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Sample records for mouse lung adenocarcinoma

  1. Anti-EGFR therapy radiosensitizes human lung adenocarcinoma xenograft in nude mouse

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    Wang Hui; Li Tianran; Tian Jiahe; Qu Baolin; Zhu Hui

    2008-01-01

    Objective: To investigate the effect of Gefitinib on radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. Methods: Human lung adenocarcinoma cell line A549 was used to establish nude mouse xenograft tumor model. The mice were derided into 4 groups: control, irradiation alone, Gefinitib alone and radiation combined with Genifitib. Radiation schedule was 3 fractions of 5 Gy, once daily. Gefitinib was daily administered by gavage at 100 mg/(kg·day -1 ) for 14 days. In the combination group, radiotherapy was performed 2 hours after Gefitinib administration. Tumor diameter was measured every other day. Percentage of tumor growth inhibition, growth delay time and regrowth delay time were evaluated. Results: For A549 xenografts in radiation alone, gefitinib alone and combination therapy groups, the percentage of tumor growth inhibition was 22.7%, 12.4% and 38.2%, respectively (F=25.75, P=0.000). Tumor growth delay time was 6.0, 7.8 and 21.6 days, respectively (F=70.49, P=0.000). Tumor regrowth delay time in combination therapy and irradiation alone groups was 23.4 and 10.2 days. (F=174.24, P= 0.000). Sensitizing enhancement ratio of combination group was 1.5 in growth and 1.7 in regrowth. Conclusions: Anti-EGFR therapy enhances the radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. (authors)

  2. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma.

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    McFadden, David G; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K; Song, Xiaoling; Pirun, Mono; Santiago, Philip M; Kim-Kiselak, Caroline; Platt, James T; Lee, Emily; Hodges, Emily; Rosebrock, Adam P; Bronson, Roderick T; Socci, Nicholas D; Hannon, Gregory J; Jacks, Tyler; Varmus, Harold

    2016-10-18

    Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

  3. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

    Science.gov (United States)

    McFadden, David G.; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K.; Song, Xiaoling; Pirun, Mono; Santiago, Philip M.; Kim-Kiselak, Caroline; Platt, James T.; Lee, Emily; Hodges, Emily; Rosebrock, Adam P.; Bronson, Roderick T.; Socci, Nicholas D.; Hannon, Gregory J.; Jacks, Tyler; Varmus, Harold

    2016-01-01

    Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity. PMID:27702896

  4. PCR detection of retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1994-01-01

    From 1971--1986, Argonne National Laboratory conducted a series of large-scale studies of tumor incidence in 40,000 BCF 1 mice irradiated with 60 Co γ-rays or JANUS fission-spectrum neutrons. Polymerase chain reaction (PCR) technique was used to detect deletions in the mouse retinoblastoma (mRb) gene. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. Absence of any of these fragments on a Southern blot indicated a deletion of that portion of the mRb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice were analyzed for mRb deletions. In all normal mouse tissues studies all six mRb exon fragments were present on Southern blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, 1 of 6 tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice showed a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

  5. PCR detection of retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1993-01-01

    From 1971 to 1986, Argonne National Laboratory conducted a series of large-scale studies of tumor incidence in 40,000 BCF 1 mice irradiated with 60 Co γ rays or JANUS fission-spectrum neutrons; normal and tumor tissues from mice in these studies were preserved in paraffin blocks. A polymerase chain reaction (PCR) technique has been developed to detect deletions in the mouse retinoblastoma (mRb) gene in the paraffin-embedded tissues. Microtomed sections were used as the DNA source in PCR reaction mixtures. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. The absence of any of these fragments (relative to control PCR products) on a Southern blot indicated a deletion of that portion of the mRb gene. The tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice (569 cGy of 60 Co γ rays or 60 cGy of JANUS neutrons, doses that have been found to have approximately equal biological effectiveness in the BCF, mouse) were analyzed for mRb deletions. In all normal mouse tissues studies, all six mRb exon fragments were present on Southem blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, I of 6 tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice had a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

  6. Polymerase chain reaction detection of retinoblastoma gene deletions in paraffin-embedded mouse lung adenocarcinomas

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1991-01-01

    A Polymerase chain reaction (PCR) technique was used to detect deletions in the mouse retinoblastoma (mRb) gene using microtomed sections from paraffin-embedded radiation-induced and spontaneous tumors as the DNA source. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. Absence of any of these fragments relative to control PCR products on a Southern blot indicated a deletion of that portion of the mRb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death. Spontaneous tumors as well as those from irradiated mice (569 cGy of 60 Co γ rays or 60 cGy of JANUS neutrons) were analyzed. Tumors in six neutron-irradiated mice also had no mRb deletions. However, one of six tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice showed a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

  7. Mastic Oil Inhibits the Metastatic Phenotype of Mouse Lung Adenocarcinoma Cells

    International Nuclear Information System (INIS)

    Loutrari, Heleni; Magkouta, Sophia; Papapetropoulos, Andreas; Roussos, Charis

    2011-01-01

    Mastic oil from Pistacia lentiscus variation chia, a natural combination of bioactive terpenes, has been shown to exert anti-tumor growth effects against a broad spectrum of cancers including mouse Lewis lung adenocarcinomas (LLC). However, no studies have addressed its anti-metastatic actions. In this study, we showed that treatment of LLC cells with mastic oil within a range of non-toxic concentrations (0.01–0.04% v/v): (a) abrogated their Matrigel invasion and migration capabilities in transwell assays; (b) reduced the levels of secreted MMP-2; (c) restricted phorbol ester-induced actin remodeling and (d) limited the length of neo-vessel networks in tumor microenvironment in the model of chick embryo chorioallantoic membrane. Moreover, exposure of LLC and endothelial cells to mastic oil impaired their adhesive interactions in a co-culture assay and reduced the expression of key adhesion molecules by endothelial cells upon their stimulation with tumor necrosis factor-alpha. Overall, this study provides novel evidence supporting a multipotent role for mastic oil in prevention of crucial processes related to cancer metastasis

  8. Detection of retinoblastoma gene deletions in spontaneous and radiation-induced mouse lung adenocarcinomas by polymerase chain reaction

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1994-01-01

    A polymerase chain reaction (PCR) technique has been developed to detect deletions in the mouse retinoblastoma gene using histological sections from radiation-induced and spontaneous tumors as the DNA source. Six mouse Rb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. The absence of any of these fragments relative to control PCR products on a Southern blot indicated a deletion of that portion of the mouse Rb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death. Spontaneous tumors as well as those from irradiated mice (5.69 Gy 60 Co γ rays or 0.6 Gy JANUS neutrons, which have been found to have approximately equal radiobiological effectiveness) were analyzed for mouse Rb deletions. Tumors in 6 neutron-irradiated mice had no mouse Rb deletions. However, 1 of 6 tumors from γ-irradiated mice (17%) and 6 of 18 spontaneous tumors from unirradiated mice (33%) showed a deletion in one or both mouse Rb alleles. All deletions detected were in the 5' region of the mouse Rb gene. 36 refs., 2 figs., 2 tabs

  9. Differential diagnosis and cancer staging of a unique case with multiple nodules in the lung - lung adenocarcinoma, metastasis of colon adenocarcinoma, and colon adenocarcinoma metastasizing to lung adenocarcinoma.

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    Bai, Yun; Qiu, Jianxing; Shang, Xueqian; Liu, Ping; Zhang, Ying; Wang, Ying; Xiong, Yan; Li, Ting

    2015-05-01

    Lung cancer is the most common cancer in the world. Despite this, there have been few cases of simultaneous primary and metastatic cancers in the lung reported, let alone coexisting with tumor-to-tumor metastasis. Herein, we describe an extremely unusual case. A 61-year-old man with a history of colon adenocarcinoma was revealed as having three nodules in the lung 11 months after colectomy. The nodule in the left upper lobe was primary lung adenocarcinoma, the larger one in the right upper lobe was a metastasis of colon adenocarcinoma, and the smaller one in the right upper lobe was colon adenocarcinoma metastasizing to lung adenocarcinoma. Our paper focused on the differential diagnosis and cancer staging of this unique case, and discussed the uncommon phenomenon of the lung acting as a recipient in tumor-to-tumor metastasis.

  10. Comparative proteome analysis of three mouse lung adenocarcinoma CMT cell lines with different metastatic potential by two-dimensional gel electrophoresis and mass spectrometry.

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    Zhang, Kelan; Wrzesinski, Krzysztof; Stephen, J Fey; Larsen, Peter Mose; Zhang, Xumin; Roepstorff, Peter

    2008-12-01

    Metastasis is a lethal attribute of a cancer and presents a continuing therapeutic challenge. Metastasis is a highly complex process and more knowledge about the mechanisms behind metastasis is highly desirable. Isogenic CMT cell lines were selected from a spontaneous mouse lung adenocarcinoma and characterized in vivo to have different metastatic potential. In this study, the comprehensive protein expression profiles of three of these CMT cell lines at passage 5, 15 and 35 were analyzed by 2-DE separation followed by MS identification. As a result, 82 and 40 unique proteins were found to be significantly up- or down-regulated between cell lines with different metastatic potential at passages 5 and 15, respectively. These proteins were identified by MS and most of them have previously been reported to be related to cancer development and/or metastasis. Bioinformatics analysis indicated that several of the proteins were involved in proteasome, cell-cycle and cell-communication pathways. Among them, some keratins, 14-3-3 proteins and 26S proteasome proteins were identified and their aberrant expression may be directly or indirectly involved in cancer development and metastasis. In conclusion, our comprehensive 2-DE-based proteomics studies revealed some candidate proteins, protein families and signaling pathways, which might be important in cancer development and metastasis.

  11. CT findings of adenocarcinoma of the lung

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    Jeon, T. J.; Kim, S. J.; Lee, D. Y.; Ahn, C. M [Yonsei Univ. College of Medicine, Seoul (Korea, Republic of)

    1996-03-01

    To evaluate CT findings of primary adenocarcinoma of the lung and to assess distant metastasis at the time of diagnosis. CT findings of 150 patients with adenocarcinoma, confirmed by histopathologic methods, were classified as central or peripheral lesion and pattern analysis of typical findings noted in this cancer was carried out. Intra and extrathoracic metastases of adenocarcinoma were also investigated. Of 150 cases of adenocarcinoma of the lung, 121 were found to be of the peripheral type and 29 were of the central type. These peripheral lesions comprised 105 nodules, 11 consolidations, four cavities and one linear lesion, while the central lesions consisted of 19 cases of atelectasis and tens of branchial wall thickening. lung to lung(nine cases), lymphangitic(five cases), and pleural metastasis(16 cases) were presented as intrathoracic metastasis, while bone(17), brain,(six), liver(two) and adrenal metastasis(one case)were presented as extrathoracic metastasis. The most common radiologic finding of adenocarcinoma is a peripheral single mass or nodule but consolidation, cavity or tubular lesions, as well as atelectasis or bronchial wall thickening alone can be presented as unusual findings of adenocarcinoma. As a consequence, it is in many cases difficult to differentially diagnose. Distant metastasis was also noted in many cases of early T-stage lesion, so to successfully manage the patient, careful evaluation of the metastasis is essential.

  12. CT findings of adenocarcinoma of the lung

    International Nuclear Information System (INIS)

    Jeon, T. J.; Kim, S. J.; Lee, D. Y.; Ahn, C. M

    1996-01-01

    To evaluate CT findings of primary adenocarcinoma of the lung and to assess distant metastasis at the time of diagnosis. CT findings of 150 patients with adenocarcinoma, confirmed by histopathologic methods, were classified as central or peripheral lesion and pattern analysis of typical findings noted in this cancer was carried out. Intra and extrathoracic metastases of adenocarcinoma were also investigated. Of 150 cases of adenocarcinoma of the lung, 121 were found to be of the peripheral type and 29 were of the central type. These peripheral lesions comprised 105 nodules, 11 consolidations, four cavities and one linear lesion, while the central lesions consisted of 19 cases of atelectasis and tens of branchial wall thickening. lung to lung(nine cases), lymphangitic(five cases), and pleural metastasis(16 cases) were presented as intrathoracic metastasis, while bone(17), brain,(six), liver(two) and adrenal metastasis(one case)were presented as extrathoracic metastasis. The most common radiologic finding of adenocarcinoma is a peripheral single mass or nodule but consolidation, cavity or tubular lesions, as well as atelectasis or bronchial wall thickening alone can be presented as unusual findings of adenocarcinoma. As a consequence, it is in many cases difficult to differentially diagnose. Distant metastasis was also noted in many cases of early T-stage lesion, so to successfully manage the patient, careful evaluation of the metastasis is essential

  13. EGFR Mutation Status in Uighur Lung Adenocarcinoma Patients

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    Li SHAN

    2013-02-01

    Full Text Available Background and objective Epidermal growth factor receptor (EGFR, a transmembrane protein, is a member of the tyrosine kinase family. Gefitinib, an EGFR tyrosine-kinase inhibitors, has shown a high response rate in the treatment of lung cancer in patients with EGFR mutation. However, significant differences in EGFR mutations exist among different ethnic groups. The aim of this study is to investigate the prevalence of EGFR mutations in Uighur lung adenocarcinoma patients by using a rapid and sensitive detection method and to analyze EGFR mutation differences compared with Han lung adenocarcinoma patients. Methods We examined lung adenocarcinoma tissues from 138 patients, including 68 Uighur lung adenocarcinoma patients and 70 Han lung adenocarcinoma patients, for EGFR mutations in exons 18, 19, 20, and 21 by using the amplification refractory mutation system (ARMS PCR method. The mutation differences between Uighur and Han lung adenocarcinoma were compared by using the chi-square test method. Results EGFR mutations were detected in 43 (31.2% of the 138 lung adenocarcinoma patients. EGFR mutations were detected in 11 (16.2% of the 68 Uighur lung adenocarcinoma patients and in 32 (45.7% of the 70 Han lung adenocarcinoma patients. Significant differences were observed in the EGFR mutations between Uighur lung adenocarcinoma patients and Han lung adenocarcinoma patients (P<0.001. Conclusion Our results indicate that the EGFR mutation in Uighur lung adenocarcinoma patients (16.2% is significantly lower than that in Han lung adenocarcinoma patients (45.7%.

  14. Characterizing the cancer genome in lung adenocarcinoma

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    Weir, Barbara A.; Woo, Michele S.; Getz, Gad; Perner, Sven; Ding, Li; Beroukhim, Rameen; Lin, William M.; Province, Michael A.; Kraja, Aldi; Johnson, Laura A.; Shah, Kinjal; Sato, Mitsuo; Thomas, Roman K.; Barletta, Justine A.; Borecki, Ingrid B.; Broderick, Stephen; Chang, Andrew C.; Chiang, Derek Y.; Chirieac, Lucian R.; Cho, Jeonghee; Fujii, Yoshitaka; Gazdar, Adi F.; Giordano, Thomas; Greulich, Heidi; Hanna, Megan; Johnson, Bruce E.; Kris, Mark G.; Lash, Alex; Lin, Ling; Lindeman, Neal; Mardis, Elaine R.; McPherson, John D.; Minna, John D.; Morgan, Margaret B.; Nadel, Mark; Orringer, Mark B.; Osborne, John R.; Ozenberger, Brad; Ramos, Alex H.; Robinson, James; Roth, Jack A.; Rusch, Valerie; Sasaki, Hidefumi; Shepherd, Frances; Sougnez, Carrie; Spitz, Margaret R.; Tsao, Ming-Sound; Twomey, David; Verhaak, Roel G. W.; Weinstock, George M.; Wheeler, David A.; Winckler, Wendy; Yoshizawa, Akihiko; Yu, Soyoung; Zakowski, Maureen F.; Zhang, Qunyuan; Beer, David G.; Wistuba, Ignacio I.; Watson, Mark A.; Garraway, Levi A.; Ladanyi, Marc; Travis, William D.; Pao, William; Rubin, Mark A.; Gabriel, Stacey B.; Gibbs, Richard A.; Varmus, Harold E.; Wilson, Richard K.; Lander, Eric S.; Meyerson, Matthew

    2008-01-01

    Somatic alterations in cellular DNA underlie almost all human cancers1. The prospect of targeted therapies2 and the development of high-resolution, genome-wide approaches3–8 are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumors (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in ~12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered. PMID:17982442

  15. File list: DNS.Lng.20.AllAg.Lung_adenocarcinoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available DNS.Lng.20.AllAg.Lung_adenocarcinoma mm9 DNase-seq Lung Lung adenocarcinoma http://...dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/DNS.Lng.20.AllAg.Lung_adenocarcinoma.bed ...

  16. File list: Pol.Lng.10.AllAg.Lung_adenocarcinoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Lng.10.AllAg.Lung_adenocarcinoma mm9 RNA polymerase Lung Lung adenocarcinoma ht...tp://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Pol.Lng.10.AllAg.Lung_adenocarcinoma.bed ...

  17. Follistatin is a novel biomarker for lung adenocarcinoma in humans.

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    Fangfang Chen

    Full Text Available Follistatin (FST, a single chain glycoprotein, is originally isolated from follicular fluid of ovary. Previous studies have revealed that serum FST served as a biomarker for pregnancy and ovarian mucinous tumor. However, whether FST can serve as a biomarker for diagnosis in lung adenocarcinoma of humans remains unclear.The study population consisted of 80 patients with lung adenocarcinoma, 40 patients with ovarian adenocarcinoma and 80 healthy subjects. Serum FST levels in patients and healthy subjects were measured using ELISA. The results showed that the positive ratio of serum FST levels was 51.3% (41/80, which was comparable to the sensitivity of FST in 40 patients with ovarian adenocarcinoma (60%, 24/40 using the 95th confidence interval for the healthy subject group as the cut-off value. FST expressions in lung adenocarcinoma were examined by immunohistochemical staining, we found that lung adenocarcinoma could produce FST and there was positive correlation between the level of FST expression and the differential degree of lung adenocarcinoma. Furthermore, the results showed that primary cultured lung adenocarcinoma cells could secrete FST, while cells derived from non-tumor lung tissues almost did not produce FST. In addition, the results of CCK8 assay and flow cytometry showed that using anti-FST monoclonal antibody to neutralize endogenous FST significantly augmented activin A-induced lung adenocarcinoma cells apoptosis.These data indicate that lung adenocarcinoma cells can secret FST into serum, which may be beneficial to the survival of adenocarcinoma cells by neutralizing activin A action. Thus, FST can serve as a promising biomarker for diagnosis of lung adenocarcinoma and a useful biotherapy target for lung adenocarcinoma.

  18. Multigene deletions in lung adenocarcinomas from irradiated and control mice

    International Nuclear Information System (INIS)

    Zhang, Y.; Woloschak, G.E.

    1996-01-01

    K-ras codon 12 point mutations mRb and p53 gene deletions were examined in tissues from 120 normal lungs and lung adenocarcinomas that were Formalin-treated and paraffin-embedded 25 years ago. The results showed that 12 of 60 (20%) lung adenocarcinomas had mRb deletions. All lung adenocarcinomas that were initially found bearing deleted mRb had p53 deletions (15 of 15; 100%). A significantly higher mutation frequency for K-ras codon 12 point mutations was also found in the lung adenocarcinomas from mice exposed to 24 once-weekly neutron irradiation (10 of 10; 100%) compared with those exposed to 24 or 60 once-weekly γ-ray doses (5 of 10; 50%). The data suggested that p53 and K-ras gene alterations were two contributory factors responsible for the increased incidence of lung adenocarcinoma in B6CF 1 male mice exposed to protracted neutron radiation

  19. Renal paraneoplastic vasculitis complicating lung adenocarcinoma

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    Besma Ben Dhaou

    2014-01-01

    Full Text Available Renal paraneoplastic vasculitis (RNPV is rare. It can be revealed by glomerulonephritis, microaneurysms or renal failure. RPNV may precede the onset of the primary tumor, and treatment and prognosis depend on the etiology (primary tumor. A 54-year-old man who had a primary lung adenocarcinoma was admitted for nephrotic syndrome. The investigations revealed RNPV. The patient was treated with corticosteroids at high dose and cyclophosphamide with improvement of the renal condition; however, the patient died from worsening of his pulmonary neoplasia.

  20. Molecular profiling identifies prognostic markers of stage IA lung adenocarcinoma.

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    Zhang, Jie; Shao, Jinchen; Zhu, Lei; Zhao, Ruiying; Xing, Jie; Wang, Jun; Guo, Xiaohui; Tu, Shichun; Han, Baohui; Yu, Keke

    2017-09-26

    We previously showed that different pathologic subtypes were associated with different prognostic values in patients with stage IA lung adenocarcinoma (AC). We hypothesize that differential gene expression profiles of different subtypes may be valuable factors for prognosis in stage IA lung adenocarcinoma. We performed microarray gene expression profiling on tumor tissues micro-dissected from patients with acinar and solid predominant subtypes of stage IA lung adenocarcinoma. These patients had undergone a lobectomy and mediastinal lymph node dissection at the Shanghai Chest Hospital, Shanghai, China in 2012. No patient had preoperative treatment. We performed the Gene Set Enrichment Analysis (GSEA) analysis to look for gene expression signatures associated with tumor subtypes. The histologic subtypes of all patients were classified according to the 2015 WHO lung Adenocarcinoma classification. We found that patients with the solid predominant subtype are enriched for genes involved in RNA polymerase activity as well as inactivation of the p53 pathway. Further, we identified a list of genes that may serve as prognostic markers for stage IA lung adenocarcinoma. Validation in the TCGA database shows that these genes are correlated with survival, suggesting that they are novel prognostic factors for stage IA lung adenocarcinoma. In conclusion, we have uncovered novel prognostic factors for stage IA lung adenocarcinoma using gene expression profiling in combination with histopathology subtyping.

  1. Primary adenocarcinoma of lung: A pictorial review of recent updates

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    Gaikwad, Anand, E-mail: anandgaik@yahoo.co.in [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Gupta, Ashish, E-mail: ashgupta@toh.on.ca [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Hare, Sam, E-mail: samanjeet@btinternet.com [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Gomes, Marcio, E-mail: mgomes@toh.on.ca [Department of Pathology and Laboratory Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Sekhon, Harman, E-mail: hsekhon@toh.on.ca [Department of Pathology and Laboratory Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Souza, Carolina, E-mail: csouza@ottawahospital.on.ca [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Inacio, Joao, E-mail: joao.r.inacio@gmail.com [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Lad, Shilpa, E-mail: slad@toh.on.ca [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada); Seely, Jean, E-mail: jeseely@ottawahospital.on.ca [Department of Diagnostic Imaging, The Ottawa Hospital, University of Ottawa, Ottawa, ON (Canada)

    2012-12-15

    Primary adenocarcinoma of lung has replaced squamous cell carcinoma as the commonest histological subtype of lung cancer and the incidence of primary lung adenocarcinoma appears to be rising. Although the main factors behind this ‘epidemic-like’ situation are largely undiscovered, filter cigarettes appear to significantly contribute to this shift in the histopathological spectrum. The new multidisciplinary classification of adenocarcinoma of lung was introduced to address advances in clinical, pathological, radiological and molecular sciences. The purpose of this essay is to discuss various classes of lung adenocarcinoma in the new classification with their classical imaging features on computed tomography and summarise the recent advances in the field of radiology and review radiology recommendations.

  2. Rb and p53 gene deletions in lung adenocarcinomas from irradiated and control mice

    International Nuclear Information System (INIS)

    Zhang, Y.; Woloschak, G.E.

    1997-01-01

    This study was conducted on mouse lung adenocarcinoma tissues that were formalin-treated and paraffin-embedded 25 years ago to investigate the large gene deletions of mRb and p53 in B6CF 1 male mice. A total of 80 lung tissue samples from irradiated mice and 40 lung samples from nonirradiated controls were randomly selected and examined in the mRb portion of this study. The results showed a significant (P 0.05) from that for spontaneous lung adenocarcinomas or lung adenocarcinomas from mice exposed to single-dose γ irradiation at a similar total dose. mRb fragments 3 (71%) and 5 (67%), the parts of the gene that encoded the pocket binding region of Rb protein to adenovirus E1A and SV40 T-antigen, were the most frequently deleted fragments. p53 gene deletion analysis was carried out on normal lungs and lung adenocarcinomas that were initially found to bear mRb deletions. Exons 1,4,5,6, and 9 were chosen to be analyzed

  3. Lung adenocarcinoma mimicking pulmonary fibrosis-a case report

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    Mehić, Bakir; Duranović Rayan, Lina; Bilalović, Nurija; Dohranović Tafro, Danina; Pilav, Ilijaz

    2016-01-01

    Lung cancer is usually presented with cough, dyspnea, pain and weight loss, which is overlapping with symptoms of other lung diseases such as pulmonary fibrosis. Pulmonary fibrosis shows characteristic reticular and nodular pattern, while lung cancers are mostly presented with infiltrative mass, thick-walled cavitations or a solitary nodule with spiculated borders. If the diagnosis is established based on clinical symptoms and CT findings, it would be a misapprehension. We report a case of lung adenocarcinoma whose symptoms as well as clinical images overlapped strongly with pulmonary fibrosis. The patient’s non-productive cough, progressive dyspnea, restrictive pattern of pulmonary function test and CT scans (showing reticular interstitial opacities) were all indicative of pulmonary fibrosis. The patient underwent a treatment consisting of corticosteroids and antibiotics, to no avail. Histopathology of the lung showed that the patient suffered from mucinous adenocarcinoma. Albeit the immunohistochemical staining was not consistent with lung adenocarcinoma, tumor’s morphological characteristics were consistent, and were used to make the definitive diagnosis. Given the fact that radiography cannot always make a clear-cut difference between pulmonary fibrosis and lung adenocarcinomas, and that clinical symptoms often overlap, histological examination should be considered as gold standard for diagnosis of lung adenocarcinoma

  4. ATM protein is deficient in over 40% of lung adenocarcinomas.

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    Villaruz, Liza C; Jones, Helen; Dacic, Sanja; Abberbock, Shira; Kurland, Brenda F; Stabile, Laura P; Siegfried, Jill M; Conrads, Thomas P; Smith, Neil R; O'Connor, Mark J; Pierce, Andrew J; Bakkenist, Christopher J

    2016-09-06

    Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000's of patients with ATM-deficient lung adenocarcinoma every year.

  5. Fibulin-1 functions as a prognostic factor in lung adenocarcinoma.

    Science.gov (United States)

    Cui, Yuan; Liu, Jian; Yin, Hai-Bing; Liu, Yi-Fei; Liu, Jun-Hua

    2015-09-01

    Fibulin-1 is a member of the fibulin gene family, characterized by tandem arrays of epidermal growth factor-like domains and a C-terminal fibulin-type module. Fibulin-1 plays important roles in a range of cellular functions including morphology, growth, adhesion and mobility. It acts as a tumor suppressor gene in cutaneous melanoma, prostate cancer and gastric cancer. However, whether fibulin-1 also acts as a tumor suppressor gene in lung adenocarcinoma remains unknown. We also determined the association of fibulin-1 expression with various clinical and pathological parameters, which would show its potential role in clinical prognosis. We investigated and followed up 140 lung adenocarcinoma patients who underwent lung resection without pre- and post-operative systemic chemotherapy at the Affiliated Hospital of Nantong University from 2009 to 2013. Western blot assay and immunohistochemistry were used to evaluate the expression of fibulin-1 in lung adenocarcinoma tissues. We then analyzed the correlations between fibulin-1 expression and clinicopathological variables as well as the patients' overall survival rate. Both western blot assay and immunohistochemistry demonstrated that the level of fibulin-1 was downregulated in human lung adenocarcinoma tissues compared with that of normal lung tissues. Fibulin-1 expression significantly correlated with histological differentiation (P = 0.046), clinical stage (P< 0.01), lymph node status (P = 0.038) and expression of Ki-67 (P = 0.013). More importantly, multivariate analysis revealed that fibulin-1 was an independent prognostic marker for lung adenocarcinoma, and high expression of fibulin-1 was significantly associated with better prognosis of lung adenocarcinoma patients. The results supported our hypothesis that fibulin-1 can act as a prognostic factor in lung adenocarcinoma progression. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. An unusual metastasis of lung adenocarcinoma: Biceps brachii muscle

    Directory of Open Access Journals (Sweden)

    Muzaffer Sariaydin

    2016-01-01

    Full Text Available Skeletal muscle metastasis of nonsmall cell lung carcinoma (NSCLC is a rare occurrence, and the most effective treatment modality is currently unknown. In this case presentation, we report a patient with NSCLC who underwent palliative radiotherapy for biceps muscle metastasis of NSLCS. Our case was a 49-year-old woman who had lung adenocarcinoma with biceps muscle metastasis. She had been followed up for 2 years due to Stage IV lung adenocarcinoma from whom a biopsy was taken from a painful mass in right arm that was found to be compatible with metastasis of lung adenocarcinoma. She had palliative radiotherapy for her painful mass and systemic chemotherapy was planned. After palliative radiotherapy, the pain originating from the metastatic mass in right biceps muscle alleviated. Palliative radiotherapy can be a valuable treatment option for cases with skeletal muscle metastasis.

  7. File list: ALL.Lng.05.AllAg.Lung_adenocarcinoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Lng.05.AllAg.Lung_adenocarcinoma mm9 All antigens Lung Lung adenocarcinoma SRX2...RX213848 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/ALL.Lng.05.AllAg.Lung_adenocarcinoma.bed ...

  8. Noninvasive Computed Tomography–based Risk Stratification of Lung Adenocarcinomas in the National Lung Screening Trial

    Science.gov (United States)

    Maldonado, Fabien; Duan, Fenghai; Raghunath, Sushravya M.; Rajagopalan, Srinivasan; Karwoski, Ronald A.; Garg, Kavita; Greco, Erin; Nath, Hrudaya; Robb, Richard A.; Bartholmai, Brian J.

    2015-01-01

    Rationale: Screening for lung cancer using low-dose computed tomography (CT) reduces lung cancer mortality. However, in addition to a high rate of benign nodules, lung cancer screening detects a large number of indolent cancers that generally belong to the adenocarcinoma spectrum. Individualized management of screen-detected adenocarcinomas would be facilitated by noninvasive risk stratification. Objectives: To validate that Computer-Aided Nodule Assessment and Risk Yield (CANARY), a novel image analysis software, successfully risk stratifies screen-detected lung adenocarcinomas based on clinical disease outcomes. Methods: We identified retrospective 294 eligible patients diagnosed with lung adenocarcinoma spectrum lesions in the low-dose CT arm of the National Lung Screening Trial. The last low-dose CT scan before the diagnosis of lung adenocarcinoma was analyzed using CANARY blinded to clinical data. Based on their parametric CANARY signatures, all the lung adenocarcinoma nodules were risk stratified into three groups. CANARY risk groups were compared using survival analysis for progression-free survival. Measurements and Main Results: A total of 294 patients were included in the analysis. Kaplan-Meier analysis of all the 294 adenocarcinoma nodules stratified into the Good, Intermediate, and Poor CANARY risk groups yielded distinct progression-free survival curves (P < 0.0001). This observation was confirmed in the unadjusted and adjusted (age, sex, race, and smoking status) progression-free survival analysis of all stage I cases. Conclusions: CANARY allows the noninvasive risk stratification of lung adenocarcinomas into three groups with distinct post-treatment progression-free survival. Our results suggest that CANARY could ultimately facilitate individualized management of incidentally or screen-detected lung adenocarcinomas. PMID:26052977

  9. Noninvasive Computed Tomography-based Risk Stratification of Lung Adenocarcinomas in the National Lung Screening Trial.

    Science.gov (United States)

    Maldonado, Fabien; Duan, Fenghai; Raghunath, Sushravya M; Rajagopalan, Srinivasan; Karwoski, Ronald A; Garg, Kavita; Greco, Erin; Nath, Hrudaya; Robb, Richard A; Bartholmai, Brian J; Peikert, Tobias

    2015-09-15

    Screening for lung cancer using low-dose computed tomography (CT) reduces lung cancer mortality. However, in addition to a high rate of benign nodules, lung cancer screening detects a large number of indolent cancers that generally belong to the adenocarcinoma spectrum. Individualized management of screen-detected adenocarcinomas would be facilitated by noninvasive risk stratification. To validate that Computer-Aided Nodule Assessment and Risk Yield (CANARY), a novel image analysis software, successfully risk stratifies screen-detected lung adenocarcinomas based on clinical disease outcomes. We identified retrospective 294 eligible patients diagnosed with lung adenocarcinoma spectrum lesions in the low-dose CT arm of the National Lung Screening Trial. The last low-dose CT scan before the diagnosis of lung adenocarcinoma was analyzed using CANARY blinded to clinical data. Based on their parametric CANARY signatures, all the lung adenocarcinoma nodules were risk stratified into three groups. CANARY risk groups were compared using survival analysis for progression-free survival. A total of 294 patients were included in the analysis. Kaplan-Meier analysis of all the 294 adenocarcinoma nodules stratified into the Good, Intermediate, and Poor CANARY risk groups yielded distinct progression-free survival curves (P < 0.0001). This observation was confirmed in the unadjusted and adjusted (age, sex, race, and smoking status) progression-free survival analysis of all stage I cases. CANARY allows the noninvasive risk stratification of lung adenocarcinomas into three groups with distinct post-treatment progression-free survival. Our results suggest that CANARY could ultimately facilitate individualized management of incidentally or screen-detected lung adenocarcinomas.

  10. Cutaneous metastasis to the face from lung adenocarcinoma ...

    African Journals Online (AJOL)

    Cutaneous metastases in the facial region occur in less than 0.5% of patients with metastatic cancer, and they usually originate from malignant melanoma. In this report, we describe an unusual case of lung adenocarcinoma metastasizing to his face at the time of initial diagnosis. The patient was 64-year-old man, a heavy ...

  11. Adenocarcinoma of the lung presenting as retinal detachment

    Directory of Open Access Journals (Sweden)

    Kaushik Saha

    2014-01-01

    Full Text Available Retinal detachment is a rare presentation of lung cancer. A young female presented with blurring of vision in her right eye for the last 10 days without any history of trauma. On indirect ophthalmoscopy, there was a presence of right sided retinal detachment which was treated with oral prednisolone (60 mg/day. After 1 month of continuous treatment, she came back with dry cough left sided chest pain and deterioration of her eye symptoms. Chest X-ray showed left lung mass. Computed tomography guided fine needle aspiration cytology and with immunohistochemistry confirmed adenocarcinoma of the lung. She was treated with 6 cycles of chemotherapy with paclitaxel and gemcitabine.

  12. Amebic lung abscess with coexisting lung adenocarcinoma: a unusual case of amebiasis

    OpenAIRE

    Zhu, Hailong; Min, Xiangyang; Li, Shuai; Feng, Meng; Zhang, Guofeng; Yi, Xianghua

    2014-01-01

    Amebic lung abscess with concurrent lung cancer, but without either a liver abscess or amebic colitis, is extremely uncommon. Here, we report a 70-year-old man presenting with pulmonary amebiasis and coexisting lung adenocarcinoma. During his first-time hospitalization, the diagnosis of lung amebiasis was confirmed by morphological observation and PCR in formalin-fixed and paraffin-embedded sediments of pleural effusion. Almost four months later, the patient was readmitted to hospital for sim...

  13. Boron absorption imaging in rat lung colon adenocarcinoma metastases

    Energy Technology Data Exchange (ETDEWEB)

    Altieri, S [Dipartimento di Fisica Nucleare e Teorica Universita degli Studi di Pavia (Italy); Bortolussi, S [Dipartimento di Fisica Nucleare e Teorica Universita degli Studi di Pavia (Italy); Bruschi, P [Dipartimento di Fisica Nucleare e Teorica Universita degli Studi di Pavia (Italy); Fossati, F [Dipartimento di Fisica Nucleare e Teorica Universita degli Studi di Pavia (Italy); Vittor, K [Dipartimento di Fisica Nucleare e Teorica Universita degli Studi di Pavia (Italy); Nano, R [Dipartimento di Biologia Animale Universita degli Studi di Pavia (Italy); Facoetti, A [Dipartimento di Biologia Animale Universita degli Studi di Pavia (Italy); Chiari, P [Dipartimento di Fisica Nucleare e Teorica Universita degli Studi di Pavia (Italy); Bakeine, J [Dipartimento di Scienze Biomediche e Biotecnologie Universita degli Studi di Brescia (Italy); Clerici, A [Dipartimento di Chirurgia Universita degli Studi di Pavia (Italy); Ferrari, C [Dipartimento di Chirurgia Universita degli Studi di Pavia (Italy); Salvucci, O [Dipartimento di Scienze Biomediche e Biotecnologie Universita degli Studi di Brescia (Italy)

    2006-05-15

    Given the encouraging results from our previous work on the clinical application of BNCT on non-resectable, chemotherapy resistant liver metastases, we explore the possibility to extend our technique to lung metastases. A fundamental requirement for BNCT is achieving higher {sup 10}B concentrations in the metastases compared to those in healthy tissue. For this reason we developed a rat model with lung metastases in order to study the temporal distribution of {sup 10}B concentration in tissues and tumoral cells. Rats with induced lung metastases from colon adenocarcinoma were sacrificed two hours after intraperitoneal Boronphenylalanine infusion. The lungs were harvested, frozen in liquid nitrogen and subsequently histological sections underwent neutron autoradiography in the nuclear reactor Triga Mark II, University of Pavia. Our findings demonstrate higher Boron uptake in tumoral nodules compared to healthy lung parenchyma 2 hours after Boronphenylalanine infusion.

  14. Inhibition of fibroblast growth factor receptor 3-dependent lung adenocarcinoma with a human monoclonal antibody

    Directory of Open Access Journals (Sweden)

    Yongjun Yin

    2016-05-01

    Full Text Available Activating mutations in fibroblast growth factor receptor 3 (FGFR3 have been identified in multiple types of human cancer and in congenital birth defects. In human lung cancer, fibroblast growth factor 9 (FGF9, a high-affinity ligand for FGFR3, is overexpressed in 10% of primary resected non-small cell lung cancer (NSCLC specimens. Furthermore, in a mouse model where FGF9 can be induced in lung epithelial cells, epithelial proliferation and ensuing tumorigenesis is dependent on FGFR3. To develop new customized therapies for cancers that are dependent on FGFR3 activation, we have used this mouse model to evaluate a human monoclonal antibody (D11 with specificity for the extracellular ligand-binding domain of FGFR3, that recognizes both human and mouse forms of the receptor. Here, we show that D11 effectively inhibits signaling through FGFR3 in vitro, inhibits the growth of FGFR3-dependent FGF9-induced lung adenocarcinoma in mice, and reduces tumor-associated morbidity. Given the potency of FGF9 in this mouse model and the absolute requirement for signaling through FGFR3, this study validates the D11 antibody as a potentially useful and effective reagent for treating human cancers or other pathologies that are dependent on activation of FGFR3.

  15. Secondhand Tobacco Smoke Exposure and Lung Adenocarcinoma In Situ/Minimally Invasive Adenocarcinoma (AIS/MIA).

    Science.gov (United States)

    Kim, Claire H; Lee, Yuan-Chin Amy; Hung, Rayjean J; Boffetta, Paolo; Xie, Dong; Wampfler, Jason A; Cote, Michele L; Chang, Shen-Chih; Ugolini, Donatella; Neri, Monica; Le Marchand, Loic; Schwartz, Ann G; Morgenstern, Hal; Christiani, David C; Yang, Ping; Zhang, Zuo-Feng

    2015-12-01

    The aim of this study was to estimate the effect of exposure to secondhand tobacco smoke on the incidence of lung adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA). Data from seven case-control studies participating in the International Lung Cancer Consortium (ILCCO) were pooled, resulting in 625 cases of AIS/MIA and 7,403 controls, of whom 170 cases and 3,035 controls were never smokers. Unconditional logistic regression was used to estimate adjusted ORs (ORadj) and 95% confidence intervals (CI), controlling for age, sex, race, smoking status (ever/never), and pack-years of smoking. Study center was included in the models as a random-effects intercept term. Ever versus never exposure to secondhand tobacco smoke was positively associated with AIS/MIA incidence in all subjects (ORadj = 1.48; 95% CI, 1.14-1.93) and in never smokers (ORadj = 1.45; 95% CI, 1.00-2.12). There was, however, appreciable heterogeneity of ORadj across studies (P = 0.01), and the pooled estimates were largely influenced by one large study (40% of all cases and 30% of all controls). These findings provide weak evidence for an effect of secondhand tobacco smoke exposure on AIS/MIA incidence. Further studies are needed to assess the impact of secondhand tobacco smoke exposure using the newly recommended classification of subtypes of lung adenocarcinoma. ©2015 American Association for Cancer Research.

  16. Amebic lung abscess with coexisting lung adenocarcinoma: a unusual case of amebiasis.

    Science.gov (United States)

    Zhu, Hailong; Min, Xiangyang; Li, Shuai; Feng, Meng; Zhang, Guofeng; Yi, Xianghua

    2014-01-01

    Amebic lung abscess with concurrent lung cancer, but without either a liver abscess or amebic colitis, is extremely uncommon. Here, we report a 70-year-old man presenting with pulmonary amebiasis and coexisting lung adenocarcinoma. During his first-time hospitalization, the diagnosis of lung amebiasis was confirmed by morphological observation and PCR in formalin-fixed and paraffin-embedded sediments of pleural effusion. Almost four months later, the patient was readmitted to hospital for similar complaints. On readmission, lung adenocarcinoma was diagnosed by liquid-based sputum cytology and thought to be delayed because coexisting amebic lung abscess. This case demonstrated that sediments of pleural effusion may be used for further pathological examination after routine cytology has shown negative results. At the same time, we concluded that lung cancer may easily go undetected in the patients with pulmonary amebiasis and repetitive evaluation by cytology and imaging follow-up are useful to find potential cancer.

  17. Gene Therapy for Human Lung Adenocarcinoma Using a Suicide Gene Driven by a Lung-Specific Promoter Delivered by JC Virus-Like Particles.

    Science.gov (United States)

    Chao, Chun-Nun; Lin, Mien-Chun; Fang, Chiung-Yao; Chen, Pei-Lain; Chang, Deching; Shen, Cheng-Huang; Wang, Meilin

    2016-01-01

    Lung adenocarcinoma, the most commonly diagnosed type of lung cancer, has a poor prognosis even with combined surgery, chemotherapy, or molecular targeted therapies. Most patients are diagnosed with an in-operable advanced or metastatic disease, both pointing to the necessity of developing effective therapies for lung adenocarcinoma. Surfactant protein B (SP-B) has been found to be overexpressed in lung adenocarcinoma. In addition, it has also been demonstrated that human lung adenocarcinoma cells are susceptible to the JC polyomavirus (JCPyV) infection. Therefore, we designed that the JCPyV virus-like particle (VLP) packaged with an SP-B promoter-driven thymidine kinase suicide gene (pSPB-tk) for possible gene therapy of human lung adenocarcinoma. Plasmids expressing the GFP (pSPB-gfp) or thymidine kinase gene (pSPB-tk) under the control of the human SP-B promoter were constructed. The promoter's tissue specificity was tested by transfection of pSPB-gfp into A549, CH27, and H460 human lung carcinoma cells and non-lung cells. The JCPyV VLP's gene transfer efficiency and the selective cytotoxicity of pSPB-tk combined with ganciclovir (GCV) were tested in vitro and in a xenograft mouse model. In the current study, we found that SP-B promoter-driven GFP was specifically expressed in human lung adenocarcinoma (A549) and large cell carcinoma (H460) cells. JCPyV VLPs were able to deliver a GFP reporter gene into A549 cells for expression. Selective cytotoxicity was observed in A549 but not non-lung cells that were transfected with pSPB-tk or infected with pSPB-tk-carrying JCPyV VLPs. In mice injected with pSPB-tk-carrying JCPyV VLPs through the tail vein and treated with ganciclovir (GCV), a potent 80% inhibition of growth of human lung adenocarcinoma nodules resulted. The JCPyV VLPs combined with the use of SP-B promoter demonstrates effectiveness as a potential gene therapy against human lung adenocarcinoma.

  18. Gene Therapy for Human Lung Adenocarcinoma Using a Suicide Gene Driven by a Lung-Specific Promoter Delivered by JC Virus-Like Particles.

    Directory of Open Access Journals (Sweden)

    Chun-Nun Chao

    Full Text Available Lung adenocarcinoma, the most commonly diagnosed type of lung cancer, has a poor prognosis even with combined surgery, chemotherapy, or molecular targeted therapies. Most patients are diagnosed with an in-operable advanced or metastatic disease, both pointing to the necessity of developing effective therapies for lung adenocarcinoma. Surfactant protein B (SP-B has been found to be overexpressed in lung adenocarcinoma. In addition, it has also been demonstrated that human lung adenocarcinoma cells are susceptible to the JC polyomavirus (JCPyV infection. Therefore, we designed that the JCPyV virus-like particle (VLP packaged with an SP-B promoter-driven thymidine kinase suicide gene (pSPB-tk for possible gene therapy of human lung adenocarcinoma. Plasmids expressing the GFP (pSPB-gfp or thymidine kinase gene (pSPB-tk under the control of the human SP-B promoter were constructed. The promoter's tissue specificity was tested by transfection of pSPB-gfp into A549, CH27, and H460 human lung carcinoma cells and non-lung cells. The JCPyV VLP's gene transfer efficiency and the selective cytotoxicity of pSPB-tk combined with ganciclovir (GCV were tested in vitro and in a xenograft mouse model. In the current study, we found that SP-B promoter-driven GFP was specifically expressed in human lung adenocarcinoma (A549 and large cell carcinoma (H460 cells. JCPyV VLPs were able to deliver a GFP reporter gene into A549 cells for expression. Selective cytotoxicity was observed in A549 but not non-lung cells that were transfected with pSPB-tk or infected with pSPB-tk-carrying JCPyV VLPs. In mice injected with pSPB-tk-carrying JCPyV VLPs through the tail vein and treated with ganciclovir (GCV, a potent 80% inhibition of growth of human lung adenocarcinoma nodules resulted. The JCPyV VLPs combined with the use of SP-B promoter demonstrates effectiveness as a potential gene therapy against human lung adenocarcinoma.

  19. Somatic mutations affect key pathways in lung adenocarcinoma

    Science.gov (United States)

    Ding, Li; Getz, Gad; Wheeler, David A.; Mardis, Elaine R.; McLellan, Michael D.; Cibulskis, Kristian; Sougnez, Carrie; Greulich, Heidi; Muzny, Donna M.; Morgan, Margaret B.; Fulton, Lucinda; Fulton, Robert S.; Zhang, Qunyuan; Wendl, Michael C.; Lawrence, Michael S.; Larson, David E.; Chen, Ken; Dooling, David J.; Sabo, Aniko; Hawes, Alicia C.; Shen, Hua; Jhangiani, Shalini N.; Lewis, Lora R.; Hall, Otis; Zhu, Yiming; Mathew, Tittu; Ren, Yanru; Yao, Jiqiang; Scherer, Steven E.; Clerc, Kerstin; Metcalf, Ginger A.; Ng, Brian; Milosavljevic, Aleksandar; Gonzalez-Garay, Manuel L.; Osborne, John R.; Meyer, Rick; Shi, Xiaoqi; Tang, Yuzhu; Koboldt, Daniel C.; Lin, Ling; Abbott, Rachel; Miner, Tracie L.; Pohl, Craig; Fewell, Ginger; Haipek, Carrie; Schmidt, Heather; Dunford-Shore, Brian H.; Kraja, Aldi; Crosby, Seth D.; Sawyer, Christopher S.; Vickery, Tammi; Sander, Sacha; Robinson, Jody; Winckler, Wendy; Baldwin, Jennifer; Chirieac, Lucian R.; Dutt, Amit; Fennell, Tim; Hanna, Megan; Johnson, Bruce E.; Onofrio, Robert C.; Thomas, Roman K.; Tonon, Giovanni; Weir, Barbara A.; Zhao, Xiaojun; Ziaugra, Liuda; Zody, Michael C.; Giordano, Thomas; Orringer, Mark B.; Roth, Jack A.; Spitz, Margaret R.; Wistuba, Ignacio I.; Ozenberger, Bradley; Good, Peter J.; Chang, Andrew C.; Beer, David G.; Watson, Mark A.; Ladanyi, Marc; Broderick, Stephen; Yoshizawa, Akihiko; Travis, William D.; Pao, William; Province, Michael A.; Weinstock, George M.; Varmus, Harold E.; Gabriel, Stacey B.; Lander, Eric S.; Gibbs, Richard A.; Meyerson, Matthew; Wilson, Richard K.

    2009-01-01

    Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers—including NF1, APC, RB1 and ATM—and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment. PMID:18948947

  20. Nonsense and missense mutation of mitochondrial ND6 gene promotes cell migration and invasion in human lung adenocarcinoma

    International Nuclear Information System (INIS)

    Yuan, Yang; Wang, Weixing; Li, Huizhong; Yu, Yongwei; Tao, Jin; Huang, Shengdong; Zeng, Zhiyong

    2015-01-01

    Previous study showed that mitochondrial ND6 (mitND6) gene missense mutation resulted in NADH dehydrogenase deficiency and was associated with tumor metastasis in several mouse tumor cell lines. In the present study, we investigated the possible role of mitND6 gene nonsense and missense mutations in the metastasis of human lung adenocarcinoma. The presence of mitND6 gene mutations was screened by DNA sequencing of tumor tissues from 87 primary lung adenocarcinoma patients and the correlation of the mutations with the clinical features was analyzed. In addition, we constructed cytoplasmic hybrid cells with denucleared primary lung adenocarcinoma cell as the mitochondria donor and mitochondria depleted lung adenocarcinoma A549 cell as the nuclear donor. Using these cells, we studied the effects of mitND6 gene nonsense and missense mutations on cell migration and invasion through wounding healing and matrigel-coated transwell assay. The effects of mitND6 gene mutations on NADH dehydrogenase activity and ROS production were analyzed by spectrophotometry and flow cytometry. mitND6 gene nonsense and missense mutations were detected in 11 of 87 lung adenocarcinoma specimens and was correlated with the clinical features including age, pathological grade, tumor stage, lymph node metastasis and survival rate. Moreover, A549 cell containing mitND6 gene nonsense and missense mutation exhibited significantly lower activity of NADH dehydrogenase, higher level of ROS, higher capacity of cell migration and invasion, and higher pAKT and pERK1/ERK2 expression level than cells with the wild type mitND6 gene. In addition, NADH dehydrogenase inhibitor rotenone was found to significantly promote the migration and invasion of A549 cells. Our data suggest that mitND6 gene nonsense and missense mutation might promote cell migration and invasion in lung adenocarcinoma, probably by NADH dehydrogenase deficiency induced over-production of ROS

  1. File list: His.Lng.20.AllAg.Lung_adenocarcinoma_cell_lines [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Lng.20.AllAg.Lung_adenocarcinoma_cell_lines hg19 Histone Lung Lung adenocarcino...ma cell lines SRX1143596,SRX1143597,SRX1143598,SRX1143599 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Lng.20.AllAg.Lung_adenocarcinoma_cell_lines.bed ...

  2. Identification and validation of candidate epigenetic biomarkers in lung adenocarcinoma

    DEFF Research Database (Denmark)

    Daugaard, Iben; Dominguez, Diana; Kjeldsen, Tina E

    2016-01-01

    -adjacent normal lung tissue from four lung adenocarcinoma (LAC) patients using DNA methylation microarrays and identified 74 differentially methylated regions (DMRs). Eighteen DMRs were selected for validation in a cohort comprising primary tumors from 52 LAC patients and tumor-adjacent normal lung tissue from 32...... patients by methylation-sensitive high resolution melting (MS-HRM) analysis. Significant increases in methylation were confirmed for 15 DMRs associated with the genes and genomic regions: OSR1, SIM1, GHSR, OTX2, LOC648987, HIST1H3E, HIST1H3G/HIST1H2BI, HIST1H2AJ/HIST1H2BM, HOXD10, HOXD3, HOXB3/HOXB4, HOXA3...

  3. Lung papillary adenocarcinoma complicated with paraneoplastic autoimmune hemolytic anemia: A case report

    OpenAIRE

    Xing, Limin; Wang, Huaquan; Qu, Wen; Fang, Fang; Dong, Qi-e; Shao, Zonghong

    2014-01-01

    A middle-aged woman presented at our facility and was diagnosed after surgery with lung papillary adenocarcinoma. Seven years earlier, she had suffered from autoimmune hemolytic anemia (AIHA), which was refractory. Following lung surgery, the AIHA was cured.

  4. EGFR and KRAS mutation coexistence in lung adenocarcinomas

    Directory of Open Access Journals (Sweden)

    Vitor Manuel Leitão de Sousa

    2015-04-01

    Full Text Available Lung cancer is one of the most common causes of cancer deaths. The development of EGFR targeted therapies, including monoclonal antibodies and tyrosine kinase inhibitors have generated an interest in the molecular characterization of these tumours. KRAS mutations are associated with resistance to EGFR TKIs. EGFR and KRAS mutations have been considered as mutually exclusive. This paper presents three bronchial-pulmonary carcinomas, two adenocarcinomas and one pleomorphic sarcomatoid carcinoma, harboring EGFR and KRAS mutations. Case 1 corresponded to an adenocarcinoma with EGFR exon 21 mutation (L858R and KRAS codon 12 point mutation (G12V; case 2, a  mucinous adenocarcinoma expressed coexistence of EGFR exon 21 mutation (L858R and KRAS codon 12 point mutation (G12V; and case 3 a sarcomatoid carcinoma with EGFR exon 19 deletion – del 9bp and KRAS codon 12 point mutation (G12C - cysteine. Based on our experience and on the literature, we conclude that EGFR and KRAS mutations can indeed coexist in the same bronchial-pulmonary carcinoma, either in the same histological type or in different patterns. The biological implications of this coexistence are still poorly understood mainly because these cases are not frequent or currently searched. It is therefore necessary to study larger series of cases with the two mutations to better understand the biological, clinical and therapeutic implications.

  5. Early Lung Adenocarcinoma in Mice: Micro-Computed Tomography Manifestations and Correlation with Pathology

    Directory of Open Access Journals (Sweden)

    Lin Deng

    2017-06-01

    Full Text Available Lung cancer is the most common fatal malignancy for both men and women and adenocarcinoma is the most common histologic type. Early diagnosis of lung cancer can significantly improve the survival rate of patients. This study aimed to investigate the micro-computed tomography (micro-CT manifestations of early lung adenocarcinoma (LAC in mice and to provide a new perspective for early clinical diagnosis. Early LAC models in 10 mice were established by subcutaneously injecting 1-methyl-3-nitro-1-nitrosoguanidine (MNNG solution. Micro-CT scan and multiple planar reconstruction (MPR were used for mouse lungs. Micro-CT features of early LAC, especially the relationships between tumor and bronchus, were analyzed and correlated with pathology. Micro-CT findings of early LAC were divided into three types: non-solid (n = 8, 6%, partly solid (n = 85, 64% and totally solid (n = 39, 30%. Tumor-bronchus relationships, which could be observed in 110 of 132(83% LAC, were classified into four patterns: type I (n = 16, 15%, bronchus was truncated at the margin of the tumor; type II (n = 33, 30%, bronchus penetrated into the tumor with tapered narrowing and interruption; type III (n = 38, 35%, bronchus penetrated into the tumor with a patent and intact lumen; type IV (n = 99, 90%, bronchus ran at the border of the tumor with an intact or compressed lumen. Micro-CT manifestations of early LAC correlated well with pathological findings. Micro-CT can clearly demonstrate the features of mouse early LAC and bronchus-tumor relationships, and can also provide a new tool and perspective for the study of early LAC.

  6. [Utility of Multiple Increased Lung Cancer Tumor Markers in Treatment of Patients with Advanced Lung Adenocarcinoma].

    Science.gov (United States)

    Peng, Yan; Wang, Yan; Hao, Xuezhi; Li, Junling; Liu, Yutao; Wang, Hongyu

    2017-10-20

    Among frequently-used tumor markers in lung cancer, carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA125), cytokeratin 19 (CYFRA21-1) and squamous carcinoma antigen (SCC), neuron specific enolase (NSE) and pro-gastrin-releasing peptide (ProGRP) are respectively expressed highly in lung adenocarcinoma, lung squamous carcinoma and small cell lung cancer. By comparing patients with multiple increased tumor markers (group A) and patients with increase of CEA and/or CA125 (group B), this study aims to investigate the utility of multiple increased tumor markers in therapeutic evaluation and prediction of disease relapsing in patients with advanced lung adenocarcinoma. Patients with stage IV lung adenocarcinoma who receiving the first line chemotherapy in Cancer Hospital, Chinese Academy of Medical Sciences were enrolled and retrospectively analyzed. Clinical characteristic, serum tumor markers before chemotherapy, efficacy evaluation, progression-free survival (PFS) were analyzed. Except CEA and CA125, the highest ratio of increased tumor markersin group A was CYFRA21-1 (93%), then was NSE (36%), SCC (13%) and ProGRP (12%). Patients with multiple increased tumor markers tend to have more distant metastasis (Ptumor markers have high risk of relapse, and maintenance therapy can reduce relapse risk.

  7. [Lung adenocarcinoma with concomitant EGFR mutation and ALK rearrangement].

    Science.gov (United States)

    Caliez, J; Monnet, I; Pujals, A; Rousseau-Bussac, G; Jabot, L; Boudjemaa, A; Leroy, K; Chouaid, C

    2017-05-01

    Among patients with non-small-cell lung cancer, coexistence of EGFR mutation and ALK rearrangement is rare. We describe the clinical features of two patients with this double anomaly. A 62-year-old Caucasian non-smoking woman was diagnosed with cT4N0M0 lung adenocarcinoma. Initial biopsy showed EGFR mutation and ALK rearrangement. She received cisplatin-gemcitabine, followed by 17 months of gemcitabine. Owing to progression, she received erlotinib for 14 months, then paclitaxel for 6 months and finally crizotinib. A partial response was achieved and maintained for 24 months. A 45-year-old Caucasian woman, light smoker, was diagnosed with cT2N3M0 lung adenocarcinoma. Only EGFR mutation was found on initial analysis. She underwent treatment with cisplatin-gemcitabine and thoracic radiotherapy. Progression occurred after 8 months and afatinbib was started. Eight months later, progression was observed with a neoplasic pleural effusion in which tumor cells expressing ALK rearrangement were found. A new FISH analysis was performed on the initial tumor but did not find this rearrangement. Despite a third line of crizotinib, the patient died one month later. The literature shows 45 other cases of these two abnormalities, observed either from the start or during follow-up. EGFR's TKI were almost always given before ALK's TKI. Therapeutic strategy needs to be clarified in cases of double alteration. With regard to the second patient, appearance of ALK rearrangement may constitute a resistance mechanism to EGFR's TKI. Copyright © 2016 SPLF. Published by Elsevier Masson SAS. All rights reserved.

  8. Lung Metastases from Bile Duct Adenocarcinoma Mimicking Chronic Airway Infection and Causing Diagnostic Difficulty.

    Science.gov (United States)

    Sato, Mitsuo; Okachi, Shotaro; Fukihara, Jun; Shimoyama, Yoshie; Wakahara, Keiko; Sakakibara, Toshihiro; Hase, Tetsunari; Onishi, Yasuharu; Ogura, Yasuhiro; Maeda, Osamu; Hasegawa, Yoshinori

    2018-05-15

    We herein report a case of lung metastases with unusual radiological appearances that mimicked those of chronic airway infection, causing diagnostic difficulty. A 60-year-old woman who underwent liver transplantation from a living donor was incidentally diagnosed with bile duct adenocarcinoma after a histopathological analysis of her explanted liver. Six months later, chest computed tomography (CT) revealed bilateral bronchogenic dissemination that had gradually worsened, suggesting chronic airway infection. A biopsy with bronchoscopy from a mass lesion beyond a segmental bronchus revealed adenocarcinoma identical to that of her bile duct adenocarcinoma, leading to the diagnosis of multiple lung metastases from bile duct adenocarcinoma.

  9. Prognostic implication of aquaporin 1 overexpression in resected lung adenocarcinoma.

    Science.gov (United States)

    Bellezza, Guido; Vannucci, Jacopo; Bianconi, Fortunato; Metro, Giulio; Del Sordo, Rachele; Andolfi, Marco; Ferri, Ivana; Siccu, Paola; Ludovini, Vienna; Puma, Francesco; Sidoni, Angelo; Cagini, Lucio

    2017-12-01

    Aquaporins (AQPs) are a group of transmembrane water-selective channel proteins thought to play a role in the regulation of water permeability for plasma membranes. Indeed, high AQP levels have been suggested to promote the progression, invasion and metastasis of tumours. Specifically, AQP1 and AQP5 overexpression in lung adenocarcinoma (AC) have been suggested to be involved in molecular mechanisms in lung cancer. The aim of this retrospective cohort single-centre study was to assess both the levels of expression and therein the prognostic significance, regarding outcome of AQP1 and AQP5 in resected AC patients. Patients with histological diagnoses of lung AC submitted to pulmonary resection were included in this cohort study. Tissue microarrays containing cores from 185 ACs were prepared. AQP1 and AQP5 expressions were assessed by immunohistochemistry. Results were scored as either low (Score 0-2) or high (Score 3-9). Clinical data, pathological tumour-node-metastasis staging and follow-up were recorded. Multivariate Cox survival analysis and Fisher's t-test were performed. AQP1 overexpression was detected in 85 (46%) patients, while AQP5 overexpression was observed in 45 (24%) patients. AQP1 did not result being significantly correlated with clinical and pathological parameters, while AQP5 resulted more expressed in AC with mucinous and papillary predominant patterns. Patients with AQP1 overexpression had shorter disease-free survival (P = 0.001) compared with patients without AQP1 overexpression. Multivariate analysis confirmed that AQP1 overexpression was significantly associated with shorter disease-free survival (P = 0.001). Our results evidenced that AQP1 overexpression resulted in a shorter disease-free survival in lung AC patients. Being so, AQP1 overexpression might be an important prognostic marker in lung AC. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights

  10. Surgery for lung adenocarcinoma with smokers’ polycythemia: a case report

    Science.gov (United States)

    2013-01-01

    Background Smoking is a cause of cancer and polycythemia. Therefore, surgeons who treat patients with cancer may also encounter patients with polycythemia. However, few cases of surgical patients with polycythemia have been reported; in particular, a surgical case involving smokers’ polycythemia has never been reported. We herein report a patient with lung cancer and smokers’ polycythemia who successfully underwent lobectomy with control of hematocrit based on a modified formula in the perioperative period. Case presentation A 67-year-old man underwent abdominoperineal resection for rectal carcinoma in June 2008. A ground glass opacity had been identified in the upper lobe of the right lung and was gradually enlarging. In March 2012, bronchoscopic cytology for investigation of the mass revealed non-small cell lung cancer, suggesting primary lung non-small cell carcinoma (T1bN0M0, Stage IA). When he was referred to our hospital for surgery, his complete blood count showed a red blood cell level of 6.50×106/μL, hemoglobin of 21.0 g/dL, and hematocrit of 60.1%. The hematologists’ diagnosis was secondary polycythemia due to heavy smoking (smokers’ polycythemia) because the white blood cell and platelet counts were within normal limits and the erythropoietin was not increased. We calculated the appropriate phlebotomy and infusion volumes based on a formula that we modified. After 550 g of blood was phlebotomized to reduce the hematocrit to approximately 55%, video-assisted right lung upper lobectomy with lymph node dissection was performed in April 2012. The hematocrit was maintained at polycythemia who underwent right upper lobectomy for adenocarcinoma. The findings in this case report are meaningful for surgeons treating cancer patients because there are few reports discussing the perioperative care of surgical patients with polycythemia. PMID:23374961

  11. Surgery for lung adenocarcinoma with smokers' polycythemia: a case report.

    Science.gov (United States)

    Sugiura, Yasoo; Nemoto, Etsuo; Shinoda, Hiromi; Nakamura, Naoya; Kaseda, Shizuka

    2013-02-01

    Smoking is a cause of cancer and polycythemia. Therefore, surgeons who treat patients with cancer may also encounter patients with polycythemia. However, few cases of surgical patients with polycythemia have been reported; in particular, a surgical case involving smokers' polycythemia has never been reported. We herein report a patient with lung cancer and smokers' polycythemia who successfully underwent lobectomy with control of hematocrit based on a modified formula in the perioperative period. A 67-year-old man underwent abdominoperineal resection for rectal carcinoma in June 2008. A ground glass opacity had been identified in the upper lobe of the right lung and was gradually enlarging. In March 2012, bronchoscopic cytology for investigation of the mass revealed non-small cell lung cancer, suggesting primary lung non-small cell carcinoma (T1bN0M0, Stage IA). When he was referred to our hospital for surgery, his complete blood count showed a red blood cell level of 6.50×106/μL, hemoglobin of 21.0 g/dL, and hematocrit of 60.1%. The hematologists' diagnosis was secondary polycythemia due to heavy smoking (smokers' polycythemia) because the white blood cell and platelet counts were within normal limits and the erythropoietin was not increased. We calculated the appropriate phlebotomy and infusion volumes based on a formula that we modified. After 550 g of blood was phlebotomized to reduce the hematocrit to approximately 55%, video-assisted right lung upper lobectomy with lymph node dissection was performed in April 2012. The hematocrit was maintained at polycythemia who underwent right upper lobectomy for adenocarcinoma. The findings in this case report are meaningful for surgeons treating cancer patients because there are few reports discussing the perioperative care of surgical patients with polycythemia.

  12. Surgery for lung adenocarcinoma with smokers’ polycythemia: a case report

    Directory of Open Access Journals (Sweden)

    Sugiura Yasoo

    2013-02-01

    Full Text Available Abstract Background Smoking is a cause of cancer and polycythemia. Therefore, surgeons who treat patients with cancer may also encounter patients with polycythemia. However, few cases of surgical patients with polycythemia have been reported; in particular, a surgical case involving smokers’ polycythemia has never been reported. We herein report a patient with lung cancer and smokers’ polycythemia who successfully underwent lobectomy with control of hematocrit based on a modified formula in the perioperative period. Case presentation A 67-year-old man underwent abdominoperineal resection for rectal carcinoma in June 2008. A ground glass opacity had been identified in the upper lobe of the right lung and was gradually enlarging. In March 2012, bronchoscopic cytology for investigation of the mass revealed non-small cell lung cancer, suggesting primary lung non-small cell carcinoma (T1bN0M0, Stage IA. When he was referred to our hospital for surgery, his complete blood count showed a red blood cell level of 6.50×106/μL, hemoglobin of 21.0 g/dL, and hematocrit of 60.1%. The hematologists’ diagnosis was secondary polycythemia due to heavy smoking (smokers’ polycythemia because the white blood cell and platelet counts were within normal limits and the erythropoietin was not increased. We calculated the appropriate phlebotomy and infusion volumes based on a formula that we modified. After 550 g of blood was phlebotomized to reduce the hematocrit to approximately 55%, video-assisted right lung upper lobectomy with lymph node dissection was performed in April 2012. The hematocrit was maintained at Conclusion We experienced a patient with smokers’ polycythemia who underwent right upper lobectomy for adenocarcinoma. The findings in this case report are meaningful for surgeons treating cancer patients because there are few reports discussing the perioperative care of surgical patients with polycythemia.

  13. The initial appearance of lung adenocarcinoma on computed tomography

    International Nuclear Information System (INIS)

    Saito, Haruhiro; Yamada, Kozo; Suzuki, Rie; Oshita, Fumihiro; Nakayama, Haruhiko; Mitsuda, Aki; Kameda, Youichi; Noda, Kazumasa

    2002-01-01

    The purpose of this study was to determine the initial appearance of lung adenocarcinoma on computed tomography and the appropriate follow-up duration. Retrospective review of 17 cases in which computed tomography (CT) of the chest was performed about 2 years prior to the diagnosis of lung cancer. The diagnosis was confirmed by surgical resection in all cases. The lung cancers were divided into four types based on their appearance on the initial CT: ground-glass opacity (GGO)-like images in which the lesion appeared as a faint opacity, BLA (bubble-like appearance) image, in which the lesion resembled a focal collection of air, a small solitary nodule, and a scar-like image. Vascular involvement, air-bronchogram, and pleural indentation were all more prominent during a serial scan obtained just prior to surgery than on the initial scan. An increase in vascular involvement occurred prior to the other changes. High attenuation areas appeared in the GGO-like lesions prior to an increase in the size of the lesion. The growth pattern was classified as slow growing, rapidly growing, and initially slow growing with accelerated growth. The doubling time was similar in lesions with the same appearance. This information can be used to guide follow-up of images suspected of lung cancer. The appropriate follow-up duration is estimated from 6 to 12 months for GGO and BLA-like images, and from 2 to 3 months for small solitary nodules. The biological behavior of lung cancer is reflected in their initial appearance on CT. (author)

  14. The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells

    Directory of Open Access Journals (Sweden)

    Roberto Gomez-Casal

    2015-05-01

    Full Text Available The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors.

  15. NFAT5 promotes proliferation and migration of lung adenocarcinoma cells in part through regulating AQP5 expression

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Kai, E-mail: gk161@163.com [Department of Respiration, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China); Department of Respiration, 161th Hospital, PLA, Wuhan 430015 (China); Jin, Faguang, E-mail: jinfag@fmmu.edu.cn [Department of Respiration, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China)

    2015-09-25

    The osmoregulated transcription factor nuclear factor of activated T-cells 5(NFAT5), has been found to play important roles in the development of many kinds of human cancers, including breast cancer, colon carcinoma, renal cell carcinoma and melanoma. The aim of the present study was to determine whether NFAT5 is involved in the proliferation and migration of lung adenocarcinoma cells. We found that NFAT5 was upregulated in lung adenocarcinoma cells and knockdown of NFAT5 decreased proliferation and migration of the cells, accompanied by a significant reduction in the expression of AQP5. AQP5 was upregulated in lung adenocarcinoma cells and knockdown of AQP5 also inhibited proliferation and migration of the cells as knockdown of NFAT5 did. Moreover, overexpression of NFAT5 promoted proliferation and migration of lung adenocarcinoma cells, accompanied by a significant increase in the expression of AQP5. These results indicate that NFAT5 plays important roles in proliferation and migration of human lung adenocarcinoma cells through regulating AQP5 expression, providing a new therapeutic option for lung adenocarcinoma therapy. - Highlights: • NFAT5 expression is higher in lung adenocarcinoma cells compared with normal cells. • NFAT5 knockdown decreases proliferation and migration of lung adenocarcinoma cells. • Knockdown of NFAT5 reduces AQP5 expression in human lung adenocarcinoma cells. • Overexpression of NFAT5 promotes proliferation and migration of lung adenocarcinoma cells. • Overexpression of NFAT5 increases AQP5 expression in human lung adenocarcinoma cells.

  16. NFAT5 promotes proliferation and migration of lung adenocarcinoma cells in part through regulating AQP5 expression

    International Nuclear Information System (INIS)

    Guo, Kai; Jin, Faguang

    2015-01-01

    The osmoregulated transcription factor nuclear factor of activated T-cells 5(NFAT5), has been found to play important roles in the development of many kinds of human cancers, including breast cancer, colon carcinoma, renal cell carcinoma and melanoma. The aim of the present study was to determine whether NFAT5 is involved in the proliferation and migration of lung adenocarcinoma cells. We found that NFAT5 was upregulated in lung adenocarcinoma cells and knockdown of NFAT5 decreased proliferation and migration of the cells, accompanied by a significant reduction in the expression of AQP5. AQP5 was upregulated in lung adenocarcinoma cells and knockdown of AQP5 also inhibited proliferation and migration of the cells as knockdown of NFAT5 did. Moreover, overexpression of NFAT5 promoted proliferation and migration of lung adenocarcinoma cells, accompanied by a significant increase in the expression of AQP5. These results indicate that NFAT5 plays important roles in proliferation and migration of human lung adenocarcinoma cells through regulating AQP5 expression, providing a new therapeutic option for lung adenocarcinoma therapy. - Highlights: • NFAT5 expression is higher in lung adenocarcinoma cells compared with normal cells. • NFAT5 knockdown decreases proliferation and migration of lung adenocarcinoma cells. • Knockdown of NFAT5 reduces AQP5 expression in human lung adenocarcinoma cells. • Overexpression of NFAT5 promotes proliferation and migration of lung adenocarcinoma cells. • Overexpression of NFAT5 increases AQP5 expression in human lung adenocarcinoma cells

  17. Napsin A levels in epithelial lining fluid as a diagnostic biomarker of primary lung adenocarcinoma.

    Science.gov (United States)

    Uchida, Akifumi; Samukawa, Takuya; Kumamoto, Tomohiro; Ohshige, Masahiro; Hatanaka, Kazuhito; Nakamura, Yoshihiro; Mizuno, Keiko; Higashimoto, Ikkou; Sato, Masami; Inoue, Hiromasa

    2017-12-12

    It is crucial to develop novel diagnostic approaches for determining if peripheral lung nodules are malignant, as such nodules are frequently detected due to the increased use of chest computed tomography scans. To this end, we evaluated levels of napsin A in epithelial lining fluid (ELF), since napsin A has been reported to be an immunohistochemical biomarker for histological diagnosis of primary lung adenocarcinoma. In consecutive patients with indeterminate peripheral lung nodules, ELF samples were obtained using a bronchoscopic microsampling (BMS) technique. The levels of napsin A and carcinoembryonic antigen (CEA) in ELF at the nodule site were compared with those at the contralateral site. A final diagnosis of primary lung adenocarcinoma was established by surgical resection. We performed BMS in 43 consecutive patients. Among patients with primary lung adenocarcinoma, the napsin A levels in ELF at the nodule site were markedly higher than those at the contralateral site, while there were no significant differences in CEA levels. Furthermore, in 18 patients who were undiagnosed by bronchoscopy and finally diagnosed by surgery, the napsin A levels in ELF at the nodule site were identically significantly higher than those at the contralateral site. In patients with non-adenocarcinoma, there were no differences in napsin A levels in ELF. The area under the receiver operator characteristic curve for identifying primary lung adenocarcinoma was 0.840 for napsin A and 0.542 for CEA. Evaluation of napsin A levels in ELF may be useful for distinguishing primary lung adenocarcinoma.

  18. Efficacy and Safety of Nintedanib Plus Docetaxel in Patients with Advanced Lung Adenocarcinoma

    DEFF Research Database (Denmark)

    Gottfried, Maya; Bennouna, Jaafar; Bondarenko, Igor

    2017-01-01

    BACKGROUND: Nintedanib is a triple angiokinase inhibitor approved with docetaxel for adenocarcinoma non-small cell lung cancer after first-line chemotherapy (FLT). In the phase III LUME-Lung 1 study, overall survival (OS) was significantly longer with nintedanib/docetaxel than with placebo....../docetaxel in all adenocarcinoma patients and those with time from start of FLT (TSFLT) Lung 1 study, specifically for adenocarcinoma patients, to explore the impact of clinically relevant characteristics on outcomes such as time...... to progression after FLT. PATIENTS AND METHODS: Exploratory analyses were conducted of the overall and European LUME-Lung 1 adenocarcinoma population according to age, prior therapy, and tumor dynamics. Analyses also used TSFLT and time from end of FLT (TEFLT). RESULTS: Treatment with nintedanib...

  19. Efficacy and safety of icotinib in patients with brain metastases from lung adenocarcinoma

    OpenAIRE

    Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

    2016-01-01

    Jianping Xu, Xiaoyan Liu, Sheng Yang, Xiangru Zhang, Yuankai Shi Department of Internal Medicine, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China Objective: The objective of this study was to evaluate the efficacy and safety of icotinib in patients with brain metastases (BMs) from lung adenocarcinoma.Patients and methods: Clinical data of 28 cases with BMs from lung adenocarcinoma were retrospectively analyzed. All the patients took 125&am...

  20. Salivary type alpha-amylase activity in serum and in urine of patients with lung adenocarcinoma

    International Nuclear Information System (INIS)

    Zakrzewska, I.; Wolska, K.; Koput, A.

    1993-01-01

    Total alpha-amylase activity in sera and urine of 30 patients with lung adenocarcinoma has been tested. The results were compared with control group of 30 healthy voluntaries. The activity of pancreatic type was differentiated from salivary alpha amylase. Salivary type was inhibited selectively by Triticum aestivum. Higher levels of total and salivary type amylase were noted in patients with lung adenocarcinoma in comparison to healthy control. The increase was significant (p<0.005). Correlation was observed between the activity of salivary type amylase and the stage of adenocarcinoma. (author)

  1. Cytomorphological features of ALK-positive lung adenocarcinomas: psammoma bodies and signet ring cells.

    Science.gov (United States)

    Pareja, Fresia; Crapanzano, John P; Mansukhani, Mahesh M; Bulman, William A; Saqi, Anjali

    2015-03-01

    Correlation between histology and genotype has been described in lung adenocarcinomas. For example, studies have demonstrated that adenocarcinomas with an anaplastic lymphoma kinase (ALK) gene rearrangement may have mucinous features. The objective of the current study was to determine whether a similar association can be identified in cytological specimens. A retrospective search for ALK-rearranged cytopathology (CP) and surgical pathology (SP) lung carcinomas was conducted. Additional ALK-negative (-) lung adenocarcinomas served as controls. For CP and SP cases, the clinical data (i.e., age, sex, and smoking history), architecture, nuclear features, presence of mucin-containing cells (including signet ring cells), and any additional salient characteristics were evaluated. The search yielded 20 ALK-positive (+) adenocarcinomas. Compared with patients with ALK(-) lung adenocarcinomas (33 patients; 12 with epidermal growth factor receptor [EGFR]-mutation, 11 with Kristen rat sarcoma [KRAS]-mutation, and 10 wild-type adenocarcinomas), patients with ALK(+) adenocarcinoma presented at a younger age; and there was no correlation noted with sex or smoking status. The most common histological pattern in SP was papillary/micropapillary. Mucinous features were associated with ALK rearrangement in SP specimens. Signet ring cells and psammoma bodies were evident in and significantly associated with ALK(+) SP and CP specimens. However, psammoma bodies were observed in rare adenocarcinomas with an EGFR mutation. Both the ALK(+) and ALK(-) groups had mostly high nuclear grade. Salient features, including signet ring cells and psammoma bodies, were found to be significantly associated with ALK(+) lung adenocarcinomas and are identifiable on CP specimens. Recognizing these may be especially helpful in the molecular triage of scant CP samples. © 2014 American Cancer Society.

  2. SIRT1 expression is associated with poor prognosis of lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Li C

    2015-04-01

    Full Text Available Chong Li,1,2,* Lingling Wang,3,* Liang Zheng,4 Xianghong Zhan,4 Bin Xu,1,2 Jingting Jiang,1,2 Changping Wu1,2 1Department of Tumor Biological Treatment, the Third Affiliated Hospital, Soochow University, Changzhou, 2Cancer Immunotherapy Engineering Research Center of Jiangsu Province, Changzhou, 3Department of Medical Education, Jinling Hospital, Medical School of Nanjing University, Nanjing, 4Department of Thoracic Surgery, the Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu, People’s Republic of China *These authors contributed equally to this work Abstract: Several studies have reported that the overexpression of Sirtuin 1 (SIRT1 was associated with poor prognosis in various human cancers. However, little is known regarding the prognostic value of SIRT1 in lung adenocarcinoma. Therefore, the aim of this study is to evaluate the role of SIRT1 in the prognosis of lung adenocarcinoma patients. Using a tissue microarray, we detected SIRT1 expression by immunohistochemistry in lung adenocarcinoma tissue, as well as in corresponding noncancerous tissues (NCTs. A high expression level of SIRT1 was observed in 74.7% (56/75 of patients with lung adenocarcinoma and 6.7% (5/75 of NCTs (P<0.001. SIRT1 expression was significantly associated with high pathological stage. Importantly, we found that SIRT1 expression was associated with worse overall survival in these lung adenocarcinoma patients (67.0 months vs 104.5 months; P=0.005. In addition, anaplastic lymphoma kinase, epidermal growth factor receptor, vascular endothelial growth factor (VEGF, and Survivin expression were evaluated by fluorescent in situ hybridization or immunohistochemistry, respectively. We found that VEGF and Survivin were both highly expressed in the lung adenocarcinoma tissues, as compared to NCTs. Moreover, the SIRT1 and VEGF expression statuses were significantly positively correlated (r=0.238, P=0.039, while SIRT1 and Survivin expression status were not

  3. Increased AAA-TOB3 correlates with lymph node metastasis and advanced stage of lung adenocarcinoma.

    Science.gov (United States)

    Liu, Yanfeng; Bu, Lina; Li, Wei; Wu, Wei; Wang, Shengyu; Diao, Xin; Zhou, Jing; Chen, Guoan; Yang, Shuanying

    2017-07-24

    This study was to investigate the differential mitochondrial protein expressions in human lung adenocarcinoma and provide preliminary data for further exploration of the carcinogenic mechanism. Total proteins of A549 and 16HBE mitochondria were extracted through 2D polyacrylamide gel electrophoresis (2-DE). The differential mitochondria proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and were further confirmed by Western blot, immunoelectron microscopy and immunohistochemistry (IHC) in A549 cells as well as lung adenocarcinoma tissues. A total of 41 differentially expressed protein spots were found in A549 mitochondria. Of them, 15 proteins were highly expressed and 26 proteins were lowly expressed in the mitochondria of A549 (by more than 1.5 times). Among the 15 more highly expressed proteins, AAA-TOB3 (by more than 3 times) was highly expressed in the mitochondria of A549 compared with the 16HBE, by LC-MS/MS identification. High electron density and clear circular colloidal gold-marked AAA-TOB3 particles were observed in the A549 cells via immunoelectron microscopy. Besides, AAA-TOB3 was confirmed to be elevated in lung adenocarcinoma by Western blot and IHC. Moreover, increased AAA-TOB3 correlated with lymph node metastasis and advanced stage of lung adenocarcinoma (pAAA-TOB3 was highly expressed in lung adenocarcinoma, and the up-regulation of AAA-TOB3 correlated with lymph node metastasis and advanced stage of lung adenocarcinoma, which suggested that it could serve as a potential molecular marker for lung adenocarcinoma.

  4. Correlation between matrix metalloproteinase-9 and vascular endothelial growth factor expression in lung adenocarcinoma.

    Science.gov (United States)

    Wen, Y L; Li, L

    2015-12-29

    The aim of this study was to investigate the correlation between the expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) and clinicopathological features of lung adenocarcinoma. The expression of MMP-9 and VEGF was evaluated by immunohistochemistry of 30 samples from lung adenocarcinoma patients and 12 paratumoral (normal) tissue samples. In addition, the change in VEGF or MMP-9 expression after MMP-9 or VEGF blockade, respectively, was measured using western blot in lung adenocarcinoma A549 cells. High expression of MMP-9 was found in 63.3% of adenocarcinoma tissues versus 16.7% in normal tissues (P correlation was identified between MMP-9 and VEGF expression (correlation coefficient = 0.7094, P < 0.001), and their mutual overexpression was associated with clinical staging and lymph node status (P < 0.05). In addition, an decrease in VEGF protein expression was observed after MMP-9 blockade by an MMP-9-specific monoclonal antibody. Similarly, a decrease in MMP-9 protein expression was found after VEGF blockade by a VEGF-specific monoclonal antibody. In conclusion, VEGF and MMP-9 are overexpressed in lung adenocarcinoma tissues, and they have a synergistic effect on the invasion and metastasis of adenocarcinoma.

  5. Sulforaphane?induced apoptosis in Xuanwei lung adenocarcinoma cell line XWLC?05

    OpenAIRE

    Zhou, Lan; Yao, Qian; Li, Yan; Huang, Yun?chao; Jiang, Hua; Wang, Chuan?qiong; Fan, Lei

    2016-01-01

    Background Xuanwei district in Yunnan Province has the highest incidence of lung cancer in China, especially among non?smoking women. Cruciferous vegetables can reduce lung cancer risk by prompting a protective mechanism against respiratory tract inflammation caused by air pollution, and are rich in sulforaphane, which can induce changes in gene expression. We investigated the effect of sulforaphane?induced apoptosis in Xuanwei lung adenocarcinoma cell line (XWCL?05) to explore the value of s...

  6. Identification of a panel of sensitive and specific DNA methylation markers for lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Hagen Jeffrey A

    2007-10-01

    Full Text Available Abstract Background Lung cancer is the number one cancer killer of both men and women in the United States. Three quarters of lung cancer patients are diagnosed with regionally or distantly disseminated disease; their 5-year survival is only 15%. DNA hypermethylation at promoter CpG islands shows great promise as a cancer-specific marker that would complement visual lung cancer screening tools such as spiral CT, improving early detection. In lung cancer patients, such hypermethylation is detectable in a variety of samples ranging from tumor material to blood and sputum. To date the penetrance of DNA methylation at any single locus has been too low to provide great clinical sensitivity. We used the real-time PCR-based method MethyLight to examine DNA methylation quantitatively at twenty-eight loci in 51 primary human lung adenocarcinomas, 38 adjacent non-tumor lung samples, and 11 lung samples from non-lung cancer patients. Results We identified thirteen loci showing significant differential DNA methylation levels between tumor and non-tumor lung; eight of these show highly significant hypermethylation in adenocarcinoma: CDH13, CDKN2A EX2, CDX2, HOXA1, OPCML, RASSF1, SFPR1, and TWIST1 (p-value Conclusion The identification of eight CpG island loci showing highly significant hypermethylation in lung adenocarcinoma provides strong candidates for evaluation in patient remote media such as plasma and sputum. The four most highly ranked loci, CDKN2A EX2, CDX2, HOXA1 and OPCML, which show significant DNA methylation even in stage IA tumor samples, merit further investigation as some of the most promising lung adenocarcinoma markers identified to date.

  7. Efficacy and safety of icotinib in patients with brain metastases from lung adenocarcinoma.

    Science.gov (United States)

    Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

    2016-01-01

    The objective of this study was to evaluate the efficacy and safety of icotinib in patients with brain metastases (BMs) from lung adenocarcinoma. Clinical data of 28 cases with BMs from lung adenocarcinoma were retrospectively analyzed. All the patients took 125 mg icotinib orally three times a day. Progression of disease, intolerable adverse reactions, and number of deaths were recorded. For all the patients, the remission rate of icotinib was 67.8% and the disease control rate was 96.4%. The median overall survival time of patients was 21.2 months, and the median progression-free survival time of patients was 10.9 months. Only mild adverse events of grade 1/2 were observed during the treatment. Icotinib was an effective and safe strategy to treat patients with BMs from lung adenocarcinoma.

  8. MMP-13 In-Vivo Molecular Imaging Reveals Early Expression in Lung Adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Mathieu Salaün

    Full Text Available Several matrix metalloproteinases (MMPs are overexpressed in lung cancer and may serve as potential targets for the development of bioactivable probes for molecular imaging.To characterize and monitor the activity of MMPs during the progression of lung adenocarcinoma.K-rasLSL-G12D mice were imaged serially during the development of adenocarcinomas using fluorescence molecular tomography (FMT and a probe specific for MMP-2, -3, -9 and -13. Lung tumors were identified using FMT and MRI co-registration, and the probe concentration in each tumor was assessed at each time-point. The expression of Mmp2, -3, -9, -13 was quantified by qRT-PCR using RNA isolated from microdissected tumor cells. Immunohistochemical staining of overexpressed MMPs in animals was assessed on human lung tumors.In mice, 7 adenomas and 5 adenocarcinomas showed an increase in fluorescent signal on successive FMT scans, starting between weeks 4 and 8. qRT-PCR assays revealed significant overexpression of only Mmp-13 in mice lung tumors. In human tumors, a high MMP-13 immunostaining index was found in tumor cells from invasive lesions (24/27, but in none of the non-invasive (0/4 (p=0.001.MMP-13 is detected in early pulmonary invasive adenocarcinomas and may be a potential target for molecular imaging of lung cancer.

  9. MMP-13 In-Vivo Molecular Imaging Reveals Early Expression in Lung Adenocarcinoma

    Science.gov (United States)

    Salaün, Mathieu; Peng, Jing; Hensley, Harvey H.; Roder, Navid; Flieder, Douglas B.; Houlle-Crépin, Solène; Abramovici-Roels, Olivia; Sabourin, Jean-Christophe; Thiberville, Luc; Clapper, Margie L.

    2015-01-01

    Introduction Several matrix metalloproteinases (MMPs) are overexpressed in lung cancer and may serve as potential targets for the development of bioactivable probes for molecular imaging. Objective To characterize and monitor the activity of MMPs during the progression of lung adenocarcinoma. Methods K-rasLSL-G12D mice were imaged serially during the development of adenocarcinomas using fluorescence molecular tomography (FMT) and a probe specific for MMP-2, -3, -9 and -13. Lung tumors were identified using FMT and MRI co-registration, and the probe concentration in each tumor was assessed at each time-point. The expression of Mmp2, -3, -9, -13 was quantified by qRT-PCR using RNA isolated from microdissected tumor cells. Immunohistochemical staining of overexpressed MMPs in animals was assessed on human lung tumors. Results In mice, 7 adenomas and 5 adenocarcinomas showed an increase in fluorescent signal on successive FMT scans, starting between weeks 4 and 8. qRT-PCR assays revealed significant overexpression of only Mmp-13 in mice lung tumors. In human tumors, a high MMP-13 immunostaining index was found in tumor cells from invasive lesions (24/27), but in none of the non-invasive (0/4) (p=0.001). Conclusion MMP-13 is detected in early pulmonary invasive adenocarcinomas and may be a potential target for molecular imaging of lung cancer. PMID:26193700

  10. CNTN-1 Enhances Chemoresistance in Human Lung Adenocarcinoma Through Induction of Epithelial-Mesenchymal Transition by Targeting the PI3K/Akt Pathway

    Directory of Open Access Journals (Sweden)

    Ruijie Zhang

    2017-09-01

    Full Text Available Background/Aims: Chemoresistance has been a major obstacle to the effective treatment of lung cancer. Previously, we found that contactin-1 (CNTN-1 is related to cisplatin resistance in lung adenocarcinoma. Here, we aimed to investigate the underlying mechanism behind the role of CNTN-1 in cisplatin resistance in lung adenocarcinoma. Methods: EMT-associated phenotypes, including alterations in cellular morphology and marker (E-cadherin, N-cadherin and Vimentin expression, were compared between A549 cells and A549/DDP cells (a cisplatin-resistant cell line of lung adenocarcinoma with abnormal CNTN-1 expression by using real-time time PCR and Western blotting. Other methods, including CNTN-1 overexpression in A549 cells and CNTN-1 knockdown in A549/DDP cells, were also used to investigate the role of CNTN-1 in mediating the EMT phenotype and thr resulting cisplatin resistance and malignant progression of cancer cells in vitro and in vivo. Results: A549/DDP cells exhibited an EMT phenotype and aggravated malignant behaviors. CNTN-1 knockdown in A549/DDP cells partly reversed the EMT phenotype, increased drug sensitivity, and attenuated the malignant progression whereas CNTN-1 overexpression in A549 cells resulted in the opposite trend. Furthermore, the PI3K/Akt pathway was involved in the effects of CNTN-1 on EMT progression in A549/DDP cells, verified by the xenograft mouse model. Conclusion: CNTN-1 promotes cisplatin resistance in human cisplatin-resistant lung adenocarcinoma through inducing the EMT process by activating the PI3K/Akt signaling pathway. CNTN-1 may be a potential therapeutic target to reverse chemoresistance in cisplatin-resistant lung adenocarcinoma.

  11. Trichostatin A suppresses lung adenocarcinoma development in Grg1 overexpressing transgenic mice

    International Nuclear Information System (INIS)

    Liu, Ju; Li, Yan; Dong, Fengyun; Li, Liqun; Masuda, Takahiro; Allen, Thaddeus D.; Lobe, Corrinne G.

    2015-01-01

    Trichostatin A (TSA) is a histone deacetylase inhibitor and a potential therapeutic for various malignancies. The in vivo effect of TSA, however, has not been investigated in a transgenic lung cancer model. Previously, we generated transgenic mice with overexpression of Groucho-related-gene 1 (Grg1) and these mice all developed mucinous lung adenocarcinoma. Grg1 is a transcriptional co-repressor protein, the function of which is thought to depend on HDAC activity. However, functions outside the nucleus have also been proposed. We tested the supposition that Grg1-induced tumorigenesis is HDAC-dependent by assaying the therapeutic effect of TSA in the Grg1 transgenic mouse model. We found that TSA significantly inhibited lung tumorigenesis in Grg1 transgenic mice (p < 0.01). TSA did not affect overall Grg1 protein levels, but instead reduced ErbB1 and ErbB2 expression, which are upregulated by Grg1 in the absence of TSA. We confirmed this effect in A549 cells. Furthermore, lapatinib, an inhibitor of both ErbB1 and ErbB2, effectively masked the effect of TSA on the inhibition of A549 cell proliferation and migration, suggesting TSA does work, at least in part, by downregulating ErbB receptors. We additionally found that TSA reduced the expression of VEGF and VEGFR2, but not basic FGF and FGFR1. Our findings indicate that TSA effectively inhibits Grg1-induced lung tumorigenesis through the down-regulation of ErbB1 and ErbB2, as well as reduced VEGF signaling. This suggests TSA and other HDAC inhibitors could have therapeutic value in the treatment of lung cancers with Grg1 overexpression. - Highlights: • TSA suppresses lung tumorigenesis in Grg1 overexpressing transgenic mice. • TSA does not affect overall Grg1 protein levels in the mice and in A549 cells. • TSA reduces ErbB1 and ErbB2 expression in the mice and in A549 cells. • Lapatinib masks TSA-induced inhibition of A549 cell proliferation and migration. • TSA inhibits VEGF signaling, but not basic FGF

  12. Trichostatin A suppresses lung adenocarcinoma development in Grg1 overexpressing transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Ju, E-mail: ju.liu@sdu.edu.cn [Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan (China); Molecular and Cellular Biology Division, Sunnybrook Health Science Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 (Canada); Li, Yan [Children' s Health Care Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, Shandong 250014 (China); Dong, Fengyun; Li, Liqun [Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan (China); Masuda, Takahiro; Allen, Thaddeus D. [Molecular and Cellular Biology Division, Sunnybrook Health Science Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 (Canada); Lobe, Corrinne G. [Molecular and Cellular Biology Division, Sunnybrook Health Science Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 (Canada); Miami Mice Research Corp., MaRS Centre, Heritage Bldg., 101 College Street, Toronto, Ontario M5G 1L7 (Canada)

    2015-08-07

    Trichostatin A (TSA) is a histone deacetylase inhibitor and a potential therapeutic for various malignancies. The in vivo effect of TSA, however, has not been investigated in a transgenic lung cancer model. Previously, we generated transgenic mice with overexpression of Groucho-related-gene 1 (Grg1) and these mice all developed mucinous lung adenocarcinoma. Grg1 is a transcriptional co-repressor protein, the function of which is thought to depend on HDAC activity. However, functions outside the nucleus have also been proposed. We tested the supposition that Grg1-induced tumorigenesis is HDAC-dependent by assaying the therapeutic effect of TSA in the Grg1 transgenic mouse model. We found that TSA significantly inhibited lung tumorigenesis in Grg1 transgenic mice (p < 0.01). TSA did not affect overall Grg1 protein levels, but instead reduced ErbB1 and ErbB2 expression, which are upregulated by Grg1 in the absence of TSA. We confirmed this effect in A549 cells. Furthermore, lapatinib, an inhibitor of both ErbB1 and ErbB2, effectively masked the effect of TSA on the inhibition of A549 cell proliferation and migration, suggesting TSA does work, at least in part, by downregulating ErbB receptors. We additionally found that TSA reduced the expression of VEGF and VEGFR2, but not basic FGF and FGFR1. Our findings indicate that TSA effectively inhibits Grg1-induced lung tumorigenesis through the down-regulation of ErbB1 and ErbB2, as well as reduced VEGF signaling. This suggests TSA and other HDAC inhibitors could have therapeutic value in the treatment of lung cancers with Grg1 overexpression. - Highlights: • TSA suppresses lung tumorigenesis in Grg1 overexpressing transgenic mice. • TSA does not affect overall Grg1 protein levels in the mice and in A549 cells. • TSA reduces ErbB1 and ErbB2 expression in the mice and in A549 cells. • Lapatinib masks TSA-induced inhibition of A549 cell proliferation and migration. • TSA inhibits VEGF signaling, but not basic FGF

  13. Prognostic Significance of Tumor Size of Small Lung Adenocarcinomas Evaluated with Mediastinal Window Settings on Computed Tomography

    OpenAIRE

    Sakao, Yukinori; Kuroda, Hiroaki; Mun, Mingyon; Uehara, Hirofumi; Motoi, Noriko; Ishikawa, Yuichi; Nakagawa, Ken; Okumura, Sakae

    2014-01-01

    BACKGROUND: We aimed to clarify that the size of the lung adenocarcinoma evaluated using mediastinal window on computed tomography is an important and useful modality for predicting invasiveness, lymph node metastasis and prognosis in small adenocarcinoma. METHODS: We evaluated 176 patients with small lung adenocarcinomas (diameter, 1-3 cm) who underwent standard surgical resection. Tumours were examined using computed tomography with thin section conditions (1.25 mm thick on high-resolution ...

  14. SPECT/CT of lung nodules using 111In-DOTA-c(RGDfK) in a mouse lung carcinogenesis model.

    Science.gov (United States)

    Hayakawa, Takuya; Mutoh, Michihiro; Imai, Toshio; Tsuta, Koji; Yanaka, Akinori; Fujii, Hirofumi; Yoshimoto, Mitsuyoshi

    2013-08-01

    Lung cancer is one of the leading causes of cancer-related deaths worldwide, including Japan. Although computed tomography (CT) can detect small lung lesions such as those appearing as ground glass opacity, it cannot differentiate between malignant and non-malignant lesions. Previously, we have shown that single photon emission computed tomography (SPECT) imaging using (111)In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo-(Arg-Gly-Asp-D-Phe-Lys) (DOTA-c(RGDfK)), an imaging probe of αvβ3 integrin, is useful for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. In this study, we aimed to assess the usefulness of SPECT/CT with (111)In-DOTA-c(RGDfK) for the evaluation of the malignancy of lung cancer. Lung tumors were induced by a single intraperitoneal injection (250 mg/kg) of urethane in male A/J mice. Twenty-six weeks after the urethane treatment, SPECT was performed an hour after injection of (111)In-DOTA-c(RGDfK). Following this, the radioactivity ratios of tumor to normal lung tissue were measured by autoradiography (ARG) in the excised lung samples. We also examined the expression of αvβ3 integrin in mouse and human lung samples. Urethane treatment induced 5 hyperplasias, 41 adenomas and 12 adenocarcinomas in the lungs of 8 A/J mice. SPECT with (111)In-DOTA-c(RGDfK) could clearly visualize lung nodules, though we failed to detect small lung nodules like adenoma and hyperplasias (adenocarcinoma: 66.7%, adenoma: 33.6%, hyperplasia: 0.0%). ARG analysis revealed significant uptake of (111)In-DOTA-c(RGDfK) in all the lesions. Moreover, tumor to normal lung tissue ratios increased along with the progression of carcinogenesis. Histopathological examination using human lung tissue samples revealed clear up-regulation of αvβ3 integrin in well-differentiated adenocarcinoma (Noguchi type B and C) rather than atypical adenomatous hyperplasia. Although there are some limitations in evaluating the malignancy of

  15. The Role of DNA Methylation in the Development and Progression of Lung Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Keith M. Kerr

    2007-01-01

    Full Text Available Lung cancer, caused by smoking in ∼87% of cases, is the leading cause of cancer death in the United States and Western Europe. Adenocarcinoma is now the most common type of lung cancer in men and women in the United States, and the histological subtype most frequently seen in never-smokers and former smokers. The increasing frequency of adenocarcinoma, which occurs more peripherally in the lung, is thought to be at least partially related to modifications in cigarette manufacturing that have led to a change in the depth of smoke inhalation. The rising incidence of lung adenocarcinoma and its lethal nature underline the importance of understanding the development and progression of this disease. Alterations in DNA methylation are recognized as key epigenetic changes in cancer, contributing to chromosomal instability through global hypomethylation, and aberrant gene expression through alterations in the methylation levels at promoter CpG islands. The identification of sequential changes in DNA methylation during progression and metastasis of lung adenocarcinoma, and the elucidation of their interplay with genetic changes, will broaden our molecular understanding of this disease, providing insights that may be applicable to the development of targeted drugs, as well as powerful markers for early detection and patient classification.

  16. Well-differentiated fetal adenocarcinoma: A very uncommon malignant lung tumor

    Directory of Open Access Journals (Sweden)

    H. El Ouazzani

    2012-01-01

    Full Text Available Well-differentiated fetal adenocarcinoma (WDFA is a very uncommon malignant tumor originating in the lung. This report describes the case of a 38-year-old woman with a WDFA treated by surgery. The malignancy is low grade and associated with a good prognosis, and so it is important for clinicians to be aware of and to identify this rare variant of adenocarcinoma. Resumo: O adenocarcinoma fetal bem diferenciado (WDFA, de acordo com a sigla em inglês é um tumor maligno no pulmão muito invulgar que tem origem no pulmão. Este relatório descreve o caso de uma mulher de 38 anos com WDFA tratada através de cirurgia. A malignidade é de baixo grau e está associada a um bom prognóstico e, por isso, é importante que os clínicos estejam atentos e identifiquem esta variante rara de adenocarcinoma. Keywords: Well-differentiated fetal adenocarcinoma, Lung, Good prognosis, Palavras-chave: Adenocarcinoma fetal bem diferenciado, pulmão, bom prognóstico

  17. Colonic Metastasis with Anemia Leading to a Diagnosis of Primary Lung Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Vasa Jevremovic

    2016-01-01

    Full Text Available Metastasis occurs with 50% of lung carcinomas, most commonly to lymph nodes, adrenal glands, liver, bone, and brain. It is extremely rare for lung cancer to present with symptoms of a gastrointestinal metastasis and even more so pertaining to the colon. To the best of our knowledge, only 12 such cases have been reported in the literature. We describe a case of a 71-year-old female presenting with refractory iron deficiency anemia that was found to have a lesion in the transverse colon. Pathology revealed adenocarcinoma of the lung and a subsequent lung lesion was discovered in a retrograde fashion.

  18. Mouse lung adhesion assay for Bordetella pertussis

    Energy Technology Data Exchange (ETDEWEB)

    Burns, K A; Freer, J H [Department of Microbiology, Alexander Stone Building, Bearsden, Glasgow, Scotland

    1982-03-01

    The ability of Bordetella pertussis to adhere to cell surfaces has been demonstrated by adhesion to tissue culture cells and adhesion to chicken, hamster or rabbit trachea in organ culture. In this report a mouse lung assay for adhesion is described and the results obtained using two virulent strains of B. pertussis and their avirulent counterparts. These were a C modulation of one of the original virulent strains and a phase IV variant of the other virulent strain. Organisms were radiolabelled by adding 1 ..mu..Ci (37 K Bq) of (/sup 14/C)glutamic acid per 10 ml of culture medium before inoculation and incubation for 5 days. The lungs were washed by perfusion in situ with at least two volumes (1 ml) of sterile 1% (w/v) casamino acids. The percentage of the inoculated organisms retained in the lungs was determined, after removal of the lungs, by one of the following two methods: viable count or radioactive count. Results for both methods were expressed as the percentage of the inoculum retained in the lungs plus or minus one standard deviation.

  19. Mouse lung adhesion assay for Bordetella pertussis

    International Nuclear Information System (INIS)

    Burns, K.A.; Freer, J.H.

    1982-01-01

    The ability of Bordetella pertussis to adhere to cell surfaces has been demonstrated by adhesion to tissue culture cells and adhesion to chicken, hamster or rabbit trachea in organ culture. In this report a mouse lung assay for adhesion is described and the results obtained using two virulent strains of B. pertussis and their avirulent counterparts. These were a C modulation of one of the original virulent strains and a phase IV variant of the other virulent strain. Organisms were radiolabelled by adding 1 μCi (37 K Bq) of [ 14 C]glutamic acid per 10 ml of culture medium before inoculation and incubation for 5 days. The lungs were washed by perfusion in situ with at least two volumes (1 ml) of sterile 1% (w/v) casamino acids. The percentage of the inoculated organisms retained in the lungs was determined, after removal of the lungs, by one of the following two methods: viable count or radioactive count. Results for both methods were expressed as the percentage of the inoculum retained in the lungs plus or minus one standard deviation. (Auth.)

  20. A rare tumoral combination, synchronous lung adenocarcinoma and mantle cell lymphoma of the pleura

    Directory of Open Access Journals (Sweden)

    Foroulis Christophoros N

    2008-12-01

    Full Text Available Abstract Background Coexistence of adenocarcinoma and mantle cell lymphoma in the same or different anatomical sites is extremely rare. We present a case of incidental discovery of primary lung adenocarcinoma and mantle cell lymphoma involving the pleura, during an axillary thoracotomy performed for a benign condition. Case presentation A 73-year old male underwent bullectomy and apical pleurectomy for persistent pneumothorax. A bulla of the lung apex was resected en bloc with a scar-like lesion of the lung, which was located in proximity with the bulla origin, by a wide wedge resection. Histologic examination of the stripped-off parietal pleura and of the bullectomy specimen revealed the synchronous occurrence of two distinct neoplasms, a lymphoma infiltrating the pleura and a primary, early lung adenocarcinoma. Immunohistochemical and fluorescence in situ hybridization assays were performed. The morphologic, immunophenotypic and genetic findings supported the diagnosis of primary lung adenocarcinoma (papillary subtype coexisting with a non-Hodgkin, B-cell lineage, mantle cell lymphoma involving both, visceral and parietal pleura and without mediastinal lymph node involvement. The neoplastic lymphoid cells showed the characteristic immunophenotype of mantle cell lymphoma and the translocation t(11;14. The patient received 6 cycles of chemotherapy, while pulmonary function tests precluded further pulmonary parenchyma resection (lobectomy for his adenocarcinoma. The patient is alive and without clinical and radiological findings of local recurrence or distant relapse from both tumors 14 months later. Conclusion This is the first reported case of a rare tumoral combination involving simultaneously lung and pleura, emphasizing at the incidental discovery of the two coexisting neoplasms during a procedure performed for a benign condition. Any tissue specimen resected during operations performed for non-tumoral conditions should be routinely sent for

  1. EGFR immunoexpression, RAS immunoexpression and their effects on survival in lung adenocarcinoma cases.

    Science.gov (United States)

    Gundogdu, Ahmet Gokhan; Onder, Sevgen; Firat, Pinar; Dogan, Riza

    2014-06-01

    The impacts of epidermal growth factor receptor (EGFR) immunoexpression and RAS immunoexpression on the survival and prognosis of lung adenocarcinoma patients are debated in the literature. Twenty-six patients, who underwent pulmonary resections between 2002 and 2007 in our clinic, and whose pathologic examinations yielded adenocarcinoma, were included in the study. EGFR and RAS expression levels were examined by immunohistochemical methods. The results were compared with the survival, stage of the disease, nodal involvement, lymphovascular invasion, and pleural invasion. Nonparametric bivariate analyses were used for statistical analyses. A significant link between EGFR immunoexpression and survival has been identified while RAS immunoexpression and survival have been proven to be irrelevant. Neither EGFR, nor RAS has displayed a significant link with the stage of the disease, nodal involvement, lymphovascular invasion, or pleural invasion. Positive EGFR immunoexpression affects survival negatively, while RAS immunoexpression has no effect on survival in lung adenocarcinoma patients.

  2. A Prediction Model for ROS1-Rearranged Lung Adenocarcinomas based on Histologic Features

    OpenAIRE

    Zhou, Jianya; Zhao, Jing; Zheng, Jing; Kong, Mei; Sun, Ke; Wang, Bo; Chen, Xi; Ding, Wei; Zhou, Jianying

    2016-01-01

    Aims To identify the clinical and histological characteristics of ROS1-rearranged non-small-cell lung carcinomas (NSCLCs) and build a prediction model to prescreen suitable patients for molecular testing. Methods and Results We identified 27 cases of ROS1-rearranged lung adenocarcinomas in 1165 patients with NSCLCs confirmed by real-time PCR and FISH and performed univariate and multivariate analyses to identify predictive factors associated with ROS1 rearrangement and finally developed predi...

  3. NMR metabolomics of human lung tumours reveals distinct metabolic signatures for adenocarcinoma and squamous cell carcinoma

    OpenAIRE

    Rocha, CM; Barros, AS; Goodfellow, BJ; Carreira, IM; Gomes, AA; Sousa, V; Bernardo, J; Carvalho, L; Gil, AM; Duarte, IF

    2015-01-01

    Lung tumour subtyping, particularly the distinction between adenocarcinoma (AdC) and squamous cell carcinoma (SqCC), is a critical diagnostic requirement. In this work, the metabolic signatures of lung carcinomas were investigated through (1)H NMR metabolomics, with a view to provide additional criteria for improved diagnosis and treatment planning. High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (NMR) spectroscopy was used to analyse matched tumour and adjacent control tissue...

  4. Prognostic factorsin inoperable adenocarcinoma of the lung: A multivariate regression analysis of 259 patiens

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn; Badsberg, Jens Henrik; Olsen, Jens

    1989-01-01

    The prognostic factors for survival in advanced adenocarcinoma of the lung were investigated in a consecutive series of 259 patients treated with chemotherapy. Twenty-eight pretreatment variables were investigated by use of Cox's multivariate regression model, including histological subtypes and ...

  5. Efficacy and safety of icotinib in patients with brain metastases from lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Xu J

    2016-05-01

    Full Text Available Jianping Xu, Xiaoyan Liu, Sheng Yang, Xiangru Zhang, Yuankai Shi Department of Internal Medicine, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China Objective: The objective of this study was to evaluate the efficacy and safety of icotinib in patients with brain metastases (BMs from lung adenocarcinoma.Patients and methods: Clinical data of 28 cases with BMs from lung adenocarcinoma were retrospectively analyzed. All the patients took 125 mg icotinib orally three times a day. Progression of disease, intolerable adverse reactions, and number of deaths were recorded.Results: For all the patients, the remission rate of icotinib was 67.8% and the disease control rate was 96.4%. The median overall survival time of patients was 21.2 months, and the median progression-free survival time of patients was 10.9 months. Only mild adverse events of grade 1/2 were observed during the treatment.Conclusion: Icotinib was an effective and safe strategy to treat patients with BMs from lung adenocarcinoma.Keywords: icotinib, lung adenocarcinoma, brain metastases 

  6. Frequency of epidermal growth factor receptor mutations in Jordanian lung adenocarcinoma patients at diagnosis

    Directory of Open Access Journals (Sweden)

    Natheir Obeidat

    2016-01-01

    Conclusion: The present study revealed that the EGFR mutations rate in Jordanian patients with adenocarcinoma of the lung was higher than in African-American, and some white Caucasian patients, and was lower than in patients in East Asia, and other countries of South Asia.

  7. Lipase member H is a novel secreted protein selectively upregulated in human lung adenocarcinomas and bronchioloalveolar carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Seki, Yasuhiro [Graduate School of Arts and Sciences, The University of Tokyo, Tokyo (Japan); Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba (Japan); Yoshida, Yukihiro [Department of Surgery, Asahi General Hospital, Chiba (Japan); Department of Thoracic Surgery, The University of Tokyo, Graduate School of Medicine, Tokyo (Japan); Ishimine, Hisako [Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba (Japan); Graduate School of Life and Environmental Sciences, The University of Tsukuba, Tsukuba, Ibaraki (Japan); Shinozaki-Ushiku, Aya [Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo (Japan); Ito, Yoshimasa [Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba (Japan); Sumitomo, Kenya [Department of Internal Medicine, JA Kochi Hospital, Kochi (Japan); Nakajima, Jun [Department of Thoracic Surgery, The University of Tokyo, Graduate School of Medicine, Tokyo (Japan); Fukayama, Masashi [Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo (Japan); Michiue, Tatsuo [Graduate School of Arts and Sciences, The University of Tokyo, Tokyo (Japan); Asashima, Makoto, E-mail: asashi@bio.c.u-tokyo.ac.jp [Graduate School of Arts and Sciences, The University of Tokyo, Tokyo (Japan); Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba (Japan); Life Science Center of Tsukuba Advanced Research Alliance (TARA), The University of Tsukuba, Tsukuba, Ibaraki (Japan); Kurisaki, Akira, E-mail: akikuri@hotmail.com [Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba (Japan); Graduate School of Life and Environmental Sciences, The University of Tsukuba, Tsukuba, Ibaraki (Japan)

    2014-01-24

    Highlights: • Most of the adenocarcinomas and bronchioloalveolar carcinomas were LIPH-positive. • LIPH is necessary for the proliferation of lung cancer cells in vitro. • A high level of LIPH in serum is correlated with better survival in early phase lung-cancer patients after surgery. - Abstract: Lung cancer is one of the most frequent causes of cancer-related death worldwide. However, molecular markers for lung cancer have not been well established. To identify novel genes related to lung cancer development, we surveyed publicly available DNA microarray data on lung cancer tissues. We identified lipase member H (LIPH, also known as mPA-PLA1) as one of the significantly upregulated genes in lung adenocarcinoma. LIPH was expressed in several adenocarcinoma cell lines when they were analyzed by quantitative real-time polymerase chain reaction (qPCR), western blotting, and sandwich enzyme-linked immunosorbent assay (ELISA). Immunohistochemical analysis detected LIPH expression in most of the adenocarcinomas and bronchioloalveolar carcinomas tissue sections obtained from lung cancer patients. LIPH expression was also observed less frequently in the squamous lung cancer tissue samples. Furthermore, LIPH protein was upregulated in the serum of early- and late-phase lung cancer patients when they were analyzed by ELISA. Interestingly, high serum level of LIPH was correlated with better survival in early phase lung cancer patients after surgery. Thus, LIPH may be a novel molecular biomarker for lung cancer, especially for adenocarcinoma and bronchioloalveolar carcinoma.

  8. Lipase member H is a novel secreted protein selectively upregulated in human lung adenocarcinomas and bronchioloalveolar carcinomas

    International Nuclear Information System (INIS)

    Seki, Yasuhiro; Yoshida, Yukihiro; Ishimine, Hisako; Shinozaki-Ushiku, Aya; Ito, Yoshimasa; Sumitomo, Kenya; Nakajima, Jun; Fukayama, Masashi; Michiue, Tatsuo; Asashima, Makoto; Kurisaki, Akira

    2014-01-01

    Highlights: • Most of the adenocarcinomas and bronchioloalveolar carcinomas were LIPH-positive. • LIPH is necessary for the proliferation of lung cancer cells in vitro. • A high level of LIPH in serum is correlated with better survival in early phase lung-cancer patients after surgery. - Abstract: Lung cancer is one of the most frequent causes of cancer-related death worldwide. However, molecular markers for lung cancer have not been well established. To identify novel genes related to lung cancer development, we surveyed publicly available DNA microarray data on lung cancer tissues. We identified lipase member H (LIPH, also known as mPA-PLA1) as one of the significantly upregulated genes in lung adenocarcinoma. LIPH was expressed in several adenocarcinoma cell lines when they were analyzed by quantitative real-time polymerase chain reaction (qPCR), western blotting, and sandwich enzyme-linked immunosorbent assay (ELISA). Immunohistochemical analysis detected LIPH expression in most of the adenocarcinomas and bronchioloalveolar carcinomas tissue sections obtained from lung cancer patients. LIPH expression was also observed less frequently in the squamous lung cancer tissue samples. Furthermore, LIPH protein was upregulated in the serum of early- and late-phase lung cancer patients when they were analyzed by ELISA. Interestingly, high serum level of LIPH was correlated with better survival in early phase lung cancer patients after surgery. Thus, LIPH may be a novel molecular biomarker for lung cancer, especially for adenocarcinoma and bronchioloalveolar carcinoma

  9. LHX6, An Independent Prognostic Factor, Inhibits Lung Adenocarcinoma Progression through Transcriptional Silencing of β-catenin.

    Science.gov (United States)

    Yang, Juntang; Han, Fei; Liu, Wenbin; Zhang, Mingqian; Huang, Yongsheng; Hao, Xianglin; Jiang, Xiao; Yin, Li; Chen, Hongqiang; Cao, Jia; Zhang, Huidong; Liu, Jinyi

    2017-01-01

    Introduction: Our previous study identified LIM homeobox domain 6 (LHX6) as a frequently epigenetically silenced tumor-suppressor gene in lung cancer. However, its clinical value has never been evaluated, and the in-depth anti-tumor mechanism remains unclear. Methods: Public database was used for lung cancer, lung adenocarcinoma and lung squamous carcinoma patients and tissue microarray data was used for lung adenocarcinoma patients to study prognostic outcome of LHX6 expression by Kaplan-Meier and Cox-regression analysis. In vitro proliferation, metastasis and in vivo nude mice model were used to evaluate the anti-tumor effect of LHX6 on lung adenocarcinoma cell lines. The mechanisms were explored using western blot, TOP/FOP flash assays and luciferase reporter assays. LHX6 expression and clinical stages data were collected from The Cancer Genome Atlas database (TCGA). Results: Expression of LHX6 was found to be a favorable independent prognostic factor for overall survival (OS) of total lung adenocarcinoma patients (P=0.014) and patients with negative lymph nodes status (P=0.014) but not related the prognostic outcome of lung squamous cell carcinoma patients. The expression status of LHX6 significantly correlated to histological grade (P<0.01), tumor size (P=0.026), lymph node status (P=0.039) and clinical stages (P<0.01) of lung adenocarcinoma patients. Functionally, LHX6 inhibited the proliferation and metastasis of lung adenocarcinoma cells in vitro and in vivo . Furthermore, LHX6 suppressed the Wnt/β-catenin pathway through transcriptionally silencing the expression of β-catenin, and the promoter region (-1161 bp to +27 bp) was crucial for its inhibitory activity. Conclusions: Our data indicate that the expression of LHX6 may serve as a favorable prognostic biomarker for lung adenocarcinoma patients and provide a novel mechanism of LHX6 involving in the tumorigenesis of lung adenocarcinoma.

  10. Coalescent pleural malignant mesothelioma and adenocarcinoma of the lung, involving only minor asbestos exposure.

    Science.gov (United States)

    Tsuzuki, Toyonori; Ninomiya, Hironori; Natori, Yuji; Ishikawa, Yuichi

    2008-07-01

    Coexistence of pulmonary adenocarcinoma and pleural malignant mesothelioma is extremely rare, although both are asbestos-related. Herein is presented a rare case of coalescent lung tumor made up of a malignant mesothelioma and a pulmonary adenocarcinoma in a 62-year-old Japanese man, a high-school teacher with only minor asbestos exposure. Preoperative diagnosis of adenocarcinoma was made on transbronchial biopsy. At surgery, multiple small white nodules were observed on the parietal pleural surface, opposite to the lung tumor. They were confirmed to be malignant mesothelioma on histopathology of paraffin section. The pulmonary tumor mass itself consisted of two distinct portions. The major part contained papillary proliferation of hobnail and columnar cells. Peripherally, neoplastic cells grew in a lepidic fashion and micropapillary growth was also detected. The other component featured tubular structures. The former was positive for adenocarcinoma markers such as CEA, Ber-EP4, PE-10, thyroid transcription factor-1 and Napsin A, and negative for mesothelial markers including calretinin, D2-40, WT-1 and HBME, while the latter was the opposite, resulting in a diagnosis of coalescing malignant mesothelioma and adenocarcinoma. The panel of antibodies used for immunohistochemistry was useful to distinguish the two different components in the one tumor.

  11. Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress

    International Nuclear Information System (INIS)

    Cheng, Ya-Hsin; Huang, Su-Chin; Lin, Chun-Ju; Cheng, Li-Chuan; Li, Lih-Ann

    2012-01-01

    Environmental cigarette smoke has been suggested to promote lung adenocarcinoma progression through aryl hydrocarbon receptor (AhR)-signaled metabolism. However, whether AhR facilitates metabolic activation or detoxification in exposed adenocarcinoma cells remains ambiguous. To address this question, we have modified the expression level of AhR in two human lung adenocarcinoma cell lines and examined their response to an extract of cigarette sidestream smoke particulates (CSSP). We found that overexpression of AhR in the CL1-5 cell line reduced CSSP-induced ROS production and oxidative DNA damage, whereas knockdown of AhR expression increased ROS level in CSSP-exposed H1355 cells. Oxidative stress sensor Nrf2 and its target gene NQO1 were insensitive to AhR expression level and CSSP treatment in human lung adenocarcinoma cells. In contrast, induction of AhR expression concurrently increased mRNA expression of xenobiotic-metabolizing genes CYP1B1, UGT1A8, and UGT1A10 in a ligand-independent manner. It appeared that AhR accelerated xenobiotic clearing and diminished associated oxidative stress by coordinate regulation of a set of phase I and II metabolizing genes. However, the AhR-signaled protection could not shield cells from constant oxidative stress. Prolonged exposure to high concentrations of CSSP induced G0/G1 cell cycle arrest via the p53–p21–Rb1 signaling pathway. Despite no effect on DNA repair rate, AhR facilitated the recovery of cells from growth arrest when CSSP exposure ended. AhR-overexpressing lung adenocarcinoma cells exhibited an increased anchorage-dependent and independent proliferation when recovery from exposure. In summary, our data demonstrated that AhR protected lung adenocarcinoma cells against CSSP-induced oxidative stress and promoted post-exposure clonogenicity. -- Highlights: ► AhR expression level influences cigarette sidestream smoke-induced ROS production. ► AhR reduces oxidative stress by coordinate regulation of

  12. Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Ya-Hsin [Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung 40402, Taiwan, ROC (China); Huang, Su-Chin; Lin, Chun-Ju; Cheng, Li-Chuan [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan, ROC (China); Li, Lih-Ann, E-mail: lihann@nhri.org.tw [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan, ROC (China)

    2012-03-15

    Environmental cigarette smoke has been suggested to promote lung adenocarcinoma progression through aryl hydrocarbon receptor (AhR)-signaled metabolism. However, whether AhR facilitates metabolic activation or detoxification in exposed adenocarcinoma cells remains ambiguous. To address this question, we have modified the expression level of AhR in two human lung adenocarcinoma cell lines and examined their response to an extract of cigarette sidestream smoke particulates (CSSP). We found that overexpression of AhR in the CL1-5 cell line reduced CSSP-induced ROS production and oxidative DNA damage, whereas knockdown of AhR expression increased ROS level in CSSP-exposed H1355 cells. Oxidative stress sensor Nrf2 and its target gene NQO1 were insensitive to AhR expression level and CSSP treatment in human lung adenocarcinoma cells. In contrast, induction of AhR expression concurrently increased mRNA expression of xenobiotic-metabolizing genes CYP1B1, UGT1A8, and UGT1A10 in a ligand-independent manner. It appeared that AhR accelerated xenobiotic clearing and diminished associated oxidative stress by coordinate regulation of a set of phase I and II metabolizing genes. However, the AhR-signaled protection could not shield cells from constant oxidative stress. Prolonged exposure to high concentrations of CSSP induced G0/G1 cell cycle arrest via the p53–p21–Rb1 signaling pathway. Despite no effect on DNA repair rate, AhR facilitated the recovery of cells from growth arrest when CSSP exposure ended. AhR-overexpressing lung adenocarcinoma cells exhibited an increased anchorage-dependent and independent proliferation when recovery from exposure. In summary, our data demonstrated that AhR protected lung adenocarcinoma cells against CSSP-induced oxidative stress and promoted post-exposure clonogenicity. -- Highlights: ► AhR expression level influences cigarette sidestream smoke-induced ROS production. ► AhR reduces oxidative stress by coordinate regulation of

  13. A case of unilateral lung edema after treatment of pulmonary adenocarcinoma

    International Nuclear Information System (INIS)

    Itoh, Hiromichi; Yamamoto, Tatsuo; Saida, Yukihisa; Ishikawa, Shigemi; Onizuka, Masataka; Noguchi, Masayuki

    2005-01-01

    As HRCT (high resolution computed tomography) has become increased commonly used, it has become apparent that GGA (ground-glass attenuation) is present in a variety of lung diseases. We report a case of unilateral lung edema represented as GGA in an opposite lung field after treatment of pulmonary adenocarcinoma. A 70-year-old man with uncontrolled diabetes was admitted because of an abnormal shadow discovered during a routine chest X-ray in June 2003. In 1994, he underwent a left lower lobectomy and post-operative mediastinal radiation for pulmonary adenocarcinoma (p-Stage IIIA). Chest CT on admission demonstrated widespread GGA in the right hilar lesion of the middle and lower lobes. Detailed examinations including transbronchial lung biopsy (TBLB), bacterial culture and a serological test could not confirm bronchioloalveolar carcinoma, interstitial pneumonia, viral pneumonia or alveolar proteinosis. The patient increased his weight by 5 kg and ultrasound examination showed dilatation of the inferior vena cava and a congestive liver. The GGA disappeared one month after the administration of furosemide. The clinical course, HRCT and pathological findings suggested that lung edema caused by volume overload affected as localized unilateral GGA in the chest CT. The decrease in pulmonary vessel beds due to surgical resection, obstruction of lymphatic circulation after mediastinal radiation, and increased permeability of microvessels associated with diabetes are supposed to be linked to lung edema. Localized lung edema should be considered as a possible cause of GGA after lung cancer treatment. (author)

  14. Gene expression signature of cigarette smoking and its role in lung adenocarcinoma development and survival.

    Directory of Open Access Journals (Sweden)

    Maria Teresa Landi

    2008-02-01

    Full Text Available Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure.We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1. Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p1.5, for each comparison, consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001 and TTK (p = 0.002 expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers.Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers.

  15. PHGDH Defines a Metabolic Subtype in Lung Adenocarcinomas with Poor Prognosis

    Directory of Open Access Journals (Sweden)

    Boxi Zhang

    2017-06-01

    Full Text Available Molecular signatures are emerging determinants of choice of therapy for lung adenocarcinomas. An evolving therapeutic approach includes targeting metabolic dependencies in cancers. Here, using an integrative approach, we have dissected the metabolic fingerprints of lung adenocarcinomas, and we show that Phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme in serine biosynthesis, is highly expressed in a adenocarcinoma subset with poor prognosis. This subset harbors a gene signature for DNA replication and proliferation. Accordingly, models with high levels of PHGDH display rapid proliferation, migration, and selective channeling of serine-derived carbons to glutathione and pyrimidines, while depletion of PHGDH shows potent and selective toxicity to this subset. Differential PHGDH protein levels were defined by its degradation, and the deubiquitinating enzyme JOSD2 is a regulator of its protein stability. Our study provides evidence that a unique metabolic program is activated in a lung adenocarcinoma subset, described by PHGDH, which confers growth and survival and may have therapeutic implications.

  16. Mammalian mediator 19 mediates H1299 lung adenocarcinoma cell clone conformation, growth, and metastasis.

    Science.gov (United States)

    Xu, Lu-Lu; Guo, Shu-Liang; Ma, Su-Ren; Luo, Yong-Ai

    2012-01-01

    Mammalian mediator (MED) is a multi-protein coactivator that has been identified by several research groups. The involvement of the MED complex subunit 19 (MED 19) in the metastasis of lung adenocarcinoma cell line (H1299), which expresses the MED 19 subunit, was here investigated. When MED 19 expression was decreased by RNA interference H1299 cells demonstrated reduced clone formation, arrest in the S phase of the cell cycle, and lowered metastatic capacity. Thus, MED 19 appears to play important roles in the biological behavior of non-small cell lung carcinoma cells. These findings may be important for the development of novel lung carcinoma treatments.

  17. Urinary bladder metastasis from lung adenocarcinoma: A rare cause of hematuria

    Directory of Open Access Journals (Sweden)

    Kan Wai Man Raymond

    2014-01-01

    Full Text Available We presented an unusual case of hematuria caused by a solitary bladder metastasis from lung adenocarcinoma. A confident diagnosis of secondary adenocarcinoma of the bladder was made by clinical suspicion based on patient′s past history, careful examination of tumor morphology, and a directed panel (cytokeratin [CK] 7/CK20/thyroid transcription factor 1 of immunohistochemistry. We sought, through sharing our experience in the investigative and diagnostic process, to contribute to the better understanding of this unusual cause of hematuria.

  18. CT and histopathologic characteristics of lung adenocarcinoma with pure ground-glass nodules 10 mm or less in diameter

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Fang [Chinese PLA General Hospital, Department of Radiology, Beijing (China); Capital Medical University, Department of Radiology, Xuanwu Hospital, Beijing (China); Tian, Shu-ping [Navy General Hospital, Department of Radiology, Beijing (China); Jin, Xin; Jing, Rui; Yang, Yue-qing; Jin, Mei; Zhao, Shao-hong [Chinese PLA General Hospital, Department of Radiology, Beijing (China)

    2017-10-15

    To evaluate CT and histopathologic features of lung adenocarcinoma with pure ground-glass nodule (pGGN) ≤10 mm in diameter. CT appearances of 148 patients (150 lesions) who underwent curative resection of lung adenocarcinoma with pGGN ≤10 mm (25 atypical adenomatous hyperplasias, 42 adenocarcinoma in situs, 38 minimally invasive adenocarcinomas, and 45 invasive pulmonary adenocarcinomas) were analyzed for lesion size, density, bubble-like sign, air bronchogram, vessel changes, margin, and tumour-lung interface. CT characteristics were compared among different histopathologic subtypes. Univariate and multivariate analysis were used to assess the relationship between CT characteristics of pGGN and lesion invasiveness, respectively. There were statistically significant differences among histopathologic subtypes in lesion size, vessel changes, and tumour-lung interface (P<0.05). Univariate analysis revealed significant differences of vessel changes, margin and tumour-lung interface between preinvasive and invasive lesions (P<0.05). Logistic regression analysis showed that the vessel changes, unsmooth margin and clear tumour-lung interface were significant predictive factors for lesion invasiveness, with odds ratios (95% CI) of 2.57 (1.17-5.62), 1.83 (1.25-2.68) and 4.25 (1.78-10.14), respectively. Invasive lesions are found in 55.3% of subcentimeter pGGNs in our cohort. Vessel changes, unsmooth margin, and clear lung-tumour interface may indicate the invasiveness of lung adenocarcinoma with subcentimeter pGGN. (orig.)

  19. The frequency and clinical impact of HER2 alterations in lung adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Eun Kyung Kim

    Full Text Available Human epidermal growth factor receptor 2 (HER2 or ErbB2 can be overexpressed, amplified and/or mutated in malignant tumors, and is a candidate for therapeutic targeting. However, molecular associations and clinical significances of these alterations were controversial in lung cancer. In this study, we investigated the frequency and clinicopathological significance of HER2 dysregulation in patients with lung adenocarcinoma. HER2 protein overexpression, gene amplification, and gene mutation were evaluated by immunohistochemistry (IHC, silver in situ hybridization, and direct sequencing, respectively. The H-scoring method and American Society of Clinical Oncology/College of American Pathologists breast cancer guidelines were used to interpret IHC results. Genetic analyses of EGFR and KRAS mutations, and of ALK and ROS1 rearrangements, were also performed. Of the 321 adenocarcinoma patients identified, HER2 overexpression (H-score ≥200 and gene amplification were found in 6 (1.9% and 46 (14.3%, respectively. HER2 overexpression was correlated with papillary predominant histology; furthermore, it indicated poor overall survival and was an independent prognostic factor. HER2 amplification was associated with pleural invasion and showed a tendency towards shorter overall and disease-free survival. High-level gene amplification (HER2/CEP17 ratio ≥5 or copy number ≥10 was a poor prognostic factor for disease-free survival. HER2 mutations were detected in 6.7% (7 of 104 of driver oncogene-negative adenocarcinomas. Our study suggests that HER2 overexpression or amplification is a poor prognostic factor in lung adenocarcinoma, although the frequency of such events is low. Since molecular targeted agents are being tested in clinical trials, awareness of the specific HER2 status can influence the prognostic stratification and treatment of patients with molecularly defined subsets of lung adenocarcinoma.

  20. Safety of Neoadjuvant Bevacizumab plus Pemetrexed and Carboplatin 
in Patients with IIIa Lung Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Songliang ZHANG

    2015-06-01

    Full Text Available Background and objective Bevacizumab has showed its efficacy in advanced non-squamous lung cancer. The aim of this study is to assess the safety of bevacizumab plus pemetrexed and carboplatin neoadjuvant chemotherapy in patients with lung adenocarcinoma. Methods 25 patients with IIIa lung adenocarcinoma undergoing lobectemy or pneumonectomy with mediastinal lymphadenectomy after induction bevacizumab (Bev plus pemetrexed/carboplatin (PC were selected. Toxicity of chemotherapy and postoperative complications were analyzed. Results Grade 3 or 4 neoadjuvant-related adverse events included fatigue (3 patients, neutropenia (3 patients, hypertension (1 patient. The adverse events thought to be related to bevacizumab included epistaxis in 2 patients (grade 1: 1; grade 2: 1 and hypertension in 3 patients (grade 1: 2; grade 3: 1. Postoperative complications included pneumonia in 2 patients, bronchial stump insufficiency in 1 case, atelectasis in 2 cases, and arrhythmia in 1 case. Hemorrhage events, thromboembolic events and wound-healing problems were not observed in the perioperative period. Conclusion The treatment modality of neoadjuvant Bev-PC appears to be safe and tolerant in patients with stage IIIa lung adenocarcinoma.

  1. Osteosclerotic lesions in patients treated with gefitinib for lung adenocarcinomas: a sign of favorable therapeutic response

    International Nuclear Information System (INIS)

    Yamashita, Yoshiko; Aoki, Takatoshi; Korogi, Yukunori; Hanagiri, Takeshi; Uramoto, Hidetaka; Yoshii, Chiharu; Mukae, Hiroshi

    2012-01-01

    To assess the frequency of osteosclerotic changes on CT that appeared after treatment with gefitinib in patients with lung adenocarcinoma and the relationship between the osteosclerotic changes and the response to the therapy. Our study included 41 patients with lung adenocarcinoma who underwent chest CT both before (CTpre) and after (CTpost) starting treatment with gefitinib. The presence or absence of bone metastases was assessed on the CTpre, and the interval bony change after the therapy was classified as lytic, sclerotic, or no changes on the CTpost. The relationship between treatment results of primary lung cancer and interval bony changes was evaluated. Osteosclerotic lesions were identified in 11 patients (27%) on CTpost; in 6 of 11 patients osteosclerotic lesions newly appeared where the CTpre showed no bone metastasis before the gefitinib therapy. There were significant differences in the therapeutic response of the primary cancers (P < 0.001) and in the survival rate (P < 0.01) in patients with osteosclerotic changes versus those without osteosclerotic changes. Osteosclerotic changes on CT, observed after gefitinib treatment in patients with lung adenocarcinomas, may be an indicator of a good therapeutic response. (orig.)

  2. Osteosclerotic lesions in patients treated with gefitinib for lung adenocarcinomas: a sign of favorable therapeutic response

    Energy Technology Data Exchange (ETDEWEB)

    Yamashita, Yoshiko; Aoki, Takatoshi; Korogi, Yukunori [University of Occupational and Environmental Health, School of Medicine, Department of Radiology, Kitakyushu (Japan); Hanagiri, Takeshi; Uramoto, Hidetaka [University of Occupational and Environmental Health, School of Medicine, Second Department of Surgery, Kitakyushu (Japan); Yoshii, Chiharu; Mukae, Hiroshi [University of Occupational and Environmental Health, School of Medicine, Department of Respiratory Disease, Kitakyushu (Japan)

    2012-04-15

    To assess the frequency of osteosclerotic changes on CT that appeared after treatment with gefitinib in patients with lung adenocarcinoma and the relationship between the osteosclerotic changes and the response to the therapy. Our study included 41 patients with lung adenocarcinoma who underwent chest CT both before (CTpre) and after (CTpost) starting treatment with gefitinib. The presence or absence of bone metastases was assessed on the CTpre, and the interval bony change after the therapy was classified as lytic, sclerotic, or no changes on the CTpost. The relationship between treatment results of primary lung cancer and interval bony changes was evaluated. Osteosclerotic lesions were identified in 11 patients (27%) on CTpost; in 6 of 11 patients osteosclerotic lesions newly appeared where the CTpre showed no bone metastasis before the gefitinib therapy. There were significant differences in the therapeutic response of the primary cancers (P < 0.001) and in the survival rate (P < 0.01) in patients with osteosclerotic changes versus those without osteosclerotic changes. Osteosclerotic changes on CT, observed after gefitinib treatment in patients with lung adenocarcinomas, may be an indicator of a good therapeutic response. (orig.)

  3. SUN1 silencing inhibits cell growth through G0/G1 phase arrest in lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Huang W

    2017-06-01

    Full Text Available Weiyi Huang,* Haihua Huang,* Lei Wang, Jiong Hu, Weifeng Song Department of Oncology, The First People’s Hospital Affiliated to Shanghai Jiaotong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: Cytoskeleton is critical for carcinoma cell proliferation, migration, and invasion. Sad-1 and UNC-84 domain containing 1 (SUN1 is one of the core linkers of nucleoskeleton and cytoskeleton. However, the functions of SUN1 in lung adenocarcinoma are largely unknown.Methods: In this study, we first transduced the lentivirus delivering the short hairpin RNA (shRNA against SUN1 to lung adenocarcinoma cells (A549 and 95D cells with high efficiency. After lentivirus infection, quantitative real-time polymerase chain reaction and Western blotting were used to detect the expressions of SUN1 mRNA and protein. The cell proliferation and colony formation were detected by MTT assay and colony formation assay, respectively. The cell distribution in the cell cycle was analyzed by flow cytometry.Results: Both mRNA and protein levels of SUN1 were significantly decreased in A549 and 95D cells after lentivirus infection, as indicated by quantitative real-time polymerase chain reaction and Western blot. Next, we found that cell proliferation and colony formation were markedly reduced in SUN1 silenced cells. Moreover, suppression of SUN1 led to cell cycle arrest at G0/G1 phase. Furthermore, Cyclin D1, CDK6, and CDK2 expressions were obviously reduced in A549 cells after SUN1 silencing.Conclusion: These results suggest that SUN1 plays an essential role in proliferation of lung adenocarcinoma cells in vitro and may be used as a potential therapeutic target for the treatment of lung adenocarcinoma in the future. Keywords: SUN1, lung cancer, proliferation

  4. Adenocarcinoma of the lung with scattered consolidation: radiological-pathological correlation and prognosis.

    Science.gov (United States)

    Jiang, Binghu; Takashima, Shodayu; Hakucho, Tomoaki; Hodaka, Numasaki; Yasuhiko, Tomita; Masahiko, Higashiyama

    2013-10-01

    To investigate the clinicopathological features and prognosis in patients with adenocarcinoma of the lung with scattered consolidation (ALSC). Between January 2006 and March 2010, 139 consecutive patients with lung adenocarcinoma of ≤3 cm, who underwent pulmonary resection for lung cancer, were investigated retrospectively. Radiologic classification was based on the findings of thin-section CT such as the presence of consolidation or ground-glass opacity (GGO). Type I (n=15) and Type II (n=14), showed a pure GGO and a mixed GGO with consolidation <50%, respectively. Type IV (n=38) and Type V (n=52) showed a mixed GGO with consolidation ≥50% and a pure consolidation, respectively. Type III (n=20) was the adenocarcinoma of the lung with scattered consolidation (ALSC). The clinicopathological features and prognosis of ALSC was investigated with comparative analysis and survival analysis. Because of the similar recurrence rate for Type I and Type II (P=1.000), Type IV and Type V (P=0.343), we merged Type I and Type II as Type I+II, Type IV and Type V as Type IV+V, respectively. In the 20 (14.4%) patients with ALSC, lymph node metastasis was not observed, and it was rare in lymphatic invasion and vascular invasion. On the basis of IASLC/ATS/ERS 2011 classification, 80% of the ALSC were preinvasive lesions. In Noguchi classification, there was no significant difference between Type I+II and ALSC (P=0.260). The prognosis of ALSC was similar to Type I+II (P=0.408), but better than Type IV+V (P=0.040). Adenocarcinoma of the lung with scattered consolidation (ALSC) on thin-section CT was a relatively favorable prognostic factor. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Metastasis to the penis in a patient with adenocarcinoma of lung, case report and literature review.

    Science.gov (United States)

    Zheng, Fu-Fu; Zhang, Zhong-Yun; Dai, Yu-Ping; Liang, Yue-You; Deng, Chun-Hua; Tao, Yu

    2009-01-01

    Metastasis of lung cancer to the penis is very rare; it causes various clinical symptoms seriously affecting the quality of life. Early recognition and appropriate management will likely enhance survival in these patients. Here, we report a case of penile metastasis secondary to pulmonary carcinoma along with a review of the literature. One case of penile metastasis secondary to pulmonary carcinoma was detected in a 51-year-old patient who was admitted to the First Affiliated Hospital of Sun Yat-Sen University with persistent cough along with swelling of the perineum and penis. The clinical features, diagnosis, and treatment of this disease along with a relevant literature are reviewed and discussed. A MEDLINE search was performed to identify similar reports in the literature. CT scan revealed lung mass, and a glans penis ulcer and enlargement of inguinal lymph nodes was discovered upon physical examination. CT-guided percutaneous puncture of the lung mass revealed adenocarcinoma of lung, and biopsies of the glans penis ulcer and inguinal lymph nodes confirmed metastatic adenocarcinoma. The patients received chemotherapy and died of acute pulmonary embolism in less than 2 months. Metastasis of lung cancer to the penis is extremely rare. It presents an advanced form of lung cancer, and thus survival is extremely short. Although treatment of penile metastasis is almost always palliative, early recognition may enhance survival for these patients.

  6. Radiogenomic correlation in lung adenocarcinoma with epidermal growth factor receptor mutations: Imaging features and histological subtypes

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Su Jin [Seoul National University Bundang Hospital, Department of Radiology, Seongnam-si, Gyeonggi-do (Korea, Republic of); Hanyang University, Department of Radiology, School of Medicine, Seoul (Korea, Republic of); Kim, Tae Jung [Seoul National University Bundang Hospital, Department of Radiology, Seongnam-si, Gyeonggi-do (Korea, Republic of); Samsung Medical Center, Department of Radiology, Seoul (Korea, Republic of); Choi, Yo Won [Hanyang University, Department of Radiology, School of Medicine, Seoul (Korea, Republic of); Park, Jeong-Soo [Dankook Universicity, Department of Biochemistry, College of Medicine, Cheonan (Korea, Republic of); Chung, Jin-Haeng [Seoul National University Bundang Hospital, Department of Pathology, Seongnam-si, Gyeonggi-do (Korea, Republic of); Lee, Kyung Won [Seoul National University Bundang Hospital, Department of Radiology, Seongnam-si, Gyeonggi-do (Korea, Republic of)

    2016-10-15

    To correlate imaging features of resected lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation and the IASLC/ATS/ERS classification histological subtypes. In 250 consecutive patients with resected lung adenocarcinoma, EGFR mutation status was correlated with demographics, imaging features including ground-glass opacity (GGO) proportion and the IASLC/ATS/ERS classification histological subtypes. EGFR mutations were significantly more frequent in women (54.5 % vs. 38.1 %, p = 0.011) and in never-smokers (54.7 % vs. 35.3 %, p = 0.003). GGO proportion was significantly higher in tumours with EGFR mutation than in those without (30.3 ± 33.8 % vs. 19.0 ± 29.3 %, p = 0.005). EGFR mutation was significantly more frequent in tumours with GGO ≥ 50 % and tumours with any GGO (p = 0.026 and 0.008, respectively). Adenocarcinomas with exon 19 or 21 mutation showed significantly higher GGO proportion than that in EGFR wild-type tumours (p = 0.009 and 0.029, respectively). Absence of GGO was an independent predictor of negative EGFR mutation (odds ratio, 1.81; 95 % confidence interval, 1.16-3.04; p = 0.018). GGO proportion in adenocarcinomas with EGFR mutation was significantly higher than that in EGFR wild-type tumours, and the absence of GGO on CT was an independent predictor of negative EGFR mutation. (orig.)

  7. Epidermal growth factor receptor mutations in lung adenocarcinoma in Malaysian patients.

    Science.gov (United States)

    Liam, Chong-Kin; Wahid, Mohamed Ibrahim A; Rajadurai, Pathmanathan; Cheah, Yoke-Kqueen; Ng, Tiffany Shi-Yeen

    2013-06-01

    Despite available data from other Asian countries, the prevalence of epidermal growth factor receptor (EGFR) mutations among lung adenocarcinoma patients has not been reported in Malaysia. This study sought to determine the frequency of EGFR mutations among multiethnic Malaysian patients diagnosed with lung adenocarcinoma. Demographic and clinical information of patients whose lung adenocarcinoma biopsy specimens were submitted for EGFR mutation testing at Sime Darby Medical Center from 2009 to 2011 were analyzed. EGFR mutations at exons 18, 19, 20, and 21 were detected either through bidirectional sequencing or real-time polymerase chain reaction. Among 812 patients in the study, 49% were female, 63.7% were ethnic Chinese, 29.4% Malay, 4.8% Indian, and 2.1% other ethnic groups. Mutations were present in the tumors of 321 patients (39.5%), with mutations at exons 19 (23.5%) and 21 (14.9%) being the most common. Mutations were significantly more frequent among women than in men (52.5% versus 27.8%, p < 0.001). Although mutations were more common among Chinese (40.8%) compared with Malay (37.2%) or Indian (33.3%) patients, the difference was not statistically significant (p = 0.591). Of 211 patients with smoking history records, never-smokers had a higher mutation rate compared with ever-smokers (54.8% versus 20.7%, p < 0.001). EGFR mutations were present in 39.5% of patients. Mutations were more common in women and never-smokers with no differences in mutation frequency between different ethnicities. Because of the high mutation rates, reflex testing for EGFR mutation should be a routine practice for advanced lung adenocarcinoma patients in Malaysia.

  8. Adenocarcinoma of the lung metastatic to the psoas muscle

    Energy Technology Data Exchange (ETDEWEB)

    Nash, S. [Department of Medical Imaging, Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 (Canada); Rubenstein, J. [Department of Medical Imaging, Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 (Canada); Chaiton, A. [Department of Internal Medicine, Division of Rheumatology, Sunnybrook Health Sciences Center and York Finch General Hospital, University of Toronto, Toronto, Ontario (Canada); Morava-Protzner, I. [Department of Pathology, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario (Canada)

    1996-08-01

    Hematogenous metastasis to the psoas muscle is rare, and the resulting clinical symptoms may mimic psoas abscess or hemorrhage. When the clinical history is not specific, CT is important in documenting the presence of a psoas mass and providing biopsy guidance for histologic diagnosis. Only three previously reported cases have been related to a primary carcinoma of the lung. (orig.). With 3 figs.

  9. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors.

    Science.gov (United States)

    Regales, Lucia; Balak, Marissa N; Gong, Yixuan; Politi, Katerina; Sawai, Ayana; Le, Carl; Koutcher, Jason A; Solit, David B; Rosen, Neal; Zakowski, Maureen F; Pao, William

    2007-08-29

    The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer. To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFR(T790M) alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. EGFR(L858R+T790M)-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFR(T790M)-expressing animals develop tumors with longer latency than EGFR(L858R+T790M)-bearing mice and in the absence of additional kinase domain mutations. These new mouse models of mutant EGFR-dependent lung adenocarcinomas provide insight into clinical observations. The models should also be useful for developing improved therapies for patients with lung cancers harboring EGFR(T790M) alone or in conjunction with drug-sensitive EGFR kinase domain mutations.

  10. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors.

    Directory of Open Access Journals (Sweden)

    Lucia Regales

    2007-08-01

    Full Text Available The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer.To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFR(T790M alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. EGFR(L858R+T790M-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFR(T790M-expressing animals develop tumors with longer latency than EGFR(L858R+T790M-bearing mice and in the absence of additional kinase domain mutations.These new mouse models of mutant EGFR-dependent lung adenocarcinomas provide insight into clinical observations. The models should also be useful for developing improved therapies for patients with lung cancers harboring EGFR(T790M alone or in conjunction with drug-sensitive EGFR kinase domain mutations.

  11. Multisystem Langerhans cell histiocytosis coexisting with metastasizing adenocarcinoma of the lung: A case report

    Directory of Open Access Journals (Sweden)

    Lovrenski Aleksandra

    2013-01-01

    Full Text Available Introduction. Langerhans cell histiocytosis (LCH is an uncommon disease of unknown etiology characterized by uncontrolled proliferation and infiltration of various organs by Langerhans cells. Case report. We presented a 54-year-old man, heavy smoker, with dyspnea, cough, hemoptysis, headache and ataxia, who died shortly after admission to our hospital. On the autopsy, tumor was found in the posterior segment of the right upper pulmonary lobe as well as a right-sided occipitoparietal lesion which penetrated into the right ventricle resulting in internal and external hematocephalus. Histologically and immunohistohemically, the diagnosis of primary lung adenocarcinoma with brain metastasis was made (tumor cells showed positivity for CK7 and TTF-1 which confirmed the diagnosis. In the lung parenchyma around the tumor, as well as in brain tissue around the metastatic adenocarcinoma histiocytic lesions were found. Light microscopic examination of the other organs also showed histiocytic lesions involving the pituitary gland, hypothalamus, spleen and mediastinal lymph nodes. Immunohistochemical studies revealed CD68, S-100 and CD1a immunoreactivity within the histiocytes upon which the diagnosis of Langerhans' cells histiocytosis was made. Conclusion. The multisystem form of LCH with extensive organ involvement was an incidental finding, while metastatic lung adenocarcinoma to the brain that led to hematocephalus was the cause of death.

  12. EGFR mutations predict a favorable outcome for malignant pleural effusion of lung adenocarcinoma with Tarceva therapy.

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    Guo, Haisheng; Wan, Yunyan; Tian, Guangyan; Liu, Qinghua; Kang, Yanmeng; Li, Yuye; Yao, Zhouhong; Lin, Dianjie

    2012-03-01

    The aim of the present study was to evaluate the therapeutic effects and adverse reactions of Tarceva treatment for malignant pleural effusion (MPE) caused by metastatic lung adenocarcinomas. One hundred and twenty-eight patients who failed first-line chemotherapy drug treatment were divided into a mutation and a non-mutation group according to the presence or absence of epidermal growth factor receptor (EGFR) mutations. Each patient received closed drainage combined with simple negative pressure suction after thoracoscopic talc poudrage pleurodesis and oral Tarceva treatment. Short-term and long-term clinical therapeutic effects of Tarceva were evaluated. The EGFR mutation rate in pleural metastatic tissues of lung adenocarcinoma acquired through video-assisted thoracoscopic surgery was higher compared to that in surgical resection specimens, plasma specimens and pleural effusion specimens compared to previously reported results. There were significant statistical differences in the average extubation time (ppleural effusion (ppleural effusion 4 weeks after surgery (ppleural hypertrophy in the mutation group was significantly higher compared to the non-mutation group (ppleural hypertrophy was significantly reduced (ppleural effusion of lung adenocarcinoma with Tarceva therapy. Detection of EGFR mutations may determine the responsiveness of malignant pleural effusion to Tarceva treatment.

  13. Sequentially administrated of pemetrexed with icotinib/erlotinib in lung adenocarcinoma cell lines in vitro

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    Feng, Xiuli; Zhang, Yan; Li, Tao; Li, Yu

    2017-01-01

    Combination of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved to be a potent anti-drug for the treatment of tumors. However, survival time was not extended for the patients with lung adenocarcinoma (AdC) compared with first-line chemotherapy. In the present study, we attempt to assess the optimal schedule of the combined administration of pemetrexed and icotinib/erlotinib in AdC cell lines. Human lung AdC cell lines with wild-type (A54...

  14. Vitiligo in a patient with lung adenocarcinoma treated with nivolumab: A case report.

    Science.gov (United States)

    Uenami, Takeshi; Hosono, Yuki; Ishijima, Mikako; Kanazu, Masaki; Akazawa, Yuki; Yano, Yukihiro; Mori, Masahide; Yamaguchi, Toshihiko; Yokota, Soichiro

    2017-07-01

    Nivolumab, an anti-programmed cell death-1 protein monoclonal antibody, is effective for treating patients with late-stage non-small-cell lung cancer. Immune checkpoint inhibitors such as nivolumab induce various kinds of immune-related adverse events, including vitiligo. Vitiligo has been reported in patients with melanoma but not lung cancer. We describe a 75-year-old man with lung adenocarcinoma, stage 4 with pleural and pericardial effusion, that progressed after first-line chemotherapy. Subsequently, he was treated with nivolumab as second-line therapy. After 6days of administering nivolumab, he developed vitiligo suddenly on the trunk of his body. Except for vitiligo, his physical examination was normal, and treatment with nivolumab was well tolerated. Therefore, this treatment was continued without further development or expansion of vitiligo. A computed tomography scan showed a reduction in the size of the lung nodule and stabilization of the pleural and pericardial effusion. This is the first case of vitiligo associated with the use of nivolumab in a patient with lung adenocarcinoma. Copyright © 2017. Published by Elsevier B.V.

  15. 020. Coexistence of lung adenocarcinoma and usual interstitial pneumonia: a case report

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    Baliaka, Aggeliki; Papaemmanouil, Styliani; Spyratos, Dionysis; Zarogoulidis, Paul; Sakkas, Leonidas

    2015-01-01

    Background Usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown cause. The most common symptoms are progressively increased shortness of breath and dry cough. Some studies suggest an association between usual interstitial pneumonia and lung cancer through different pathogenetic mechanisms. Objective The case presentation of a patient with lung adenocarcinoma and UIP. Methods A 66-year-old male presented with persistent dry cough, hemoptysis and dyspnea. The chest radiographs revealed a mass in the lower lobe of the left lung, measuring 3 cm, as well as diffuse interstitial changes in the same lobe. Two partial lobectomies were performed. Results Histological examination of the mass showed moderately differentiated adenocarcinoma, focally with bronchoalveolar pattern (Immunohistochemical detection of EGFR: positive). The rest lung parenchyma presented histological appearance of UIP. Conclusions According to clinicopathological studies, the prevalence of lung cancer among patients with UIP/IPF varies between 4% and 9%. The overall median survival of IPF-Ca patients is seven months in comparison with IPF only patients (14 months).

  16. Expression of PFKFB3 and Ki67 in lung adenocarcinomas and targeting PFKFB3 as a therapeutic strategy.

    Science.gov (United States)

    Li, Xiaoli; Liu, Jian; Qian, Li; Ke, Honggang; Yao, Chan; Tian, Wei; Liu, Yifei; Zhang, Jianguo

    2018-01-11

    Phosphofructokinase-2/fructose-2, 6-bisphosphatase 3 (PFKFB3) catalyzes the synthesis of F2,6BP, which is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1): the rate-limiting enzyme of glycolysis. During tumorigenesis, PFKFB3 increases glycolysis, angiogenesis, and tumor progression. In this study, our aim was to investigate the significance of PFKFB3 and Ki67 in human lung adenocarcinomas and to target PFKFB3 as a therapeutic strategy. In this study, we determined the expression levels of PFKFB3 mRNA and proteins in cancerous and normal lung adenocarcinomas by quantitative reverse transcription PCR (qRT-PCR), Western blot analysis, and tissue microarray immunohistochemistry analysis, respectively. In human adenocarcinoma tissues, PFKFB3 and Ki67 protein levels were related to the clinical characteristics and overall survival. Both PFKFB3 mRNA and protein were significantly higher in lung adenocarcinoma cells (all P targeting PFKFB3, it inhibited cell viability and glycolytic activity. It also caused apoptosis and induced cell cycle arrest. Furthermore, the migration and invasion of A549 cells was inhibited. We conclude that PFKFB3 bears an oncogene-like regulatory element in lung adenocarcinoma progression. In the treatment of lung adenocarcinoma, targeting PFKFB3 would be a promising therapeutic strategy.

  17. Nrf2 and Keap1 Abnormalities in 104 Lung Adenocarcinoma Cases and Association with Clinicopathologic Features

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    Yu XIAO

    2018-03-01

    Full Text Available Background and objective There are significantly interindividual variations of the expression level of nuclear factor erythroid-2-related factor 2 (Nrf2 and/or Kelch-like ECH-associated protein 1 (Keap1 in our previous studies. It has been proven that Nrf2 or Keap1 is related to resistance of chemotherapeutic drugs and/or epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs. However, the expression of Nrf2 and Keap1 in lung adenocarcinoma patients with different “driver gene” is not clear. The aim of this study is to investigate the protein expression level of Nrf2 and Keap1 in lung adenocarcinoma and to elucidate the correlation between Nrf2 or Keap1 expression and the status of EGFR gene mutation and to determine the effects of Nrf2 and Keap1 on the patients. Methods Immunohistochemical analysis of Nrf2 and Keap1 in tumor specimens was performed in a total of 104 lung adenocarcinoma patients with the status of EGFR gene mutations or EGFR wide-type. Results The Nrf2 positive rate was 71.2% and Keap1 high expression rate was 34.6% in 104 patients. The Nrf2 positive rate significantly correlated with gender, stage and status of EGFR gene mutation (P0.05. The high expression of Keap1 was not significantly correlated with gender, age, smoking, differentiation, subtype of lung adenocarcinoma and status of EGFR gene mutation (P>0.05. The progression -free survival (PFS and overall survival (OS of the patients treated by EGFR-TKIs were significantly correlated with the expression level of Nrf2, but not with Keap1. The PFS and OS of the patients with Nrf2 high expression were significantly shorter than the patients with low/negative expression (P<0.05. Furthermore, Nrf2 high expression was the independent predictive factor for EGFR-TKIs induced PFS and OS (P<0.05. Conclusion The Nrf2 positive rate significantly correlated with the status of EGFR gene mutation in lung adenocarcinoma. The Nrf2 high expression significantly

  18. Small cell lung cancer transformation from EGFR-mutated lung adenocarcinoma: A case report and literatures review.

    Science.gov (United States)

    Liu, Yangyang

    2018-06-03

    Epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved the response of non-small cell lung cancer (NSCLC) with EGFR-mutant patients. However, these patients inevitably come cross acquired resistance to EGFR-TKIs. The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with EGFR-TKIs is rare, which leads to resistance to EGFR-TKIs. The present case concerns a case of a 38-year-old man presenting with cough and dyspnea. Radical resection was performed and confirmed an EGFR exon 21 L858R lung adenocarcinoma. However, the patient suffered pleural metastasis after successful treatment with surgery and adjuvant treatment. So, erlotinib was administered with 18 months. Because of enlarged pleural nodule, repeat biopsy identified an SCLC and chemotherapy was started. However, despite the brief success of chemotherapy, our patient suffered brain metastasis. Our case emaphsizes both the profile of transformation from NSCLC to SCLC and the importance of repeat biopsy dealing with drug resistance. We also summarize the clinical characteristics, mechanisms, predictors of SCLC transformation, treatment after transformation and other types of transformation to SCLC.

  19. Origin of Androgen-Insensitive Poorly Differentiated Tumors in the Transgenic Adenocarcinoma of Mouse Prostate Model

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    Wendy J. Huss

    2007-11-01

    Full Text Available Following castration, the transgenic adenocarcinoma of mouse prostate (TRAMP model demonstrates rapid development of SV40-Tag-driven poorly differentiated tumors that express neuroendocrine cell markers. The cell population dynamics within the prostates of castrated TRAMP mice were characterized by analyzing the incorporation of 5-bromodeoxyuridine (BrdUrd and the expression of SV40-Tag, synaptophysin, and androgen receptor (AR. Fourteen days postcastration, the remaining epithelial cells and adenocarcinoma cells were nonproliferative and lacked detectable SV40-Tag or synaptophysin expression. In contrast, morphologically distinct intraglandular foci were identified which expressed SV40-Tag, synaptophysin, and Ki67, but that lacked AR expression. These proliferative SV40-Tag and synaptophysin-expressing intraglandular foci were associated with the rare BrdUrd-retaining cells. These foci expanded rapidly in the postcastration prostate environment, in contrast to the AR- and SV40-Tag-expressing adenocarcinoma cells that lost SV40-Tag expression and underwent apoptosis after castration. Intraglandular foci of synaptophysin-expressing cells were also observed in the prostates of intact TRAMP mice at a comparable frequency; however, they did not progress to rapidly expanding tumors until much later in the life of the mice. This suggests that the foci of neuroendocrine-like cells that express SV40-Tag and synaptophysin, but lack AR, arise independent of androgen-deprivation and represent the source of the poorly differentiated tumors that are the lethal phenotype in the TRAMP model.

  20. Diabetes Insipidus: An Unusual Presentation of Adenocarcinoma of the Lung in a Patient with no Identifiable Lung Mass.

    Science.gov (United States)

    Gulati, Shuchi; Kiefer, Christoper; Karim, Nagla Abdel

    2015-10-01

    Lung cancers are known to metastasize to unusual sites. Despite this knowledge often times the diagnosis of a primary lung cancer gets delayed especially when the patient presents without respiratory symptoms. The patient discussed in our review is a 47-year-old female, smoker who had presented to several hospitals with months of headache, nausea and intermittent episodes of vomiting. She was noted to have hypernatremia due to diabetes insipidus and a pituitary lesion on her magnetic resonance images. The pituitary mass on biopsy was found to represent a metastatic focus from a primary lung adenocarcinoma. Clinicians should be aware of malignancies that are well known to metastasize to the posterior pituitary. Conversely, since not every patient presents with symptoms of metastasis, there is a need to recognize the clinical syndromes (e. g., diabetes insipidus-like symptoms or more subtle symptoms like cranial nerve palsies) associated with potential metastasis to the pituitary.

  1. Distinct HIC1-SIRT1-p53 Loop Deregulation in Lung Squamous Carcinoma and Adenocarcinoma Patients

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    Ruo-Chia Tseng

    2009-08-01

    Full Text Available A HIC1-SIRT1-p53 circular loop in which hypermethylation in cancer 1 (HIC1 represses the transcription of SIRT1 that deacetylates and inactivates p53 thus leading to HIC1 inactivation has been identified in cell and animal models. However, the alteration and prognostic effects of HIC1-SIRT1-p53 circular loop have never been demonstrated in human cancer patients. We examine the HIC1-SIRT1-p53 alterations in 118 lung cancer patients to define their etiological roles in tumorigenesis. We found that patients with lung squamous cell carcinoma with low p53 acetylation and SIRT1 expression mostly showed low HIC1 expression, confirming deregulation of HIC1-SIRT1-p53 circular loop in the clinical model. Interestingly, the expression of deleted in breast cancer 1 (DBC1, which blocks the interaction between SIRT1 deacetylase and p53, led to acetylated p53 in patients with lung adenocarcinoma. However, epigenetic alteration of HIC1 promoter by posttranslational modifications of histones and promoter hypermethylation favoring the compacted chromatin production attenuated the transcriptional induction by acetylated p53. Importantly, lung cancer patients with altered HIC1-SIRT1-p53 circular regulation showed poor prognosis. Our data show the first valid clinical evidence of the deregulation of HIC1-SIRT1-p53 loop in lung tumorigenesis and prognosis. Distinct status of p53 acetylation/deacetylation and HIC1 alteration mechanism result from different SIRT1-DBC1 control and epigenetic alteration in lung squamous cell carcinoma and lung adenocarcinoma.

  2. TWIST1 a new determinant of epithelial to mesenchymal transition in EGFR mutated lung adenocarcinoma.

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    Karine Pallier

    Full Text Available Metastasis is a multistep process and the main cause of mortality in lung cancer patients. We previously showed that EGFR mutations were associated with a copy number gain at a locus encompassing the TWIST1 gene on chromosome 7. TWIST1 is a highly conserved developmental gene involved in embryogenesis that may be reactivated in cancers promoting both malignant conversion and cancer progression through an epithelial to mesenchymal transition (EMT. The aim of this study was to investigate the possible implication of TWIST1 reactivation on the acquisition of a mesenchymal phenotype in EGFR mutated lung cancer. We studied a series of consecutive lung adenocarcinoma from Caucasian non-smokers for which surgical frozen samples were available (n = 33 and showed that TWIST1 expression was linked to EGFR mutations (P<0.001, to low CDH1 expression (P<0.05 and low disease free survival (P = 0.044. To validate that TWIST1 is a driver of EMT in EGFR mutated lung cancer, we used five human lung cancer cell lines and demonstrated that EMT and the associated cell mobility were dependent upon TWIST1 expression in cells with EGFR mutation. Moreover a decrease of EGFR pathway stimulation through EGF retrieval or an inhibition of TWIST1 expression by small RNA technology reversed the phenomenon. Collectively, our in vivo and in vitro findings support that TWIST1 collaborates with the EGF pathway in promoting EMT in EGFR mutated lung adenocarcinoma and that large series of EGFR mutated lung cancer patients are needed to further define the prognostic role of TWIST1 reactivation in this subgroup.

  3. Cell division cycle 20 overexpression predicts poor prognosis for patients with lung adenocarcinoma.

    Science.gov (United States)

    Shi, Run; Sun, Qi; Sun, Jing; Wang, Xin; Xia, Wenjie; Dong, Gaochao; Wang, Anpeng; Jiang, Feng; Xu, Lin

    2017-03-01

    The cell division cycle 20, a key component of spindle assembly checkpoint, is an essential activator of the anaphase-promoting complex. Aberrant expression of cell division cycle 20 has been detected in various human cancers. However, its clinical significance has never been deeply investigated in non-small-cell lung cancer. By analyzing The Cancer Genome Atlas database and using some certain online databases, we validated overexpression of cell division cycle 20 in both messenger RNA and protein levels, explored its clinical significance, and evaluated the prognostic role of cell division cycle 20 in non-small-cell lung cancer. Cell division cycle 20 expression was significantly correlated with sex (p = 0.003), histological classification (p overexpression of cell division cycle 20 was significantly associated with bigger primary tumor size (p = 0.0023), higher MKI67 level (r = 0.7618, p Overexpression of cell division cycle 20 is associated with poor prognosis in lung adenocarcinoma patients, and its overexpression can also be used to identify high-risk groups. In conclusion, cell division cycle 20 might serve as a potential biomarker for lung adenocarcinoma patients.

  4. Molecular typing of lung adenocarcinoma on cytological samples using a multigene next generation sequencing panel.

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    Aldo Scarpa

    Full Text Available Identification of driver mutations in lung adenocarcinoma has led to development of targeted agents that are already approved for clinical use or are in clinical trials. Therefore, the number of biomarkers that will be needed to assess is expected to rapidly increase. This calls for the implementation of methods probing the mutational status of multiple genes for inoperable cases, for which limited cytological or bioptic material is available. Cytology specimens from 38 lung adenocarcinomas were subjected to the simultaneous assessment of 504 mutational hotspots of 22 lung cancer-associated genes using 10 nanograms of DNA and Ion Torrent PGM next-generation sequencing. Thirty-six cases were successfully sequenced (95%. In 24/36 cases (67% at least one mutated gene was observed, including EGFR, KRAS, PIK3CA, BRAF, TP53, PTEN, MET, SMAD4, FGFR3, STK11, MAP2K1. EGFR and KRAS mutations, respectively found in 6/36 (16% and 10/36 (28% cases, were mutually exclusive. Nine samples (25% showed concurrent alterations in different genes. The next-generation sequencing test used is superior to current standard methodologies, as it interrogates multiple genes and requires limited amounts of DNA. Its applicability to routine cytology samples might allow a significant increase in the fraction of lung cancer patients eligible for personalized therapy.

  5. Lung adenocarcinoma with intraoperatively diagnosed pleural seeding: Is main tumor resection beneficial for prognosis?

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    Li, Chi; Kuo, Shuenn-Wen; Hsu, Hsao-Hsun; Lin, Mong-Wei; Chen, Jin-Shing

    2018-03-01

    To evaluate whether main tumor resection improves survival compared with pleural biopsy alone in patients with lung adenocarcinoma with intraoperatively diagnosed pleural seeding. Forty-three patients with lung adenocarcinoma with pleural seeding diagnosed unexpectedly during surgery performed between January 2006 and December 2014 were included in this retrospective study using a prospectively collected lung cancer database. Each surgeon decided whether to perform main tumor resection or pleural biopsy alone. Main tumor and visible pleural nodule resection was performed in 30 patients (tumor resection group). The remaining 13 patients underwent pleural nodule biopsy alone (open-close group). The clinical T stage was higher in the open-close group than in the tumor resection group (P = .02). The tumor resection group had longer operative times compared with the open-close group (mean, 141.8 vs 80.3 minutes). There were no other statistically significant differences in perioperative parameters. The surgical method was the sole statistically significant prognostic factor. Patients in the tumor resection group had better progression-free survival (3-year survival: 44.5% vs 0%; P = .009) and overall survival (3-year survival: 82.9% vs 38.5%; P = .013) than did the open-close group. There was no significant survival difference between sublobar resection and lobectomy for the main tumor resection. Our study demonstrated improved progression-free and overall survival after main tumor and visible pleural nodule resection in patients with lung adenocarcinoma with intraoperatively diagnosed pleural seeding. Further randomized trials are needed to define the role of main tumor resection in these patients. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  6. [Lung Abscess Diagnosed as Adenocarcinoma by Needle Biopsy;Report of a Case].

    Science.gov (United States)

    Shomura, Shin; Suzuki, Hitoshi; Yada, Masaki; Kondo, Chiaki

    2015-07-01

    We report a case of lung abscess misdiagnosed as adenocarcinoma based on cytologic findings of the sample obtained from needle biopsy. A 45-year-old man consulted our hospital because of fever, wet cough and an abnormal shadow on a chest X-ray film. A chest computed tomography revealed gradually enlarging pulmonary mass in the left S6 infiltrating the S5. A diagnosis of lung cancer was suspected and surgery was performed. Pathological findings of the specimen showed atypical cells with a large nucleus and a gross papillary neoplasm by needle biopsy. The patient underwent left lower lobectomy and partial resection of upper lobe with standard nodal dissection. The final diagnosis was a lung abscess with pneumonia without evidence of malignancy. When an indeterminate pulmonary tumor must be diagnosed during an operation, we should perform partial resection if possible.

  7. Small RNA sequencing reveals metastasis-related microRNAs in lung adenocarcinoma

    DEFF Research Database (Denmark)

    Daugaard, Iben; Venø, Morten T.; Yan, Yan

    2017-01-01

    The majority of lung cancer deaths are caused by metastatic disease. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression and miRNA dysregulation can contribute to metastatic progression. Here, small RNA sequencing was used to profile the miRNA and piwi-interacting RNA (piRNA......) transcriptomes in relation to lung cancer metastasis. RNA-seq was performed using RNA extracted from formalin-fixed paraffin embedded (FFPE) lung adenocarcinomas (LAC) and brain metastases from 8 patients, and LACs from 8 patients without detectable metastatic disease. Impact on miRNA and piRNA transcriptomes...... was subtle with 9 miRNAs and 8 piRNAs demonstrating differential expression between metastasizing and non-metastasizing LACs. For piRNAs, decreased expression of piR-57125 was the most significantly associated with distant metastasis. Validation by RT-qPCR in a LAC cohort comprising 52 patients confirmed...

  8. MicroRNA-449a enhances radiosensitivity in CL1-0 lung adenocarcinoma cells.

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    Yi-Jyun Liu

    Full Text Available Lung cancer is the leading cause of cancer-related mortality worldwide. Radiotherapy is often applied for treating lung cancer, but it often fails because of the relative non-susceptibility of lung cancer cells to radiation. MicroRNAs (miRNAs have been reported to modulate the radiosensitivity of lung cancer cells and have the potential to improve the efficacy of radiotherapy. The purpose of this study was to identify a miRNA that can adjust radiosensitivity in lung adenocarcinoma cells. Two lung adenocarcinoma cell lines (CL1-0 and CL1-5 with different metastatic ability and radiosensitivity were used. In order to understand the regulatory mechanisms of differential radiosensitivity in these isogenic tumor cells, both CL1-0 and CL1-5 were treated with 10 Gy radiation, and were harvested respectively at 0, 1, 4, and 24 h after radiation exposure. The changes in expression of miRNA upon irradiation were examined using Illumina Human microRNA BeadChips. Twenty-six miRNAs were identified as having differential expression post-irradiation in CL1-0 or CL1-5 cells. Among these miRNAs, miR-449a, which was down-regulated in CL1-0 cells at 24 h after irradiation, was chosen for further investigation. Overexpression of miR-449a in CL1-0 cells effectively increased irradiation-induced DNA damage and apoptosis, altered the cell cycle distribution and eventually led to sensitization of CL1-0 to irradiation.

  9. Gene-targeted radiation therapy mediated by radiation-sensitive promoter in lung adenocarcinoma and the feasibility of micro-PET / CT in evaluation of therapeutic effectiveness in small animals

    Institute of Scientific and Technical Information of China (English)

    徐昊平

    2014-01-01

    Objective To explore the combined anti-tumor effect of radiation therapy and gene-targeted suppression of tumor neovasculature in lung adenocarcinoma in vivo,and to explore the feasibility of micro-PET/CT in dynamic evaluation of treatment effectiveness.Methods Thirty5-6 week old male BALB/c nude mice were used in this study.The mouse models of xenotransplanted human

  10. WIF-1 and Ihh Expression and Clinical Significance in Patients With Lung Squamous Cell Carcinoma and Adenocarcinoma.

    Science.gov (United States)

    Zhang, Yue; Hu, Chunhong

    2016-10-31

    This study investigated the expression of wingless-type inhibitory factor-1 (WIF-1) and Ihh protein in tumor tissues and their clinical significance in patients with lung squamous cell carcinoma and adenocarcinoma. The expression of WIF-1 and Ihh protein in 74 squamous cell carcinomas and 76 adenocarcinomas was measured by immunohistochemistry. The percentage of positive WIF-1 protein expression was significantly higher, while positive Ihh protein expression was significantly lower in patients with well-differentiated lung squamous cell carcinoma and adenocarcinoma, tumor node metastasis (TNM) stage I disease, and lymph node metastasis than that in patients with poorly differentiated tumor, TNM stage III disease, and lymph node metastasis (PIhh protein expression survived significantly shorter than patients with negative Ihh protein expression. In contrast, no significant difference in mean survival was observed in patients with lung squamous cell carcinoma and adenocarcinoma with positive and negative WIF-1 protein expression (P>0.05). Ihh is a marker for poor prognosis in patients with lung squamous cell carcinoma and adenocarcinoma. WIF-1 is not a predictive marker for lung cancer.

  11. Icotinib as initial treatment in lung adenocarcinoma patients with brain metastases.

    Science.gov (United States)

    Xu, Jian-Ping; Liu, Xiao-Yan; Yang, Sheng; Zhang, Chang-Gong; Wang, Lin; Shi, Yuan-Kai

    2016-07-01

    To evaluate the antitumor activity and toxicity of icotinib as initial treatment in lung adenocarcinoma patients with brain metastases. Twenty-one patients with histologically or pathologically documented brain metastatic lung cancer were administered icotinib as initial treatment from 2011 to 2015 at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences. Chemotherapy response was assessed by Response Evaluation Criteria in Solid Tumors and toxicity was evaluated according to National Cancer Institute-Common Toxicity Criteria. Icotinib was administered three times per day at a dose of 125mg. The median overall and progression-free survival rates were 15.2 (1.2-31.5 months, 95% confidence interval [CI] 6.6-23.7 months) and 8.9 months (0.6-30.5 months, 95% CI 3.4-14.3 months), respectively. The overall response and disease control rates were 61.9% and 90.5%, respectively. Icotinib was well tolerated, and no grade 3/4 adverse events were observed. The most common grade 1/2 adverse events included acneiform eruptions (38.1%), diarrhea (19.0%), and stomatitis (9.5%). Icotinib is effective and well tolerated as initial treatment in lung adenocarcinoma patients with brain metastases.

  12. Lung adenocarcinoma presenting as obstructive jaundice: a case report and review of literature

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    Mukherjee Samrat

    2008-11-01

    Full Text Available Abstract Background Lung cancer is known to metastasize to the pancreas with several case reports found in the literature, however, most patients are at an advanced stage and receive palliative treatment. Case presentation We describe the case of a 56 year old male patient who presented with a picture of obstructive jaundice. Investigations revealed an obstructing lesion in the pancreas and a further lesion in the lung with benign appearances. The patient underwent a pancreatectomy and, unexpectedly, the histology of the resected specimen demonstrated metastatic adenocarcinoma of bronchogenic origin. He was referred to a cardiothoracic team who proceeded to resect the patient's thoracic lesion before administration of adjuvant chemotherapy. The patient was reviewed 18 months post operatively and remains symptom free with no clinical or radiological evidence of recurrence. We were unable to identify any previous case reports (of lung adenocarcinoma with such a presentation which were ultimately treated with resection of both lesions. Conclusion Similar situations are bound to arise again in the future and we believe that this report could demonstrate that there is a case for aggressive surgical management in a highly selected group of patients: those with NSCLC and a synchronous solitary pancreatic deposit.

  13. Generating a robust prediction model for stage I lung adenocarcinoma recurrence after surgical resection.

    Science.gov (United States)

    Wu, Yu-Chung; Wei, Nien-Chih; Hung, Jung-Jyh; Yeh, Yi-Chen; Su, Li-Jen; Hsu, Wen-Hu; Chou, Teh-Ying

    2017-10-03

    Lung cancer mortality remains high even after successful resection. Adjuvant treatment benefits stage II and III patients, but not stage I patients, and most studies fail to predict recurrence in stage I patients. Our study included 211 lung adenocarcinoma patients (stages I-IIIA; 81% stage I) who received curative resections at Taipei Veterans General Hospital between January 2001 and December 2012. We generated a prediction model using 153 samples, with validation using an additional 58 clinical outcome-blinded samples. Gene expression profiles were generated using formalin-fixed, paraffin-embedded tissue samples and microarrays. Data analysis was performed using a supervised clustering method. The prediction model generated from mixed stage samples successfully separated patients at high vs. low risk for recurrence. The validation tests hazard ratio (HR = 4.38) was similar to that of the training tests (HR = 4.53), indicating a robust training process. Our prediction model successfully distinguished high- from low-risk stage IA and IB patients, with a difference in 5-year disease-free survival between high- and low-risk patients of 42% for stage IA and 45% for stage IB ( p model for identifying lung adenocarcinoma patients at high risk for recurrence who may benefit from adjuvant therapy. Our prediction performance of the difference in disease free survival between high risk and low risk groups demonstrates more than two fold improvement over earlier published results.

  14. Exogenous wild type p53 gene affects radiosensitivity of human lung adenocarcinoma cell line under hypoxia

    International Nuclear Information System (INIS)

    Wang Jianhua; Wang Feng; Liu Yongping; Zhang Yaping; Ni Yan; Li Shirong

    2008-01-01

    Objective: To evaluate the effect of exogenous wild type p53 (wtp53) gene on radiosensitivity of human lung adenocarcinoma cell line under hypoxia. Methods: Human lung adenocarcinoma cell line A549 was transfected with adenovirus carrying recombinant exogenous wtp53. Four irradiation groups were studied: normal cell (Group A), wtp53 transfected cell (Group B), normal cell under hypoxia (Group C) and wtp53 transfected cell under hypoxia(Group D). Cells were irradiated with 9 MeV electron beams. Cellular survival fraction was analyzed. Multi-target single-hit model was used to plot the survival curve. D 0 , D q , oxygen enhancement ratio (OER), sensitizing enhancement ratio (SER) and other parameters were used to evaluate the effects of wtp53 gene on radiosensitivity of A549. The cell apoptotic rate of each group was examined by flow cytometry. Results: OER was 1.75 and 0.81 before and after wtp53 transfection. SER was 1.77 in oxic circumstance and 3.84 under hypoxia. The cell apoptotic rate of Group A and B was lower than Group C and D (F=7.92, P=0.048), with Group A lower than B and Group C lower than D (F=82.50, P=0.001). But Group B and D were similar(t=2.04, P=0.111). Conclusions: Hypoxia can increase the radiation resistance of lung adenocarcinoma cell line A549. The wtp53 can promote apoptosis and improve tumor radiosensitivity, especially under hypoxia. (authors)

  15. Clinical and CT characteristics of surgically resected lung adenocarcinomas harboring ALK rearrangements or EGFR mutations

    International Nuclear Information System (INIS)

    Wang, Hua; Schabath, Matthew B.; Liu, Ying; Han, Ying; Li, Qi; Gillies, Robert J.; Ye, Zhaoxiang

    2016-01-01

    Purpose: To determine if clinical and CT characteristics of surgically resected lung adenocarcinomas can distinguish those harboring ALK rearrangements from EGFR mutations. Materials and methods: Patients who had surgical resection and histologically confirmed lung adenocarcinoma were enrolled, including 41 patients with ALK rearrangements and 66 patients with EGFR mutations. Eighteen categorical and six quantitative CT characteristics were used to evaluate the tumors. Differences in clinical and CT characteristics between the two groups were investigated. Results: Age (P = 0.003), histological subtypes (P < 0.001), pathological stage (P = 0.007), and five CT characteristics, including size (P < 0.001), GGO (P = 0.001), bubble-like lucency (P = 0.048), lymphadenopathy (P = 0.001), and tumor shadow disappearance rate (P = 0.005) were significantly different between patients harboring ALK rearrangements compared to patients with EGFR mutations. When we compared histologic components, a solid pattern was more common (P = 0.009) in tumors with ALK rearrangements, and lepidic and acinar patterns were more common (P < 0.001 and P = 0.040, respectively) in those with EGFR mutations. Backward elimination analyses revealed that age (OR = 0.93; 95% CI 0.89–0.98), GGO (OR = 0.14; 95% CI 0.03–0.67), and lymphadenopathy (OR = 4.15; 95% CI 1.49–11.60) were significantly associated with ALK rearrangement status. Conclusion: Our analyses revealed that clinical and CT characteristics of lung adenocarcinomas harboring ALK rearrangements were significantly different, compared with those with EGFR mutations. These differences may be related to the molecular pathology of these diseases.

  16. Clinical and CT characteristics of surgically resected lung adenocarcinomas harboring ALK rearrangements or EGFR mutations

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Hua [Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin (China); Schabath, Matthew B. [Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Liu, Ying [Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin (China); Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Han, Ying [Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin (China); Li, Qi [Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin (China); Gillies, Robert J. [Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Ye, Zhaoxiang, E-mail: yezhaoxiang@163.com [Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin (China)

    2016-11-15

    Purpose: To determine if clinical and CT characteristics of surgically resected lung adenocarcinomas can distinguish those harboring ALK rearrangements from EGFR mutations. Materials and methods: Patients who had surgical resection and histologically confirmed lung adenocarcinoma were enrolled, including 41 patients with ALK rearrangements and 66 patients with EGFR mutations. Eighteen categorical and six quantitative CT characteristics were used to evaluate the tumors. Differences in clinical and CT characteristics between the two groups were investigated. Results: Age (P = 0.003), histological subtypes (P < 0.001), pathological stage (P = 0.007), and five CT characteristics, including size (P < 0.001), GGO (P = 0.001), bubble-like lucency (P = 0.048), lymphadenopathy (P = 0.001), and tumor shadow disappearance rate (P = 0.005) were significantly different between patients harboring ALK rearrangements compared to patients with EGFR mutations. When we compared histologic components, a solid pattern was more common (P = 0.009) in tumors with ALK rearrangements, and lepidic and acinar patterns were more common (P < 0.001 and P = 0.040, respectively) in those with EGFR mutations. Backward elimination analyses revealed that age (OR = 0.93; 95% CI 0.89–0.98), GGO (OR = 0.14; 95% CI 0.03–0.67), and lymphadenopathy (OR = 4.15; 95% CI 1.49–11.60) were significantly associated with ALK rearrangement status. Conclusion: Our analyses revealed that clinical and CT characteristics of lung adenocarcinomas harboring ALK rearrangements were significantly different, compared with those with EGFR mutations. These differences may be related to the molecular pathology of these diseases.

  17. A hybrid of coumarin and phenylsulfonylfuroxan induces caspase-dependent apoptosis and cytoprotective autophagy in lung adenocarcinoma cells.

    Science.gov (United States)

    Wang, Qian; Guo, Yalan; Jiang, Shanshan; Dong, Mengxue; Kuerban, Kudelaidi; Li, Jiyang; Feng, Meiqing; Chen, Ying; Ye, Li

    2018-01-15

    Lung adenocarcinoma is the most primary histologic subtype of non-small cell lung cancer (NSCLC). Compound 8b, a novel coumarin derivative with phenylsulfonylfuroxan group, shows significant antiproliferation activity against lung adenocarcinoma cell with low toxicity. This study aims to uncover the potential of compound 8b in relation to apoptosis as well as autophagy induction in lung adenocarcinoma cells. The cytotoxicity and apoptosis of A549 and H1299 cells induced by compound 8b were detected by MTT, microscope and western blot analysis. Autophagy was determined by TEM, confocal microscopy and western blot analysis. Akt/mTOR and Erk signaling pathway were also examined by western blot analysis. First, significant growth inhibition and caspase-dependent apoptosis were observed in compound 8b-treated A549 and H1299 cells. Then, we confirmed compound 8b-induced autophagy by autophagosomes formation, upregulated expression of autophagy-related protein LC3-II and autophagic flux. Importantly, abolishing autophagy using inhibitors and ATG5 siRNA enhanced the cytotoxicity of compound 8b, indicating the cytoprotective role of autophagy in lung adenocarcinoma. Further mechanistic investigations suggested that Akt/mTOR and Erk signaling pathways contributed to autophagy induction by compound 8b. This results demonstrate that compound 8b induces caspase-dependent apoptosis as well as cytoprotective autophagy in lung adenocarcinoma cells, which may provide scientific evidence for developing this furoxan-based NO-releasing coumarin derivative as a potential anti-lung adenocarcinoma therapeutic agents. Copyright © 2017 Elsevier GmbH. All rights reserved.

  18. A robust prognostic gene expression signature for early stage lung adenocarcinoma

    DEFF Research Database (Denmark)

    Krzystanek, Marcin; Moldvay, Judit; Szüts, David

    2016-01-01

    Stage I lung adenocarcinoma is usually not treated with adjuvant chemotherapy; however, around half of these patients do not survive 5 years. Therefore, a reliable prognostic biomarker for early stage patients would be critical to identify those most likely to benefit from early additional treatm...... not given adjuvant therapy. Seven genes consistently obtained statistical significance in Cox regression for overall survival. The combined signature has a weighted mean hazard ratio of 3.2 in all cohorts and 3.0 (C.I. 1.3-7.4, p ...

  19. Comparison of the diagnosis using FDG-PET and AC-PET with histopathological features in lung adenocarcinomas

    International Nuclear Information System (INIS)

    Koizumi, Satoko

    2011-01-01

    Fluorodeoxyglucose-positron emission tomography (FDG-PET) is a useful tool for lung cancer diagnosis because of its good sensitivity and specificity. However, FDG-PET is problematically causing the false negative in cases of well differentiated lung adenocarcinomas which are low grade malignancies. Acetate (AC)-PET using 11 C-acetate is thought to be a superior detection tool for low grade malignancies. In this study, comparison of each type of PET in relation with histopathological features of lung adenocarcinomas was conducted. Samples obtained from 81 lesions in 75 patients with a lung adenocarcinoma who were operated at various institutions of our collaborators between 2005 and 2009 following FDG-PET and AC-PET procedures were examined. These samples consisted of fifty-seven cases of a well differentiated adenocarcinoma and twenty-four cases of a moderately- or a poorly-differentiated adenocarcinoma. Relationships between the histopathological factors (ly, v, p) as well as the lymphatic microvessel and microvessel densities in a tumor and FDG- and AC-PET findings were evaluated. AC-PET was more sensitive than FDG-PET (0.58 vs 0.74, p=0.0001). FDG-PET showed a correlation with invasiveness of the tumor and intratumoral lymphatic microvessel density (p<0.05). Furthermore, AC-PET possessed a superior sensitivity for the detection of well differentiated adenocarcinomas, and tumors without ly, v, or p factors. In lung adenocarcinoma AC-PET showed better sensitivity than FDG-PET and true positive in all cases of stage I B or more. FDG-PET showed the correlation with the pathological invasiveness (ly, v, p) of a tumor and the intratumoral lymphatic microvessel density. (author)

  20. Lung Adenocarcinomas and Lung Cancer Cell Lines Show Association of MMP-1 Expression With STAT3 Activation

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    Alexander Schütz

    2015-04-01

    Full Text Available Signal transducer and activator of transcription 3 (STAT3 is constitutively activated in the majority of lung cancer. This study aims at defining connections between STAT3 function and the malignant properties of non–small cell lung carcinoma (NSCLC cells. To address possible mechanisms by which STAT3 influences invasiveness, the expression of matrix metalloproteinase-1 (MMP-1 was analyzed and correlated with the STAT3 activity status. Studies on both surgical biopsies and on lung cancer cell lines revealed a coincidence of STAT3 activation and strong expression of MMP-1. MMP-1 and tyrosine-phosphorylated activated STAT3 were found co-localized in cancer tissues, most pronounced in tumor fronts, and in particular in adenocarcinomas. STAT3 activity was constitutive, although to different degrees, in the lung cancer cell lines investigated. Three cell lines (BEN, KNS62, and A549 were identified in which STAT3 activitation was inducible by Interleukin-6 (IL-6. In A549 cells, STAT3 activity enhanced the level of MMP-1 mRNA and stimulated transcription from the MMP-1 promoter in IL-6–stimulated A549 cells. STAT3 specificity of this effect was confirmed by STAT3 knockdown through RNA interference. Our results link aberrant activity of STAT3 in lung cancer cells to malignant tumor progression through up-regulation of expression of invasiveness-associated MMPs.

  1. Epidermal growth factor receptor tyrosine kinase defines critical prognostic genes of stage I lung adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Mai Yamauchi

    Full Text Available PURPOSE: To identify stage I lung adenocarcinoma patients with a poor prognosis who will benefit from adjuvant therapy. PATIENTS AND METHODS: Whole gene expression profiles were obtained at 19 time points over a 48-hour time course from human primary lung epithelial cells that were stimulated with epidermal growth factor (EGF in the presence or absence of a clinically used EGF receptor tyrosine kinase (RTK-specific inhibitor, gefitinib. The data were subjected to a mathematical simulation using the State Space Model (SSM. "Gefitinib-sensitive" genes, the expressional dynamics of which were altered by addition of gefitinib, were identified. A risk scoring model was constructed to classify high- or low-risk patients based on expression signatures of 139 gefitinib-sensitive genes in lung cancer using a training data set of 253 lung adenocarcinomas of North American cohort. The predictive ability of the risk scoring model was examined in independent cohorts of surgical specimens of lung cancer. RESULTS: The risk scoring model enabled the identification of high-risk stage IA and IB cases in another North American cohort for overall survival (OS with a hazard ratio (HR of 7.16 (P = 0.029 and 3.26 (P = 0.0072, respectively. It also enabled the identification of high-risk stage I cases without bronchioalveolar carcinoma (BAC histology in a Japanese cohort for OS and recurrence-free survival (RFS with HRs of 8.79 (P = 0.001 and 3.72 (P = 0.0049, respectively. CONCLUSION: The set of 139 gefitinib-sensitive genes includes many genes known to be involved in biological aspects of cancer phenotypes, but not known to be involved in EGF signaling. The present result strongly re-emphasizes that EGF signaling status in cancer cells underlies an aggressive phenotype of cancer cells, which is useful for the selection of early-stage lung adenocarcinoma patients with a poor prognosis. TRIAL REGISTRATION: The Gene Expression Omnibus (GEO GSE31210.

  2. Circulating microRNAs in relation to EGFR status and survival of lung adenocarcinoma in female non-smokers.

    Directory of Open Access Journals (Sweden)

    Huan Zhang

    Full Text Available OBJECTIVES: Lung adenocarcinoma is considered a unique disease for Asian female non-smokers. We investigated whether plasma microRNA (miRNA expression profiles are different by the EGFR status and are associated with survival outcomes of the patients. METHODS: Using real-time RT-PCR, we analyzed the expression of 20 miRNAs in the plasma of 105 female patients with lung adenocarcinoma. Kaplan-Meier survival analysis and Cox proportional hazards regression were performed to determine the association between miRNA expression and overall survival. Time dependent receiver operating characteristic (ROC analysis was also performed. RESULTS: In the 20 miRNAs, miR-122 were found differently expressed between wild and mutant EGFR carriers (P=0.018. Advanced disease stage and tumor metastasis were independently associated with poor prognosis of patients with lung adenocarcinoma (P=0.010 and 1.0×10(-4. Plasma levels of miR-195 and miR-122 expression were also associated with overall survival in the patients, especially in those with advanced stage (HR=0.23, 95%CI:0.07-0.84; and HR=0.22, 95%CI:0.06-0.77 and EGFR mutation (HR=0.27, 95%CI:0.08-0.96; and HR=0.23, 95%CI=0.06-0.81. Moreover, a model including miR-195, miR-122 may predict survival outcomes of female patients with lung adenocarcinoma (AUC=0.707. CONCLUSIONS: Circulating miR-195 and miR-122 may have prognostic values in predicting the overall survival as well as predicting EGFR mutation status in non-smoking female patients with lung adenocarcinoma. Measuring plasma levels of miR-195 and miR-122 may especially be useful in EGFR mutant patients with lung adenocarcinoma.

  3. An active treatment of lung adenocarcinoma cancer with brain metastases: icotinib

    Directory of Open Access Journals (Sweden)

    Zhang Y

    2015-06-01

    Full Text Available Ying Zhang, Huaping Tang, Jun Li, Meng Li Department of Respiration Medicine, Municipal Hospital, Qingdao, People’s Republic of China Abstract: Lung cancer has the highest mortality rate of all cancers world­wide. A total of 70%–75% of all lung cancers are non-small cell lung cancer (NSCLC with two-thirds presenting with locally advanced or metastatic disease at diagnosis. Brain metastasis is one of the most common problems in the management of NSCLC, worsening the prognosis and quality of life of NSCLC patients. The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs gefitinib and erlotinib have been tested in patients with NSCLC and brain metastasis. Icotinib is a new type of oral EGFR-TKI. In this report, we describe a patient with lung adenocarcinoma cancer with brain metastases who received icotinib treatment and kept satisfactory health-related quality of life for 1 year. Keywords: EGFR, non-small cell lung cancer, tyrosine kinase inhibitor

  4. Ground-glass opacity in lung metastasis from adenocarcinoma of the stomach: a case report

    International Nuclear Information System (INIS)

    Jung, Mi Ran; Kim, Jeong Kon; Lee, Jin Seong; Song, Koun Sik; Lim, Tae Hwan

    2000-01-01

    Ground-glass opacity is a frequent but nonspecific finding seen on high-resolution CT scans of lung parenchyma. Histologically, this appearance is observed when thickening of the alveolar wall and septal interstitium is minimal or the alveolar lumen is partially filled with fluid, macrophage, neutrophils, or amorphous material. It has been shown that ground-glass opacity may be caused not only by an active inflammatory process but also by fibrotic processes. When a focal area of ground-glass opacity persists or increases in size, the possibility of neoplasm-bronchioloalveolar carcinoma or adenoma, or lymphoma, for example, should be considered. Diffuse nonsegmental ground-glass opacity in both lung fields was incidentally found on follow up abdominal CT in a stomach cancer patient and signet-ring cell-type metastatic lung cancer was confirmed by transbronchial lung biopsy. We report a case of diffuse ground-glass opacity seen in metastatic lung cancer from adenocarcinoma of the stomach. (author)

  5. Clinicopathologic Analysis of Microscopic Extension in Lung Adenocarcinoma: Defining Clinical Target Volume for Radiotherapy

    International Nuclear Information System (INIS)

    Grills, Inga S.; Fitch, Dwight L.; Goldstein, Neal S.; Yan Di; Chmielewski, Gary W.; Welsh, Robert J.; Kestin, Larry L.

    2007-01-01

    Purpose: To determine the gross tumor volume (GTV) to clinical target volume margin for non-small-cell lung cancer treatment planning. Methods: A total of 35 patients with Stage T1N0 adenocarcinoma underwent wedge resection plus immediate lobectomy. The gross tumor size and microscopic extension distance beyond the gross tumor were measured. The nuclear grade and percentage of bronchoalveolar features were analyzed for association with microscopic extension. The gross tumor dimensions were measured on a computed tomography (CT) scan (lung and mediastinal windows) and compared with the pathologic dimensions. The potential coverage of microscopic extension for two different lung stereotactic radiotherapy regimens was evaluated. Results: The mean microscopic extension distance beyond the gross tumor was 7.2 mm and varied according to grade (10.1, 7.0, and 3.5 mm for Grade 1 to 3, respectively, p < 0.01). The 90th percentile for microscopic extension was 12.0 mm (13.0, 9.7, and 4.4 mm for Grade 1 to 3, respectively). The CT lung windows correlated better with the pathologic size than did the mediastinal windows (gross pathologic size overestimated by a mean of 5.8 mm; composite size [gross plus microscopic extension] underestimated by a mean of 1.2 mm). For a GTV contoured on the CT lung windows, the margin required to cover microscopic extension for 90% of the cases would be 9 mm (9, 7, and 4 mm for Grade 1 to 3, respectively). The potential microscopic extension dosimetric coverage (55 Gy) varied substantially between the stereotactic radiotherapy schedules. Conclusion: For lung adenocarcinomas, the GTV should be contoured using CT lung windows. Although a GTV based on the CT lung windows would underestimate the gross tumor size plus microscopic extension by only 1.2 mm for the average case, the clinical target volume expansion required to cover the microscopic extension in 90% of cases could be as large as 9 mm, although considerably smaller for high-grade tumors

  6. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma.

    Science.gov (United States)

    Travis, William D; Brambilla, Elisabeth; Noguchi, Masayuki; Nicholson, Andrew G; Geisinger, Kim R; Yatabe, Yasushi; Beer, David G; Powell, Charles A; Riely, Gregory J; Van Schil, Paul E; Garg, Kavita; Austin, John H M; Asamura, Hisao; Rusch, Valerie W; Hirsch, Fred R; Scagliotti, Giorgio; Mitsudomi, Tetsuya; Huber, Rudolf M; Ishikawa, Yuichi; Jett, James; Sanchez-Cespedes, Montserrat; Sculier, Jean-Paul; Takahashi, Takashi; Tsuboi, Masahiro; Vansteenkiste, Johan; Wistuba, Ignacio; Yang, Pan-Chyr; Aberle, Denise; Brambilla, Christian; Flieder, Douglas; Franklin, Wilbur; Gazdar, Adi; Gould, Michael; Hasleton, Philip; Henderson, Douglas; Johnson, Bruce; Johnson, David; Kerr, Keith; Kuriyama, Keiko; Lee, Jin Soo; Miller, Vincent A; Petersen, Iver; Roggli, Victor; Rosell, Rafael; Saijo, Nagahiro; Thunnissen, Erik; Tsao, Ming; Yankelewitz, David

    2011-02-01

    Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies. An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤ 5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100

  7. Aptamer based electrochemical sensor for detection of human lung adenocarcinoma A549 cells

    Science.gov (United States)

    Sharma, Rachna; Varun Agrawal, Ved; Sharma, Pradeep; Varshney, R.; Sinha, R. K.; Malhotra, B. D.

    2012-04-01

    We report results of the studies relating to development of an aptamer-based electrochemical biosensor for detection of human lung adenocarcinoma A549 cells. The aminated 85-mer DNA aptamer probe specific for the A549 cells has been covalently immobilized onto silane self assembled monolayer (SAM) onto ITO surface using glutaraldehyde as the crosslinker. The results of cyclic voltammetry and differential pulse voltammetry studies reveal that the aptamer functionalized bioelectrode can specifically detect lung cancer cells in the concentration range of 103 to 107 cells/ml with detection limit of 103 cells/ml within 60 s. The specificity studies of the bioelectrode have been carried out with control KB cells. No significant change in response is observed for control KB cells as compared to that of the A549 target cells.

  8. The prevalence and prognostic significance of KRAS mutation subtypes in lung adenocarcinomas from Chinese populations

    Directory of Open Access Journals (Sweden)

    Zheng DF

    2016-02-01

    Full Text Available Difan Zheng,1,2,* Rui Wang,1,2,* Yang Zhang,1,2 Yunjian Pan,1,2 Xinghua Cheng,3 Chao Cheng,1,2 Shanbo Zheng,1,2 Hang Li,1,2 Ranxia Gong,1,2 Yuan Li,2,4 Xuxia Shen,2,4 Yihua Sun,1,2 Haiquan Chen1–3,51Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, 2Department of Oncology, Shanghai Medical College, Fudan University, 3Shanghai Chest Hospital, Shanghai Jiao Tong University, 4Department of Pathology, Fudan University Shanghai Cancer Center, 5Institutes of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workBackground: We performed this retrospective study to identify the prevalence of KRAS mutation in Chinese populations and make a comprehensive investigation of the clinicopathological features of KRAS mutation in these patients.Patients and methods: Patients from 2007 to 2013 diagnosed with primary lung adenocarcinoma who received a radical resection were examined for KRAS, EGFR, HER2, BRAF mutations, and ALK, RET, and ROS1 fusions. Clinicopathological features, including sex, age, tumor–lymph node–metastasis stage, tumor differentiation, smoking status, histological subtypes, and survival information were analyzed.Result: KRAS mutation was detected in 113 of 1,368 patients. Nine different subtypes of KRAS mutation were identified in codon 12, codon 13, and codon 61. KRAS mutation was more frequently found in male patients and former/current smoker patients. Tumors with KRAS mutation had poorer differentiation. Invasive mucinous adenocarcinoma predominant and solid predominant subtypes were more frequent in KRAS mutant patients. No statistical significance was found in relapse-free survival or overall survival between patients with KRAS mutation and patients with other mutations.Conclusion: In Chinese populations, we identified KRAS mutation in 8.3% (113/1,368 of the patients with lung adenocarcinoma. KRAS mutation defines a molecular subset of

  9. Suppression subtractive hybridization identified differentially expressed genes in lung adenocarcinoma: ERGIC3 as a novel lung cancer-related gene

    International Nuclear Information System (INIS)

    Wu, Mingsong; Tu, Tao; Huang, Yunchao; Cao, Yi

    2013-01-01

    To understand the carcinogenesis caused by accumulated genetic and epigenetic alterations and seek novel biomarkers for various cancers, studying differentially expressed genes between cancerous and normal tissues is crucial. In the study, two cDNA libraries of lung cancer were constructed and screened for identification of differentially expressed genes. Two cDNA libraries of differentially expressed genes were constructed using lung adenocarcinoma tissue and adjacent nonmalignant lung tissue by suppression subtractive hybridization. The data of the cDNA libraries were then analyzed and compared using bioinformatics analysis. Levels of mRNA and protein were measured by quantitative real-time polymerase chain reaction (q-RT-PCR) and western blot respectively, as well as expression and localization of proteins were determined by immunostaining. Gene functions were investigated using proliferation and migration assays after gene silencing and gene over-expression. Two libraries of differentially expressed genes were obtained. The forward-subtracted library (FSL) and the reverse-subtracted library (RSL) contained 177 and 59 genes, respectively. Bioinformatic analysis demonstrated that these genes were involved in a wide range of cellular functions. The vast majority of these genes were newly identified to be abnormally expressed in lung cancer. In the first stage of the screening for 16 genes, we compared lung cancer tissues with their adjacent non-malignant tissues at the mRNA level, and found six genes (ERGIC3, DDR1, HSP90B1, SDC1, RPSA, and LPCAT1) from the FSL were significantly up-regulated while two genes (GPX3 and TIMP3) from the RSL were significantly down-regulated (P < 0.05). The ERGIC3 protein was also over-expressed in lung cancer tissues and cultured cells, and expression of ERGIC3 was correlated with the differentiated degree and histological type of lung cancer. The up-regulation of ERGIC3 could promote cellular migration and proliferation in vitro. The

  10. Identifying candidate agents for lung adenocarcinoma by walking the human interactome

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    Sun Y

    2016-09-01

    Full Text Available Yajiao Sun,1 Ranran Zhang,2 Zhe Jiang,1 Rongyao Xia,1 Jingwen Zhang,1 Jing Liu,1 Fuhui Chen1 1Department of Respiratory, The Second Affiliated Hospital of Harbin Medical University, 2Department of Respiratory, Harbin First Hospital, Harbin, People’s Republic of China Abstract: Despite recent advances in therapeutic strategies for lung cancer, mortality is still increasing. Therefore, there is an urgent need to identify effective novel drugs. In the present study, we implement drug repositioning for lung adenocarcinoma (LUAD by a bioinformatics method followed by experimental validation. We first identified differentially expressed genes between LUAD tissues and nontumor tissues from RNA sequencing data obtained from The Cancer Genome Atlas database. Then, candidate small molecular drugs were ranked according to the effect of their targets on differentially expressed genes of LUAD by a random walk with restart algorithm in protein–protein interaction networks. Our method identified some potentially novel agents for LUAD besides those that had been previously reported (eg, hesperidin. Finally, we experimentally verified that atracurium, one of the potential agents, could induce A549 cells death in non-small-cell lung cancer-derived A549 cells by an MTT assay, acridine orange and ethidium bromide staining, and electron microscopy. Furthermore, Western blot assays demonstrated that atracurium upregulated the proapoptotic Bad and Bax proteins, downregulated the antiapoptotic p-Bad and Bcl-2 proteins, and enhanced caspase-3 activity. It could also reduce the expression of p53 and p21Cip1/Waf1 in A549 cells. In brief, the candidate agents identified by our approach may provide greater insights into improving the therapeutic status of LUAD. Keywords: lung adenocarcinoma, drug repositioning, bioinformatics, protein–protein interaction network, atracurium

  11. Clinicopathological and immunohistochemical features of lung invasive mucinous adenocarcinoma based on computed tomography findings

    Directory of Open Access Journals (Sweden)

    Shimizu K

    2016-12-01

    Full Text Available Katsuhiko Shimizu, Riki Okita, Shinsuke Saisho, Ai Maeda, Yuji Nojima, Masao Nakata Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Okayama, Japan Background: We performed an analysis to clarify differences in clinicopathological and molecular features of lung invasive mucinous adenocarcinoma (IMA based on computed tomography (CT findings and their impact on prognosis.Patients and methods: On the basis of CT findings, we divided lung IMA into three subtypes: solid, bubbling, and pneumonic. We then investigated differences in clinicopathological characteristics, prognosis, and the expressions of well-identified biomarkers, including cyclooxygenase-2 (Cox-2, excision repair cross-complementation group 1 (ERCC1, ribonucleotide reductase M1 (RRM1, class III beta-tubulin, thymidylate synthase (TS, secreted protein acidic and rich in cysteine (SPARC, programmed cell death-1 ligand-1 (PD-L1, and epidermal growth factor receptor mutation, among the three subtypes.Results: A total of 29 patients with resected lung IMA were analyzed. Compared with the solid or bubbling type, the pneumonic type had a higher proportion of symptoms, a larger tumor size, a higher pathological stage, and a significantly worse prognosis. The immunohistochemical findings tended to show high expression of RRM1, class III beta-tubulin, and Cox-2 in the tumor and of SPARC in the stroma, but not of ERCC1, TS, and PD-L1 in the tumor. None of the biomarkers with high expression levels in the tumor were prognostic biomarkers, but the expression of SPARC in the stroma was correlated with a poor outcome.Conclusion: Clinical and pathological features, in conjunction with molecular data, indicate that IMA should be divided into different subgroups. In our results, the pneumonic type was correlated with a significantly worse outcome. Further studies should be performed to confirm our conclusion and to explore its molecular implications. Keywords: non-small cell

  12. Erlotinib Versus Radiation Therapy for Brain Metastases in Patients With EGFR-Mutant Lung Adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Gerber, Naamit K.; Yamada, Yoshiya; Rimner, Andreas [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Shi, Weiji [Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Riely, Gregory J. [Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Beal, Kathryn [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Yu, Helena A. [Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Chan, Timothy A. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Zhang, Zhigang [Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Wu, Abraham J., E-mail: wua@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2014-06-01

    Purpose/Objectives: Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system, it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. Methods and Materials: Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. Results: 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole brain RT (WBRT), and 15 with stereotactic radiosurgery (SRS). The median overall survival (OS) for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median, 35 vs 26 months; P=.62), whereas patients treated with SRS had a longer OS than did those in the erlotinib group (median, 64 months; P=.004). The median time to intracranial progression was 17 months. There was a longer time to intracranial progression in patients who received WBRT than in those who received erlotinib upfront (median, 24 vs 16 months, P=.04). Patients in the erlotinib or SRS group were more likely to experience intracranial failure as a component of first failure, whereas WBRT patients were more likely to experience failure outside the brain (P=.004). Conclusions: The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison with a targeted biologic agent with known central nervous system activity.

  13. Radioimmunoimaging of nude mice bearing human lung adenocarcinoma xenografts after injecting 131I-McAbs

    International Nuclear Information System (INIS)

    Liu Liang

    1992-01-01

    Monoclonal antibodies (Lc86a-C5, Lc86a-H8) directed against human lung adenocarcinoma cell line LTEP-a-2 and normal BALB/c IgG were labelled with iodine-131 by chloramine T. The 131 I-McAbs and 131 I-IgG were respectively injected into the peritoneal cavities of nude mice bearing transplanted human lung adenocarcinoma cell line LTEP-a-2. After 72 h, the tumor tissue in nude mice injected with 131 I-McAbs was distinguishable from normal tissues as a very clear image obtained during gamma scintigraphy. No difference was found between tumor and normal tissues in the nude mice injected with 131 I-IgG. The tumor: blood ration was 3.1:1 in nude injected with 131 I McAb(H8) and 0.9:1 in nude mice injected with 131 I-IgG respectively. This indicates that the tumor tissue image was the result of specific binding of the 131 I-McAbs, which have high specificity and affinity both in vitro and in vivo, to tumor cells, and these monoclonal antibodies may serve as potential agents in tumor diagnosis and treatment

  14. Effect of repeated irradiation on biological characteristics of lung adenocarcinoma cell line Anip973 in vitro

    International Nuclear Information System (INIS)

    Xu Qingyong; Xu Xiangying; Yang Zhiwei

    2008-01-01

    Objective: To study the effect of repeated irradiation on biological characteristics of human lung adenocarcinoma cell line Anip973 in vitro. Methods: Anip973 cells were treated with high energy X-ray to a total dose of 60 Gy at 4 Gy fractions. The radiosensitivity of Anip973R and its parental cell were measured by clonogenic assay. The biological parameters were fitted to the single hit multitarget formula. Furthermore, the population double time(PDT) and cell cycle distribution were measured by cell growth curve and flow cytometry, respectively. Results: Comparing with its parental cell, Anip973 R acquired radioresistance showing increased D 0 , D q and SF 2 and a broader shoulder. PDT of Anip973R extended 3 h more than that of Anip973. The Anip973R also showed higher and lower percentage of cells in G 1 and S phase (P 2 /M distribution (P>0.05). Conclusions: A radioresistant lung adenocarcinoma cell line Anip973R is established by repeatedly irradiation. Its radioresistance displays obviously in lower dose area. However, its characteristic of cell cycle is not completely coincident with the classical radiobiological theory. (authors)

  15. Sesamol induced apoptotic effect in lung adenocarcinoma cells through both intrinsic and extrinsic pathways.

    Science.gov (United States)

    Siriwarin, Boondaree; Weerapreeyakul, Natthida

    2016-07-25

    Sesamol is a phenolic lignan found in sesame seeds (Sesamum indicum L.) and sesame oil. The anticancer effects and molecular mechanisms underlying its apoptosis-inducing effect were investigated in human lung adenocarcinoma (SK-LU-1) cells. Sesamol inhibited SK-LU-1 cell growth with an IC50 value of 2.7 mM and exhibited less toxicity toward normal Vero cells after 48 h of treatment (Selective index = 3). Apoptotic bodies-the hallmark of apoptosis-were observed in sesamol-treated SK-LU-1 cells, stained with DAPI. Sesamol increased the activity of caspase 8, 9, and 3/7, indicating that apoptotic cell death occurred through both extrinsic and intrinsic pathways. Sesamol caused the loss of mitochondrial transmembrane potential signifying intrinsic apoptosis induction. Decreasing Bid expression revealed crosstalk between the intrinsic and extrinsic apoptotic pathways; demonstrating clearly that sesamol induces apoptosis through both pathways in human lung adenocarcinoma (SK-LU-1) cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Comparative analysis of clinicoradiologic characteristics of lung adenocarcinomas with ALK rearrangements or EGFR mutations

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, J.Y.; Zheng, J.; Chen, X.; Zhou, J.Y. [Zhejiang University, Department of Respiratory Disease, Thoracic Disease Center, First Affiliated Hospital, College of Medicine, Hangzhou (China); Yu, Z.F.; Xiao, W.B.; Jiang, L.N. [Zhejiang University, Department of Radiology, First Affiliated Hospital, College of Medicine, Hangzhou (China); Zhao, J.; Sun, K.; Wang, B.; Ding, W. [Zhejiang University, Department of Pathology, First Affiliated Hospital, College of Medicine, Hangzhou (China)

    2015-05-01

    To compare the clinicoradiologic features of tumours with echinoderm anaplastic lymphoma kinase (ALK) rearrangements, epidermal growth factor receptor (EGFR) mutations, or wild type (WT) for both genes in a cohort of patients with lung adenocarcinoma to identify useful characteristics of different gene statuses. In 346 lung adenocarcinoma patients, ALK rearrangements were confirmed with fluorescence in situ hybridisation, and EGFR mutations were determined by pyrosequencing assay. Patients were divided into three groups: ALK rearrangement (ALK+ group, n = 48), EGFR mutation (EGFR+ group, n = 166), and WT for both genes (WT group, n = 132). Chest computed tomography (CT) examinations were performed in all patients. The percentages of ground-glass opacity volume (pGGO) and tumour shadow disappearance rate (TDR) were measured using semi-automated nodule assessment software. The pGGO was significantly lower in the ALK+ group (25.1 % ± 24.3) than in the EGFR+ group (37.2 % ± 25.7, p < 0.001) and the WT group (36.1 % ± 24.6, p = 0.001). The TDR in the ALK+ group (17.3 % ± 25.1) was significantly lower than in the EGFR+ group (26.8 % ± 24.9, p = 0.002) and the WT group (25.7 % ± 24.6, p = 0.003). Solid pattern with lower incidence of lobulated border, finely spiculated margins, pleural retraction, and bubble-like lucency on CT imaging are the main characteristics of ALK rearrangement tumours. (orig.)

  17. Quantitative image variables reflect the intratumoral pathologic heterogeneity of lung adenocarcinoma.

    Science.gov (United States)

    Choi, E-Ryung; Lee, Ho Yun; Jeong, Ji Yun; Choi, Yoon-La; Kim, Jhingook; Bae, Jungmin; Lee, Kyung Soo; Shim, Young Mog

    2016-10-11

    We aimed to compare quantitative radiomic parameters from dual-energy computed tomography (DECT) of lung adenocarcinoma and pathologic complexity.A total 89 tumors with clinical stage I/II lung adenocarcinoma were prospectively included. Fifty one radiomic features were assessed both from iodine images and non-contrast images of DECT datasets. Comprehensive histologic subtyping was evaluated with all surgically resected tumors. The degree of pathologic heterogeneity was assessed using pathologic index and the number of mixture histologic subtypes in a tumor. Radiomic parameters were correlated with pathologic index. Tumors were classified as three groups according to the number of mixture histologic subtypes and radiomic parameters were compared between the three groups.Tumor density and 50th through 97.5th percentile Hounsfield units (HU) of histogram on non-contrast images showed strong correlation with the pathologic heterogeneity. Radiomic parameters including 75th and 97.5th percentile HU of histogram, entropy, and inertia on 1-, 2- and 3 voxel distance on non-contrast images showed incremental changes while homogeneity showed detrimental change according to the number of mixture histologic subtypes (all Ps heterogeneity, which may help in the prediction of intratumoral heterogeneity of the whole tumor.

  18. Managed hypertensive crisis induced by bevacizumab in patient with metastatic lung adenocarcinoma

    International Nuclear Information System (INIS)

    Gracova, K.; Dolakova, L.

    2015-01-01

    Purpose and objective: The aim of the casuistry is to present a case report of a patient with metastatic lung adenocarcinoma and describe the successful management of hypertensive crisis, which is one of the most common cardiovascular complications of bevacizumab therapy. Casuistry: We describe 82-year old patient with lung adenocarcinoma verified by cytology of fluidothorax. Patient started chemotherapy in the scheme of carboplatin + paclitaxel with addition of bevacizumab since the third cycle. We provided a CT-scan which described partial tumour regression after six cycles of chemotherapy and four cycles of bevacizumab. Before the first cycle of maintenance therapy with bevacizumab patient overcame hypertensive crisis with neurological symptomatology which reacted positively to standard antihypertensives added to the therapy. After the stabilization we continued oncological treatment until disease progression and post chemotherapeutic ischemic colitis occurrence. Conclusion: Arterial hypertension is a common adverse effect of treatment with VEGF inhibitors. Considering the fact that the hypertension may occur at any time during the treatment with bevacizumab, blood pressure should be measured before, during and after the infusion. This side effect is reversible. On the basis of several case studies a positive association between arterial hypertension and prolonged survival in cancer patients has been found, as a difference from those without arterial hypertension during the treatment. Antihypertensive treatment does not reduce the antitumor effect of bevacizumab treatment. (author)

  19. Interstitial lung disease pattern turned out to be a predominantly lepidic lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Irena Hammen, Dr. Med

    2017-01-01

    Full Text Available We report a case of a 46-year-old woman without any medical history who presented to our Respiratory Department with exertional dyspnoea for the last 6 weeks associated with non-productive cough. Chest radiography showed bilateral diffuse interstitial opacity. Bronchoalveolar lavage and transbronchial biopsies performed during flexible bronchoscopy as a step in the diagnostic workup of idiopathic interstitial pneumonia showed cells of pulmonary adenocarcinoma.

  20. X-ray phase-contrast CT of a pancreatic ductal adenocarcinoma mouse model.

    Directory of Open Access Journals (Sweden)

    Arne Tapfer

    Full Text Available To explore the potential of grating-based x-ray phase-contrast computed tomography (CT for preclinical research, a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC was investigated. One ex-vivo mouse specimen was scanned with different grating-based phase-contrast CT imaging setups covering two different settings: i high-resolution synchrotron radiation (SR imaging and ii dose-reduced imaging using either synchrotron radiation or a conventional x-ray tube source. These experimental settings were chosen to assess the potential of phase-contrast imaging for two different types of application: i high-performance imaging for virtual microscopy applications and ii biomedical imaging with increased soft-tissue contrast for in-vivo applications. For validation and as a reference, histological slicing and magnetic resonance imaging (MRI were performed on the same mouse specimen. For each x-ray imaging setup, attenuation and phase-contrast images were compared visually with regard to contrast in general, and specifically concerning the recognizability of lesions and cancerous tissue. To quantitatively assess contrast, the contrast-to-noise ratios (CNR of selected regions of interest (ROI in the attenuation images and the phase images were analyzed and compared. It was found that both for virtual microscopy and for in-vivo applications, there is great potential for phase-contrast imaging: in the SR-based benchmarking data, fine details about tissue composition are accessible in the phase images and the visibility of solid tumor tissue under dose-reduced conditions is markedly superior in the phase images. The present study hence demonstrates improved diagnostic value with phase-contrast CT in a mouse model of a complex endogenous cancer, promoting the use and further development of grating-based phase-contrast CT for biomedical imaging applications.

  1. Fluorodeoxyglucose-positron emission tomography/computed tomography imaging features of colloid adenocarcinoma of the lung: a case report.

    Science.gov (United States)

    Wang, ZhenGuang; Yu, MingMing; Chen, YueHua; Kong, Yan

    2017-07-27

    Colloid adenocarcinoma of the lung is a rare subtype of variants of invasive adenocarcinomas. We report the appearance of this unusual entity on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. A 60-year-old man of Chinese Han nationality coughed with a little white sputum for 1 month. Chest computed tomography showed multiple bilateral subpleural nodules and plaques accompanied by air bronchograms, which were most concentrated in the lower lobe of his right lung. Positron emission tomography indicated increased radioactivity uptake with a maximum standardized uptake value of 3.5. Positron emission tomography/computed tomography showed a soft tissue density lesion in his left adrenal gland with a maximum standardized uptake value of 4.1. The positron emission tomography/computed tomography appearance suggested a primary colloid adenocarcinoma in the lower lobe of his right lung accompanied by intrapulmonary and left adrenal gland metastases. The diagnostic rate of colloid adenocarcinoma can be increased by combining the anatomic and metabolic information of lesions. The advantage of positron emission tomography/computed tomography in the diagnosis of colloid adenocarcinoma, as with other cancers, is the ability to locate extrapulmonary disease, facilitating clinical staging.

  2. A case of lung adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene

    International Nuclear Information System (INIS)

    Tanaka, Hisashi; Hayashi, Akihito; Morimoto, Takeshi; Taima, Kageaki; Tanaka, Yoshihito; Shimada, Michiko; Kurose, Akira; Takanashi, Shingo; Okumura, Ken

    2012-01-01

    Lung cancer is the leading cause of cancer-related death worldwide. Epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitor (TKI) is used for the patients with EGFR-mutant lung cancer. Recently, phase III studies in the patients with EGFR-mutant demonstrated that EGFR-TKI monotherapy improved progression-free survival compared with platinum-doublet chemotherapy. The echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion oncogene represents one of the newest molecular targets in non-small cell lung cancer (NSCLC). Patients who harbor EML4-ALK fusions have been associated with a lack of EGFR or KRAS mutations. We report a 39-year-old patient diagnosed as adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene. We treated this patient with erlotinib as the third line therapy, but no clinical benefit was obtained. We experienced a rare case with EGFR mutation and EML4-ALK. Any clinical benefit using EGFR-TKI was not obtained in our case. The therapeutic choice for the patients with more than one driver mutations is unclear. We needs further understanding of the lung cancer molecular biology and the biomarker infomation

  3. Difference in Postsurgical Prognostic Factors between Lung Adenocarcinoma and Squamous Cell Carcinoma

    Science.gov (United States)

    Sakai, Hiroki; Kimura, Hiroyuki; Miyazawa, Tomoyuki; Marushima, Hideki; Saji, Hisashi

    2017-01-01

    Purpose: The aim of this study was to compare the clinicopathologic prognostic factors between patients who underwent lung resection for adenocarcinoma (AD) and those with squamous cell carcinoma (SQ). Methods: A database of patients with lung AD or SQ who underwent surgery with curative intent in our department from January 2008 to December 2014 was reviewed. Associations between various clinicopathologic factors, postsurgical recurrence-free survival (RFS), and overall survival (OS) were analyzed to find significant prognostic factors. Results: A total of 537 lung cancer patients (AD, 434; SQ, 103) were included in this study. Although RFS was similar in patients with AD and SQ, OS was significantly poorer in those with SQ. Multivariate analysis in patients with AD revealed that age (≥69 vs. <69), lymphatic invasion, and histologic pleural invasion (p0 vs. p1–3) were associated with RFS, while gender and pleural invasion were associated with OS. In SQ, however, smoking, clinical stage, and pulmonary metastasis were associated with RFS in the multivariate analysis. Conclusion: Since significant postoperative prognostic factors are quite different between lung AD and SQ, these two histologic types should be differently analyzed in a clinical study. PMID:28966230

  4. Comparative Proteomic Analysis of Human Lung Adenocarcinoma Cisplatin-resistant Cell Strain A549/CDDP

    Directory of Open Access Journals (Sweden)

    Sien SHI

    2009-11-01

    Full Text Available Background and objective Chemotherapy plays an important role in the comprehensive therapy of lung cancer. However, the drug-resistance often causes the failure of the chemotherapy. The aim of this study is to identify differently expressed protein before and after cisplatin resistance of human lung adenocarcinoma cell A549 by proteomic analysis. Methods Cisplatin-resistant cell strain A549/CDDP was established by combining gradually increasing concentration of cisplatin with large dosage impact. Comparative proteomic analysis of A549 and A549/CDDP were carried out by means of two-dimensional gel electrophoresis. The differentially expressed proteins were detected and identified by MALDI-TOF mass spectrometry. Results Eighty-two differentially expressed proteins were screened by analysis the electrophoretic maps of A549 and A549/CDDP. Six differential proteins were analyzed by peptide mass fingerprinting. Glucose regulating protein 75, ribosomal protein S4, mitochondrial ATP synthase F1 complex beta subunit and immunoglobulin heavy chain variable region were identified. All four differentially expressed proteins were over-expressed in A549/CDDP, whereas low-expressed or no-expressed in A549. Conclusion These differentially expressed proteins give some clues to elucidate the mechanism of lung cancer cell resistant of cisplatin, providing the basis of searching for potential target of chemotherapy of lung cancer.

  5. Divergent epidermal growth factor receptor mutation patterns between smokers and non-smokers with lung adenocarcinoma.

    Science.gov (United States)

    Tseng, Jeng-Sen; Wang, Chih-Liang; Yang, Tsung-Ying; Chen, Chih-Yi; Yang, Cheng-Ta; Chen, Kun-Chieh; Hsu, Kuo-Hsuan; Tsai, Chi-Ren; Chang, Gee-Chen

    2015-12-01

    Smoking status is an important determinant of the prevalence of epidermal growth factor receptor (EGFR) mutations in lung cancer patients. However, it is unclear whether smoking status could also influence the spectrum of EGFR mutations. We enrolled patients with lung adenocarcinoma from three medical centers in Taiwan. EGFR mutations were assessed by Sanger direct sequencing. The objective of this study was to evaluate the influence of smoking status on both the frequency and patterns of EGFR mutations. From 2001 to 2013, a total of 1175 patients with lung adenocarcinoma were enrolled for EGFR mutation analysis. The overall EGFR mutation rate was 59.6%, which was significantly higher in females than males (69.1% vs. 49.8%) and in non-smokers than current/former smokers (73.8% vs. 29.8%) (both Psmokers expressed L858R mutation less frequently (35.2% vs. 50.2%, P=0.005) and exon 19 deletions more frequently (52.8% vs 38.8%, P=0.008) than non-smokers. Smokers and non-smokers also had divergent exon 19 deletions subtypes (Del E746-A750 82.5% vs. 57.6%, respectively, Psmokers were associated with a higher rate of complex mutations than non-smokers (34.2% vs. 8.4%, P<0.001). Our results suggested that smoking status could influence not only the frequency but also the spectrum of EGFR mutations. These findings provide a clue for further investigation of EGFR mutagenesis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  6. Sulforaphane-induced apoptosis in Xuanwei lung adenocarcinoma cell line XWLC-05.

    Science.gov (United States)

    Zhou, Lan; Yao, Qian; Li, Yan; Huang, Yun-Chao; Jiang, Hua; Wang, Chuan-Qiong; Fan, Lei

    2017-01-01

    Xuanwei district in Yunnan Province has the highest incidence of lung cancer in China, especially among non-smoking women. Cruciferous vegetables can reduce lung cancer risk by prompting a protective mechanism against respiratory tract inflammation caused by air pollution, and are rich in sulforaphane, which can induce changes in gene expression. We investigated the effect of sulforaphane-induced apoptosis in Xuanwei lung adenocarcinoma cell line (XWCL-05) to explore the value of sulforaphane in lung cancer prevention and treatment. Cell growth inhibition was determined by methyl thiazolyl tetrazolium assay; cell morphology and apoptosis were observed under transmission electron microscope; cell cycle and apoptosis rates were detected using flow cytometry; B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax) messenger RNA expression were determined by quantitative PCR; and p53, p73, p53 upregulated modulator of apoptosis (PUMA), Bax, Bcl-2, and caspase-9 protein expression were detected by Western blotting. Sulforaphane inhibited XWLC-05 cell growth with inhibitory concentration (IC) 50 of 4.04, 3.38, and 3.02 μg/mL at 24, 48, and 72 hours, respectively. Sulforaphane affected the XWLC-05 cell cycle as cells accumulated in the G2/M phase. The proportion of apoptotic cells observed was 27.6%. Compared with the control, the sulforaphane group showed decreased Bcl-2 and p53 expression, and significantly increased p73, PUMA, Bax, and caspase-9 protein expression (P cell apoptosis. Its possible mechanism may involve the upregulation of p73 expression and its effector target genes PUMA and Bax in lung cancer cells, downregulation of the anti-apoptotic gene B cl -2, and activation of caspase-9. It may also involve downregulation of the mutant p53 protein. © 2016 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  7. Erlotinib treatment in patients with advanced lung adenocarcinoma with CISH-positive and CISH-negative EGFR gene alterations.

    Science.gov (United States)

    Hou, Ming-Mo; Huang, Shiu-Feng; Kuo, Han-Pin; Yang, Cheng-Ta; Tsai, Ying-Huang; Yu, Chih-Teng; Lin, Horng-Chyuan; Chen, Chih-Hung; Wang, Chih-Liang; Chung, Fu-Tsai; Hsieh, Jia-Juan; Hsu, Todd; Cheng, Hsin-Yi; Ou, Li-Ying; Wang, Hung-Ming; Lin, Yung-Chang; Chang, Nai-Jen; Chang, John Wen-Cheng

    2012-03-01

    Epidermal growth factor receptor (EGFR) positivity as assessed by chromogenic in situ hybridization (CISH) has been demonstrated to be associated with EGFR mutation status. This study was conducted to compare the responsiveness of CISH-positive and CISH-negative lung adenocarcinomas to erlotinib. Patients received erlotinib (150 mg/day) alone until disease progression or intolerable toxicity. EGFR gene status was examined by CISH. The response rate (RR), progression-free survival (PFS), overall survival (OS) and toxicity profiles were assessed. Thirty-one patients underwent response evaluations and CISH analyses, 12 of whom harboured CISH-positive adenocarcinomas. The overall RR (p=0.035), median PFS (p=0.091) and median OS (p=0.408) were higher in the CISH-positive group. No difference in toxicity profiles was observed between these two groups. EGFR status as assessed by CISH can predict the response to erlotinib in patients with advanced lung adenocarcinoma.

  8. Overexpression of the p53 tumor suppressor gene product in primary lung adenocarcinomas is associated with cigarette smoking

    NARCIS (Netherlands)

    Westra, W. H.; Offerhaus, G. J.; Goodman, S. N.; Slebos, R. J.; Polak, M.; Baas, I. O.; Rodenhuis, S.; Hruban, R. H.

    1993-01-01

    Mutations in the p53 tumor suppressor gene are frequently observed in primary lung adenocarcinomas, suggesting that these mutations are critical events in the malignant transformation of airway cells. These mutations are often associated with stabilization of the p53 gene product, resulting in the

  9. Next-generation sequencing for molecular diagnosis of lung adenocarcinoma specimens obtained by fine needle aspiration cytology

    Science.gov (United States)

    Qiu, Tian; Guo, Huiqin; Zhao, Huan; Wang, Luhua; Zhang, Zhihui

    2015-06-01

    Identification of multi-gene variations has led to the development of new targeted therapies in lung adenocarcinoma patients, and identification of an appropriate patient population with a reliable screening method is the key to the overall success of tumor targeted therapies. In this study, we used the Ion Torrent next-generation sequencing (NGS) technique to screen for mutations in 89 cases of lung adenocarcinoma metastatic lymph node specimens obtained by fine-needle aspiration cytology (FNAC). Of the 89 specimens, 30 (34%) were found to harbor epidermal growth factor receptor (EGFR) kinase domain mutations. Seven (8%) samples harbored KRAS mutations, and three (3%) samples had BRAF mutations involving exon 11 (G469A) and exon 15 (V600E). Eight (9%) samples harbored PIK3CA mutations. One (1%) sample had a HRAS G12C mutation. Thirty-two (36%) samples (36%) harbored TP53 mutations. Other genes including APC, ATM, MET, PTPN11, GNAS, HRAS, RB1, SMAD4 and STK11 were found each in one case. Our study has demonstrated that NGS using the Ion Torrent technology is a useful tool for gene mutation screening in lung adenocarcinoma metastatic lymph node specimens obtained by FNAC, and may promote the development of new targeted therapies in lung adenocarcinoma patients.

  10. Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer of adenocarcinoma histology

    DEFF Research Database (Denmark)

    Popat, Sanjay; Mellemgaard, Anders; Reck, Martin

    2017-01-01

    PATIENTS & METHODS: We provide an update to a network meta-analysis evaluating the relative efficacy of nintedanib + docetaxel versus other second-line agents in adenocarcinoma histology non-small-cell lung cancer. RESULTS: Overall similarity of nintedanib + docetaxel versus ramucirumab + docetaxel...

  11. Influence of thorax irradiation on the survival of mice with spontaneous or artificial lung metastases from a transplantable mammary adenocarcinoma

    International Nuclear Information System (INIS)

    Wondergem, J.; Haveman, J.; van der Schueren, E.

    1985-01-01

    The effect of thorax irradiation on lung metastases, either occurring spontaneously from a primary mammary adenocarcinoma (M8013X) transplanted on the leg or artificially induced by intravenous injection of tumor cells was studied. Increasing the interval between the moment at which lung metastases are supposed to originate and the thorax irradiation resulted in a rapid decrease of the effectiveness of this treatment in preventing the development of lung metastases. Increasing the radiation dose led to an increased number of cures; however, an increased number of mice dying of lethal lung damage was also observed. Irradiation of the lungs of mice with 5 or 10 Gy, 24 hours, 7 days or 14 days prior to i.v. injection with tumor cells, did not significantly increase the number of mice with lung metastases. Immunological resistance against the tumor played a role in our experiments with both spontaneous and artificial lung metastases

  12. A new receptor tyrosine kinase inhibitor, icotinib, for patients with lung adenocarcinoma cancer without indication for chemotherapy.

    Science.gov (United States)

    Zheng, Xiao; Liu, Guan; Wang, Shengye; Zhang, Yunli; Bao, Wenlong; Deng, Dehou; Mao, Weiming; Fang, Meiyu

    2014-10-01

    Epidermal growth factor receptor (EGFR) is an important therapeutic target in lung cancer. Gefitinib and erlotinib, two reversible EGFR receptor tyrosine kinases inhibitors (TKIs), have been approved for the treatment of patients with metastatic non small-cell lung cancer. Icotinib, which is a selective EGFR-TKI, provides a similar efficacy to gefitinib. The present study aimed to investigate the survival and safety of icotinib in patients with lung adenocarcinoma with a poor performance status (PS). A total of 42 cases of lung adenocarcinoma, including 35 females and 7 males, were enrolled. Icotinib was used as the first-line of treatment due to poor PS of the patient or a more advanced age. Icotinib (125 mg) was orally administered three times per day. The overall response rate and disease control rates were 33.3 and 85.7%, respectively. The median survival time was 13.0 months (95% CI, 5.6-20.4), The median progression-free survival time was 7.0 months, and the 1-year survival rate was 71.4%. A total of 79% of patients had an improved PS following icotinib treatment. Grade 1 to 2 rashes and diarrhea were the most frequent side effects. One patient succumbed during the study due to interstitial pneumonia. In conclusion, this is the first study indicating that patients with lung adenocarcinoma and poor PS may benefit from first-line icotinib therapy, but should be cautious of the occurrence of interstitial lung disease.

  13. Fisetin, a dietary phytochemical, overcomes Erlotinib-resistance of lung adenocarcinoma cells through inhibition of MAPK and AKT pathways.

    Science.gov (United States)

    Zhang, Liang; Huang, Yi; Zhuo, Wenlei; Zhu, Yi; Zhu, Bo; Chen, Zhengtang

    2016-01-01

    Erlotinib (Tarceva) is a selective epidermal growth factor receptor tyrosine kinase inhibitor for treatment of non-small cell lung cancer (NSCLC). However, its efficacy is usually reduced by the occurrence of drug resistance. Our recent study showed that a flavonoid found in many plants, Fisetin, might have a potential to reverse the acquired Cisplatin-resistance of lung adenocarcinoma. In the present study, we aimed to test whether Fisetin could have the ability to reverse Erlotinib-resistance of lung cancer cells. Erlotinib-resistant lung adenocarcinoma cells, HCC827-ER, were cultured from the cell line HCC827, and the effects of Fisetin and Erlotinib on the cell viability and apoptosis were evaluated. The possible signaling pathways in this process were also detected. As expected, the results showed that Fisetin effectively increased sensitivity of Erlotinib-resistant lung cancer cells to Erlotinib, possibly by inhibiting aberrant activation of MAPK and AKT signaling pathways resulted from AXL suppression. In conclusion, Fisetin was a potential agent for reversing acquired Erlotinib-resistance of lung adenocarcinoma. Inactivation of AXL, MAPK and AKT pathways might play a partial role in this process.

  14. Lung regeneration by fetal lung tissue implantation in a mouse pulmonary emphysema model.

    Science.gov (United States)

    Uyama, Koh; Sakiyama, Shoji; Yoshida, Mitsuteru; Kenzaki, Koichiro; Toba, Hiroaki; Kawakami, Yukikiyo; Okumura, Kazumasa; Takizawa, Hiromitsu; Kondo, Kazuya; Tangoku, Akira

    2016-01-01

    The mortality and morbidity of chronic obstructive pulmonary disease are high. However, no radical therapy has been developed to date. The purpose of this study was to evaluate whether fetal mouse lung tissue can grow and differentiate in the emphysematous lung. Fetal lung tissue from green fluorescent protein C57BL/6 mice at 16 days' gestation was used as donor material. Twelve-month-old pallid mice were used as recipients. Donor lungs were cut into small pieces and implanted into the recipient left lung by performing thoracotomy under anesthesia. The recipient mice were sacrificed at day 7, 14, and 28 after implantation and used for histological examination. Well-developed spontaneous pulmonary emphysema was seen in 12-month-old pallid mice. Smooth and continuous connection between implanted fetal lung tissue and recipient lung was recognized. Air space expansion and donor tissue differentiation were observed over time. We could clearly distinguish the border zones between injected tissue and native tissue by the green fluorescence of grafts. Fetal mouse lung fragments survived and differentiated in the emphysematous lung of pallid mice. Implantation of fetal lung tissue in pallid mice might lead to further lung regeneration research from the perspective of respiratory and exercise function. J. Med. Invest. 63: 182-186, August, 2016.

  15. The benefit of cisplatin-based polychemotherapy for adenocarcinoma of the lung. The Kyushu Lung Cancer Chemotherapy Study Group.

    Science.gov (United States)

    Hara, N; Ohta, M; Ichikawa, Y; Kanda, T; Shima, K; Tamura, K; Hokama, M

    1990-01-01

    We studied the efficacy of cisplatin-based polychemotherapy for adenocarcinoma of the lung. A total of 136 patients were randomized for treatment with either cyclophosphamide, Adriamycin, cisplatin and mitomycin C (CAPM) or mitomycin C, cytosine arabinoside and tegafur (MCT). Radiation was given to the chests of patients at stage III. The differences in the response rate (35% in the CAPM arm and 13% in the MCT arm) were statistically significant (P less than 0.01). However, the significant difference was observed in stage-IV patients (CAPM, 33%; MCT, 4%; P less than 0.001) and not in stage-III patients (CAPM, 40%; MCT, 40%). The median period of survival was 9.5 months for the CAPM arm and 5.5 months for the MCT arm (P less than 0.035, Wilcoxon-Gehan test; P less than 0.1, log-rank test). Improved median survival for the CAPM regimen was demonstrated only by stage-IV patients (CAPM, 10 months; MCT, 5.5 months; P less than 0.025, Wilcoxon-Gehan test; P less than 0.05, log-rank test). The duration of the response, including PRs and NCs, was significantly different depending on the treatment, showing 5 months for the CAPM arm and 3 months for the MCT arm (P less than 0.05). The significant difference was also only observed in stage-IV patients. Myelosuppression was more severe with CAPM than with the MCT regimen. Nausea and vomiting were significantly increased in patients receiving the CAPM regimen. However, all toxicities were acceptable and there were no treatment-related deaths. We concluded that cisplatin-based chemotherapy, CAPM therapy, was of more benefit to patients with adenocarcinoma of the lung than MCT therapy.

  16. Development of Mouse Lung Deposition Models

    Science.gov (United States)

    2015-07-01

    foot-pound-force gallon (U.S. liquid ) inch jerk joule/kilogram (J/kg) radiation dose absorbed kilotons kip (1000 lbf) kip/inch (ksi...AND PHYSIOLOGY PARAMETERS Lung ventilation is driven by the difference in pressure between the pleural space and the outside environment. The... pleural pressure 8 variation. However, lung expansion and contraction is uniform in rodents because rodents are typically positioned horizontally

  17. WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma.

    Science.gov (United States)

    Shinmura, Kazuya; Kato, Hisami; Kawanishi, Yuichi; Igarashi, Hisaki; Inoue, Yusuke; Yoshimura, Katsuhiro; Nakamura, Satoki; Fujita, Hidehiko; Funai, Kazuhito; Tanahashi, Masayuki; Niwa, Hiroshi; Ogawa, Hiroshi; Sugimura, Haruhiko

    2017-08-01

    Human WDR62, which is localized in the cytoplasm including the centrosome, is known to be responsible for primary microcephaly; however, the role of WDR62 abnormality in cancers remains largely unknown. In this study, we aimed to reveal the pathological role of WDR62 abnormality in lung adenocarcinoma (LAC). We first examined the WDR62 mRNA expression level of LAC (n = 64) using a QRT-PCR analysis and found that WDR62 mRNA transcripts were significantly overexpressed in LAC (P = 0.0432, Wilcoxon matched pairs test). An immunohistochemical analysis for LAC (n = 237) showed that WDR62 proteins were also significantly overexpressed in LAC (P overexpression have a short overall survival (P = 0.0378, log-rank test), and a multivariate analysis revealed that WDR62 overexpression was an independent predictor of a poor survival outcome among LAC patients (hazard ratio, 2.032; 95% confidence interval, 1.071-3.777; P = 0.0305). Next, we examined the functional effect of WDR62 overexpression on the lung cancer cell line H1299. WDR62-overexpressing lung cancer cells exhibited an increase in cell growth. Moreover, the concurrent overexpression of WDR62 and TPX2, a WDR62-interacting protein that is also overexpressed in LAC, induced centrosome amplification in the lung cells. Finally, we disclosed that the concurrent overexpression of WDR62 and TPX2 is common in diverse human cancers, using data from the Cancer Genome Atlas. These results suggested that WDR62 overexpression is associated with a poor prognosis in patients with LAC and leads to an increase in the malignant potential of lung cells. © 2017 Wiley Periodicals, Inc.

  18. High Frequency of Programmed Death-ligand 1 Expression in Emphysematous Bullae-associated Lung Adenocarcinomas.

    Science.gov (United States)

    Toyokawa, Gouji; Takada, Kazuki; Okamoto, Tatsuro; Kozuma, Yuka; Matsubara, Taichi; Haratake, Naoki; Takamori, Shinkichi; Akamine, Takaki; Katsura, Masakazu; Shoji, Fumihiro; Oda, Yoshinao; Maehara, Yoshihiko

    2017-09-01

    Emphysematous bullae (EB) are known to be associated with a high incidence of lung cancer; however, the reason for this has yet to be elucidated. The objective of the present study was to clarify the prevalence of programmed death-ligand-1 (PD-L1) expression in EB-associated lung adenocarcinomas. A total of 369 patients with resected lung adenocarcinoma whose preoperative computed tomography findings were available for the examination of EB were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and EB-related adenocarcinomas. Among 369 patients, EB and cancer adjoining EB (Ca-ADJ) were identified in 81 (22.0%) and 50 (13.6%) patients, respectively. EB and Ca-ADJ were significantly associated with male gender, a smoking habit, a decreased forced expiratory volume in 1 second, a relatively higher tumor grade, advanced T status and stage, the presence of pleural and vessel invasion, invasive pathologic subtypes, and wild-type epidermal growth factor receptor. Seventy patients (19.0%) were positive for PD-L1 expression, whereas the remaining 299 patients (81.0%) were negative. Thirty-six (44.4%) and 29 (58.0%) of 81 and 50 patients with EB and Ca-ADJ, respectively, were positive for PD-L1 expression, which was shown to be significant by the Fisher exact test (P < .001 and P < .001, respectively). Among the 81 lung adenocarcinomas with EB, Ca-ADJ was significantly associated with PD-L1 expression (P = .021). In a multivariate analysis, the presence of Ca-ADJ was found to be an independent predictor of PD-L1 expression. EB-associated lung adenocarcinomas express PD-L1 protein more frequently than those without EB. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Sequentially administrated of pemetrexed with icotinib/erlotinib in lung adenocarcinoma cell lines in vitro.

    Science.gov (United States)

    Feng, Xiuli; Zhang, Yan; Li, Tao; Li, Yu

    2017-12-26

    Combination of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved to be a potent anti-drug for the treatment of tumors. However, survival time was not extended for the patients with lung adenocarcinoma (AdC) compared with first-line chemotherapy. In the present study, we attempt to assess the optimal schedule of the combined administration of pemetrexed and icotinib/erlotinib in AdC cell lines. Human lung AdC cell lines with wild-type (A549), EGFR T790M (H1975) and activating EGFR mutation (HCC827) were applied in vitro to assess the differential efficacy of various sequential regimens on cell viability, cell apoptosis and cell cycle distribution. The results suggested that the antiproliferative effect of the sequence of pemetrexed followed by icotinib/erlotinib was more effective than that of icotinib/erlotinib followed by pemetrexed. Additionally, a reduction of G1 phase and increased S phase in sequence of pemetrexed followed by icotinib/erlotinib was also observed, promoting cell apoptosis. Thus, the sequential administration of pemetrexed followed by icotinib/erlotinib exerted a synergistic effect on HCC827 and H1975 cell lines compared with the reverse sequence. The sequential treatment of pemetrexed followed by icotinib/erlotinib has been demonstrated promising results. This treatment strategy warrants further confirmation in patients with advanced lung AdC.

  20. Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma.

    Science.gov (United States)

    Sivakumar, Smruthy; Lucas, F Anthony San; McDowell, Tina L; Lang, Wenhua; Xu, Li; Fujimoto, Junya; Zhang, Jianjun; Futreal, P Andrew; Fukuoka, Junya; Yatabe, Yasushi; Dubinett, Steven M; Spira, Avrum E; Fowler, Jerry; Hawk, Ernest T; Wistuba, Ignacio I; Scheet, Paul; Kadara, Humam

    2017-11-15

    There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic BRAF variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in AAHs from 4 of 22 (18%) of patients. KRAS mutations in AAH were only found in ever-smokers and were exclusive to BRAF -mutant cases. Integrative analysis revealed profiles expressed in KRAS -mutant cases ( UBE2C, REL ) and BRAF -mutant cases ( MAX ) of AAH, or common to both sets of cases (suppressed AXL ). Gene sets associated with suppressed antitumor (Th1; IL12A, GZMB ) and elevated protumor ( CCR2, CTLA-4 ) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. Cancer Res; 77(22); 6119-30. ©2017 AACR . ©2017 American Association for Cancer Research.

  1. Paraneoplastic Seronegative Pauci-Immune Glomerulonephritis Associated with Lung Adenocarcinoma Responds to Rituximab: A Case Report

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    Pragnan Kancharla

    2018-06-01

    Full Text Available Anti-neutrophil cytoplasmic antibodies (ANCA play an important role in the pathogenesis of pauci-immune renal vasculitis. However, in 10% of the cases, ANCA are absent. We present a case of a 64-year-old man with a chronic untreated hepatitis C virus infection and Middle Eastern thalassemia who was ANCA-negative when he was hospitalized due to acute kidney injury and accounts for an uncommon presentation of renal vasculitis. The patient had earlier reported to have undergone local lobectomy and adjuvant chemotherapy (carboplatin/pemetrexed for lung adenocarcinoma a month prior. IL-6 has been reported to be involved in the pathophysiological cascade causing pauci-immune glomerulonephritis amongst non-small cell lung cancer patients. Previous studies with subgroup analysis have demonstrated that ANCA negativity has been associated with more chronic glomerular lesions and less crescent formation, which tends to have a critical outcome in the renal system. However, our patient underwent kidney biopsy exhibiting active crescentic glomerulonephritis, pauci-immune type with 5 cellular crescents amongst 15 glomeruli. To our knowledge, this is the third reported case of ANCA-negative vasculitis with typical presentation on biopsy in non-small cell lung cancer patients.

  2. Effect of radiation on the expression of tumor-associated antigens of human lung adenocarcinoma cells

    International Nuclear Information System (INIS)

    Hareyama, Masato

    1988-01-01

    We studied the effects of irradiation on the expression of a tumor-associated antigen (YH206 antigen) of cultured human lung adenocarcinoma A549 cells by using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. YH206 antigen is preferentially expressed on adenocarcinoma cells. Irradiation of A549 cells remarkably increased the expression of YH206 antigen on the cell surface and the level of the antigen in the culture supernatant as well as in the cell lysate, whereas it significantly affected the expression of HLA (MHC-class I) antigen on the same cells. The expression of HLA antigen on the cell was also increased after treatment of the cells with interferon-γ. In an additional experiment, cells were stained simultaneously for surface antigens (fluorescein coupled antibodies) and for DNA content (propidium iodide), and then dual parameter measurements were performed by flow cytometry to analyse the relationship between antigen levels and the cell cycle. YH206 antigen and HLA antigen increased more in the S and G 2 /M phases of the cell cycle than in G 0 /G 1 . The expression of YH206 antigen was enhanced in the S and G 2 /M phases by irradiation, whereas the expression of HLA antigen was enhanced in each phase of the cell cycle with irradiation or IFN. These results suggest that irradiation plays a key role in the change of the expression of certain tumor-associated antigens. (author)

  3. Imaging Characteristics in ALK Fusion-Positive Lung Adenocarcinomas by Using HRCT

    Science.gov (United States)

    Okumura, Sakae; Kuroda, Hiroaki; Uehara, Hirofumi; Mun, Mingyon; Takeuchi, Kengo; Nakagawa, Ken

    2014-01-01

    Objectives: We aimed to identify high-resolution computed tomography (HRCT) features useful to distinguish the anaplastic lymphoma kinase gene (ALK) fusion-positive and negative lung adenocarcinomas. Methods: We included 236 surgically resected adenocarcinoma lesions, which included 27 consecutive ALK fusion-positive (AP) lesions, 115 epidermal growth factor receptor mutation-positive lesions, and 94 double-negative lesions. HRCT parameters including size, air bronchograms, pleural indentation, spiculation, and tumor disappearance rate (TDR) were compared. In addition, prevalence of small lesions (≤20 mm) and solid lesions (TDR ≤20%) were compared. Results: AP lesions were significantly smaller and had lower TDR (%) than ALK fusion-negative (AN) lesions (tumor diameter: 20.7 mm ± 14.1 mm vs. 27.4 mm ± 13.8 mm, respectively, p 20 mm (n = 7, 25.9%) showed a solid pattern. Among all small lesions, AP lesions had lower TDR and more frequent spiculation than AN lesions (p 20 mm lesions may be ALK fusion-negative. PMID:24899136

  4. Antimigratory Effects of the Methanol Extract from Momordica charantia on Human Lung Adenocarcinoma CL1 Cells

    Directory of Open Access Journals (Sweden)

    Hsue-Yin Hsu

    2012-01-01

    Full Text Available Momordica charantia has been found to exhibit anticancer activity, in addition to its well-known therapeutic functions. We have demonstrated that the leaf extract of Momordica charantia (MCME induces apoptosis in several human cancer cells through caspase- and mitochondria-dependent pathways. In this study, a different susceptibility to MCME was found in human lung adenocarcinoma CL1 cells with different metastatic ability, leading to the significant difference of cell viability and invasiveness between MCME-treated CL1-0 and CL1-5 cells. MCME was found to upregulate the expression of Wnt-2 and affect the migratory and invasive ability of CL1 cells through suppressed MMP-2 and MMP-9 enzymatic activities. We proposed that MCME mediates inhibition against migration of CL1 cells by reducing the expression and activation of Src and FAK to decrease the expression of downstream Akt, β-catenin, and MMPs.

  5. Change from lung adenocarcinoma to small cell lung cancer as a mechanism of resistance to afatinib.

    Science.gov (United States)

    Manca, Paolo; Russano, Marco; Pantano, Francesco; Tonini, Giuseppe; Santini, Daniele

    2017-08-29

    We report the case of a patient affected by advanced EGFR mutation-positive lung who experienced resistance to therapy during treatment with Afatinib through the occurrence of a switch of tumor histotype to small cell lung cancer (SCLC) with features of a G3 neuroendocrine carcinoma. Unexpectedly, the switch to SCLC histotype occurred in the only site not responsive to afatinib and subsequently the most responsive to chemotherapy. Our case shows that occurrence of switch to SCLC is a possible mechanism of resistance during treatment with Afatinib.

  6. Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1

    Science.gov (United States)

    Pirazzoli, Valentina; Nebhan, Caroline; Song, Xiaoling; Wurtz, Anna; Walther, Zenta; Cai, Guoping; Zhao, Zhongming; Jia, Peilin; de Stanchina, Elisa; Shapiro, Erik M.; Gale, Molly; Yin, Ruonan; Horn, Leora; Carbone, David P.; Stephens, Philip J; Miller, Vincent; Gettinger, Scott; Pao, William; Politi, Katerina

    2014-01-01

    SUMMARY Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation TKIs develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. Addition of rapamycin reversed resistance in vivo. Analysis of afatinib+cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib+cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs. PMID:24813888

  7. Long noncoding RNA TUG1 is a diagnostic factor in lung adenocarcinoma and suppresses apoptosis via epigenetic silencing of BAX

    OpenAIRE

    Liu, Huan; Zhou, Guizhi; Fu, Xin; Cui, Haiyan; Pu, Guangrui; Xiao, Yao; Sun, Wei; Dong, Xinhua; Zhang, Libin; Cao, Sijia; Li, Guiqin; Wu, Xiaowei; Yang, Xu

    2017-01-01

    Lung cancer is one of the leading causes of cancer-related mortality, and responds badly to existing treatment. Thus, it is of urgent need to identify novel diagnostic markers and therapeutic targets. Increasing evidences have indicated that long non-coding RNAs (lncRNAs) play an important role in initiation and progression of lung cancer. However, the role of lncRNA Taurine upregulated 1 (TUG1) in lung adenocarcinoma (LAD) progression is not well known. In this study, we determined the diagn...

  8. Response to crizotinib in a lung adenocarcinoma patient harboring a novel SLC34A2-ROS1 fusion variant

    Science.gov (United States)

    Zhao, Zheng; Song, Zhangjun; Wang, Xuwei; Sun, Haifeng; Yang, Xiaomin; Yuan, Yong; Yu, Pan

    2017-01-01

    ROS1 fusion is a common genetic alteration in non-small-cell lung cancer. Crizotinib, an anaplastic lymphoma kinase inhibitor, shows efficacy in the treatment of lung cancer cases with ROS1 translocation. We report the response to crizotinib of a lung adenocarcinoma patient harboring a novel SLC34A2-ROS1 fusion variant, which was different from the two common SLC34A2-ROS1 fusion types reported in the literature. After crizotinib administration, overall recovery was good in this patient; the primary lesion was successfully treated, the lymph node metastases had disappeared, and the metabolism was normal. PMID:28860822

  9. Podoplanin expression in cancer-associated fibroblasts predicts unfavourable prognosis in patients with pathological stage IA lung adenocarcinoma.

    Science.gov (United States)

    Kubouchi, Yasuaki; Yurugi, Yohei; Wakahara, Makoto; Sakabe, Tomohiko; Haruki, Tomohiro; Nosaka, Kanae; Miwa, Ken; Araki, Kunio; Taniguchi, Yuji; Shiomi, Tatsushi; Nakamura, Hiroshige; Umekita, Yoshihisa

    2018-02-01

    Podoplanin expression in cancer-associated fibroblasts (CAFs) has been proposed as an unfavourable indicator in squamous cell carcinoma of the lung, but little is known about its clinical significance in early-stage lung adenocarcinoma. We evaluated the prognostic impact of podoplanin expression in patients with pathological stage (p-stage) IA lung adenocarcinoma as categorised by the 8th edition of the tumour-node-metastasis classification for lung cancer. Immunohistochemical analyses using anti-podoplanin antibody were performed on resected specimens from 158 patients with p-stage IA lung adenocarcinoma. When more than 10% of cancer cells or CAFs showed immunoreactivity with podoplanin, the specimens were classified as podoplanin-positive. Podoplanin-positive status in cancer cells (n = 8) was not correlated with clinicopathological factors or with patient prognosis. Podoplanin-positive status in CAFs (n = 41) was correlated significantly with poorer tumour differentiation (P < 0.001), the presence of lymphatic invasion (P < 0.001) and high-grade (solid and/or micropapillary) components constituting ≥1% of the entire tumour (P < 0.001). The log-rank test showed that podoplanin-positive status in CAFs was associated significantly with shorter disease-free survival (DFS) (P < 0.001) and disease-specific survival (P = 0.015). In Cox's multivariate analysis, podoplanin-positive status in CAFs had the most significant effect on shorter DFS [hazard ratio (HR) = 4.411, P = 0.004], followed by the presence of high-grade components (HR = 3.581, P = 0.013). Podoplanin expression in CAFs could be an independent predictor of increased risk of recurrence in patients with p-stage IA lung adenocarcinoma. © 2017 John Wiley & Sons Ltd.

  10. Using Dual Fluorescence Reporting Genes to Establish an In Vivo Imaging Model of Orthotopic Lung Adenocarcinoma in Mice.

    Science.gov (United States)

    Lai, Cheng-Wei; Chen, Hsiao-Ling; Yen, Chih-Ching; Wang, Jiun-Long; Yang, Shang-Hsun; Chen, Chuan-Mu

    2016-12-01

    Lung adenocarcinoma is characterized by a poor prognosis and high mortality worldwide. In this study, we purposed to use the live imaging techniques and a reporter gene that generates highly penetrative near-infrared (NIR) fluorescence to establish a preclinical animal model that allows in vivo monitoring of lung cancer development and provides a non-invasive tool for the research on lung cancer pathogenesis and therapeutic efficacy. A human lung adenocarcinoma cell line (A549), which stably expressed the dual fluorescence reporting gene (pCAG-iRFP-2A-Venus), was used to generate subcutaneous or orthotopic lung cancer in nude mice. Cancer development was evaluated by live imaging via the NIR fluorescent signals from iRFP, and the signals were verified ex vivo by the green fluorescence of Venus from the gross lung. The tumor-bearing mice received miR-16 nucleic acid therapy by intranasal administration to demonstrate therapeutic efficacy in this live imaging system. For the subcutaneous xenografts, the detection of iRFP fluorescent signals revealed delicate changes occurring during tumor growth that are not distinguishable by conventional methods of tumor measurement. For the orthotopic xenografts, the positive correlation between the in vivo iRFP signal from mice chests and the ex vivo green fluorescent signal from gross lung tumors and the results of the suppressed tumorigenesis by miR-16 treatment indicated that lung tumor size can be accurately quantified by the emission of NIR fluorescence. In addition, orthotopic lung tumor localization can be accurately visualized using iRFP fluorescence tomography in vivo, thus revealing the trafficking of lung tumor cells. We introduced a novel dual fluorescence lung cancer model that provides a non-invasive option for preclinical research via the use of NIR fluorescence in live imaging of lung.

  11. A Comprehensive Peptidome Profiling Technology for the Identification of Early Detection Biomarkers for Lung Adenocarcinoma

    Science.gov (United States)

    Ueda, Koji; Saichi, Naomi; Takami, Sachiko; Kang, Daechun; Toyama, Atsuhiko; Daigo, Yataro; Ishikawa, Nobuhisa; Kohno, Nobuoki; Tamura, Kenji; Shuin, Taro; Nakayama, Masato; Sato, Taka-Aki; Nakamura, Yusuke; Nakagawa, Hidewaki

    2011-01-01

    The mass spectrometry-based peptidomics approaches have proven its usefulness in several areas such as the discovery of physiologically active peptides or biomarker candidates derived from various biological fluids including blood and cerebrospinal fluid. However, to identify biomarkers that are reproducible and clinically applicable, development of a novel technology, which enables rapid, sensitive, and quantitative analysis using hundreds of clinical specimens, has been eagerly awaited. Here we report an integrative peptidomic approach for identification of lung cancer-specific serum peptide biomarkers. It is based on the one-step effective enrichment of peptidome fractions (molecular weight of 1,000–5,000) with size exclusion chromatography in combination with the precise label-free quantification analysis of nano-LC/MS/MS data set using Expressionist proteome server platform. We applied this method to 92 serum samples well-managed with our SOP (standard operating procedure) (30 healthy controls and 62 lung adenocarcinoma patients), and quantitatively assessed the detected 3,537 peptide signals. Among them, 118 peptides showed significantly altered serum levels between the control and lung cancer groups (p5.0). Subsequently we identified peptide sequences by MS/MS analysis and further assessed the reproducibility of Expressionist-based quantification results and their diagnostic powers by MRM-based relative-quantification analysis for 96 independently prepared serum samples and found that APOA4 273–283, FIBA 5–16, and LBN 306–313 should be clinically useful biomarkers for both early detection and tumor staging of lung cancer. Our peptidome profiling technology can provide simple, high-throughput, and reliable quantification of a large number of clinical samples, which is applicable for diverse peptidome-targeting biomarker discoveries using any types of biological specimens. PMID:21533267

  12. Methods of in-vivo mouse lung micro-CT

    Science.gov (United States)

    Recheis, Wolfgang A.; Nixon, Earl; Thiesse, Jacqueline; McLennan, Geoffrey; Ross, Alan; Hoffman, Eric

    2005-04-01

    Micro-CT will have a profound influence on the accumulation of anatomical and physiological phenotypic changes in natural and transgenetic mouse models. Longitudinal studies will be greatly facilitated, allowing for a more complete and accurate description of events if in-vivo studies are accomplished. The purpose of the ongoing project is to establish a feasible and reproducible setup for in-vivo mouse lung micro-computed tomography (μCT). We seek to use in-vivo respiratory-gated μCT to follow mouse models of lung disease with subsequent recovery of the mouse. Methodologies for optimizing scanning parameters and gating for the in-vivo mouse lung are presented. A Scireq flexiVent ventilated the gas-anesthetized mice at 60 breaths/minute, 30 cm H20 PEEP, 30 ml/kg tidal volume and provided a respiratory signal to gate a Skyscan 1076 μCT. Physiologic monitoring allowed the control of vital functions and quality of anesthesia, e.g. via ECG monitoring. In contrary to longer exposure times with ex-vivo scans, scan times for in-vivo were reduced using 35μm pixel size, 158ms exposure time and 18μm pixel size, 316ms exposure time to reduce motion artifacts. Gating via spontaneous breathing was also tested. Optimal contrast resolution was achieved at 50kVp, 200μA, applying an aluminum filter (0.5mm). There were minimal non-cardiac related motion artifacts. Both 35μm and 1μm voxel size images were suitable for evaluation of the airway lumen and parenchymal density. Total scan times were 30 and 65 minutes respectively. The mice recovered following scanning protocols. In-vivo lung scanning with recovery of the mouse delivered reasonable image quality for longitudinal studies, e.g. mouse asthma models. After examining 10 mice, we conclude μCT is a feasible tool evaluating mouse models of lung pathology in longitudinal studies with increasing anatomic detail available for evaluation as one moves from in-vivo to ex-vivo studies. Further developments include automated

  13. Androgen receptor levels during progression of prostate cancer in the transgenic adenocarcinoma of mouse prostate model

    Directory of Open Access Journals (Sweden)

    Krisna Murti

    2010-02-01

    Full Text Available Aim To construct tissue microarrays (TMAs that consisted of prostate tumours from the transgenic adenocarcinoma of mouse prostate (TRAMP mice and non-transgenic murine prostates and to assess androgen receptor (AR levels during progression of prostate cancer in TRAMP mice by immunohistochemistry.Methods Haematoxylin and eosin (H&E sections from the ventral and dorso-lateral prostate lobes of non-transgenic, intact TRAMP and castrated TRAMP were used to demarcate regions of interest for TMAs construction. The samples on TMAs were used to evaluate AR expression using video image analysis (VIA.Results AR was expressed during cancer progression, but AR levels were reduced or absent in late stage disease. Furthermore, when AR levels were compared in tumours from intact and castrate animals, a significant increase in AR levels was observed following androgen ablation.Conclusion Similar to clinical prostate cancer, in the TRAMP model, prostate tumours evolve mechanisms to maintain AR expression and AR responsive gene pathways following castration to facilitate continued tumour growth. (Med J Indones 2010; 19:5-13Keywords : androgen ablation therapy, tissue microarrays, haematoxylin and eosin, video image analysis

  14. Mechanism of arctigenin-mediated specific cytotoxicity against human lung adenocarcinoma cell lines.

    Science.gov (United States)

    Susanti, Siti; Iwasaki, Hironori; Inafuku, Masashi; Taira, Naoyuki; Oku, Hirosuke

    2013-12-15

    The lignan arctigenin (ARG) from the herb Arctium lappa L. possesses anti-cancer activity, however the mechanism of action of ARG has been found to vary among tissues and types of cancer cells. The current study aims to gain insight into the ARG mediated mechanism of action involved in inhibiting proliferation and inducing apoptosis in lung adenocarcinoma cells. This study also delineates the cancer cell specificity of ARG by comparison with its effects on various normal cell lines. ARG selectively arrested the proliferation of cancer cells at the G0/G1 phase through the down-regulation of NPAT protein expression. This down-regulation occurred via the suppression of either cyclin E/CDK2 or cyclin H/CDK7, while apoptosis was induced through the modulation of the Akt-1-related signaling pathway. Furthermore, a GSH synthase inhibitor specifically enhanced the cytotoxicity of ARG against cancer cells, suggesting that the intracellular GSH content was another factor influencing the susceptibility of cancer cells to ARG. These findings suggest that specific cytotoxicity of ARG against lung cancer cells was explained by its selective modulation of the expression of NPAT, which is involved in histone biosynthesis. The cytotoxicity of ARG appeared to be dependent on the intracellular GSH level. Copyright © 2013 Elsevier GmbH. All rights reserved.

  15. TROP2 overexpression promotes proliferation and invasion of lung adenocarcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Zanhua [Medical School of Nanchang University (China); The Chest Hospital of Jiangxi Province Department of Respiration (China); Jiang, Xunsheng [Department of Respiration, Medical School of Nanchang University (China); Zhang, Wei, E-mail: weizhangncu@gmail.com [Department of Respiration, The First Affiliated Hospital of Nanchang University (China)

    2016-01-29

    Recent studies suggest that the human trophoblast cell-surface antigen TROP2 is highly expressed in a number of tumours and is correlated with poor prognosis. However, its role in non-small cell lung carcinoma (NSCLC) remains largely unknown. Here we examined TROP2 expression by immunohistochemistry in a series of 68 patients with adenocarcinoma (ADC). We found significantly elevated TROP2 expression in ADC tissues compared with normal lung tissues (P < 0.05), and TROP2 overexpression was significantly associated with TNM (tumour, node, metastasis) stage (P = 0.012), lymph node metastasis (P = 0.038), and histologic grade (P = 0.013). Kaplan–Meier survival analysis revealed that high TROP2 expression correlated with poor prognosis (P = 0.046). Multivariate analysis revealed that TROP2 expression was an independent prognostic marker for overall survival of ADC patients. Moreover, TROP2 overexpression enhanced cell proliferation, migration, and invasion in the NSCLC cell line A549, whereas knockdown of TROP2 induced apoptosis and impaired proliferation, migration, and invasion in the PC-9 cells. Altogether, our data suggest that TROP2 plays an important role in promoting ADC and may represent a novel prognostic biomarker and therapeutic target for the disease.

  16. Adenocarcinoma of the lung with EGFR gene mutation and subsequent resistance mechanisms exploration: case report

    Directory of Open Access Journals (Sweden)

    Xu L

    2017-09-01

    Full Text Available Li Xu,1,2 Qian Z Wang,1,2 Lin Wu1,2 1Department of the Second Chest Medicine, Hunan Cancer Hospital, Changsha, Hunan, People’s Republic of China; 2Department of the Second Chest Medicine, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China Abstract: The treatment of lung cancer has made paradigm-shift advancements in the past decade with the development of therapies directed at specific genetic alterations, such as epidermal growth factor receptor (EGFR. Here, we present a rare case of lung adenocarcinoma harboring EGFR activating mutation and ALK overexpression. During the EGFR-tyrosine kinase inhibitors treatment, next-generation sequencing revealed phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway amplifications in tumor specimen and subsequent T790M mutation via plasma circulating tumor DNA. In conclusion, this case illustrates the existence of concomitant resistance mechanisms and demonstrates that circulating tumor DNA can reflect tumor heterogeneity. Keywords: epidermal growth factor receptor, PI3K/Akt/mTOR pathway, T790M, next-generation sequencing, circulating tumor DNA

  17. Lung Adenocarcinoma Presenting as Worsening of Chronic Neck Pain—A Cautionary Tale

    Directory of Open Access Journals (Sweden)

    Neeka N Akhavan

    2017-02-01

    Full Text Available Introduction: Neck pain is a common musculoskeletal problem that up to 70% of the world population will experience at some point in their lives. Intramedullary spinal cord metastasis is an exceedingly rare complication of malignancy that affects less than 1% of all patients with cancer. Case report: We report a case of a 61-year-old man who presented to primary care clinic with 1-month history of worsening neck pain with associated neurologic deficits. Despite initial conservative management, the patient continued to have progressive worsening of sensory and motor deficits. Magnetic resonance imaging of the cervical spine showed vasogenic edema of the brain and spinal cord and nodularity at the C4-C5 level. A computed tomography of the chest showed a dense lesion in the left lower lobe of the lung; histopathology of the biopsied specimen was consistent with moderately differentiated lung adenocarcinoma. Conclusions: A high index of suspicion is necessary when chronic neck pain acutely worsens, changes in character, or is accompanied by neurologic deficits. These clinical signs warrant further investigation into a secondary cause of neck pain. Intramedullary spinal cord metastases are rare complications of systemic cancer that commonly present with neck pain and upper extremity paraesthesias; early diagnosis and management are necessary to prevent complications such as spinal cord hemisection syndrome or spinal cord transection.

  18. An analysis of peripheral small lung carcinomas less than 20 mm in diameter in non-adenocarcinomas and carcinoids. Computed tomographic findings based on radiologic-pathologic correlation

    International Nuclear Information System (INIS)

    Tanaka, Gaku; Yamada, Kouzo; Oshita, Fumihiro; Nomura, Ikuo; Noda, Kazumasa; Nakayama, Haruhiko; Mitsuda, Aki; Kameda, Youichi; Yamakido, Michio

    2000-01-01

    With the introduction of computed tomography (CT) for chest screening in recent years, more cases of resected peripheral small lung carcinomas have been reported. Many of these were adenocarcinomas. To focus on CT findings of peripheral non-adenocarcinoma nodules, we performed a retrospective analysis based on radiographic-pathologic correlations. We analyzed CT findings based on the pathology of peripheral small lung carcinomas, excluding the histological type of adenocarcinomas. We compared our findings with those observed in adenocarcinomas. We reviewed 28 peripheral small lung carcinoma nodules less than 20 mm in diameter, including 13 squamous cell carcinomas, 4 small cell carcinomas, 2 adeno- squamous cell carcinomas, 1 large cell carcinoma, and 8 carcinoids. The carcinomas were classified into two different patterns; non-adenocarcinomas excluding carcinoids, and carcinoids. Both were solid-density types on high-resolution CT (HR-CT) images. The HR-CT findings regarding the shape and number of notching, and the presence or absence of ground glass opacity (GGO) were different between non-adenocarcinomas excluding carcinoids and adenocarcinomas. On the other hand, the HR-CT findings regarding spiculations, GGO and pleural indentations, and the absence of bronchial compression were different between carcinoids and adenocarcinomas. The shape characteristics and internal and marginal analysis on HR-CT images can contribute to the differential diagnosis of the histological type of peripheral small lung carcinomas. (author)

  19. Diagnostic value of tumor markers for lung adenocarcinoma-associated malignant pleural effusion: a validation study and meta-analysis.

    Science.gov (United States)

    Feng, Mei; Zhu, Jing; Liang, Liqun; Zeng, Ni; Wu, Yanqiu; Wan, Chun; Shen, Yongchun; Wen, Fuqiang

    2017-04-01

    Pleural effusion is one of the most common complications of lung adenocarcinoma and is diagnostically challenging. This study aimed to investigate the diagnostic performance of carcinoembryonic antigen (CEA), cytokeratin fragment (CYFRA) 21-1, and cancer antigen (CA) 19-9 for lung adenocarcinoma-associated malignant pleural effusion (MPE) through a validation study and meta-analysis. Pleural effusion samples were collected from 81 lung adenocarcinoma-associated MPEs and 96 benign pleural effusions. CEA, CYFRA 21-1, and CA19-9 were measured by electrochemiluminescence immunoassay. The capacity of tumor markers was assessed with receiver operating characteristic curve analyses and the area under the curve (AUC) was calculated. Standard methods for meta-analysis of diagnostic studies were used to summarize the diagnostic performance of CEA, CYFRA 21-1, and CA19-9 for lung adenocarcinoma-associated MPE. The pleural levels of CEA, CYFRA 21-1, and CA19-9 were significantly increased in lung adenocarcinoma-associated MPE compared to benign pleural effusion. The cut-off points for CEA, CYFRA 21-1, and CA19-9 were optimally set at 4.55 ng/ml, 43.10 μg/ml, and 12.89 U/ml, and corresponding AUCs were 0.93, 0.85, and 0.81, respectively. The combination of CEA, CYFRA 21-1, and CA19-9 increased the sensitivity to 95.06%, with an AUC of 0.95. Eight studies were included in this meta-analysis. CEA showed the best diagnostic performance with pooled sensitivity, specificity, positive/negative likelihood ratio, and diagnostic odds ratio of 0.75, 0.96, 16.01, 0.23, and 81.49, respectively. The AUC was 0.93. CEA, CYFRA 21-1, and CA19-9 play a role in the diagnosis of lung adenocarcinoma-associated MPE. The combination of these tumor markers increases the diagnostic accuracy.

  20. Expression and Clinical Significance of CD147 and MMP-2 
in Squamous Cell Carcinoma and Adenocarcinoma of the Lungs

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    Siwen WANG

    2011-09-01

    Full Text Available Background and objective It has been proven that CD147 was an extracellular matrix metalloproteinase inducer reportedly involved in the invasion and metastasis of malignancies. The aim of this study is to investigate CD147 and MMP-2 expression in squamous cell carcinoma and adenocarcinoma of the lungs and to analyze their clinical significance. Methods Tissue samples from 55 patients with squamous cell carcinoma and adenocarcinoma of the lungs and their corresponding non-cancerous tissues were examined for CD147 and MMP-2 expression using immunohistochemistry. Results The positive expression rates of CD147 and MMP-2 in the squamous cell carcinoma and adenocarcinoma among the lung tissues were significantly higher than those in the corresponding normal lung tissues. Moreover, the CD147 and MMP-2 expression in squamous cell carcinoma and adenocarcinoma of the lungs were related to lymph node metastasis and TNM stages (P<0.05, but not to age, gender and histologic type (P>0.05. MMP-2 expression was highly correlated with CD147 expression. Conclusion CD147 and MMP-2 expression is correlated with the invasion and metastasis of squamous cell carcinoma and adenocarcinoma of the lungs and may be used as objective markers for predicting the behavior of squamous cell carcinoma and adenocarcinoma of the lungs.

  1. Sequential treatment of icotinib after first-line pemetrexed in advanced lung adenocarcinoma with unknown EGFR gene status.

    Science.gov (United States)

    Zheng, Yulong; Fang, Weijia; Deng, Jing; Zhao, Peng; Xu, Nong; Zhou, Jianying

    2014-07-01

    In non-small cell lung cancer (NSCLC), the well-developed epidermal growth factor receptor (EGFR) is an important therapeutic target. EGFR activating gene mutations have been proved strongly predictive of response to EGFR-tyrosine kinase inhibitors (TKI) in NSCLC. However, both in daily clinical practice and clinical trials, patients with unknown EGFR gene status (UN-EGFR-GS) are very common. In this study, we assessed efficacy and tolerability of sequential treatment of first-line pemetrexed followed by icotinib in Chinese advanced lung adenocarcinoma with UN-EGFR-GS. We analyzed 38 patients with advanced lung adenocarcinoma with UN-EGFR-GS treated with first-line pemetrexed-based chemotherapy followed by icotinib as maintenance or second-line therapy. The response rates to pemetrexed and icotinib were 21.1% and 42.1%, respectively. The median overall survival was 27.0 months (95% CI, 19.7-34.2 months). The 12-month overall survival probability was 68.4%. The most common toxicities observed in icotinib phase were rashes, diarrheas, and elevated aminotransferase. Subgroup analysis indicated that the overall survival is correlated with response to icotinib. The sequence of first-line pemetrexed-based chemotherapy followed by icotinib treatment is a promising option for advanced lung adenocarcinoma with UN-EGFR-GS in China.

  2. Population effect model identifies gene expression predictors of survival outcomes in lung adenocarcinoma for both Caucasian and Asian patients.

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    Guoshuai Cai

    Full Text Available We analyzed and integrated transcriptome data from two large studies of lung adenocarcinomas on distinct populations. Our goal was to investigate the variable gene expression alterations between paired tumor-normal tissues and prospectively identify those alterations that can reliably predict lung disease related outcomes across populations.We developed a mixed model that combined the paired tumor-normal RNA-seq from two populations. Alterations in gene expression common to both populations were detected and validated in two independent DNA microarray datasets. A 10-gene prognosis signature was developed through a l1 penalized regression approach and its prognostic value was evaluated in a third independent microarray cohort.Deregulation of apoptosis pathways and increased expression of cell cycle pathways were identified in tumors of both Caucasian and Asian lung adenocarcinoma patients. We demonstrate that a 10-gene biomarker panel can predict prognosis of lung adenocarcinoma in both Caucasians and Asians. Compared to low risk groups, high risk groups showed significantly shorter overall survival time (Caucasian patients data: HR = 3.63, p-value = 0.007; Asian patients data: HR = 3.25, p-value = 0.001.This study uses a statistical framework to detect DEGs between paired tumor and normal tissues that considers variances among patients and ethnicities, which will aid in understanding the common genes and signalling pathways with the largest effect sizes in ethnically diverse cohorts. We propose multifunctional markers for distinguishing tumor from normal tissue and prognosis for both populations studied.

  3. Efficacy of Gefitinib for Young Patients with Unknown EGFR Gene Mutation 
in Advanced Lung Adenocarcinoma

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    Yutao LIU

    2014-05-01

    Full Text Available Background and objective Lung cancer in young patients (less or equal to 45 years is relatively rare. We explored the efficacy and survival of Gefitinib for young patients with unknown epidermal growth factor receptor (EGFR gene mutation of advanced lung adenocarcinoma. Methods The clinical data of 55 young patients with unknown EGFR gene mutation in advanced lung adenocarcinoma referred to the Cancer Hospital & Institute, Chinese Academy of Medical Sciences from Jan 2006 through Dec 2010 were analyzed retrospectively. Results Of 55 young patients enrolled, the median age was 41 years. The objective response rate and disease control rate were 43.6% and 90.9%, respectively.. The median progression-free survival (PFS was 9.0 months. Among the factors analyzed, brain metastasis had significant effect on PFS (P=0.017. The median overall survival (OS was 24.0 months. The independent prognostic factors to significantly improve OS included non-smoking history (P=0.028 and receiving other anti-cancer treatment after Gefitinib therapy (P<0.001. Conclusion The median PFS and OS of the young patients with Unknown EGFR gene mutation in advanced lung adenocarcinoma were similar with general population.

  4. Adjuvant Chemotherapy Improves the Probability of Freedom From Recurrence in Patients With Resected Stage IB Lung Adenocarcinoma.

    Science.gov (United States)

    Hung, Jung-Jyh; Wu, Yu-Chung; Chou, Teh-Ying; Jeng, Wen-Juei; Yeh, Yi-Chen; Hsu, Wen-Hu

    2016-04-01

    The benefit of adjuvant chemotherapy remains controversial for patients with stage IB non-small-cell lung cancer (NSCLC). This study investigated the effect of adjuvant chemotherapy and the predictors of benefit from adjuvant chemotherapy in patients with stage IB lung adenocarcinoma. A total of 243 patients with completely resected pathologic stage IB lung adenocarcinoma were included in the study. Predictors of the benefits of improved overall survival (OS) or probability of freedom from recurrence (FFR) from platinum-based adjuvant chemotherapy in patients with resected stage IB lung adenocarcinoma were investigated. Among the 243 patients, 70 (28.8%) had received platinum-based doublet adjuvant chemotherapy. A micropapillary/solid-predominant pattern (versus an acinar/papillary-predominant pattern) was a significantly worse prognostic factor for probability of FFR (p = 0.033). Although adjuvant chemotherapy (versus surgical intervention alone) was not a significant prognostic factor for OS (p = 0.303), it was a significant prognostic factor for a better probability of FFR (p = 0.029) on multivariate analysis. In propensity-score-matched pairs, there was no significant difference in OS between patients who received adjuvant chemotherapy and those who did not (p = 0.386). Patients who received adjuvant chemotherapy had a significantly better probability of FFR than those who did not (p = 0.043). For patients with a predominantly micropapillary/solid pattern, adjuvant chemotherapy (p = 0.033) was a significant prognostic factor for a better probability of FFR on multivariate analysis. Adjuvant chemotherapy is a favorable prognostic factor for the probability of FFR in patients with stage IB lung adenocarcinoma, particularly in those with a micropapillary/solid-predominant pattern. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  5. Identification of crucial microRNAs and genes in hypoxia-induced human lung adenocarcinoma cells

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    Geng Y

    2016-07-01

    Full Text Available Ying Geng,1,* Lili Deng,2,* Dongju Su,1 Jinling Xiao,1 Dongjie Ge,3 Yongxia Bao,1 Hui Jing4 1Department of Respiratory, 2Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, 3Department of Respiratory, The First Hospital of Harbin, 4Department of Emergency, The Second Affiliated Hospital of Harbin Medical University Harbin, Heilongjiang, People’s Republic of China *These authors contributed equally to this work Background: Variations of microRNA (miRNA expression profile in hypoxic lung cancer cells have not been studied so far. Therefore, using miRNA microarray technology, this study aimed to study the miRNA expression profile and investigate the potential crucial miRNAs and their target genes in hypoxia-induced human lung adenocarcinoma cells.Materials and methods: Based on miRNA microarray, miRNA expression profiling of hypoxia-induced lung adenocarcinoma A549 cells was obtained. After identification of differentially expressed miRNAs (DE-miRNAs in hypoxic cells, target genes of DE-miRNAs were predicted, and functional enrichment analysis of targets was conducted. Furthermore, the expression levels of DE-miRNAs and their target genes were validated by real-time quantitative polymerase chain reaction. In addition, using miRNA mimics, the effect of overexpressed DE-miRNAs on A549 cell behaviors (cell proliferation, cell cycle, and apoptosis was evaluated.Results: In total, 14 DE-miRNAs (nine upregulated miRNAs and five downregulated miRNAs were identified in hypoxic cells, compared with normoxic cells. Target genes of both upregulated and downregulated miRNAs were enriched in the functions such as chromatin modification, and pathways such as Wnt signaling pathway and transforming growth factor (TGF-β signaling pathway. The expression levels of several miRNAs and their target genes were confirmed, including hsa-miR-301b/FOXF2, hsa-miR-148b-3p/WNT10B, hsa-miR-769-5p/(SMAD2, ARID1A, and hsa-miR-622. Among them

  6. Therapeutic Potential of Andrographolide Isolated from the Leaves of Andrographis paniculata Nees for Treating Lung Adenocarcinomas

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    Yu-Tang Tung

    2013-01-01

    Full Text Available Andrographolide is one of the major diterpene lactones found in Andrographis paniculata Nees and exhibits remarkable inhibitory effects on various cancers. In this study, the antipulmonary cancer effects of andrographolide were studied in a lung tumor mouse model induced by human vascular endothelial growth factor A165 (hVEGF-A165. These results demonstrated that andrographolide significantly reduced the expression of hVEGF-A165 compared with a mock group in the Clara cells of the lungs. In addition, andrographolide also decreased tumor formation by reducing VEGF, EGFR, Cyclin A, and Cyclin B expression on the transcriptional and translational levels. These results indicated that andrographolide treatment on the overexpression of VEGF can arrest the cell cycle, which induced pulmonary tumors in transgenic mice. In conclusion, the antiangiogenesis and chemotherapeutic potential of andrographolide may provide a cure for pulmonary tumors in the future.

  7. Surveillance of the remaining nodules after resection of the dominant lung adenocarcinoma is an appropriate follow-up strategy

    Directory of Open Access Journals (Sweden)

    Massimo eCastiglioni

    2015-01-01

    Full Text Available IntroductionAdenocarcinomas, commonly present as a dominant lesion (DL with additional nodules in the ipsilateral or contralateral lung. We sought to determine the fate and management of the secondary nodules and to assess the risk of these nodules using the Lung CT Screening Reporting and Data System (Lung-RADS criteria and the National Comprehensive Cancer Network (NCCN guidelines to determine if surveillance is an appropriate strategy.MethodsWe retrospectively evaluated patients with lepidic growth pattern adenocarcinoma and secondary nodules from 2000 to 2013. Risk assessment of the additional lesions was completed with a simplified model of Lung-RADS and NCCN-Guidelines. ResultsEighty-seven patients underwent resection of 87 DLs (Group 1 concurrently with 60 additional pulmonary nodules (Group 2 while 157 non-DLs were radiologically surveyed over a median follow-up time of 3.2 years (Group 3. Malignancy was found in 29/60 (48% nodules in Group 2. Whereas, only 9/157 (6% of the lesions in Group 3 enlarged, 4 of which (2.5% of total were found to be malignant, and then treated, while the remaining nodules continued surveillance. After applying the Lung-RADS and NCCN simplified models, nodules in Group 2 were at higher risk for lung cancer than those in Group 3. ConclusionsIn patients with lepidic growth pattern adenocarcinoma associated with multiple secondary nodules, surveillance of the remaining nodules, after resection of the DL, is a reasonable strategy since these nodules exhibited a slow rate of growth and minimal malignancy. In contrast, nodules resected from the ipsilateral lung at the time of the DL, harbor malignancy in 48%. Risk assessment models may provide a useful and standardized tool for clinical assessment of pulmonary nodules.

  8. Comparison of erlotinib and pemetrexed as second-/third-line treatment for lung adenocarcinoma patients with asymptomatic brain metastases

    Directory of Open Access Journals (Sweden)

    He YY

    2016-04-01

    Full Text Available Yayi He,1,* Wenwen Sun,2,* Yan Wang,3,* Shengxiang Ren,1 Xuefei Li,3 Jiayu Li,3 Christopher J Rivard,4 Caicun Zhou,1 Fred R Hirsch4 1Department of Oncology, Shanghai Pulmonary Hospital, 2Clinic and Research Center of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, 3Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, People’s Republic of China; 4Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO, USA *These authors contributed equally to this work Objective: Brain metastases occur in one-third of all non-small-cell lung cancer patients. Due to restrictive transport at the blood–brain barrier, many drugs provide poor control of metastases in the brain. The aim of this study was to compare erlotinib with pemetrexed as second-/third-line treatment in patients with lung adenocarcinoma with asymptomatic brain metastases.Methods: From January 2012 to June 2014, all lung adenocarcinoma patients with asymptomatic brain metastases who received treatment with erlotinib or pemetrexed as second-/third-line treatment were retrospectively reviewed. Chi-square and log-rank tests were used to perform statistical analysis.Results: The study enrolled 99 patients, of which 44 were positive for EGFR mutation. Median progression-free survival (PFS in months was not significantly different between the erlotinib- and pemetrexed-treated groups (4.2 vs 3.4 months; 95% confidence interval [CI]: 2.01–6.40 vs 2.80–5.00, respectively; P=0.635. Median PFS was found to be significantly longer in EGFR mutation–positive patients in the erlotinib-treated group (8.0 months; 95% CI 5.85–10.15 compared to the pemetrexed group (3.9 months; 95% CI: 1.25–6.55; P=0.032. The most common treatment-related side effect was mild-to-moderate rash and the most common drug-related side

  9. Progressive multiple cystic changes in both lungs in a patient treated with gefitinib for lung adenocarcinoma with multiple lung metastases

    International Nuclear Information System (INIS)

    Ryu, Yon Ju; Chun, Eun Mi; Lee, Soon Nam; Shim, Sung Shin

    2014-01-01

    Gefitinib is regarded as a relatively safe agent for the treatment of an advanced non-small cell lung cancer (NSCLC). Pulmonary toxicity such as interstitial lung disease associated with gefitinib is uncommon with an estimated all time incidence around 1% worldwide. Moreover, a case of gefitinib associated with pulmonary cystic changes has not been reported yet. In this report we present a case of progressive multiple air cystic changes in both lungs in a patient with NSCLC and intrapulmonary metastases who underwent a gefitinib therapy.

  10. Prognostic significance of tumor size of small lung adenocarcinomas evaluated with mediastinal window settings on computed tomography.

    Directory of Open Access Journals (Sweden)

    Yukinori Sakao

    Full Text Available BACKGROUND: We aimed to clarify that the size of the lung adenocarcinoma evaluated using mediastinal window on computed tomography is an important and useful modality for predicting invasiveness, lymph node metastasis and prognosis in small adenocarcinoma. METHODS: We evaluated 176 patients with small lung adenocarcinomas (diameter, 1-3 cm who underwent standard surgical resection. Tumours were examined using computed tomography with thin section conditions (1.25 mm thick on high-resolution computed tomography with tumour dimensions evaluated under two settings: lung window and mediastinal window. We also determined the patient age, gender, preoperative nodal status, tumour size, tumour disappearance ratio, preoperative serum carcinoembryonic antigen levels and pathological status (lymphatic vessel, vascular vessel or pleural invasion. Recurrence-free survival was used for prognosis. RESULTS: Lung window, mediastinal window, tumour disappearance ratio and preoperative nodal status were significant predictive factors for recurrence-free survival in univariate analyses. Areas under the receiver operator curves for recurrence were 0.76, 0.73 and 0.65 for mediastinal window, tumour disappearance ratio and lung window, respectively. Lung window, mediastinal window, tumour disappearance ratio, preoperative serum carcinoembryonic antigen levels and preoperative nodal status were significant predictive factors for lymph node metastasis in univariate analyses; areas under the receiver operator curves were 0.61, 0.76, 0.72 and 0.66, for lung window, mediastinal window, tumour disappearance ratio and preoperative serum carcinoembryonic antigen levels, respectively. Lung window, mediastinal window, tumour disappearance ratio, preoperative serum carcinoembryonic antigen levels and preoperative nodal status were significant factors for lymphatic vessel, vascular vessel or pleural invasion in univariate analyses; areas under the receiver operator curves were 0

  11. Prognostic Significance of Tumor Size of Small Lung Adenocarcinomas Evaluated with Mediastinal Window Settings on Computed Tomography

    Science.gov (United States)

    Sakao, Yukinori; Kuroda, Hiroaki; Mun, Mingyon; Uehara, Hirofumi; Motoi, Noriko; Ishikawa, Yuichi; Nakagawa, Ken; Okumura, Sakae

    2014-01-01

    Background We aimed to clarify that the size of the lung adenocarcinoma evaluated using mediastinal window on computed tomography is an important and useful modality for predicting invasiveness, lymph node metastasis and prognosis in small adenocarcinoma. Methods We evaluated 176 patients with small lung adenocarcinomas (diameter, 1–3 cm) who underwent standard surgical resection. Tumours were examined using computed tomography with thin section conditions (1.25 mm thick on high-resolution computed tomography) with tumour dimensions evaluated under two settings: lung window and mediastinal window. We also determined the patient age, gender, preoperative nodal status, tumour size, tumour disappearance ratio, preoperative serum carcinoembryonic antigen levels and pathological status (lymphatic vessel, vascular vessel or pleural invasion). Recurrence-free survival was used for prognosis. Results Lung window, mediastinal window, tumour disappearance ratio and preoperative nodal status were significant predictive factors for recurrence-free survival in univariate analyses. Areas under the receiver operator curves for recurrence were 0.76, 0.73 and 0.65 for mediastinal window, tumour disappearance ratio and lung window, respectively. Lung window, mediastinal window, tumour disappearance ratio, preoperative serum carcinoembryonic antigen levels and preoperative nodal status were significant predictive factors for lymph node metastasis in univariate analyses; areas under the receiver operator curves were 0.61, 0.76, 0.72 and 0.66, for lung window, mediastinal window, tumour disappearance ratio and preoperative serum carcinoembryonic antigen levels, respectively. Lung window, mediastinal window, tumour disappearance ratio, preoperative serum carcinoembryonic antigen levels and preoperative nodal status were significant factors for lymphatic vessel, vascular vessel or pleural invasion in univariate analyses; areas under the receiver operator curves were 0.60, 0.81, 0

  12. Discordance of Mutation Statuses of Epidermal Growth Factor Receptor and K-ras between Primary Adenocarcinoma of Lung and Brain Metastasis

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    Kun-Ming Rau

    2016-04-01

    Full Text Available Mutations on epidermal growth factor receptor (EGFR of adenocarcinomas of lung have been found to be associated with increased sensitivity to EGFR tyrosine kinase inhibitors and K-ras mutations may correlate with primary resistance. We aimed to explore the discordant mutation statuses of EGFR and K-ras between primary tumors and matched brain metastases in adenocarcinomas of lung. We used a sensitive Scorpion ARMS method to analyze EGFR mutation, and Sanger sequencing followed by allele-specific real-time polymerase chain reaction to analyze K-ras mutation. Forty-nine paired tissues with both primary adenocarcinoma of lung and matched brain metastasis were collected. Thirteen patients (26.5% were discordant for the status of EGFR between primary and metastatic sites. K-ras gene could be checked in paired specimens from 33 patients, thirteen patients (39.6% were discordant for the status of K-ras. In primary lung adenocarcinoma, there were 14 patients of mutant EGFR had mutant K-ras synchronously. This study revealed that the status of EGFR mutation in lung adenocarcinomas is relatively consistent between primary and metastatic sites compared to K-ras mutation. However, there are still a few cases of adenocarcinoma of lung showing discordance for the status of EGFR mutation. Repeated analysis of EGFR mutation is highly recommended if tissue from metastatic or recurrent site is available for the evaluation of target therapy.

  13. [Killing effect of icotinib combined with CIK on human lung adenocarcinoma cells in vitro].

    Science.gov (United States)

    Yao, B Q; Jia, Y; Guo, J Q; Zhao, Q; Sun, H; Zhang, J P

    2017-08-23

    Objective: To explore the inhibitory effect of icotinib combined with cytokine induced killer (CIK) on various human lung adenocarcinoma cell lines in vitro. Methods: The inhibitory effect of icotinib alone or icotinib combined with CIK on HCC827 and A549 cells was detected by cell counting kit-8(CCK-8). The apoptosis was detected by flow cytometry via Annexin V/PI staining. The effect of icotinib on CIK phenotype was detected by flow cytometry. Results: The inhibitory rates of HCC827 cells treated with 1.5, 3, 6, 12 μmol/L icotinib were (5.64±0.05)%, (8.62±0.45)%, (14.57±0.65)% and (18.52±0.91)%, respectively. The inhibitory rates of A549 cells were (1.64±0.48)%, (2.09±0.28)%, (3.69±0.45)%, (4.41±0.58)%, respectively. At the same concentration, the inhibitory rate of HCC827 cells with icotinib treatment was significantly higher than that of A549 cells ( P icotinib was 10∶1, 20∶1 or 40∶1, the inhibitory rates of HCC827 cells were (37.07±3.50)%, (76.03±6.55)%, (80.34±10.69)%, respectively, and the inhibitory rates of A549 cells were(25.72±1.41)%, (52.76±3.82)%, (62.26±1.94)%, respectively. The inhibitory rates of 6 μmol/L icotinib combined with CIK were significantly higher than those of icotinib group and CIK group alone at the same effector/target ratio ( P icotinib combined with CIK were significantly higher than those of icotinib group and blank control group ( P icotinib treatment was not significantly different from each other( P >0.05). Conclusions: EGFR mutant lung adenocarcinoma cells are more sensitive to icotinib, while the EGFR mutation status has no effect on the killing effect of CIK cells. icotinib combined with CIK has a synergistic effect on the inhibition of tumor growth, and icotinib has no any impact on the phenotype of CIK cells.

  14. Association of non-traumatic complex regional pain syndrome with adenocarcinoma lung on 99mTc-MDP bone scan

    International Nuclear Information System (INIS)

    Damle, Nishikant A.; Tripathi, Madhavi; Singhal, Abhinav; Bal, Chandrasekhar; Praveen Kumar; Kandasamy, Devasenathipathi; Jana, Manisha

    2012-01-01

    Complex regional pain syndrome (CRPS) is usually associated with trauma. Rarely, it may be seen in association with malignancies. We present here the bone scan and X-ray findings in the case of a 56-year-male-patient with adenocarcinoma lung who also had non-traumatic CRPS without involvement of the stellate ganglion. The case highlights the fact that spontaneous development of reflex sympathetic dystrophy may be associated with a neoplastic etiology. (author)

  15. Lung adenocarcinoma originates from retrovirus infection of proliferating type 2 pneumocytes during pulmonary post-natal development or tissue repair.

    Science.gov (United States)

    Murgia, Claudio; Caporale, Marco; Ceesay, Ousman; Di Francesco, Gabriella; Ferri, Nicola; Varasano, Vincenzo; de las Heras, Marcelo; Palmarini, Massimo

    2011-03-01

    Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer.

  16. Enhancement of radiosensitivity of recombinant Ad-p53 gene on human lung adenocarcinoma cell with different p53 status

    International Nuclear Information System (INIS)

    Pang Dequan; Wang Peiguo; Wang Ping; Zhang Weiming

    2008-01-01

    Objective: To investigate the enhancement of radiosensitivity of recombinant Ad-p53 gene on human lung adenocarcinoma cell lines(A549 and GLC-82) with different p53 status in vitro. Methods: Two human lung adenocarcinoma cell lines of A549 and GLC-82 were examined on their difference in p53 status with immunohistochemistry stain and PCR-SSCP technique. Expand Ad-wtp53 was transfected into tumor cells. Clonogenic assays were performed to evaluate the inhibition effect on cell growth and the degree of sensitization to irradiation. Apoptosis and cell cycle changes were determined using the flow cytometry assay. Results: The A549 cell line presented positive P53 expression while GLC-82 negative. GLC-82 bore mutant p53 on the exon 7. The wtp53 gene could be efficiently expressed in the two cell lines and greatly inhibit the cell growth. Its efficiency didn't depend on the intrinsic p53 genetic status. After irradiation, its function of inducing G 1 arrest and apoptosis on GLC-82 cell line was much stronger than the A549 cell line. In both the A549 and GLC-82 cell lines, the combination of Ad-p53 plus radiation resulted in more apoptosis than the others. There was no significant difference between two groups. Conclusions: Ad-p53 can depress the tumor growth and enhance the radiosensitivity of human lung adenocarcinoma cells. And this effect is independent of endogenous p53 status. (authors)

  17. Establishment and Characterization of a Novel Chinese Human Lung Adenocarcinoma Cell Line CPA-Yang2 in Immunodeficient Mice

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    Shunfang YANG

    2009-10-01

    Full Text Available Background and objective The recurrence, metastasis and multidrug resistance (MDR in lung cancer are the tough problems worldwide. This study was to establish a novel chinese lung adenocarcinoma cell line with high metastasis potential for exploring the mechanism of reccurrence, development and MDR in lung cancer. Methods The cell came from the abdominal dropsy of a fifty-six years old female patient with lung adenocarcinoma and the tumor markers CA125, CYFRA21-1, CEA, NSE were detected to be higher secretion by radioimmunoassay in the abdominal dropsy. Tumorigenicity of immunodeficient mice was confirmed in 8th passage. The cell growth curve was mapped. Analysis of chromosome karyotype was tested. The gene expression was measured by real-time quantitative PCR. Results The tumorigenesis rate started at 8th passage in 3/10 immunodeficient mice via subcutaneously and the fully tumorigenicity was at 11th passage as well as later passages. Under the microscope, the cell showed oval-shap and adherence. The chromosome karyotype analysis of the cells was sub-triploid. Approximately 1×106 and 1.5×106 cancerous cells were injected into left cardiac ventricle and tail vein of immunodeficient mice respectively. The results showed multiorgan metastasis in the mice after three-four weeks, including mandible, scapula, humerus, vertebral column, femur, rib and brain, liver, adrenal gland, pulmonary in the mice after inoculation. The bone metastasis rate was 100% in the tumor bearing mice by bone scintigraphy and pathology. Quantitative real-time PCR was used to examined and compared with SPC-A-1 lung adenocarcinoma, ESM1, VEGF-C, IL-6, IL-8, AR genes were overexpressed. The novel cell was named CPA-Yang2. Conclusion The characteristics of novel strain CPA-Yang2 is a highly metastasis cell line of Chinese lung adenocarcinoma. It has stable traits, highly metastasis ability and maybe is a MDR lung cancerous cell line. Of course, it’s a good experimental

  18. Immunotherapy “Shock” with vitiligo due to nivolumab administration as third line therapy in lung adenocarcinoma

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    Paul Zarogoulidis

    2017-01-01

    Full Text Available Non-small cell lung cancer is still diagnosed at late stage due to the lack of early symptoms and methods of diagnostic prevention. In the past ten years several targeted therapies have been introduced or explored. Tyrosine kinase inhibitors and immunotherapy are currently considered the most effective and safe therapies in comparison to the non-specific cytotoxic agents. Regarding tyrosine kinase inhibitors the adverse effects have been fully explored, however; on the other hand for immunotherapy there are still several issues to be clarified. We report a rare case of a patient with lung cancer adenocarcinoma who developed vitiligo throughout his body after nivolumab administration.

  19. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.

    LENUS (Irish Health Repository)

    Sequist, Lecia V

    2013-09-20

    The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR\\/ErbB1), human epidermal growth factor receptor 2 (HER2\\/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).

  20. Gamma-aminobutyric acid, a potential tumor suppressor for small airway-derived lung adenocarcinoma.

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    Schuller, Hildegard M; Al-Wadei, Hussein A N; Majidi, Mourad

    2008-10-01

    Pulmonary adenocarcinoma (PAC) is the leading type of lung cancer in smokers and non-smokers that arises in most cases from small airway epithelial cells. PAC has a high mortality due to its aggressive behavior and resistance to cancer therapeutics. We have shown previously that the proliferation of human PAC cells NCI-H322 and immortalized human small airway epithelial cells HPL1D is stimulated by cyclic adenosine monophosphate (cAMP)/protein kinase A-dependent phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein and transactivation of the epidermal growth factor receptor and that this pathway is activated by beta-1-adrenoreceptors (beta(1)-ARs) and the non-genomic estrogen receptor beta. Our current in vitro studies with HPL1D and NCI-H322 cells showed that signaling via the gamma-amino butyric acid receptor (GABA(B)R) strongly inhibited base level and isoproterenol-induced cAMP, p-CREB, cyclic adenosine monophosphate response element-luciferase activity and p-extracellular regulated kinase-1 (ERK1)/2 and effectively blocked DNA synthesis and cell migration. The inhibitory effects of gamma-amino butyric acid (GABA) were disinhibited by the GABA(B)R antagonist CGP-35348 or GABA(B)R knockdown. Immunohistochemical investigation of hamster lungs showed significant underexpression of GABA in animals with small airway-derived PACs induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These findings suggest that GABA may have tumor suppressor function in small airway epithelia and the PACs derived from them and that downregulation of GABA by NNK may contribute to the development of this cancer in smokers. Our findings suggest that marker-guided treatment with GABA or a GABA(B)R agonist of individuals with downregulated pulmonary GABA may provide a novel targeted approach for the prevention of PAC in smokers.

  1. DNA damage response signaling in lung adenocarcinoma A549 cells following gamma and carbon beam irradiation.

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    Ghosh, Somnath; Narang, Himanshi; Sarma, Asitikantha; Krishna, Malini

    2011-11-01

    Carbon beams (5.16MeV/u, LET=290keV/μm) are high linear energy transfer (LET) radiation characterized by higher relative biological effectiveness than low LET radiation. The aim of the current study was to determine the signaling differences between γ-rays and carbon ion-irradiation. A549 cells were irradiated with 1Gy carbon or γ-rays. Carbon beam was found to be three times more cytotoxic than γ-rays despite the fact that the numbers of γ-H2AX foci were same. Percentage of cells showing ATM/ATR foci were more with γ-rays however number of foci per cell were more in case of carbon irradiation. Large BRCA1 foci were found in all carbon irradiated cells unlike γ-rays irradiated cells and prosurvival ERK pathway was activated after γ-rays irradiation but not carbon. The noteworthy finding of this study is the early phase apoptosis induction by carbon ions. In the present study in A549 lung adenocarcinoma, authors conclude that despite activation of same repair molecules such as ATM and BRCA1, differences in low and high LET damage responses might be due to their distinct macromolecular complexes rather than their individual activation and the activation of cytoplasmic pathways such as ERK, whether it applies to all the cell lines need to be further explored. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Apoptosis signal-regulating kinase 1 mediates denbinobin-induced apoptosis in human lung adenocarcinoma cells

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    Pan Shiow-Lin

    2009-05-01

    Full Text Available Abstract In the present study, we explore the role of apoptosis signal-regulating kinase 1 (ASK1 in denbinobin-induced apoptosis in human lung adenocarcinoma (A549 cells. Denbinobin-induced cell apoptosis was attenuated by an ASK1 dominant-negative mutant (ASK1DN, two antioxidants (N-acetyl-L-cysteine (NAC and glutathione (GSH, a c-Jun N-terminal kinase (JNK inhibitor (SP600125, and an activator protein-1 (AP-1 inhibitor (curcumin. Treatment of A549 cells with denbinobin caused increases in ASK1 activity and reactive oxygen species (ROS production, and these effects were inhibited by NAC and GSH. Stimulation of A549 cells with denbinobin caused JNK activation; this effect was markedly inhibited by NAC, GSH, and ASK1DN. Denbinobin induced c-Jun phosphorylation, the formation of an AP-1-specific DNA-protein complex, and Bim expression. Bim knockdown using a bim short interfering RNA strategy also reduced denbinobin-induced A549 cell apoptosis. The denbinobin-mediated increases in c-Jun phosphorylation and Bim expression were inhibited by NAC, GSH, SP600125, ASK1DN, JNK1DN, and JNK2DN. These results suggest that denbinobin might activate ASK1 through ROS production to cause JNK/AP-1 activation, which in turn induces Bim expression, and ultimately results in A549 cell apoptosis.

  3. Pneumatosis intestinalis and portal venous gas secondary to Gefitinib therapy for lung adenocarcinoma

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    Lee Joo

    2012-03-01

    Full Text Available Abstract Background Pneumatosis intestinalis (PI, defined as the presence of gas in the bowel wall, and portal venous gas (PVG are relatively rare radiological findings. Although several chemotherapeutic agents and anti-vascular endothelial growth factor agents are reported to be associated with PI and PVG, an association with anti-epidermal growth factor receptor (EGFR agents has not been described previously. Case presentation The present report describes a case of PI and PVG secondary to treatment with an EGFR tyrosine kinase inhibitor. A 66-year-old woman who had been diagnosed with metastatic lung adenocarcinoma presented with nausea, vomiting and abdominal distension after commencing gefitinib. A computed tomography (CT scan of the abdomen revealed PI extending from the ascending colon to the rectum, hepatic PVG, and infarction of the liver. Gefitinib therapy was discontinued immediately and the patient was managed conservatively. A follow-up CT scan 2 weeks later revealed that the PI and hepatic PVG had completely resolved. Conclusion This is the first report of PI and PVG caused by EGFR tyrosine kinase inhibitor. Although these complications are extremely rare, clinicians should be aware of the risk of PI and PVG in patients undergoing targeted molecular therapy.

  4. Frequency of brain metastasis in adenocarcinoma and large cell carcinoma of the lung: correlation with survival

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    Komaki, R.; Cox, J.D.; Stark, R.

    1983-01-01

    From January 1970 through December 1981, 469 patients with histologically or cytologically proven adenocarcinoma (AC) (349) and large cell carcinoma (LC) (120) of the lung were seen at the Department of Radiation Oncology, Medical College of Wisconsin Affiliated Hospitals. One quarter (126/469) of these patients had brain metastasis: 48 patients presented with brain metastasis and 78 patients subsequently developed brain metastasis. Brain was the dominant site of metastasis in 82 patients who received only cranial + thoracic irradiation; 37 patients (17 simultaneous, 20 metachronous) also required irradiation of other sites of metastasis. All 17 patients with LC, and 47/61 (77%) with AC who developed metachronous brain metastasis did so within one year. The cumulative probability of brain metastasis increased with survival to the levels predicted by autopsy studies. Therapeutic brain irradiation may result in long-term survival in patients with single organ brain metastasis. Since patients with AC and LC so frequently develop brain metastasis and the brain may be the only site of metastasis, prophylactic cranial irradiation may significantly reduce morbidity and mortality from these diseases

  5. Aberrant Long Noncoding RNAs Expression Profiles Affect Cisplatin Resistance in Lung Adenocarcinoma

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    Lijuan Hu

    2017-01-01

    Full Text Available Background. Long noncoding RNAs (lncRNAs have been shown to be involved in the mechanism of cisplatin resistance in lung adenocarcinoma (LAD. However, the roles of lncRNAs in cisplatin resistance in LAD are not well understood. Methods. We used a high-throughput microarray to compare the lncRNA and mRNA expression profiles in cisplatin resistance cell A549/DDP and cisplatin sensitive cell A549. Several candidate cisplatin resistance-associated lncRNAs were verified by real-time quantitative reverse transcription polymerase chain reaction (PCR analysis. Results. We found that 1,543 lncRNAs and 1,713 mRNAs were differentially expressed in A549/DDP cell and A549 cell, hinting that many lncRNAs were irregular from cisplatin resistance in LAD. We also obtain the fact that 12 lncRNAs were aberrantly expressed in A549/DDP cell compared with A549 cell by quantitative PCR. Among these, UCA1 was the aberrantly expressed lncRNA and can significantly reduce the IC50 of cisplatin in A549/DDP cell after knockdown, while it can increase the IC50 of cisplatin after UCA1 was overexpressed in NCI-H1299. Conclusions. We obtained patterns of irregular lncRNAs and they may play a key role in cisplatin resistance of LAD.

  6. Pneumatosis intestinalis and portal venous gas secondary to Gefitinib therapy for lung adenocarcinoma

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    Lee, Joo Young; Han, Hye-Suk; Lim, Sung-Nam; Shim, Young Kwang; Choi, Yong Hyeok; Lee, Ok-Jun; Lee, Ki Hyeong; Kim, Seung Taik

    2012-01-01

    Pneumatosis intestinalis (PI), defined as the presence of gas in the bowel wall, and portal venous gas (PVG) are relatively rare radiological findings. Although several chemotherapeutic agents and anti-vascular endothelial growth factor agents are reported to be associated with PI and PVG, an association with anti-epidermal growth factor receptor (EGFR) agents has not been described previously. The present report describes a case of PI and PVG secondary to treatment with an EGFR tyrosine kinase inhibitor. A 66-year-old woman who had been diagnosed with metastatic lung adenocarcinoma presented with nausea, vomiting and abdominal distension after commencing gefitinib. A computed tomography (CT) scan of the abdomen revealed PI extending from the ascending colon to the rectum, hepatic PVG, and infarction of the liver. Gefitinib therapy was discontinued immediately and the patient was managed conservatively. A follow-up CT scan 2 weeks later revealed that the PI and hepatic PVG had completely resolved. This is the first report of PI and PVG caused by EGFR tyrosine kinase inhibitor. Although these complications are extremely rare, clinicians should be aware of the risk of PI and PVG in patients undergoing targeted molecular therapy

  7. Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study.

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    Jianxin Shi

    2016-12-01

    Full Text Available Lung adenocarcinoma (LUAD is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression.We performed an integrative genomic analysis, incorporating whole exome sequencing (WES, determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE study. We detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. We performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. We also tested the association between mutation signatures and clinical outcomes, including distant metastasis, survival, and tumor grade. We identified and replicated two novel candidate driver genes, POU class 4 homeobox 2 (POU4F2 (mutated in 9 [8.9%] samples and ZKSCAN1 (mutated in 6 [5.9%] samples, and characterized their major deleterious mutations. ZKSCAN1 was part of a mutually exclusive gene set that included the RTK/RAS/RAF pathway genes BRAF, EGFR, KRAS, MET, and NF1, indicating an important driver role for this gene. Moreover, we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. In the tumor evolution analysis, four driver genes had a significantly lower fraction of subclonal mutations (FSM, including TP53 (p = 0.007, KEAP1 (p = 0.012, STK11 (p = 0.0076, and EGFR (p = 0.0078, suggesting a tumor initiation role for these genes. Subclonal mutations were significantly enriched in APOBEC-related signatures (p < 2.5×10-50. The total number of somatic mutations (p = 0.0039 and the fraction of transitions (p = 5.5×10-4 were associated with increased risk of

  8. Different fatty acid metabolism effects of (−-Epigallocatechin-3-Gallate and C75 in Adenocarcinoma lung cancer

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    Relat Joana

    2012-07-01

    Full Text Available Abstract Background Fatty acid synthase (FASN is overexpressed and hyperactivated in several human carcinomas, including lung cancer. We characterize and compare the anti-cancer effects of the FASN inhibitors C75 and (−-epigallocatechin-3-gallate (EGCG in a lung cancer model. Methods We evaluated in vitro the effects of C75 and EGCG on fatty acid metabolism (FASN and CPT enzymes, cellular proliferation, apoptosis and cell signaling (EGFR, ERK1/2, AKT and mTOR in human A549 lung carcinoma cells. In vivo, we evaluated their anti-tumour activity and their effect on body weight in a mice model of human adenocarcinoma xenograft. Results C75 and EGCG had comparable effects in blocking FASN activity (96,9% and 89,3% of inhibition, respectively. In contrast, EGCG had either no significant effect in CPT activity, the rate-limiting enzyme of fatty acid β-oxidation, while C75 stimulated CPT up to 130%. Treating lung cancer cells with EGCG or C75 induced apoptosis and affected EGFR-signaling. While EGCG abolished p-EGFR, p-AKT, p-ERK1/2 and p-mTOR, C75 was less active in decreasing the levels of EGFR and p-AKT. In vivo, EGCG and C75 blocked the growth of lung cancer xenografts but C75 treatment, not EGCG, caused a marked animal weight loss. Conclusions In lung cancer, inhibition of FASN using EGCG can be achieved without parallel stimulation of fatty acid oxidation and this effect is related mainly to EGFR signaling pathway. EGCG reduce the growth of adenocarcinoma human lung cancer xenografts without inducing body weight loss. Taken together, EGCG may be a candidate for future pre-clinical development.

  9. CA 19-9 and CA 125 as potential predictors of disease recurrence in resectable lung adenocarcinoma.

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    Sofi Isaksson

    Full Text Available Among patients who underwent primary surgery for non-small cell lung cancer (NSCLC, recurrent disease is frequent and cannot be accurately predicted solely from TNM stage and histopathological features. The aim of this study was to examine the association of tumor markers in pre-operative serum with recurrent disease.Blood samples were collected prior to lung cancer surgery from 107 patients with stage I-III lung adenocarcinoma surgically treated at Lund University hospital, Lund, Sweden, between 2005 and 2011. The serum tumor markers Carcinoembryonic antigen (CEA, Neuron-specific enolase (NSE, Cancer antigen 125 (CA 125, Human epididymis protein 4 (HE4 and Carbohydrate antigen (CA 19-9 were analyzed retrospectively and clinical follow-up data were collected from patient charts. Forty (37% patients were diagnosed with recurrent disease.Sixty-eight (64% patients had at least one elevated tumor marker prior to surgery. In analysis of disease-free survival (DFS, CA 125 and/or CA 19-9 were significantly associated with recurrent disease adjusted to stage and adjuvant treatment (hazard ratio 2.8, 95% confidence interval 1.4-5.7, p = 0.006.High pre-operative serum CA 19-9 and/or CA 125 might indicate an increased incidence of recurrent disease in resectable lung adenocarcinomas.

  10. Differential N-glycan patterns identified in lung adenocarcinoma by N-glycan profiling of formalin-fixed paraffin-embedded (FFPE) tissue sections.

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    Wang, Xiaoning; Deng, Zaian; Huang, Chuncui; Zhu, Tong; Lou, Jiatao; Wang, Lin; Li, Yan

    2018-02-10

    N-glycan profiling is a powerful approach for analyzing the functional relationship between N-glycosylation and cancer. Current methods rely on either serum or fresh tissue samples; however, N-glycan patterns may differ between serum and tissue, as the proteins of serum originate from a variety of tissues. Furthermore, fresh tissue samples are difficult to ship and store. Here, we used a profiling method based on formalin-fixed paraffin-embedded (FFPE) tissue sections from lung adenocarcinoma patients. We found that our method was highly reproducible. We identified 58 N-glycan compositions from lung adenocarcinoma FFPE samples, 51 of which were further used for MS n -based structure prediction. We show that high mannose type N-glycans are upregulated, while sialylated N-glycans are downregulated in our FFPE lung adenocarcinoma samples, compared to the control samples. Our receiver operating characteristic (ROC) curve analysis shows that high mannose type and sialylated N-glycans are useful discriminators to distinguish between lung adenocarcinoma and control tissue. Together, our results indicate that expression levels of specific N-glycans correlate well with lung adenocarcinoma, and strongly suggest that our FFPE-based method will be useful for N-glycan profiling of cancer tissues. Glycosylation is one of the most important post-translational protein modifications, and is associated with several physiopathological processes, including carcinogenesis. In this study, we tested the feasibility of using formalin-fixed paraffin-embedded (FFPE) tissue sections to identify changes in N-glycan patterns and identified the differentially expressed N-glycans of lung adenocarcinoma. Our study shows that the FFPE-based N-glycan profiling method is useful for clinical diagnosis as well as identification of potential biomarkers, and our data expand current knowledge of differential N-glycan patterns of lung adenocarcinoma. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. miR-24-3p/FGFR3 Signaling as a Novel Axis Is Involved in Epithelial-Mesenchymal Transition and Regulates Lung Adenocarcinoma Progression

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    Pengyu Jing

    2018-01-01

    Full Text Available Our previous studies showed that Fibroblast growth factor receptor 3 (FGFR3 contributed to cell growth in lung cancer. However, the correlation between FGFR3 and tumor progression, coupled with the underlying mechanisms, are not fully understood. The clinical significance of FGFR3 was determined in two cohorts of clinical samples (n=22, n=78. A panel of biochemical assays and functional experiments was utilized to elucidate the underlying mechanisms and effects of FGFR3 and miR-24-3p on lung adenocarcinoma progression. Upregulated FGFR3 expression indicated an adverse prognosis for lung adenocarcinoma individuals and promoted metastatic potential of lung adenocarcinoma cells. Owing to the direct regulation towards FGFR3, miR-24-3p could interfere with the potential of proliferation, migration, and invasion in lung adenocarcinoma, following variations of EMT-related protein expression. As a significant marker of EMT, E-cadherin was negatively correlated with FGFR3, of which ectopic overexpression could neutralize the antitumour effects of miR-24-3p and reverse its regulatory effects on EMT markers. Taken together, these findings define a novel insight into the miR-24-3p/FGFR3 signaling axis in regulating lung adenocarcinoma progression and suggest that targeting the miR-24-3p/FGFR3 axis could be an effective and efficient way to prevent tumor progression.

  12. LAP TGF-Beta Subset of CD4+CD25+CD127− Treg Cells is Increased and Overexpresses LAP TGF-Beta in Lung Adenocarcinoma Patients

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    Islas-Vazquez, Lorenzo; Aguilar-Cazares, Dolores; Meneses-Flores, Manuel; Galicia-Velasco, Miriam; Romero-Garcia, Susana; Camacho-Mendoza, Catalina; Lopez-Gonzalez, Jose Sullivan

    2015-01-01

    Lung cancer is the leading cause of cancer death worldwide. Adenocarcinoma, the most commonly diagnosed histologic type of lung cancer, is associated with smoking. Cigarette smoke promotes inflammation on the airways, which might be mediated by Th17 cells. This inflammatory environment may contribute to tumor development. In contrast, some reports indicate that tumors may induce immunosuppressive Treg cells to dampen immune reactivity, supporting tumor growth and progression. Thus, we aimed to analyze whether chronic inflammation or immunosuppression predominates at the systemic level in lung adenocarcinoma patients, and several cytokines and Th17 and Treg cells were studied. Higher proportions of IL-17-producing CD4+ T-cells were found in smoking control subjects and in lung adenocarcinoma patients compared to nonsmoking control subjects. In addition, lung adenocarcinoma patients increased both plasma concentrations of IL-2, IL-4, IL-6, and IL-10, and proportions of Latency Associated Peptide (LAP) TGF-β subset of CD4+CD25+CD127− Treg cells, which overexpressed LAP TGF-β. This knowledge may lead to the development of immunotherapies that could inhibit the suppressor activity mediated by the LAP TGF-β subset of CD4+CD25+CD127− Treg cells to promote reactivity of immune cells against lung adenocarcinoma cells. PMID:26582240

  13. LAP TGF-Beta Subset of CD4+CD25+CD127− Treg Cells is Increased and Overexpresses LAP TGF-Beta in Lung Adenocarcinoma Patients

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    Lorenzo Islas-Vazquez

    2015-01-01

    Full Text Available Lung cancer is the leading cause of cancer death worldwide. Adenocarcinoma, the most commonly diagnosed histologic type of lung cancer, is associated with smoking. Cigarette smoke promotes inflammation on the airways, which might be mediated by Th17 cells. This inflammatory environment may contribute to tumor development. In contrast, some reports indicate that tumors may induce immunosuppressive Treg cells to dampen immune reactivity, supporting tumor growth and progression. Thus, we aimed to analyze whether chronic inflammation or immunosuppression predominates at the systemic level in lung adenocarcinoma patients, and several cytokines and Th17 and Treg cells were studied. Higher proportions of IL-17-producing CD4+ T-cells were found in smoking control subjects and in lung adenocarcinoma patients compared to nonsmoking control subjects. In addition, lung adenocarcinoma patients increased both plasma concentrations of IL-2, IL-4, IL-6, and IL-10, and proportions of Latency Associated Peptide (LAP TGF-β subset of CD4+CD25+CD127− Treg cells, which overexpressed LAP TGF-β. This knowledge may lead to the development of immunotherapies that could inhibit the suppressor activity mediated by the LAP TGF-β subset of CD4+CD25+CD127− Treg cells to promote reactivity of immune cells against lung adenocarcinoma cells.

  14. Histologic Subtype in Core Lung Biopsies of Early-Stage Lung Adenocarcinoma is a Prognostic Factor for Treatment Response and Failure Patterns After Stereotactic Body Radiation Therapy

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    Leeman, Jonathan E.; Rimner, Andreas [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Montecalvo, Joseph [Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Hsu, Meier; Zhang, Zhigang [Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Reibnitz, Donata von; Panchoo, Kelly [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Yorke, Ellen [Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Adusumilli, Prasad S. [Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Travis, William [Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Wu, Abraham J., E-mail: wua@mskcc.org [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States)

    2017-01-01

    Purpose: Stereotactic body radiation therapy (SBRT) has emerged as an effective treatment for early-stage lung cancer. The histologic subtype of surgically resected lung adenocarcinoma is recognized as a prognostic factor, with the presence of solid or micropapillary patterns predicting poor outcomes. We describe the outcomes after SBRT for early-stage lung adenocarcinoma stratified by histologic subtype. Methods and Materials: We identified 119 consecutive patients (124 lesions) with stage I to IIA lung adenocarcinoma who had undergone definitive SBRT at our institution from August 2008 to August 2015 and had undergone core biopsy. Histologic subtyping was performed according to the 2015 World Health Organization classification. Of the 124 tumors, 37 (30%) were a high-risk subtype, defined as containing a component of solid and/or micropapillary pattern. The cumulative incidences of local, nodal, regional, and distant failure were compared between the high-risk and non–high-risk adenocarcinoma subtypes using Gray's test, and multivariable-adjusted hazard ratios (HRs) were estimated from propensity score–weighted Cox regression models. Results: The median follow-up for the entire cohort was 17 months and for surviving patients was 21 months. The 1-year cumulative incidence of and adjusted HR for local, nodal, regional, and distant failure in high-risk versus non–high-risk lesions was 7.3% versus 2.7% (HR 16.8; 95% confidence interval [CI] 3.5-81.4), 14.8% versus 2.6% (HR 3.8; 95% CI 0.95-15.0), 4.0% versus 1.2% (HR 20.9; 95% CI 2.3-192.3), and 22.7% versus 3.6% (HR 6.9; 95% CI 2.2-21.1), respectively. No significant difference was seen with regard to overall survival. Conclusions: The outcomes after SBRT for early-stage adenocarcinoma of the lung correlate highly with histologic subtype, with micropapillary and solid tumors portending significantly higher rates of locoregional and metastatic progression. In this context, the histologic subtype

  15. Associations Between PET Textural Features and GLUT1 Expression, and the Prognostic Significance of Textural Features in Lung Adenocarcinoma.

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    Koh, Young Wha; Park, Seong Yong; Hyun, Seung Hyup; Lee, Su Jin

    2018-02-01

    We evaluated the association between positron emission tomography (PET) textural features and glucose transporter 1 (GLUT1) expression level and further investigated the prognostic significance of textural features in lung adenocarcinoma. We evaluated 105 adenocarcinoma patients. We extracted texture-based PET parameters of primary tumors. Conventional PET parameters were also measured. The relationships between PET parameters and GLUT1 expression levels were evaluated. The association between PET parameters and overall survival (OS) was assessed using Cox's proportional hazard regression models. In terms of PET textural features, tumors expressing high levels of GLUT1 exhibited significantly lower coarseness, contrast, complexity, and strength, but significantly higher busyness. On univariate analysis, the metabolic tumor volume, total lesion glycolysis, contrast, busyness, complexity, and strength were significant predictors of OS. Multivariate analysis showed that lower complexity (HR=2.017, 95%CI=1.032-3.942, p=0.040) was independently associated with poorer survival. PET textural features may aid risk stratification in lung adenocarcinoma patients. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  16. Impact of active smoking on survival of patients with metastatic lung adenocarcinoma harboring an epidermal growth factor receptor (EGFR mutation

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    Bulent Erdogan

    2016-11-01

    Full Text Available Lung cancer in smokers and non-smokers demonstrates distinct genetic profiles, and cigarette smoking affects epidermal growth factor receptor (EGFR function and causes secondary EGFR tyrosine kinase resistance. We evaluated the effect of active smoking in patients with metastatic lung adenocarcinoma. A total of 132 metastatic lung adenocarcinoma patients, diagnosed between 2008 and 2013, with known EGFR mutation status, were evaluated retrospectively. Among these patients, 40 had an activating EGFR mutation. Patients who continued smoking during the treatment were defined as active smokers. Former smokers and never smokers were together defined as non-smokers. The outcomes of the treatment in relation to the EGFR mutation and smoking status were evaluated. The median follow-up time was 10.5 months. The overall response rate for the first-line therapy was significantly higher among the EGFR-mutant patients (p = 0.01, however, smoking status had no impact on the response rate (p = 0.1. The EGFR-mutant active smokers progressed earlier than the non-smokers (p < 0.01. The overall survival (OS of the non-smokers and patients treated with erlotinib was significantly longer (p = 0.02 and p = 0.01, respectively. Smoking status did not affect the OS in EGFR wild type tumors (p = 0.49 but EGFR-mutant non-smokers had a longer OS than the active smokers (p = 0.01.The active smokers treated with erlotinib had poorer survival than the non-smokers (p = 0.03. Multivariate analysis of EGFR-mutant patients showed that erlotinib treatment at any line and non-smoking were independent prognostic factors for the OS (p = 0.04 and p = 0.01, respectively. Smoking during treatment is a negative prognostic factor in metastatic lung adenocarcinoma with an EGFR mutation.

  17. Impact of active smoking on survival of patients with metastatic lung adenocarcinoma harboring an epidermal growth factor receptor (EGFR) mutation.

    Science.gov (United States)

    Erdogan, Bulent; Kodaz, Hilmi; Karabulut, Senem; Cinkaya, Ahmet; Tozkir, Hilmi; Tanriverdi, Ozgur; Cabuk, Devrim; Hacioglu, Muhammed Bekir; Turkmen, Esma; Hacibekiroglu, Ilhan; Uzunoglu, Sernaz; Cicin, Irfan

    2016-11-10

    Lung cancer in smokers and non-smokers demonstrates distinct genetic profiles, and cigarette smoking affects epidermal growth factor receptor (EGFR) function and causes secondary EGFR tyrosine kinase resistance. We evaluated the effect of active smoking in patients with metastatic lung adenocarcinoma. A total of 132 metastatic lung adenocarcinoma patients, diagnosed between 2008 and 2013, with known EGFR mutation status, were evaluated retrospectively. Among these patients, 40 had an activating EGFR mutation. Patients who continued smoking during the treatment were defined as active smokers. Former smokers and never smokers were together defined as non-smokers. The outcomes of the treatment in relation to the EGFR mutation and smoking status were evaluated. The median follow-up time was 10.5 months. The overall response rate for the first-line therapy was significantly higher among the EGFR-mutant patients (p = 0.01), however, smoking status had no impact on the response rate (p = 0.1). The EGFR-mutant active smokers progressed earlier than the non-smokers (p non-smokers and patients treated with erlotinib was significantly longer (p = 0.02 and p = 0.01, respectively). Smoking status did not affect the OS in EGFR wild type tumors (p = 0.49) but EGFR-mutant non-smokers had a longer OS than the active smokers (p = 0.01).The active smokers treated with erlotinib had poorer survival than the non-smokers (p = 0.03). Multivariate analysis of EGFR-mutant patients showed that erlotinib treatment at any line and non-smoking were independent prognostic factors for the OS (p = 0.04 and p = 0.01, respectively). Smoking during treatment is a negative prognostic factor in metastatic lung adenocarcinoma with an EGFR mutation.

  18. MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma.

    Science.gov (United States)

    Tinder, Teresa L; Subramani, Durai B; Basu, Gargi D; Bradley, Judy M; Schettini, Jorge; Million, Arefayene; Skaar, Todd; Mukherjee, Pinku

    2008-09-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer.

  19. MUC1 enhances tumor progression and contributes towards immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma

    Science.gov (United States)

    Tinder, Teresa L.; Subramani, Durai B.; Basu, Gargi D.; Bradley, Judy M.; Schettini, Jorge; Million, Arefayene; Skaar, Todd

    2008-01-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune competent host. Significant enhancement in the development of pancreatic intraepithelial pre-neoplastic lesions (PanINs) and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and indoleamine 2,3, dioxygenase compared to PDA mice lacking MUC1, especially during early stages of tumor development. The increased pro-inflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease which in turn regulate the immune responses. Thus, the mouse model is ideally-suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

  20. Adenocarcinoma of the Lung Acquiring Resistance to Afatinib by Transformation to Small Cell Carcinoma: A Case Report

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    Jun Nishimura

    2017-07-01

    Full Text Available A 65-year-old woman visited our hospital due to right chest pain and dyspnea on exertion. Chest radiography revealed decreased permeability of the right lung. Computed tomography demonstrated a huge mass in the right upper lobe and right pleural effusion. Right pleural effusion cytology yielded a diagnosis of adenocarcinoma and was positive for mutation of epidermal growth factor receptor (EGFR; exon 21 L858R. Afatinib was selected for the initial treatment. Multiple tumors regressed remarkably, but then rapidly progressed 3 months later. We performed re-biopsy to detect the mechanism of resistance to afatinib. Histopathology revealed a mixture of small cell carcinoma (SCC and adenocarcinoma harboring same EGFR mutation. To the best of our knowledge, this is the first report of transformation to SCC after treatment with afatinib.

  1. Chemosensitivity of irradiated resistant cells of multicellular spheroids in A549 lung adenocarcinoma

    International Nuclear Information System (INIS)

    Shi Degang; Shi Genming; Huang Gang

    2006-01-01

    Objective: To investigate the chemosensitivity of irradiated resistant cells of multicellular spheroids in A549 lung adenocarcinoma. Methods: The A549 irradiated resistant cells were the 10th regrowth generations after irradiated with 2.5 Gy of 6 MV X-ray, the control groups were A549 parent cells and MCFY/VCR resistant cells. The 6 kinds of chemotherapeutic drugs were DDP, VDS, 5-FU, HCP, MMC and ADM respectively, with verapamil (VPL) as reverse agent. The treatment effect was compared with MTT assay, and the multidrug resistant gene expressions of mdrl and MRP were measured with RT-PCR method. Results: A549 cells and irradiated resistant cells were resistant to DDP, but sensitivity to VDS,5-FU, HCP, MMC and ADM. The inhibitory rates of VPL to the above two cells were 98% and 25% respectively(P 2 -MG and MRP/β 2 -MG of all A549 cells were about 0 and 0.7 respectively, and those of MCFT/VCR cells were 35 and 4.36. Conclusion: The chemosensitivity of A549 irradiated resistant cells had not changed markedly, the decreased sensitivity to VPL could not be explained by the gene expression of mdrl and MRP. It is conferred that some kinds of changes in the cell membrane and decreased regrowth ability to result in resistance. Unlike multidrug resistance induced by chemotherapy, VPL may be not an ideal reverser to irradiated resistant cells. The new kinds of biological preparation should be sought to combine chemotherapy to treat recurring tumor with irradiated resistance. (authors)

  2. Effects of TGF-β signaling blockade on human A549 lung adenocarcinoma cell lines.

    Science.gov (United States)

    Xu, Cheng-Cheng; Wu, Lei-Ming; Sun, Wei; Zhang, Ni; Chen, Wen-Shu; Fu, Xiang-Ning

    2011-01-01

    Transforming growth factor β (TGF-β) is overexpressed in a wide variety of cancer types including lung adenocarcinoma (LAC), and the TGF-β signaling pathway plays an important role in tumor development. To determine whether blockade of the TGF-β signaling pathway can inhibit the malignant biological behavior of LAC, RNA interference (RNAi) technology was used to silence the expression of TGF-β receptor, type II (TGFβRII) in the LAC cell line, A549, and its effects on cell proliferation, invasion and metastasis were examined. Three specific small interfering RNAs (siRNAs) designed for targeting human TGFβRII were transfected into A549 cells. The expression of TGFβRII was detected by Western blot analysis. Cell proliferation was measured by MTT and clonogenic assays. Cell apoptosis was assessed by flow cytometry. The invasion and metastasis of A549 cells were investigated using the wound healing and Matrigel invasion assays. The expression of PI3K, phosphorylated Smad2, Smad4, Akt, Erk1/2, P38 and MMPs was detected by Western blot analysis. The TGFβRII siRNA significantly reduced the expression of TGFβRII in A549 cells. The knockdown of TGFβRII in A549 cells resulted in the suppression of cell proliferation, invasion and metastasis and induced cell apoptosis. In addition to the Smad-dependent pathway, independent pathways including the Erk MAPK, PI3K/Akt and p38 MAPK pathways, as well as the expression of MMPs and VEGF, were inhibited. In conclusion, TGF-β signaling is required for LAC progression. Therefore, the blockade of this signaling pathway by the down-regulation of TGFβRII using SiRNA may provide a potential gene therapy for LAC.

  3. Four-miRNA signature as a prognostic tool for lung adenocarcinoma.

    Science.gov (United States)

    Lin, Yan; Lv, Yufeng; Liang, Rong; Yuan, Chunling; Zhang, Jinyan; He, Dan; Zheng, Xiaowen; Zhang, Jianfeng

    2018-01-01

    The aim of this study was to generate a novel miRNA expression signature to accurately predict prognosis for patients with lung adenocarcinoma (LUAD). Using expression profiles downloaded from The Cancer Genome Atlas database, we identified multiple miRNAs with differential expression between LUAD and paired healthy tissues. We then evaluated the prognostic values of the differentially expressed miRNAs using univariate/multivariate Cox regression analysis. This analysis was ultimately used to construct a four-miRNA signature that effectively predicted patient survival. Finally, we analyzed potential functional roles of the target genes for these four miRNAs using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Based on our cutoff criteria ( P 1.0), we identified a total of 187 differentially expressed miRNAs, including 148 that were upregulated in LUAD tissues and 39 that were downregulated. Four miRNAs (miR-148a-5p, miR-31-5p, miR-548v, and miR-550a-5p) were independently associated with survival based on Kaplan-Meier analysis. We generated a signature index based on the expression of these four miRNAs and stratified patients into low- and high-risk groups. Patients in the high-risk group had significantly shorter survival times than those in the low-risk group ( P =0.002). A functional enrichment analysis suggested that the target genes of these four miRNAs were involved in protein phosphorylation and the Hippo and sphingolipid signaling pathways. Taken together, our results suggest that our four-miRNA signature can be used as a prognostic tool for patients with LUAD.

  4. Adenocarcinoma do pulmão em doente com esclerodermia: Um caso clínico Lung adenocarcinoma associated with systemic sclerosis: A case report

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    João Bento

    2009-01-01

    Full Text Available A esclerodermia é uma doença do tecido conjuntivo de etiologia desconhecida, que tem sido associada a um risco acrescido de malignidade. O cancro do pulmão é a neoplasia mais frequente, nestes doentes. Apresenta-se o caso clínico de uma mulher de 42 anos, não fumadora, com esclerodermia, que desenvolveu agravamento progressivo do seu estado geral e derrame pleural com características de exsudado, sem evidência de infecção ou malignidade. A TAC torácica mostrou zonas de fibrose, a broncofibroscopia, os lavados brônquico e broncoalveolar foram normais. Foi excluída neoplasia extrapulmonar. Na pleuroscopia, observaram-se formações nodulares, cujas biópsias revelaram tratar-se de adenocarcinoma pulmonar. Iniciou quimioterapia, desenvolvendo ao 48.º dia neutropenia febril e sépsis, vindo a morrer 12 dias depois. Salientamos este caso pela relação, apesar de rara, entre a esclerodermia e o cancro do pulmão e pela importância de uma vigilância pulmonar cuidadosa, em indivíduos com esta doença reumatológica, pelo risco acrescido de neoplasia.Systemic sclerosis (scleroderma is a connective tissue disorder of unknown aetiology characterised by immune abnormalities, which has been related to an increased risk of malignancy. Lung cancer is the most prevalent among these patients. We present a clinical case of a 42 years old non smoker female with systemic sclerosis. She presented progressive general health status worsening and an exudative pleural effusion, with no evidence of infection or malignancy. Chest high resolution computed tomography revealed pulmonary fibrosis. Bronchoscopy, bronchial and bronchoalveolar lavage were normal. Extra-pulmonary malignancies were excluded. Pleural nodularities were found on pleuroscopy and the biopsy was compatible with lung adenocarcinoma. Chemotherapy was then started, which complicated with febrile neutropenia, sepsis and patient death 12 days after. The purpose of this case report is to

  5. Sex-specific incidence of EGFR mutation and its association with age and obesity in lung adenocarcinomas: a retrospective analysis.

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    Kim, Hye-Ryoun; Kim, Seo Yun; Kim, Cheol Hyeon; Yang, Sung Hyun; Lee, Jae Cheol; Choi, Chang-Min; Na, Im Il

    2017-11-01

    Age and obesity are well-known risk factors for various cancers, but the potential roles of age and obesity in lung cancer, especially in those with activating EGFR mutations, have not been thoroughly evaluated. The aim of this retrospective study is to evaluate the associations between the sex-specific incidence of EGFR mutations and age and obesity. We conducted a retrospective study based on the data from 1378 lung adenocarcinoma cases. The degree of obesity was categorized by body mass index (BMI). The associations between EGFR mutational status and clinical factors, including stage, smoking history, age group (≤45 years, 46-55, 56-65 and >65), and BMI group (obesity (adjusted OR for BMI group = 1.23, p-trend = 0.04). In contrast, in women, the incidence of EGFR mutation was positively associated with age (adjusted OR for age group = 1.19, p-trend = 0.02). However, the incidence of EGFR mutation was not statistically associated with obesity (adjusted OR for BMI group = 1.03, p-trend = 0.76). Our data suggests that age and obesity may contribute to the sex-specific incidence of EGFR mutation in lung adenocarcinoma in different manners.

  6. Icotinib versus docetaxel used in lung adenocarcinoma patients who failed platinum-based chemotherapy: a retrospective study.

    Science.gov (United States)

    He, Wei; Zhang, Yan; Xiong, Yu; Dai, Feng-Juan; Fan, Qing-Xia

    2016-01-01

    The efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors have been studied worldwide. However, there are few reports directly comparing the efficacy and safety between icotinib and docetaxel as second-line treatment in lung adenocarcinoma patients who have failed platinum-based chemotherapy. This article offers insight into this field. A total of 137 patients with stage III or IV lung adenocarcinoma who had progressed on first-line platinum-based therapies and received icotinib or docetaxel therapy between October 2011 and February 2013 were retrospectively reviewed. Patients in the icotinib group received oral icotinib at a dose of 125 mg tid, while patients in the docetaxel group received infusion docetaxel at a dose of 75 mg/m(2) on day 1 of every 21 days (four to six cycles) until disease progression or unacceptable toxicity occurred after which best supportive care was given. There was no statistically significant difference in the objective response rate (23.3% vs 12.5%, P=0.103), progression-free survival (121 days vs 106 days, P=0.083), and overall survival (307 days vs 254 days, P=0.070) between the two groups. As compared to the docetaxel group, the disease control rate (75.3% vs 54.7%, P=0.011) was significantly better in the icotinib group. In the icotinib group, the most common adverse events were rash (35.62%) and diarrhea (24.66%), whereas in the docetaxel group, elevation of transaminase (37.50%), leukopenia (50.00%), and anemia (54.69%) were the most common. Icotinib had similar efficacy and a lower adverse events rate in epidermal growth factor receptor-unselected patients as compared to docetaxel, thereby making it an effective second-line therapy option for lung adenocarcinoma.

  7. Endostar, a recombined humanized endostatin, enhances the radioresponse for human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts in mice

    International Nuclear Information System (INIS)

    Wen Qinglian; Meng Maobin; Tu Lingli; Jia Li; Zhou Lin; Xu Yong; Lu You; Yang Bo

    2009-01-01

    The purpose of this paper is to determine the efficacy of combining radiation therapy with endostar, a recombined humanized endostatin, in human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts. Tumor xenografts were established in the hind limb of male athymic nude mice (BALB/c-nu) by subcutaneous transplantation. The tumor-bearing mice were assigned into four treatment groups: sham therapy (control), endostar (20 mg/kg, once daily for 10 days), radiation therapy (6 Gray per day to 30 Gray, once a day for 1 week), and endostar plus radiation therapy (combination). The experiment was repeated and mice were killed at days 3, 6, and 10 after initiation therapy, and the tumor tissues and blood samples were collected to analyze the kinetics of antitumor, antiangiogenesis, and antivascularization responses of different therapies. In human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts, endostar significantly enhanced the effects of tumor growth inhibition, endothelial cell and tumor cell apoptosis induction, and improved tumor cell hypoxia of radiation therapy. Histological analyses demonstrated that endostar plus radiation also induced a significant reduction in microvascular density, microvascular area, and vascular endothelial growth factor and matrix metalloproteinase-2 expression compared with radiation and endostar alone respectively. We concluded that endostar significantly sensitized the function of radiation in antitumor and antiangiogenesis in human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts by increasing the apoptosis of the endothelial cell and tumor cell, improving the hypoxia of the tumor cell, and changing the proangiogenic factors. These data provided a rational basis for clinical practice of this multimodality therapy. (author)

  8. Effect of silencing of ATM expression by siRNA on radiosensitivity of human lung adenocarcinoma A549 cells

    International Nuclear Information System (INIS)

    Liu Xiaoqun; Qiao Tiankui

    2014-01-01

    Objective: To investigate the effect of silencing of ataxia-telangiectasia mutated (ATM) expression by plasmid-mediated RNA interference on the radiosensitivity of human lung adenocarcinoma A 549 cells. Methods: Eukaryotic expression plasmid containing ATM small interfering RNA (siRNA) (pSilencer2.1-ATM), as well as pSilencer2.1-nonspecific, was constructed.Lung adenocarcinoma A 549 cells were divided into positive group, negative group,and control group to be transfected with pSilencer2.1-ATM, pSilencer2.1-nonspecific, and no plasmid, respectively. The mRNA and protein expression of ATM was measured by RT-PCR and Western blot, respectively. The change in cell radiosensitivity was observed by colony-forming assay. Cell cycle and cell apoptosis were analyzed by flow cytometry. Results: The eukaryotic expression plasmid containing ATM siRNA was successfully constructed. The RT-PCR and Western blot demonstrated that the expression of ATM was down-regulated in the positive group. The sensitization enhancement ratios (D 0 ratios) for the positive group and negative group were 1.50 and 1.01, respectively. The flow cytometry revealed that the proportions of A 549 cells in G 1 and G 2 /M phases were significantly lower in the positive group than in the control group (51.27% vs 61.85%, P = 0.012; 6.34% vs 10.91%, P = 0.008) and that the apoptosis rate was significantly higher in the positive group than in the control group and negative group (49.31% vs 13.58%, P = 0.000; 49.31% vs 13.17%, P = 0.000). Conclusions: Silencing of ATM expression may increase the radiosensitivity of human lung adenocarcinoma A 549 cells, probably by affecting the cell cycle and promoting cell apoptosis. (authors)

  9. Antitumor activity and systemic effects of PVM/MA-shelled selol nanocapsules in lung adenocarcinoma-bearing mice

    International Nuclear Information System (INIS)

    De Souza, Ludmilla Regina; Muehlmann, Luis Alexandre; Matos, Lívia Carneiro; Lacava, Zulmira Guerreiro Marques; Báo, Sônia Nair; Azevedo, Ricardo Bentes; Simón-Vázquez, Rosana; González-Fernández, África; De-Paula, Alfredo Maurício Batista; Mosiniewicz-Szablewska, Ewa; Suchocki, Piotr; Morais, Paulo César

    2015-01-01

    Selol is a semi-synthetic compound containing selenite that is effective against cancerous cells and safer for clinical applications in comparison with other inorganic forms of selenite. Recently, we have developed a formulation of poly(methyl vinyl ether-co-maleic anhydride)-shelled selol nanocapsules (SPN), which reduced the proliferative activity of lung adenocarcinoma cells and presented little deleterious effects on normal cells in in vitro studies. In this study, we report on the antitumor activity and systemic effects induced by this formulation in chemically induced lung adenocarcinoma-bearing mice. The in vivo antitumor activity of the SPN was verified by macroscopic quantification, immunohistochemistry and morphological analyses. Toxicity analyses were performed by evaluations of the kidney, liver, and spleen; analyses of hemogram and plasma levels of alanine aminotransferase, aspartate transaminase, urea, and creatinine; and DNA fragmentation and cell cycle activity of the bone marrow cells. Furthermore, we investigated the potential of the SPN formulation to cause hemolysis, activate the complement system, provoke an inflammatory response and change the conformation of the plasma proteins. Our results showed that the SPN reduced the area of the surface tumor nodules but not the total number of tumor nodules. The biochemical and hematological findings were suggestive of the low systemic toxicity of the SPN formulation. The surface properties of the selol nanocapsules point to characteristics that are consistent with the treatment of the tumors in vivo: low hemolytic activity, weak inflammatory reaction with no activation of the complement system, and mild or absent conformational changes of the plasma proteins. In conclusion, this report suggests that the SPN formulation investigated herein exhibits anti-tumoral effects against lung adenocarcinoma in vivo and is associated with low systemic toxicity and high biocompatibility. (paper)

  10. Aberrant status and clinicopathologic characteristic associations of 11 target genes in 1,321 Chinese patients with lung adenocarcinoma.

    Science.gov (United States)

    Zhao, Mengnan; Zhan, Cheng; Li, Ming; Yang, Xiaodong; Yang, Xinyu; Zhang, Yong; Lin, Miao; Xia, Yifeng; Feng, Mingxiang; Wang, Qun

    2018-01-01

    The aberrant status of target genes and their associations with clinicopathologic characteristics are still unclear in primary lung adenocarcinoma. The common mutations and translocations of nine target genes were evaluated in 1,247 specimens of surgically-resected primary lung adenocarcinoma. Immunohistochemistry was used to analyze the expressions of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) in 731 specimens. The frequency of the aberrations and their associations with clinicopathologic characteristics were analyzed. Overall, 952 (76.3%) of 1,247 patients harbored at least one target mutation or translocation: epidermal growth factor receptor ( EGFR ) (729, 58.5%), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) (83, 6.7%), human epidermal growth factor receptor 2 ( HER2 ) (82, 6.6%), anaplastic lymphoma kinase ( ALK) (23, 1.8%), phosphoinositide-3-kinase catalytic alpha polypeptide ( PIK3CA ) (20, 1.6%), Ret proto-oncogene RET (15, 1.2%), ROS proto-oncogene 1 receptor tyrosine kinase ( ROS1 ) (12, 1.0%), B-raf proto-oncogene ( BRAF ) (9, 0.7%), neuroblastoma RAS viral (v-ras) oncogene homolog ( NRAS ) (3, 0.2%). Fourteen (1.9%) of 731 patients were PD-1 positive and 95 (13.0%) were PD-L1 positive in tumor cells. In men and smokers, there were more frequent KRAS mutations (both Ppatients, while HER2 (Ppatients with EGFR mutations (all Ppatients with primary lung adenocarcinoma harbored target gene aberrations. The frequency of each alteration differed in patients depending on clinicopathologic characteristics.

  11. Icotinib versus docetaxel used in lung adenocarcinoma patients who failed platinum-based chemotherapy: a retrospective study

    Directory of Open Access Journals (Sweden)

    He W

    2016-07-01

    Full Text Available Wei He, Yan Zhang, Yu Xiong, Feng-juan Dai, Qing-xia Fan The Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China Background: The efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors have been studied worldwide. However, there are few reports directly comparing the efficacy and safety between icotinib and docetaxel as second-line treatment in lung adenocarcinoma patients who have failed platinum-based chemotherapy. This article offers insight into this field.Methods: A total of 137 patients with stage III or IV lung adenocarcinoma who had progressed on first-line platinum-based therapies and received icotinib or docetaxel therapy between October 2011 and February 2013 were retrospectively reviewed. Patients in the icotinib group received oral icotinib at a dose of 125 mg tid, while patients in the docetaxel group received infusion docetaxel at a dose of 75 mg/m2 on day 1 of every 21 days (four to six cycles until disease progression or unacceptable toxicity occurred after which best supportive care was given.Results: There was no statistically significant difference in the objective response rate (23.3% vs 12.5%, P=0.103, progression-free survival (121 days vs 106 days, P=0.083, and overall survival (307 days vs 254 days, P=0.070 between the two groups. As compared to the docetaxel group, the disease control rate (75.3% vs 54.7%, P=0.011 was significantly better in the icotinib group. In the icotinib group, the most common adverse events were rash (35.62% and diarrhea (24.66%, whereas in the docetaxel group, elevation of transaminase (37.50%, leukopenia (50.00%, and anemia (54.69% were the most common.Conclusion: Icotinib had similar efficacy and a lower adverse events rate in epidermal growth factor receptor-unselected patients as compared to docetaxel, thereby making it an effective second-line therapy option for lung adenocarcinoma

  12. Comparison of a radiomic biomarker with volumetric analysis for decoding tumour phenotypes of lung adenocarcinoma with different disease-specific survival

    International Nuclear Information System (INIS)

    Yuan, Mei; Zhang, Yu-Dong; Pu, Xue-Hui; Zhong, Yan; Yu, Tong-Fu; Li, Hai; Wu, Jiang-Fen

    2017-01-01

    To compare a multi-feature-based radiomic biomarker with volumetric analysis in discriminating lung adenocarcinomas with different disease-specific survival on computed tomography (CT) scans. This retrospective study obtained institutional review board approval and was Health Insurance Portability and Accountability Act (HIPAA) compliant. Pathologically confirmed lung adenocarcinoma (n = 431) manifested as subsolid nodules on CT were identified. Volume and percentage solid volume were measured by using a computer-assisted segmentation method. Radiomic features quantifying intensity, texture and wavelet were extracted from the segmented volume of interest (VOI). Twenty best features were chosen by using the Relief method and subsequently fed to a support vector machine (SVM) for discriminating adenocarcinoma in situ (AIS)/minimally invasive adenocarcinoma (MIA) from invasive adenocarcinoma (IAC). Performance of the radiomic signatures was compared with volumetric analysis via receiver-operating curve (ROC) analysis and logistic regression analysis. The accuracy of proposed radiomic signatures for predicting AIS/MIA from IAC achieved 80.5% with ROC analysis (Az value, 0.829; sensitivity, 72.1%; specificity, 80.9%), which showed significantly higher accuracy than volumetric analysis (69.5%, P = 0.049). Regression analysis showed that radiomic signatures had superior prognostic performance to volumetric analysis, with AIC values of 81.2% versus 70.8%, respectively. The radiomic tumour-phenotypes biomarker exhibited better diagnostic accuracy than traditional volumetric analysis in discriminating lung adenocarcinoma with different disease-specific survival. (orig.)

  13. Comparison of a radiomic biomarker with volumetric analysis for decoding tumour phenotypes of lung adenocarcinoma with different disease-specific survival

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Mei; Zhang, Yu-Dong; Pu, Xue-Hui; Zhong, Yan; Yu, Tong-Fu [First Affiliated Hospital of Nanjing Medical University, Department of Radiology, Nanjing, Jiangsu Province (China); Li, Hai [First Affiliated Hospital of Nanjing Medical University, Department of Pathology, Nanjing (China); Wu, Jiang-Fen [GE Healthcare, Shanghai (China)

    2017-11-15

    To compare a multi-feature-based radiomic biomarker with volumetric analysis in discriminating lung adenocarcinomas with different disease-specific survival on computed tomography (CT) scans. This retrospective study obtained institutional review board approval and was Health Insurance Portability and Accountability Act (HIPAA) compliant. Pathologically confirmed lung adenocarcinoma (n = 431) manifested as subsolid nodules on CT were identified. Volume and percentage solid volume were measured by using a computer-assisted segmentation method. Radiomic features quantifying intensity, texture and wavelet were extracted from the segmented volume of interest (VOI). Twenty best features were chosen by using the Relief method and subsequently fed to a support vector machine (SVM) for discriminating adenocarcinoma in situ (AIS)/minimally invasive adenocarcinoma (MIA) from invasive adenocarcinoma (IAC). Performance of the radiomic signatures was compared with volumetric analysis via receiver-operating curve (ROC) analysis and logistic regression analysis. The accuracy of proposed radiomic signatures for predicting AIS/MIA from IAC achieved 80.5% with ROC analysis (Az value, 0.829; sensitivity, 72.1%; specificity, 80.9%), which showed significantly higher accuracy than volumetric analysis (69.5%, P = 0.049). Regression analysis showed that radiomic signatures had superior prognostic performance to volumetric analysis, with AIC values of 81.2% versus 70.8%, respectively. The radiomic tumour-phenotypes biomarker exhibited better diagnostic accuracy than traditional volumetric analysis in discriminating lung adenocarcinoma with different disease-specific survival. (orig.)

  14. Seven-microRNA panel for lung adenocarcinoma early diagnosis in patients presenting with ground-glass nodules

    Directory of Open Access Journals (Sweden)

    He Y

    2017-12-01

    Full Text Available Yayi He,1,2,* Yang Yang,3,* Peng Kuang,1 Shengxiang Ren,1 Leslie Rozeboom,2 Christopher J Rivard,2 Xuefei Li,4 Caicun Zhou,1 Fred R Hirsch2 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, People’s Republic of China; 2Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 3Department of Surgery, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, 4Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: MicroRNA (miRNA expression is correlated with tumor histology, differentiation, invasiveness and treatment outcome. We aimed to identify miRNAs whose differential expression might enable early diagnosis of lung adenocarcinoma in patients presenting with ground-glass nodules (GGNs.Methods: To identify potential miRNAs of interest, we analyzed the miRNA expression profile of tumor and adjacent non-para-tumor tissue in three participants by next-generation sequencing (NGS. We then assessed the expression levels of the miRNAs of interest in 73 lung adenocarcinomas presenting with GGNs with matched adjacent non-tumor tissue by quantitative real-time polymerase chain reaction (qRT-PCR. We also detected the miRNA panel in 66 lung benign diseases and 66 lung adenocarcinomas presenting with GGN lesion tissues by qRT-PCR. Target genes of our selected miRNA panel were predicted using Miranda with default parameters.Results: Twenty-three miRNAs showed differential expression between tumor and adjacent non-tumor tissue by NGS. Five miRNAs exhibited higher expression in tumor tissue compared to adjacent non-tumor tissue (P

  15. Prognostic significance of DNA content in stage I adenocarcinoma of the lung

    International Nuclear Information System (INIS)

    Roberts, Heidi L.; Komaki, Ritsuko; Allen, Pamela; El-Naggar, Adel K.

    1998-01-01

    Purpose: Up to 30% of lung cancers (Stage I) with the most favorable outcome recur within 5 years after surgery. This study reviews the pattern of failure after surgical resection in early lung cancers and determines whether flow cytometric DNA variables were prognostic indicators for survival, disease-free survival (DFS), or distant metastasis-free survival (DMFS). Methods and Materials: Pathologic specimens from 45 patients at The University of Texas M. D. Anderson Cancer Center who underwent surgical resection and mediastinal nodal dissection for stage I (AJCC) adenocarcinomas of the lung were analyzed by flow cytometry for DNA content. Survival was calculated by the method of Desu and Lee. Chi-square and cross tabulation were used in the analysis. Results: The mean age of the patients was 62 years, and 52.3% were male. All patients were clinical Stage I (T1-2 N0), Karnofsky performance status ≥70, and had a weight loss <10 lbs. Median overall survival (OS) and DFS were 50 months and 33 months, respectively. OS, DFS, and DMFS at 1, 3 and 5 years were 73%, 57%, and 35%; 63%, 53%, and 45%; and 67%, 56%, and 48%, respectively. Analysis of all 45 patients revealed 86% of patients developing brain metastasis had an abnormal DNA content ≥ 30%, whereas 4% of patients with brain metastasis had abnormal DNA content < 30% (p = 0.01). This correlation maintained significance when only pT1/2 lesions were analyzed. There was a significant statistical correlation between abnormal DNA and 5-year OS, with 74% OS for those with abnormal DNA < 30% vs. 42% for ≥ 30% (p = 0.036). The 5-year DFS for pT1/2 patients was significantly correlated with abnormal DNA content: 53% for patients with abnormal DNA < 30% vs. 17% for patients with abnormal DNA ≥ 30%, respectively (p = 0.03). Of those with %S fraction (%S) < 2, 13% failed locally compared to 41% of those with %S ≥ 2. There was a highly significant correlation between DNA index (DNAI) and aneuploid %S: 68% of patients

  16. CT-guided needle biopsy in the diagnosis of lung adenocarcinoma accompanied by extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue: a rare combination.

    Science.gov (United States)

    Tian, Panwen; Wang, Ye; Wan, Chun; Shen, Yongchun; Wen, Fuqiang

    2015-01-01

    We represent a rare case of lung adenocarcinoma accompanied by extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). The patient was a 66-year-old male presented with 1 month history of recurrent cough and hemoptysis. Chest CT showed solitary ground-glass opacity (GGO) in the upper lobe of the right lung and mediastinal lymph node enlargement in station 3p. A CT-guided transthoracic needle biopsy was performed. Tissue specimens of the GGO revealed a typical adenocarcinoma. Histopathologic diagnosis of mediastinal lymph node was extranodal marginal zone lymphoma of MALT. Because of its rarity, extranodal marginal zone lymphoma of MALT should be considered in the differential diagnosis when we encounter mediastinal lymphadenopathy in patients with lung adenocarcinoma.

  17. The kinetics of repair in mouse lung after fractionated irradiation

    International Nuclear Information System (INIS)

    Travis, E.L.; Thames, H.D.; Watkins, T.L.; Kiss, I.

    1987-01-01

    The kinetics of repair of sublethal damage in mouse lung was studied after fractionated doses of 137 Cs γ-rays. A wide range of doses per fraction (1.7-12 Gy) was given with interfraction intervals ranging from 0.5 to 24 h. Data were analysed by a direct method of analysis using the incomplete repair model. The half-time of repair (Tsub(1/2)) was 0.76 h for the pneumonitis phase of damage (up to 8 months) and 0.65 h for the later phase of damage up to 12 months. Rate of repair was dependent on fraction size for both phases of lung damage and was faster after large dose fractions than after small fractions. Tsub(1/2) was 0.6 h (95% c.1. 0.53, 0.69) for doses per fraction greater than 5 Gy and 0.83 h (95% c.1. 0.76, 0.92) for doses per fraction of 2 Gy. Repair was nearly complete by 6 h at least for the pneumonitis phase of damage. If extrapolated to humans, these results imply that treatments with multiple fractions per day involving the lung will not be limited by the necessity for interfraction intervals much longer than 6 h. (author)

  18. Differentially expressed and survival-related proteins of lung adenocarcinoma with bone metastasis.

    Science.gov (United States)

    Yang, Mengdi; Sun, Yi; Sun, Jing; Wang, Zhiyu; Zhou, Yiyi; Yao, Guangyu; Gu, Yifeng; Zhang, Huizhen; Zhao, Hui

    2018-04-01

    Despite recent advances in targeted and immune-based therapies, the poor prognosis of lung adenocarcinoma (LUAD) with bone metastasis (BM) remains a challenge. First, two-dimensional gel electrophoresis (2-DE) was used to identify proteins that were differentially expressed in LUAD with BM, and then matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) was used to identify these proteins. Second, the Cancer Genome Atlas (TCGA) was used to identify mutations in these differentially expressed proteins and Kaplan-Meier plotter (KM Plotter) was used to generate survival curves for the analyzed cases. Immunohistochemistry (IHC) was used to check the expression of proteins in 28 patients with BM and nine patients with LUAD. Lastly, the results were analyzed with respect to clinical features and patient's follow-up. We identified a number of matched proteins from 2-DE. High expression of enolase 1 (ENO1) (HR = 1.67, logrank P = 1.9E-05), ribosomal protein lateral stalk subunit P2 (RPLP2) (HR = 1.77, logrank P = 2.9e-06), and NME/NM23 nucleoside diphosphate kinase 2 (NME1-NME2) (HR = 2.65, logrank P = 3.9E-15) was all significantly associated with poor survival (P < 0.05). Further, ENO1 was upregulated (P = 0.0004) and calcyphosine (CAPS1) was downregulated (P = 5.34E-07) in TCGA LUAD RNA-seq expression data. IHC revealed that prominent ENO1 staining (OR = 7.5, P = 0.034) and low levels of CAPS1 (OR = 0.01, P < 0.0001) staining were associated with BM incidence. Finally, we found that LUAD patients with high expression of ENO1 and RPLP2 had worse overall survival. This is the first instance where the genes ENO1, RPLP2, NME1-NME2 and CAPS1 were associated with disease severity and progression in LUAD patients with BM. Thus, with this study, we have identified potential biomarkers and therapeutic targets for this disease. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  19. Enhanced efficacy of radiation-induced gene therapy in mice bearing lung adenocarcinoma xenografts using hypoxia responsive elements

    International Nuclear Information System (INIS)

    Wang Wei-dong; Chen Zheng-tang; Li De-zhi; Duan Yu-zhong; Cao Zheng-huai; Li Rong

    2005-01-01

    The aim of the present study was to investigate whether the hypoxia responsive element (HRE) could be used to enhance suicide gene (HSV-tk) expression and tumoricidal activity in radiation-controlled gene therapy of human lung adenocarcinoma xenografts. A chimeric promoter, HRE-Egr, was generated by directly linking a 0.3-kb fragment of HRE to a 0.6-kb human Egr-1 promoter. Retroviral vectors containing luciferase or the HSV-tk gene driven by Egr-1 or HRE-Egr were constructed. A human adenocarcinoma cell line (A549) was stably transfected with the above vectors using the lipofectamine method. The sensitivity of transfected cells to prodrug ganciclovir (GCV) and cell survival rates were analyzed after exposure to a dose of 2 Gy radiation and hypoxia (1%). In vivo, tumor xenografts in BALB/c mice were transfected with the constructed retroviruses and irradiated to a total dose of 6 Gy, followed by GCV treatment (20 mg/kg for 14 days). When the HSV-tk gene controlled by the HRE-Egr promoter was introduced into A549 cells by a retroviral vector, the exposure to 1% O 2 and 2 Gy radiation induced significant enhancement of GCV cytotoxicity to the cells. Moreover, in nude mice bearing solid tumor xenografts, only the tumors infected with the hybrid promoter-containing virus gradually disappeared after GCV administration and radiation. These results indicate that HRE can enhance transgene expression and tumoricidal activity in HSV-tk gene therapy controlled by ionizing radiation in hypoxic human lung adenocarcinoma. (author)

  20. A combination of preoperative CT findings and postoperative serum CEA levels improves recurrence prediction for stage I lung adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Yamazaki, Motohiko, E-mail: xackey2001@gmail.com [Department of Radiology, Niigata University Graduate School of Medical and Dental Sciences (Japan); Ishikawa, Hiroyuki [Department of Radiology, Niigata University Graduate School of Medical and Dental Sciences (Japan); Kunii, Ryosuke [Division of Cellular and Molecular Pathology, Niigata University Graduate School of Medical and Dental Sciences (Japan); Tasaki, Akiko; Sato, Suguru; Ikeda, Yohei; Yoshimura, Norihiko [Department of Radiology, Niigata University Graduate School of Medical and Dental Sciences (Japan); Hashimoto, Takehisa; Tsuchida, Masanori [Division of Thoracic and Cardiovascular Surgery, Niigata University Graduate School of Medical and Dental Sciences (Japan); Aoyama, Hidefumi [Department of Radiology, Niigata University Graduate School of Medical and Dental Sciences (Japan)

    2015-01-15

    Objectives: To assess the prognostic value of combined evaluation of preoperative CT findings and pre/postoperative serum carcinoembryonic antigen (CEA) levels for pathological stage I lung adenocarcinoma. Methods: This retrospective study included 250 consecutive patients who underwent complete resection for ≤3-cm pathological stage I (T1–2aN0M0) adenocarcinomas (132 men, 118 women; mean age, 67.8 years). Radiologists evaluated following CT findings: maximum tumor diameter, percentage of solid component (%solid), air bronchogram, spiculation, adjacency of bullae or interstitial pneumonia (IP) around the tumor, notch, and pleural indent. These CT findings, pre/postoperative CEA levels, age, gender, and Brinkman index were assessed by Cox proportional hazards model to determine the best prognostic model. Prognostic accuracy was examined using the area under the receiver operating characteristic curve (AUC). Results: Median follow-up period was 73.2 months. In multivariate analysis, high %solid, adjacency of bullae or IP around the tumor, and high postoperative CEA levels comprised the best combination for predicting recurrence (P < 0.05). A combination of these three findings had a greater accuracy in predicting 5-year disease-free survival than did %solid alone (AUC = 0.853 versus 0.792; P = 0.023), with a sensitivity of 85.7% and a specificity of 74.3% at the optimal threshold. The best cut-off values of %solid and postoperative CEA levels for predicting high-risk patients were ≥48% and ≥3.7 ng/mL, respectively. Conclusion: Compared to %solid alone, combined evaluation of %solid, adjacency of bullae or IP change around the tumor, and postoperative CEA levels improves recurrence prediction for stage I lung adenocarcinoma.

  1. Long-term survival with repeat resection for lung oligometastasis from pancreatic ductal adenocarcinoma: a case report.

    Science.gov (United States)

    Matsuki, Ryota; Sugiyama, Masanori; Takei, Hidefumi; Kondo, Haruhiko; Fujiwara, Masachika; Shibahara, Junji; Furuse, Junji

    2018-03-27

    Long-term survival after resection of metastases from pancreatic ductal adenocarcinoma is rare. A 54-year-old man underwent pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) with UICC staging pT3N1M0 followed by adjuvant chemotherapy with gemcitabine (GEM). Three years after radical resection of the primary tumor, a tiny nodule was found in the lower lobe of the left lung. Despite treatment with GEM, it increased gradually, but no other metastases were found. Eighteen months after the first indication of the nodule, wedge resection was performed. Pathological examination of the nodule indicated a metastatic tumor from PDAC. Pulmonary metastasectomy was again performed for lung oligometastases at 77 and 101 months after PD. The patient has been asymptomatic without tumor recurrence for 4 years since the last pulmonary resection. In PDAC, the treatment strategy for oligometastasis is controversial. However, a few cases of long-term survival after pulmonary metastasectomy for oligometastasis of PDAC have been reported. More such cases need to be studied to address this issue effectively.

  2. Radiosensitivity of a monoclonal human lung adenocarcinoma cell line with MDR phenotype induced by CDDP: an in vitro study

    International Nuclear Information System (INIS)

    Zhang Junxiang; Kong Zhaolu; Shen Zhifen; Tong Shungao; Jin Yizun

    2006-01-01

    The study was to evaluate radiosensitivity of a monoclonal human lung adenocarcinoma cell line SPC-A-1/CDDP-4 with MDR phenotype induced by cisplatin (CDDP) compared with its parental cell SPC-A-1 in vitro. The glutathione (GSH) content and the radiosensitivity of SPC-A-1/CDDP-4 and SPC-A-1 cells were investigated in aerobic and under hypoxia, respectively. The radiosensitization effect of buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, to SPC-A-1/CDDP-4 and SPC-A-1 cells was observed. The results indicated that the monoclonal human lung adenocarcinoma cell line SPC-A-1/CDDP-4 showed, to some extent, a cross-resistance to 137 Cs γ-ray, in addition to its resistance to anticancer drugs (CDDP, ADM, MTX and VCR). The GSH content of SPC-A-1/CDDP-4 cells was higher than that of SPC-A-1 cells both in aerobic and under hypoxia which might account for it. BSO had radiosensitization effect to SPC-A-1/CDDP-4 and SPC-A-1 cells both in aerobic and under hypoxia, but it was stronger under hypoxia than in aerobic and it was stronger to SPC-A-1/CDDP-4 cells than to SPC-A-1 cells. (authors)

  3. Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

    Directory of Open Access Journals (Sweden)

    Jenifer L Marks

    2007-05-01

    Full Text Available Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis.We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16 of FGFR4 (Glu681Lys, identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr in a lung adenocarcinoma cell line.This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

  4. Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1

    Directory of Open Access Journals (Sweden)

    Valentina Pirazzoli

    2014-05-01

    Full Text Available Patients with EGFR-mutant lung adenocarcinomas (LUADs who initially respond to first-generation tyrosine kinase inhibitors (TKIs develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.

  5. Prognostic impact of serum CYFRA 21–1 in patients with advanced lung adenocarcinoma: a retrospective study

    International Nuclear Information System (INIS)

    Ono, Akira; Nakajima, Takashi; Endo, Masahiro; Yamamoto, Nobuyuki; Takahashi, Toshiaki; Mori, Keita; Akamatsu, Hiroaki; Shukuya, Takehito; Taira, Tetsuhiko; Kenmotsu, Hirotsugu; Naito, Tateaki; Murakami, Haruyasu

    2013-01-01

    Serum CYFRA 21–1 is one of the most important serum markers in the diagnosis of non-small cell lung cancer (NSCLC), especially squamous-cell carcinoma. However, it remains unknown whether pretreatment serum CYFRA 21–1 values (PCV) may also have prognostic implications in patients with advanced lung adenocarcinoma. We retrospectively reviewed the data of 284 patients (pts) who were diagnosed as having advanced lung adenocarcinoma and had received initial therapy. Of the study subjects, 121 pts (43%) had activating epidermal growth factor receptor (EGFR) mutations (Mt+), while the remaining 163 pts (57%) had wild-type EGFR (Mt-). Univariate analysis identified gender (male/ female), ECOG performance status (PS) (0-1/ ≥2), PCV (<2.2 ng/ml/ ≥2.2 ng/ml), EGFR mutation status (Mt+/ Mt-), pretreatment serum CEA values (<5.0 ng/ml/ ≥5.0 ng/ml), smoking history (yes/ no) and EGFR-TKI treatment (yes/ no) as prognostic factors (p = .008, p < .0001, p < .0001, p < .0001, p = .036, p = .0012, p < .0001 respectively). Cox's multivariate regression analysis identified PCV < 2.2ng/ml as the only factor significantly associated with prolonged survival (p < .0001, hazard ratio: 0.43, 95% CI 0.31-0.59), after adjustments for PS (p < .0001), EGFR mutation status (p = .0069), date of start of initial therapy (p = .07), gender (p = .75), serum CEA level (p = .63), smoking history (p = .39) and EGFR-TKI treatment (p = .20). Furthermore, pts with Mt+ and PCV of <2.2 ng/ml had a more favorable prognosis than those with Mt+ and PCV of ≥2.2 ng/ml (MST: 67.0 vs. 21.0 months, p < .0001), and patients with Mt- and PCV of <2.2 ng/ml had a more favorable prognosis than those with Mt- and PCV of ≥2.2 ng/ml (MST: 24.1 vs. 10.2 months, p < .0001). PCV may be a potential independent prognostic factor in both Mt+ and Mt- patients with advanced lung adenocarcinoma

  6. Histologic transformation from adenocarcinoma to both small cell lung cancer and squamous cell carcinoma after treatment with gefitinib: A case report.

    Science.gov (United States)

    Yao, Yufeng; Zhu, Zhouyu; Wu, Yimin; Chai, Ying

    2018-05-01

    In the past decade, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) treatment had been an important therapy for treating advanced EGFR-mutated lung cancer patients. However, a large number of these patients with EGFR-TKIs treatment always acquired resistance to these drugs in one year. The histologic transformation is an important resistance mechanism. Here we reported a 41-year-old man with EGFR-mutated lung adenocarcinoma and he showed histologic transformation to both small-cell lung cancer (SCLC) and squamous cell carcinoma (SCC) after treatment of gefitinib. A case of EGFR-mutated lung cancer. Medical thoracoscopy examination was performed and the patient was diagnosed as a EGFR-mutated lung adenocarcinoma. Then gefitinib was administered orally at a dose of 250 mg daily. The patient received treatment with chemotherapy (etoposide 0.1 g day 2-5 +  cis-platinum 30 mg day 2-4) after acquiring resistance to gefitinib. The patient died in April 2017 that survived for 32 months from lung cancer was found for the first time. To the best of our knowledge, it is the first case of EGFR-mutated lung adenocarcinoma transforming to both SCLC and SCC which was treated with and responded to gefitinib.

  7. Morphological Lesions in Mouse Liver and Lungs After Lung Exposure to Carbon Nanotubes

    DEFF Research Database (Denmark)

    Szarek, J.; Mortensen, Alicja; Jackson, P.

    2013-01-01

    Introduction: Engineered nanoparticles are smaller than 100 nm in at least one direction and designed to improve or achieve new physicochemical properties. Consequently, toxicological properties may also change. Carbon nanotubes have attracted industrial interest due to their unique properties....... Materials and Methods: One day before mating, 30 mice (C57BL/6BomTac, Taconic Europe, Denmark) were given 67 μg multi-walled carbon nanotubes (NM-400, Nanocyl, Belgium) intratracheally (group A). A further 30 control mice (group B) received vehicle (Millipore water with 2% mouse serum). Lungs and liver were...... taken from six animals from each group for histopathological examination (haematoxylin and eosin staining) 6 weeks (A1, B1 group) and 4 months (A2, B2) after exposure. Results: Lungs in A1 mice showed bronchiolar subepithelial oedema and perivascular oedema and sporadic hyperaemia and the presence...

  8. Pemetrexed-carboplatin with intercalated icotinib in the treatment of patient with advanced EGFR wild-type lung adenocarcinoma

    Science.gov (United States)

    Xu, Tongpeng; Wu, Hao; Jin, Shidai; Min, Huang; Zhang, Zhihong; Shu, Yongqian; Wen, Wei; Guo, Renhua

    2017-01-01

    Abstract Rationale: Tyrosine kinase inhibitors (TKIs) are known to have greater efficacy in epidermal growth factor receptor (EGFR) mutation nonsmall cell lung cancer (NSCLC). However, about 10% of EGFR wild-type (wt) patients respond to TKIs. Patient concerns: Several strategies to increase the efficacy of TKIs in wt NSCLC are the subjects of ongoing investigations. One of them is combining EGFR TKI with intercalated chemotherapy. Diagnoses: We describe a patient with EGFR wt NSCLC, who was found with ovarian and lung metastasis, was treated with pemetrexed and intercalated icotinib. Interventions: In this case, we reported the successful long-term maintenance treatment of a patient with EGFR wt NSCLC with pemetrexed and Icotinib. The patient (40-year-old female) was found with ovarian masses and lung masses. Pathological, immunohistochemical, and amplification refractory mutation system (ARMS) assay examinations of ovarian specimen suggested the expression of metastatic lung adenocarcinoma with wt EGFR. After failure treatment with paclitaxel-carboplatin, the patient received 4 cycles of pemetrexed plus platinum with intercalated icotinib and then remained on pemetrexed and icotinib. Outcomes: A partial response was achieved after the treatment. The patient's condition had remained stable on pemetrexed and icotinib for more than 20 months, with no evidence of progression. Lessons: To our knowledge, this is the first report using the long-term maintenance treatment with pemetrexed and intercalated icotinib in EGFR wt patient. The therapeutic strategies warrant further exploration in selected populations of NSCLC. PMID:28816950

  9. Chromogenic in situ hybridization is a reliable assay for detection of ALK rearrangements in adenocarcinomas of the lung.

    Science.gov (United States)

    Schildhaus, Hans-Ulrich; Deml, Karl-Friedrich; Schmitz, Katja; Meiboom, Maren; Binot, Elke; Hauke, Sven; Merkelbach-Bruse, Sabine; Büttner, Reinhard

    2013-11-01

    Reliable detection of anaplastic lymphoma kinase (ALK) rearrangements is a prerequisite for personalized treatment of lung cancer patients, as ALK rearrangements represent a predictive biomarker for the therapy with specific tyrosine kinase inhibitors. Currently, fluorescent in situ hybridization (FISH) is considered to be the standard method for assessing formalin-fixed and paraffin-embedded tissue for ALK inversions and translocations. However, FISH requires a specialized equipment, the signals fade rapidly and it is difficult to detect overall morphology and tumor heterogeneity. Chromogenic in situ hybridization (CISH) has been successfully introduced as an alternative test for the detection of several genetic aberrations. This study validates a newly developed ALK CISH assay by comparing FISH and CISH signal patterns in lung cancer samples with and without ALK rearrangements. One hundred adenocarcinomas of the lung were included in this study, among them 17 with known ALK rearrangement. FISH and CISH were carried out and evaluated according to the manufacturers' recommendations. For both assays, tumors were considered positive if ≥15% of tumor cells showed either isolated 3' signals or break-apart patterns or a combination of both. A subset of tumors was exemplarily examined by using a novel EML4 (echinoderm microtubule-associated protein-like 4) CISH probe. Red, green and fusion CISH signals were clearcut and different signal patterns were easily recognized. The percentage of aberrant tumor cells was statistically highly correlated (PCISH. On the basis of 86 samples that were evaluable by ALK CISH, we found a 100% sensitivity and 100% specificity of this assay. Furthermore, EML4 rearrangements could be recognized by CISH. CISH is a highly reliable, sensitive and specific method for the detection of ALK gene rearrangements in pulmonary adenocarcinomas. Our results suggest that CISH might serve as a suitable alternative to FISH, which is the current gold

  10. SU-D-207B-03: A PET-CT Radiomics Comparison to Predict Distant Metastasis in Lung Adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Coroller, T; Yip, S; Lee, S; Mak, R; Aerts, H [Dana Farber Cancer Institute, Brigham and Women’s Hospital, Havard Medical School, Boston, MA (United States); Kim, J [Brigham and Women’s Hospital, Children’s hospital, Harvard Medical School, Boston, MA (United States)

    2016-06-15

    Purpose: Early prediction of distant metastasis may provide crucial information for adaptive therapy, subsequently improving patient survival. Radiomic features that extracted from PET and CT images have been used for assessing tumor phenotype and predicting clinical outcomes. This study investigates the values of radiomic features in predicting distant metastasis (DM) in non-small cell lung cancer (NSCLC). Methods: A total of 108 patients with stage II–III lung adenocarcinoma were included in this retrospective study. Twenty radiomic features were selected (10 from CT and 10 from PET). Conventional features (metabolic tumor volume, SUV, volume and diameter) were included for comparison. Concordance index (CI) was used to evaluate features prognostic value. Noether test was used to compute p-value to consider CI significance from random (CI = 0.5) and were adjusted for multiple testing using false rate discovery (FDR). Results: A total of 70 patients had DM (64.8%) with a median time to event of 8.8 months. The median delivered dose was 60 Gy (range 33–68 Gy). None of the conventional features from PET (CI ranged from 0.51 to 0.56) or CT (CI ranged from 0.57 to 0.58) were significant from random. Five radiomics features were significantly prognostic from random for DM (p-values < 0.05). Four were extracted from CT (CI = 0.61 to 0.63, p-value <0.01) and one from PET which was also the most prognostic (CI = 0.64, p-value <0.001). Conclusion: This study demonstrated significant association between radiomic features and DM for patients with locally advanced lung adenocarcinoma. Moreover, conventional (clinically utilized) metrics were not significantly associated with DM. Radiomics can potentially help classify patients at higher risk of DM, allowing clinicians to individualize treatment, such as intensification of chemotherapy) to reduce the risk of DM and improve survival. R.M. has consulting interests with Amgen.

  11. Why do pathological stage IA lung adenocarcinomas vary from prognosis?: a clinicopathologic study of 176 patients with pathological stage IA lung adenocarcinoma based on the IASLC/ATS/ERS classification.

    Science.gov (United States)

    Zhang, Jie; Wu, Jie; Tan, Qiang; Zhu, Lei; Gao, Wen

    2013-09-01

    Patients with pathological stage IA adenocarcinoma (AC) have a variable prognosis, even if treated in the same way. The postoperative treatment of pathological stage IA patients is also controversial. We identified 176 patients with pathological stage IA AC who had undergone a lobectomy and mediastinal lymph node dissection at the Shanghai Chest Hospital, Shanghai, China, between 2000 and 2006. No patient had preoperative treatment. The histologic subtypes of all patients were classified according to the 2011 International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) international multidisciplinary lung AC classification. Patients' 5-year overall survival (OS) and 5-year disease-free survival (DFS) were calculated using Kaplan-Meier and Cox regression analyses. One hundred seventy-six patients with pathological stage IA AC had an 86.6% 5-year OS and 74.6% 5-year DFS. The 10 patients with micropapillary predominant subtype had the lowest 5-year DFS (40.0%).The 12 patients with solid predominant with mucin production subtype had the lowest 5-year OS (66.7%). Univariate and multivariate analysis showed that sex and prognositic groups of the IASLC/ATS/ERS histologic classification were significantly associated with 5-year DFS of pathological stage IA AC. Our study revealed that sex was an independent prognostic factor of pathological stage IA AC. The IASLC/ATS/ERS classification of lung AC identifies histologic categories with prognostic differences that could be helpful in clinical therapy.

  12. MLH1 V384D polymorphism associates with poor response to EGFR tyrosine kinase inhibitors in patients with EGFR L858R-positive lung adenocarcinoma.

    Science.gov (United States)

    Chiu, Chao-Hua; Ho, Hsiang-Ling; Doong, Howard; Yeh, Yi-Chen; Chen, Mei-Yu; Chou, Teh-Ying; Tsai, Chun-Ming

    2015-04-10

    A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short ( 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.

  13. Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations

    NARCIS (Netherlands)

    Seow, Wei Jie; Matsuo, Keitaro; Hsiung, Chao Agnes; Shiraishi, Kouya; Song, Minsun; Kim, Hee Nam; Wong, Maria Pik; Hong, Yun-Chul; Hosgood, H. Dean; Wang, Zhaoming; Chang, I-Shou; Wang, Jiu-Cun; Chatterjee, Nilanjan; Tucker, Margaret; Wei, Hu; Mitsudomi, Tetsuya; Zheng, Wei; Kim, Jin Hee; Zhou, Baosen; Caporaso, Neil E; Albanes, Demetrius; Shin, Min-Ho; Chung, Lap Ping; An, She-Juan; Wang, Ping; Zheng, Hong; Yatabe, Yasushi; Zhang, Xu-Chao; Kim, Young Tae; Shu, Xiao Ou; Kim, Young-Chul; Bassig, Bryan A.; Chang, Jiang; Ho, James Chung Man; Ji, Bu Tian; Kubo, Michiaki; Daigo, Yataro; Ito, Hidemi; Momozawa, Yukihide; Ashikawa, Kyota; Kamatani, Yoichiro; Honda, Takayuki; Sakamoto, Hiromi; Kunitoh, Hideo; Tsuta, Koji; Watanabe, Shun-Ichi; Nokihara, Hiroshi; Miyagi, Yohei; Nakayama, Haruhiko; Matsumoto, Shingo; Tsuboi, Masahiro; Goto, Koichi; Yin, Zhihua; Shi, Jianxin; Takahashi, Atsushi; Goto, Akiteru; Minamiya, Yoshihiro; Shimizu, Kimihiro; Tanaka, Kazumi; Wu, Tangchun; Wei, Fusheng; Wong, Jason Y Y; Matsuda, Fumihiko; Su, Jian; Kim, Yeul Hong; Oh, In-Jae; Song, Fengju; Lee, Victor Ho Fun; Su, Wu-Chou; Chen, Yuh-Min; Chang, Gee-Chen; Chen, Kuan-Yu; Huang, Ming-Shyan; Yang, Pan-Chyr; Lin, Hsien-Chih; Xiang, Yong-Bing; Seow, Adeline; Park, Jae Yong; Kweon, Sun-Seog; Chen, Chien-Jen; Li, Haixin; Gao, Yu Tang; Wu, Chen; Qian, Biyun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Wang, Wen-Chang; Chung, Charles C.; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Jacobs, Kevin B.; Hutchinson, Amy; Berndt, Sonja I.; He, Xingzhou; Wu, Wei; Wang, Junwen; Li, Yuqing; Choi, Jin Eun; Park, Kyong Hwa; Sung, Sook Whan; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Wang, Chih-Liang; Sihoe, Alan Dart Loon; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Chen, Chih-Yi; Vermeulen, Roel; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chan, John K C; Chu, Minjie; Li, Yao-Jen; Li, Jihua; Chen, Hongyan; Yu, Chong-Jen; Jin, Li; Lo, Yen-Li; Chen, Ying-Hsiang; Fraumeni, Joseph F.; Liu, Jie; Yamaji, Taiki; Yang, Yang; Hicks, Belynda; Wyatt, Kathleen; Li, Shengchao A; Dai, Juncheng; Ma, Hongxia; Jin, Guangfu; Song, Bao; Wang, Zhehai; Cheng, Sensen; Li, Xuelian; Ren, Yangwu; Cui, Ping; Iwasaki, Motoki; Shimazu, Taichi; Tsugane, Shoichiro; Zhu, Junjie; Jiang, Gening; Fei, Ke; Wu, Guoping; Chien, Li-Hsin; Chen, Hui-Ling; Su, Yu-Chun; Tsai, Fang-Yu; Chen, Yi-Song; Yu, Jinming; Stevens, Victoria L; Laird-Offringa, Ite A; Marconett, Crystal N; Lin, Dongxin; Chen, Kexin; Wu, Yi-Long; Landi, Maria Teresa; Shen, Hongbing; Rothman, Nathaniel; Kohno, Takashi; Chanock, Stephen J.; Lan, Qing

    2017-01-01

    To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking

  14. Ly6/uPAR-related protein C4.4A as a marker of solid growth pattern and poor prognosis in lung adenocarcinoma

    DEFF Research Database (Denmark)

    Jacobsen, Benedikte; Muley, Thomas; Meister, Michael

    2013-01-01

    We have recently shown that the protein C4.4A is induced in early precursor lesions of pulmonary adenocarcinomas and squamous cell carcinomas. In the present study, we aimed at analyzing the impact of C4.4A on the survival of non-small cell lung cancer patients and determining whether its...

  15. Efficacy of S-1 plus nedaplatin compared to standard second-line chemotherapy in EGFR-negative lung adenocarcinoma after failure of first-line chemotherapy.

    Science.gov (United States)

    Tang, Yu; Wang, Wei; Teng, Xiu-Zhi; Shi, Lin

    2014-09-01

    For patients with advanced non-small cell lung adenocarcinoma that fail to respond to first-line chemotherapy and that do not involve epidermal growth factor receptor (EGFR) mutations, previous empirical analysis showed that a single second-line chemotherapy agent may be inadequate for the control of further tumor development. This study examines the combination of S-1 drugs and nedaplatin that has no cross-resistance to first-line treatments; 179 cases of IIIb-IV stage non-small-cell lung adenocarcinoma that failed to respond to first-line chemotherapy were included, and these subjects did not have mutated EGFRs. In the present study, S-1 plus nedaplatin chemotherapy was better than standard second-line chemotherapy options in the treatment of advanced lung adenocarcinoma that did not involve EGFR mutations and that failed to respond to first-line chemotherapy. Additionally, the combination of S-1 and nedaplatin seemed to be well tolerated, making this chemotherapy technique a potentially strong candidate for the treatment of advanced non-small-cell lung adenocarcinoma.

  16. CT characteristics and pathological implications of early stage (T1N0M0) lung adenocarcinoma with pure ground-glass opacity

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Xin; Zhao, Shao-hong; Wu, Jian; Wu, Chong-chong; Chang, Rui-ping; Ju, Hai-yue [Chinese PLA General Hospital, Department of Radiology, Beijing (China); Gao, Jie; Wang, Dian-jun [Chinese PLA General Hospital, Department of Pathology, Beijing (China)

    2015-09-15

    To analyze the CT characteristics and pathological classification of early lung adenocarcinoma (T1N0M0) with pure ground-glass opacity (pGGO). Ninety-four lesions with pGGO on CT in 88 patients with T1N0M0 lung adenocarcinoma were selected from January 2010 to December 2012. All lesions were confirmed by pathology. CT appearances were analyzed including lesion location, size, density, uniformity, shape, margin, tumour-lung interface, internal and surrounding malignant signs. Lesion size and density were compared using analysis of variance, lesion size also assessed using ROC curves. Gender of patients, lesion location and CT appearances were compared using χ2-test. There were no significant differences in gender, lesion location and density with histological invasiveness (P > 0.05). The ROC curve showed that the possibility of invasive lesion was 88.73 % when diameter of lesion was more than 10.5 mm. There was a significant difference between lesion uniformity and histological invasiveness (P = 0.01). There were significant differences in margin, tumour-lung interface, air bronchogram with histological invasiveness (P = 0.02,P = 0.00,P = 0.048). The correlation index of lesion size and uniformity was r = 0.45 (P = 0.00). The lesion size and uniformity, tumour-lung interface and the air bronchogram can help predict invasive extent of early stage lung adenocarcinoma with pGGO. (orig.)

  17. [Correlation between Serum Tumor Markers and Efficacy of First-line EGFR-TKIs in Patients with Advanced Lung Adenocarcinoma].

    Science.gov (United States)

    Chen, Hanxiao; Yang, Xue; Liu, Huijun; Ma, Kun; Zhong, Jia; Dong, Zhi; Zhuo, Minglei; Wang, Yuyan; Li, Jianjie; An, Tongtong; Wu, Meina; Wang, Ziping; Zhao, Jun

    2017-09-20

    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve the survival of advanced lung adenocarcinoma patients harboring EGFR mutation. Limited to the standards of tumor tissue samples and detection methods, still some people can't receive target therapy following genetic guidance. This study was to explore the relevance between serum tumor markers and treatment of EGFR-TKIs. We retrospectively collected the clinical information of advanced lung adenocarcinoma patients harboring EGFR mutation, who received EGFR-TKIs as first-line therapy from June 2009 to June 2014 in Peking University Cancer Hospital, analyzed the relationship between serum tumor markers and efficacy of EGFR-TKIs. The objective response rate (ORR) was 52.8% and the disease control rate (DCR) was 89.3%. The results showed that, patients with high CEA level before treatment responded better to TKIs (ORR 61.3% vs 35.9%, DCR 95.2% vs 74.4%, PCEA decreased 1 month later (61.5% vs 25%, P=0.002). Progression-free survival (PFS) significantly prolonged in patients with elevated baseline CEA (mPFS 9.8 mo vs 5.9 mo, P=0.027). To the opposite, PFS was significantly shorter in patients with elevated baseline CYFRA21-1 and CA125 (mPFS 9.0 mo vs 11.4 mo, P=0.029; 9.0 mo vs 11.5 mo, P=0.023, respectively). Multivariate analysis showed that Eastern Cooperative Oncology Group (ECOG) score of 0-1, normal baseline CYFRA21-1 and CEA decline predicted longer PFS. The overall survival (OS) was highly associated with elevated CYFRA21-1 and CA125 (median OS 25.1 mo vs 52.5 mo, P=0.003; 22.7 mo vs 55.0 mo, PCEA. High level of baseline CEA and decline 1 month after treatment could predict the efficacy of EGFR-TKIs in patients with advanced lung adenocarcinoma. While high levels of baseline CYFRA21-1 and CA125 indicated shortened survival.

  18. Multi-walled carbon nanotube-induced gene expression in the mouse lung: Association with lung pathology

    International Nuclear Information System (INIS)

    Pacurari, M.; Qian, Y.; Porter, D.W.; Wolfarth, M.; Wan, Y.; Luo, D.; Ding, M.; Castranova, V.; Guo, N.L.

    2011-01-01

    Due to the fibrous shape and durability of multi-walled carbon nanotubes (MWCNT), concerns regarding their potential for producing environmental and human health risks, including carcinogenesis, have been raised. This study sought to investigate how previously identified lung cancer prognostic biomarkers and the related cancer signaling pathways are affected in the mouse lung following pharyngeal aspiration of well-dispersed MWCNT. A total of 63 identified lung cancer prognostic biomarker genes and major signaling biomarker genes were analyzed in mouse lungs (n = 80) exposed to 0, 10, 20, 40, or 80 μg of MWCNT by pharyngeal aspiration at 7 and 56 days post-exposure using quantitative PCR assays. At 7 and 56 days post-exposure, a set of 7 genes and a set of 11 genes, respectively, showed differential expression in the lungs of mice exposed to MWCNT vs. the control group. Additionally, these significant genes could separate the control group from the treated group over the time series in a hierarchical gene clustering analysis. Furthermore, 4 genes from these two sets of significant genes, coiled-coil domain containing-99 (Ccdc99), muscle segment homeobox gene-2 (Msx2), nitric oxide synthase-2 (Nos2), and wingless-type inhibitory factor-1 (Wif1), showed significant mRNA expression perturbations at both time points. It was also found that the expression changes of these 4 overlapping genes at 7 days post-exposure were attenuated at 56 days post-exposure. Ingenuity Pathway Analysis (IPA) found that several carcinogenic-related signaling pathways and carcinogenesis itself were associated with both the 7 and 11 gene signatures. Taken together, this study identifies that MWCNT exposure affects a subset of lung cancer biomarkers in mouse lungs. - Research highlights: → Multi-Walled Carbon Nanotubes affect lung cancer biomarkers in mouse lungs. → The results suggest potentially harmful effects of MWCNT exposure on human lungs. → The results could potentially be used

  19. β-Catenin/POU5F1/SOX2 transcription factor complex mediates IGF-I receptor signaling and predicts poor prognosis in lung adenocarcinoma.

    Science.gov (United States)

    Xu, Chuan; Xie, Dan; Yu, Shi-Cang; Yang, Xiao-Jun; He, Li-Ru; Yang, Jing; Ping, Yi-Fang; Wang, Bin; Yang, Lang; Xu, Sen-Lin; Cui, Wei; Wang, Qing-Liang; Fu, Wen-Juan; Liu, Qing; Qian, Cheng; Cui, You-Hong; Rich, Jeremy N; Kung, Hsiang-Fu; Zhang, Xia; Bian, Xiu-Wu

    2013-05-15

    Cancer stem-like cells (CSLC) are crucial in tumor initiation and progression; however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma showed that high expression of insulin-like growth factor I receptor (IGF-IR) in lung adenocarcinoma cells was positively correlated with the expressions of cancer stem cell markers CD133 and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). IGF-IR activation enhanced POU class 5 homeobox 1 (POU5F1) expression on human lung adenocarcinoma stem-like cells (LACSLC) through PI3K/AKT/GSK3β/β-catenin cascade. POU5F1 could form a novel complex with β-catenin and SOX2 to bind Nanog promoter for transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-IR. Genetic and pharmacologic inhibition of IGF-IR abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-IR or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathologic specimens excised from 200 patients with lung adenocarcinoma, we found that colocalization of highly expressed IGF-IR with β-catenin and POU5F1 predicted poor prognosis. Taken together, we show that IGF-IR-mediated POU5F1 expression to form a complex with β-catenin and SOX2 is crucial for the self-renewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions of IGF-IR, β-catenin, and POU5F1 is indicatory for predicting prognosis in the patients of lung adenocarcinoma. ©2013 AACR.

  20. Detection of EML4-ALK in lung adenocarcinoma using pleural effusion with FISH, IHC, and RT-PCR methods.

    Directory of Open Access Journals (Sweden)

    Leilei Liu

    Full Text Available Anaplastic lymphoma kinase (ALK and echinoderm microtubule-associated protein-like 4 (EML4 gene rearrangements occur in approximately 5% of non-small-cell lung cancers (NSCLC, leading to the overexpression of anaplastic lymphoma kinase and predicting a response to the targeted inhibitor, crizotinib. Malignant pleural effusion occurs in most patients with advanced lung cancer, especially adenocarcinoma, and tissue samples are not always available from these patients. We attempted to clarify the feasibility of detecting the EML4-ALK fusion gene in pleural effusion cells using different methods. We obtained 66 samples of pleural effusion from NSCLC patients. The pleural effusion fluid was centrifuged, and the cellular components obtained were formalin fixed and paraffin embedded. The EML4-ALK fusion gene status was determined with fluorescent in situ hybridization (FISH, reverse transcription-polymerase chain reaction (RT-PCR, and immunohistochemistry (IHC. EML4-ALK was detected in three of 66 patient samples (4.5% with RT-PCR. When the RT-PCR data were used as the standard, one false positive and one false negative samples were identified with IHC; and one false negative sample was identified with FISH. These results suggest that a block of pleural effusion cells can be used to detect the EML4-ALK fusion gene. IHC had good sensitivity, but low specificity. FISH had low sensitivity, but high specificity. RT-PCR is a good candidate method for detecting EML4-ALK in blocks of pleural effusion cells from lung cancer patients.

  1. MO-DE-207B-08: Radiomic CT Features Complement Semantic Annotations to Predict EGFR Mutations in Lung Adenocarcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Rios Velazquez, E; Parmar, C; Narayan, V; Aerts, H [Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (United States); Liu, Y; Gillies, R [H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States)

    2016-06-15

    Purpose: To compare the complementary value of quantitative radiomic features to that of radiologist-annotated semantic features in predicting EGFR mutations in lung adenocarcinomas. Methods: Pre-operative CT images of 258 lung adenocarcinoma patients were available. Tumors were segmented using the sing-click ensemble segmentation algorithm. A set of radiomic features was extracted using 3D-Slicer. Test-retest reproducibility and unsupervised dimensionality reduction were applied to select a subset of reproducible and independent radiomic features. Twenty semantic annotations were scored by an expert radiologist, describing the tumor, surrounding tissue and associated findings. Minimum-redundancy-maximum-relevance (MRMR) was used to identify the most informative radiomic and semantic features in 172 patients (training-set, temporal split). Radiomic, semantic and combined radiomic-semantic logistic regression models to predict EGFR mutations were evaluated in and independent validation dataset of 86 patients using the area under the receiver operating curve (AUC). Results: EGFR mutations were found in 77/172 (45%) and 39/86 (45%) of the training and validation sets, respectively. Univariate AUCs showed a similar range for both feature types: radiomics median AUC = 0.57 (range: 0.50 – 0.62); semantic median AUC = 0.53 (range: 0.50 – 0.64, Wilcoxon p = 0.55). After MRMR feature selection, the best-performing radiomic, semantic, and radiomic-semantic logistic regression models, for EGFR mutations, showed a validation AUC of 0.56 (p = 0.29), 0.63 (p = 0.063) and 0.67 (p = 0.004), respectively. Conclusion: Quantitative volumetric and textural Radiomic features complement the qualitative and semi-quantitative radiologist annotations. The prognostic value of informative qualitative semantic features such as cavitation and lobulation is increased with the addition of quantitative textural features from the tumor region.

  2. MO-DE-207B-08: Radiomic CT Features Complement Semantic Annotations to Predict EGFR Mutations in Lung Adenocarcinomas

    International Nuclear Information System (INIS)

    Rios Velazquez, E; Parmar, C; Narayan, V; Aerts, H; Liu, Y; Gillies, R

    2016-01-01

    Purpose: To compare the complementary value of quantitative radiomic features to that of radiologist-annotated semantic features in predicting EGFR mutations in lung adenocarcinomas. Methods: Pre-operative CT images of 258 lung adenocarcinoma patients were available. Tumors were segmented using the sing-click ensemble segmentation algorithm. A set of radiomic features was extracted using 3D-Slicer. Test-retest reproducibility and unsupervised dimensionality reduction were applied to select a subset of reproducible and independent radiomic features. Twenty semantic annotations were scored by an expert radiologist, describing the tumor, surrounding tissue and associated findings. Minimum-redundancy-maximum-relevance (MRMR) was used to identify the most informative radiomic and semantic features in 172 patients (training-set, temporal split). Radiomic, semantic and combined radiomic-semantic logistic regression models to predict EGFR mutations were evaluated in and independent validation dataset of 86 patients using the area under the receiver operating curve (AUC). Results: EGFR mutations were found in 77/172 (45%) and 39/86 (45%) of the training and validation sets, respectively. Univariate AUCs showed a similar range for both feature types: radiomics median AUC = 0.57 (range: 0.50 – 0.62); semantic median AUC = 0.53 (range: 0.50 – 0.64, Wilcoxon p = 0.55). After MRMR feature selection, the best-performing radiomic, semantic, and radiomic-semantic logistic regression models, for EGFR mutations, showed a validation AUC of 0.56 (p = 0.29), 0.63 (p = 0.063) and 0.67 (p = 0.004), respectively. Conclusion: Quantitative volumetric and textural Radiomic features complement the qualitative and semi-quantitative radiologist annotations. The prognostic value of informative qualitative semantic features such as cavitation and lobulation is increased with the addition of quantitative textural features from the tumor region.

  3. 11C-acetate for positron emission tomography imaging of clinical stage IA lung adenocarcinoma. Comparison with 18F-fluorodeoxyglucose for imaging and evaluation of tumor aggressiveness

    International Nuclear Information System (INIS)

    Shibata, Hidekatsu; Nomori, Hiroaki; Uno, Kimiichi

    2009-01-01

    To determine the usefulness of positron emission tomography (PET) with 11 C-acetate (AC) for imaging lung adenocarcinoma and evaluating its tumor aggressiveness, AC- and 18 F-fluorodeoxyglucose (FDG)-PET were compared. One hundred and sixty-nine adenocarcinomas with clinical stage IA and 53 benign nodules were examined by both AC- and FDG-PET before surgery. The sensitivity and specificity for discriminating benign/adenocarcinoma were compared between AC- and FDG-PET. The AC and FDG uptakes were examined to determine the relationship with tumor aggressiveness, id est (i.e.), pathological tumor stage, lymphatic, vascular, or pleural involvement, and proliferative activity determined by Ki-67 staining score. While the sensitivity of AC-PET was significantly higher than FDG-PET for bronchioloalveolar carcinoma (BAC) and well-differentiated (W/D) adenocarcinoma (p<0.001 and 0.006, respectively), there was no significant difference for moderately or poorly differentiated adenocarcinoma. The specificity was not different between them. While FDG uptakes were significantly higher in tumors with pathological advanced stages or those with lymphatic, vascular and/or pleural involvements than in tumors with pathological stage IA or those without these tumor involvements (p=0.04 to p<0.001), AC uptake did not show significant differences between the respective sub-groups except according to the tumor stage. While both AC and FDG uptakes showed a significant correlation with Ki-67 staining scores (p=0.03 and p<0.001, respectively), the correlation coefficient of former was lower than that of latter (p=0.07). While AC-PET can image BAC and W/D adenocarcinoma with a higher sensitivity than FDG-PET, it cannot evaluate tumor aggressiveness of clinical stage IA lung adenocarcinoma as well as FDG-PET. (author)

  4. Upregulation of miR-3607 promotes lung adenocarcinoma proliferation by suppressing APC expression.

    Science.gov (United States)

    Lin, Yong; Gu, Qiangye; Sun, Zongwen; Sheng, Baowei; Qi, Congcong; Liu, Bing; Fu, Tian; Liu, Cun; Zhang, Yan

    2017-11-01

    Lung cancer is the leading cause of worldwide cancer-related deaths, although many drugs and new therapeutic approaches have been used, the 5-years survival rate is still low for lung cancer patients. microRNAs have been shown to regulate lung cancer initiation and development, here we studied the role of miR-3607 in lung cancer cell proliferation. We found miR-3607 was upregulated in lung cancer tissues and cells, miR-3607 overexpression promoted lung cancer cell A549 proliferation determined by MTT assay, colony formation assay, anchorage-independent growth ability assay and bromodeoxyuridine incorporation assay, while the opposite phenotypes were shown when miR-3607 was knocked down. Predicted analysis suggested a Wnt signaling pathway regulator adenomatous polyposis coli (APC) was the target of miR-3607, miR-3607 could directly bind to the 3'UTR of APC, and promoted Cyclin D1 and c-Myc expression which can be suppressed by APC. Double knockdown of miR-3607 and APC copied the phenotypes of miR-3607 overexpression, suggesting miR-3607 promoted lung cancer cell A549 proliferation by targeting APC. In conclusion, our study suggested miR-3607 contributes to lung cancer cell proliferation by inhibiting APC. Copyright © 2017. Published by Elsevier Masson SAS.

  5. Predicting adenocarcinoma recurrence using computational texture models of nodule components in lung CT

    International Nuclear Information System (INIS)

    Depeursinge, Adrien; Yanagawa, Masahiro; Leung, Ann N.; Rubin, Daniel L.

    2015-01-01

    Purpose: To investigate the importance of presurgical computed tomography (CT) intensity and texture information from ground-glass opacities (GGO) and solid nodule components for the prediction of adenocarcinoma recurrence. Methods: For this study, 101 patients with surgically resected stage I adenocarcinoma were selected. During the follow-up period, 17 patients had disease recurrence with six associated cancer-related deaths. GGO and solid tumor components were delineated on presurgical CT scans by a radiologist. Computational texture models of GGO and solid regions were built using linear combinations of steerable Riesz wavelets learned with linear support vector machines (SVMs). Unlike other traditional texture attributes, the proposed texture models are designed to encode local image scales and directions that are specific to GGO and solid tissue. The responses of the locally steered models were used as texture attributes and compared to the responses of unaligned Riesz wavelets. The texture attributes were combined with CT intensities to predict tumor recurrence and patient hazard according to disease-free survival (DFS) time. Two families of predictive models were compared: LASSO and SVMs, and their survival counterparts: Cox-LASSO and survival SVMs. Results: The best-performing predictive model of patient hazard was associated with a concordance index (C-index) of 0.81 ± 0.02 and was based on the combination of the steered models and CT intensities with survival SVMs. The same feature group and the LASSO model yielded the highest area under the receiver operating characteristic curve (AUC) of 0.8 ± 0.01 for predicting tumor recurrence, although no statistically significant difference was found when compared to using intensity features solely. For all models, the performance was found to be significantly higher when image attributes were based on the solid components solely versus using the entire tumors (p < 3.08 × 10 −5 ). Conclusions: This study

  6. Effects of dietary saw palmetto on the prostate of transgenic adenocarcinoma of the mouse prostate model (TRAMP).

    Science.gov (United States)

    Wadsworth, Teri L; Worstell, Teresa R; Greenberg, Norman M; Roselli, Charles E

    2007-05-01

    Several of the proposed mechanisms for the actions of the liposterolic extract of saw palmetto (SPE) are exerted on known risk factors for prostate cancer (CaP). This study investigated whether SPE could prevent the progression of CaP in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Two different doses of SPE designed to deliver 50 mg/kg/day SPE and 300 mg/kg/day SPE were administered in a custom diet to TRAMP mice for 12 or 24 weeks. Body and organ weights were used to evaluate toxicity, and radioimmunoassay was used to measure plasma and tissue androgen levels to monitor effects of SPE on 5alpha reductase activity. Prostate tissues were evaluated histologically to determine the effect of treatment on tumor grade, cell proliferation, and apoptosis. Treatment with 300 mg/kg/day SPE from 4 to 24 weeks of age significantly reduced the concentration of 5alpha-dihydrotestosterone (DHT) in the prostate and resulted in a significant increase in apoptosis and significant decrease in pathological tumor grade and frank tumor incidence. Dietary supplementation with SPE may be effective in controlling CaP tumorigenesis. SPE suppression of prostatic DHT levels lends support to the hypothesis that inhibition of the enzyme 5alpha-reductase is a mechanism of action of this substance. (c) 2007 Wiley-Liss, Inc.

  7. A case of lung adenocarcinoma with multiple intracranial hemorrhages of brain metastases after whole-brain radiation therapy

    International Nuclear Information System (INIS)

    Nakamichi, Shinji; Hirano, Satoshi; Asao, Tetsuhiko; Takeda, Yuichiro; Sugiyama, Haruhito; Kobayashi, Nobuyuki

    2011-01-01

    Whole-brain radiation therapy (WBRT) is widely applied in cases of brain metastases of non-small cell lung cancer (NSCLC). However, there are few case reports on hemorrhages of brain metastases occurring after WBRT. A 63-year-old woman was given a diagnosis of stage IV (T4N0M1b) lung adenocarcinoma about 4 years previously, and received chemotherapy regimens and gamma knife radiosurgery. However, her brain metastases exacerbated and she received WBRT in November 2010 and docetaxel monotherapy in December 2010. Two weeks after completing WBRT, she experienced dysarthria and an MRI showed multiple hemorrhages within brain metastases. Over a period of careful observation, these hemorrhages repeatedly alternated between improvement and exacerbation. Radiotherapy for metastatic brain tumors is considered to suppress hemorrhagic events of brain metastases. However, multiple intracranial hemorrhages of brain metastases occurred after WBRT in the present case. The accumulation of further studies of similar cases is necessary to identify the exact mechanism of these hemorrhages. (author)

  8. Cryptosporidium parvum-induced ileo-caecal adenocarcinoma and Wnt signaling in a mouse model

    Directory of Open Access Journals (Sweden)

    Sadia Benamrouz

    2014-06-01

    Full Text Available Cryptosporidium species are apicomplexan protozoans that are found worldwide. These parasites constitute a large risk to human and animal health. They cause self-limited diarrhea in immunocompetent hosts and a life-threatening disease in immunocompromised hosts. Interestingly, Cryptosporidium parvum has been related to digestive carcinogenesis in humans. Consistent with a potential tumorigenic role of this parasite, in an original reproducible animal model of chronic cryptosporidiosis based on dexamethasone-treated or untreated adult SCID mice, we formerly reported that C. parvum (strains of animal and human origin is able to induce digestive adenocarcinoma even in infections induced with very low inoculum. The aim of this study was to further characterize this animal model and to explore metabolic pathways potentially involved in the development of C. parvum-induced ileo-caecal oncogenesis. We searched for alterations in genes or proteins commonly involved in cell cycle, differentiation or cell migration, such as β-catenin, Apc, E-cadherin, Kras and p53. After infection of animals with C. parvum we demonstrated immunohistochemical abnormal localization of Wnt signaling pathway components and p53. Mutations in the selected loci of studied genes were not found after high-throughput sequencing. Furthermore, alterations in the ultrastructure of adherens junctions of the ileo-caecal neoplastic epithelia of C. parvum-infected mice were recorded using transmission electron microscopy. In conclusion, we found for the first time that the Wnt signaling pathway, and particularly the cytoskeleton network, seems to be pivotal for the development of the C. parvum-induced neoplastic process and cell migration of transformed cells. Furthermore, this model is a valuable tool in understanding the host-pathogen interactions associated with the intricate infection process of this parasite, which is able to modulate host cytoskeleton activities and several host

  9. Genetic and Epigenetic Determinants of Lung Cancer Subtype: Adenocarcinoma to Small Cell Conversion

    Science.gov (United States)

    2016-10-01

    reported in other contexts including breast cancer and bladder cancer . While beyond the scope of this grant, and not funded by this mechanism, we...have participated in a recent collaborative analysis of common genomic alterations in small cell bladder cancer vs. small cell lung cancer . A paper...of the project is to study drug resistance mechanisms in vitro and using tumors from lung cancer patients with epidermal growth factor receptor

  10. [An experimental study on the Chinese lung adenocarcinoma cell clone CPA-Yang1-BR with brain metastasis potency in nude mice and in vivo imaging research].

    Science.gov (United States)

    Lei, Bei; Cao, Jie; Shen, Jie; Zhao, Lanxiang; Liang, Sheng; Meng, Qinggang; Xie, Wenhui; Yang, Shunfang

    2013-08-20

    Lung cancer is the leading cause of cancer-related death in men and women. It is also the most common cause of brain metastases. A brain metastasis model is difficult to be established because of the presence of the blood-brain barrier (BBB) and the lack of optimal methods for detecting brain metastasis in nude mice. Thus, the establishment of a Chinese lung adenocarcinoma cell line and its animal model with brain metastasis potency and in vivo research is of great significance. CPA-Yang1 cells were obtained from a patient with human lung adenocarcinoma by lentiviral vector-mediated transfection of green fluorescence protein. Intracardiac inoculation of the cells was performed in nude mice, and brain metastatic lesions were detected using micro ¹⁸F FDG-PET/CT scanners, small animal in vivo imaging system for fluorescence, radionuclide and X ray fused imaging, magnetic resonance imaging (MRI) with sense body detection, and resection. The samples were divided into two parts for cell culture and histological diagnosis. The process was repeated in vivo and in vitro for four cycles to obtain a novel cell clone, CPA-Yang1-BR. A novel cell clone, CPA-Yang1-BR, was obtained with a brain metastatic rate of 50%. The use of MRI for the detection of brain metastases has obvious advantages. An experimental Chinese lung adenocarcinoma cell clone (CPA-Yang1-BR) and its animal model with brain metastasis potency in nude mice were established. MRI with sense body or micro MRI may be used as a sensitive, accurate, and noninvasive method to detect experimental brain metastases in intact live immunodeficient mice. The results of this study may serve as a technical platform for brain metastases from lung adenocarcinoma.

  11. Difference in prognostic significance of maximum standardized uptake value on [18F]-fluoro-2-deoxyglucose positron emission tomography between adenocarcinoma and squamous cell carcinoma of the lung

    International Nuclear Information System (INIS)

    Tsutani, Yasuhiro; Miyata, Yoshihiro; Misumi, Keizo; Ikeda, Takuhiro; Mimura, Takeshi; Hihara, Jun; Okada, Morihito

    2011-01-01

    This study evaluates the prognostic significance of [18F]-fluoro-2-deoxyglucose positron emission tomography/computed tomography findings according to histological subtypes in patients with completely resected non-small cell lung cancer. We examined 176 consecutive patients who had undergone preoperative [18F]-fluoro-2-deoxyglucose-positron emission tomography/computed tomography imaging and curative surgical resection for adenocarcinoma (n=132) or squamous cell carcinoma (n=44). Maximum standardized uptake values for the primary lesions in all patients were calculated as the [18F]-fluoro-2-deoxyglucose uptake and the surgical results were analyzed. The median values of maximum standardized uptake value for the primary tumors were 2.60 in patients with adenocarcinoma and 6.95 in patients with squamous cell carcinoma (P 6.95 (P=0.83) among patients with squamous cell carcinoma, 2-year disease-free survival rates were 93.9% for maximum standardized uptake value ≤3.7 and 52.4% for maximum standardized uptake value >3.7 (P<0.0001) among those with adenocarcinoma, and notably, 100 and 57.2%, respectively, in patients with Stage I adenocarcinoma (P<0.0001). On the basis of the multivariate Cox analyses of patients with adenocarcinoma, maximum standardized uptake value (P=0.008) was a significantly independent factor for disease-free survival as well as nodal metastasis (P=0.001). Maximum standardized uptake value of the primary tumor was a powerful prognostic determinant for patients with adenocarcinoma, but not with squamous cell carcinoma of the lung. (author)

  12. MRI to assess chemoprevention in transgenic adenocarcinoma of mouse prostate (TRAMP)

    International Nuclear Information System (INIS)

    Arbab, Ali S; Shankar, Adarsh; Varma, Nadimpalli RS; Deeb, Dorrah; Gao, Xiaohua; Iskander, ASM; Janic, Branislava; Ali, Meser M; Gautam, Subhash C

    2011-01-01

    The current method to determine the efficacy of chemoprevention in TRAMP mouse model of carcinoma of prostate (CaP) is by extracting and weighing the prostate at different time points or by immunohistochemistry analysis. Non-invasive determination of volumes of prostate glands and seminal vesicles before, during and after treatment would be valuable in investigating the efficacy of newer chemopreventive agents in CaP. The purpose of this study was to determine whether in vivo magnetic resonance imaging (MRI) using a 3 tesla clinical MRI system can be used to follow the effect of chemoprevention in TRAMP model of mouse CaP. Mice were randomized into control and treated groups. The animals in treated group received 10 µmol/kg of CDDO, 5 days a week for 20 weeks. Animals underwent in vivo MRI of prostate gland and seminal vesicles by a clinical 3 Tesla MRI system just before (at 5 weeks), during and at the end of treatment, at 25 weeks. T1-weighted and fat saturation (FATSAT) multiecho fast spin echo T2- weighted images (T2WI) were acquired. Volume of the prostate glands and seminal vesicles was determined from MR images. T2 signal intensity changes in the seminal vesicles were determined by subtracting higher echo time (TE) from lower TE T2WI. Following treatments all animals were sacrificed, prostate and seminal vesicles collected, and the tissues prepared for histological staining. All data were expressed as mean ± 1 standard deviation. Two-way or multivariate analysis of variance followed by post-hoc test was applied to determine the significant differences. A p-value of <0.05 was considered significant. Histological analysis indicated tumor in 100% of control mice, whereas 10% of the treated mice showed tumor in prostate gland. Both MRI and measured prostate weights showed higher volume/weight in control mouse group. MRI showed significantly higher volume of seminal vesicles in control animals and T2 signal intensity changes in seminal vesicles of control mice

  13. Long noncoding RNA TUG1 is a diagnostic factor in lung adenocarcinoma and suppresses apoptosis via epigenetic silencing of BAX.

    Science.gov (United States)

    Liu, Huan; Zhou, Guizhi; Fu, Xin; Cui, Haiyan; Pu, Guangrui; Xiao, Yao; Sun, Wei; Dong, Xinhua; Zhang, Libin; Cao, Sijia; Li, Guiqin; Wu, Xiaowei; Yang, Xu

    2017-11-24

    Lung cancer is one of the leading causes of cancer-related mortality, and responds badly to existing treatment. Thus, it is of urgent need to identify novel diagnostic markers and therapeutic targets. Increasing evidences have indicated that long non-coding RNAs (lncRNAs) play an important role in initiation and progression of lung cancer. However, the role of lncRNA Taurine upregulated 1 (TUG1) in lung adenocarcinoma (LAD) progression is not well known. In this study, we determined the diagnostic value of TUG1 in LAD patients, and further uncovered the underlying functional mechanism. Our results showed that TUG1 was significantly upregulated in LAD cells and serum samples. Receiver operator characteristic (ROC) analysis suggested a relatively higher area under the curve (AUC) of TUG1 (0.756) contrast to cyfra21-1 (0.619). In addition, high TUG1 level was associated with enhanced tumor size, degree of differentiation, lymph node metastases, distant metastasis and TNM stage. Cell functional assays showed that knockdown of TUG1 suppressed LAD cell viability and promoted cell apoptosis. We then sought to reveal the underlying regulatory mechanism, and the pro-apoptotic protein BAX was then identified as the downstream target of TUG1. Gain and loss functional assays showed that inhibition of BAX reversed the induced apoptosis by TUG1 knockdown. Finally, RNA immunoprecipitation and Chromatin immunoprecipitation revealed that TUG1 suppressed BAX expression through physically interacting with EZH2. In conclusion, lncRNA TUG1 is a promising diagnostic marker for LAD patients and suppression of TUG1 levels could be a future direction to promote the prognosis of LAD patients.

  14. Early pneumothorax as a feature of response to crizotinib therapy in a patient with ALK rearranged lung adenocarcinoma

    International Nuclear Information System (INIS)

    Gennatas, Spyridon; Stanway, Susana J; Thomas, Robert; Min, Toon; Shah, Riyaz; O’Brien, Mary ER; Popat, Sanjay

    2013-01-01

    Single arm phase 1 and 2 studies on Crizotinib in ALK-positive patients so far have shown rapid and durable responses. Spontaneous pneumothoraces as a result of response to anti-cancer therapy are rare in oncology but have been documented in a number of tumour types including lung cancer. This includes cytotoxic chemotherapy as well as molecular targeted agents such as gefitinib and Bevacizumab. These often require chest drain insertion or surgical intervention with associated morbidity and mortality. They have also been associated with response to treatment. This is the first report we are aware of documenting pneumothorax as response to crizotinib therapy. A 48-year-old Caucasian male presented with a Stage IV, TTF1 positive, EGFR wild-type adenocarcinoma of the lung. He received first line chemotherapy with three cycles of cisplatin-pemetrexed chemotherapy with a differential response, and then second-line erlotinib for two months before further radiological evidence of disease progression. Further analysis of his diagnostic specimen identified an ALK rearrangement by fluorescence in situ hybridization (FISH). He was commenced on crizotinib therapy 250 mg orally twice daily. At his 4-week assessment he had a chest radiograph that identified a large left-sided pneumothorax with disease response evident on the right. Chest CT confirmed a 50% left-sided pneumothorax on a background of overall disease response. A chest tube was inserted with complete resolution of the pneumothorax that did not recur following its removal. Our case demonstrates this potential complication of crizotinib therapy and we therefore recommend that pneumothorax be considered in patients on crizotinib presenting with high lung metastatic burden and with worsening dyspnoea

  15. Toxins secreted by Bacillus isolated from lung adenocarcinomas favor the penetration of toxic substances

    Directory of Open Access Journals (Sweden)

    Alexandra eMerlos

    2015-11-01

    Full Text Available The aim was to explore the eventual role of bacteria in the induction of lung cancer by smoking habits. Viable bacteria closely related to the genus Bacillus were detected at high frequencies in lung-cancer biopsies. Similar, if not identical, microbes were isolated from cigarettes and in smog. Bacteria present in cigarettes could be transferred to a physiological solution via a smoker device that mimicked their potential transfer during smoking those bacteria produce exotoxins able to open transmembrane pores. These channels can be used as a way to penetrate cells of benzopyrenes and other toxic substances present in tobacco products. We hypothesize that Bacillaceae present in tobacco play a key role in the development of lung cancer.

  16. Hand-foot syndrome in a patient with metastatic lung adenocarcinoma induced by high-dose icotinib: A case report and review of the literature

    OpenAIRE

    ZHENG, YULONG; FANG, WEIJIA; XU, NONG

    2012-01-01

    Icotinib is a new oral epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI). The most frequent side-effects of icotinib include rash and diarrhea. Hand-foot syndrome (HFS) induced by EGFR-TKI is rare. The present study describes, for the first time, HFS induced by high-dose icotinib in a 65-year old female with metastatic lung adenocarcinoma. The patient developed HFS during the first week of icotinib treatment with characteristic clinical presentation. HFS regressed after icotinib do...

  17. Factors Associated with Life Expectancy in Patients with Metastatic Spine Disease from Adenocarcinoma of the Lung

    Science.gov (United States)

    Goodwin, C. Rory; Khattab, Mohamed H.; Sankey, Eric W.; Elder, Benjamin D.; Kosztowski, Thomas A.; Sarabia-Estrada, Rachel; Bydon, Ali; Witham, Timothy F.; Wolinsky, Jean-Paul; Gokaslan, Ziya L.; Sciubba, Daniel M.

    2015-01-01

    Study Design Retrospective study. Objective Our objective was to identify preoperative prognostic factors associated with survival in patients with spinal metastasis from lung carcinoma. Methods A retrospective analysis of 26 patients diagnosed with lung carcinoma metastatic to the spinal column was performed to determine factors associated with survival. We used 3 months survival as the clinical cutoff for whether surgical intervention should be performed. We analyzed patients who survived less than 3 months compared with those who survived more than 3 months. Demographic, preoperative, operative, and postoperative factors including functional scores were collected for analysis. Results The median survival for all patients in our study was 3.5 months. We found a statistically significant difference between the group that survived less than 3 months and the group that survived greater than 3 months in terms of extrathoracic metastasis, visceral metastasis, and average postoperative modified Rankin score. Conclusion Determining which patients with lung cancer spinal metastases will benefit from surgical intervention is often dictated by the patient's predicted life expectancy. Factors associated with poorer prognosis include age, functional status, visceral metastases, and extrathoracic metastases. Although the prognosis for patients with lung cancer spinal metastases is poor, some patients may experience long-term benefit from surgical intervention. PMID:26430597

  18. Salivary type alpha-amylase activity in serum and in urine of patients with lung adenocarcinoma; Aktywnosc alfa-amylazy sliniankowej w surowicy i moczu chorych na gruczolakoraka pluca

    Energy Technology Data Exchange (ETDEWEB)

    Zakrzewska, I.; Wolska, K.; Koput, A. [Zaklad Laboratoryjnej Diagnostyki Klinicznej, Akademia Medyczna, Bialystok (Poland)

    1993-12-31

    Total alpha-amylase activity in sera and urine of 30 patients with lung adenocarcinoma has been tested. The results were compared with control group of 30 healthy voluntaries. The activity of pancreatic type was differentiated from salivary alpha amylase. Salivary type was inhibited selectively by Triticum aestivum. Higher levels of total and salivary type amylase were noted in patients with lung adenocarcinoma in comparison to healthy control. The increase was significant (p<0.005). Correlation was observed between the activity of salivary type amylase and the stage of adenocarcinoma. (author). 12 refs, 3 figs, 1 tab.

  19. The role of JAK/STAT3 signaling pathway on apoptosis of lung adenocarcinoma cell line PC-9 induced by icotinib.

    Science.gov (United States)

    Zhang, Yuping; Meng, Xia; Shi, Hongyang; Li, Wei; Ming, Zongjuan; Zhong, Yujie; Deng, Wenjing; Zhang, Qiuhong; Fan, Na; Niu, Zequn; Chen, Guo'an; Yang, Shuanying

    2016-01-01

    The aim of this study is to estimate the role of JAK/STAT3 signaling pathway on apoptosis of lung adenocarcinoma induced by icotinib. EGFR mutation was detected in lung adenocarcinoma cell line PC-9 by ARMS assay; The inhibitory rates of cell proliferation of PC-9 cells which were exposed to different concentrations of icotinib (0~100 μMol/L) for different time (24~72 h) respectively were evaluated by MTT assay; Apoptosis of PC-9 cells exposed to different concentrations of icotinib (0, 0.1, 1 and 10 μMol/L) for 48 h were evaluated by TUNEL assay; JAK2, STAT3, Bcl-2, Bax mRNA expressions were evaluated by Real-time PCR assay; The protein levels of P-STAT3 and IL-6 were evaluated by Western-blot assay. Human lung adenocarcinoma cell line PC-9 had an exon 19 deletion mutation in EGFR gene; Followed by treatment of icotinib, the proliferation of PC-9 cells were all inhibited significantly, especially in 48 and 72 h (Picotinib. The most likely mechanism is icotinib inhibited the gene expression levels of JAK2, STAT3 and Bcl-2, so with the P-STAT3 and IL-6 protein levels, and mediated gene Bax overexpression.

  20. [Detection of serum proteins in the patients of lung adenocarcinoma by the method of magnetic bead based sample fractionation and MALDI-TOF-MS].

    Science.gov (United States)

    Liu, Dan; Liu, Lun-Xu; Yuan, Quan; Li, Xiao-Liang; Huang, Na; Yang, Xiao-Dong

    2010-05-01

    To screen the serum proteins related to human lung adenocarcinoma using matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) technology. The blood samples were collected from 10 patients of lung adenocarcinoma before and one week after the surgery, while 10 healthy subjects were used as control. The differential protein expression between the two groups and the change of those proteins after surgery were studied by ClinProt magnetic bead enrichment and MALDI-TOF-MS. Six protein peaks were identified, 2 of them were highly expressed protein biomarkers with relative molecular weights of 2661, 2991, and increased after the surgery, 4 of them were lowly expressed protein biomarkers with relative molecular weights of 4091, 4210, 4644, 5336, which continuously decreased after the surgery. ClinProt magnetic bead enrichment and MALDI-TOF-MS is a quick, easy and sensitive method of proteomics. The differential expressed proteins may be the latent tumor marker of lung adenocarcinoma. The alteration of those proteins after surgery might be helpful to assess the therapeutic effect and prognosis.

  1. Antitumour and Antioxidant Activities of Activin in Kidney Tissue of Mouse Bearing Murine Mammary Adenocarcinoma and Exposed to Gamma Radiation

    International Nuclear Information System (INIS)

    EI-Tahawy, N.A.; Hanafi, N.; Said, U.Z.

    2009-01-01

    Activin (a grape seed-derived proanthocyanidins extract) possess a broad spectrum of biological, pharmacological and therapeutic activities. The present study performed to investigate the preventive and modulating effects of dietary activin in radiation or murine mammary adenocarcinoma (MMA) induced damage in kidneys of albino mice throughout in vitro and in vivo studies. Activin was orally administered to mice for 5 consecutive days (100 mg/ kg body wt) before and 10 days post tumour inoculation. In irradiated group, animals were exposed to 6 Gy whole body gamma-radiations on the fifth day of tumour inoculation. Biochemical and histopathological studies were investigated. In vitro studies using MMA cells revealed that activin increase non viable tumour cell counts. In vivo studies, either MMA or gamma-irradiation resulted in biochemical, and histopathological changes leading to kidney damage. Biochemical studies revealed that activin treatment significantly restored the elevated activity of lactate dehydrogenase (LDH), ameliorated kidney functions profile, and depressed the levels of tumour markers, also enhanced glutathione content (GSH) and activities of superoxide dismutase (SOD) and catalase (CAT). It also reduced kidney lipid peroxides and improves serum total protein level. Histopathological changes in the kidney tissues were attenuated by activin treatment either in MMA-bearing mice group or irradiation group. Exposure of MMA-bearing mouse to gamma- radiations slightly improves the above mentioned damage. While dual treatment of MMA-bearing mice with activin and subsequence with gamma-radiation exposure was more effective. It could be concluded that activin through its antioxidant properties might attenuate radiation or MMA induced renal damage suggesting that activin may have a potential benefit in enhancing radiotherapy

  2. Preliminary Study on the Effect of Adipocytes on the Biological Behaviors of
Lung Adenocarcinoma A549 Cells in Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Hang ZHANG

    2018-05-01

    Full Text Available Background and objective Adipocytes in the tumor microenvironment may provide the metabolic fuel or signal transduction through media and other means to promote a variety of malignant proliferation and invasion, of tumor cells, but their role in lung cancer progression is still unclear. The purpose of this study was to investigate the effect of adipocytes on lung cancer cell biology. Methods 3T3-L1 pre-adipocytes were induced into mature adipocytes. The cell morphology was observed by microscopy and Oil Red O staining. MTT assay, colony formation assay, wound-healing and Transwell methods were used to detect lung cancer cell proliferation, migration and invasion ability. The content of triglyceride in cells was determined by colorimetry. Results The morphology of lung adenocarcinoma A549 cells became more slender after co-culture with mature adipocytes, and the proliferation and cloning ability were significantly enhanced (P<0.05. In addition, mature adipocytes can also promote the migration ability (P<0.05, invasion ability (P<0.01 and accumulation of intracellular lipid (P<0.05 of A549 cells. Conclusion These findings suggested that adipocytes in tumor microenvironment can promote the proliferation, migration and invasion of lung adenocarcinoma A549 cells, which may be related to lipid metabolism.

  3. Air-space pattern in lung metastasis from adenocarcinoma of the GI tract

    Energy Technology Data Exchange (ETDEWEB)

    Gaeta, M.; Volta, S.; Scribano, E. [Univ. of Messina (Italy)] [and others

    1996-03-01

    We retrospectively reviewed a series of proven lung metastasis to evaluate the frequency and CT features of metastases showing an air-space (lepidic) pattern of growth. CT examinations of 65 patients with proven lung metastasis from GI carcinomas were reviewed by three observers. Four CT features were used to classify lesions as air-space metastases: (a) air-space nodules; (b) parenchymal consolidation containing air bronchogram and/or showing angiogram sign; (c) focal or extensive ground-glass opacities; and (d) nodule(s) with a {open_quotes}halo{close_quotes} sign. Six of 65 patients showed air-space metastases: three from pancreatic carcinoma. two from colonic carcinoma, and one from jejunal carcinoma. In one case, metastasis appeared as extensive parenchymal consolidation associated with ground-glass opacities; in one as an area of ground-glass opacity; in one as an extensive parenchymal consolidation with air bronchogram; in one as parenchymal consolidations with angiogram sign and multiple nodules, some of these with halo sign; in one as air-space nodules and patchy air-space consolidations; and in one as a solitary nodule with halo sign. Our study shows that air-space lung metastasis from GI carcinomas is uncommon but not rare. On CT as well as microscopically, differential diagnosis between air-space metastasis and bronchioloalveolar carcinoma may be impossible. 13 refs., 5 figs., 1 tab.

  4. Metastasis of Lung Adenocarcinoma to the Gingiva: A Rare Case Report

    Directory of Open Access Journals (Sweden)

    M. Rajini Kanth

    2015-05-01

    Full Text Available Metastatic tumors account for 1% of all oral malignancies. Metastasis to jaw bones is common, particularly in the mandible, rare in the oral soft tissues, and account for only 0.1% of oral malignancies. The majority of metastatic cases (70% reported in the literature have primary tumors located in the lung, breast, kidney, and colon. Metastasis is a biological complex process that involves detachment from the surrounding cells, regulation of cell motility, invasion, survival, proliferation, and evasion of the immune system. Clinical presentation of metastatic tumors is variable, which may create diagnostic dilemma or may lead to erroneous diagnosis. Metastatic tumors clinically mimic as dental infections. Metastasis to the oral soft tissue from lung cancer, especially gingiva is a rare condition. Metastasis to the gingiva can affect the oral function, speech, and nutrition. Most of the cases in the literature reported that lesion presented in oral soft tissues before the diagnosis of primary tumors. Here we report a case of 62-year-old male patient with metastasis from lung to the gingiva, where the metastasis was detected before primary tumor.

  5. Anticancer Effects of Sinulariolide-Conjugated Hyaluronan Nanoparticles on Lung Adenocarcinoma Cells

    Directory of Open Access Journals (Sweden)

    Kuan Yin Hsiao

    2016-03-01

    Full Text Available Lung cancer is one of the most clinically challenging malignant diseases worldwide. Sinulariolide (SNL, extracted from the farmed coral species Sinularia flexibilis, has been used for suppressing malignant cells. For developing anticancer therapeutic agents, we aimed to find an alternative for non-small cell lung cancer treatment by using SNL as the target drug. We investigated the SNL bioactivity on A549 lung cancer cells by conjugating SNL with hyaluronan nanoparticles to form HA/SNL aggregates by using a high-voltage electrostatic field system. SNL was toxic on A549 cells with an IC50 of 75 µg/mL. The anticancer effects of HA/SNL aggregates were assessed through cell viability assay, apoptosis assays, cell cycle analyses, and western blotting. The size of HA/SNL aggregates was approximately 33–77 nm in diameter with a thin continuous layer after aggregating numerous HA nanoparticles. Flow cytometric analysis revealed that the HA/SNL aggregate-induced apoptosis was more effective at a lower SNL dose of 25 µg/mL than pure SNL. Western blotting indicated that caspases-3, -8, and -9 and Bcl-xL and Bax played crucial roles in the apoptotic signal transduction pathway. In summary, HA/SNL aggregates exerted stronger anticancer effects on A549 cells than did pure SNL via mitochondria-related pathways.

  6. Effects of X-ray irradiation on expression of Pokemon gene in A549 cells of human lung adenocarcinoma

    International Nuclear Information System (INIS)

    Wang Lu; Zou Yue; Jiang Qisheng; Li Wei; Song Xiujun; Zhou Xiangyan; Wang Cuilan

    2011-01-01

    Objective: To study the dose-and time-effects of X-ray irradiation on the expression of Pokemon gene in A549 cells of human lung adenocarcinoma. Methods: A549 cells were cultured in vitro and exposed to X-rays with the doses of 2, 4, 6 and 8 Gy, respectively. Untreated A549 cells were used as control group. The relative levels of Pokemon mRNA expression in the cells were detected by using quantitative real-time PCR at 2, 4, 8, 12, 24, 48 and 72 h after irradiation. Results: The Pokemon mRNA expression levels decreased in the early period after irradiation (except 2 and 4 h after irradiation in 2 Gy group) and then increased in the later stage (48 h after irradiation) with significant statistical differences at the most time points in comparison with the control group (t=3.40-154.76, P<0.05). Conclusions: Higher doses of X-rays may degrade the expression of Pokemon mRNA in the human A549 cells and induce apoptosis in the early period, hut also may upgrade its expression in the later period, which might be correlated with the cell cycle regulation and DNA damage repair in the A549 cells. (authors)

  7. Icotinib combined whole brain radiotherapy for patients with brain metastasis from lung adenocarcinoma harboring epidermal growth factor receptor mutation.

    Science.gov (United States)

    Li, Jin-Rui; Zhang, Ye; Zheng, Jia-Lian

    2016-07-01

    The brain is a metastatic organ that is most prone to lung adenocarcinoma (LAC). However, the prognosis of patients with brain metastasis remains very poor. In this study, we evaluated the efficacy of icotinib plus whole brain radiation therapy (WBRT) for treating patients with brain metastasis from epidermal growth factor receptor (EGFR)-mutated LAC. All patients received standard WBRT administered to the whole brain in 30 Gy in 10 daily fractions. Each patient was also instructed to take 125 mg icotinib thrice per day beginning from the first day of the WBRT. After completing the WBRT, maintenance icotinib was administered until the disease progressed or intolerable adverse effects were observed. Cranial progression-free survival (CPFS) and overall survival (OS) times were the primary endpoints. A total of 43 patients were enrolled in this study. Two patients (4.7%) presented a complete response (CR), whereas 20 patients (46.5%) presented a partial response (PR). The median CPFS and OS times were 11.0 and 15.0 months, respectively. The one-year CPFS rate was 40.0% for the patients harboring EGFR exon 19 deletion and 16.7% for the patients with EGFR exon 21 L858R (P=0.027). The concurrent administration of icotinib and WBRT exhibited favorable effects on the patients with brain metastasis. EGFR exon 19 deletion was predictive of a long CPFS following icotinib plus WBRT.

  8. 17-AAG suppresses growth and invasion of lung adenocarcinoma cells via regulation of the LATS1/YAP pathway.

    Science.gov (United States)

    Ye, Xiang-Yun; Luo, Qing-Quan; Xu, Yun-Hua; Tang, Nai-Wang; Niu, Xiao-Min; Li, Zi-Ming; Shen, Sheng-Ping; Lu, Shun; Chen, Zhi-Wei

    2015-03-01

    The large tumour suppressor 1 (LATS1) signalling network has been proved to be an essential regulator within the cell, participating in multiple cellular phenotypes. However, it is unclear concerning the clinical significance of LATS1 and the regulatory mechanisms of 17-Allylamino-17- demethoxygeldanamycin (17-AAG) in lung adenocarcinoma (LAC). The aim of the present study was to investigate the correlation of LATS1 and yes-associated protein (YAP) expression with clinicopathological characteristics in LAC patients, and the effects of 17-AAG on biological behaviours of LAC cells. Subcutaneous LAC tumour models were further established to observe the tumour growth in nude mice. The results showed that the positive expression of LATS1 was significantly lowered (26.7% versus 68.0%, P AAG inhibited proliferation and invasion, and induced cell apoptosis and cycle arrest in LAC cells together with increased expression of E-cadherin and p-LATS1, and decreased expression of YAP and connective tissue growth factor. Tumour volumes and weight were much smaller in 17-AAG-treated groups than those in untreated group (P AAG suppresses growth and invasion of LAC cells via regulation of the LATS1/YAP pathway in vitro and in vivo, suggesting that we may provide a promising therapeutic strategy for the treatment of human LAC. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  9. 17-AAG suppresses growth and invasion of lung adenocarcinoma cells via regulation of the LATS1/YAP pathway

    Science.gov (United States)

    Ye, Xiang-Yun; Luo, Qing-Quan; Xu, Yun-Hua; Tang, Nai-Wang; Niu, Xiao-Min; Li, Zi-Ming; Shen, Sheng-Ping; Lu, Shun; Chen, Zhi-Wei

    2015-01-01

    The large tumour suppressor 1 (LATS1) signalling network has been proved to be an essential regulator within the cell, participating in multiple cellular phenotypes. However, it is unclear concerning the clinical significance of LATS1 and the regulatory mechanisms of 17-Allylamino-17- demethoxygeldanamycin (17-AAG) in lung adenocarcinoma (LAC). The aim of the present study was to investigate the correlation of LATS1 and yes-associated protein (YAP) expression with clinicopathological characteristics in LAC patients, and the effects of 17-AAG on biological behaviours of LAC cells. Subcutaneous LAC tumour models were further established to observe the tumour growth in nude mice. The results showed that the positive expression of LATS1 was significantly lowered (26.7% versus 68.0%, P AAG inhibited proliferation and invasion, and induced cell apoptosis and cycle arrest in LAC cells together with increased expression of E-cadherin and p-LATS1, and decreased expression of YAP and connective tissue growth factor. Tumour volumes and weight were much smaller in 17-AAG-treated groups than those in untreated group (P AAG suppresses growth and invasion of LAC cells via regulation of the LATS1/YAP pathway in vitro and in vivo, suggesting that we may provide a promising therapeutic strategy for the treatment of human LAC. PMID:25712415

  10. Autophagy influences the low-dose hyper-radiosensitivity of human lung adenocarcinoma cells by regulating MLH1.

    Science.gov (United States)

    Wang, Qiong; Xiao, Zhuya; Lin, Zhenyu; Zhou, Jie; Chen, Weihong; Jie, Wuyun; Cao, Xing; Yin, Zhongyuan; Cheng, Jing

    2017-06-01

    To investigate the impact of autophagy on the low-dose hyper-radiosensitivity (HRS) of human lung adenocarcinoma cells via MLH1 regulation. Immunofluorescent staining, Western blotting, and electron microscopy were utilized to detect autophagy in A549 and H460 cells. shRNA was used to silence MLH1 expression. The levels of MLH1, mTOR, p-mTOR, BNIP3, and Beclin-1 were measured by real-time polymerase chain reaction (PCR) and Western blotting. A549 cells, which have low levels of MLH1 expression, displayed HRS/induced radioresistance (IRR). Conversely, the radiosensitivity of H460 cells, which express high levels of MLH1, conformed to the linear-quadratic (LQ) model. After down-regulating MLH1 expression, A549 cells showed increased HRS and inhibition of autophagy, whereas H460 cells exhibited HRS/IRR. The levels of mTOR, p-mTOR, and BNIP3 were reduced in cells harboring MLH1 shRNA, and the changes in the mTOR/p-mTOR ratio mirrored those in MLH1 expression. Low MLH1-expressing A549 cells may exhibit HRS. Both the mTOR/p-mTOR and BNIP3/Beclin-1 signaling pathways were found to be related to HRS, but only mTOR/p-mTOR is involved in the regulation of HRS via MLH1 and autophagy.

  11. Apoptosis of human lung adenocarcinoma A549 cells induced by prodigiosin analogue obtained from an entomopathogenic bacterium Serratia marcescens.

    Science.gov (United States)

    Zhou, Wei; Jin, Zhi-Xiong; Wan, Yong-Ji

    2010-12-01

    An entomopathogenic bacterial strain SCQ1 was isolated from silkworm (Bombyx mori) and identified as Serratia marcescens via 16S rRNA gene analysis. This strain produces a red pigment that causes acute septicemia of silkworm. The red pigment of strain SCQ1 was identified as prodigiosin analogue (PGA) with various reported biological activities. In this study, we found that low concentration of PGA showed significant anticancer activity in human lung adenocarcinoma A549 cells, but has little effect in human bone marrow stem cells, in vitro. By exposure to different concentrations of PGA for 24 h, morphological changes and the MTT assay showed that A549 cell line was very sensitive to PGA, with IC(50) value about 2.2 mg/L. Early stage of apoptosis was detected by flow cytometry while A549 cells were treated with PGA for 4 and 12 h, respectively. The proportion of dead cells was increased with treatment time or the concentrations of PGA, but it was inversely proportional to that of apoptotic cells. These results indicate that PGA obtained from strain SCQ1 induces apoptosis in A549 cells, but the molecular mechanisms of cell death are complicated, and the S. marcescens strain SCQ1 may serve as a source of the anticancer compound, PGA.

  12. Melatonin inhibits the migration of human lung adenocarcinoma A549 cell lines involving JNK/MAPK pathway.

    Directory of Open Access Journals (Sweden)

    Qiaoyun Zhou

    Full Text Available OBJECTIVE: Melatonin, an indolamine produced and secreted predominately by the pineal gland, exhibits a variety of physiological functions, possesses antioxidant and antitumor properties. But, the mechanisms for the anti-cancer effects are unknown. The present study explored the effects of melatonin on the migration of human lung adenocarcinoma A549 cells and its mechanism. METHODS: MTT assay was employed to measure the viability of A549 cells treated with different concentrations of melatonin. The effect of melatonin on the migration of A549 cells was analyzed by wound healing assay. Occludin location was observed by immunofluorescence. The expression of occludin, osteopontin (OPN, myosin light chain kinase (MLCK and phosphorylation of myosin light chain (MLC, JNK were detected by western blots. RESULTS: After A549 cells were treated with melatonin, the viability and migration of the cells were inhibited significantly. The relative migration rate of A549 cells treated with melatonin was only about 20% at 24 h. The expression level of OPN, MLCK and phosphorylation of MLC of A549 cells were reduced, while the expression of occludin was conversely elevated, and occludin located on the cell surface was obviously increased. The phosphorylation status of JNK in A549 cells was also reduced when cells were treated by melatonin. CONCLUSIONS: Melatonin significantly inhibits the migration of A549 cells, and this may be associated with the down-regulation of the expression of OPN, MLCK, phosphorylation of MLC, and up-regulation of the expression of occludin involving JNK/MAPK pathway.

  13. Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma.

    Science.gov (United States)

    Kajiura, Koichiro; Masuda, Kiyoshi; Naruto, Takuya; Kohmoto, Tomohiro; Watabnabe, Miki; Tsuboi, Mitsuhiro; Takizawa, Hiromitsu; Kondo, Kazuya; Tangoku, Akira; Imoto, Issei

    2017-01-10

    In this study, we aimed to identify novel drivers that would be epigenetically altered through aberrant methylation in early-stage lung adenocarcinoma (LADC), regardless of the presence or absence of tobacco smoking-induced epigenetic field defects. Through genome-wide screening for aberrantly methylated CpG islands (CGIs) in 12 clinically uniform, stage-I LADC cases affecting six non-smokers and six smokers, we identified candidate tumor-suppressor genes (TSGs) inactivated by hypermethylation. Through systematic expression analyses of those candidates in panels of additional tumor samples and cell lines treated or not treated with 5-aza-deoxycitidine followed by validation analyses of cancer-specific silencing by CGI hypermethylation using a public database, we identified TRIM58 as the most prominent candidate for TSG. TRIM58 was robustly silenced by hypermethylation even in early-stage primary LADC, and the restoration of TRIM58 expression in LADC cell lines inhibited cell growth in vitro and in vivo in anchorage-dependent and -independent manners. Our findings suggest that aberrant inactivation of TRIM58 consequent to CGI hypermethylation might stimulate the early carcinogenesis of LADC regardless of smoking status; furthermore, TRIM58 methylation might be a possible early diagnostic and epigenetic therapeutic target in LADC.

  14. Haptoglobin is a serological biomarker for adenocarcinoma lung cancer by using the ProteomeLab PF2D combined with mass spectrometry.

    Science.gov (United States)

    Chang, You-Kang; Lai, Yu-Heng; Chu, Yen; Lee, Ming-Cheng; Huang, Chun-Yao; Wu, Semon

    2016-01-01

    Identification of serological biomarker is urgently needed for cancer screening, monitoring cancer progression, treatment response, and surveillance for recurrence in lung cancer. Therefore, we try to find new serological biomarker that has more specificity and sensitivity for lung cancer diagnostics. In this study, the 2-D liquid phase fractionation system (PF2D) and mass spectrometry approach has been used for comparison the serum profiles between lung cancer patients and healthy individuals. Eight proteins were identified form PF2D and subsequently by mass spectrometry. Among these proteins, haptoglobin (HP) and apolipoprotein AI (APOA1) were chosen and validated with turbidimetric assay. We found that HP levels were significantly higher and APOA1 levels were significantly lower in lung cancer patients. However, after the participants were stratified by gender, the expression trends of HP and APOA1 in lung cancer patients existed only in men, which is gender specific phenomenon. HP, APOA1 and carcinoembryonic antigen (CEA), used for distinguishing lung adenocarcinoma, had a sensitivity of 64%, 64% and 79%, respectively. Area under the ROC curve (AUC) of HP, APOA1 and CEA were 0.768, 0.761 and 0.884, respectively. When restricted to male subjects, HP, APOA1 and CEA showed sensitivity of 89%, 73% and 100%, respectively. AUC of HP, APOA1 and CEA were 0.929, 0.840 and 0.877, respectively. Therefore, our results showed that combined with PF2D system and mass spectrometry, this is a promising novel approach to identify new serological biomarkers for lung cancer research. In addition, HP may be a potential serological biomarker for lung adenocarcinoma diagnostics, especially in male subjects.

  15. Modulation of epithelial sodium channel (ENaC expression in mouse lung infected with Pseudomonas aeruginosa

    Directory of Open Access Journals (Sweden)

    Radzioch Danuta

    2005-01-01

    Full Text Available Abstract Background The intratracheal instillation of Pseudomonas aeruginosa entrapped in agar beads in the mouse lung leads to chronic lung infection in susceptible mouse strains. As the infection generates a strong inflammatory response with some lung edema, we tested if it could modulate the expression of genes involved in lung liquid clearance, such as the α, β and γ subunits of the epithelial sodium channel (ENaC and the catalytic subunit of Na+-K+-ATPase. Methods Pseudomonas aeruginosa entrapped in agar beads were instilled in the lung of resistant (BalB/c and susceptible (DBA/2, C57BL/6 and A/J mouse strains. The mRNA expression of ENaC and Na+-K+-ATPase subunits was tested in the lung by Northern blot following a 3 hours to 14 days infection. Results The infection of the different mouse strains evoked regulation of α and β ENaC mRNA. Following Pseudomonas instillation, the expression of αENaC mRNA decreased to a median of 43% on days 3 and 7 after infection and was still decreased to a median of 45% 14 days after infection (p 1Na+-K+-ATPase mRNA, the catalytic subunit of the sodium pump, was recorded. The distinctive expression profiles of the three subunits were not different, between the susceptible and resistant mouse strains. Conclusions These results show that Pseudomonas infection, by modulating ENaC subunit expression, could influence edema formation and clearance in infected lungs.

  16. The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia.

    Directory of Open Access Journals (Sweden)

    Chao Agnes Hsiung

    2010-08-01

    Full Text Available Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10(-7 or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30 x 10(-11. This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38 x 10(-11. A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60 x 10(-20, allelic risk = 1.54, 95% Confidence Interval (CI 1.41-1.68. Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40-1.87, and 2.35 (95% CI: 1.95-2.83, respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.

  17. Molecular testing guidelines for lung adenocarcinoma: Utility of cell blocks and concordance between fine-needle aspiration cytology and histology samples

    Science.gov (United States)

    Heymann, Jonas J.; Bulman, William A.; Maxfield, Roger A.; Powell, Charles A.; Halmos, Balazs; Sonett, Joshua; Beaubier, Nike T.; Crapanzano, John P.; Mansukhani, Mahesh M.; Saqi, Anjali

    2014-01-01

    Background: Lung cancer is a leading cause of mortality, and patients often present at a late stage. More recently, advances in screening, diagnosing, and treating lung cancer have been made. For instance, greater numbers of minimally invasive procedures are being performed, and identification of lung adenocarcinoma driver mutations has led to the implementation of targeted therapies. Advances in molecular techniques enable use of scant tissue, including cytology specimens. In addition, per recently published consensus guidelines, cytology-derived cell blocks (CBs) are preferred over direct smears. Yet, limited comparison of molecular testing of fine-needle aspiration (FNA) CBs and corresponding histology specimens has been performed. This study aimed to establish concordance of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) virus homolog testing between FNA CBs and histology samples from the same patients. Materials and Methods: Patients for whom molecular testing for EGFR or KRAS was performed on both FNA CBs and histology samples containing lung adenocarcinoma were identified retrospectively. Following microdissection, when necessary, concordance of EGFR and KRAS molecular testing results between FNA CBs and histology samples was evaluated. Results: EGFR and/or KRAS testing was performed on samples obtained from 26 patients. Concordant results were obtained for all EGFR (22/22) and KRAS (17/17) mutation analyses performed. Conclusions: Identification of mutations in lung adenocarcinomas affects clinical decision-making, and it is important that results from small samples be accurate. This study demonstrates that molecular testing on cytology CBs is as sensitive and specific as that on histology. PMID:24987443

  18. Molecular testing guidelines for lung adenocarcinoma: Utility of cell blocks and concordance between fine-needle aspiration cytology and histology samples

    Directory of Open Access Journals (Sweden)

    Jonas J. Heymann

    2014-01-01

    Full Text Available Background: Lung cancer is a leading cause of mortality, and patients often present at a late stage. More recently, advances in screening, diagnosing, and treating lung cancer have been made. For instance, greater numbers of minimally invasive procedures are being performed, and identification of lung adenocarcinoma driver mutations has led to the implementation of targeted therapies. Advances in molecular techniques enable use of scant tissue, including cytology specimens. In addition, per recently published consensus guidelines, cytology-derived cell blocks (CBs are preferred over direct smears. Yet, limited comparison of molecular testing of fine-needle aspiration (FNA CBs and corresponding histology specimens has been performed. This study aimed to establish concordance of epidermal growth factor receptor (EGFR and Kirsten rat sarcoma (KRAS virus homolog testing between FNA CBs and histology samples from the same patients. Materials and Methods: Patients for whom molecular testing for EGFR or KRAS was performed on both FNA CBs and histology samples containing lung adenocarcinoma were identified retrospectively. Following microdissection, when necessary, concordance of EGFR and KRAS molecular testing results between FNA CBs and histology samples was evaluated. Results: EGFR and/or KRAS testing was performed on samples obtained from 26 patients. Concordant results were obtained for all EGFR (22/22 and KRAS (17/17 mutation analyses performed. Conclusions: Identification of mutations in lung adenocarcinomas affects clinical decision-making, and it is important that results from small samples be accurate. This study demonstrates that molecular testing on cytology CBs is as sensitive and specific as that on histology.

  19. Molecular Epidemiology of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung Cancer of Adenocarcinoma Histology – Mainland China Subset Analysis of the PIONEER study

    Science.gov (United States)

    Shi, Yuankai; Li, Junling; Zhang, Shucai; Wang, Mengzhao; Yang, Shujun; Li, Ning; Wu, Gang; Liu, Wei; Liao, Guoqing; Cai, Kaican; Chen, Liang’an; Zheng, Meizhen; Yu, Ping; Wang, Xiuwen; Liu, Yunpeng; Guo, Qisen; Nie, Ligong; Liu, Jiwei; Han, Xiaohong

    2015-01-01

    Epidermal growth factor receptor (EGFR) mutations are the strongest response predictors to EGFR tyrosine kinase inhibitors (TKI) therapy, but knowledge of the EGFR mutation frequency on lung adenocarcinoma is still limited to retrospective studies. The PIONEER study (NCT01185314) is a prospective molecular epidemiology study in Asian patients with newly diagnosed advanced lung adenocarcinoma, aiming to prospectively analyze EGFR mutation status in IIIB/IV treatment-naïve lung adenocarcinomas in Asia. We report the mainland China subset results. Eligible patients (≥20 yrs old, IIIB/IV adenocarcinoma and treatment-naïve) were registered in 17 hospitals in mainland China. EGFR was tested for mutations by amplification refractory mutation system using biopsy samples. Demographic and clinical characteristics were collected for subgroup analyses. A total of 747 patients were registered. Successful EGFR mutation analysis was performed in 741, with an overall mutation rate of 50.2%. The EGFR active mutation rate is 48.0% (with 1.3% of combined active and resistance mutations). Tobacco use (>30 pack-year vs. 0–10 pack-year, OR 0.27, 95%CI: 0.17–0.42) and regional lymph nodes involvement (N3 vs. N0, OR 0.47, 95%CI: 0.29–0.76) were independent predictors of EGFR mutation in multivariate analysis. However, even in regular smokers, the EGFR mutation frequency was 35.3%. The EGFR mutation frequency was similar between diverse biopsy sites and techniques. The overall EGFR mutation frequency of the mainland China subset was 50.2%, independently associated with the intensity of tobacco use and regional lymph nodes involvement. The relatively high frequency of EGFR mutations in the mainland China subset suggest that any effort to obtain tissue sample for EGFR mutation testing should be encouraged. PMID:26599344

  20. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk. Copyright © 2016 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

  1. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  2. Blockade of the IL-6 trans-signalling/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma.

    Science.gov (United States)

    Miller, A; McLeod, L; Alhayyani, S; Szczepny, A; Watkins, D N; Chen, W; Enriori, P; Ferlin, W; Ruwanpura, S; Jenkins, B J

    2017-05-25

    Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130 F/F knock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis. Specifically, exacerbated weight loss, early mortality and reduced muscle and adipose tissue mass were features of the gp130 F/F :Kras G12D model, but not parental Kras G12D mice in which STAT3 was not hyperactivated. Gene expression profiling of muscle tissue in cachectic gp130 F/F :Kras G12D mice revealed the upregulation of IL-6 and STAT3-target genes compared with Kras G12D muscle tissue. These cachectic features of gp130 F/F :Kras G12D mice were abrogated upon the genetic normalization of STAT3 activation or ablation of IL-6 in gp130 F/F :Kras G12D :Stat3 -/+ or gp130 F/F :Kras G12D :Il6 -/- mice, respectively. Furthermore, protein levels of the soluble IL-6 receptor (sIL-6R), which is the central facilitator of IL-6 trans-signalling, were elevated in cachectic muscle from gp130 F/F :Kras G12D mice, and the specific blockade of IL-6 trans-signalling, but not classical signalling, with an anti-IL-6R antibody ameliorated cachexia-related characteristics in gp130 F/F :Kras G12D mice. Collectively, these preclinical findings identify trans-signalling via STAT3 as the signalling modality by which IL-6 promotes muscle wasting in lung cancer cachexia, and therefore support the clinical evaluation of the IL-6 trans-signalling/STAT3 axis as a therapeutic target in advanced lung cancer patients presenting with cachexia.

  3. [A Case of Central Diabetes Insipidus That Was Caused by Pituitary Metastasis of Lung Adenocarcinoma and Was Controlled by Radiation Therapy].

    Science.gov (United States)

    Izumi, Yusuke; Masuda, Takeshi; Nabeshima, Shinji; Horimasu, Yasushi; Nakashima, Taku; Miyamoto, Shintaro; Iwamoto, Hiroshi; Fujitaka, Kazunori; Murakami, Yuji; Hamada, Hironobu; Nagata, Yasushi; Hattori, Noboru

    2017-06-01

    Pituitary metastasis of lung cancer is rare; however, it often causes diabetes insipidus. Although the majority of such patients are treated with radiation therapy, it remains unclear whether diabetes insipidus can be controlled by radiation therapy. A 72-year-old man was admitted to our hospital for hemosputum, headache, and polyuria. A chest CT scan showed a 3.0 cm mass in the left upper lobe of his lung. Bronchofiberscopy results confirmed the pathological diagnosis of lung adenocarcinoma. Based on the findings from PET-CT, head MRI, and endocrine tests, the diagnosis of lung adenocarcinoma( cT1bN0M1b, stage IV)accompanied with central diabetes insipidus caused by pituitary metastasis was made. Oral administration of desmopressin reduced urine volumes; however, chemotherapy for achieving stable disease in the primary tumor was ineffective in controlling the symptoms of diabetes insipidus. Chemotherapy was discontinued after 4 months because of severe hematological toxicity. During 2 months after the cessation of chemotherapy, polyuria worsened and, therefore, radiation therapy for pituitary metastasis was started. Following the radiation therapy, an apparent reduction in urine volume was observed. Our experience of this case suggests that radiation therapy for pituitary metastasis should be considered at the time when diabetes insipidus becomes clinically overt.

  4. Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jian, E-mail: zhangjian197011@yahoo.com [Department of Respiratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi' an 710032 (China); Zhang, Tao [Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi' an 710038 (China); Ti, Xinyu; Shi, Jieran; Wu, Changgui; Ren, Xinling [Department of Respiratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi' an 710032 (China); Yin, Hong, E-mail: yinnhong@yahoo.com [The Medical Image Center, Xijing Hospital, The Fourth Military Medical University, Xi' an 710032 (China)

    2010-08-13

    Research highlights: {yields} Curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells {yields} Curcumin promotes apoptosis in A549/DDP cells through a miRNA signaling pathway {yields} Curcumin induces A549/DDP cell apoptosis by downregulating miR-186* {yields} miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin -- Abstract: Curcumin extracted from the rhizomes of Curcuma longa L. has been shown to have inhibitory effects on cancers through its anti-proliferative and pro-apoptotic activities. Emerging evidence demonstrates that curcumin can overcome drug resistance to classical chemotherapies. Thus, the mechanisms underlying the anti-tumor activities of curcumin require further study. In our study, we first demonstrated that curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells. Further studies showed that curcumin altered miRNA expression; in particular, significantly downregulated the expression of miR-186* in A549/DDP. In addition, transfection of cells with a miR-186* inhibitor promoted A549/DDP apoptosis, and overexpression of miR-186* significantly inhibited curcumin-induced apoptosis in A549/DDP cells. These observations suggest that miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin.

  5. A case of central diabetes insipidus that was caused by pituitary metastasis of lung adenocarcinoma and was controlled by radiation therapy

    International Nuclear Information System (INIS)

    Izumi, Yusuke; Masuda, Takeshi; Nabeshima, Shinji

    2017-01-01

    Pituitary metastasis of lung cancer is rare; however, it often causes diabetes insipidus. Although the majority of such patients are treated with radiation therapy, it remains unclear whether diabetes insipidus can be controlled by radiation therapy. A 72-year-old man was admitted to our hospital for hemosputum, headache, and polyuria. A chest CT scan showed a 3.0 cm mass in the left upper lobe of his lung. Bronchofiberscopy results confirmed the pathological diagnosis of lung adenocarcinoma. Based on the findings from PET-CT, head MRI, and endocrine tests, the diagnosis of lung adenocarcinoma (cT1bN0M1b, stage four) accompanied with central diabetes insipidus caused by pituitary metastasis was made. Oral administration of desmopressin reduced urine volumes; however, chemotherapy for achieving stable disease in the primary tumor was ineffective in controlling the symptoms of diabetes insipidus. Chemotherapy was discontinued after 4 months because of severe hematological toxicity. During 2 months after the cessation of chemotherapy, polyuria worsened and, therefore, radiation therapy for pituitary metastasis was started. Following the radiation therapy, an apparent reduction in urine volume was observed. Our experience of this case suggests that radiation therapy for pituitary metastasis should be considered at the time when diabetes insipidus becomes clinically overt. (author)

  6. Identification of protein expression alterations in gefitinib-resistant human lung adenocarcinoma: PCNT and mPR play key roles in the development of gefitinib-associated resistance

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Chi-Chen [Institute of Biomedical Science, National Chung-Hsing University, Taichung, Taiwan (China); Institute of Biomedical Science, and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taiwan (China); Department of Medical Research and Education, Taichung Veterans General Hospital, Taichung, Taiwan (China); Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan (China); Chen, Jing-Ting [Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (China); Lin, Meng-Wei [Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (China); Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan (China); Chan, Chia-Hao [Department of Obstetrics and Gynecology, Hsinchu Mackay Memorial Hospital, Hsinchu 30071, Taiwan (China); Wen, Yueh-Feng [Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (China); Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan (China); Wu, Shin-Bei [Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan (China); Chung, Ting-Wen [Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (China); Lyu, Kevin W. [Lutheran Medical Center, Brooklyn, NY (United States); Global Scholars Program, St. George' s University/Northumbria University, Newcastle upon Tyne (United Kingdom); Chou, Hsiu-Chuan, E-mail: chouhc@mail.nhcue.edu.tw [Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan (China); and others

    2015-11-01

    Gefitinib is the first-line chemotherapeutic drug for treating non-small cell lung cancer (NSCLC), which comprises nearly 85% of all lung cancer cases worldwide. However, most patients eventually develop drug resistance after 12–18 months of treatment. Hence, investigating the drug resistance mechanism and resistance-associated biomarkers is necessary. Two lung adenocarcinoma cell lines, PC9 and gefitinib-resistant PC9/Gef, were established for examining resistance mechanisms and identifying potential therapeutic targets. Two-dimensional differential gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used for examining global protein expression changes between PC9 and PC9/Gef. The results revealed that 164 identified proteins were associated with the formation of gefitinib resistance in PC9 cells. Additional studies using RNA interference showed that progesterone receptor membrane component 1 and pericentrin proteins have major roles in gefitinib resistance. In conclusion, the proteomic approach enabled identifying of numerous proteins involved in gefitinib resistance. The results provide useful diagnostic markers and therapeutic candidates for treating gefitinib-resistant NSCLC. - Highlights: • 164 proteins associated with gefitinib resistance were identified through proteomic analysis. • In this study, a lung adenocarcinoma and its gefitinib resistant partner were established. • mPR and PCNT proteins have evidenced to play important roles in gefitinib resistance.

  7. Identification of protein expression alterations in gefitinib-resistant human lung adenocarcinoma: PCNT and mPR play key roles in the development of gefitinib-associated resistance

    International Nuclear Information System (INIS)

    Lin, Chi-Chen; Chen, Jing-Ting; Lin, Meng-Wei; Chan, Chia-Hao; Wen, Yueh-Feng; Wu, Shin-Bei; Chung, Ting-Wen; Lyu, Kevin W.; Chou, Hsiu-Chuan

    2015-01-01

    Gefitinib is the first-line chemotherapeutic drug for treating non-small cell lung cancer (NSCLC), which comprises nearly 85% of all lung cancer cases worldwide. However, most patients eventually develop drug resistance after 12–18 months of treatment. Hence, investigating the drug resistance mechanism and resistance-associated biomarkers is necessary. Two lung adenocarcinoma cell lines, PC9 and gefitinib-resistant PC9/Gef, were established for examining resistance mechanisms and identifying potential therapeutic targets. Two-dimensional differential gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used for examining global protein expression changes between PC9 and PC9/Gef. The results revealed that 164 identified proteins were associated with the formation of gefitinib resistance in PC9 cells. Additional studies using RNA interference showed that progesterone receptor membrane component 1 and pericentrin proteins have major roles in gefitinib resistance. In conclusion, the proteomic approach enabled identifying of numerous proteins involved in gefitinib resistance. The results provide useful diagnostic markers and therapeutic candidates for treating gefitinib-resistant NSCLC. - Highlights: • 164 proteins associated with gefitinib resistance were identified through proteomic analysis. • In this study, a lung adenocarcinoma and its gefitinib resistant partner were established. • mPR and PCNT proteins have evidenced to play important roles in gefitinib resistance.

  8. Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway

    International Nuclear Information System (INIS)

    Zhang, Jian; Zhang, Tao; Ti, Xinyu; Shi, Jieran; Wu, Changgui; Ren, Xinling; Yin, Hong

    2010-01-01

    Research highlights: → Curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells → Curcumin promotes apoptosis in A549/DDP cells through a miRNA signaling pathway → Curcumin induces A549/DDP cell apoptosis by downregulating miR-186* → miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin -- Abstract: Curcumin extracted from the rhizomes of Curcuma longa L. has been shown to have inhibitory effects on cancers through its anti-proliferative and pro-apoptotic activities. Emerging evidence demonstrates that curcumin can overcome drug resistance to classical chemotherapies. Thus, the mechanisms underlying the anti-tumor activities of curcumin require further study. In our study, we first demonstrated that curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells. Further studies showed that curcumin altered miRNA expression; in particular, significantly downregulated the expression of miR-186* in A549/DDP. In addition, transfection of cells with a miR-186* inhibitor promoted A549/DDP apoptosis, and overexpression of miR-186* significantly inhibited curcumin-induced apoptosis in A549/DDP cells. These observations suggest that miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin.

  9. Establishment of A Novel Chinese Human Lung Adenocarcinoma Cell Line CPA-Yang3 and Its Real Bone Metastasis Clone CPA-Yang3BM in Immunodeficient Mice

    Directory of Open Access Journals (Sweden)

    Shunfang YANG

    2011-02-01

    Full Text Available Background and objective The recurrence and metastasis of lung cancer is a tough problem worldwide. The aim of this study is to establish a novel Chinese lung adenocarcinoma cell line and its real bone-seeking clone sub-line for exploring the molecular mechanism of lung cancer metastasis. Methods The cells came from the pleural effusion of a sixtyfive years old female patient with lung adenocarcinoma and supraclavicular lymph node metastases. The gene expression was detected by real-time quantitative PCR. Intracardiac injection of the cells into nude mice was performed and in vivo imaging was obtained by bone scintigraphy and conventional radiography. Bone metastases were determined on bone scintigraphy and then the lesions were resected under deep anesthesia for bone metastasis cancer cell culture. The process was repeated for four cycles to obtain a real bone-seeking clone. Results The tumorigenesis rate started at 4th passage in immunodeficient mice via subcutaneously and as well as later passages. Approximately 1×106 cancer cells were injected into left cardiac ventricle of immunodeficient mice resulted bone metastasis sites were successfully revealed by bone scintigraphy and pathological diagnosis, the mandible (100%, scapula (33%, humerus (50%, vertebral column (50%, femur (66.7% and accompanied invasion with other organs, the adrenal gland (17%, pulmonary (33%, liver (50%, submaxillary gland (33% in the mice after inoculation two-three weeks. The chromosome karyotype analysis of the cells was subdiploid. Quantitative real-time PCR was used to examined and compared with SPC-A-1 lung adenocarcinoma, ESM1, VEGF-C, IL-6, IL-8, AR, SVIL, FN1 genes were overexpress. The novel cell was named CPA-Yang3. The femur metastasis cell was repeated in vivo-in vitro-in vivo with three cycles and harvested a real bone metastasis clone. It was named CPA-Yang3BM. Conclusion Tne characteristics of novel strain CPAYang3 is a highly metastasis cell line of

  10. Retention index of thallium-201 single photon emission computerised tomography (SPECT) as an indicator of metastasis in adenocarcinoma of the lung.

    Science.gov (United States)

    Takekawa, H.; Itoh, K.; Abe, S.; Ogura, S.; Isobe, H.; Sukou, N.; Furudate, M.; Kawakami, Y.

    1994-01-01

    We examined the relationship between the retention of thallium-201 (201Tl) on a delayed scan and the metastatic potential of adenocarcinomas of the lung. We studied 43 patients with adenocarcinoma of the lung and divided them into two groups according to the presence or absence of lymph node metastasis. 201Tl single photon emission computerised tomography (SPECT) was conducted twice: 15 min (early scan) and 120 min (delayed scan) after intravenous injection of 3 mCi of 201Tl chloride. We calculated the retention index in order to evaluate the degree of 201Tl retention in the primary tumour. The retention indices were significantly higher in the group that was positive for lymph node metastasis than in the negative group. In adenocarcinomas with high metastatic potential, 201Tl SPECT demonstrated slow washout or increased retention on the delayed scan. The retention index of 201Tl SPECT is a useful indicator of metastatic potential, thereby facilitating the prediction of prognosis, and provides insight into the relationship between 201Tl uptake and malignancy. This is the first report demonstrating a significant relationship between the retention of 201Tl SPECT and lymph node metastasis. Images Figure 1 PMID:8054281

  11. Correlation of 18F-fluorodeoxyglucose uptake on positron emission tomography with Ki-67 index and pathological invasive area in lung adenocarcinomas 30 mm or less in size

    International Nuclear Information System (INIS)

    Murakami, Shuji; Saito, Haruhiro; Sakuma, Yuji; Mizutani, Yumiko; Ishikawa, Yoshihiro; Kondou, Tetsuro; Oshita, Fumihiro; Yokose, Tomoyuki; Kameda, Youichi; Suga, Yasuhiro; Ito, Hiroyuki; Tsuboi, Masahiro; Nakayama, Haruhiko; Noda, Kazumasa; Yamada, Kouzo

    2010-01-01

    Background: 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) is commonly used to distinguish benign from malignant lesion. Recently, maximum standardized uptake value (SUVmax) on FDG-PET has found to have prognostic value. We examined the relationship between SUVmax and proliferative activities as indicated by maximum diameter of tumor opacity on mediastinal-window images (TOM), Ki-67 index, and diameter of the pathological invasive area in lung adenocarcinomas ≤30 mm. Methods: Thin-section computed tomography (TS-CT) and FDG-PET were performed on 140 patients with resectable lung adenocarcinomas ≤30 mm between March 2006 and May 2008. Tumors were classified as air-type or solid-type based on TS-CT findings. In all resected specimens, diameter of the pathological invasive area and Ki-67 index were assessed. Results: SUVmax was significantly lower for air-type than for solid-type tumors (0.97 vs. 3.96, p 5 mm was determined as 2.15 by ROC analysis, with sensitivity of 88.3% and specificity of 84.6%. Conclusions: SUVmax correlated significantly with Ki-67 index and diameter of the pathological invasive area. The present results suggest the potential role of FDG-PET in predicting adenocarcinomas with invasive characteristics.

  12. Dramatic response to high-dose icotinib in a lung adenocarcinoma patient after erlotinib failure.

    Science.gov (United States)

    Guan, Yin; Zhao, Hong; Meng, Jing; Yan, Xiang; Jiao, ShunChang

    2014-02-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) retreatment is rarely administered for non-small cell lung cancer (NSCLC) patients who did not respond to previous TKI treatment. A high dose of TKI may overcome resistance to the standard dose of TKI and have different effectiveness toward cancer compared with the standard dose of TKI. This manuscript describes a dramatic and durable response to high-dose icotinib in a NSCLC patient who did not respond to a previous standard dose of erlotinib. The treatment extended the life of the patient for one additional year. A higher dose of icotinib deserves further study not only for patients whose therapy failed with the standard dose of TKI but also for newly diagnosed NSCLC patients with a sensitive mutation. Serial mutation testing during disease development is necessary for analysis and evaluation of EGFR TKI treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  13. Novel mouse model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis

    DEFF Research Database (Denmark)

    Hoffmann, Nadine; Rasmussen, Thomas Bovbjerg; Jensen, Peter Østrup

    2005-01-01

    (NH57388C) from the mucoid isolate (NH57388A) and a nonmucoid isolate (NH57388B) deficient in AHL were almost cleared from the lungs of the mice. This model, in which P. aeruginosa is protected against the defense system of the lung by alginate, is similar to the clinical situation. Therefore...... pulmonary mouse model without artificial embedding. The model is based on a stable mucoid CF sputum isolate (NH57388A) with hyperproduction of alginate due to a deletion in mucA and functional N-acylhomoserine lactone (AHL)-based quorum-sensing systems. Chronic lung infection could be established in both CF...

  14. Role of ATM in bystander signaling between human monocytes and lung adenocarcinoma cells.

    Science.gov (United States)

    Ghosh, Somnath; Ghosh, Anu; Krishna, Malini

    2015-12-01

    The response of a cell or tissue to ionizing radiation is mediated by direct damage to cellular components and indirect damage mediated by radiolysis of water. Radiation affects both irradiated cells and the surrounding cells and tissues. The radiation-induced bystander effect is defined by the presence of biological effects in cells that were not themselves in the field of irradiation. To establish the contribution of the bystander effect in the survival of the neighboring cells, lung carcinoma A549 cells were exposed to gamma-irradiation, 2Gy. The medium from the irradiated cells was transferred to non-irradiated A549 cells. Irradiated A549 cells as well as non-irradiated A549 cells cultured in the presence of medium from irradiated cells showed decrease in survival and increase in γ-H2AX and p-ATM foci, indicating a bystander effect. Bystander signaling was also observed between different cell types. Phorbol-12-myristate-13-acetate (PMA)-stimulated and gamma-irradiated U937 (human monocyte) cells induced a bystander response in non-irradiated A549 (lung carcinoma) cells as shown by decreased survival and increased γ-H2AX and p-ATM foci. Non-stimulated and/or irradiated U937 cells did not induce such effects in non-irradiated A549 cells. Since ATM protein was activated in irradiated cells as well as bystander cells, it was of interest to understand its role in bystander effect. Suppression of ATM with siRNA in A549 cells completely inhibited bystander effect in bystander A549 cells. On the other hand suppression of ATM with siRNA in PMA stimulated U937 cells caused only a partial inhibition of bystander effect in bystander A549 cells. These results indicate that apart from ATM, some additional factor may be involved in bystander effect between different cell types. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Mouse lung contains endothelial progenitors with high capacity to form blood and lymphatic vessels

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    Barleon Bernhard

    2010-07-01

    Full Text Available Abstract Background Postnatal endothelial progenitor cells (EPCs have been successfully isolated from whole bone marrow, blood and the walls of conduit vessels. They can, therefore, be classified into circulating and resident progenitor cells. The differentiation capacity of resident lung endothelial progenitor cells from mouse has not been evaluated. Results In an attempt to isolate differentiated mature endothelial cells from mouse lung we found that the lung contains EPCs with a high vasculogenic capacity and capability of de novo vasculogenesis for blood and lymph vessels. Mouse lung microvascular endothelial cells (MLMVECs were isolated by selection of CD31+ cells. Whereas the majority of the CD31+ cells did not divide, some scattered cells started to proliferate giving rise to large colonies (> 3000 cells/colony. These highly dividing cells possess the capacity to integrate into various types of vessels including blood and lymph vessels unveiling the existence of local microvascular endothelial progenitor cells (LMEPCs in adult mouse lung. EPCs could be amplified > passage 30 and still expressed panendothelial markers as well as the progenitor cell antigens, but not antigens for immune cells and hematopoietic stem cells. A high percentage of these cells are also positive for Lyve1, Prox1, podoplanin and VEGFR-3 indicating that a considerabe fraction of the cells are committed to develop lymphatic endothelium. Clonogenic highly proliferating cells from limiting dilution assays were also bipotent. Combined in vitro and in vivo spheroid and matrigel assays revealed that these EPCs exhibit vasculogenic capacity by forming functional blood and lymph vessels. Conclusion The lung contains large numbers of EPCs that display commitment for both types of vessels, suggesting that lung blood and lymphatic endothelial cells are derived from a single progenitor cell.

  16. Synchrotron microradiography study on acute lung injury of mouse caused by PM2.5 aerosols

    International Nuclear Information System (INIS)

    Tong Yongpeng; Zhang Guilin; Li Yan; Tan Mingguan; Wang Wei; Chen Jianmin; Hwu Yeukuang; Hsu, Pei-Chebg; Je, Jung Ho; Margaritondo, Giorgio; Song Weiming; Jiang, Rongfang; Jiang Zhihai

    2006-01-01

    In order to investigate FeSO 4 , ZnSO 4 (the two of main metal compositions of Shanghai PM 2.5 (particle matter with those aerodynamical diameter 2.5 aerosol particles, FeSO 4 , ZnSO 4 and their mixtures were instilled intratracheally into mouse lungs for experiment. By 2 days after instillation, the live mice were checked in vivo by synchrotron refractive index microradiography. In addition after extracted and examined by dissection, the right lobes of lung were fixed by formalin, then imaged by synchrotron microradiography again. Corresponding parts of those lung tissues were embedded in paraffin for histopathologic study. The synchrotron X-ray microradiographs of live mouse lung showed different lung texture changes after instilled with different toxic solutions. Hemorrhage points in lung were observed more from those mice instilled by FeSO 4 contained toxin solutions groups. Bronchial epithelial hyperplasia can be observed in ZnSO 4 contained solution-instilled groups from histopathologic analysis. It was found that the acute lung injury of mice caused by solution of PM 2.5 + FeSO 4 + ZnSO 4 was more serious than other toxin solutions. Results suggested that FeSO 4 mainly induced hemorrhage and ZnSO 4 mainly induced inflammation and bronchiolar epithelial hyperplasia in the early toxicological effects of PM 2.5

  17. Promoter hypermethylation of DNA repair genes MLH1 and MSH2 in adenocarcinomas and squamous cell carcinomas of the lung

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    A. Gomes

    2014-01-01

    Full Text Available Five years survival of lung cancer is 16%, significantly lower than in prostate (99.9%, breast (88.5% and colon (64.1% carcinomas. When diagnosed in the surgical stage it increases to 50% but this group only comprises 14–16% of the cases. DNA methylation has emerged as a potential cancer-specific biomarker. Hypermethylation of CpG islands located in the promoter regions of tumour suppressor genes is now firmly established as an important mechanism for gene inactivation.This retrospective study included 40 squamous cell carcinomas and 40 adenocarcinomas in various surgical TNM stages to define methylation profile and possible silencing of DNA repair genes – MLH1 and MSH2 – using Methylation-Specific PCR and protein expression by immunohistochemistry in tumoural tissue, preneoplastic lesions and respiratory epithelium with normal histological features.The protein expression of MLH1 and MSH2 genes, in the available preneoplastic lesions and in normal cylindrical respiratory epithelium appeared reduced. The frequency of promoter hypermethylation found on these DNA repair genes was elevated, with a higher prevalence of methylation of MLH1 gene in 72% of squamous cell carcinoma. The differences are not so obvious for MSH2 promoter hypermethylation. No correlation was found among the status of methylation, the protein expression and the clinicopathological characteristics.With a larger study, a better characterization of the hypermethylation status of neoplastic and preneoplastic lesions in small biopsies would be achieved, inherent to tumour histology, heterogeneity and preservation, and finally differences in the study population to elucidate other possible mechanisms of altered expression of the hMLH1 and hMSH. Resumo: A sobrevivência aos cinco anos no cancro do pulmão é de 16%, significativamente inferior que nos carcinomas na próstata (99,9%, mama (88,5% e cólon (64,1%. Quando diagnosticado na fase cir

  18. Morphological analysis of mouse lungs after treatment with magnetite-based magnetic fluid stabilized with DMSA

    International Nuclear Information System (INIS)

    Pereira Garcia, Monica; Miranda Parca, Renata; Braun Chaves, Sacha; Paulino Silva, Luciano; Djalma Santos, Antonio; Guerrero Marques Lacava, Zulmira; Cesar Morais, Paulo; Azevedo, Ricardo Bentes

    2005-01-01

    Mouse lungs injected with magnetic fluids based on magnetite nanoparticles stabilized by 2,3-dimercaptosuccinic acid were studied. We observed clusters of magnetic nanoparticles inside blood vessels, within the organ parenchyma and cells, as well as increased numbers of leukocytes in the organ. Both the particle concentration and organ inflammation diminished in a time-dependent manner

  19. Inhibition of Pyk2 blocks lung inflammation and injury in a mouse model of acute lung injury

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    Duan Yingli

    2012-01-01

    Full Text Available Abstract Background Proline-rich tyrosine kinase 2 (Pyk2 is essential in neutrophil degranulation and chemotaxis in vitro. However, its effect on the process of lung inflammation and edema formation during LPS induced acute lung injury (ALI remains unknown. The goal of the present study was to determine the effect of inhibiting Pyk2 on LPS-induced acute lung inflammation and injury in vivo. Methods C57BL6 mice were given either 10 mg/kg LPS or saline intratracheally. Inhibition of Pyk2 was effected by intraperitoneal administration TAT-Pyk2-CT 1 h before challenge. Bronchoalveolar lavage analysis of cell counts, lung histology and protein concentration in BAL were analyzed at 18 h after LPS treatment. KC and MIP-2 concentrations in BAL were measured by a mouse cytokine multiplex kit. The static lung compliance was determined by pressure-volume curve using a computer-controlled small animal ventilator. The extravasated Evans blue concentration in lung homogenate was determined spectrophotometrically. Results Intratracheal instillation of LPS induced significant neutrophil infiltration into the lung interstitium and alveolar space, which was attenuated by pre-treatment with TAT-Pyk2-CT. TAT-Pyk2-CT pretreatment also attenuated 1 myeloperoxidase content in lung tissues, 2 vascular leakage as measured by Evans blue dye extravasation in the lungs and the increase in protein concentration in bronchoalveolar lavage, and 3 the decrease in lung compliance. In each paradigm, treatment with control protein TAT-GFP had no blocking effect. By contrast, production of neutrophil chemokines MIP-2 and keratinocyte-derived chemokine in the bronchoalveolar lavage was not reduced by TAT-Pyk2-CT. Western blot analysis confirmed that tyrosine phosphorylation of Pyk2 in LPS-challenged lungs was reduced to control levels by TAT-Pyk2-CT pretreatment. Conclusions These results suggest that Pyk2 plays an important role in the development of acute lung injury in mice and

  20. Effects of X-ray irradiation on the expression of Pokemon gene in human lung adenocarcinoma cell line

    International Nuclear Information System (INIS)

    Liang Xiaofang; Zou Yue; Wang Lu; Jiang Qisheng; Li Fengsheng

    2012-01-01

    Objective: To study the dose and time effects of X-ray radiation on the expression of Pokemon gene and protein in human lung adenocarcinoma cell line A 549 . Methods: A 549 cells was exposed to different doses of X-ray (2, 4, 6 and 8 Gy), and the expression of Pokemon mRNA and protein of the cells was detected by using Quantitative real-time PCR and western-blotting at 2, 4, 8, 12, 24, and 48 h after irradiation. 3-( 4, 5-Dimethylthiazole-2-yl )-2, 5-diphenyltetrazolium bromide was used to detect the proliferation of A 549 cells at 1, 2, 3, 4, and 5 d after 2 Gy X-ray irradiation. The mock treated A 549 cells were used as the control. Results: The expression of Pokemon mRNA trended to decrease after irradiated with 4, 6 and 8 Gy in the earlier period and increased in the later period with statistical difference at the most time points (t =3.40 -154.76, P =0.000 -0.041). The expression of Pokemon protein trended to increase and reached the peak at 8 h after irradiated of 2, 4, 6 and 8 Gy with statistical difference at the most time points (t =4.18 - 89.64, P =0.000 - 0.039). Compared with the control, the proliferation of A 549 cells was significantly inhibited during 3 to 5 d after irradiation of 2 Gy (t =2.34 - 18.19, P =0.000 -0.040). Conclusions: X-ray irradiation may increase the expression of Pokemon mRNA and protein in A 549 cells, which might be correlated with radiation-resistance of A 549 cells. (authors)

  1. Clinical Response to Gefitinib Retreatment of Lung Adenocarcinoma Patients Who Benefited from An Initial Gefitinib Therapy: A Retrospective Analysis

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    Junling LI

    2012-01-01

    Full Text Available Background and objective Gefitinib is an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI that has been widely used for the treatment of non-small cell lung cancer (NSCLC. It is most effective in women, as well as in patients who have never smoked, have pulmonary adenocarcinomas, or are of Asian origin. Several treatment options are available for NSCLC patients who responded to initial gefitinib therapy but demonstrated tumor progression, of which gefitinib readministration is the chosen therapeutic option. The present study aims to evaluate the efficacy and toxicity of gefitinib readministration. Methods The clinical data of 18 patients with NSCLC who had shown partial response (PR or achieved a stable disease (SD status after gefitinib administration and were retreated with gefitinib due to failure of the initial therapy were reviewed and retrospectively analyzed. Results Of the 18 patients studied, 1 (6% showed partial remission (PR, 11 (61% achieved SD, and 6 (33% experienced disease progression. The disease control rate was 67%, and the median progression-free survival was 5.16 months (range, 1 to 24.8 months. The median overall survival from the start of the gefitinib therapy was 39.4 months (range, 15.38 to 52.44 months. Moreover, the median overall survival from the beginning of the 2nd therapy was 12.41 months (range, 3.98 to 38.24 months. Mild toxicity was observed with the 2nd gefitinib therapy. Conclusion The results of the present study indicate that patients with NSCLC may still be expected to achieve prolonged survival through gefitinib readministration if they initially responded to gefitinib and underwent various subsequent treatments.

  2. Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung

    International Nuclear Information System (INIS)

    Kalinina, Tatyana; Simon, Ronald; Otto, Benjamin; Dierlamm, Judith; Schwarzenbach, Heidi; Effenberger, Katharina E; Bockhorn, Maximilian; Izbicki, Jakob R; Yekebas, Emre F; Güngör, Cenap; Thieltges, Sabrina; Möller-Krull, Maren; Murga Penas, Eva Maria; Wicklein, Daniel; Streichert, Thomas; Schumacher, Udo; Kalinin, Viacheslav

    2010-01-01

    Pancreatic cancer is still associated with devastating prognosis. Real progress in treatment options has still not been achieved. Therefore new models are urgently needed to investigate this deadly disease. As a part of this process we have established and characterized a new human pancreatic cancer cell line. The newly established pancreatic cancer cell line PaCa 5061 was characterized for its morphology, growth rate, chromosomal analysis and mutational analysis of the K-ras, EGFR and p53 genes. Gene-amplification and RNA expression profiles were obtained using an Affymetrix microarray, and overexpression was validated by IHC analysis. Tumorigenicity and spontaneous metastasis formation of PaCa 5061 cells were analyzed in pfp -/- /rag2 -/- mice. Sensitivity towards chemotherapy was analysed by MTT assay. PaCa 5061 cells grew as an adhering monolayer with a doubling time ranging from 30 to 48 hours. M-FISH analyses showed a hypertriploid complex karyotype with multiple numerical and unbalanced structural aberrations. Numerous genes were overexpressed, some of which have previously been implicated in pancreatic adenocarcinoma (GATA6, IGFBP3, IGFBP6), while others were detected for the first time (MEMO1, RIOK3). Specifically highly overexpressed genes (fold change > 10) were identified as EGFR, MUC4, CEACAM1, CEACAM5 and CEACAM6. Subcutaneous transplantation of PaCa 5061 into pfp -/- /rag2 -/- mice resulted in formation of primary tumors and spontaneous lung metastasis. The established PaCa 5061 cell line and its injection into pfp -/- /rag2 -/- mice can be used as a new model for studying various aspects of the biology of human pancreatic cancer and potential treatment approaches for the disease

  3. Sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors in males, smokers, and non-adenocarcinoma lung cancer in patients with EGFR mutations.

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    Zeng, Zhu; Chen, Hua-Jun; Yan, Hong-Hong; Yang, Jin-Ji; Zhang, Xu-Chao; Wu, Yi-Long

    2013-09-27

    The demographical/clinical characteristics of being Asian, having an adenocarcinoma, being female, and being a "never-smoker" are regarded as favorable predictors for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) efficacy in non-small cell lung cancer (NSCLC) with unknown EGFR gene status. In this study, we examined the effects of the supposedly unfavorable clinical variables in EGFR-mutant patients. In total, 159 EGFR-mutant NSCLC patients' clinical features were correlated with progression-free survival (PFS), response rate (RR), and overall survival (OS). Multivariate analysis of clinical characteristics was performed using the Cox and logistic regression methods. There were 90 females (56.6%), 112 never-smokers (70.4%), and 153 patients with adenocarcinomas (96.2%). All patients were treated with EGFR-TKI, and 52.8% received TKI in a first-line setting. The median PFS of patients receiving first-line TKI was similar, regardless of gender (males vs females: 9.1 vs 9.7 months, p=0.793), smoking status (never-smokers vs smokers: 9.9 vs 9.1 months, p=0.570), or histology (adenocarcinoma vs non-adenocarcinoma: 9.7 vs 9.2 months, p=0.644). OS curves of first-line TKI-treated patients were also not associated with gender (p=0.722), smoking status (p=0.579), or histology (p=0.480). Similar results of PFS and OS were obtained for patients who received TKI beyond first-line. Multivariate analysis indicated that none of these clinical factors was an independent predictor of survival. The supposedly 'favorable' clinical factors of female gender, non-smoking status, and adenocarcinoma were not independent predictive factors for PFS or OS in this population of EGFR-mutant NSCLC patients.

  4. Expression of Axl in Lung Adenocarcinoma and Correlation with Tumor Progression

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    Yi-Shing Shinh

    2005-12-01

    Full Text Available We used the Transwell system to select highly invasive cell lines from minimally invasive parent cells, and we compared gene expression in paired cell lines with high and low invasive potentials. Axl was relatively overexpressed in the highly invasive cell lines when compared with their minimally invasive counterparts. However, there is only limited information about the role of Axl in cancer invasion. The biologic function of Axl in tumor invasion was investigated by overexpression of full-length Axl in minimally invasive cells and by siRNA knockdown of Axl expression in highly invasive cells. Overexpression of Axl in minimally invasive cells increased their invasiveness. siRNA reduced cell invasiveness as Axl was downregulated in highly invasive cells. We further investigated the protein expression of Axl by immunohistochemistry and its correlation with clinicopathologic features. Data from a study of 58 patient specimens showed that Axl immunoreactivity was statistically significant with respect to lymph node status (P < .0001 and the patient's clinical stage (P < .0001. Our results demonstrate that Axl protein kinase seems to play an important role in the invasion and progression of lung cancer.

  5. Clinical value of miR-452-5p expression in lung adenocarcinoma: A retrospective quantitative real-time polymerase chain reaction study and verification based on The Cancer Genome Atlas and Gene Expression Omnibus databases.

    Science.gov (United States)

    Gan, Xiao-Ning; Luo, Jie; Tang, Rui-Xue; Wang, Han-Lin; Zhou, Hong; Qin, Hui; Gan, Ting-Qing; Chen, Gang

    2017-05-01

    The role and mechanism of miR-452-5p in lung adenocarcinoma remain unclear. In this study, we performed a systematic study to investigate the clinical value of miR-452-5p expression in lung adenocarcinoma. The expression of miR-452-5p in 101 lung adenocarcinoma patients was detected by quantitative real-time polymerase chain reaction. The Cancer Genome Atlas and Gene Expression Omnibus databases were joined to verify the expression level of miR-452-5p in lung adenocarcinoma. Via several online prediction databases and bioinformatics software, pathway and network analyses of miR-452-5p target genes were performed to explore its prospective molecular mechanism. The expression of miR-452-5p in lung adenocarcinoma in house was significantly lower than that in adjacent tissues (p < 0.001). Additionally, the expression level of miR-452-5p was negatively correlated with several clinicopathological parameters including the tumor size (p = 0.014), lymph node metastasis (p = 0.032), and tumor-node-metastasis stage (p = 0.036). Data from The Cancer Genome Atlas also confirmed the low expression of miR-452 in lung adenocarcinoma (p < 0.001). Furthermore, reduced expression of miR-452-5p in lung adenocarcinoma (standard mean deviations = -0.393, 95% confidence interval: -0.774 to -0.011, p = 0.044) was validated by a meta-analysis. Five hub genes targeted by miR-452-5p, including SMAD family member 4, SMAD family member 2, cyclin-dependent kinase inhibitor 1B, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon, and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta, were significantly enriched in the cell-cycle pathway. In conclusion, low expression of miR-452-5p tends to play an essential role in lung adenocarcinoma. Bioinformatics analysis might be beneficial to reveal the potential mechanism of miR-452-5p in lung adenocarcinoma.

  6. Pulmonary adenocarcinoma in cattle

    OpenAIRE

    Sousa Z, Diogo; Rivera C, Luis; Quevedo C, Didier; Gorino, Ana Claudia; Biagio C, Simone; Laufer A, Renée

    2014-01-01

    The Macroscopic, histological and immunohistochemical aspects of lung acinar adenocarcinoma and the presence of nodules in the abdominal cavity of an adult female bovine are reported. In the necropsy analysis samples were collected from the: lung, heart, spleen, liver, pancreas, kidney, uterus, intestine, brain, and from nodules found in the lung and abdominal cavity, which were routinely processed to be stained by hematoxylin-eosin and for an immunohistochemistry exam with the antibodies: cy...

  7. Nanostructured delivery system for zinc phthalocyanine: preparation, characterization, and phototoxicity study against human lung adenocarcinoma A549 cells

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    Mariana da Volta Soares

    2011-01-01

    Full Text Available Mariana da Volta Soares1, Mainara Rangel Oliveira1, Elisabete Pereira dos Santos1, Lycia de Brito Gitirana2, Gleyce Moreno Barbosa3, Carla Holandino Quaresma3, Eduardo Ricci-Júnior11Department of Medicines, Laboratório de Desenvolvimento Galênico (LADEG, Faculty of Pharmacy, 2Laboratory of Animal and Comparative Histology, Glycobiology Research Program, Institute of Biomedical Science, 3Department of Medicines, Laboratório Multidisciplinar de Ciências Farmacêuticas, Faculty of Pharmacy, Federal University of Rio de Janeiro (UFRJ, Rio de Janeiro, BrazilAbstract: In this study, zinc phthalocyanine (ZnPc was loaded onto poly-ε-caprolactone (PCL nanoparticles (NPs using a solvent emulsification–evaporation method. The process yield and encapsulation efficiency were 74.2% ± 1.2% and 67.1% ± 0.9%, respectively. The NPs had a mean diameter of 187.4 ± 2.1 nm, narrow distribution size with a polydispersity index of 0.096 ± 0.004, zeta potential of -4.85 ± 0.21 mV, and spherical shape. ZnPc has sustained release, following Higuchi’s kinetics. The photobiological activity of the ZnPc-loaded NPs was evaluated on human lung adenocarcinoma A549 cells. Cells were incubated with free ZnPc or ZnPc-loaded NPs for 4 h and then washed with phosphate-buffered saline. Culture medium was added to the wells containing the cells. Finally, the cells were exposed to red light (660 nm with a light dose of 100 J/cm2. The cellular viability was determined after 24 h of incubation. ZnPc-loaded NPs and free photosensitizer eliminated about 95.9% ± 1.8% and 28.7% ± 2.2% of A549 cells, respectively. The phototoxicity was time dependent up to 4 h and concentration dependent at 0–5 µg ZnPc. The cells viability decreased with the increase of the light dose in the range of 10–100 J/cm2. Intense lysis was observed in the cells incubated with the ZnPc-loaded NPs and irradiated with red light. ZnPc-loaded PCL NPs are the release systems that promise photodynamic

  8. Genotoxicity of 3-nitrobenzanthrone and 3-aminobenzanthrone in MutaMouse and lung epithelial cells derived from MutaMouse.

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    Arlt, Volker M; Gingerich, John; Schmeiser, Heinz H; Phillips, David H; Douglas, George R; White, Paul A

    2008-11-01

    FE1 lung epithelial cells derived from MutaMouse are a new model system to provide in vitro mutagenicity data with the potential to predict the outcome of an in vivo MutaMouse test. 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust and urban air pollution. We investigated the mutagenicity and DNA binding of 3-NBA and its main metabolite 3-aminobenzanthrone (3-ABA) in vitro and in vivo in the MutaMouse assay. Mice were treated with 3-NBA or 3-ABA (0, 2 or 5 mg/kg body weight/day) by gavage for 28 days and 28 days later lacZ mutant frequency (MF) was determined in liver, lung and bone marrow. For both compounds, dose-related increases in MF were seen in liver and bone marrow, but not in lung; mutagenic activity was approximately 2-fold lower for 3-ABA than for 3-NBA. With 3-NBA, highest DNA adduct levels (measured by (32)P-post-labelling) were found in liver (approximately 230 adducts per 10(8) nucleotides) with levels 20- to 40-fold lower in bone marrow and lung. With 3-ABA, DNA adduct levels were again highest in the liver, but approximately 4-fold lower than for 3-NBA. FE1 cells were exposed to up to 10 microg/ml 3-NBA or 3-ABA for 6 h with or without exogenous activation (S9) and harvested after 3 days. For 3-NBA, there was a dose-related increase in MF both with and without S9 mix, which was >10 times higher than observed in vivo. At the highest concentration of 3-ABA (10 microg/ml), we found only around a 2-fold increase in MF relative to controls. DNA adduct formation in FE1 cells was dose-dependent for both compounds, but 10- to 20-fold higher for 3-NBA compared to 3-ABA. Collectively, our data indicate that MutaMouse FE1 cells are well suited for cost-effective testing of suspected mutagens with different metabolic activation pathways as a guide for subsequent in vivo MutaMouse testing.

  9. Failure of catalase to protect against aflatoxin B1-induced mouse lung tumorigenicity

    International Nuclear Information System (INIS)

    Guindon, Katherine A.; Foley, Julie F.; Maronpot, Robert R.; Massey, Thomas E.

    2008-01-01

    The carcinogenic mycotoxin aflatoxin B 1 (AFB 1 ) induces 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in mouse lung, an effect that can be prevented by treatment with polyethylene glycol-conjugated catalase (PEG-CAT). G → T transversion mutation in K-ras, an early event in AFB 1 -induced mouse lung carcinogenesis, is thought to result from AFB 1 -8,9-exo-epoxide binding to DNA to form AFB 1 -N 7 -guanine, but may also result from formation of 8-OHdG. Therefore, oxidative DNA damage may be important in AFB 1 carcinogenicity. The objective of this study was to determine whether PEG-CAT would prevent AFB 1 tumorigenicity. Mouse lung tumorigenesis was assessed following treatment of female A/J mice with 300 kU/kg PEG-CAT ip and/or 50 mg/kg AFB 1 . Mice were killed 7 months post-treatment and tumors greater than 1 mm in diameter were excised. Unexpectedly, the mean number of tumors per mouse in the PEG-CAT + AFB 1 group (8.81 ± 3.64, n = 47) was greater than that of the group treated with AFB 1 alone (7.05 ± 3.45, n = 42) (P 1 were larger than those from mice treated with AFB 1 alone (P 1 and PEG-CAT + AFB 1 groups (P > 0.05). In vitro incubation with mouse liver catalase (CAT) resulted in conversion of [ 3 H]AFB 1 into a DNA-binding species, a possible explanation for the results observed in vivo. These results demonstrate that PEG-CAT is not protective against AFB 1 carcinogenicity in mouse lung despite preventing DNA oxidation

  10. Genomic Aberrations in Crizotinib Resistant Lung Adenocarcinoma Samples Identified by Transcriptome Sequencing.

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    Ali Saber

    Full Text Available ALK-break positive non-small cell lung cancer (NSCLC patients initially respond to crizotinib, but resistance occurs inevitably. In this study we aimed to identify fusion genes in crizotinib resistant tumor samples. Re-biopsies of three patients were subjected to paired-end RNA sequencing to identify fusion genes using deFuse and EricScript. The IGV browser was used to determine presence of known resistance-associated mutations. Sanger sequencing was used to validate fusion genes and digital droplet PCR to validate mutations. ALK fusion genes were detected in all three patients with EML4 being the fusion partner. One patient had no additional fusion genes. Another patient had one additional fusion gene, but without a predicted open reading frame (ORF. The third patient had three additional fusion genes, of which two were derived from the same chromosomal region as the EML4-ALK. A predicted ORF was identified only in the CLIP4-VSNL1 fusion product. The fusion genes validated in the post-treatment sample were also present in the biopsy before crizotinib. ALK mutations (p.C1156Y and p.G1269A detected in the re-biopsies of two patients, were not detected in pre-treatment biopsies. In conclusion, fusion genes identified in our study are unlikely to be involved in crizotinib resistance based on presence in pre-treatment biopsies. The detection of ALK mutations in post-treatment tumor samples of two patients underlines their role in crizotinib resistance.

  11. Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression

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    Zhang Xuchao

    2010-07-01

    Full Text Available Abstract Background The anaplastic lymphoma kinase (ALK gene is frequently involved in translocations that lead to gene fusions in a variety of human malignancies, including lymphoma and lung cancer. Fusion partners of ALK include NPM, EML4, TPM3, ATIC, TFG, CARS, and CLTC. Characterization of ALK fusion patterns and their resulting clinicopathological profiles could be of great benefit in better understanding the biology of lung cancer. Results RACE-coupled PCR sequencing was used to assess ALK fusions in a cohort of 103 non-small cell lung carcinoma (NSCLC patients. Within this cohort, the EML4-ALK fusion gene was identified in 12 tumors (11.6%. Further analysis revealed that EML4-ALK was present at a frequency of 16.13% (10/62 in patients with adenocarcinomas, 19.23% (10/52 in never-smokers, and 42.80% (9/21 in patients with adenocarcinomas lacking EGFR and KRAS mutations. The EML4-ALK fusion was associated with non-smokers (P = 0.03, younger age of onset (P = 0.03, and adenocarcinomas without EGFR/KRAS mutations (P = 0.04. A trend towards improved survival was observed for patients with the EML4-ALK fusion, although it was not statistically significant (P = 0.20. Concurrent deletion in EGFR exon 19 and fusion of EML4-ALK was identified for the first time in a Chinese female patient with an adenocarcinoma. Analysis of ALK expression revealed that ALK mRNA levels were higher in tumors positive for the EML-ALK fusion than in negative tumors (normalized intensity of 21.99 vs. 0.45, respectively; P = 0.0018. However, expression of EML4 did not differ between the groups. Conclusions The EML4-ALK fusion gene was present at a high frequency in Chinese NSCLC patients, particularly in those with adenocarcinomas lacking EGFR/KRAS mutations. The EML4-ALK fusion appears to be tightly associated with ALK mRNA expression levels. RACE-coupled PCR sequencing is a highly sensitive method that could be used clinically for the identification of EML4-ALK

  12. USP22 Induces Cisplatin Resistance in Lung Adenocarcinoma by Regulating γH2AX-Mediated DNA Damage Repair and Ku70/Bax-Mediated Apoptosis

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    Aman Wang

    2017-05-01

    Full Text Available Resistance to platinum-based chemotherapy is one of the most important reasons for treatment failure in advanced non-small cell lung cancer, but the underlying mechanism is extremely complex and unclear. The present study aimed to investigate the correlation of ubiquitin-specific peptidase 22 (USP22 with acquired resistance to cisplatin in lung adenocarcinoma. In this study, we found that overexpression of USP22 could lead to cisplatin resistance in A549 cells. USP22 and its downstream proteins γH2AX and Sirt1 levels are upregulated in the cisplatin- resistant A549/CDDP cell line. USP22 enhances DNA damage repair and induce cisplatin resistance by promoting the phosphorylation of histone H2AX via deubiquitinating histone H2A. In addition, USP22 decreases the acetylation of Ku70 by stabilizing Sirt1, thus inhibiting Bax-mediated apoptosis and inducing cisplatin resistance. The cisplatin sensitivity in cisplatin-resistant A549/CDDP cells was restored by USP22 inhibition in vivo and vitro. In summary, our findings reveal the dual mechanism of USP22 involvement in cisplatin resistance that USP22 can regulate γH2AX-mediated DNA damage repair and Ku70/Bax-mediated apoptosis. USP22 is a potential target in cisplatin-resistant lung adenocarcinoma and should be considered in future therapeutic practice.

  13. Successful oral desensitization against skin rash induced by alectinib in a patient with anaplastic lymphoma kinase-positive lung adenocarcinoma: A case report.

    Science.gov (United States)

    Shirasawa, Masayuki; Kubotaa, Masaru; Harada, Shinya; Niwa, Hideyuki; Kusuhara, Seiichiro; Kasajima, Masashi; Hiyoshi, Yasuhiro; Ishihara, Mikiko; Igawa, Satoshi; Masuda, Noriyuki

    2016-09-01

    Alectinib has been approved for the treatment of patients with anaplastic lymphoma kinase (ALK) gene rearrangement-positive advanced non-small cell lung cancer. In terms of adverse effects, the occurrence of a severe skin rash induced by alectinib is reportedly rare, compared with the occurrence of skin rash induced by epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). In the present case report, a 76-year-old woman with ALK-positive lung adenocarcinoma experienced disease progression after undergoing first-line chemotherapy. Subsequently, alectinib was administered as a second-line therapy. However, she discontinued alectinib therapy after 11days because of the occurrence of an alectinib-induced skin rash. Since the skin rash improved within one week, we attempted to perform oral desensitization to alectinib. The patient has not shown any recurrence of the rash or disease progression for 7 months since the successful oral desensitization to alectinib. Here, we describe the first case of successful oral desensitization against a skin rash induced by alectinib in a patient with ALK-positive lung adenocarcinoma. Desensitization to overcome adverse effects and to enable sustained treatment with alectinib should be considered in patients who develop alectinib sensitivities. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. NF-κB signaling is activated and confers resistance to apoptosis in three-dimensionally cultured EGFR-mutant lung adenocarcinoma cells

    International Nuclear Information System (INIS)

    Sakuma, Yuji; Yamazaki, Yukiko; Nakamura, Yoshiyasu; Yoshihara, Mitsuyo; Matsukuma, Shoichi; Koizume, Shiro; Miyagi, Yohei

    2012-01-01

    Highlights: ► EGFR-mutant cells in 3D culture resist EGFR inhibition compared with suspended cells. ► Degradation of IκB and activation of NF-κB are observed in 3D-cultured cells. ► Inhibiting NF-κB enhances the efficacy of the EGFR inhibitor in 3D-cultured cells. -- Abstract: Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells in suspension undergo apoptosis to a greater extent than adherent cells in a monolayer when EGFR autophosphorylation is inhibited by EGFR tyrosine kinase inhibitors (TKIs). This suggests that cell adhesion to a culture dish may activate an anti-apoptotic signaling pathway other than the EGFR pathway. Since the microenvironment of cells cultured in a monolayer are substantially different to that of cells existing in three-dimension (3D) in vivo, we assessed whether two EGFR-mutant lung adenocarcinoma cell lines, HCC827 and H1975, were more resistant to EGFR TKI-induced apoptosis when cultured in a 3D extracellular matrix (ECM) as compared with in suspension. The ECM-adherent EGFR-mutant cells in 3D were significantly less sensitive to treatment with WZ4002, an EGFR TKI, than the suspended cells. Further, a marked degradation of IκBα, the inhibitor of nuclear factor (NF)-κB, was observed only in the 3D-cultured cells, leading to an increase in the activation of NF-κB. Moreover, the inhibition of NF-κB with pharmacological inhibitors enhanced EGFR TKI-induced apoptosis in 3D-cultured EGFR-mutant cells. These results suggest that inhibition of NF-κB signaling would render ECM-adherent EGFR-mutant lung adenocarcinoma cells in vivo more susceptible to EGFR TKI-induced cell death.

  15. A human lung xenograft mouse model of Nipah virus infection.

    Directory of Open Access Journals (Sweden)

    Gustavo Valbuena

    2014-04-01

    Full Text Available Nipah virus (NiV is a member of the genus Henipavirus (family Paramyxoviridae that causes severe and often lethal respiratory illness and encephalitis in humans with high mortality rates (up to 92%. NiV can cause Acute Lung Injury (ALI in humans, and human-to-human transmission has been observed in recent outbreaks of NiV. While the exact route of transmission to humans is not known, we have previously shown that NiV can efficiently infect human respiratory epithelial cells. The molecular mechanisms of NiV-associated ALI in the human respiratory tract are unknown. Thus, there is an urgent need for models of henipavirus infection of the human respiratory tract to study the pathogenesis and understand the host responses. Here, we describe a novel human lung xenograft model in mice to study the pathogenesis of NiV. Following transplantation, human fetal lung xenografts rapidly graft and develop mature structures of adult lungs including cartilage, vascular vessels, ciliated pseudostratified columnar epithelium, and primitive "air" spaces filled with mucus and lined by cuboidal to flat epithelium. Following infection, NiV grows to high titers (10(7 TCID50/gram lung tissue as early as 3 days post infection (pi. NiV targets both the endothelium as well as respiratory epithelium in the human lung tissues, and results in syncytia formation. NiV infection in the human lung results in the production of several cytokines and chemokines including IL-6, IP-10, eotaxin, G-CSF and GM-CSF on days 5 and 7 pi. In conclusion, this study demonstrates that NiV can replicate to high titers in a novel in vivo model of the human respiratory tract, resulting in a robust inflammatory response, which is known to be associated with ALI. This model will facilitate progress in the fundamental understanding of henipavirus pathogenesis and virus-host interactions; it will also provide biologically relevant models for other respiratory viruses.

  16. Hand-foot syndrome in a patient with metastatic lung adenocarcinoma induced by high-dose icotinib: A case report and review of the literature.

    Science.gov (United States)

    Zheng, Yulong; Fang, Weijia; Xu, Nong

    2012-12-01

    Icotinib is a new oral epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI). The most frequent side-effects of icotinib include rash and diarrhea. Hand-foot syndrome (HFS) induced by EGFR-TKI is rare. The present study describes, for the first time, HFS induced by high-dose icotinib in a 65-year old female with metastatic lung adenocarcinoma. The patient developed HFS during the first week of icotinib treatment with characteristic clinical presentation. HFS regressed after icotinib dose-reduction was initiated. HFS may occur with icotinib, especially when administered in high doses.

  17. Alcohol Exposure Alters Mouse Lung Inflammation in Response to Inhaled Dust

    Directory of Open Access Journals (Sweden)

    Jill A. Poole

    2012-07-01

    Full Text Available Alcohol exposure is associated with increased lung infections and decreased mucociliary clearance. Occupational workers exposed to dusts from concentrated animal feeding operations (CAFOs are at risk for developing chronic inflammatory lung diseases. Agricultural worker co-exposure to alcohol and organic dust has been established, although little research has been conducted on the combination effects of alcohol and organic dusts on the lung. Previously, we have shown in a mouse model that exposure to hog dust extract (HDE collected from a CAFO results in the activation of protein kinase C (PKC, elevated lavage fluid cytokines/chemokines including interleukin-6 (IL-6, and the development of significant lung pathology. Because alcohol blocks airway epithelial cell release of IL-6 in vitro, we hypothesized that alcohol exposure would alter mouse lung inflammatory responses to HDE. To test this hypothesis, C57BL/6 mice were fed 20% alcohol or water ad libitum for 6 weeks and treated with 12.5% HDE by intranasal inhalation method daily during the final three weeks. Bronchoalveolar lavage fluid (BALF, tracheas and lungs were collected. HDE stimulated a 2–4 fold increase in lung and tracheal PKCε (epsilon activity in mice, but no such increase in PKCε activity was observed in dust-exposed mice fed alcohol. Similarly, alcohol-fed mice demonstrated significantly less IL-6 in lung lavage in response to dust than that observed in control mice instilled with HDE. TNFα levels were also inhibited in the alcohol and HDE-exposed mouse lung tissue as compared to the HDE only exposed group. HDE-induced lung inflammatory aggregates clearly present in the tissue from HDE only exposed animals were not visually detectable in the HDE/alcohol co-exposure group. Statistically significant weight reductions and 20% mortality were also observed in the mice co-exposed to HDE and alcohol. These data suggest that alcohol exposure depresses the ability

  18. Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis

    International Nuclear Information System (INIS)

    Hu, Xin; Fernandes, Jolyn; Jones, Dean P.; Go, Young-Mi

    2017-01-01

    Highlights: • Low-dose Cd stimulates differentiation of human lung fibroblast to myofibroblast. • Cd-stimulated fibrosis signaling involves activation of SMAD transcription factor. • Low-dose Cd intake in mice activates myofibroblast differentiation. - Abstract: Increasing evidence suggests that Cd at levels found in the human diet can cause oxidative stress and activate redox-sensitive transcription factors in inflammatory signaling. Following inflammation, tissue repair often involves activation of redox-sensitive transcription factors in fibroblasts. In lungs, epithelial barrier remodeling is required to restore gas exchange and barrier function, and aberrant myofibroblast differentiation leads to pulmonary fibrosis. Contributions of exogenous exposures, such as dietary Cd, to pulmonary fibrosis remain inCompletely defined. In the current study, we tested whether Cd activates fibrotic signaling in human fetal lung fibroblasts (HFLF) at micromolar and submicromolar Cd concentrations that do not cause cell death. Exposure of HFLF to low-dose Cd (≤1.0 μM) caused an increase in stress fibers and increased protein levels of myofibroblast differentiation markers, including α-smooth muscle actin (α-SMA) and extra-domain-A-containing fibronectin (ED-A-FN). Assay of transcription factor (TF) activity using a 45-TF array showed that Cd increased activity of 12 TF, including SMAD2/3/4 (mothers against decapentaplegic homolog) signaling differentiation and fibrosis. Results were confirmed by real-time PCR and supported by increased expression of target genes of SMAD2/3/4. Immunocytochemistry of lungs of mice exposed to low-dose Cd (0.3 and 1.0 mg/L in drinking water) showed increased α-SMA protein level with lung Cd accumulation similar to lung Cd in non-smoking humans. Together, the results show that relatively low Cd exposures stimulate pulmonary fibrotic signaling and myofibroblast differentiation by activating SMAD2/3/4-dependent signaling. The results

  19. Immunohistochemical analysis of Clara cell secretory protein expression in a transgenic model of mouse lung carcinogenesis

    International Nuclear Information System (INIS)

    Hicks, Sarah M.; Vassallo, Jeffrey D.; Dieter, Matthew Z.; Lewis, Cindy L.; Whiteley, Laurence O.; Fix, Andrew S.; Lehman-McKeeman, Lois D.

    2003-01-01

    Immunohistochemical methods have been widely used to determine the histogenesis of spontaneous and chemically-induced mouse lung tumors. Typically, antigens for either alveolar Type II cells or bronchiolar epithelial Clara cells are studied. In the present work, the morphological and immunohistochemical phenotype of a transgenic mouse designed to develop lung tumors arising from Clara cells was evaluated. In this model, Clara cell-specific transformation is accomplished by directed expression of the SV40 large T antigen (TAg) under the mouse Clara cell secretory protein (CC10) promoter. In heterozygous mice, early lesions at 1 month of age consisted of hyperplastic bronchiolar epithelial cells. These progressed to adenoma by 2 months as proliferating epithelium extended into adjacent alveolar spaces. By 4 months, a large portion of the lung parenchyma was composed of tumor masses. Expression of constitutive CC10 was diminished in transgenic animals at all time points. Only the occasional cell or segment of the bronchiolar epithelium stained positively for CC10 by immunohistochemistry, and all tumors were found to be uniformly negative for staining. These results were corroborated by Western blotting, where CC10 was readily detectable in whole lung homogenate from nontransgenic animals, but not detected in lung from transgenic animals at any time point. Tumors were also examined for expression of surfactant apoprotein C (SPC), an alveolar Type II cell-specific marker, and found to be uniformly negative for staining. These results indicate that, in this transgenic model, expression of CC10, which is widely used to determine whether lung tumors arise from Clara cells, was reduced and subsequently lost during Clara cell tumor progression

  20. Two-gene signature improves the discriminatory power of IASLC/ATS/ERS classification to predict the survival of patients with early-stage lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Sun Y

    2016-07-01

    Full Text Available Yifeng Sun,1,* Likun Hou,2,* Yu Yang,1 Huikang Xie,2 Yang Yang,1 Zhigang Li,1 Heng Zhao,1 Wen Gao,3 Bo Su4 1Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, 2Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 3Department of Thoracic Surgery, Shanghai Huadong Hospital, Fudan University School of Medicine, Shanghai, 4Central Lab, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: In this study, we investigated the contribution of a gene expression–based signature (composed of BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, SH3BGR to survival prediction for early-stage lung adenocarcinoma categorized by the new International Association for the Study of Lung Cancer (IASLC/the American Thoracic Society (ATS/the European Respiratory Society (ERS classification. We also aimed to verify whether gene signature improves the risk discrimination of IASLC/ATS/ERS classification in early-stage lung adenocarcinoma. Patients and methods: Total RNA was extracted from 93 patients with pathologically confirmed TNM stage Ia and Ib lung adenocarcinoma. The mRNA expression levels of ten genes in the signature (BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, and SH3BGR were detected using real-time polymerase chain reaction. Each patient was categorized according to the new IASLC/ATS/ERS classification by accessing hematoxylin–eosin-stained slides. The corresponding Kaplan–Meier survival analysis by the log-rank statistic, multivariate Cox proportional hazards modeling, and c-index calculation were conducted using the programming language R (Version 2.15.1 with the “risksetROC” package. Results: The multivariate analysis demonstrated that the risk factor of the ten-gene expression signature can significantly improve the discriminatory

  1. Development of a metastatic fluorescent Lewis Lung carcinoma mouse model

    DEFF Research Database (Denmark)

    Rask, Lene; Fregil, Marianne; Høgdall, Estrid

    2013-01-01

    Cancer metastasis is the foremost cause of death in cancer patients. A series of observable pathological changes takes place during progression and metastasis of cancer, but the underlying genetic changes remain unclear. Therefore, new approaches are required, including insights from cancer mouse...... and the model is well suited for the identification of novel microRNAs and mRNAs involved in malignant progression. Our results suggest that increases in metalloproteinase expression and impairment of microRNA processing are involved in the acquirement of metastatic ability....

  2. Osthole inhibits the invasive ability of human lung adenocarcinoma cells via suppression of NF-κB-mediated matrix metalloproteinase-9 expression

    Energy Technology Data Exchange (ETDEWEB)

    Kao, Shang-Jyh [Department of Chest Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan (China); School of Respiratory Therapy, Taipei Medical University, Taipei Taiwan (China); Su, Jen-Liang [Graduate Institute of Cancer Biology, College of Medicine, China Medical University, Taichung, Taiwan (China); Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan (China); Department of Biotechnology, Asia University, Taichung, Taiwan (China); Chen, Chi-Kuan [Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Yu, Ming-Chih; Bai, Kuan-Jen; Chang, Jer-Hua [Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan (China); Bien, Mauo-Ying [School of Respiratory Therapy, Taipei Medical University, Taipei Taiwan (China); Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan (China); Yang, Shun-Fa [Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan (China); Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China); Chien, Ming-Hsien, E-mail: mhchien1976@gmail.com [Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan (China)

    2012-05-15

    The induction of matrix metalloproteinase (MMP)-9 is particularly important for the invasiveness of various cancer cells. Osthole, a natural coumarin derivative extracted from traditional Chinese medicines, is known to inhibit the proliferation of a variety of tumor cells, but the effect of osthole on the invasiveness of tumor cells is largely unknown. This study determines whether and by what mechanism osthole inhibits invasion in CL1-5 human lung adenocarcinoma cells. Herein, we found that osthole effectively inhibited the migratory and invasive abilities of CL1-5 cells. A zymographic assay showed that osthole inhibited the proteolytic activity of MMP-9 in CL1-5 cells. Inhibition of migration, invasion, and MMP2 and/or MMP-9 proteolytic activities was also observed in other lung adenocarcinoma cell lines (H1299 and A549). We further found that osthole inhibited MMP-9 expression at the messenger RNA and protein levels. Moreover, a chromatin immunoprecipitation assay showed that osthole inhibited the transcriptional activity of MMP-9 by suppressing the DNA binding activity of nuclear factor (NF)-κB in the MMP-9 promoter. Using reporter assays with point-mutated promoter constructs further confirmed that the inhibitory effect of osthole requires an NF-κB binding site on the MMP-9 promoter. Western blot and immunofluorescence assays demonstrated that osthole inhibited NF-κB activity by inhibiting IκB-α degradation and NF-κB p65 nuclear translocation. In conclusion, we demonstrated that osthole inhibits NF-κB-mediated MMP-9 expression, resulting in suppression of lung cancer cell invasion and migration, and osthole might be a potential agent for preventing the invasion and metastasis of lung cancer. -- Highlights: ► Osthole treatment inhibits lung adenocarcinoma cells migration and invasion. ► Osthole reduces the expression and proteolytic activity of MMP-9. ► Osthole inhibits MMP-9 transcription via suppression of NF-κB binding activity. ► Osthole

  3. Imaging Characteristics of Driver Mutations in EGFR, KRAS, and ALK among Treatment-Naïve Patients with Advanced Lung Adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Jangchul Park

    Full Text Available This study aimed to identify the computed tomography characteristics of treatment-naïve patients with lung adenocarcinoma and known driver mutations in EGFR, KRAS, or ALK. Patients with advanced lung adenocarcinoma (stage IIIB-IV and known mutations in EGFR, KRAS, or ALK were assessed. The radiological findings for the main tumor and intra-thoracic status were retrospectively analyzed in each group, and the groups' characteristics were compared. We identified 265 treatment-naïve patients with non-small-cell carcinoma, who had EGFR mutations (n = 159, KRAS mutations (n = 55, or ALK rearrangements (n = 51. Among the three groups, we evaluated only patients with stage IIIB-IV lung adenocarcinoma who had EGFR mutations (n = 126, KRAS mutations (n = 35, or ALK rearrangements (n = 47. We found that ground-glass opacity at the main tumor was significantly more common among EGFR-positive patients, compared to ALK-positive patients (p = 0.009. Lymphadenopathy was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.003. Extranodal invasion was significantly more common among ALK-positive patients, compared to EGFR-positive patients and KRAS-positive patients (p = 0.001 and p = 0.049, respectively. Lymphangitis was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.049. Pleural effusion was significantly less common among KRAS-positive patients, compared to EGFR-positive patients and ALK-positive patients (p = 0.046 and p = 0.026, respectively. Lung metastases were significantly more common among EGFR-positive patients, compared to KRAS-positive patients and ALK-positive patients (p = 0.007 and p = 0.04, respectively. In conclusion, EGFR mutations were associated with ground-glass opacity, KRAS-positive tumors were generally solid and less likely to metastasize to the lung and pleura, and ALK-positive tumors tended to present with lymphadenopathy, extranodal

  4. E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells

    OpenAIRE

    Lee, Hyun-Wook; Park, Sung-Hyun; Weng, Mao-wen; Wang, Hsiang-Tsui; Huang, William C.; Lepor, Herbert; Wu, Xue-Ru; Chen, Lung-Chi; Tang, Moon-shong

    2018-01-01

    Significance E-cigarette smoke (ECS) delivers nicotine through aerosols without burning tobacco. ECS is promoted as noncarcinogenic. We found that ECS induces DNA damage in mouse lung, bladder, and heart and reduces DNA-repair functions and proteins in lung. Nicotine and its nitrosation product 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone can cause the same effects as ECS and enhance mutations and tumorigenic cell transformation in cultured human lung and bladder cells. These results indica...

  5. High Frequency of Interactions between Lung Cancer Susceptibility Genes in the Mouse : Mapping of Sluc5 to Sluc14

    NARCIS (Netherlands)

    Fijneman, Remond J.A.; Jansen, Ritsert C.; Valk, Martin A. van der; Demant, Peter

    1998-01-01

    Although several genes that cause monogenic familial cancer syndromes have been identified, susceptibility to sporadic cancer remains unresolved. Animal experiments have demonstrated multigenic control of tumor susceptibility. Recently, we described four mouse lung cancer susceptibility (Sluc) loci,

  6. Matched-pair analysis of a multi-institutional cohort reveals that epidermal growth factor receptor mutation is not a risk factor for postoperative recurrence of lung adenocarcinoma.

    Science.gov (United States)

    Matsumura, Yuki; Suzuki, Hiroyuki; Ohira, Tetsuya; Shiono, Satoshi; Abe, Jiro; Sagawa, Motoyasu; Sakurada, Akira; Katahira, Masato; Machida, Yuichiro; Takahashi, Satomi; Okada, Yoshinori

    2017-12-01

    It is unclear whether epidermal growth factor receptor (EGFR) mutation status is a risk factor for postoperative recurrence of surgically resected lung adenocarcinoma (ADC). Therefore, we conducted a multi-institutional study employing matched-pair analysis to compare recurrence-free survival (RFS) and overall survival (OS) of patients with lung ADC according to EGFR mutation status. We collected the records of 909 patients who underwent surgical resection for lung ADC between 2005 and 2012 at five participating institutions and were also examined their EGFR mutation status. For each patient with an EGFR mutation, we selected one with the wild-type EGFR sequence and matched them according to institution, age, gender, smoking history, pathological stage (pStage), and adjuvant treatment. We compared RFS and OS of the matched cohort. The patients were allocated into groups (n=181 each) with mutated or wild-type EGFR sequences. Both cohorts had identical characteristics as follows: institution, median age (68 years), men (85, 47%), ever smokers (77, 43%), and pStage (IA, 108, 60%; IB, 48, 27%; II, 14, 8%; III, 11, 6%). The 3- and 5-year RFS rates of patients with mutated or wild-type EGFR sequence were 79%, 68% and 77%, 68%, respectively (p=0.557). The respective OS rates were 92%, 81%, and 89%, 79% (p=0.574). Matched-pair and multi-institutional analysis reveals that an EGFR mutation was not a significant risk factor for recurrence of patients with surgically resected lung adenocarcinoma. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Negative effect of cyclin D1 overexpression on recurrence-free survival in stage II-IIIA lung adenocarcinoma and its expression modulation by vorinostat in vitro.

    Science.gov (United States)

    Lee, Eunju; Jin, DongHao; Lee, Bo Bin; Kim, Yujin; Han, Joungho; Shim, Young Mog; Kim, Duk-Hwan

    2015-12-17

    This study was aimed at identifying prognostic biomarkers for stage II-IIIA non-small cell lung cancer (NSCLC) according to histology and at investigating the effect of vorinostat on the expression of these biomarkers. Expression levels of cyclin D1, cyclin A2, cyclin E, and p16 proteins that are involved in the G1-to-S phase progression of cell cycle were analyzed using immunohistochemistry in formalin-fixed paraffin-embedded tissues from 372 samples of stage II-IIIA NSCLC. The effect of vorinostat on the expression of these proteins, impacts on cell cycle, and histone modification was explored in lung cancer cells. Abnormal expression of cyclin A2, cyclin D1, cyclin E, and p16 was found in 66, 47, 34, and 51 % of 372 cases, respectively. Amongst the four proteins, only cyclin D1 overexpression was significantly associated with poor recurrence-free survival (adjusted hazard ratio = 1.87; 95 % confidence interval = 1.12 - 2.69, P = 0.02) in adenocarcinoma but not in squamous cell carcinoma (P = 0.44). Vorinostat inhibited cell cycle progression to the S-phase and induced down-regulation of cyclin D1 in vitro. The down-regulation of cyclin D1 by vorinostat was comparable to a siRNA-mediated knockdown of cyclin D1 in A549 cells, but vorinostat in the presence of benzo[a]pyrene showed a differential effect in different lung cancer cell lines. Cyclin D1 down-regulation by vorinostat was associated with the accumulation of dimethyl-H3K9 at the promoter of the gene. The present study suggests that cyclin D1 may be an independent prognostic factor for recurrence-free survival in stage II-IIIA adenocarcinoma of lung and its expression may be modulated by vorinostat.

  8. Immunocytochemical characterization of lung tumors in fine-needle aspiration. The use of cytokeratin monoclonal antibodies for the differential diagnosis of squamous cell carcinoma and adenocarcinoma.

    Science.gov (United States)

    Bruderman, I; Cohen, R; Leitner, O; Ronah, R; Guber, A; Griffel, B; Geiger, B

    1990-10-15

    In the current study, immunocytochemical typing of intermediate filaments was used for a differential diagnosis of human lung tumors from transthoracic fine-needle aspiration biopsies (TFNAB). The authors have compared the cytologic diagnosis of 53 lung cancer cases with the immunofluorescence patterns obtained using a panel of monoclonal antibodies, five of which (KG 8.13, KM 4.62, Ks B.17, KS 8.12, KK 8.60) react with specific cytokeratin polypeptides and one with vimentin (VIM 13.2). Only in six of 23 samples cytologically diagnosed as squamous cell carcinoma did the immunocytochemical typing of cytokeratins (ICTC) confirm the cytologic diagnosis. In seven cases some of the tumor cells stained positively with antibody Ks B.17 specific for simple epithelial keratin (No: 18), suggesting the presence of some cells of glandular origin. In ten additional cases the ICTC was in conflict with the cytologic diagnosis of squamous cell carcinoma (i.e., antibodies Ks 8.12 and KK 8.60 were negative, and antibody Ks B.17, positive) supporting a diagnosis of adenocarcinoma. In 14 of 18 cases cytologically diagnosed as adenocarcinoma, the ICTC confirmed the diagnosis whereas in four cases additional presence of some squamous cells was noticed. The ICTC labeling of cases cytologically diagnosed as undifferentiated and large cell carcinomas was similar to that of the group of adenocarcinomas. Thus, the application of cytokeratin typing for TFNAB samples seems to provide a vital complementation to routine cytologic study, especially for cases cytologically diagnosed as squamous carcinoma.

  9. Prognostic impact of nomogram based on whole tumour size, tumour disappearance ratio on CT and SUVmax on PET in lung adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Song, So Hee; Lee, Ho Yun; Kim, Eun Young; Lee, Kyung Soo [Sungkyunkwan University School of Medicine, Department of Radiology and Center for Imaging Science, Samsung Medical Center, Gangnam-Gu, Seoul (Korea, Republic of); Ahn, Joong Hyun [Samsung Biomedical Research Institute, Biostatistics Team, Seoul (Korea, Republic of); Lee, Geewon [Pusan National University Hospital, Pusan National University School of Medicine, Department of Radiology and Medical Research Institute, Busan (Korea, Republic of); Choi, Joon Young [Sungkyunkwan University School of Medicine, Departments of Nuclear Medicine, Samsung Medical Center, Seoul (Korea, Republic of); Kang, Jun [Catholic University of Korea, Department of Pathology, Inchun St. Mary' s Hospital, College of Medicine, Inchun (Korea, Republic of); Han, Joungho [Sungkyunkwan University School of Medicine, Department of Pathology, Samsung Medical Center, Seoul (Korea, Republic of); Kwon, O.J. [Sungkyunkwan University School of Medicine, Division of Respiratory and Critical Medicine of the Department of Internal Medicine, Samsung Medical Center, Seoul (Korea, Republic of); Kim, Hong Kwan; Choi, Yong Soo; Kim, Jhingook; Shim, Young Mog [Sungkyunkwan University School of Medicine, Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Seoul (Korea, Republic of)

    2016-06-15

    Lung adenocarcinoma frequently manifests as subsolid nodules, and the solid portion and ground-glass-opacity (GGO) portion on CT have different prognostic significance. Therefore, current T descriptor, defined as the whole tumour diameter without discrimination between solid and GGO, is insufficient. We aimed to determine the prognostic significance of solid tumour size and attempt to include prognostic factors such as tumour disappearance rate (TDR) on CT and SUVmax on PET/CT. Five hundred and ninety-five patients with completely resected lung adenocarcinoma were analyzed. We developed a nomogram using whole tumour size, TDR, and SUVmax. External validation was performed in another 102 patients. In patients with tumours measuring ≤2 cm and >2 to 3 cm, disease free survival (DFS) was significantly associated with solid tumour size (P < 0.001), but not with whole tumour size (P = 0.052). Developed nomogram was significantly superior to the conventional T stage (area under the curve of survival ROC; P = 0.013 by net reclassification improvement) in stratification of patient survival. In the external validation group, significant difference was noted in DFS according to proposed T stage (P = 0.009). Nomogram-based T descriptors provide better prediction of survival and assessment of individual risks than conventional T descriptors. (orig.)

  10. Neferine augments therapeutic efficacy of cisplatin through ROS- mediated non-canonical autophagy in human lung adenocarcinoma (A549 cells).

    Science.gov (United States)

    Kalai Selvi, Sivalingam; Vinoth, Amirthalingam; Varadharajan, Thiyagarajan; Weng, Ching Feng; Vijaya Padma, Viswanadha

    2017-05-01

    Combination of dietary components with chemotherapy drugs is an emerging new strategy for cancer therapy to increase antitumor responses. Neferine, major bisbenzylisoquinoline alkaloid isolated from the seed embryo of Nelumbo nucifera (Lotus). In the present study, we investigated the efficacy of the combinatorial regimen of neferine and cisplatin compared to cisplatin high dose in human lung adenocarcinoma (A549) cells. Co-treatment with neferine enhanced cisplatin-induced autophagy in A549 cells was accompanied by Acidic vesicular accumulation (AVO), enhanced generation of reactive oxygen species (ROS) and depletion of intracellular glutathione (GSH), down regulation of PI3K/AKT/mTOR pathway, conversion of LC3B-I to LC3B-II. This enhanced autophagy developed via a non-canonical mechanism that did not require Beclin-1, PI3KCIII. In conclusion, these results suggest that neferine enhances cisplatin -induced autophagic cancer cell death through downregulation of PI3K/Akt/mTOR signaling pro-survival pathway and ROS- mediated Beclin-1 and PI3K CIII independent autophagy in human lung adenocarcinoma (A549 cells). Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Lipopolysaccharide does not alter small airway reactivity in mouse lung slices.

    Science.gov (United States)

    Donovan, Chantal; Royce, Simon G; Vlahos, Ross; Bourke, Jane E

    2015-01-01

    The bacterial endotoxin, lipopolysaccharide (LPS) has been associated with occupational airway diseases with asthma-like symptoms and in acute exacerbations of COPD. The direct and indirect effects of LPS on small airway reactivity have not been fully elucidated. We tested the hypothesis that both in vitro and in vivo LPS treatment would increase contraction and impair relaxation of mouse small airways. Lung slices were prepared from naïve Balb/C mice and cultured in the absence or presence of LPS (10 μg/ml) for up to 48 h for measurement of TNFα levels in conditioned media. Alternatively, mice were challenged with PBS or LPS in vivo once a day for 4 days for preparation of lung slices or for harvest of lungs for Q-PCR analysis of gene expression of pro-inflammatory cytokines and receptors involved in airway contraction. Reactivity of small airways to contractile agonists, methacholine and serotonin, and bronchodilator agents, salbutamol, isoprenaline and rosiglitazone, were assessed using phase-contrast microscopy. In vitro LPS treatment of slices increased TNFα release 6-fold but did not alter contraction or relaxation to any agonists tested. In vivo LPS treatment increased lung gene expression of TNFα, IL-1β and ryanodine receptor isoform 2 more than 5-fold. However there were no changes in reactivity in lung slices from these mice, even when also incubated with LPS ex vivo. Despite evidence of LPS-induced inflammation, neither airway hyperresponsiveness or impaired dilator reactivity were evident. The increase in ryanodine receptor isoform 2, known to regulate calcium signaling in vascular smooth muscle, warrants investigation. Since LPS failed to elicit changes in small airway reactivity in mouse lung slices following in vitro or in vivo treatment, alternative approaches are required to define the potential contribution of this endotoxin to altered small airway reactivity in human lung diseases.

  12. Lipopolysaccharide does not alter small airway reactivity in mouse lung slices.

    Directory of Open Access Journals (Sweden)

    Chantal Donovan

    Full Text Available The bacterial endotoxin, lipopolysaccharide (LPS has been associated with occupational airway diseases with asthma-like symptoms and in acute exacerbations of COPD. The direct and indirect effects of LPS on small airway reactivity have not been fully elucidated. We tested the hypothesis that both in vitro and in vivo LPS treatment would increase contraction and impair relaxation of mouse small airways. Lung slices were prepared from naïve Balb/C mice and cultured in the absence or presence of LPS (10 μg/ml for up to 48 h for measurement of TNFα levels in conditioned media. Alternatively, mice were challenged with PBS or LPS in vivo once a day for 4 days for preparation of lung slices or for harvest of lungs for Q-PCR analysis of gene expression of pro-inflammatory cytokines and receptors involved in airway contraction. Reactivity of small airways to contractile agonists, methacholine and serotonin, and bronchodilator agents, salbutamol, isoprenaline and rosiglitazone, were assessed using phase-contrast microscopy. In vitro LPS treatment of slices increased TNFα release 6-fold but did not alter contraction or relaxation to any agonists tested. In vivo LPS treatment increased lung gene expression of TNFα, IL-1β and ryanodine receptor isoform 2 more than 5-fold. However there were no changes in reactivity in lung slices from these mice, even when also incubated with LPS ex vivo. Despite evidence of LPS-induced inflammation, neither airway hyperresponsiveness or impaired dilator reactivity were evident. The increase in ryanodine receptor isoform 2, known to regulate calcium signaling in vascular smooth muscle, warrants investigation. Since LPS failed to elicit changes in small airway reactivity in mouse lung slices following in vitro or in vivo treatment, alternative approaches are required to define the potential contribution of this endotoxin to altered small airway reactivity in human lung diseases.

  13. Radiologic Predictors for Clinical Stage IA Lung Adenocarcinoma with Ground Glass Components: A Multi-Center Study of Long-Term Outcomes.

    Directory of Open Access Journals (Sweden)

    Zhao Li

    Full Text Available This study was to define preoperative predictors from radiologic findings for the pathologic risk groups based on long-term surgical outcomes, in the aim to help guide individualized patient management.We retrospectively reviewed 321 consecutive patients with clinical stage IA lung adenocarcinoma with ground glass component on computed tomography (CT scanning. Pathologic diagnosis for resection specimens was based on the 2011 IASLC/ATS/ERS classification of lung adenocarcinoma. Patients were classified into different pathologic risk grading groups based on their lymph node status, local regional recurrence and overall survival. Radiologic characteristics of the pulmonary nodules were re-evaluated by reconstructed three-dimension CT (3D-CT. Univariate and multivariate analysis identifies independent radiologic predictors from tumor diameter, total volume (TV, average CT value (AVG, and solid-to-tumor (S/T ratio. Receiver operating characteristic curves (ROC studies were carried out to determine the cutoff value(s for the predictor(s. Univariate cox regression model was used to determine the clinical significance of the above findings.A total of 321 patients with clinical stage IA lung adenocarcinoma with ground glass components were included in our study. Patients were classified into two pathologic low- and high- risk groups based on their distinguished surgical outcomes. A total of 134 patients fell into the low-risk group. Univariate and multivariate analyses identified AVG (HR: 32.210, 95% CI: 3.020-79.689, P<0.001 and S/T ratio (HR: 12.212, 95% CI: 5.441-27.408, P<0.001 as independent predictors for pathologic risk grading. ROC curves studies suggested the optimal cut-off values for AVG and S/T ratio were-198 (area under the curve [AUC] 0.921, 2.9 (AUC 0.996 and 54% (AUC 0.907, respectively. The tumor diameter and TV were excluded for the low AUCs (0.778 and 0.767. Both the cutoff values of AVG and S/T ratio were correlated with pathologic

  14. Is the shape of the decline in risk following quitting smoking similar for squamous cell carcinoma and adenocarcinoma of the lung? A quantitative review using the negative exponential model.

    Science.gov (United States)

    Fry, John S; Lee, Peter N; Forey, Barbara A; Coombs, Katharine J

    2015-06-01

    One possible contributor to the reported rise in the ratio of adenocarcinoma to squamous cell carcinoma of the lung may be differences in the pattern of decline in risk following quitting for the two lung cancer types. Earlier, using data from 85 studies comparing overall lung cancer risks in current smokers, quitters (by time quit) and never smokers, we fitted the negative exponential model, deriving an estimate of 9.93years for the half-life - the time when the excess risk for quitters compared to never smokers becomes half that for continuing smokers. Here we applied the same techniques to data from 16 studies providing RRs specific for lung cancer type. From the 13 studies where the half-life was estimable for each type, we derived estimates of 11.68 (95% CI 10.22-13.34) for squamous cell carcinoma and 14.45 (11.92-17.52) for adenocarcinoma. The ratio of the half-lives was estimated as 1.32 (95% CI 1.20-1.46, p<0.001). The slower decline in quitters for adenocarcinoma, evident in subgroups by sex, age and other factors, may be one of the factors contributing to the reported rise in the ratio of adenocarcinoma to squamous cell carcinoma. Others include changes in the diagnosis and classification of lung cancer. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  15. Establishment of an experimental human lung adenocarcinoma cell line SPC-A-1BM with high bone metastases potency by 99mTc-MDP bone scintigraphy

    International Nuclear Information System (INIS)

    Yang Shunfang; Dong Qianggang; Yao Ming; Shi Meiping; Ye Jianding; Zhao Langxiang; Su Jianzhong; Gu Weiyong; Xie Wenhui; Wang Kankan; Du Yanzhi; Li Yao; Huang Yan

    2009-01-01

    Background: Bone metastasis is one of the most common clinical phenomena of late stage lung cancer. A major impediment to understanding the pathogenesis of bone metastasis has been the lack of an appropriate animal and cell model. This study aims to establish human lung adenocarcinoma cell line with highly bone metastases potency with 99m Tc-MDP bone scintigraphy. Methods: The human lung adenocarcinoma cancer cells SPC-A-1 were injected into the left cardiac ventricle of NIH-Beige-Nude-XID (NIH-BNX) immunodeficient mice. The metastatic lesions of tumor-bearing mice were imaged with 99m Tc-MDP bone scintigraphy on a Siemens multi-single photon emission computed tomography. Pinhole images were acquired on a GZ-B conventional gamma camera with a self-designed pinhole collimator. The mice with bone metastasis were sacrificed under deep anesthesia, and the lesions were resected. Bone metastatic cancer cells in the resected lesions were subjected for culture and then reinoculated into the NIH-BNX mice through left cardiac ventricle. The process was repeated for eight cycles to obtain a novel cell subline SPC-A-1BM. Real-time polymerase chain reaction (PCR) was used to compare the gene expression differences in the parental and SPC-A-1BM cells. Results: The bone metastasis sites were successfully revealed by bone scintigraphy. The established bone metastasis cell line SPC-A-1BM had a high potential to metastasize in bone, including mandible, humerus, thoracic vertebra, lumbar, femur, patella, ilium and cartilage rib. The expression level of vascular endothelial growth factor gene family, Bcl-2 and cell adhesion-related genes ECM1, ESM1, AF1Q, SERPINE2 and FN1 were examined. Gene expression difference was found between parental and bone-seeking metastasis cell SPC-A-1BM, which indicates SPC-A-1BM has metastatic capacity vs. its parental cells. Conclusion: SPC-A-1BM is a bone-seeking metastasis human lung adenocarcinoma cell line. Bone scintigraphy may be used as an

  16. Pemetrexed-carboplatin with intercalated icotinib in the treatment of patient with advanced EGFR wild-type lung adenocarcinoma: A case report.

    Science.gov (United States)

    Xu, Tongpeng; Wu, Hao; Jin, Shidai; Min, Huang; Zhang, Zhihong; Shu, Yongqian; Wen, Wei; Guo, Renhua

    2017-08-01

    Tyrosine kinase inhibitors (TKIs) are known to have greater efficacy in epidermal growth factor receptor (EGFR) mutation nonsmall cell lung cancer (NSCLC). However, about 10% of EGFR wild-type (wt) patients respond to TKIs. Several strategies to increase the efficacy of TKIs in wt NSCLC are the subjects of ongoing investigations. One of them is combining EGFR TKI with intercalated chemotherapy. We describe a patient with EGFR wt NSCLC, who was found with ovarian and lung metastasis, was treated with pemetrexed and intercalated icotinib. In this case, we reported the successful long-term maintenance treatment of a patient with EGFR wt NSCLC with pemetrexed and Icotinib. The patient (40-year-old female) was found with ovarian masses and lung masses. Pathological, immunohistochemical, and amplification refractory mutation system (ARMS) assay examinations of ovarian specimen suggested the expression of metastatic lung adenocarcinoma with wt EGFR. After failure treatment with paclitaxel-carboplatin, the patient received 4 cycles of pemetrexed plus platinum with intercalated icotinib and then remained on pemetrexed and icotinib. A partial response was achieved after the treatment. The patient's condition had remained stable on pemetrexed and icotinib for more than 20 months, with no evidence of progression. To our knowledge, this is the first report using the long-term maintenance treatment with pemetrexed and intercalated icotinib in EGFR wt patient. The therapeutic strategies warrant further exploration in selected populations of NSCLC.

  17. α(V)β(6) integrin expression is induced in the POET and Pten(pc-/-) mouse models of prostatic inflammation and prostatic adenocarcinoma.

    Science.gov (United States)

    Garlick, David S; Li, Jing; Sansoucy, Brian; Wang, Tao; Griffith, Leeanne; Fitzgerald, Tj; Butterfield, Julie; Charbonneau, Bridget; Violette, Shelia M; Weinreb, Paul H; Ratliff, Timothy L; Liao, Chun-Peng; Roy-Burman, Pradip; Vietri, Michele; Lian, Jane B; Stein, Gary S; Altieri, Dario C; Languino, Lucia R

    2012-01-01

    Chronic inflammation is proposed to prime the development of prostate cancer. However, the mechanisms of prostate cancer initiation and development are not completely understood. The α(v)β(6) integrin has been shown to play a role in epithelial development, wound healing and some epithelial cancers [1, 2]. Here, we investigate the expression of α(v)β(6) in mouse models of prostatic inflammation and prostate cancer to establish a possible relationship between inflammation of the prostate, α(v)β(6) expression and the progression of prostate cancer. Using immunohistochemical techniques, we show expression of α(v)β(6) in two in vivo mouse models; the Pten(pc)-/- model containing a prostate- specific Pten tumor suppressor deletion that causes cancer, and the prostate ovalbumin-expressing transgenic (POET) inflammation mouse model. We show that the α(v)β(6) integrin is induced in prostate cancer and inflammation in vivo in these two mouse models. α(v)β(6) is expressed in all the mice with cancer in the Pten(pc-/-) model but not in age-matched wild-type mice. In the POET inflammation model, α(v)β(6) is expressed in mice injected with activated T-cells, but in none of the control mice. In the POET model, we also used real time PCR to assess the expression of Transforming Growth Factor Beta 1 (TGFβ1), a factor in inflammation that is activated by α(v)β(6). In conclusion, through in vivo evidence, we conclude that α(v)β(6) integrin may be a crucial link between prostatic inflammation and prostatic adenocarcinoma.

  18. αVβ6 integrin expression is induced in the POET and Ptenpc-/- mouse models of prostatic inflammation and prostatic adenocarcinoma

    Science.gov (United States)

    Garlick, David S; Li, Jing; Sansoucy, Brian; Wang, Tao; Griffith, Leeanne; FitzGerald, TJ; Butterfield, Julie; Charbonneau, Bridget; Violette, Shelia M; Weinreb, Paul H; Ratliff, Timothy L; Liao, Chun-Peng; Roy-Burman, Pradip; Vietri, Michele; Lian, Jane B; Stein, Gary S; Altieri, Dario C; Languino, Lucia R

    2012-01-01

    Chronic inflammation is proposed to prime the development of prostate cancer. However, the mechanisms of prostate cancer initiation and development are not completely understood. The αvβ6 integrin has been shown to play a role in epithelial development, wound healing and some epithelial cancers [1, 2]. Here, we investigate the expression of αvβ6 in mouse models of prostatic inflammation and prostate cancer to establish a possible relationship between inflammation of the prostate, αvβ6 expression and the progression of prostate cancer. Using immunohistochemical techniques, we show expression of αvβ6 in two in vivo mouse models; the Ptenpc-/- model containing a prostate- specific Pten tumor suppressor deletion that causes cancer, and the prostate ovalbumin-expressing transgenic (POET) inflammation mouse model. We show that the αvβ6 integrin is induced in prostate cancer and inflammation in vivo in these two mouse models. αvβ6 is expressed in all the mice with cancer in the Ptenpc-/- model but not in age-matched wild-type mice. In the POET inflammation model, αvβ6 is expressed in mice injected with activated T-cells, but in none of the control mice. In the POET model, we also used real time PCR to assess the expression of Transforming Growth Factor Beta 1 (TGFβ1), a factor in inflammation that is activated by αvβ6. In conclusion, through in vivo evidence, we conclude that αvβ6 integrin may be a crucial link between prostatic inflammation and prostatic adenocarcinoma. PMID:22611469

  19. Biodistribution of gold nanoparticles following intratracheal instillation in mouse lung

    DEFF Research Database (Denmark)

    Sadauskas, Evaldas; Jacobsen, Nicklas R.; Danscher, Gorm

    2009-01-01

    plasma mass spectrometry (ICP-MS) and neutron activation analysis (NAA). The liver is the major site of deposition of circulating gold nanoparticles. Therefore the degree of translocation was determined by the hepatic deposition of gold. Mice were instilled with 5 intratracheal doses of gold...... repeatedly during 3 weeks, the load was substantial. Ultrastructurally, AMG silver enhanced gold nanoparticles were found in lysosome-/endosome-like organelles of the macrophages and analysis with AMG, ICP-MS and NAA of the liver revealed an almost total lack of translocation of nanoparticles. In mice given...... repeated instillations of 2 nm gold nanoparticles, 1.4‰ (by ICP-MS) to 1.9‰ (by NAA) of the instilled gold was detected in the liver. With the 40 nm gold, no gold was detected in the liver (detection level 2 ng, 0.1‰) except for one mouse in which 3‰ of the instilled gold was found in the liver. No gold...

  20. Establishment of Orthotopic Xuanwei Lung Cancer SCID Mouse Model 
and Analysis of Biological Properties

    Directory of Open Access Journals (Sweden)

    Yongchun ZHOU

    2012-08-01

    Full Text Available Background and objective The incidence of Xuanwei lung cancer ranks first in China, and its pathogenesis requires in-depth investigation. This study aims to establish an orthotopic Xuanwei lung cancer severe combined immunodeficiency (SCID mouse model and to provide a basic experimental platform for further study. Methods The Xuanwei lung cancer cell line XWLC-05 was inoculated into the lung tissue of SCID mice in high and low doses. The tumor formation rates, tumor characteristics, spontaneous metastases, and survival times of the mice were observed, taking a subcutaneously transplanted tumor as control. Results The tumor formation rates of the orthotopic transplantation of lung cancer cells in high and low doses were 81% and 83%, respectively, among which mice in the high-dose group appeared cachectic on day 13. Extensive invasion and adhesion were observed in the contralateral lung and thoracic cavity, but no distant metastasis was exhibited. Mice with low-dose cells in the orthotopic transplantation group appeared cachectic and distant metastasis occurred on day 25. The tumor formation rates in the subcutaneous inoculation group by the high and low doses of cells were 100% and 94.5%, respectively, and no distant metastasis was observed. The rate of metastasis within the orthotopic transplantation group and between the orthotopic and subcutaneous inoculation groups showed a significant difference (P<0.05. A significant difference was indicated by the survival rate within and between the groups (P<0.001. Conclusion We successfully established an orthotopic XWLC SCID mouse model, which lays the foundation for a more in-depth study.

  1. Deep Sequence Analysis of Non-Small Cell Lung Cancer: Integrated Analysis of Gene Expression, Alternative Splicing, and Single Nucleotide Variations in Lung Adenocarcinomas with and without Oncogenic KRAS Mutations

    International Nuclear Information System (INIS)

    Kalari, Krishna R.; Rossell, David; Necela, Brian M.; Asmann, Yan W.; Nair, Asha

    2012-01-01

    KRAS mutations are highly prevalent in non-small cell lung cancer (NSCLC), and tumors harboring these mutations tend to be aggressive and resistant to chemotherapy. We used next-generation sequencing technology to identify pathways that are specifically altered in lung tumors harboring a KRAS mutation. Paired-end RNA-sequencing of 15 primary lung adenocarcinoma tumors (8 harboring mutant KRAS and 7 with wild-type KRAS) were performed. Sequences were mapped to the human genome, and genomic features, including differentially expressed genes, alternate splicing isoforms and single nucleotide variants, were determined for tumors with and without KRAS mutation using a variety of computational methods. Network analysis was carried out on genes showing differential expression (374 genes), alternate splicing (259 genes), and SNV-related changes (65 genes) in NSCLC tumors harboring a KRAS mutation. Genes exhibiting two or more connections from the lung adenocarcinoma network were used to carry out integrated pathway analysis. The most significant signaling pathways identified through this analysis were the NFκB, ERK1/2, and AKT pathways. A 27 gene mutant KRAS-specific sub network was extracted based on gene–gene connections from the integrated network, and interrogated for druggable targets. Our results confirm previous evidence that mutant KRAS tumors exhibit activated NFκB, ERK1/2, and AKT pathways and may be preferentially sensitive to target therapeutics toward these pathways. In addition, our analysis indicates novel, previously unappreciated links between mutant KRAS and the TNFR and PPARγ signaling pathways, suggesting that targeted PPARγ antagonists and TNFR inhibitors may be useful therapeutic strategies for treatment of mutant KRAS lung tumors. Our study is the first to integrate genomic features from RNA-Seq data from NSCLC and to define a first draft genomic landscape model that is unique to tumors with oncogenic KRAS mutations.

  2. Gene expression profiling in mouse lung following polymeric hexamethylene diisocyanate exposure

    International Nuclear Information System (INIS)

    Lee, C.-T.; Ylostalo, Joni; Friedman, Mitchell; Hoyle, Gary W.

    2005-01-01

    Isocyanates are a common cause of occupational lung disease. Hexamethylene diisocyanate (HDI), a component of polyurethane spray paints, can induce respiratory symptoms, inflammation, lung function impairment, and isocyanate asthma. The predominant form of HDI in polyurethane paints is a nonvolatile polyisocyanate known as HDI biuret trimer (HDI-BT). Exposure of mice to aerosolized HDI-BT results in pathological effects, including pulmonary edema, lung inflammation, cellular proliferation, and fibrotic lesions, which occur with distinct time courses following exposure. To identify genes that mediate lung pathology in the distinct temporal phases after exposure, gene expression profiles in HDI-BT-exposed C57BL/6J mouse lungs were analyzed. RNase protection assay (RPA) of genes involved in apoptosis, cell survival, and inflammation revealed increased expression of IκBα, Fas, Bcl-X L , TNFα, KC, MIP-2, IL-6, and GM-CSF following HDI-BT exposure. Microarray analysis of approximately 10 000 genes was performed on lung RNA collected from mice 6, 18, and 90 h after HDI-BT exposure and from unexposed mice. Classes of genes whose expression was increased 6 h after exposure included those involved in stress responses (particularly oxidative stress and thiol redox balance), growth arrest, apoptosis, signal transduction, and inflammation. Types of genes whose expression was increased at 18 h included proteinases, anti-proteinases, cytoskeletal molecules, and inflammatory mediators. Transcripts increased at 90 h included extracellular matrix components, transcription factors, inflammatory mediators, and cell cycle regulators. This characterization of the gene expression profile in lungs exposed to HDI-BT will provide a basis for investigating injury and repair pathways that are operative during isocyanate-induced lung disease

  3. Effect of CPAP in a Mouse Model of Hyperoxic Neonatal Lung Injury

    Science.gov (United States)

    Reyburn, Brent; Fiore, Juliann M. Di; Raffay, Thomas; Martin, Richard J.; Y.S., Prakash; Jafri, Anjum; MacFarlane, Peter M.

    2015-01-01

    Background Continuous positive airway pressure [CPAP] and supplemental oxygen have become the mainstay of neonatal respiratory support in preterm infants. Although oxygen therapy is associated with respiratory morbidities including bronchopulmonary dysplasia [BPD], the long-term effects of CPAP on lung function are largely unknown. We used a hyperoxia-induced mouse model of BPD to explore the effects of daily CPAP during the first week of life on later respiratory system mechanics. Objective To test the hypothesis that daily CPAP in a newborn mouse model of BPD improves longer term respiratory mechanics. Methods Mouse pups from C57BL/6 pregnant dams were exposed to room air [RA] or hyperoxia [50% O2, 24hrs/day] for the first postnatal week with or without exposure to daily CPAP [6cmH2O, 3hrs/day]. Respiratory system resistance [Rrs] and compliance [Crs] were measured following a subsequent 2 week period of room RA recovery. Additional measurements included radial alveolar counts and macrophage counts. Results Mice exposed to hyperoxia had significantly elevated Rrs, decreased Crs, reduced alveolarization, and increased macrophage counts at three weeks compared to RA treated mice. Daily CPAP treatment significantly improved Rrs, Crs and alveolarization, and decreased lung macrophage infiltration in hyperoxia-exposed pups. Conclusions We have demonstrated that daily CPAP had a longer term benefit on baseline respiratory system mechanics in a neonatal mouse model of BPD. We speculate that this beneficial effect of CPAP was the consequence of a decrease in the inflammatory response and resultant alveolar injury associated with hyperoxic newborn lung injury. PMID:26394387

  4. Benzyl Isothiocyanate Inhibits Prostate Cancer Development in the Transgenic Adenocarcinoma Mouse Prostate (TRAMP Model, Which Is Associated with the Induction of Cell Cycle G1 Arrest

    Directory of Open Access Journals (Sweden)

    Han Jin Cho

    2016-02-01

    Full Text Available Benzyl isothiocyanate (BITC is a hydrolysis product of glucotropaeolin, a compound found in cruciferous vegetables, and has been shown to have anti-tumor properties. In the present study, we investigated whether BITC inhibits the development of prostate cancer in the transgenic adenocarcinoma mouse prostate (TRAMP mice. Five-week old, male TRAMP mice and their nontransgenic littermates were gavage-fed with 0, 5, or 10 mg/kg of BITC every day for 19 weeks. The weight of the genitourinary tract increased markedly in TRAMP mice and this increase was suppressed significantly by BITC feeding. H and E staining of the dorsolateral lobes of the prostate demonstrated that well-differentiated carcinoma (WDC was a predominant feature in the TRAMP mice. The number of lobes with WDC was reduced by BITC feeding while that of lobes with prostatic intraepithelial neoplasia was increased. BITC feeding reduced the number of cells expressing Ki67 (a proliferation marker, cyclin A, cyclin D1, and cyclin-dependent kinase (CDK2 in the prostatic tissue. In vitro cell culture results revealed that BITC decreased DNA synthesis, as well as CDK2 and CDK4 activity in TRAMP-C2 mouse prostate cancer cells. These results indicate that inhibition of cell cycle progression contributes to the inhibition of prostate cancer development in TRAMP mice treated with BITC.

  5. EGFR mutations in patients with lung adenocarcinoma in southwest China: are G719S/A and L861Q more likely detected in tumors derived from smokers?

    Directory of Open Access Journals (Sweden)

    Wang QS

    2013-07-01

    Full Text Available Qiushi Wang,1 Jianghong Mou,1 Xin Yang,1 Yong He,2 Zengpeng Li,1 Qingya Luo,1 Yanqing Li,1 Li Lin,1 Yu Ma,1 Hualiang Xiao11Department of Pathology, 2Department of Respiration, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of ChinaBackground: The clinical characteristics of epidermal growth factor receptor (EGFR hotspot mutations, such as deletions in exon 19, substitution of L858R in exon 21, and mutations in exon 20, have been widely reported in nonsmall cell lung cancer. However, the clinical features of other low frequency EGFR mutations in these four exons (especially the relationship with smoking history, eg, substitutions of G719S/A/C in exon 18 and L861Q in exon 21, remain unclear. This study investigated the relationship between G719S/A/C and L861Q mutations (in exon 18 and 21 and smoking history.Methods: Specimens from 194 patients with lung adenocarcinoma were analyzed for EGFR mutations in exons 18–21 by high-resolution melting curve analysis and amplification refractory mutation technology to establish the relationship between G719S/A/C and L861Q mutations and smoking history.Results: Ninety-six of 194 tumors (49.5% were confirmed to be EGFR mutation-positive. Among these mutations, 71 of 104 (68.3% were from never smokers, six of 17 (35.3% were from former smokers, and 19 of 73 (26.0% were from current smokers (P < 0.001. The mutation rate in heavy smokers (5/23, 21.7% was significantly lower than in light smokers (20/67, 29.9% and never smokers (71/104, 68.3%, P < 0.001. Seven low frequency EGFR mutations (four substitutions of G719S, and G719 A, respectively, and three of L861Q in exon 21 were identified. Five of these mutations were derived from smokers (one former light smoker, one current heavy smoker, and three current light smokers. Four of these patients had been treated with tyrosine kinase inhibitors and all had a partial response, with median overall

  6. Monitoring of high-density lipoprotein cholesterol level is predictive of EGFR mutation and efficacy of EGFR-TKI in patients with advanced lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Lv Y

    2016-01-01

    Full Text Available Yang Lv,1,2 Li-Yun Miao,2 Qiu-Fang Chen,1 Yan Li,2 Zhi-Xiang Shi,1 Xuan-Sheng Ding1 1Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China; 2Division of Respiratory Medicine, Department of Respiration, The Affiliated Drum Tower Hospital of Nanjing University Medical College, Nanjing University Medical School, Nanjing, Jiangsu, People’s Republic of China Abstract: High-density lipoprotein cholesterol (HDL-C has an inverse association with the incidence of lung cancer. However, whether it can be used as a predictive factor in advanced lung adenocarcinoma patients treated with epidermal growth factor receptor (EGFR tyrosine kinase inhibitors (TKI still remains undefined. This research aimed at studying the relationship of serum HDL-C baseline level and HDL-C kinetics to EGFR mutation, the efficacy of EGFR-TKI, and the predictive value of PFS. The presence of mutation rate in the 192 patients with lung adenocarcinoma was compared within stratified groups. Levels of baseline HDL-C and kinetics of HDL-C were analyzed retrospectively in patients treated with EGFR-TKI harboring EGFR mutation. Univariate and multivariate analyses were performed to investigate the prognostic value of HDL-C. EGFR mutation rate of HDL-C high-level group was significantly higher than that of low-level group (59.0% vs 35.6%, P=0.001. Multivariate logistic analysis showed that high-level HDL-C was an independent predictive factor for EGFR gene mutation (P=0.005; odds ratio =0.417; 95% confidence interval [CI], 0.227–0.768. Patients with a low level of HDL-C before therapy showed a progression of disease in most cases (P<0.001. According to HDL-C kinetics, patients who received EGFR-TKI treatment harboring EGFR mutation were divided into four groups. Univariate analysis showed that patients in nondecreased group had longer progression-free survival (P<0.001; hazard ratio =0.003; 95% CI, 0.001–0.018. Multivariate

  7. TLG-S criteria are superior to both EORTC and PERCIST for predicting outcomes in patients with metastatic lung adenocarcinoma treated with erlotinib

    Energy Technology Data Exchange (ETDEWEB)

    Ho, Kung-Chu [National Taiwan University, Graduate Institute of Biomedical Electronics and Bioinformatics, Taipei (China); Chang Gung Memorial Hospital and Chang Gung University, Department of Nuclear Medicine and Center for Advanced Molecular Imaging and Translation, Taoyuan (China); Fang, Yu-Hua Dean [National Cheng Kung University, Department of Biomedical Engineering, Tainan (China); Chung, Hsiao-Wen [National Taiwan University, Graduate Institute of Biomedical Electronics and Bioinformatics, Taipei (China); Liu, Yuan-Chang [Chang Gung Memorial Hospital and Chang Gung University, Department of Medical Imaging and Intervention, Taoyuan (China); Chang, John Wen-Cheng; Hou, Ming-Mo [Chang Gung Memorial Hospital and Chang Gung University, Division of Hematology-Oncology, Department of Internal Medicine, Taoyuan (China); Yang, Cheng-Ta [Chang Gung Memorial Hospital and Chang Gung University, Department of Thoracic Medicine, Taoyuan (China); Cheng, Nai-Ming; Yen, Tzu-Chen [Chang Gung Memorial Hospital and Chang Gung University, Department of Nuclear Medicine and Center for Advanced Molecular Imaging and Translation, Taoyuan (China); Su, Tzu-Pei [Chang Gung Memorial Hospital, Department of Nuclear Medicine, Keelung (China)

    2016-11-15

    In this retrospective review of prospectively collected data, we sought to investigate whether early FDG-PET assessment of treatment response based on total lesion glycolysis measured using a systemic approach (TLG-S) would be superior to either local assessment with EORTC (European Organization for Research and Treatment of Cancer) criteria or single-lesion assessment with PERCIST (PET Response Criteria in Solid Tumors) for predicting clinical outcomes in patients with metastatic lung adenocarcinoma treated with erlotinib. We also examined the effect of bone flares on tumor response evaluation by single-lesion assessment with PERCIST in patients with metastatic bone lesions. We performed a retrospective review of prospectively collected data from 23 patients with metastatic lung adenocarcinoma treated with erlotinib. All participants underwent FDG-PET imaging at baseline and on days 14 and 56 after completion of erlotinib treatment. In addition, diagnostic CT scans were performed at baseline and on day 56. FDG-PET response was assessed with TLG-S, EORTC, and PERCIST criteria. Response assessment based on RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) from diagnostic CT imaging was used as the reference standard. Two-year progression-free survival (PFS) and overall survival (OS) served as the main outcome measures. We identified 13 patients with bone metastases. Of these, four (31 %) with persistent bone uptake due to bone flares on day 14 were erroneously classified as non-responders according to the PERCIST criteria, but they were correctly classified as responders according to both the EORTC and TLG-S criteria. Patients who were classified as responders on day 14 based on TLG-S criteria had higher rates of 2-year PFS (26.7 % vs. 0 %, P = 0.007) and OS (40.0 % vs. 7.7 %, P = 0.018). Similar rates were observed in patients who showed a response on day 56 based on CT imaging according to the RECIST criteria. Patients classified as responders on day 14

  8. Low-frequency ultrasound increases non-viral gene transfer to the mouse lung.

    Science.gov (United States)

    Xenariou, Stefania; Liang, Hai-Dong; Griesenbach, Uta; Zhu, Jie; Farley, Raymond; Somerton, Lucinda; Singh, Charanjit; Jeffery, Peter K; Scheule, Ronald K; Cheng, Seng H; Geddes, Duncan M; Blomley, Martin; Alton, Eric W F W

    2010-01-01

    The aim of the study was to assess if low-frequency ultrasound (US), in the range of 30-35 kHz, increases non-viral gene transfer to the mouse lung. US is greatly attenuated in the lung due to large energy losses at the air/tissue interfaces. The advantages of low-frequency US, compared with high-frequency US are: (i) increased cavitation (responsible for the formation of transient pores in the cell membrane) and (ii) reduced energy losses during lung penetration. Cationic lipid GL67/plasmid DNA (pDNA), polyethylenimine (PEI)/pDNA and naked pDNA were delivered via intranasal instillation and the animals were then exposed to US (sonoporation) at 0.07 or 0.1 MPa for 10 min. Under these conditions, US did not enhance GL67 or PEI-mediated transfection. It did, however, increase naked pDNA gene transfer by approximately 4 folds. Importantly, this was achieved in the absence of microbubbles, which are crucial for the commonly used high-frequency (1 MHz) sonoporation but may not be able to withstand nebulization in a clinically relevant setup. Lung hemorrhage was also assessed and shown to increase with US pressure in a dose-dependent manner. We have thus, established that low-frequency US can enhance lung gene transfer with naked pDNA and this enhancement is more effective than the previously reported 1 MHz US.

  9. Pharmacokinetic and Genomic Effects of Arsenite in Drinking Water on Mouse Lung in a 30-Day Exposure

    Directory of Open Access Journals (Sweden)

    Jaya Chilakapati

    2015-06-01

    Full Text Available The 2 objectives of this subchronic study were to determine the arsenite drinking water exposure dependent increases in female C3H mouse liver and lung tissue arsenicals and to characterize the dose response (to 0, 0.05, 0.25, 1, 10, and 85 ppm arsenite in drinking water for 30 days and a purified AIN-93M diet for genomic mouse lung expression patterns. Mouse lungs were analyzed for inorganic arsenic, monomethylated, and dimethylated arsenicals by hydride generation atomic absorption spectroscopy. The total lung mean arsenical levels were 1.4, 22.5, 30.1, 50.9, 105.3, and 316.4 ng/g lung tissue after 0, 0.05, 0.25, 1, 10, and 85 ppm, respectively. At 85 ppm, the total mean lung arsenical levels increased 14-fold and 131-fold when compared to either the lowest noncontrol dose (0.05 ppm or the control dose, respectively. We found that arsenic exposure elicited minimal numbers of differentially expressed genes (DEGs; 77, 38, 90, 87, and 87 DEGs after 0.05, 0.25, 1, 10, and 85 ppm, respectively, which were associated with cardiovascular disease, development, differentiation, apoptosis, proliferation, and stress response. After 30 days of arsenite exposure, this study showed monotonic increases in mouse lung arsenical (total arsenic and dimethylarsinic acid concentrations but no clear dose-related increases in DEG numbers.

  10. Radial gradient and radial deviation radiomic features from pre-surgical CT scans are associated with survival among lung adenocarcinoma patients.

    Science.gov (United States)

    Tunali, Ilke; Stringfield, Olya; Guvenis, Albert; Wang, Hua; Liu, Ying; Balagurunathan, Yoganand; Lambin, Philippe; Gillies, Robert J; Schabath, Matthew B

    2017-11-10

    The goal of this study was to extract features from radial deviation and radial gradient maps which were derived from thoracic CT scans of patients diagnosed with lung adenocarcinoma and assess whether these features are associated with overall survival. We used two independent cohorts from different institutions for training (n= 61) and test (n= 47) and focused our analyses on features that were non-redundant and highly reproducible. To reduce the number of features and covariates into a single parsimonious model, a backward elimination approach was applied. Out of 48 features that were extracted, 31 were eliminated because they were not reproducible or were redundant. We considered 17 features for statistical analysis and identified a final model containing the two most highly informative features that were associated with lung cancer survival. One of the two features, radial deviation outside-border separation standard deviation, was replicated in a test cohort exhibiting a statistically significant association with lung cancer survival (multivariable hazard ratio = 0.40; 95% confidence interval 0.17-0.97). Additionally, we explored the biological underpinnings of these features and found radial gradient and radial deviation image features were significantly associated with semantic radiological features.

  11. Mechanisms underlying regulation of cell cycle and apoptosis by hnRNP B1 in human lung adenocarcinoma A549 cells.

    Science.gov (United States)

    Han, Juan; Tang, Feng-ming; Pu, Dan; Xu, Dan; Wang, Tao; Li, Weimin

    2014-01-01

    Overexpression of heterogeneous nuclear ribonucleoprotein B1 (hnRNP B1), a nuclear RNA binding protein, has been reported to occur in early-stage lung cancer and in premalignant lesions. DNA-dependent protein kinase (DNA-PK) is known to be involved in the repair of double-strand DNA breaks. Reduced capacity to repair DNA has been associated with the risk of lung cancer. We investigated a link between hnRNP B1 and DNA-PK and their effects on proliferation, cell cycle, and apoptosis in the human lung adenocarcinoma cell line A549. We found that hnRNP B1 and DNA-PK interact with each other in a complex fashion. Reducing hnRNP B1 expression in A549 cells with the use of RNAi led to upregulation of p53 activity through upregulation of DNA-PK activity but without inducing p53 expression. Further, suppression of hnRNP B1 in A549 cells slowed cell proliferation, promoted apoptosis, and induced cell cycle arrest at the G1 stage. The presence of NU7026 reduced the arrest of cells at the G1 stage and reduced the apoptosis rate while promoting cell growth. Taken together, our results demonstrate that by regulating DNA-PK activity, hnRNP B1 can affect p53-mediated cell cycle progression and apoptosis, resulting in greater cell survival and subsequent proliferation.

  12. Effect of radiation on the expression of tumor-associated antigens of human lung adenocarcinoma cells. Immunological study using monoclonal antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Hareyama, Masato

    1988-12-01

    We studied the effects of irradiation on the expression of a tumor-associated antigen (YH206 antigen) of cultured human lung adenocarcinoma A549 cells by using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. YH206 antigen is preferentially expressed on adenocarcinoma cells. Irradiation of A549 cells remarkably increased the expression of YH206 antigen on the cell surface and the level of the antigen in the culture supernatant as well as in the cell lysate, whereas it significantly affected the expression of HLA (MHC-class I) antigen on the same cells. The expression of HLA antigen on the cell was also increased after treatment of the cells with interferon-..gamma... In an additional experiment, cells were stained simultaneously for surface antigens (fluorescein coupled antibodies) and for DNA content (propidium iodide), and then dual parameter measurements were performed by flow cytometry to analyse the relationship between antigen levels and the cell cycle. YH206 antigen and HLA antigen increased more in the S and G/sub 2//M phases of the cell cycle than in G/sub 0//G/sub 1/. The expression of YH206 antigen was enhanced in the S and G/sub 2//M phases by irradiation, whereas the expression of HLA antigen was enhanced in each phase of the cell cycle with irradiation or IFN. These results suggest that irradiation plays a key role in the change of the expression of certain tumor-associated antigens.

  13. Modification of radiation damage in mouse lung by DNA-binding radioprotectors

    International Nuclear Information System (INIS)

    Budd, R.; D'Abrew, S.; Coultas, P.; Martin, R.F.

    1996-01-01

    Full text: The limited diffusion of Hoechst 33342 through cell layers, which has been exploited in mapping the location of cells in multi-cellular spheroids, and in vivo, reflects a general characteristic of DNA-ligands. This property may confer special advantages on DNA-binding radioprotectors in the context of radiotherapy, where it is important to minimise delivery of the radioprotector to the tumour. For example, one might expect limited diffusion to capillaries and systemic uptake following topical application to epithelial cells, which can be dose-limiting tissues in radiotherapy. These potential applications will require delivery of sufficient concentrations of the DNA-binding radioprotectors to cells in vivo. In this context, the findings of Young and Hill, who could not detect any radioprotective effect in an in vivo setting, is of concern. We have re-examined this question by investigating radioprotection in the mouse lung model. A single intravenous injection of Hoechst 33342 (80mg/kg) given 30min prior to the lung irradiation, extends the radiation dose required for death in 50% of mice at 16 weeks post irradiation, from 19Gy to 23Gy (ie: a DMF of 1.2). This is similar to the extent of radioprotection reported by Travis et al for WR2721 (300 mg/kg) in this model. These results auger well for the potential of the more potent radioprotectors, and indeed preliminary experiments with methylproamine in the mouse lung model suggests a DMF of 1.35

  14. Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations.

    Science.gov (United States)

    Seow, Wei Jie; Matsuo, Keitaro; Hsiung, Chao Agnes; Shiraishi, Kouya; Song, Minsun; Kim, Hee Nam; Wong, Maria Pik; Hong, Yun-Chul; Hosgood, H Dean; Wang, Zhaoming; Chang, I-Shou; Wang, Jiu-Cun; Chatterjee, Nilanjan; Tucker, Margaret; Wei, Hu; Mitsudomi, Tetsuya; Zheng, Wei; Kim, Jin Hee; Zhou, Baosen; Caporaso, Neil E; Albanes, Demetrius; Shin, Min-Ho; Chung, Lap Ping; An, She-Juan; Wang, Ping; Zheng, Hong; Yatabe, Yasushi; Zhang, Xu-Chao; Kim, Young Tae; Shu, Xiao-Ou; Kim, Young-Chul; Bassig, Bryan A; Chang, Jiang; Ho, James Chung Man; Ji, Bu-Tian; Kubo, Michiaki; Daigo, Yataro; Ito, Hidemi; Momozawa, Yukihide; Ashikawa, Kyota; Kamatani, Yoichiro; Honda, Takayuki; Sakamoto, Hiromi; Kunitoh, Hideo; Tsuta, Koji; Watanabe, Shun-Ichi; Nokihara, Hiroshi; Miyagi, Yohei; Nakayama, Haruhiko; Matsumoto, Shingo; Tsuboi, Masahiro; Goto, Koichi; Yin, Zhihua; Shi, Jianxin; Takahashi, Atsushi; Goto, Akiteru; Minamiya, Yoshihiro; Shimizu, Kimihiro; Tanaka, Kazumi; Wu, Tangchun; Wei, Fusheng; Wong, Jason Y Y; Matsuda, Fumihiko; Su, Jian; Kim, Yeul Hong; Oh, In-Jae; Song, Fengju; Lee, Victor Ho Fun; Su, Wu-Chou; Chen, Yuh-Min; Chang, Gee-Chen; Chen, Kuan-Yu; Huang, Ming-Shyan; Yang, Pan-Chyr; Lin, Hsien-Chih; Xiang, Yong-Bing; Seow, Adeline; Park, Jae Yong; Kweon, Sun-Seog; Chen, Chien-Jen; Li, Haixin; Gao, Yu-Tang; Wu, Chen; Qian, Biyun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Wang, Wen-Chang; Chung, Charles C; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Jacobs, Kevin B; Hutchinson, Amy; Berndt, Sonja I; He, Xingzhou; Wu, Wei; Wang, Junwen; Li, Yuqing; Choi, Jin Eun; Park, Kyong Hwa; Sung, Sook Whan; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Wang, Chih-Liang; Sihoe, Alan Dart Loon; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Chen, Chih-Yi; Vermeulen, Roel; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chan, John K C; Chu, Minjie; Li, Yao-Jen; Li, Jihua; Chen, Hongyan; Yu, Chong-Jen; Jin, Li; Lo, Yen-Li; Chen, Ying-Hsiang; Fraumeni, Joseph F; Liu, Jie; Yamaji, Taiki; Yang, Yang; Hicks, Belynda; Wyatt, Kathleen; Li, Shengchao A; Dai, Juncheng; Ma, Hongxia; Jin, Guangfu; Song, Bao; Wang, Zhehai; Cheng, Sensen; Li, Xuelian; Ren, Yangwu; Cui, Ping; Iwasaki, Motoki; Shimazu, Taichi; Tsugane, Shoichiro; Zhu, Junjie; Jiang, Gening; Fei, Ke; Wu, Guoping; Chien, Li-Hsin; Chen, Hui-Ling; Su, Yu-Chun; Tsai, Fang-Yu; Chen, Yi-Song; Yu, Jinming; Stevens, Victoria L; Laird-Offringa, Ite A; Marconett, Crystal N; Lin, Dongxin; Chen, Kexin; Wu, Yi-Long; Landi, Maria Teresa; Shen, Hongbing; Rothman, Nathaniel; Kohno, Takashi; Chanock, Stephen J; Lan, Qing

    2017-01-15

    To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications. Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.

  15. Effect of concomitant use of immunomodulator (OK-432 and/or PSK) on advanced lung cancer (squamous cell carcinoma and adenocarcinoma) treated with radiation with combined chemotherapy

    International Nuclear Information System (INIS)

    Ogawa, Yasuhiro; Kimura, Shuji; Imajo, Yoshinari

    1982-01-01

    Between 1975 and 1979, 209 cases of primary lung cancer admitted to the department of radiology were treated with radiation with combined chemotherapy. OK-432 and/or PSK as an immunomodulator was administered to 130 of these cases, and survival curves were evaluated between the patients with OK-432 and/or PSK and those without immunomodulator. In 61 cases (squamous cell carcinoma and adenocarcinoma) in stage III (UICC, 1978), fifty percent survival period was found to be 12.5 months for 16 cases with OK-432, 13.5 months for 9 cases with OK-432 and PSK, 9.0 months for 18 cases with PSK, and 8.0 months for 18 cases without immunotherapy, respectively. (author)

  16. Multitracer Stable Isotope Quantification of Arginase and Nitric Oxide Synthase Activity in a Mouse Model of Pseudomonas Lung Infection

    Directory of Open Access Journals (Sweden)

    Hartmut Grasemann

    2014-01-01

    Full Text Available Cystic fibrosis airways are deficient for L-arginine, a substrate for nitric oxide synthases (NOSs and arginases. The rationale for this study was to quantify NOS and arginase activity in the mouse lung. Anesthetized unventilated mice received a primed constant stable isotope intravenous infusion containing labeled L-arginine, ornithine, and citrulline. The isotopic enrichment of each of the infused isotopomers and its product amino acids were measured in plasma and organ homogenates using liquid chromatography-tandem mass spectrometry. The effect of infection was studied three days after direct tracheal instillation of Pseudomonas-coated agar beads. In the infusion model, lung infection resulted in a significant (28-fold increase in NOS activity in lung but not in trachea, kidney, liver, or plasma. Absolute rates of arginase activity in solid tissues could not be calculated in this model. In an isolated lung perfusion model used for comparison increased NOS activity in infected lungs was confirmed (28.5-fold and lung arginase activity was increased 9.7-fold. The activity of L-arginine metabolizing enzymes can be measured using stable isotope conversion in the mouse. Accumulation of L-ornithine in the whole mouse model hindered the exact quantification of arginase activity in the lung, a problem that was overcome utilizing an isolated lung perfusion model.

  17. Flavonoids and Tannins from Smilax china L. Rhizome Induce Apoptosis Via Mitochondrial Pathway and MDM2-p53 Signaling in Human Lung Adenocarcinoma Cells.

    Science.gov (United States)

    Fu, San; Yang, Yanfang; Liu, Dan; Luo, Yan; Ye, Xiaochuan; Liu, Yanwen; Chen, Xin; Wang, Song; Wu, Hezhen; Wang, Yuhang; Hu, Qiwei; You, Pengtao

    2017-01-01

    In vitro evidence indicates that Smilax china L. rhizome (SCR) can inhibit cell proliferation. Therefore, in the present study, we analyzed the effects in vitro of SCR extracts on human lung adenocarcinoma A549 cells. Our results showed that A549 cell growth was inhibited in a dose- and time-dependent manner after treatment with SCR extracts. Total flavonoids and total tannins from SCR induced A549 apoptosis in a dose-dependent manner, as shown by our flow cytometry analysis, which was consistent with the alterations in nuclear morphology we observed. In addition, the total apoptotic rate induced by total tannins was higher than the rate induced by total flavonoids at the same dose. Cleaved-caspase-3 protein levels in A549 cells after treatment with total flavonoids or total tannins were increased in a dose-dependent manner, followed by the activation of caspase-8 and caspase-9, finally triggering to PARP cleavage. Furthermore, total flavonoids and total tannins increased the expression of Bax, decreased the expression of Bcl-2, and promoted cytochrome [Formula: see text] release. Moreover, MDM2 and p-MDM2 proteins were decreased, while p53 and p-p53 proteins were increased, both in a dose-dependent manner, after A549 treatment with total flavonoids and total tannins. Finally, cleaved-caspase-3 protein levels in the total flavonoids or total tannins-treated H1299 (p53 null) and p53-knockdown A549 cells were increased. Our results indicated that total flavonoids and total tannins from SCR exerted a remarkable effect in reducing A549 growth through their action on mitochondrial pathway and disruption of MDM2-p53 balance. Hence, our findings demonstrated a potential application of total flavonoids and total tannins from SCR in the treatment of human lung adenocarcinoma.

  18. Gene expression profiles of lung adenocarcinoma linked to histopathological grading and survival but not to EGF-R status: a microarray study

    Directory of Open Access Journals (Sweden)

    Passlick Bernward

    2010-03-01

    Full Text Available Abstract Background Several different gene expression signatures have been proposed to predict response to therapy and clinical outcome in lung adenocarcinoma. Herein, we investigate if elements of published gene sets can be reproduced in a small dataset, and how gene expression profiles based on limited sample size relate to clinical parameters including histopathological grade and EGFR protein expression. Methods Affymetrix Human Genome U133A platform was used to obtain gene expression profiles of 28 pathologically and clinically annotated adenocarcinomas of the lung. EGFR status was determined by fluorescent in situ hybridization and immunohistochemistry. Results Using unsupervised clustering algorithms, the predominant gene expression signatures correlated with the histopathological grade but not with EGFR protein expression as detected by immunohistochemistry. In a supervised analysis, the signature of high grade tumors but not of EGFR overexpressing cases showed significant enrichment of gene sets reflecting MAPK activation and other potential signaling cascades downstream of EGFR. Out of four different previously published gene sets that had been linked to prognosis, three showed enrichment in the gene expression signature associated with favorable prognosis. Conclusions In this dataset, histopathological tumor grades but not EGFR status were associated with dominant gene expression signatures and gene set enrichment reflecting oncogenic pathway activation, suggesting that high immunohistochemistry EGFR scores may not necessarily be linked to downstream effects that cause major changes in gene expression patterns. Published gene sets showed association with patient survival; however, the small sample size of this study limited the options for a comprehensive validation of previously reported prognostic gene expression signatures.

  19. Stereotactic Body Radiation Therapy Delivery in a Genetically Engineered Mouse Model of Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Du, Shisuo; Lockamy, Virginia [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Zhou, Lin [Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan (China); Xue, Christine; LeBlanc, Justin [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Glenn, Shonna [Xstrahl, Inc, Suwanee, Georgia (United States); Shukla, Gaurav; Yu, Yan; Dicker, Adam P.; Leeper, Dennis B. [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Lu, You [Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan (China); Lu, Bo, E-mail: bo.lu@jefferson.edu [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States)

    2016-11-01

    Purpose: To implement clinical stereotactic body radiation therapy (SBRT) using a small animal radiation research platform (SARRP) in a genetically engineered mouse model of lung cancer. Methods and Materials: A murine model of multinodular Kras-driven spontaneous lung tumors was used for this study. High-resolution cone beam computed tomography (CBCT) imaging was used to identify and target peripheral tumor nodules, whereas off-target lung nodules in the contralateral lung were used as a nonirradiated control. CBCT imaging helps localize tumors, facilitate high-precision irradiation, and monitor tumor growth. SBRT planning, prescription dose, and dose limits to normal tissue followed the guidelines set by RTOG protocols. Pathologic changes in the irradiated tumors were investigated using immunohistochemistry. Results: The image guided radiation delivery using the SARRP system effectively localized and treated lung cancer with precision in a genetically engineered mouse model of lung cancer. Immunohistochemical data confirmed the precise delivery of SBRT to the targeted lung nodules. The 60 Gy delivered in 3 weekly fractions markedly reduced the proliferation index, Ki-67, and increased apoptosis per staining for cleaved caspase-3 in irradiated lung nodules. Conclusions: It is feasible to use the SARRP platform to perform dosimetric planning and delivery of SBRT in mice with lung cancer. This allows for preclinical studies that provide a rationale for clinical trials involving SBRT, especially when combined with immunotherapeutics.

  20. Nicotinic receptor-associated modulation of stimulatory and inhibitory neurotransmitters in NNK-induced adenocarcinoma of the lungs and pancreas

    Science.gov (United States)

    Al-Wadei, Hussein A. N.; Schuller, Hildegard M.

    2012-01-01

    Small airway-derived pulmonary adenocarcinoma (PAC) and pancreatic ductal adenocarcinoma (PDAC) are among the most common human cancers and smoking is a risk factor for both. Emerging research has identified cAMP signaling stimulated by the stress neurotransmitters adrenaline and noradrenaline as important stimulators of several adenocarcinomas, including PAC and PDAC. The nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent mutagen and the most powerful tobacco carcinogen. NNK is also an agonist for nicotinic acetylcholine receptors (nAChRs). Using hamster models of NNK-induced PAC and PDAC, we have tested the hypothesis that in analogy to chronic effects of nicotine in the brain, NNK may modulate the α7- and α4β2nAChRs, causing an increase in stress neurotransmitters and decrease in the inhibitory neurotransmitter γ-aminobutyric acid (GABA). In support of our hypothesis, immunoassays showed a significant increase in serum adrenaline/noradrenaline and increased intracellular cAMP in the cellular fraction of blood of NNK treated hamsters. Western blots were done with cells harvested by laser capture microcopy from control small airway epithelia, alveolar epithelia, pancreatic islet and pancreatic duct epithelia and from NNK-induced PACs and PDACs. The GABA synthesizing enzyme glutamate decarboxylase 65 (GAD65) and GABA were suppressed in NNK-induced PACs and PDACs whereas protein expression of the α7nAChR, α4nAChR as well as p-CREB and p-ERK1/2 were upregulated. These findings suggest, for the first time, that NNK-induced alterations in regulatory nAChRs may contribute to the development of smoking-associated PAC and PDAC by disturbing the balance between cancer stimulating and inhibiting neurotransmitters. PMID:19274673

  1. Mesenchymal stem cells promote cell invasion and migration and autophagy-induced epithelial-mesenchymal transition in A549 lung adenocarcinoma cells.

    Science.gov (United States)

    Luo, Dan; Hu, Shiyuan; Tang, Chunlan; Liu, Guoxiang

    2018-03-01

    Mesenchymal stem cells (MSCs) are recruited into the tumour microenvironment and promote tumour growth and metastasis. Tumour microenvironment-induced autophagy is considered to suppress primary tumour formation by impairing migration and invasion. Whether these recruited MSCs regulate tumour autophagy and whether autophagy affects tumour growth are controversial. Our data showed that MSCs promote autophagy activation, reactive oxygen species production, and epithelial-mesenchymal transition (EMT) as well as increased migration and invasion in A549 cells. Decreased expression of E-cadherin and increased expression of vimentin and Snail were observed in A549 cells cocultured with MSCs. Conversely, MSC coculture-mediated autophagy positively promoted tumour EMT. Autophagy inhibition suppressed MSC coculture-mediated EMT and reduced A549 cell migration and invasion slightly. Furthermore, the migratory and invasive abilities of A549 cells were additional increased when autophagy was further enhanced by rapamycin treatment. Taken together, this work suggests that microenvironments containing MSCs can promote autophagy activation for enhancing EMT; MSCs also increase the migratory and invasive abilities of A549 lung adenocarcinoma cells. Mesenchymal stem cell-containing microenvironments and MSC-induced autophagy signalling may be potential targets for blocking lung cancer cell migration and invasion. Copyright © 2018 John Wiley & Sons, Ltd.

  2. Repair capacity of mouse lung after total body irradiation alone or combined with cyclophosphamide

    International Nuclear Information System (INIS)

    Safwat, Akmal; Bentzen, Soeren M.; Nielsen, Ole S.; Mahmoud, Hossam K.; Overgaard, Jens

    1996-01-01

    Purpose. Cyclophosphamide (CTX) combined with fractionated total body irradiation (TBI) is frequently used in the conditioning of patients prior to bone marrow transplantation (BMT). This study was performed to investigate the effect of CTX on the repair capacity of lung tissue after TBI in a mouse model for BMT. Materials and methods. TBI was given as a single fraction, 3 fractions in 3 days (Fx 3) or 9 fractions in 3 days (Fx 9) either alone or 24 h after a single dose of CTX. The single fraction TBI was given at either high dose rate (HDR) of 0.71 Gy/min or low dose rate (LDR) of 0.08 Gy/min. All mice were transplanted 4-6 h after the last TBI fraction. Lung damage was assessed using ventilation rate (VR) and lethality between 28 and 180 days. The repair capacity of lung tissue was estimated using the direct analysis method with the probability of reaching the end point described by a logistic formulation of the linear quadratic model. Results. The VR data confirmed the high repair capacity of lung tissue with an α/β ratio of 4.4 Gy though with a wide 95% confidence interval (CI = 0.03-10.5). Giving CTX before fractionated TBI marked reduced the doses needed to cause response in 50% of the animals. The sparing effect of using fractionated TBI was still evident in the combined CTX-TBI schedules. The estimated α/β ratio was 1.6 Gy (CI = 0.01-4.7) which is within the range of values reported after thoracic radiation only. On the other hand, the sparing effect seen in going from single fraction HDR to LDR was completely abolished when CTX was given 24 h before TBI. The same pattern was repeated when lethality between 28-180 days was used. Yet, the use of lethality to estimate lung damage in a TBI model, markedly underestimated the repair capacity. Conclusions. These results confirm the high repair capacity of lung tissue after TBI and emphasize the value of using a specific end point in testing lung damage after TBI. It also shows that there can be a negative

  3. Administration of the optimized β-Lapachone-poloxamer-cyclodextrin ternary system induces apoptosis, DNA damage and reduces tumor growth in a human breast adenocarcinoma xenograft mouse model.

    Science.gov (United States)

    Seoane, Samuel; Díaz-Rodríguez, Patricia; Sendon-Lago, Juan; Gallego, Rosalia; Pérez-Fernández, Román; Landin, Mariana

    2013-08-01

    β-Lapachone (β-Lap) is a 1,2-orthonaphthoquinone that selectively induces cell death in human cancer cells through NAD(P)H:quinone oxidoreductase-1 (NQO1). NQO1 is overexpressed in a variety of tumors, as compared to normal adjacent tissue. However, the low solubility and non-specific distribution of β-Lap limit its suitability for clinical assays. We formulated β-Lap in an optimal random methylated-β-cyclodextrin/poloxamer 407 mixture (i.e., β-Lap ternary system) and, using human breast adenocarcinoma MCF-7 cells and immunodeficient mice, performed in vitro and in vivo evaluation of its anti-tumor effects on proliferation, cell cycle, apoptosis, DNA damage, and tumor growth. This ternary system is fluid at room temperature, gels over 29 °C, and provides a significant amount of drug, thus facilitating intratumoral delivery, in situ gelation, and the formation of a depot for time-release. Administration of β-Lap ternary system to MCF-7 cells induces an increase in apoptosis and DNA damage, while producing no changes in cell cycle. Moreover, in a mouse xenograft tumor model, intratumoral injection of the system significantly reduces tumor volume, while increasing apoptosis and DNA damage without visible toxicity to liver or kidney. These anti-tumoral effects and lack of visible toxicity make this system a promising new therapeutic agent for breast cancer treatment. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. INDUCTION OF DNA ADDUCTS, TUMORS, AND KI-RAS ONCOGENE MUTATIONS IN STRAIN A/J MOUSE LUNG BY IP. ADMINISTRATION OF DIBENZ[A,H]ANTHRACENE

    Science.gov (United States)

    Induction of DNA adducts, tumors, and Ki-ras oncogene mutations in strain AlJ mouse lung by ip. administration of dibenz[a,h]anthracene Previous studies of polycyclic aromatic hydrocarbon (P AH) induced lung tumors in the strain NJ mouse model system have demonstrated qua...

  5. Urachal Adenocarcinoma

    African Journals Online (AJOL)

    Urachal adenocarcinoma is a rare tumor and represents. 0.17–0.34% of all bladder tumors. Most of the reported cases are in western literature and to the best of our knowledge this is the first case report of urachal adenocarcinoma in sub-Saharan Africa. It has an insidious course and variable clinical presentation. We.

  6. Prognostic importance of pleural attachment status measured by pretreatment CT images in patients with stage IA lung adenocarcinoma: measurement of the ratio of the interface between nodule and neighboring pleura to nodule surface area

    Science.gov (United States)

    Kawata, Y.; Niki, N.; Kusumoto, M.; Ohmatsu, H.; Aokage, K.; Ishii, G.; Matsumoto, Y.; Tsuchida, T.; Eguchi, K.; Kaneko, M.

    2018-02-01

    Screening for lung cancer with low-dose computed tomography (CT) has led to increased recognition of small lung cancers and is expected to increase the rate of detection of early-stage lung cancer. Major concerns in the implementation of the CT screening of large populations include determining the appropriate management of pulmonary nodules found on a scan. The identification of patients with early-stage lung cancer who have a higher risk for relapse and who require more aggressive surveillance has been a target of intense investigation. This study was performed to investigate whether image features of internal intensity in combination with surrounding structure characteristics are associated with an increased risk of relapse in patients with stage IA lung adenocarcinoma. We focused on pleural attachment status which is one of morphological characteristics associated with prognosis in three-dimensional thoracic CT images.

  7. Modulation of lung inflammation by vessel dilator in a mouse model of allergic asthma

    Directory of Open Access Journals (Sweden)

    Cormier Stephania A

    2009-07-01

    Full Text Available Abstract Background Atrial natriuretic peptide (ANP and its receptor, NPRA, have been extensively studied in terms of cardiovascular effects. We have found that the ANP-NPRA signaling pathway is also involved in airway allergic inflammation and asthma. ANP, a C-terminal peptide (amino acid 99–126 of pro-atrial natriuretic factor (proANF and a recombinant peptide, NP73-102 (amino acid 73–102 of proANF have been reported to induce bronchoprotective effects in a mouse model of allergic asthma. In this report, we evaluated the effects of vessel dilator (VD, another N-terminal natriuretic peptide covering amino acids 31–67 of proANF, on acute lung inflammation in a mouse model of allergic asthma. Methods A549 cells were transfected with pVD or the pVAX1 control plasmid and cells were collected 24 hrs after transfection to analyze the effect of VD on inactivation of the extracellular-signal regulated receptor kinase (ERK1/2 through western blot. Luciferase assay, western blot and RT-PCR were also performed to analyze the effect of VD on NPRA expression. For determination of VD's attenuation of lung inflammation, BALB/c mice were sensitized and challenged with ovalbumin and then treated intranasally with chitosan nanoparticles containing pVD. Parameters of airway inflammation, such as airway hyperreactivity, proinflammatory cytokine levels, eosinophil recruitment and lung histopathology were compared with control mice receiving nanoparticles containing pVAX1 control plasmid. Results pVD nanoparticles inactivated ERK1/2 and downregulated NPRA expression in vitro, and intranasal treatment with pVD nanoparticles protected mice from airway inflammation. Conclusion VD's modulation of airway inflammation may result from its inactivation of ERK1/2 and downregulation of NPRA expression. Chitosan nanoparticles containing pVD may be therapeutically effective in preventing allergic airway inflammation.

  8. Interactions between ethanol and cigarette smoke in a mouse lung carcinogenesis model

    International Nuclear Information System (INIS)

    Balansky, Roumen; Ganchev, Gancho; Iltcheva, Marietta; Nikolov, Manasi; La Maestra, S.; Micale, Rosanna T.; Steele, Vernon E.; De Flora, Silvio

    2016-01-01

    Highlights: • Cigarette smoke and ethanol are known to synergize in the upper aerodigestive tract. • Their interactions in the lower respiratory tract have poorly been explored. • Prenatal and postnatal treatments of mice with ethanol caused pulmonary alterations. • However, ethanol attenuated smoke-induced preneoplastic and neoplastic lesions in lung. • The interaction between smoke and alcohol depends on life stage and target tissue. - Abstract: Both ethanol and cigarette smoke are classified as human carcinogens. They can synergize, especially in tissues of the upper aerodigestive tract that are targeted by both agents. The main objective of the present study was to evaluate the individual and combined effects of ethanol and smoke in the respiratory tract, either following transplacental exposure and/or postnatal exposure. We designed two consecutive studies in mouse models by exposing Swiss H mice to oral ethanol and/or inhaled mainstream cigarette smoke for up to 4 months, at various prenatal and postnatal life stages. Clastogenic effects and histopathological alterations were evaluated after 4 and 8 months, respectively. Ethanol was per se devoid of clastogenic effects in mouse peripheral blood erythrocytes. However, especially in mice exposed both transplacentally throughout pregnancy and in the postnatal life, ethanol administration was associated not only with liver damage but also with pro-angiogenetic effects in the lung by stimulating the proliferation of blood vessels. In addition, these mice developed pulmonary emphysema, alveolar epithelial hyperplasias, microadenomas, and benign tumors. On the other hand, ethanol interfered in the lung carcinogenesis process resulting from the concomitant exposure of mice to smoke. In fact, ethanol significantly attenuated some smoke-related preneoplastic and neoplastic lesions in the respiratory tract, such as alveolar epithelial hyperplasia, microadenomas, and even malignant tumors. In addition, ethanol

  9. Strain-dependent Damage in Mouse Lung After Carbon Ion Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Moritake, Takashi [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan); Proton Medical Research Center, University of Tsukuba, Tsukuba (Japan); Fujita, Hidetoshi; Yanagisawa, Mitsuru; Nakawatari, Miyako; Imadome, Kaori; Nakamura, Etsuko; Iwakawa, Mayumi [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan); Imai, Takashi, E-mail: imait@nirs.go.jp [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan)

    2012-09-01

    Purpose: To examine whether inherent factors produce differences in lung morbidity in response to carbon ion (C-ion) irradiation, and to identify the molecules that have a key role in strain-dependent adverse effects in the lung. Methods and Materials: Three strains of female mice (C3H/He Slc, C57BL/6J Jms Slc, and A/J Jms Slc) were locally irradiated in the thorax with either C-ion beams (290 MeV/n, in 6 cm spread-out Bragg peak) or with {sup 137}Cs {gamma}-rays as a reference beam. We performed survival assays and histologic examination of the lung with hematoxylin-eosin and Masson's trichrome staining. In addition, we performed immunohistochemical staining for hyaluronic acid (HA), CD44, and Mac3 and assayed for gene expression. Results: The survival data in mice showed a between-strain variance after C-ion irradiation with 10 Gy. The median survival time of C3H/He was significantly shortened after C-ion irradiation at the higher dose of 12.5 Gy. Histologic examination revealed early-phase hemorrhagic pneumonitis in C3H/He and late-phase focal fibrotic lesions in C57BL/6J after C-ion irradiation with 10 Gy. Pleural effusion was apparent in C57BL/6J and A/J mice, 168 days after C-ion irradiation with 10 Gy. Microarray analysis of irradiated lung tissue in the three mouse strains identified differential expression changes in growth differentiation factor 15 (Gdf15), which regulates macrophage function, and hyaluronan synthase 1 (Has1), which plays a role in HA metabolism. Immunohistochemistry showed that the number of CD44-positive cells, a surrogate marker for HA accumulation, and Mac3-positive cells, a marker for macrophage infiltration in irradiated lung, varied significantly among the three mouse strains during the early phase. Conclusions: This study demonstrated a strain-dependent differential response in mice to C-ion thoracic irradiation. Our findings identified candidate molecules that could be implicated in the between-strain variance to early

  10. Deficiency of Functional Iron-Sulfur Domains in ABCE1 Inhibits the Proliferation and Migration of Lung Adenocarcinomas By Regulating the Biogenesis of Beta-Actin In Vitro

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    Qian Yu

    2017-11-01

    Full Text Available Background/Aims: ATP-binding cassette transporter E1 (ABCE1, a unique ABC superfamily member that bears two Fe-S clusters, is essential for metastatic progression in lung cancer. Fe-S clusters within ABCE1 are crucial for ribosome dissociation and translation reinitiation; however, whether these clusters promote tumor proliferation and migration is unclear. Methods: The interaction between ABCE1 and β-actin was confirmed using GST pull-down. The lung adenocarcinoma (LUAD cell line A549 was transduced with lentiviral packaging vectors overexpressing either wild-type ABCE1 or ABCE1 with Fe-S cluster deletions (ΔABCE1. The role of Fe-S clusters in the viability and migration of cancer cells was evaluated using clonogenic, MTT, Transwell and wound healing assays. Cytoskeletal rearrangement was determined using immunofluorescent techniques. Results: Fe-S clusters were the key domains in ABCE1 involved in binding to β-actin. The proliferative and migratory capacity increased in cells overexpressing ABCE1. However, the absence of Fe-S clusters reversed these effects. A549 cells overexpressing ABCE1 exhibited irregular morphology and increased levels of cytoskeletal polymerization as indicated by the immunofluorescence images. In contrast, cells expressing the Fe-S cluster deletion mutant presented opposing effects. Conclusion: These results demonstrate the indispensable role of Fe-S clusters when ABCE1 participates in the proliferation and migration of LUADs by interacting with β-actin. The Fe-S clusters of ABCE1 may be potential targets for the prevention of lung cancer metastasis.

  11. A pilot study: sequential gemcitabine/cisplatin and icotinib as induction therapy for stage IIB to IIIA non-small-cell lung adenocarcinoma

    Science.gov (United States)

    2013-01-01

    Background A phase II clinical trial previously evaluated the sequential administration of erlotinib after chemotherapy for advanced non-small-cell lung cancer (NSCLC). This current pilot study assessed the feasibility of sequential induction therapy in patients with stage IIB to IIIA NSCLC adenocarcinoma. Methods Patients received gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 75 mg/m2 on day 1, followed by oral icotinib (125 mg, three times a day) on days 15 to 28. A repeatcomputed tomography(CT) scan evaluated the response to the induction treatment after two 4-week cycles and eligible patients underwent surgical resection. The primary objective was to assess the objective response rate (ORR), while EGFR and KRAS mutations and mRNA and protein expression levels of ERCC1 and RRM1 were analyzed in tumor tissues and blood samples. Results Eleven patients, most with stage IIIA disease, completed preoperative treatment. Five patients achieved partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (ORR=45%) and six patients underwent resection. Common toxicities included neutropenia, alanine transaminase (ALT) elevation, fatigue, dry skin, rash, nausea, alopecia and anorexia. No serious complications were recorded perioperatively. Three patients had exon 19 deletions and those with EGFR mutations were more likely to achieve a clinical response (P= 0.083). Furthermore, most cases who achieved a clinical response had low levels of ERCC1 expression and high levels of RRM1. Conclusions Two cycles of sequentially administered gemcitabine/cisplatin with icotinib as an induction treatment is a feasible and efficacious approach for stage IIB to IIIA NSCLC adenocarcinoma, which provides evidence for the further investigation of these chemotherapeutic and molecularly targeted therapies. PMID:23621919

  12. Randomized Phase II Trial of Erlotinib Alone or With Carboplatin and Paclitaxel in Patients Who Were Never or Light Former Smokers With Advanced Lung Adenocarcinoma: CALGB 30406 Trial

    Science.gov (United States)

    Jänne, Pasi A.; Wang, Xiaofei; Socinski, Mark A.; Crawford, Jeffrey; Stinchcombe, Thomas E.; Gu, Lin; Capelletti, Marzia; Edelman, Martin J.; Villalona-Calero, Miguel A.; Kratzke, Robert; Vokes, Everett E.; Miller, Vincent A.

    2012-01-01

    Purpose Erlotinib is clinically effective in patients with non–small-cell lung cancer (NSCLC) who have adenocarcinoma, are never or limited former smokers, or have EGFR mutant tumors. We investigated the efficacy of erlotinib alone or in combination with chemotherapy in patients with these characteristics. Patients and Methods Patients with advanced NSCLC (adenocarcinoma) who were epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy naive never or light former smokers (smokers of > 100 cigarettes and ≤ 10 pack years and quit ≥ 1 year ago) were randomly assigned to continuous erlotinib or in combination with carboplatin and paclitaxel (ECP) for six cycles followed by erlotinib alone. The primary end point was progression-free survival (PFS). Tissue collection was mandatory. Results PFS was similar (5.0 v 6.6 months; P = .1988) in patients randomly assigned to erlotinib alone (arm A; n = 81) or to ECP (arm B; n = 100). EGFR mutation analysis was possible in 91% (164 of 181) of patients, and EGFR mutations were detected in 40% (51 of 128) of never smokers and in 42% (15 of 36) of light former smokers. In arm A, response rate (70% v 9%), PFS (14.1 v 2.6 months), and overall survival (OS; 31.3 v 18.1 month) favored EGFR-mutant patients. In arm B, response rate (73% v 30%), PFS (17.2 v 4.8 months), and OS (38.1 v 14.4 months) favored EGFR-mutant patients. Incidence of grades 3 to 4 hematologic (2% v 49%; P < .001) and nonhematologic (24% v 52%; P < .001) toxicity was greater in patients treated with ECP. Conclusion Erlotinib and erlotinib plus chemotherapy have similar efficacy in clinically selected populations of patients with advanced NSCLC. EGFR mutations identify patients most likely to benefit. PMID:22547605

  13. Lipid peroxidation in radiation pneumonitis in mouse lung and its preventation

    International Nuclear Information System (INIS)

    Kodama, Akihisa; Tsujino, Kayoko; Kono, Michio

    1998-01-01

    Lipid peroxidation of the lung in irradiated C57BL6J mice was analyzed by gas chromatography. Among six major fatty acids in the mouse lung tissue, the amounts of two unsaturated fatty acids, arachidonic acid and DHA reduced one day after irradiation, and then recovered up to the level of in the control group four weeks after irradiation. In contrast, the amounts of stearic and palmitic acid did not change significantly. The mice fed with vitamin E-enriched food showed no significant changes of fatty acids which were compatible with pathophysiological findings 4 weeks after irradiation. Reduction of both arachidonic acid and DHA following lipid peroxidation in lung tissue, was assumed to play an important role in development of radiation pneumonitis. Vitamin E seems to enable to prevent or reduce the occurrence and progression of radiation pneumonitis, but as a radical scavenger, it may also weaken the anti-tumor growth effect of low linear energy transfer (LET) irradiation as photon. (author)

  14. Double-hit mouse model of cigarette smoke priming for acute lung injury.

    Science.gov (United States)

    Sakhatskyy, Pavlo; Wang, Zhengke; Borgas, Diana; Lomas-Neira, Joanne; Chen, Yaping; Ayala, Alfred; Rounds, Sharon; Lu, Qing

    2017-01-01

    Epidemiological studies indicate that cigarette smoking (CS) increases the risk and severity of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). The mechanism is not understood, at least in part because of lack of animal models that reproduce the key features of the CS priming process. In this study, using two strains of mice, we characterized a double-hit mouse model of ALI induced by CS priming of injury caused by lipopolysaccharide (LPS). C57BL/6 and AKR mice were preexposed to CS briefly (3 h) or subacutely (3 wk) before intratracheal instillation of LPS and ALI was assessed 18 h after LPS administration by measuring lung static compliance, lung edema, vascular permeability, inflammation, and alveolar apoptosis. We found that as little as 3 h of exposure to CS enhanced LPS-induced ALI in both strains of mice. Similar exacerbating effects were observed after 3 wk of preexposure to CS. However, there was a strain difference in susceptibility to CS priming for ALI, with a greater effect in AKR mice. The key features we observed suggest that 3 wk of CS preexposure of AKR mice is a reproducible, clinically relevant animal model that is useful for studying mechanisms and treatment of CS priming for a second-hit-induced ALI. Our data also support the concept that increased susceptibility to ALI/ARDS is an important adverse health consequence of CS exposure that needs to be taken into consideration when treating critically ill individuals.

  15. Clinical and radiological characteristics of central pulmonary adenocarcinoma: a comparison with central squamous cell carcinoma and small cell lung cancer and the impact on treatment response

    Directory of Open Access Journals (Sweden)

    Wang Z

    2018-05-01

    Full Text Available Zhe Wang,1,2 Minghuan Li,2 Yong Huang,3 Li Ma,3 Hui Zhu,2 Li Kong,2 Jinming Yu2 1School of Medicine, Shandong University, Jinan, Shandong, China; 2Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong, China; 3Department of Radiology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong, China Purpose: The proportion of central pulmonary adenocarcinoma (ADC in central-type lung cancer has been gradually increasing due to the overall increasing incidence of pulmonary ADC. But the clinical and radiological characteristics of central ADCs remain unclear. In this study, we compared the clinical and radiological characteristics of central ADCs with those of small cell lung cancers (SCLCs and squamous cell carcinomas (SQCCs and investigated the impact of these characteristics on patients’ treatment response. Patients and methods: The medical records of 302 consecutive patients with central lung cancer from July 2014 to September 2016 were retrospectively reviewed. There were 99 patients with ADC, 95 with SQCC and 108 with SCLC. Computed tomography images were interpreted by two radiologists. Treatment response was determined by Response Evaluation Criteria In Solid Tumors 1.1. Results: Univariate analyses found that younger age, female sex, no history of smoking, higher levels of carcinoembryonic antigen (CEA, contralateral hilum lymphadenopathy, contralateral lung metastasis, pleural nodules and pleural metastasis to the interlobular fissure were significantly correlated with central ADC. Multivariate logistic regression analyses revealed that compared with central SQCC, female sex, younger age, no history of smoking, higher levels of CEA and contralateral hilum lymphadenopathy were the significantly independent indicators of central pulmonary ADC. Furthermore, compared with central SCLC, younger age, higher levels of CEA and cytokeratin 19 fragment (Cyfra21-1, lower

  16. Prognostic impact of initial maximum standardized uptake value of 18F-FDG PET/CT on treatment response in patients with metastatic lung adenocarcinoma treated with erlotinib

    Directory of Open Access Journals (Sweden)

    Kus T

    2015-12-01

    Full Text Available Tulay Kus,1 Gokmen Aktas,1 Alper Sevinc,1 Mehmet Emin Kalender,1 Mustafa Yilmaz,2 Seval Kul,3 Serdar Oztuzcu,4 Cemil Oktay,5 Celaletdin Camci1 1Department of Internal Medicine, Division of Medical Oncology, Gaziantep Oncology Hospital, 2Department of Nuclear Medicine, 3Department of Biostatistics, Faculty of Medicine, 4Department of Medical Biology, Faculty of Medicine, University of Gaziantep, Gaziantep, 5Department of Radiology, Faculty of Medicine, University of Akdeniz, Antalya, Turkey Purpose: To investigate whether the initial maximum standardized uptake value (SUVmax on fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT has a prognostic significance in metastatic lung adenocarcinoma.Patients and methods: Sixty patients (24 females, mean age: 57.9±12 years with metastatic stage lung adenocarcinoma who used erlotinib and underwent 18F-FDG PET/CT at the time of diagnosis between May 2010 and May 2014 were enrolled in this retrospective study. The patients were stratified according to the median SUVmax value, which was found as 11. Progression-free survival (PFS rates for 3, 6, and 12 months were examined for SUVmax values and epidermal growth factor receptor (EGFR mutation status.Results: The number of EGFR-sensitizing mutation positive/negative/unknown was 26/17/17, respectively, and the number of patients using erlotinib at first-line, second-line, and third-line therapy was 15, 31, and 14 consecutively. The PFS rates of EGFR mutation positive, negative, and unknown patients for 3 months were 73.1%, 35.3%, and 41.2% (P=0.026, odds ratio [OR]=4.39; 95% confidence interval [CI]: 1.45–13.26, respectively. The PFS rates of EGFR positive, negative, and unknown patients for 6 months were 50%, 29.4%, and 29.4% (P=0.267, OR: 2.4; 95% CI: 0.82–6.96, respectively. The PFS rates of EGFR positive, negative, and unknown patients for 12 months were 42.3%, 29.4%, 23.5% (P=0.408, OR: 2.0; 95% CI: 0.42

  17. Survival significance of epidermal growth factor receptor tyrosine kinase inhibitors and current staging system for survival after recurrence in patients with completely resected lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Saji H

    2017-08-01

    Full Text Available Hisashi Saji,1,2 Hiroki Sakai,1 Hiroyuki Kimura,1 Tomoyuki Miyazawa,1 Hideki Marushima,1 Haruhiko Nakamura1 1Department of Chest Surgery, St Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa, Japan; 2Department of Thoracic Surgery, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan Objective: We previously reported that the staging system and epidermal growth factor receptor (EGFR mutation status are key factors for treatment strategy and predicting survival. However, the significance of these factors as predictors of overall survival (OS and postoperative recurrence survival (PRS has not been sufficiently elucidated. The objective here was to investigate EGFR mutation status and p-stage, which affect PRS and OS in patients with completely resected lung adenocarcinoma, using a different database.Patients and methods: We retrospectively reviewed 56 consecutive lung adenocarcinoma patients with disease recurrence in St. Marianna University Hospital between January 2010 and December 2014.Results: EGFR mutants (M were detected in 16/56 patients (29%. The patients with EGFR M had a better OS than those with EGFR wild-type (WT status (5-year survival: 50.3% vs 43.1, P=0.133. There was no significant difference in the 3-year recurrence-free survival rate between patients with M and WT (6.3% vs 7.7%, P=0.656, and the patients with EGFR M had a significantly better 3-year PRS than those with WT (77.4% vs 51.7%, P=0.033. The 3-year PRS rate for patients with M/pathologic stage (p-stage I–II (87.5% was better than that for patients with M/p-stage III (60.0%, WT/p-stage I–II (52.7%, and WT/p-stage III (43.8%. There was a significant difference between patients with M/p-stage I and WT/p-stage I–II or WT/p-stage III (P=0.021 and 0.030, respectively. During the study period, of the 16 patients with mutants, 12 patients (75% received EGFR-tyrosine kinase inhibitor (TKI therapy and among the 40 patients with WT, no patient received

  18. Detection of ROS1 Gene Rearrangement in Lung Adenocarcinoma: Comparison of IHC, FISH and Real-Time RT-PCR

    OpenAIRE

    Shan, Ling; Lian, Fang; Guo, Lei; Qiu, Tian; Ling, Yun; Ying, Jianming; Lin, Dongmei

    2015-01-01

    Aims To compare fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and quantitative real-time reverse transcription-PCR (qRT-PCR) assays for detection of ROS1 fusion in a large number of ROS1-positive lung adenocatcinoma (ADC) patients. Methods Using IHC analysis, sixty lung ADCs including 16 cases with ROS1 protein expression and 44 cases without ROS1 expression were selected for this study. The ROS1 fusion status was examined by FISH and qRT-PCR assay. Results Among 60 ca...

  19. Dissecting epigenetic silencing complexity in the mouse lung cancer suppressor gene Cadm1.

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    Stella Marie Reamon-Buettner

    Full Text Available Disease-oriented functional analysis of epigenetic factors and their regulatory mechanisms in aberrant silencing is a prerequisite for better diagnostics and therapy. Yet, the precise mechanisms are still unclear and