Faculty Profiles - SHIEN Kazuhiko

Papers - SHIEN Kazuhiko

Division display 101 - 120 of about 148 ／ All the affair displays >>

Predictive biomarkers of response to PD-1/PD-L1 immune checkpoint inhibitors in non-small cell lung cancer. Reviewed International journal

Shien K, Papadimitrakopoulou VA, Wistuba II

Lung cancer (Amsterdam, Netherlands) 99 79 - 87 2016.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Inhibitors of the programmed cell death 1 (PD-1) pathway show the potential to substantially increase the efficacy of therapy for various malignancies, including non-small cell lung cancer (NSCLC). At the same time, substantial effort has been invested in finding biomarkers predicting which patients will respond best to this immune checkpoint inhibition. PD-L1 expression in tumor cells and the tumor microenvironment, genetic alterations and mutational load in tumor cells, and pre-existing immunity and its enhancement during treatment through tumor-infiltrating immune cells have been associated with outcomes of immune checkpoint inhibition. Here, we review the reported predictive biomarkers of response to PD-1 pathway immune checkpoint inhibitors in NSCLC, mainly focusing on results obtained with clinical trials.

DOI： 10.1016/j.lungcan.2016.06.016

Role of surgery in N2 NSCLC: pros. Reviewed International journal

Shien K, Toyooka S

Japanese journal of clinical oncology 46 ( 12 ) 1168 - 1173 2016.9

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

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.

DOI： 10.1093/jjco/hyw125

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

Watanabe M, Yamamoto H, Eikawa S, Shien K, Shien T, Soh J, Hotta K, Wada J, Hinotsu S, Fujiwara T, Kiura K, Doihara H, Miyoshi S, Udono H, Toyooka S

Acta medica Okayama 70 ( 4 ) 327 - 30 2016.8

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/54514

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

Maki Y, Nishimura Y, Toyooka S, Soh J, Tsukuda K, Shien K, Furukawa M, Muraoka T, Ueno T, Tanaka N, Yamamoto H, Asano H, Maeda M, Kumagai-Takei N, Lee S, Matsuzaki H, Otsuki T, Miyoshi S

Oncology letters 11 ( 5 ) 3308 - 3316 2016.5

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.3892/ol.2016.4412

Genetic alterations in lung adenocarcinoma with a micropapillary component. Reviewed International journal

Furukawa M, Toyooka S, Ichimura K, Yamamoto H, Soh J, Hashida S, Ouchida M, Shien K, Asano H, Tsukuda K, Miyoshi S

Molecular and clinical oncology 4 ( 2 ) 195 - 200 2016.2

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.3892/mco.2015.690

Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma. Reviewed International journal

Suzawa K, Yamamoto H, Murakami T, Katayama H, Furukawa M, Shien K, Hashida S, Okabe K, Aoe K, Soh J, Asano H, Tsukuda K, Mimura Y, Toyooka S, Miyoshi S

Oncology letters 11 ( 1 ) 705 - 712 2016.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

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.

DOI： 10.3892/ol.2015.3955

DNA copy number gains in malignant pleural mesothelioma. Reviewed International journal

Furukawa M, Toyooka S, Hayashi T, Yamamoto H, Fujimoto N, Soh J, Hashida S, Shien K, Asano H, Aoe K, Okabe K, Pass HI, Tsukuda K, Kishimoto T, Miyoshi S

Oncology letters 10 ( 5 ) 3274 - 3278 2015.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

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.

DOI： 10.3892/ol.2015.3652

Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib Reviewed International journal

Hashida, S., Yamamoto, H., Shien, K., Miyoshi, Y., Ohtsuka, T., Suzawa, K., Watanabe, M., Maki, Y., Soh, J., Asano, H., Tsukuda, K., Miyoshi, S., Toyooka, S.

Cancer Sci 106 ( 10 ) 1377 - 84 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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.

DOI： 10.1111/cas.12749

Hsp90 inhibitor NVP-AUY922 enhances the radiation sensitivity of lung cancer cell lines with acquired resistance to EGFR-tyrosine kinase inhibitors Reviewed International journal

Hashida, S., Yamamoto, H., Shien, K., Ohtsuka, T., Suzawa, K., Maki, Y., Furukawa, M., Soh, J., Asano, H., Tsukuda, K., Miyoshi, S., Kanazawa, S., Toyooka, S.

Oncol Rep 33 ( 3 ) 1499 - 504 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

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 G2/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 G2/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.

DOI： 10.3892/or.2015.3735

Lower lobe origin is a poor prognostic factor in locally advanced non-small-cell lung cancer patients treated with induction chemoradiotherapy Reviewed International journal

Shien, K., Toyooka, S., Soh, J., Hotta, K., Katsui, K., Oto, T., Kanazawa, S., Kiura, K., Date, H., Miyoshi, S.

Mol Clin Oncol 3 ( 3 ) 706 - 712 2015

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.3892/mco.2015.509

Clinicopathological characteristics and lymph node metastasis pathway of non-small-cell lung cancer located in the left lingular division Reviewed International journal

Shien, K., Toyooka, S., Soh, J., Okami, J., Higashiyama, M., Kadota, Y., Maeda, H., Hayama, M., Chida, M., Funaki, S., Okumura, M., Miyoshi, S.

Interact Cardiovasc Thorac Surg 20 ( 6 ) 791 - 6 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

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.

DOI： 10.1093/icvts/ivv062

Extended sleeve lobectomy after induction chemoradiotherapy for non-small cell lung cancer Reviewed

Toyooka, S., Soh, J., Yamamoto, H., Yamane, M., Hattori, S., Shien, K., Miyoshi, K., Sugimoto, S., Oto, T., Miyoshi, S.

Surg Today 45 ( 9 ) 1121 - 6 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

PURPOSE: 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. METHODS: The medical records of patients who underwent a surgery for NSCLC after ChRT were reviewed. RESULTS: 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. CONCLUSIONS: Our experience suggests that an extended sleeve lobectomy after induction ChRT is feasible, but careful patient selection and perioperative management are mandatory.

DOI： 10.1007/s00595-014-1025-y

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

Preclinical evaluation of microRNA-34b/c delivery for malignant pleural mesothelioma. Reviewed

Ueno T, Toyooka S, Fukazawa T, Kubo T, Soh J, Asano H, Muraoka T, Tanaka N, Maki Y, Shien K, Furukawa M, Sakaguchi M, Yamamoto H, Tsukuda K, Miyoshi S

Acta medica Okayama 68 ( 1 ) 23 - 6 2014.1

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/amo/52140

Drug resistance to EGFR tyrosine kinase inhibitors for non-small cell lung cancer. Reviewed

Shien K, Yamamoto H, Soh J, Miyoshi S, Toyooka S

Acta medica Okayama 68 ( 4 ) 191 - 200 2014.1

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/amo/52785

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

Miyoshi, S., Shien, K., Toyooka, S., Miyoshi, K., Yamamoto, H., Sugimoto, S., Soh, J., Hayama, M., Yamane, M., Oto, T.

Surg Today 44 ( 11 ) 2028 - 36 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

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.

DOI： 10.1007/s00595-013-0772-5

Presence of the minor EGFR T790M mutation is associated with drug-sensitive EGFR mutations in lung adenocarcinoma patients Reviewed International journal

Hashida, S., Soh, J., Toyooka, S., Tanaka, T., Furukawa, M., Shien, K., Yamamoto, H., Asano, H., Tsukuda, K., Hagiwara, K., Miyoshi, S.

Oncol Rep 32 ( 1 ) 145 - 52 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

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 <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.

DOI： 10.3892/or.2014.3197

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

Tao, H., Shien, K., Soh, J., Matsuda, E., Toyooka, S., Okabe, K., Miyoshi, S.

Ann Thorac Cardiovasc Surg 20 ( 6 ) 980 - 6 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：MEDICAL TRIBUNE INC

PURPOSE: To examine the relationship between the density of tumor-infiltrating T cell subpopulations 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 <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.

DOI： 10.5761/atcs.oa.13-00237

Anti-cancer effects of REIC/Dkk-3-encoding adenoviral vector for the treatment of non-small cell lung cancer Reviewed International journal

Shien, K., Tanaka, N., Watanabe, M., Soh, J., Sakaguchi, M., Matsuo, K., Yamamoto, H., Furukawa, M., Asano, H., Tsukuda, K., Nasu, Y., Huh, N. H., Miyoshi, S., Kumon, H., Toyooka, S.

PLoS One 9 ( 2 ) e87900 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

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 non-malignant 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.

DOI： 10.1371/journal.pone.0087900

Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas Reviewed International journal

Yamamoto, H., Higasa, K., Sakaguchi, M., Shien, K., Soh, J., Ichimura, K., Furukawa, M., Hashida, S., Tsukuda, K., Takigawa, N., Matsuo, K., Kiura, K., Miyoshi, S., Matsuda, F., Toyooka, S.

J Natl Cancer Inst 106 ( 1 ) djt338 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

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.

DOI： 10.1093/jnci/djt338

　 PREV - NEXT 　

1
2
3
4
5
6
7
8