred, one case developed a bronchopleural fistula on postoperative day (POD) 25 and one case developed a bronchovascular fistula on POD 163. No cases of local recurrence developed.
    Our experience suggests that an extended sleeve lobectomy after induction ChRT is feasible, but careful patient selection and perioperative management are mandatory.

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  • Ethnicity affects EGFR and KRAS gene alterations of lung adenocarcinoma Reviewed

    Junichi Soh, Shinichi Toyooka, Keitaro Matsuo, Hiromasa Yamamoto, Ignacio I. Wistuba, Stephen Lam, Kwun M. Fong, Adi F. Gazdar, Shinichiro Miyoshi

    ONCOLOGY LETTERS   10 ( 3 )   1775 - 1782   2015.9

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    Mutations or copy number gains (CNGs) of the EGFR and KRAS genes are representative alterations in lung adenocarcinomas that are individually associated with patient characteristics such as ethnicity, smoking status and gender. However, the effects of combinations of these genetic alterations have not been statistically examined. The present study analyzed previously examined lung adenocarcinoma cases in Asian (n=166) and non-Asian (n=136) individuals in whom all four EGFR and KRAS alterations had been studied. The polynomial logistic regression models were used following adjustment for gender and smoking status, and using patients without any type of EGFR/KRAS alterations as a reference. Between the two ethnic groups, EGFR CNGs (gEGFR) occurred more frequently than EGFR mutations (mEGFR) (46 vs. 38% in Asians; 21 vs. 10% in non-Asians), whereas KRAS mutations (mKRAS) were more frequent than KRAS CNGs (gKRAS) (13 vs. 7% and 35 vs. 4%, respectively). Additionally, gEGFR and gKRAS occurred significantly more frequently in respective mutant cases, and all EGFR alterations were almost exclusive of all KRAS alterations. The polynomial logistic regression models confirmed that all types of EGFR alterations were significantly more frequent among Asian individuals than among non-Asian individuals, independent of gender and smoking status (odds ratios, 2.36-6.67). KRAS alterations occurred less frequently among Asian individuals than among non-Asian individuals, although a significant difference was not detected. The present study results indicated that the EGFR and KRAS profiles, including mutations and CNGs, differ between Asian and non-Asian individuals with lung adenocarcinoma, suggesting that ethnicity strongly affects the molecular characteristics of lung adenocarcinoma.

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  • Primary pulmonary melanoma: a report of two cases Reviewed

    Mototsugu Watanabe, Hiromasa Yamamoto, Shinsuke Hashida, Junichi Soh, Seiichiro Sugimoto, Shinichi Toyooka, Shinichiro Miyoshi

    WORLD JOURNAL OF SURGICAL ONCOLOGY   13   274   2015.9

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    Malignant melanoma is a refractory malignancy with a dismal prognosis. It generally arises from the skin in most cases, and cases of primary pulmonary malignant melanoma are rare and often behave aggressively. We have treated two cases of localized primary pulmonary malignant melanoma using surgical resection. Pulmonary malignant melanomas often metastasize to the brain and liver; one of our cases exhibited metastasis to the cecum at about 8 months after surgery. Because cutaneous melanomas often carry activating mutations in the BRAF gene (V600E), we performed a BRAF mutational analysis using direct sequencing for both of these tumors arising from the lung. However, no BRAF mutations were detected. We detected a p53 mutation, which was thought to be a potential somatic mutation, in one of the two cases using a sequencing panel targeting 20 lung cancer-related genes. Although we also checked the expression of programmed death ligand 1 (PD-L1) on the surface of the tumor cells by immunohistochemical testing, neither of our two cases expressed PD-L1. Further molecular analyses may uncover the characteristics of primary pulmonary malignant melanomas.

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  • TAE226, a Bis-Anilino Pyrimidine Compound, Shows Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells including T790M Mutant Reviewed

    Hiromasa Yamamoto, Hiroki Otani, Munenori Takaoka, Masakiyo Sakaguchi, Junichi Soh, Masaru Jida, Tsuyoshi Ueno, Takafumi Kubo, Hiroaki Asano, Kazunori Tsukuda, Katsuyuki Kiura, Shinji Hatakeyama, Eiji Kawahara, Yoshio Naomoto, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC ONCOLOGY   10 ( 9 )   S311 - S312   2015.9

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  • Distant Bystander Effect of REIC/Dkk-3 Gene Therapy through Immune System Stimulation in a Murine Model of Thoracic Malignancies Reviewed

    Suzawa Ken, Shien Kazuhiko, Huang Peng, Sakaguchi Masakiyo, Watanabe Masami, Hashida Shinsuke, Soh Junichi, Yamamoto Hiromasa, Maki Yuho, Asano Hiroaki, Tsukuda Kazunori, Nasu Yasutomo, Kumon Hiromi, Miyoshi Shinichiro, Toyooka Shinichi

    JOURNAL OF THORACIC ONCOLOGY   10 ( 9 )   S599   2015.9

  • Anti-tumor effect of afatinib, an irreversible EGFR/HER2 dual inhibitor, in lung cancers harboring HER2 oncogene Reviewed

    Suzawa Ken, Toyooka Shinichi, Sakaguchi Masakiyo, Ohtsuka Tomoaki, Watanabe Mototsugu, Hashida Shinsuke, Maki Yuho, Yamamoto Hiromasa, Soh Junichi, Asano Hiroaki, Tsukuda Kazunori, Miyoshi Shinichiro

    CANCER RESEARCH   75   2015.8

  • Identification of a novel binding protein playing a critical role in HER2 activation in lung cancer cells Reviewed

    Ohtsuka Tomoaki, Sakaguchi Masakiyo, Takata Katsuyoshi, Hashida Shinsuke, Watanabe Mototsugu, Suzawa Ken, Maki Yuho, Yamamoto Hiromasa, Soh Junichi, Asano Hiroaki, Tsukuda Kazunori, Miyoshi Shinichiro, Toyooka Shinichi

    CANCER RESEARCH   75   2015.8

  • Anti-tumor effect of Dasatinib in HER2 positive breast cancer with Trastuzumab resistance Reviewed

    Takeda Tatsuaki, Kanzaki Hirotaka, Toyooka Shinichi, Watanabe Mototsugu, Ohtsuka Tomoaki, Suzawa Ken, Hashida Shinsuke, Maki Yuho, Yamamoto Hiromasa, Soh Junichi, Asano Hiroaki, Tsukuda Kazunori, Miyoshi Shinichiro, Kitamura Yoshihisa, Sendo Toshiaki

    CANCER RESEARCH   75   2015.8

  • Simultaneous Multiple Preoperative Localizations of Small Pulmonary Lesions Using a Short Hook Wire and Suture System Reviewed

    Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Seiichiro Sugimoto, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi, Susumu Kanazawa

    CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY   38 ( 4 )   971 - 976   2015.8

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    The aim of the study was to retrospectively evaluate simultaneous multiple hook wire placement outcomes before video-assisted thoracoscopic surgery (VATS).
    Thirty-eight procedures were performed on 35 patients (13 men and 22 women; mean age, 59.9 years) with 80 lung lesions (mean diameter 7.9 mm) who underwent simultaneous multiple hook wire placements for preoperative localizations. The primary endpoints were technical success, complications, procedure duration, and VATS outcome; secondary endpoints included comparisons between technical success rates, complication rates, and procedure durations of the 238 single-placement procedures performed. Complications were also evaluated.
    In 35 procedures including 74 lesions, multiple hook wire placements were technically successful; in the remaining three procedures, the second target placement was aborted because of massive pneumothorax after the first placement. Although complications occurred in 34 procedures, no grade 3 or above adverse event was observed. The mean procedure duration was 36.4 +/- A 11.8 min. Three hook wires dislodged during patient transport to the surgical suite. Seventy-four successfully marked lesions were resected. Six lesions without hook wires were successfully resected after detection by palpation with an additional mini-thoracotomy or using subtle pleural changes as a guide. The complication rates and procedure durations of multiple-placement procedures were significantly higher (P = 0.04) and longer (P &lt; 0.001) than those in the single-placement group, respectively, while the technical success rate was not significantly different (P = 0.051).
    Simultaneous multiple hook wire placements before VATS were clinically feasible, but increased the complication rate and lengthened the procedure time.

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  • 【家族性腫瘍学-家族性腫瘍の最新研究動向-】臓器・領域別家族性腫瘍の臨床 家族性肺癌

    山本 寛斉, 牧 佑歩, 宗 淳一, 三好 新一郎, 豊岡 伸一

    日本臨床   73 ( 増刊6 家族性腫瘍学 )   433 - 436   2015.8

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  • TAE226, a Bis-Anilino Pyrimidine Compound, Inhibits the EGFR-Mutant Kinase Including T790M Mutant to Show Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells Reviewed

    Hiroki Otani, Hiromasa Yamamoto, Munenori Takaoka, Masakiyo Sakaguchi, Junichi Soh, Masaru Jida, Tsuyoshi Ueno, Takafumi Kubo, Hiroaki Asano, Kazunori Tsukuda, Katsuyuki Kiura, Shinji Hatakeyama, Eiji Kawahara, Yoshio Naomoto, Shinichiro Miyoshi, Shinichi Toyooka

    PLOS ONE   10 ( 6 )   e0129838   2015.6

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    TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). In this study, we investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The antitumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity. In summary, we showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation.

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  • Kissing-stents technique after living-donor lobar lung transplantation Reviewed

    Seiichiro Sugimoto, Takahiro Oto, Shinichi Toyooka, Shinichiro Miyoshi

    EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY   47 ( 6 )   1105 - 1106   2015.6

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    Stent placement has become common practice for bronchial stenosis (BS) after lung transplantation (LT). Especially, segmental BS after lobar LT requires a complex stenting technique. We describe a case of multiple segmental bronchial stenoses treated by the kissing-stents technique using balloon-expandable metallic stents after living-donor lobar LT. Based on the vascular kissing-stents technique, we simultaneously placed two stents, side by side, in the superior segmental bronchus and the basal segmental bronchus of the right transplanted lobar lung. This technique may represent a valuable option for complex segmental BS after lobar LT.

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  • Clinicopathological characteristics and lymph node metastasis pathway of non-small-cell lung cancer located in the left lingular division Reviewed

    Kazuhiko Shien, Shinichi Toyooka, Junichi Soh, Jiro Okami, Masahiko Higashiyama, Yoshihisa Kadota, Hajime Maeda, Makio Hayama, Masayuki Chida, Soichiro Funaki, Meinoshin Okumura, Shinichiro Miyoshi

    INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY   20 ( 6 )   791 - 797   2015.6

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    OBJECTIVES: The purpose of this study is to assess the clinicopathological characteristics of non-small-cell lung cancer (NSCLC) occurring in the left lingular division (LLD) in association with a proposal of the LLD-specific regional lymph node stations.
    METHODS: Medical records of patients, who underwent complete tumour resection with mediastinal lymph node dissection (MLND) for LLD-NSCLC from 2000 to 2009 in multiple institutions, were retrospectively examined. We analysed patient clinicopathological characteristics and obtained the LLD-specific regional lymph node stations, and then the validity of intraoperative navigation in lymphadenectomy for LLD-NSCLC was investigated.
    RESULTS: One hundred and eighty-four LLD-NSCLC patients (97 males and 87 females, and 128 adenocarcinomas and 56 non-adenocarcinomas) were studied. The 5-year overall survival (OS) and disease-free survival (DFS) rates for all LLD-NSCLC patients were 72.9 and 58.3%, respectively. We examined the lymph node metastasis patterns in 42 node-positive tumours. The frequent metastatic lymph node stations were #12u lobar node (n = 22), #5 subaortic node (n = 15) and #11 interlobar node (n = 13) in order. These three node stations were also single metastatic sites in some patients. Metastases to sub-carinal (#7) or inferior mediastinal nodes (#8) were rare. Thus, we assigned the three stations (#5, #11, #12u) as the regional lymph node stations for LLD-NSCLC. If these regional lymph node stations had been examined pathologically during surgery for a total of 160 LLD-NSCLC patients with c-T2N1M0 or lower stage disease, 125 p-N0 and 5 p-N1 patients diagnosed with no metastasis would have been subjected to selective MLND, while 14 p-N1 and all 16 p-N2 patients diagnosed with metastasis would have had complete MLND carried out. As a result, these regional lymph node stations could accurately predict the existence of p-N2 metastasis, and appropriately lead to a selective or complete MLND.
    CONCLUSIONS: An intraoperative pathological examination using our proposed LLD-specific regional lymph node stations may accurately diagnose the status of node metastasis, and appropriately lead to selective or complete MLND in LLD-NSCLC patients with c-T2N1M0 or lower stage disease.

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  • Radiofrequency Ablation of Lung Metastases from Adenoid Cystic Carcinoma of the Head and Neck: Retrospective Evaluation of Nine Patients Reviewed

    Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Shinichi Toyooka, Kazunori Nishizaki, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   26 ( 5 )   703 - 708   2015.5

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    Purpose: To retrospectively evaluate the outcomes of radiofrequency (RF) ablation of lung metastases from head and neck adenoid cystic carcinoma (ACC).
    Materials and Methods: Nine patients (two men and seven women; mean age, 61.6 y) with 45 lung metastases (mean diameter, 1.1 cm; range, 0.4-2.7 cm) from head and neck ACC underwent RF ablation in 30 sessions. Primary endpoints were technical success, technique effectiveness, and procedural complications. Secondary endpoints included overall survival (OS).
    Results: RF ablation was technically successful for all 45 metastases. The median tumor follow-up period was 37.1 months (range, 12.9-128.3 mo). Local progression occurred in six tumors, two of which were treated again and subsequently showed complete response. Major complications (pneumothorax requiring chest tube placement) occurred in five sessions (16.7%). The median patient follow-up period was 61.6 months (range, 20.5-134.5 mo). Two patients died of disease progression at 38.9 and 61.6 months after RF ablation, respectively, whereas the other seven remained alive at the end of the study. OS rates from the initial RF ablation were 100% at 3 years and 83.3% at 5 years (mean survival time, 106.4 mo). OS rates from the treatment of the primary site were 100% at 5 years and 62.5% at 10 years (mean survival time, 210.1 mo).
    Conclusions: Radiofrequency ablation is an acceptable and effective local treatment for lung metastases from head and neck ACC. However, further study is needed to evaluate its effect on patient survival.

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  • Lower lobe origin is a poor prognostic factor in locally advanced non-small-cell lung cancer patients treated with induction chemoradiotherapy. Reviewed International journal

    Kazuhiko Shien, Shinichi Toyooka, Junichi Soh, Katsuyuki Hotta, Kuniaki Katsui, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Hiroshi Date, Shinichiro Miyoshi

    Molecular and clinical oncology   3 ( 3 )   706 - 712   2015.5

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    The AIM of this study was to identify prognostic factors in patients receiving trimodality therapy for locally advanced non-small-cell lung cancer (NSCLC). Among patients who underwent induction chemoradiotherapy (CRT) followed by surgery between 1999 and 2011 at our institution, 76 NSCLC patients with clinical (c) N2/3 stage III were enrolled in this retrospective study. Induction CRT consisted of docetaxel and cisplatin with concurrent 40-60 Gy radiation therapy. In total, 76 patients were assessed (53 men and 23 women) with 43 adenocarcinomas and 33 non-adenocarcinomas. Of the 76 patients, 44 had cStage IIIA and 32 had cStage IIIB disease. The primary tumors were located in the right upper lobe (N=33), right middle lobe (N=5), right lower lobe (N=11), left upper lobe (N=20s) and left lower lobe (N=7). For all 76 patients, lower lobe tumors were associated with a significantly shorter overall survival (OS) and disease-free survival (DFS) compared to non-lower lobe tumors (OS, P=0.022; and DFS, P=0.0007). When the analysis was limited to pathologically proven N2/3 disease prior to induction CRT (n=36), lower lobe location, compared to other locations, tended to be a poor prognostic factor (OS, P=0.068; and DFS, P=0.0075). Our results indicated that a lower lobe tumor origin is associated with unfavorable prognosis in NSCLC patients treated with induction CRT, strongly suggesting the significance of appropriate patient selection in order to maximize the benefits of trimodality therapy.

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  • Percutaneous Radiofrequency Ablation of Lung Cancer Presenting as Ground-Glass Opacity Reviewed

    Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Junichi Soh, Shinichi Toyooka, Katsuyuki Kiura, Susumu Kanazawa

    CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY   38 ( 2 )   409 - 415   2015.4

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    We retrospectively evaluated the outcomes of lung cancer patients presenting with ground-glass opacity (GGO) who received radiofrequency ablation (RFA).
    Sixteen patients (5 men and 11 women; mean age, 72.6 years) with 17 lung cancer lesions showing GGO (mean long axis diameter, 1.6 cm) underwent a total of 20 percutaneous computed tomography (CT) fluoroscopy-guided RFA sessions, including three repeated sessions for local progression. Lung cancer with GGO was defined as a histologically confirmed malignant pulmonary lesion with a GGO component accounting for &gt; 50 % of the lesion on high-resolution CT. Procedure outcomes were evaluated.
    There were no major complications. Pneumothorax occurred in 15 of 20 treatment sessions: 14 were asymptomatic, and 1 required chest tube placement but resolved satisfactorily within 48 h. Minor pulmonary hemorrhage occurred in two and mild pneumonitis in one. The median tumor follow-up period was 61.5 (range 6.1-96.6) months. The effectiveness rates of the primary and secondary techniques were 100 and 100 % at 1 year, 93.3 and 100 % at 2 years, and 78.3 and 92.3 % at 3 years, respectively. The median patient follow-up period was 65.6 (range 6.1-96.6) months. One patient died owing to recurrent other cancer 11.7 months after RFA, whereas the other 15 remained alive. Overall survival and disease-specific survival rates were 93.3 and 100 % at 1 year and 93.3 and 100 % at 5 years, respectively.
    RFA for lung cancer with GGO was safe and effective, and resulted in promising survival rates.

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  • 悪性胸膜中皮腫におけるDNAコピー数の増加(DNA copy number gains in malignant pleural mesothelioma)

    古川 公之, 豊岡 伸一, 林 達朗, 山本 寛斉, 宗 淳一, 橋田 真輔, 枝園 和彦, 浅野 博昭, 岡部 和倫, 佃 和憲, 三好 新一郎

    日本呼吸器外科学会雑誌   29 ( 3 )   O56 - 6   2015.4

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  • 局所進行性肺癌に対する胸骨正中切開アプローチの利用可能性(Feasibility of median sternotomy approach for locally advanced lung cancer)

    佐藤 博紀, 豊岡 伸一, 岡田 真典, 伊賀 徳周, 牧 佑歩, 三好 健太郎, 山本 寛斉, 杉本 誠一郎, 宗 淳一, 山根 正修, 大藤 剛宏, 三好 新一郎

    日本呼吸器外科学会雑誌   29 ( 3 )   O39 - 1   2015.4

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  • 胸腔鏡下拡大胸腺摘除術を施行した重症筋無力症の1例

    尾山 貴徳, 野田 卓男, 谷本 光隆, 牧 佑歩, 宗 淳一, 豊岡 伸一, 三好 新一郎, 柴田 敬, 井上 拓志, 吉永 治美

    日本小児外科学会雑誌   51 ( 2 )   279 - 279   2015.4

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  • 局所進行非小細胞肺癌に対する根治的放射線化学療法後手術の治療成績

    宗 淳一, 豊岡 伸一, 諏澤 憲, 岡田 真典, 牧 佑歩, 伊賀 徳周, 三好 健太郎, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 伊達 洋至, 三好 新一郎

    日本呼吸器外科学会雑誌   29 ( 3 )   RO2 - 2   2015.4

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  • EGFR Mutation Testing Practices within the Asia Pacific Region Results of a Multicenter Diagnostic Survey Reviewed

    Yasushi Yatabe, Keith M. Kerr, Ahmad Utomo, Pathmanathan Rajadurai, Van Khanh Tran, Xiang Du, Teh-Ying Chou, Ma. Luisa D. Enriquez, Geon Kook Lee, Jabed Iqbal, Shanop Shuangshoti, Jin-Haeng Chung, Koichi Hagiwara, Zhiyong Liang, Nicola Normanno, Keunchil Park, Shinichi Toyooka, Chun-Ming Tsai, Paul Waring, Li Zhang, Rose McCormack, Marianne Ratcliffe, Yohji Itoh, Masatoshi Sugeno, Tony Mok

    JOURNAL OF THORACIC ONCOLOGY   10 ( 3 )   438 - 445   2015.3

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    Introduction: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients necessitates accurate, timely testing. Although EGFR mutation testing has been adopted by many laboratories in Asia, data are lacking on the proportion of NSCLC patients tested in each country, and the most commonly used testing methods.
    Methods: A retrospective survey of records from NSCLC patients tested for EGFR mutations during 2011 was conducted in 11 Asian Pacific countries at 40 sites that routinely performed EGFR mutation testing during that period. Patient records were used to complete an online questionnaire at each site.
    Results: Of the 22,193 NSCLC patient records surveyed, 31.8% (95% confidence interval: 31.2%-32.5%) were tested for EGFR mutations. The rate of EGFR mutation positivity was 39.6% among the 10,687 cases tested. The majority of samples were biopsy and/or cytology samples (71.4%). DNA sequencing was the most commonly used testing method accounting for 40% and 32.5% of tissue and cytology samples, respectively. A pathology report was available only to 60.0% of the sites, and 47.5% were not members of a Quality Assurance Scheme.
    Conclusions: In 2011, EGFR mutation testing practices varied widely across Asia. These data provide a reference platform from which to improve the molecular diagnosis of NSCLC, and EGFR mutation testing in particular, in Asia.

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  • Pneumocephalus and Chylothorax Complicating Vertebrectomy for Lung Cancer Reviewed

    Seiichiro Sugimoto, Masato Tanaka, Ken Suzawa, Hitoshi Nishikawa, Shinichi Toyooka, Takahiro Oto, Toshifumi Ozaki, Shinichiro Miyoshi

    ANNALS OF THORACIC SURGERY   99 ( 4 )   1425 - 1428   2015.3

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    Pneumocephalus is a rare, but potentially fatal complication of thoracic surgery. We describe a case of successful management of pneumocephalus complicated by persistent chylothorax developing after en bloc partial vertebrectomy performed after induction chemoradiotherapy for lung cancer invading the spine. Surgical treatment should be considered for pneumocephalus complicated by any condition requiring persistent chest drainage. (C) 2015 by The Society of Thoracic Surgeons

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  • Hsp90 inhibitor NVP-AUY922 enhances the radiation sensitivity of lung cancer cell lines with acquired resistance to EGFR-tyrosine kinase inhibitors Reviewed

    Shinsuke Hashida, Hiromasa Yamamoto, Kazuhiko Shien, Tomoaki Ohtsuka, Ken Suzawa, Yuho Maki, Masashi Furukawa, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Susumu Kanazawa, Shinichi Toyooka

    ONCOLOGY REPORTS   33 ( 3 )   1499 - 1504   2015.3

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    Acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a critical issue that needs to be overcome in the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. EGFR and AKT are client proteins of the 90-kDa heat shock protein (Hsp90). Therefore, it was hypothesized that the use of Hsp90 inhibitors might allow the resistance to EGFR-TKIs to be overcome. Furthermore, Hsp90 inhibitors are known to function as radiosensitizers in various types of cancer. In the present study, we evaluated the radiosensitizing effect of the novel Hsp90 inhibitor, NVP-AUY922 (AUY), on NSCLC cell lines harboring EGFR activating mutations and showing acquired resistance to EGFR-TKIs via any of several mechanisms. We used HCC827 and PC-9, which are NSCLC cell lines harboring EGFR exon 19 deletions, and gefitinib-resistant sublines derived from the same cell lines with T790M mutation, MET amplification or stem-cell like properties. AUY was more effective against the gefitinib-resistant sublines with T790M mutation and MET amplification than against the parental cell lines, although the subline with stem cell-like properties showed more than a 10-fold higher resistance to AUY than the parental cell line. AUY exerted a significant radiosensitizing effect on the parental cell line and the MET-amplified subline through inducing G(2)/M arrest and inhibition of non-homologous end joining (NHEJ). In contrast, the radiosensitizing effect of AUY was limited on the subline with stem cell-like properties, in which it did not induce G(2)/M arrest or inhibition of NHEJ. In conclusion, combined inhibition of Hsp90 plus radiation was effective, and therefore a promising treatment alternative for overcoming major EGFR-TKI resistance, such as that induced by T790M mutation or MET amplification. However, other approaches are required to overcome minor resistance to EGFR-TKIs, such as that observed in cells with stem cell-like properties.

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  • Long-Term Survival following Percutaneous Radiofrequency Ablation of Colorectal Lung Metastases Reviewed

    Yusuke Matsui, Takao Hiraki, Hideo Gobara, Toshihiro Iguchi, Hiroyasu Fujiwara, Takeshi Nagasaka, Shinichi Toyooka, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   26 ( 3 )   303 - 310   2015.3

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    Purpose: To retrospectively evaluate long-term survival outcomes of radiofrequency (RF) ablation of colorectal lung metastases and evaluate factors associated with improved survival.
    Materials and Methods: Eighty-four patients (46 male and 38 female; median age, 65 y) with 172 colorectal lung metastases (median size, 1.2 cm) underwent 113 RF ablation sessions. Thirteen patients had viable extrapulmonary recurrences at the time of RF ablation. The primary endpoint was patient survival. Prognostic factors associated with survival were determined by univariate and multivariate analyses. Secondary endpoints were local tumor progression and adverse events (per National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0).
    Results: During follow-up (median duration, 37.5 mo), 36 patients (42.9%) died. The estimated overall survival (OS) rates were 95.2%, 65.0%, and 51.6% at 1, 3, and 5 years, respectively (median OS time, 67.0 mo). Multivariate analysis revealed that a carcinoembryonic antigen (CEA) level of at least 5 ng/mL before RE ablation (P = .03) and the presence of viable extrapulmonary recurrences at the time of RF ablation (P = .001) were independent negative prognostic factors. The local tumor progression rate was 14.0% (24 of 172 tumors). Grade 3 adverse events were observed after two sessions (1.8%), and grade 415 adverse events were not observed.
    Conclusions: RF ablation of colorectal lung metastases provided favorable long-term survival With a low incidence of severe adverse events. Independent prognostic factors were a high CEA level before RF ablation and the presence of viable extrapulmonary recurrences at the time of RF ablation.

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  • Transfissural Route Used for Preoperative Localization of Small Pulmonary Lesions with a Short Hook Wire and Suture System Reviewed

    Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Seiichiro Sugimoto, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi, Susumu Kanazawa

    CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY   38 ( 1 )   222 - 226   2015.2

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    We retrospectively evaluated the results of the transfissural route for preoperative localization with a short hook wire and suture system for video-assisted thoracoscopic surgery (VATS).
    Eleven patients with 11 tumors underwent CT-guided transfissural placement of a hook wire before VATS. This route was selected for all patients, because the distance between the tumor and interlobar fissure was much shorter than the required distance traversed using the conventional approach. Complications were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
    The hook wire was successfully placed using the transfissural route in all but one case. Of these ten successful placements, two tumors needed a second puncture for optimal placement, because the CT scan showed that the first hook wire was not properly placed in the lung. In one patient, we did not attempt replacement after the first placement was incorrect. In ten successful procedures, the mean distance traversed in the parenchyma of the unaffected lung lobe was 27.9 mm. The distance between the pleura and placed hook wire was significantly shorter than the estimated distance between the pleura and hook wire using the conventional route (mean 16.3 vs. 40.9 mm; P = 0.0002). Grade 1 adverse events occurred (11 pneumothoraxes and 4 pulmonary hemorrhages). No grade 2 or higher adverse event was observed.
    The transfissural route used for preoperative localization before VATS is useful for selected patients because this route may allow for more limited lung parenchyma resection.

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  • 呼吸器外科領域における周術期管理について

    宗 淳一, 豊岡 伸一, 足羽 孝子, 小林 求, 福田 智美, 村田 尚道, 井上 真一郎, 牧 佑歩, 三好 新一郎

    臨床呼吸生理   47   21 - 25   2015.2

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    呼吸器外科領域における周術期管理について検討した。術前評価不足や抗凝固薬中止忘れなど、術前評価や準備不足により中止となった症例はPERIO導入により減少した。PERIO群は従来群に比較して有意に術後歩行開始日数が早かった。63歳以上呼吸器外科手術症例において、嚥下チーム介入群では術後肺炎の発症が減少した。せん妄発症率はD-mac群で有意に低下し、せん妄発症リスク因子数が多い症例でせん妄発症予防効果が顕著であった。特に75歳以上の患者で有意な低下を認めた。82歳以上の原発性肺癌手術症例における包括評価方式(DPC)と出来高方式による入院費差額の年次推移を比較し、PERIO、嚥下チーム、せん妄対策チームの導入により、経時的にDPC差額が増額した。

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  • Validity of using lobe-specific regional lymph node stations to assist navigation during lymph node dissection in early stage non-small cell lung cancer patients Reviewed

    Shinichiro Miyoshi, Kazuhiko Shien, Shinichi Toyooka, Kentaroh Miyoshi, Hiromasa Yamamoto, Seiichiro Sugimoto, Junichi Soh, Makio Hayama, Masaomi Yamane, Takahiro Oto

    SURGERY TODAY   44 ( 11 )   2028 - 2036   2014.11

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    Purpose The validity of our proposed lobe-specific regional lymph node stations (LSRLNS) was evaluated as a method for navigation during lymphadenectomy in patients with early stage non-small cell lung cancer (NSCLC).
    Methods A total of 725 NSCLC patients with c-T2N1M0 or less extensive disease who had undergone a curative operation with complete mediastinal lymph node dissection (MLND) were studied. The LSRLNS were #2, #3, #4 and #10 for the right upper lobe, #11i, #11s, #7 and #8 for the right lower lobe, #4, #5 and #6 for the left superior division, #11, #5 and #7 for the left lingular division and #11, #7 and #8 for the left lower lobe.
    Results If the LSRLNS were used for pathological examinations during surgery, 599 p-N0 and 39 p-N1 patients diagnosed with no metastasis would have been subjected to a selective MLND, while 20 p-N1 and 65 p-N2 patients who had a diagnosis of metastasis would have been navigated to a complete MLND. Two p-N2 patients with a diagnosis of no metastasis would have inappropriately undergone a selective MLND, resulting in the false negative rate at 0.3 %.
    Conclusion Intra-operative pathological examination using our LSRLNS may accurately reveal the status of metastasis, and appropriately lead to a selective or complete MLND in patients with c-T2N1M0 or less extensive disease.

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  • 【肺癌:最新の分子標的療法】肺癌のマイクロRNA異常

    牧 佑歩, 山本 寛斉, 宗 淳一, 三好 新一郎, 豊岡 伸一

    Pharma Medica   32 ( 11 )   49 - 52   2014.11

  • A New Human Lung Adenocarcinoma Cell Line Harboring the EML4-ALK Fusion Gene Reviewed

    Hideko Isozaki, Masayuki Yasugi, Nagio Takigawa, Katsuyuki Hotta, Eiki Ichihara, Akihiko Taniguchi, Shinichi Toyooka, Shinsuke Hashida, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   44 ( 10 )   963 - 968   2014.10

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    Objective: The echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was identified in patients with non-small cell lung cancer. To the best of our knowledge, there are only three cell lines harboring the EML4-ALK fusion gene, which have contributed to the development of therapeutic strategies. Therefore, we tried to establish a new lung cancer cell line harboring EML4-ALK.
    Methods: A 61-year-old Japanese female presented with chest discomfort. She was diagnosed with left lung adenocarcinoma with T4N3M1 Stage IV. Although she was treated with chemotherapy, her disease progressed with massive pleural effusion. Because the EML4-ALK rearrangement was found in a biopsied specimen using fluorescence in situ hybridization, she was treated with crizotinib. She did well for 3 months.
    Results: Tumor cells were obtained from the malignant pleural effusion before treatment with crizotinib. Cells continued to proliferate substantially for several weeks. The cell line was designated ABC-11. The EML4-ALK fusion protein and genes were identified in ABC-11 cells using fluorescence in situ hybridization and immunohistochemistry, respectively. ABC-11 cells were sensitive to crizotinib and next-generation ALK inhibitors (ceritinib and AP26113), as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Phosphorylated ALK protein and its downstream signaling were suppressed by treatment with crizotinib in western blotting. Furthermore, we could transplant ABC-11 cells subcutaneously into BALB/c nu/nu mice.
    Conclusions: We successfully established a new lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. This cell line could contribute to future research of EML4-ALK-positive lung cancer both in vivo and in vitro.

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  • Percutaneous Radiofrequency Ablation for Pulmonary Metastases from Esophageal Cancer: Retrospective Evaluation of 21 Patients Reviewed

    Yusuke Matsui, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Toshihiro Iguchi, Yasuhiro Shirakawa, Toshiyoshi Fujiwara, Shinichi Toyooka, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   25 ( 10 )   1566 - 1572   2014.10

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    Purpose: To evaluate retrospectively Outcomes after radiofrequency (RF) ablation for pulmonary Metastases from esophageal cancer.
    Materials and Methods: This study included 21 consecutive patients who met inclusion. criteria (all men; mean age, 66.0 y) and had pulmonary metastases from esophageal cancer. There were 31 tumors (mean size, 1.7 cm) that Were treated with 27 planned ablation sessions. At the initial RF ablation sessions, 3 patients had viable extrapulmonary recurrences, and 18 patients had Viable recurrences confined to the lung. Primary study endpoints included patient survival and the determination of prognostic factors. Secondary endpoints included local efficacy and safety of the treatment. The log-rank test was used to identify prognostic factors. Adverse events Were evaluated according to,the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
    Results: Median follow-up duration after the initial RF ablation was 22.4 months (range, 6.2-76.1 mo). Estimated overall survival rates were 85.7% at 1 year, 54.8% at 2 years, and 38.4% at 3 years after the initial RF ablation session. The presence of viable extrapulmonary recurrences at the initial RF ablation session was an unfavorable prognostic factor (P &lt; .001). Local tumor progression was observed in 25.8% (8 of 31) of tumors and occurred 2.6-10.0 months (median, 4.8 mo) after RP ablation. Grade 3 adverse events occurred in 7.4% (2 of 27) of sessions, including pleural effusion requiring chest tube placement and pneumoderma requiring surgical intervention. No grade 4 or greater adverse events occurred.
    Conclusions: RF ablation is a promising treatment option for patients with pulmonary metastases from esophageal cancer.

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  • Novel germline G660D mutation in HER2 gene detected by whole-exome sequencing can predispose a patient to developing familial lung adenocarcinoma Reviewed

    Hiromasa Yamamoto, Koichiro Higasa, Masakiyo Sakaguchi, Kazuhiko Shien, Junichi Soh, Koichi Ichimura, Masashi Furukawa, Shinsuke Hashida, Kazunori Tsukuda, Nagio Takigawa, Keitaro Matsuo, Katsuyuki Kiura, Sinichiro Miyoshi, Fumihiko Matsuda, Shinichi Toyooka

    CANCER RESEARCH   74 ( 19 )   2014.10

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    DOI: 10.1158/1538-7445.AM2014-LB-291

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  • アファチニブ耐性を獲得した非小細胞肺癌細胞株の分子生物学的特徴(The molecular characters of acquired resistant non-small cell lung cancer cells to afatinib)

    橋田 真輔, 枝園 和彦, 渡邉 元嗣, 大塚 智昭, 諏澤 憲, 牧 佑歩, 山本 寛斉, 宗 淳一, 浅野 博昭, 佃 和憲, 三好 新一郎, 豊岡 伸一

    日本癌学会総会記事   73回   J - 1044   2014.9

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  • Field Cancerizationによる非小細胞肺癌発現遺伝子の探索(Analysis of molecular alterations in non-small cell lung cancers based on Field cancerization effect)

    牧 佑歩, 渡辺 元嗣, 大塚 智昭, 諏澤 憲, 橋田 真輔, 山本 寛斉, 宗 淳一, 浅野 博昭, 佃 和憲, 豊岡 伸一, 三好 新一郎

    日本癌学会総会記事   73回   J - 1068   2014.9

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  • がんマーカー、サイトケラチン19(CK19)機能の新展開 HER2活性化におけるCK19の役割(Critical role of Cytokeratin-19 in an oncogenic activation of HER2)

    大塚 智昭, 阪口 政清, 渡邉 元嗣, 諏澤 憲, 橋田 真輔, 牧 佑歩, 山本 寛斉, 宗 淳一, 浅野 博昭, 佃 和憲, 三好 新一郎, 豊岡 伸一

    日本癌学会総会記事   73回   E - 2071   2014.9

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  • 新規HER2膜貫通部領域遺伝子変異の機能解析(Novel HER2 mutations in transmembrane dmain result in constitutive autophosphorylation of HER2)

    諏澤 憲, 阪口 政清, 山本 寛斉, 宗 淳一, 牧 佑歩, 橋田 真輔, 大塚 智昭, 渡邉 元嗣, 浅野 博昭, 佃 和憲, 三好 新一郎, 豊岡 伸一

    日本癌学会総会記事   73回   P - 1328   2014.9

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  • 家族性・孤発性肺腺癌におけるHER2膜貫通領域の新規遺伝子変異(Novel functional mutations in the transmembrane domain of HER2 gene in familial and sporadic lung adenocarcinomas)

    山本 寛斉, 日笠 幸一郎, 阪口 政清, 枝園 和彦, 宗 淳一, 市村 浩一, 佃 和憲, 瀧川 奈義夫, 松尾 恵太郎, 木浦 勝行, 三好 新一郎, 松田 文彦, 豊岡 伸一

    日本癌学会総会記事   73回   E - 2012   2014.9

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  • Drug Resistance to EGFR Tyrosine Kinase Inhibitors for Non-small Cell Lung Cancer Reviewed

    Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Shinichiro Miyoshi, Shinichi Toyooka

    ACTA MEDICA OKAYAMA   68 ( 4 )   191 - 200   2014.8

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    Non-small cell lung cancer (NSCLC) harboring an activating mutation within the epidermal growth factor receptor (EGFR) was defined as a clinically distinct molecular group. These lesions show oncogene addiction to EGFR and dramatic responses to the EGFR tyrosine kinase inhibitors (TKIs). Several large Phase III trials have shown that EGFR-TKIs improved the progression-free survival of patients with EGFR mutant NSCLC compared to conventional chemotherapy. However, the long-term effectiveness of EGFR-TKIs is usually limited because of acquired drug resistance. To overcome this resistance to EGFR-TKIs, it will be essential to identify the specific mechanisms underlying the resistance. Many investigators have attempted to identify the mechanisms using preclinical models and drug-resistant clinical samples. As a result, several mechanisms have been showed to be responsible for the resistance, but not all of the relevant mechanisms have been uncovered. In this review, we provide an overview of mechanisms underlying drug-resistance to EGFR-TKIs, focusing on results obtained with preclinical models, and we present some possible strategies to overcome the EGFR-TKI resistance.

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  • Presence of the minor EGFR T790M mutation is associated with drug-sensitive EGFR mutations in lung adenocarcinoma patients Reviewed

    Shinsuke Hashida, Junichi Soh, Shinichi Toyooka, Tomoaki Tanaka, Masashi Furukawa, Kazuhiko Shien, Hiromasa Yamamoto, Hiroaki Asano, Kazunori Tsukuda, Koichi Hagiwara, Shinichiro Miyoshi

    ONCOLOGY REPORTS   32 ( 1 )   145 - 152   2014.7

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    The T790M mutation in the epidermal growth factor receptor (EGFR) gene is known to be associated with the acquired resistance of lung adenocarcinoma patients to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). The minor T790M mutant allele is occasionally detected in EGFR-TKI-naive tumor samples, yet findings concerning the clinical impact of the minor T790M mutation vary among previous studies. In the present study, we assessed the clinical impact of the minor T790M mutation using a novel, highly sensitive assay combining high-resolution melting (HRM), mutant-enriched PCR and co-amplification at a lower denaturation temperature (COLD)-PCR. We determined the T790M mutational status in 146 surgically resected lung adenocarcinomas without a history of EGFR-TKI treatment using mutant-enriched COLD-HRM (MEC-HRM) and standard HRM assays. The sensitivities of the MEC-HRM and standard HRM assays for the detection of T790M-mutant alleles among wild-type alleles were 0.01 and 10%, respectively. Although the T790M mutation was not detected using a standard HRM assay, we identified 19 (13%) T790M mutations using the MEC-HRM assay and defined these 19 mutations as minor T790M mutations. The proportion of T790M alleles was &lt;0.1% in 17 (84%) of the 19 samples. Multivariate analyses revealed that a minor T790M mutation was significantly associated with the presence of EGFR exon 19 deletions or the L858R mutation (both of which are drug-sensitive EGFR mutations) (P=0.04). In conclusion, the minor EGFR T790M mutations were present in 13% of EGFR-TKI-naive surgically resected lung adenocarcinomas and were associated with drug-sensitive EGFR mutations.

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  • 小児がん治療のUp to Date AYA世代のがんをどう治療するか? 稀少がん肉腫の新治療戦略 水平分業型治療連携とパゾパニブ血管新生阻害剤による分子標的治療

    高橋 克仁, 山村 倫子, 冨田 裕彦, 矢嶋 淳, 寺岡 慧, 波多江 亮, 大野 烈士, 宗 淳一, 山本 寛斉, 豊岡 伸一, 小池 幸宏, 烏野 隆博, 小山 隆文, 楢原 啓之, 大山 優

    日本癌治療学会誌   49 ( 3 )   764 - 764   2014.6

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  • アスベスト問題 予防・診断・治療を科学する 悪性胸膜中皮腫におけるマイクロRNA異常

    豊岡 伸一, 宗 淳一, 橋田 真輔, 山本 寛斉, 牧 祐歩, 三好 新一郎

    日本衛生学雑誌   69 ( Suppl. )   S115 - S115   2014.5

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  • A case of carcinoma showing thymus-like differentiation with a rapidly lethal course Reviewed

    Tomohiro Nogami, Naruto Taira, Shinichi Toyooka, Takehiro Tanaka, Taeko Mizoo, Takayuki Iwamoto, Tadahiko Shien, Junichi Soh, Shinichiro Miyoshi, Hiroyoshi Doihara

    Case Reports in Oncology   7 ( 3 )   840 - 844   2014.4

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    A 55-year-old woman underwent a total thyroidectomy for carcinoma showing thymus-like differentiation (CASTLE). The patient was referred to our hospital after the tumor was found to have directly invaded the cervical esophagus and the entire circumference of the trachea. A total thyroidectomy was performed, followed by end-to-end anastomosis of the trachea, suprahyoid release and dissection of bilateral pulmonary ligaments. No major complications, including anastomotic dehiscence or stenosis, were observed. The patient experienced some swallowing disturbances and hoarseness during the perioperative period but fully recovered. Radiotherapy to the neck was performed as an adjuvant therapy. Eleven months after surgery, lower back pain and right leg numbness developed and led to gait inability. Multiple lung and bone recurrences were observed, but no local recurrence. Palliative radiotherapy to the bone metastasis was performed. The patient died of pleural metastasis 14 months after the initial diagnosis of CASTLE.

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  • Massive Subcutaneous and Mediastinal Emphysema with Little Pneumothorax Treated by Surgery after Pulmonary Radiofrequency Ablation Reviewed

    Yusuke Konishi, Hiromasa Yamamoto, Takao Hiraki, Junichi Soh, Shinichi Toyooka, Susumu Kanazawa, Shinichiro Miyoshi

    CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY   37 ( 2 )   548 - 551   2014.4

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  • Hereditary Lung Cancer Syndrome Targets Never Smokers with Germline EGFR Gene T790M Mutations Reviewed

    Adi Gazdar, Linda Robinson, Dwight Oliver, Chao Xing, William D. Travis, Junichi Soh, Shinichi Toyooka, Lori Watumull, Yang Xie, Kemp Kernstine, Joan H. Schiller

    JOURNAL OF THORACIC ONCOLOGY   9 ( 4 )   456 - 463   2014.4

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    Introduction: Hereditary lung cancer syndromes are rare, and T790M germline mutations of the epidermal growth factor receptor (EGFR) gene predispose to the development of lung cancer. The goal of this study was to determine the clinical features and smoking status of lung cancer cases and unaffected family members with this germline mutation and to estimate its incidence and penetrance.
    Methods: We studied a family with germline T790M mutations over five generations (14 individuals) and combined our observations with data obtained from a literature search (15 individuals).
    Results: T790M germline mutations occurred in approximately 1% of non-small-cell lung cancer cases and in less than one in 7500 subjects without lung cancer. Both sporadic and germline T790M mutations were predominantly adenocarcinomas, favored female gender, and were occasionally multifocal. Of lung cancer tumors arising in T790M germline mutation carriers, 73% contained a second activating EGFR gene mutation. Inheritance was dominant. The odds ratio that T790M germline carriers who are smokers will develop lung cancer compared with never smoker carriers was 0.31 (p = 6.0E-05). There was an overrepresentation of never smokers with lung cancer with this mutation compared with the general lung cancer population (p = 7.4E-06).
    Conclusion: Germline T790M mutations result in a unique hereditary lung cancer syndrome that targets never smokers, with a preliminary estimate of 31% risk for lung cancer in never smoker carriers, and this risk may be lower for heavy smokers. The resultant cancers share several features and differences with lung cancers containing sporadic EGFR mutations.

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  • Wedge Resection of the Bronchial Corner at the Bifurcation of the Lobar Bronchi for a Low-Grade Bronchial Tumor Reviewed

    Hiromasa Yamamoto, Shinichi Toyooka, Shinichiro Miyoshi

    THORACIC AND CARDIOVASCULAR SURGEON   62 ( 2 )   181 - 183   2014.3

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    We experienced a case of wedge resection of the bronchus for a bronchial carcinoid of the left upper bronchus located near the bifurcation of the upper and lower lobar bronchi. Bronchial resection was performed longitudinally including the bronchial corner of the upper and lower lobar bronchi, and the length of resected bronchus from the bronchial corner to distant sites was made nearly equal. The presented procedure is useful as a parenchyma-preserving bronchial resection.

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  • Asymptomatic but Functional Paraganglioma of the Posterior Mediastinum Reviewed

    Ken Suzawa, Hiromasa Yamamoto, Koichi Ichimura, Shinichi Toyooka, Shinichiro Miyoshi

    ANNALS OF THORACIC SURGERY   97 ( 3 )   1077 - 1080   2014.3

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    A 72-year-old woman was referred to our hospital because of a posterior mediastinal tumor. On the basis of detailed imaging tests, including I-123-metaiodobenzylguanidine single photon emission computed tomography-computed tomography, and elevated values of catecholamines in the plasma and urine, the tumor was diagnosed as a functional mediastinal paraganglioma even in the absence of symptoms. After preoperative blood pressure control, surgical resection was performed. During the operation, the systemic blood pressure increased transiently as a result of surgical manipulation of the tumor. Soon after the tumor was removed, the patient conversely experienced hypotension. The postoperative course was uneventful, and pathologic diagnosis revealed a paraganglioma. (C) 2014 by The Society of Thoracic Surgeons

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  • Use of a vessel sealing system versus conventional electrocautery for lung parenchymal resection: a comparison of the clinicopathological outcomes in porcine lungs Reviewed

    Seiichiro Sugimoto, Shinichi Toyooka, Norichika Iga, Masashi Furukawa, Ryujiro Sugimoto, Kazuhiko Shien, Hitoshi Nishikawa, Junichi Soh, Masaomi Yamane, Takahiro Oto, Shinichiro Miyoshi

    SURGERY TODAY   44 ( 3 )   540 - 545   2014.3

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    LigaSure, a vessel sealing system, has been shown to have excellent hemostatic properties; however, its use for lung parenchymal resection has been limited. We herein examined the hemostatic properties and potential for inducing histological lung injury of the LigaSure system in non-anatomic pulmonary resection to estimate the feasibility of its clinical application.
    Non-anatomic pulmonary wedge resections of the right cranial, middle, and caudal lobes were performed in four pigs using the LigaSure system (Group A) or electrocautery (Group B). In each resection, the resection time, blood loss, and weight of the resected lung were measured. The thermal effect on the lung tissue was examined by means of intraoperative thermography and histology.
    A total of 12 lung wedge resections were performed in each group. For an equivalent length of operation and weight of the resected lung parenchyma, Group A showed significantly lower blood loss and lower maximum and minimum temperatures of the lung tissue, as assessed by thermography, than Group B. The degree of thermal injury as estimated by a histological examination was lower in Group A than in Group B.
    Our study suggests that the LigaSure system may be superior to conventional electrocautery, indicating its clinical usefulness for non-anatomic pulmonary resection.

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  • Detection of airway ischaemic damage after lung transplantation by using autofluorescence imaging bronchoscopy Reviewed

    Norichika Iga, Takahiro Oto, Masanori Okada, Masaaki Harada, Hitoshi Nishikawa, Kentaroh Miyoshi, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka, Shinichiro Miyoshi

    EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY   45 ( 3 )   509 - 513   2014.3

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    OBJECTIVES: Airway complications related to ischaemia are a major cause of morbidity after lung transplantation. Early detection of airway ischaemia and optimal management of the anastomotic site could reduce the risk of airway complications. Autofluorescence imaging (AFI) bronchoscopy has been increasingly recognized as an effective technique for detecting abnormal mucosal thickening. The aim of this study was to investigate whether AFI bronchoscopy can facilitate the detection of airway ischaemic damage in lung transplant patients.
    METHODS: Twenty Landrace pigs were used to create a tracheal autotransplantation model. A four-ring length of trachea was excised and implanted orthotopically. The tracheal autograft was observed on postoperative days 0, 2, 4 and 7 with AFI bronchoscopy. The extent and origin of graft autofluorescence were examined using histology and measured according to fluorescence intensity.
    RESULTS: The lesions on the tracheal autografts appeared as bright green fluorescence on AFI bronchoscopy. On confocal fluorescence microscopy, high-intensity green fluorescence was observed in the elastin fibre layer of the submucosa. The fluorescence intensity of elastin was significantly higher in the graft showing fluorescence than the graft that did not show fluorescence and that at the control site.
    CONCLUSIONS: Bright green fluorescence was seen in an elastin fibre layer in the submucosa, which was likely a result of epithelial sloughing. There is a close relationship between the bright green fluorescence pattern observed using AFI bronchoscopy and airway ischaemic damage. We conclude that AFI bronchoscopy may detect airway ischaemic damage after lung transplantation.

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  • 気管支鏡検査で診断し外科的切除を行った肺原発悪性黒色腫の1例

    萱谷 紘枝, 南 大輔, 渡邉 元嗣, 山本 寛斉, 宗 淳一, 久保 寿夫, 堀田 勝幸, 田端 雅弘, 豊岡 伸一, 三好 新一郎, 谷本 光音, 木浦 勝行

    気管支学   36 ( 2 )   208 - 208   2014.3

  • Preclinical Evaluation of MicroRNA-34b/c Delivery for Malignant Pleural Mesothelioma Reviewed

    Tsuyoshi Ueno, Shinichi Toyooka, Takuya Fukazawa, Takafumi Kubo, Junichi Soh, Hiroaki Asano, Takayuki Muraoka, Norimitsu Tanaka, Yuho Maki, Kazuhiko Shien, Masashi Furukawa, Masakiyo Sakaguchi, Hiromasa Yamamoto, Kazunori Tsukuda, Shinichiro Miyoshi

    ACTA MEDICA OKAYAMA   68 ( 1 )   23 - 26   2014.2

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    The microRNA-34s (miR-34s) have p53 response elements in their 5'-flanking regions and demonstrate tumor-suppressive functions. In malignant pleural mesothelioma (MPM), we previously reported that expression of miR-34b and miR-34c (miR-34b/c) was frequently downregulated by methylation in MPM cell lines and primary tumors. The forced overexpression of miR-34b/c showed significant antitumor effects with the induction of apoptosis in MPM cells. In this study, we examined the in vivo antitumor effects of miR-34b/c using adenovirus vector on MPM. We subcutaneously transplanted NCI-H290, a human MPM cell line, into BALB/C mice and injected adenovirus vector expressing miR-34b/c, luciferase driven by the cytomegalovirus promoter (Ad-miR-34b/c or Ad-Luc), or PBS control into tumors over 5mm in diameter. A statistically significant growth inhibition of the tumor volume was observed in the Ad-miR-34b/c group from day 6 onward compared to the Ad-Luc group. The inhibition rate of Ad-miR-34b/c, compared to the tumor volume treated with Ad-Luc, was 58.6% on day 10 and 54.7% on day13. Our results indicate that adenovirus-mediated miR-34b/c gene therapy could be useful for the clinical treatment of MPM.

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  • Anti-Cancer Effects of REIC/Dkk-3-encoding Adenoviral Vector for the Treatment of Non-small Cell Lung Cancer Reviewed

    Kazuhiko Shien, Norimitsu Tanaka, Masami Watanabe, Junichi Soh, Masakiyo Sakaguchi, Keitaro Matsuo, Hiromasa Yamamoto, Masashi Furukawa, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Nam-Ho Huh, Shinichiro Miyoshi, Hiromi Kumon, Shinichi Toyooka

    PLOS ONE   9 ( 2 )   e87900   2014.2

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    Objectives: REIC/Dkk-3 is down-regulated in a broad range of human cancer cells and is considered to function as a tumor suppressor. We previously reported that REIC/Dkk-3-expressing adenovirus vector (Ad-REIC) induced endoplasmic reticulum (ER) stress and cancer-specific apoptosis in human prostate cancer. In this study, we examined the therapeutic impact of Ad-REIC on non-small cell lung cancer (NSCLC).
    Materials and Methods: We examined the anti-tumor effect of Ad-REIC on 25 NSCLC cell lines in vitro and A549 cells in vivo. Two of these cell lines were artificially established as EGFR-tyrosine kinase inhibitor (TKI) resistant sublines.
    Results: Ad-REIC-treatment inhibited the cell viability by 40% or more in 13 (52%) of the 25 cell lines at multiplicity of infection (MOI) of 20 (20 MOI). These cell lines were regarded as being highly sensitive cells. The cell viability of a nonmalignant immortalized cell line, OUMS-24, was not inhibited at 200 MOI of Ad-REIC. The effects of Ad-REIC on EGFR-TKI resistant sublines were equivalent to those in the parental cell lines. Here, we demonstrated that Ad-REIC treatment activated c-Jun N-terminal kinase (JNK) in NSCLC cell lines, indicating the induction of ER stress with GRP78/BiP (GRP78) up-regulation and resulting in apoptosis. A single intratumoral injection of Ad-REIC significantly inhibited the tumorigenic growth of A549 cells in vivo. As predictive factors of sensitivity for Ad-REIC treatment in NSCLC, we examined the expression status of GRP78 and coxsackievirus and adenovirus receptor (CAR). We found that the combination of the GRP78 and CAR expressional statuses may be used as a predictive factor for Ad-REIC sensitivity in NSCLC cells.
    Conclusion: Ad-REIC induced JNK activation and subsequent apoptosis in NSCLC cells. Our study indicated that Ad-REIC has therapeutic potential against NSCLC and that the expression statuses of GRP78 and CAR may predict a potential therapeutic benefit of Ad-REIC.

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  • 非小細胞肺癌におけるF-18 FDG PET/CTの有用性 転移性リンパ節と胸膜浸潤の診断に関して

    新家 崇義, 田中 高志, アラファト・アルキン, 小河 七子, 佐野 由佳, 井田 健太郎, 加藤 勝也, 佐藤 修平, 金澤 右, 宗 淳一, 豊岡 伸一, 三好 新一郎, 田中 健大, 市村 浩一, 吉野 正, 加地 充昌

    Japanese Journal of Radiology   32 ( Suppl. )   61 - 61   2014.2

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  • Novel Germline Mutation in the Transmembrane Domain of HER2 in Familial Lung Adenocarcinomas Reviewed

    Hiromasa Yamamoto, Koichiro Higasa, Masakiyo Sakaguchi, Kazuhiko Shien, Junichi Soh, Koichi Ichimura, Masashi Furukawa, Shinsuke Hashida, Kazunori Tsukuda, Nagio Takigawa, Keitaro Matsuo, Katsuyuki Kiura, Shinichiro Miyoshi, Fumihiko Matsuda, Shinichi Toyooka

    JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE   106 ( 1 )   djt338   2014.1

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    We encountered a family of Japanese descent in which multiple members developed lung cancer. Using whole-exome sequencing, we identified a novel germline mutation in the transmembrane domain of the human epidermal growth factor receptor 2 (HER2) gene (G660D). A novel somatic mutation (V659E) was also detected in the transmembrane domain of HER2 in one of 253 sporadic lung adenocarcinomas. Because the transmembrane domain of HER2 is considered to be responsible for the dimerization and subsequent activation of the HER family and downstream signaling pathways, we performed functional analyses of these HER2 mutants. Mutant HER2 G660D and V659E proteins were more stable than wild-type protein. Both the G660D and V659E mutants activated Akt. In addition, they activated p38, which is thought to promote cell proliferation in lung adenocarcinoma. Our findings strongly suggest that mutations in the transmembrane domain of HER2 may be oncogenic, causing hereditary and sporadic lung adenocarcinomas.

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  • [The role of 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) in liposarcoma of the chest wall]. Reviewed

    Yamamoto H, Sugimoto S, Miyoshi K, Yamamoto H, Soh J, Yamane M, Toyooka S, Oto T, Miyoshi S

    Kyobu geka. The Japanese journal of thoracic surgery   67 ( 1 )   4 - 8   2014.1

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  • 【胸壁・横隔膜の手術-その1】診断 胸壁原発脂肪肉腫におけるFDG PET/CTの有用性

    山本 治慎, 杉本 誠一郎, 三好 健太郎, 山本 寛斉, 宗 淳一, 山根 正修, 豊岡 伸一, 大藤 剛宏, 三好 新一郎

    胸部外科   67 ( 1 )   4 - 8   2014.1

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    76歳男性。増大する右胸壁腫瘤と右上肢のしびれ、脱力感を主訴に近医を受診、精査にて右大小胸筋や鎖骨下動静脈を背側から圧排する10cm大の腫瘤を指摘された。今回、穿刺吸引細胞診にて多形性細胞肉腫の診断にて精査加療目的で著者らの施設へ紹介となった。胸部造影CTでは右胸壁の胸郭出口に10cm大の腫瘍が存在しており、内部は不均一で脂肪成分を含み、右鎖骨下動静脈を背側から圧排するも、右腕神経叢や骨性胸郭への明らかな浸潤は認められなかった。PET/CTでは腫瘍内部にはFDGの高集積がみられたが辺縁部は低集積であり、遠隔臓器転移は認められなかった。以上、これらの所見より、本症例は右胸壁原発脂肪肉腫が疑われ、治療は腫瘍辺縁部が低悪性度のため浸潤や癒着は軽度と予測して腫瘍摘出術が施行された。その結果、摘出標本は11.4×6.3×8.8cm大で、被膜に覆われ黄白色調であり、内部は充実性で一部に出血が認められた。また、病理組織学的所見では腫瘍の辺縁部には高分化型脂肪肉腫の増殖がみられ、腫瘍内部では多形性を示す異型性の強い細胞が出血・壊死を伴って増殖し、脱分化型脂肪肉腫と診断された。尚、術後1年でPETにて右腕神経叢腹側にFDGの高集積を認め腫瘍の局所再発と診断され、広範囲切除術が計画されたが、患者の意思により目下は近医にて放射線治療の施行中である。

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  • Density of Tumor-Infiltrating FOXP3+T Cells as a Response Marker for Induction Chemoradiotherapy and a Potential Prognostic Factor in Patients Treated with Trimodality Therapy for Locally Advanced Non-Small Cell Lung Cancer Reviewed

    Hiroyuki Tao, Kazuhiko Shien, Junichi Soh, Eisuke Matsuda, Shinichi Toyooka, Kazunori Okabe, Shinichiro Miyoshi

    ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY   20 ( 6 )   980 - 986   2014

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    Purpose: To examine the relationship between the density of tumor-infiltrating T cell sub-populations and the pathological response to induction chemoradiotherapy (CRT) in patients with locally advanced NSCLC, and to assess the impact of T cell density on patient prognosis.
    Methods: A total of 64 patients with c-stages IIA-IIIB NSCLC who underwent induction CRT followed by R0 surgery were enrolled. Tumor-infiltrating T cells expressing either FOXP3 or CD8 were detected by immunohistochemical staining.
    Results: Mean numbers of tumor-infiltrating FOXP3+ T cells were 39.9 for patients with minor pathological responses (n = 9), 18.4 for those with major pathological responses (n = 25), and 12.9 for those with complete pathological responses (n = 30; P &lt; 0.001). The number of CD8+ T cells was not associated with pathological responses. Patients with lower FOXP3+ T cell densities showed better survival, although the difference was not statistically significant.
    Conclusion: Our study demonstrated that the density of tumor-infiltrating FOXP3+ T cells indicated the degree of response for induction CRT and prognosis in patients treated with trimodality therapy for locally advanced NSCLC, suggesting that FOXP3+ T cells may be target for adjunct immunotherapy.

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  • Thoracoscopic Lobectomy as Salvage Surgery for Local Recurrence of Non-Small Cell Lung Cancer after Carbon Ion Radiotherapy in an Initially Operable Patient Reviewed

    Seiichiro Sugimoto, Shinichi Toyooka, Ken Suzawa, Kouichi Ichimura, Osamu Fujii, Shinichiro Miyoshi

    ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY   20   501 - 504   2014

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    Carbon ion radiotherapy (CIRT) for patients with early-stage non-small cell lung cancer (NSCLC) has recently provided favorable local control with very few toxic reactions. Because CIRT for NSCLC has been mostly performed for elderly or inoperable patients, salvage surgery for NSCLC after CIRT has rarely been reported. We describe a case of complete thoracoscopic right upper lobectomy with mediastinal lymphadenectomy performed as salvage surgery for local recurrence of stage IA NSCLC after CIRT in an initially operable patient who had refused surgery 27 months previously. Pleural adhesions caused by CIRT were localized to the pulmonary apex and the central pulmonary structures were intact at the time of the salvage surgery, which allowed us to successfully perform thoracoscopic lobectomy without any complications. Thus, salvage surgery for NSCLC after CIRT may be feasible in an initially operable patient, as CIRT appears to be unlikely to cause any difficulties in the salvage surgery.

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  • Adult Mesenchymal Hamartoma of the Chest Wall: Report of a Case Reviewed

    Hiromasa Yamamoto, Junichi Soh, Koichi Ichimura, Yusuke Konishi, Shinichi Toyooka, Takayuki Nojima, Shinichiro Miyoshi

    ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY   20   663 - 665   2014

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    We present an adult case of the chest wall tumor, which was accidentally pointed out by a medical checkup. Surgical resection was performed for the tumor, as preoperative biopsy of the tumor suggested the possibility of malignancy. Postoperative pathological examination revealed the diagnosis of mesenchymal hamartoma of the chest wall, which usually occurs in early infancy and childhood. Immunohistochemical staining for Sox9 was positive for chondrocytes and partially positive for spindle tumor cells. It is considered that the present case was not pointed out until the patient became an adult, because the tumor was relatively small and thus asymptomatic.

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  • Surgical Resection of a Massive Primary Mediastinal Liposarcoma Using Clamshell Incision Combined with Lower Median Sternotomy: Report of a Case Reviewed

    Yutaka Hirano, Hiromasa Yamamoto, Koichi Ichimura, Shinichi Toyooka, Shinichiro Miyoshi

    ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY   20   606 - 608   2014

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    We experienced a case of massive mediastinal liposarcoma expanding to the bilateral pleural cavities. Preoperative positron emission tomography-computed tomography scan showed that the uptake of F-18-fluorodeoxyglucose (FDG) into the tumor was slight for its size. Clamshell incision together with lower median sternotomy provided the excellent visualization and the complete resection of the tumor. The surgical resection should be performed even for a massive liposarcoma, especially if the uptake of F-FDG into the tumor is low, as complete surgical resection is the only definitive treatment for liposarcoma.

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  • The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma Reviewed

    Takayuki Muraoka, Junichi Soh, Shinichi Toyooka, Keisuke Aoe, Nobukazu Fujimoto, Shinsuke Hashida, Yuho Maki, Norimitsu Tanaka, Kazuhiko Shien, Masashi Furukawa, Hiromasa Yamamoto, Hiroaki Asano, Kazunori Tsukuda, Takumi Kishimoto, Takemi Otsuki, Shinichiro Miyoshi

    LUNG CANCER   82 ( 3 )   485 - 490   2013.12

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    Objectives: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. microRNA-34b/c (miR-34b/c), which plays an important role in the pathogenesis of MPM, is frequently downregulated by DNA methylation in approximately 90% of MPM cases. In this study, we estimated the degree of miR-34b/c methylation in serum-circulating DNA using a digital methylation specific PCR assay (MSP).
    Materials and methods: A real-time MSP assay was performed using the SYBR Green method. The melting temperature (Tm) of each PCR product was examined using a melting curve analysis. For a digital MSP assay, 40 wells were analyzed per sample. A total of 110 serum samples from 48 MPM cases, 21 benign asbestos pleurisy (BAP) cases, and 41 healthy volunteers (HVs) were examined.
    Results: Positive range of Tm value for miR-34b/c methylation was defined as 77.71-78.79 degrees C which was the mean 3 standard deviations of 40 wells of a positive control. The number of miR-34b/c methylated wells was counted per sample according to this criterion. The number of miR-34b/c methylated wells in MPM cases was significantly higher than that in BAP cases (P = 0.03) or HVs (P &lt; 0.001). Advanced MPM cases tended to have higher number of miR-34b/c methylated wells than early MPM cases. Receiver-operating characteristic (ROC) curve analysis revealed that three number of miR-34b/c methylated wells per sample was the best cut-off of positivity of MPM with a 67% of sensitivity and a 77% specificity for prediction. The area under the ROC curve was 0.77.
    Conclusions: Our digital MSP assay can quantify miR-34b/c methylation in serum-circulating DNA. The degree of miR-34b/c methylation in serum-circulating DNA is associated with MPM, suggesting that this approach might be useful for the establishment of a new detection system for MPM. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

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  • 【最新肺癌学-基礎と臨床の最新研究動向-】肺癌の分子生物学と発癌機序 分子生物学 マイクロRNA変化

    山本 寛斉, 宗 淳一, 三好 新一郎, 豊岡 伸一

    日本臨床   71 ( 増刊6 最新肺癌学 )   109 - 113   2013.11

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  • キュアサルコーマボード共同治療連携 病院間"水平"連携による肉腫、GISTの集学的治療

    高橋 克仁, 山村 倫子, 冨田 裕彦, 上浦 祥司, 矢嶋 淳, 寺岡 慧, 波多江 亮, 大野 烈士, 宗 淳一, 豊岡 伸一, 小池 幸宏, 烏野 隆博, 楢原 啓之, 小山 隆文, 大山 優

    日本癌治療学会誌   48 ( 3 )   1214 - 1214   2013.9

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  • Bleeding into a pulmonary cyst caused by pulmonary radiofrequency ablation Reviewed

    Ryotaro Kishi, Hidefumi Mimura, Takao Hiraki, Hideo Gobara, Mayu Uka, Shinichi Toyooka, Susumu Kanazawa

    Journal of Vascular and Interventional Radiology   24 ( 7 )   1069 - 1071   2013.7

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  • Different sizes of centrilobular ground-glass opacities in chest high-resolution computed tomography of patients with pulmonary veno-occlusive disease and patients with pulmonary capillary hemangiomatosis Reviewed

    Aya Miura, Satoshi Akagi, Kazufumi Nakamura, Keiko Ohta-Ogo, Katsushi Hashimoto, Satoshi Nagase, Kunihisa Kohno, Kengo Kusano, Aiko Ogawa, Hiromi Matsubara, Shinichi Toyooka, Takahiro Oto, Aiji Ohtsuka, Tohru Ohe, Hiroshi Ito

    CARDIOVASCULAR PATHOLOGY   22 ( 4 )   287 - 293   2013.7

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    Background: Centrilobular ground-glass opacity (GGO) is one of the characteristic findings in chest high-resolution computed tomography (HRCT) of patients with pulmonary veno-occlusive disease (PVOD) and patients with pulmonary capillary hemangiomatosis (PCH). However, clinical differential diagnosis of these two diseases is difficult and has not been established. In order to clarify their differences, we compared the sizes of GGOs in chest HRCT and the sizes of capillary assemblies in pulmonary vascular casts between patients diagnosed pathologically with PVOD and PCH.
    Methods: We evaluated chest HRCT images for four patients with idiopathic pulmonary arterial hypertension (IPAH), three patients with PVOD and three patients with PCH, and we evaluated pulmonary vascular casts of lung tissues obtained from those patients at lung transplantation or autopsy.
    Results: Centrilobular GGOs in chest HRCT were observed in patients with PVOD and patients with PCH but not in patients with IPAH. We measured the longest diameter of the GGOs. The size of centrilobular GGOs was significantly larger in patients with PCH than in patients with PVOD (5.60 +/- 1.43 mm versus 2.51 +/- 0.79 mm, P&lt;.01). We succeeded in visualization of the 3-dimensional structures of pulmonary capillary vessels obtained from the same patients with PVOD and PCH undergoing lung transplantation or autopsy and measured the diameters of capillary assemblies. The longest diameter of capillary assemblies was also significantly larger in patients with PCH than in patients with PVOD (5.44 +/- 1.71 mm versus 3.07 +/- 1.07 mm, P&lt;.01).
    Conclusion: Measurement of the sizes of centrilobular GGOs in HRCT is a simple and useful method for clinical differential diagnosis of PVOD and PCH. (C) 2013 Elsevier Inc. All rights reserved.

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