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  • American Association for Cancer Research (AACR)  (20)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 16 ( 2023-08-15), p. 2704-2715
    Abstract: Significant progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) by generating and using murine models. To accelerate drug discovery by identifying novel therapeutic targets on a systemic level, here we generated a Drosophila model mimicking the genetic signature in PDAC (KRAS, TP53, CDKN2A, and SMAD4 alterations), which is associated with the worst prognosis in patients. The ‘4-hit’ flies displayed epithelial transformation and decreased survival. Comprehensive genetic screening of their entire kinome revealed kinases including MEK and AURKB as therapeutic targets. Consistently, a combination of the MEK inhibitor trametinib and the AURKB inhibitor BI-831266 suppressed the growth of human PDAC xenografts in mice. In patients with PDAC, the activity of AURKB was associated with poor prognosis. This fly-based platform provides an efficient whole-body approach that complements current methods for identifying therapeutic targets in PDAC. Significance: Development of a Drosophila model mimicking genetic alterations in human pancreatic ductal adenocarcinoma provides a tool for genetic screening that identifies MEK and AURKB inhibition as a potential treatment strategy.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. CT137-CT137
    Abstract: Objectives: Salivary gland cancer is a rare cancer that has no effective drug therapy available. It comprises salivary duct carcinoma (SDC) as a major histology, which resembles high-grade breast ductal carcinoma and often overexpresses HER2. The purpose of this study is to evaluate the efficacy and safety of trastuzumab and docetaxel therapy in patients (pts) with HER2-positive salivary gland carcinoma. Methods: We conducted a multicenter, single-arm Phase II study of trastuzumab and docetaxel for pts with HER2-positive recurrent and/or metastatic salivary gland carcinoma pursuant to the J-GCP. HER2 positivity was defined as immunohistochemistry (IHC) 3+ or IHC 2+/dual color in situ hybridization (DISH) +. Eligible pts were treated with trastuzumab 6 mg/kg (loading dose 8 mg/kg) and docetaxel 70 mg/m2 every 3 weeks up to 8 cycles. The primary endpoint was overall response rate (ORR) using RECIST v1.1 assessed by the blinded independent review committee (BIRC). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. This study required 16 pts, with ORR of 25% considered non-promising and 70% promising (two-sided alpha = 0.05; beta = 0.1) and with 2 withdrawal pts. Results: Sixteen pts were recruited in this trial. The median age was 59 (range 26-72), 3 pts were female, and all pts had performance status 0-1. All pts had carcinomas histologically compatible with SDCs by central pathology review of samples used for HER2 evaluation, 14 of which were readily confirmed as SDCs. All pts had HER2 IHC 3+ tumors. Two pts were previously untreated and had metastatic disease. The remaining 14 pts had recurrence after surgery that was followed by adjuvant chemoradiotherapy in 5 pts and by adjuvant radiotherapy in 6 pts. No pts were previously treated with chemotherapy alone. After excluding a pt without measurable lesions evaluated by BIRC, ORR by BIRC was 60% (9/15; 95% CI, 32.3~83.7) with one complete response. Median PFS was 8.5 months (95% CI, 6.0~12.7). Median OS was not reached at a median follow-up of 17.9 months in survivors. Common grade 3/4 adverse events ( & gt; 10%) were neutropenia (16 pts, 100%), leukopenia (15 pts, 93.8%), lymphopenia (3 pts, 18.8%), and febrile neutropenia (2 pts, 12.5%). Treatment-related death occurred in 1 pt (6.3%) due to hypoalbuminemia. Conclusions: This study demonstrated a promising efficacy with predictable toxicities. Trastuzumab and docetaxel therapy may be an effective treatment option in pts with HER2-positive recurrent and/or metastatic salivary gland carcinoma. Citation Format: Ichiro Kinoshita, Satoshi Kano, Yasushi Shimizu, Naomi Kiyota, Yuichiro Tada, Kei Ijichi, Tmoko Yamazaki, Akihiro Homma, Yoichi M. Ito, Kota Ono, Keiko Kobayashi, Toshiyuki Isoe, Yutaka Hatanaka, Hitoshi Tsuda, Shojiroh Morinaga, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita. Phase II study of trastuzumab and docetaxel therapy in patients with HER2-positive recurrent and/or metastatic salivary gland carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT137.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 3
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 18 ( 2007-09-15), p. 5385-5390
    Abstract: Purpose: Epidermal growth factor receptor (EGFR) mutations, especially deletional mutations in exon 19 (DEL) and L858R, predict gefitinib sensitivity in patients with non–small cell lung cancer (NSCLC). In this study, we validated EGFR mutation detection using high-resolution melting analysis (HRMA) and evaluated the associations between EGFR mutations and clinical outcomes in advanced NSCLC patients treated with gefitinib on a larger scale. Experimental Design: The presence of DEL or L858R was evaluated using HRMA and paraffin-embedded tissues and/or cytologic slides from 212 patients. In 66 patients, the results were compared with direct sequencing data. Results: HRMA using formalin-fixed tissues had a 92% sensitivity and a 100% specificity. The analysis was successfully completed in 207 patients, and DEL or L858R mutations were detected in 85 (41%) patients. The response rate (78% versus 8%), time-to-progression (median, 9.2 versus 1.6 months), and overall survival (median, 21.7 versus 8.7 months) were significantly better in patients with EGFR mutations (P & lt; 0.001). Even among the 34 patients with stable diseases, the time-to-progression was significantly longer in patients with EGFR mutations. Patients with DEL (n = 49) tended to have better outcomes than those with L858R (n = 36); the response rates were 86% and 67%, respectively (P = 0.037), and the median time-to-progression was 10.5 and 7.4 months, respectively (P = 0.11). Conclusions: HRMA is a precise method for detecting DEL and L858R mutations and is useful for predicting clinical outcomes in patients with advanced NSCLC treated with gefitinib.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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  • 4
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 14, No. 12 ( 2008-06-15), p. 3746-3753
    Abstract: Purpose: The p16 gene is frequently inactivated in lung adenocarcinoma. In particular, homozygous deletions (HD) have been frequently detected in cell lines; however, their frequency and specificity is not well-established in primary tumors. The purpose of this study was to elucidate the prevalence and the timing for the occurrence of p16 HDs in lung adenocarcinoma progression in vivo. Experimental Design: Multiple ligation-dependent probe amplification was used for the detection of p16 HDs in 28 primary small-sized lung adenocarcinomas and 22 metastatic lung adenocarcinomas to the brain. Cancer cells were isolated from primary adenocarcinoma specimens by laser capture microdissection. HDs were confirmed by quantitative real-time genomic PCR analysis. Results: HDs were detected in 8 of 28 (29%) primary tumors, including 2 of 8 (25%) noninvasive bronchioloalveolar carcinomas, and 5 of 22 (26%) brain metastases, respectively. No significant associations were observed between p16 HDs and gender, age, smoking history, stage, and prognosis. HDs were detected with similar frequencies (17–29%) among adenocarcinomas with epidermal growth factor receptor (EGFR) mutations, with KRAS mutations, and without EGFR/KRAS mutations, and with similar frequencies (22–28%) between adenocarcinomas with and without p53 mutations. Conclusions: p16 HDs occur early in the development of lung adenocarcinomas and with similar frequencies among EGFR type, KRAS type, and non-EGFR/KRAS type lung adenocarcinomas. Tobacco carcinogens would not be a major factor inducing p16 HDs in lung adenocarcinoma progression.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3927-3927
    Abstract: Background: Approximately 20-30% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutations are not responsive to EGFR-tyrosine kinase inhibitors (TKIs). Although, primary resistance to EGFR-TKI is attributed to various genetic alterations, little is known about the clinical and immunopathological features of patients with primary resistance. The tumor immune microenvironment including tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) has been reported to play an important role in tumor progression in NSCLC. However, few studies have directly focused on the relationship between the tumor immune microenvironment and primary resistance to EGFR-TKI. Materials and Methods: Characteristics of 124 NSCLC patients with EGFR mutations who received EGFR-TKI were analyzed. Primary resistance was defined as disease progression within 3 months after EGFR-TKI treatment. Tumor specimens obtained before EGFR-TKI treatment were assessed for the density of TILs expressing CD4 or CD8, and for the expression rate of PD-L1 on tumor cells and tumor-infiltrating immune cells, immunohistochemically. Results: Primary resistance was observed in 13.7% (17/124) of patients. Smoking Tobacco correlated significantly with primary resistance compared to non-primary resistance. Lower density of total TILs and negative PD-L1 expression as per immunohistochemical analysis correlated significantly with primary resistance. Moreover, immune ignorant phenotype of tumor microenvironment, negative PD-L1 expression with low TIL density, was significantly observed in primary resistance. Conclusions: Smoking and immune ignorance in the tumor microenvironment might result in primary resistance to EGFR-TKIs. Citation Format: Yuta Takashima, Jun Sakakibara-Konishi, Yutaka Hatanaka, Kanako C. Hatanaka, Yoshihito Ohhara, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Yoshihiro Matsuno, Masaharu Nishimura. Clinicopathologic features and immune microenvironment of non-small cell lung cancer with primary resistance to epidermal growth factor receptor-tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3927.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 6
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 11, No. 8 ( 2005-04-15), p. 2954-2961
    Abstract: Purpose: DAL-1/4.1B is an actin-binding protein originally identified as a molecule whose expression is down-regulated in lung adenocarcinoma. We have previously shown that a lung tumor suppressor, TSLC1, associates with DAL-1, suggesting that both proteins act in the same cascade. The purpose of this study is to understand the molecular mechanisms and clinical significance of DAL-1 inactivation in lung cancer. Experimental Design: We studied aberration of the DAL-1 in 103 primary non–small cell lung cancers (NSCLC) and 18 lung cancer cells. Expression and allelic and methylation status of DAL-1 was examined by reverse transcription-PCR, microsatellite analysis, and bisulfite sequencing or bisulfite single-strand conformational polymorphism, respectively. Results: Loss of DAL-1 expression was strongly correlated with promoter methylation in lung cancer cells, whereas DAL-1 expression was restored by a demethylating agent, 5-aza-2′-deoxycytidine. The DAL-1 promoter was methylated in 59 (57%) primary NSCLC tumors, 37% of which were associated with loss of heterozygosity around the DAL-1 on chromosomal region 18p11.3. In squamous cell carcinomas, DAL-1 methylation was observed in 9 of 10 tumors at stage I, whereas the incidence of methylation gradually increased in adenocarcinomas as they progressed [13 of 36 (36%), 4 of 12 (33%), 14 of 17 (82%), and 3 of 3 (100%) tumors at stages I, II, III, and IV, respectively; P = 0.0026]. Furthermore, in adenocarcinomas, disease-free survival and overall survival were significantly shorter in patients with tumors harboring the methylated DAL-1 (P = 0.0011 and P = 0.045, respectively). Conclusions: DAL-1 methylation is involved in the development and progression of NSCLC and provides an indicator for poor prognosis.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4662-4662
    Abstract: Salivary gland duct carcinoma (SDC) is one of the high-grade salivary gland carcinoma, classified into two patterns; i) carcinoma ex pleomorphic adenoma (Ca-ex-PA) type, which is derived from benign pleomorphic adenoma (PA), ii) de novo type, which is generated from normal salivary gland tissue. According to current WHO classification, Ca-ex-PA is diagnosed when pathological examination proves as follows, a) the mixture of the component of cancer cells and that of pre-existing PA cells, b) the existence of malignant cells after the resection of PA. However, current criteria cannot entirely be accurate from the viewpoint of disease onset. For example, i) if a benign component of PA is replaced completely by Ca-ex-PA, the Ca-ex-PA type can be misdiagnosed as de novo type because histopathological examination cannot clarify the existence of PA in its surgery specimen. Moreover, ii) if a de novo type SDC, arising from normal salivary tissue, is growing and infiltrate to the preexisting PA, the de novo type can be misdiagnosed as Ca-ex-PA type. Recently, Pleomorphic adenoma gene 1 (PLAG1) has been identified as the gene associated with tumorigenesis of PA. Subsequently, the overexpression of PLAG1 protein has been reported to be observed in both PAs and Ca-ex-PAs and useful for diagnosis of them. Thus, we considered that PLAG1 immunohistochemistry can enable us to distinguish Ca-ex-PA type and de novo type in SDCs more definitively. In this study, 23 SDC patients who underwent primary surgery for cancer at our institution were enrolled, including 14 Ca-ex-PA types and 9 de novo types. In each case, we had its formalin-fixed-paraffin-embedded tissue sample stained for PLAG1-antibodies (clone 3B7, Mouse mAb, 1:100, Abnova) and evaluated PLAG1 protein expression in the component of glandular-epithelial component and that of non-glandular-epithelial, respectively. PLAG1 immunostaining was scored as positive when the more than 10% nuclear staining of tumor cells are observed. In all 23 SDCs, there was no PLAG1 protein overexpression in glandular-epithelial component, irrespective of benign or malignant. In all 14 Ca-ex-PA types, positive findings of PLAG1 overexpression were observed in non-glandular-epithelial component. In all 9 de novo types, no non-glandular-epithelial component showed any signs of PLAG1 protein overexpression. There was no discrepancy of conventional criteria and the status of PLAG1, which are the cases; i) Ca-ex-PA which is misdiagnosed as de novo type, ii) de novo type which is misdiagnosed as Ca-ex-PA type. Conclusions : There is no difference between conventional criteria and PLAG1-based criteria in our cases. However, in the cases with obscure characteristics of PA morphologically, such as mucoid/myxoid or cartilaginous-like materials, findings of PLAG1-positive cells can help us to distinguish Ca-ex-PA type from de novo type more definitively. Citation Format: Takayoshi Suzuki, Satoshi Kano, Kanako Hatanaka, Yutaka Hatanaka, Tomohiro Sakashita, Takatsugu Mizumachi, Hiromitsu Hatakeyama, Akihiro Homma, Yoshihiro Matsuno, Satoshi Fukuda. Expression of PLAG1 in salivary duct carcinomas: its efficacy of the distinction of carcinoma ex pleomorphic adenoma type and de novo type [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4662. doi:10.1158/1538-7445.AM2017-4662
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 4 ( 2009-02-15), p. 1615-1623
    Abstract: Seventy-two small-sized (≤2 cm in diameter) lung adenocarcinomas consisting of 15 noninvasive and 57 invasive tumors were subjected to whole genome allelic imbalance (AI) scanning and mutational analysis of the EGFR, KRAS, and TP53 genes to elucidate genetic pathways of early-stage lung adenocarcinomas. The chromosome 13q13 region showed the most frequent AI (58%) and was affected at similar frequencies between noninvasive and invasive tumors (53% and 60%, respectively), as EGFR and KRAS mutations were. The number of AI regions as well as the frequency of TP53 mutations in invasive tumors was significantly higher than those in noninvasive ones [9.8 ± 5.6 versus 4.8 ± 2.8 (P = 0.00002) and 61% versus 13% (P = 0.001), respectively]. In particular, AIs at the chromosome 11p11-p12, 17p12-p13, and 18p11 regions in invasive tumors were significantly more frequent than those in noninvasive ones (P & lt; 0.01). The results indicated that noninvasive tumors were developed by EGFR, KRAS, and 13q alterations and progressed to invasive ones by subsequent alterations of several tumor suppressor genes, including those on 11p11-p12, 17p12-p13, and 18p11 and TP53. AI at 8p21 was significantly more frequent in advanced stages ( & gt;IA) and associated with worse prognoses (P = 0.04) and, thus, would be involved in invasion and/or metastasis of adenocarcinoma cells and useful for the prediction of prognosis of patients with small-sized lung adenocarcinoma. [Cancer Res 2009;69(4):1615–23]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 9
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 3 ( 2007-02-01), p. 799-805
    Abstract: Purpose: We aimed to identify candidate proteins for tumor markers to predict the response to gefitinib treatment. Experimental Design: We did two-dimensional difference gel electrophoresis to create the protein expression profile of lung adenocarcinoma tissues from patients who showed a different response to gefitinib treatment. We used a support vector machine algorithm to select the proteins that best distinguished 31 responders from 16 nonresponders. The prediction performance of the selected spots was validated by an external sample set, including six responders and eight nonresponders. The results were validated using specific antibodies. Results: We selected nine proteins that distinguish responders from nonresponders. The predictive performance of the nine proteins was validated examining an additional six responders and eight nonresponders, resulting in positive and negative predictive values of 100% (six of six) and 87.5% (seven of eight), respectively. The differential expression of one of the nine proteins, heart-type fatty acid–binding protein, was successfully validated by ELISA. We also identified 12 proteins as a signature to distinguish tumors based on their epidermal growth factor receptor gene mutation status. Conclusions: Study of these proteins may contribute to the development of personalized therapy for lung cancer patients.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 10
    Online Resource
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    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2574-2574
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2574-2574
    Abstract: [Backgroud and Purpose]: Tumor endothelial cells (TECs) have been reported to have various abnormalities. For example, TECs demonstrate higher expression levels of several molecules (TEC markers) compared with normal endothelial cells (NECs). Recently we identified biglycan (Bgn) as one of TEC markers. Bgn has been reported to be associated with tumor progression in various cancers. In addition, we have found that Bgn secreted by TEC promoted intravasation of tumor cells and lung metastasis in vivo mouse tumors. Lung cancer, of which non-small-cell lung cancer (NSCLC) is the most common form, remains the leading cause of cancer-related mortality worldwide, with many patients presenting with advanced disease at initial diagnosis. Moreover, in spite of recent advances in chemotherapy and targeted therapy, 5-year survival for patients with NSCLC is still disappointingly low at less than 20%. Therefore, it is urgent need to develop effective biomarkers for early diagnosis or new therapeutic target. In this study, we analyzed the association between Bgn expression in TEC in lung cancer and the cancer progression of these patients to evaluate the possibility of Bgn as a biomarker. [Method] : A total 46 patients with lung cancer, who had undergone thoracic surgery at Hokkaido university hospital from February 2015 to March 2017 , were enrolled in this study. First, we performed immunohistochemistry of CD31 and Bgn with serial sections of resected lung tumor tissues, and analyzed the correlation between Bgn positive vessel density in primary lung tumors and clinicopathological factors. Second, we measured the Bgn levels in preoperative serum by ELISA,and the correlation between Bgn positive vessel density in lung tumor tissue and blood Bgn levels. [Result]: The Bgn positive vessel density in primary lung tumor tissue was significantly correlated with primary tumor invasion (p=0.036) and pleural invasion (p=0.036). The preoperative serum Bgn level was also significantly correlated with primary tumor invasion (p=0.0017), pleural invasion (p=0.046) and preoperative blood c-reactive protein level (p=0.012). The Bgn positive vessel density in primary lung tumors was significantly correlated with preoperative serum Bgn level (p & lt;0.0001). In case of lung adenocarcinoma, average of serum Bgn level in Ground Glass Opacity (GGO) positive cases (178ng/ml) was significantly lower than that in GGO negative cases (473ng/ml) (p=0.043). The serum Bgn level was significantly higher in the patients classified into high-grade group (1082ng/ml) by IASLC/ATS/ERS classification than that in intermediate-grade or low-grade groups (264ng/ml, p=0.037). [Conclusion]: In conclusion, these results suggested that Bgn expression in TEC could be a biomarker of lung cancer Citation Format: Hirofumi Morimoto, Nako Maishi, Yasuhiro Hida, Hiroshi Nishihara, Yutaka Hatanaka, Yoshihiro Matsuno, Toru Nakamura, Satoshi Hirano, Kyoko Hida. Biglycan, tumor endothelial secreting proteoglycan, as possible biomarker for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2574.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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