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Sample records for invasive non-small cell

  1. Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44.

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    Dohadwala, M; Luo, J; Zhu, L; Lin, Y; Dougherty, G J; Sharma, S; Huang, M; Pold, M; Batra, R K; Dubinett, S M

    2001-06-15

    Elevated tumor cyclooxygenase (COX-2) expression is associated with increased angiogenesis, tumor invasion, and suppression of host immunity. We have previously shown that genetic inhibition of tumor COX-2 expression reverses the immunosuppression induced by non-small cell lung cancer (NSCLC). To assess the impact of COX-2 expression in lung cancer invasiveness, NSCLC cell lines were transduced with a retroviral vector expressing the human COX-2 cDNA in the sense (COX-2-S) and antisense (COX-2-AS) orientations. COX-2-S clones expressed significantly more COX-2 protein, produced 10-fold more prostaglandin E(2), and demonstrated an enhanced invasive capacity compared with control vector-transduced or parental cells. CD44, the cell surface receptor for hyaluronate, was overexpressed in COX-2-S cells, and specific blockade of CD44 significantly decreased tumor cell invasion. In contrast, COX-2-AS clones had a very limited capacity for invasion and showed diminished expression of CD44. These findings suggest that a COX-2-mediated, CD44-dependent pathway is operative in NSCLC invasion. Because tumor COX-2 expression appears to have a multifaceted role in conferring the malignant phenotype, COX-2 may be an important target for gene or pharmacologic therapy in NSCLC.

  2. miR-1271 promotes non-small-cell lung cancer cell proliferation and invasion via targeting HOXA5

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    Wang, Yongfang; Xu, Lianhong; Jiang, Lixin, E-mail: jianglx66766@163.com

    2015-03-13

    MicroRNAs (miRNAs) are short, non-coding RNAs (∼22 nt) that play important roles in the pathogenesis of human diseases by negatively regulating numerous target genes at posttranscriptional level. However, the role of microRNAs in lung cancer, particularly non-small-cell lung cancer (NSCLC), has remained elusive. In this study, two microRNAs, miR-1271 and miR-628, and their predicted target genes were identified differentially expressed in NSCLC by analyzing the miRNA and mRNA expression data from NSCLC tissues and their matching normal controls. miR-1271 and its target gene HOXA5 were selected for further investigation. CCK-8 proliferation assay showed that the cell proliferation was promoted by miR-1271 in NSCLC cells, while miR-1271 inhibitor could significantly inhibited the proliferation of NSCLC cells. Interestingly, migration and invasion assay indicated that overexpression of miR-1271 could significantly promoted the migration and invasion of NSCLC cells, whereas miR-1271 inhibitor could inhibited both cell migration and invasion of NSCLC cells. Western blot showed that miR-1271 suppressed the protein level of HOXA5, and luciferase assays confirmed that miR-1271 directly bound to the 3'untranslated region of HOXA5. This study indicated indicate that miR-1271 regulates NSCLC cell proliferation and invasion, via the down-regulation of HOXA5. Thus, miR-1271 may represent a potential therapeutic target for NSCLC intervention. - Highlights: • Overexpression of miR-1271 promoted proliferation and invasion of NSCLC cells. • miR-1271 inhibitor inhibited the proliferation and invasion of NSCLC cells. • miR-1271 targets 3′ UTR of HOXA5 in NSCLC cells. • miR-1271 negatively regulates HOXA5 in NSCLC cells.

  3. MicroRNA-211 promotes non-small-cell lung cancer proliferation and invasion by targeting MxA

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    Kang M

    2017-11-01

    Full Text Available Mafei Kang, Jieqiong Shi, Na Peng, Shaozhong He Department of Medical Oncology, Affiliated Hospital of Guilin Medical College, Guilin, People’s Republic of China Abstract: Recent studies have shown that microRNAs play a pivotal role in the pathogenesis of cancer. In our current study, the expression levels of microRNA-211 (miR-211 were measured in human non-small-cell lung cancer (NSCLC tissues and cell lines. We found that miR-211 expression levels were increased in NSCLC tissues and cell lines and that the overexpression of miR-211 promotes cell proliferation and invasion. Using bioinformatics, we demonstrated that miR-211 binds to the 3'-untranslated region of MxA and overexpression of miR-211 suppresses the expression of MxA at both the transcriptional and translational levels in NSCLC cell lines. Furthermore, knockdown of MxA increased the proliferation and invasion of NSCLC cell lines in vitro. High levels of miR-211 expression were associated with a shorter survival time in patients with NSCLC. Taken together, these results suggest that miR-211 promotes tumor proliferation and invasion by regulating MxA expression in NSCLC. This study provides insights into molecular mechanisms of miR-211-mediated tumorigenesis and oncogenesis. Keywords: miR-211, MxA, non-small-cell lung cancer, proliferation, invasion

  4. Placenta-specific protein 1 promotes cell proliferation and invasion in non-small cell lung cancer

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    Yang, Li; Zha, Tian-Qi; He, Xiang; Chen, Liang; Zhu, Quan; Wu, Wei-Bing; Nie, Feng-Qi; Wang, Qian; Zang, Chong-Shuang; Zhang, Mei-Ling; He, Jing; Li, Wei; Jiang, Wen; Lu, Kai-Hua

    2018-01-01

    Pulmonary carcinoma-associated proteins have emerged as crucial players in governing fundamental biological processes such as cell proliferation, apoptosis and metastasis in human cancers. Placenta-specific protein 1 (PLAC1) is a cancer-related protein, which is activated and upregulated in a variety of malignant tissues, including prostate cancer, gastric adenocarcinoma, colorectal, epithelial ovarian and breast cancer. However, its biological role and clinical significance in non-small cell lung cancer (NSCLC) development and progression are still unknown. In the present study, we found that PLAC1 was significantly upregulated in NSCLC tissues, and its expression level was associated with advanced pathological stage and it was also correlated with shorter progression-free survival of lung cancer patients. Furthermore, knockdown of PLAC1 expression by siRNA inhibited cell proliferation, induced apoptosis and impaired invasive ability in NSCLC cells partly via regulation of epithelial-mesenchymal transition (EMT)-related protein expression. Our findings present that increased PLAC1 could be identified as a negative prognostic biomarker in NSCLC and regulate cell proliferation and invasion. Thus, we conclusively demonstrated that PLAC1 plays a key role in NSCLC development and progression, which may provide novel insights on the function of tumor-related gene-driven tumorigenesis. PMID:29138842

  5. Long noncoding RNA LINC00961 inhibits cell invasion and metastasis in human non-small cell lung cancer.

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    Jiang, Bin; Liu, Jing; Zhang, Yu-Hong; Shen, Dong; Liu, Shaoping; Lin, Feng; Su, Jun; Lin, Qing-Feng; Yan, Shuai; Li, Yong; Mao, Wei-Dong; Liu, Zhi-Li

    2018-01-01

    Long noncoding RNAs (LncRNAs) expression has been found to be misregulated in multiple human cancers, and a growing number of studies have revealed that lncRNAs can function as important oncogenes or tumor suppressors. In this study, we identified a lncRNA-LINC00961, which was significantly down-regulated in human non-small cell lung cancer tissues. Decreased LINC00961 was associated with NSCLC patients advanced clinical stage, lymph node metastasis, and shorter survival time. Further experiments demonstrated that LSD1 could directly bind to LINC00961 promoter regions and epigenetically repress its transcription in NSCLC cells. Moreover, MTT assays showed that LINC00961 had no influence on NSCLC cell proliferation. Ectopic overexpression of LINC00961 inhibits NSCLC cell migration, invasion in vitro and metastasis in vivo. Finally, qRT-PCR and western blot assays revealed that LINC00961 could act as a tumor suppressor partially via affecting β-catenin expression. Collectively, decreased LINC00961 might play a key role in NSCLC progression, and may serve as a novel prognostic marker in human NSCLC. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Punica granatum (pomegranate) leaves extract induces apoptosis through mitochondrial intrinsic pathway and inhibits migration and invasion in non-small cell lung cancer in vitro.

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    Li, Yali; Yang, Fangfang; Zheng, Weidong; Hu, Mingxing; Wang, Juanxiu; Ma, Sisi; Deng, Yuanle; Luo, Yi; Ye, Tinghong; Yin, Wenya

    2016-05-01

    Most conventional treatments on non-small cell lung carcinoma always accompany with awful side effects, and the incidence and mortality rates of this cancer are increasing rapidly worldwide. The objective of this study was to examine the anticancer effects of extract of Punica granatum (pomegranate) leaves extract (PLE) on the non-small cell lung carcinoma cell line A549, H1299 and mouse Lewis lung carcinoma cell line LL/2 in vitro, and explore its mechanisms of action. Our results have shown that PLE inhibited cell proliferation in non-small cell lung carcinoma cell line in a concentration- and time-dependent manner. Flow cytometry (FCM) assay showed that PLE affected H1299 cell survival by arresting cell cycle progression in G2/M phase in a dose-dependent manner and inducing apoptosis. Moreover, PLE could also decrease the reactive oxygen species (ROS) and the mitochondrial membrane potential (ΔYm), indicating that PLE may induce apoptosis via mitochondria-mediated apoptotic pathway. Furthermore, PLE blocked H1299 cell migration and invasion, and the reduction of matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression were also observed in vitro. These results suggested that PLE could be an effective and safe chemotherapeutic agent in non-small cell lung carcinoma treatment by inhibiting proliferation, inducing apoptosis, cell cycle arrest and impairing cell migration and invasion. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  7. Podophyllotoxin acetate blocks IR-induced invasion of non-small cell lung cancer cell, A549

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    Cho, Jeong Hyun; Choi, Jae Yeon; Hwang, Sang-Gu; Um, Hong-Duck; Park, Jong Kuk [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2015-05-15

    Some research result presented that local radiotherapy administered to primary tumors speeds their metastatic growth in vivo (4-6), thereby suggesting that besides its therapeutic effects, IR promotes the malignant behaviors of surviving cancer cells. Our findings demonstrate podophyllotoxin acetate (PA), one of new natural products, prevented side effects of IR such as invasion or metastasis promotion for improve the efficacy of radiotherapy. In this study, we demonstrated that PA inhibits IR-induced invasion and migration of A549 cells. We also observed that IR stimulates several intracellular pathway involving EMT and MAPKinses; EMT-associated events including an increase of vimentin levels and increased phosphorylation of p38 ERK, JNK in A549 cells. PA could decrease these activations of several intracellular signaling molecules. Therefore, PA might inhibit IRinduced invasion and migration via blocking EMT and MAPKiase pathway of A549 cells.

  8. FPPS mediates TGF-β1-induced non-small cell lung cancer cell invasion and the EMT process via the RhoA/Rock1 pathway.

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    Lin, Lin; Li, Ming; Lin, Lei; Xu, Xiaolin; Jiang, Gening; Wu, Liang

    2018-02-05

    Farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway, was recently shown to play a role in cancer progression. However, its role in non-small cell lung cancer (NSCLC) metastasis and the underlying mechanism remain unclear. In this study, FPPS expression was significantly correlated with TNM stage, and metastasis. Inhibition or knockdown of FPPS blocked TGF-β1-induced cell invasion and epithelial-to-mesenchymal transition (EMT) process. FPPS expression of FPPS was induced by TGF-β1 and FPPS promoted cell invasion and EMT via the RhoA/Rock1 pathway. In conclusion, FPPS mediates TGF-β1-induced lung cancer cell invasion and EMT via the RhoA/Rock1 pathway. These findings suggest new treatment strategies to reduce mortality associated with metastasis in patients with NSCLC. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. Lung cancer - non-small cell

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    Cancer - lung - non-small cell; Non-small cell lung cancer; NSCLC; Adenocarcinoma - lung; Squamous cell carcinoma - lung ... Smoking causes most cases (around 90%) of lung cancer. The risk depends on the number of cigarettes ...

  10. PED interacts with Rac1 and regulates cell migration/invasion processes in human non-small cell lung cancer cells.

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    Zanca, Ciro; Cozzolino, Flora; Quintavalle, Cristina; Di Costanzo, Stefania; Ricci-Vitiani, Lucia; Santoriello, Margherita; Monti, Maria; Pucci, Piero; Condorelli, Gerolama

    2010-10-01

    PED (phosphoprotein enriched in diabetes) is a 15 kDa protein involved in many cellular pathways and human diseases including type II diabetes and cancer. We recently reported that PED is overexpressed in human cancers and mediates resistance to induced apoptosis. To better understand its role in cancer, we investigated on PED interactome in non-small cell lung cancer (NSCLC). By the Tandem Affinity Purification (TAP), we identified and characterized among others, Rac1, a member of mammalian Rho GTPase protein family, as PED-interacting protein. In this study we show that PED coadiuvates Rac1 activation by regulating AKT mediated Rac1-Ser(71) phosphorylation. Furthermore, we show that the expression of a constitutively active Rac, affected PED-Ser(104) phosphorylation, which is important for PED-regulated ERK 1/2 nuclear localization. Through specific Rac1-siRNA or its pharmacological inhibition, we demonstrate that PED augments migration and invasion in a Rac1-dependent manner in NSCLC. In conclusion, we show for the first time that PED and Rac1 interact and that this interaction modulates cell migration/invasion processes in cancer cells through ERK1/2 pathway. (c) 2010 Wiley-Liss, Inc.

  11. Ski prevents TGF-β-induced EMT and cell invasion by repressing SMAD-dependent signaling in non-small cell lung cancer.

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    Yang, Haiping; Zhan, Lei; Yang, Tianjie; Wang, Longqiang; Li, Chang; Zhao, Jun; Lei, Zhe; Li, Xiangdong; Zhang, Hong-Tao

    2015-07-01

    Epithelial-mesenchymal transition (EMT) is a key event in cancer metastasis, which confers cancer cells with increased motility and invasiveness, and EMT is characterized by loss of epithelial marker E-cadherin and gain of mesenchymal marker N-cadherin. Transforming growth factor-β (TGF-β) signaling is a crucial inducer of EMT in various types of cancer. Ski is an important negative regulator of TGF-β signaling, which interacts with SMADs to repress TGF-β signaling activity. Although there is accumulating evidence that Ski functions as a promoter or suppressor in human types of cancer, the molecular mechanisms by which Ski affects TGF-β-induced EMT and invasion in non-small cell lung cancer (NSCLC) are not largely elucidated. In the present study, we investigated the mechanistic role of Ski in NSCLC metastasis. Ski was significantly reduced in metastatic NSCLC cells or tissues when compared with non-metastatic NSCLC cells or tissues. Moreover, following TGF-β stimulation Ski-silenced A549 cells had more significant features of EMT and a higher invasive activity when compared with A549 cells overexpressing Ski. Mechanistically, Ski-silenced and overexpressed A549 cells showed an increase and a reduction in the SMAD3 phosphorylation level, respectively. This was supported by plasminogen activator inhibitor-1 (PAI-1) promoter activity obtained in Ski-silenced and overexpressed A549 cells. However, after treatment of SIS3 (inhibitor of SMAD3 phosphorylation) followed by TGF-β1 stimulation, we did not observe any effect of Ski on TGF-β-induced EMT, and invasion in Ski-silenced and overexpressed A549 cells. In conclusion, our findings suggest that Ski represses TGF-β-induced EMT and invasion by inhibiting SMAD-dependent signaling in NSCLC.

  12. Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cells regulates matrix metalloproteinase-2 and CD44 in cyclooxygenase-2-dependent invasion.

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    Dohadwala, Mariam; Batra, Raj K; Luo, Jie; Lin, Ying; Krysan, Kostyantyn; Pold, Mehis; Sharma, Sherven; Dubinett, Steven M

    2002-12-27

    Tumor cyclooxygenase-2 (COX-2) expression is known to be associated with enhanced tumor invasiveness. In the present study, we evaluated the importance of the COX-2 product prostaglandin E2 (PGE2) and its signaling through the EP4 receptor in mediating non-small cell lung cancer (NSCLC) invasiveness. Genetic inhibition of tumor COX-2 led to diminished matrix metalloproteinase (MMP)-2, CD44, and EP4 receptor expression and invasion. Treatment of NSCLC cells with exogenous 16,16-dimethylprostaglandin E2 significantly increased EP4 receptor, CD44, and MMP-2 expression and matrigel invasion. In contrast, anti-PGE2 decreased EP4 receptor, CD44, and MMP-2 expression in NSCLC cells. EP4 receptor signaling was found to be central to this process, because antisense oligonucleotide-mediated inhibition of tumor cell EP4 receptors significantly decreased CD44 expression. In addition, agents that increased intracellular cAMP, as is typical of EP4 receptor signaling, markedly increased CD44 expression. Moreover, MMP-2-AS treatment decreased PGE2-mediated CD44 expression, and CD44-AS treatment decreased MMP-2 expression. Thus, PGE2-mediated effects through EP4 required the parallel induction of both CD44 and MMP-2 expression because genetic inhibition of either MMP-2 or CD44 expression effectively blocked PGE2-mediated invasion in NSCLC. These findings indicate that PGE2 regulates COX-2-dependent, CD44- and MMP-2-mediated invasion in NSCLC in an autocrine/paracrine manner via EP receptor signaling. Thus, blocking PGE2 production or activity by genetic or pharmacological interventions may prove to be beneficial in chemoprevention or treatment of NSCLC.

  13. Human papillomavirus type 16 E6 oncoprotein promotes proliferation and invasion of non-small cell lung cancer cells through Toll-like receptor 3 signaling pathway.

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    Wang, Xia; Zhang, Zhiqiang; Cao, Huimin; Niu, Wenyi; Li, Mingying; Xi, Xiu'e; Wang, Jing

    2017-10-01

    Human papillomavirus (HPV) oncoproteins play vital roles in non-small cell lung cancer (NSCLC) pathogenesis, and Toll-like receptors (TLRs) contribute to tumor progression. However, interaction between HPV oncoproteins and TLR signaling in NSCLC progression remains unclear. Thus, the aim of the study was to explore effects of HPV16 E6 oncoprotein-induced TLRs pathway on growth and invasion of NSCLC cells and to examine potential mechanisms being involved. Recombinant plasmid (pcDNA-HPV16 E6) expressing HPV16 E6 protein was constructed. The expression prolife of TLRs was measured in NSCLC cell line A549 with or without pcDNA-HPV16 E6 transfection by real-time reverse polymerase chain reaction and Western blot. Cellular proliferation, invasion, cytokine productions, and downstream signaling pathways were also examined in TLR3-silencing/pcDNA-HPV16 E6 transfect A549 cells. Overexpression of HPV16 E6 increased proliferation, invasion, proliferation cytokine secretion, and TLR3 expression of A549 cells, while TLR3 silence inhibited HPV16 E6-induced tumor bioactivities of A549 cells. Down-regulation of TLR3 suppressed HPV16 E6-induced phosphorylation of Src, but did not affect TRIF expression. Moreover, inhibition of Src pathway also suppressed proliferation and invasion of A549 cells. In conclusion, HPV16 E6 oncoprotein promoted the bioactivities of NSCLC cells. TLR3-Src signaling pathway might be involved in this procession by up-regulation of cytokine production. The interaction between HPV16 E6 protein and TLR3 might contribute to the poor prognosis of NSCLC. © 2017 Wiley Periodicals, Inc.

  14. HER2 induces cell proliferation and invasion of non-small-cell lung cancer by upregulating COX-2 expression via MEK/ERK signaling pathway

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    Chi F

    2016-05-01

    Full Text Available Feng Chi, Rong Wu, Xueying Jin, Min Jiang, Xike Zhu Department of Medical Oncology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China Abstract: HER2 positivity has been well studied in various cancers, but its importance in non-small-cell lung cancer (NSCLC is still being explored. In this study, quantitative reverse transcription polymerase chain reaction (qRT-PCR was performed to detect HER2 and COX-2 expression in NSCLC tissues. Then, pcDNA3.1-HER2 was used to overexpress HER2, while HER2 siRNA and COX-2 siRNA were used to silence HER2 and COX-2 expression. MTT assay and invasion assay were used to detect the effects of HER2 on cell proliferation and invasion. Our study revealed that HER2 and COX-2 expression were upregulated in NSCLC tissues and HER2 exhibited a significant positive correlation with the levels of COX-2 expression. Overexpression of HER2 evidently elevated COX-2 expression, while silencing of HER2 evidently decreased COX-2 expression. Furthermore, overexpressed HER2 induced the ERK phosphorylation, and this was abolished by the treatment with U0126, a pharmacological inhibitor of MEK, an upstream kinase of ERK. HER2-induced expression and promoter activity of COX-2 were also suppressed by U0126, suggesting that the MEK/ERK signaling pathway regulates COX-2 expression. In addition, HER2 induced activation of AKT signaling pathway, which was reversed by pretreatment with U0126 and COX-2 siRNA. MTT and invasion assays revealed that HER2 induced cell proliferation and invasion that were reversed by pretreatment with U0126 and COX-2 siRNA. In this study, our results demonstrated for the first time that HER2 elevated COX-2 expression through the activation of MEK/ERK pathway, which subsequently induced cell proliferation and invasion via AKT pathway in NSCLC tissues. Keywords: HER2, MEK/ERK, COX-2, AKT signaling pathway, non-small-cell lung cancer

  15. hsa-miR-125a-5p Enhances Invasion Ability in Non-Small Lung Carcinoma Cell Lines

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    Enhua WANG

    2009-09-01

    Full Text Available Background and objective MicroRNAs (miRNAs are short non-coding RNAs that posttranscriptionally regulate gene expression by partially binding complementary to target sites in mRNAs. Although some impaired miRNA regulations have been observed in many human cancers, the functions of miR-125a are still unclear. The aim of this study is to investigate the expression of hsa-miR-125a-5p in NSCLC cell lines and the relationship between hsa-miR-125a-5p and the invasion of lung cancer cells. Methods The expression of hsa-miR-125a-5p and the effectiveness for a given period time after being transfected sense hsa-miR-125a-5p 2’-O-methyl oligonucleotide, which were 24 h, 36 h, 48 h, 60 h and 72 h, were examined by realtime PCR. Meanwhile, we investigated the modification of invasive ability in A549 and NCI-H460 cells by transwell. Results Real-time PCR showed that hsa-miR-125a-5p was poorly-expressed in 6 lung cancer cell lines, especially in LH7, NCI-H460, SPC-A-1 and A549. The highest expression of hsa-miR-125a-5p occurred in the cells transfected with sense hsa-miR-125a-5p 2’-O-methyl oligonucleotide 36 h. Furthermore, the invasive abilities of A549 and NCI-H46O were enhanced by up-regulating hsa-miR-125a-5p. Conclusion hsa-miR-125a-5p was poorly-expressed in lung cancer cells and it could enhance lung cancer cell invasion by up-regulating hsa-miR-125a-5p.

  16. A Preclinical Evaluation of Antrodia camphorata Alcohol Extracts in the Treatment of Non-Small Cell Lung Cancer Using Non-Invasive Molecular Imaging

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    Jeng-Feng Chiou

    2011-01-01

    Full Text Available This study was carried out to provide a platform for the pre-clinical evaluation of anti-cancer properties of a unique CAM (complementary and alternative medicine agent, Antrodia camphorata alcohol extract (ACAE, in a mouse model with the advantageous non-invasive in vivo bioluminescence molecular imaging technology. In vitro analyses on the proliferation, migration/invasion, cell cycle and apoptosis were performed on ACAE-treated non-small cell lung cancer cells, H441GL and control CGL1 cells. In vivo, immune-deficient mice were inoculated subcutaneously with H441GL followed by oral gavages of ACAE. The effect of ACAE on tumor progression was monitored by non-invasive bioluminescence imaging. The proliferation and migration/invasion of H441GL cells were inhibited by ACAE in a dose-dependent manner. In addition, ACAE induced cell cycle arrest at G0/G1 phase and apoptosis in H441GL cells as shown by flow cytometric analysis, Annexin-V immunoflourescence and DNA fragmentation. In vivo bioluminescence imaging revealed that tumorigenesis was significantly retarded by oral treatment of ACAE in a dose-dependent fashion. Based on our experimental data, ACAE contains anti-cancer properties and could be considered as a potential CAM agent in future clinical evaluation.

  17. The role of cytochrome c oxidase subunit Va in non-small cell lung carcinoma cells: association with migration, invasion and prediction of distant metastasis

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    Chen Wen-Liang

    2012-06-01

    Full Text Available Abstract Background Lung cancer is one of the most lethal malignancies worldwide, but useful biomarkers of lung cancer are still insufficient. The aim of this study is to identify some membrane-bound protein(s associated with migration and invasion in human non-small cell lung cancer (NSCLC cells. Methods We classified four NSCLC cell lines into high and low migration/invasion groups by Transwell and Matrigel assays. Using two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS, we identified 10 membrane-associated proteins being significantly overexpressed in the high migration/invasion group. The expression of the target protein in the four NSCLC cell lines was then confirmed by reverse transcription polymerase chain reaction (RT-PCR, western blot and immunostaining. RNA interference technique was applied to observe the influence of the target protein on migration and invasion. Gelatin zymography was also performed to evaluate the activities of matrix metalloproteinase (MMP-2 and MMP-9. Expression condition of the target protein on surgical specimens was further examined by immunohistochemical staining and the clinicopathologic data were analyzed. Results We identified a mitochondria-bound protein cytochrome c oxidase subunit Va (COX Va because of its abundant presence found exclusively in tumorous areas. We also demonstrated that migration and invasion of NSCLC cells decreased substantially after knocking down COX Va by siRNA. Meanwhile, we found a positive correlation between COX Va expression, Bcl-2 expression and activities of MMP-2 and MMP-9 in NSCLC cells. Immunohistochemical staining of surgically resected lung adenocarcinomas in 250 consecutive patients revealed that strong COX Va expression was found in 54.8% (137/250 of patients and correlated positively with the status of lymph node metastasis (P = 0.032. Furthermore, strong COX Va expression was

  18. The role of cytochrome c oxidase subunit Va in non-small cell lung carcinoma cells: association with migration, invasion and prediction of distant metastasis

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    Chen, Wen-Liang; Kuo, Kuang-Tai; Chou, Teh-Ying; Chen, Chien-Lung; Wang, Chih-Hao; Wei, Yau-Huei; Wang, Liang-Shun

    2012-01-01

    Lung cancer is one of the most lethal malignancies worldwide, but useful biomarkers of lung cancer are still insufficient. The aim of this study is to identify some membrane-bound protein(s) associated with migration and invasion in human non-small cell lung cancer (NSCLC) cells. We classified four NSCLC cell lines into high and low migration/invasion groups by Transwell and Matrigel assays. Using two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), we identified 10 membrane-associated proteins being significantly overexpressed in the high migration/invasion group. The expression of the target protein in the four NSCLC cell lines was then confirmed by reverse transcription polymerase chain reaction (RT-PCR), western blot and immunostaining. RNA interference technique was applied to observe the influence of the target protein on migration and invasion. Gelatin zymography was also performed to evaluate the activities of matrix metalloproteinase (MMP)-2 and MMP-9. Expression condition of the target protein on surgical specimens was further examined by immunohistochemical staining and the clinicopathologic data were analyzed. We identified a mitochondria-bound protein cytochrome c oxidase subunit Va (COX Va) because of its abundant presence found exclusively in tumorous areas. We also demonstrated that migration and invasion of NSCLC cells decreased substantially after knocking down COX Va by siRNA. Meanwhile, we found a positive correlation between COX Va expression, Bcl-2 expression and activities of MMP-2 and MMP-9 in NSCLC cells. Immunohistochemical staining of surgically resected lung adenocarcinomas in 250 consecutive patients revealed that strong COX Va expression was found in 54.8% (137/250) of patients and correlated positively with the status of lymph node metastasis (P = 0.032). Furthermore, strong COX Va expression was associated with the presence of distant metastasis (P = 0

  19. p0071 interacts with E-cadherin in the cytoplasm so as to promote the invasion and metastasis of non-small cell lung cancer.

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    Zhao, Huanyu; Zhang, Di; Yang, Lianhe; Wang, Enhua

    2018-01-01

    As a member of the p120-catenin (p120ctn) subfamily, the p0071 study in tumor is very limited. We demonstrated the clinicopathological significance of p0071 in non-small cell lung cancer (NSCLC), as well as E-cadherin. Co-immunoprecipitation was used to detect the interaction of p0071 with E-cadherin in A549 and SPC cells (E-cadherin is mainly expressed in the cytoplasm of these cells). p0071 cytoplasmic expression was knocked down by siRNA in these cells and this effect on the RhoA activity and cell invasion and migration ability were measured. p0071 overexpression in the cytoplasm of tumor cell was correlated with lymphatic metastase and poor prognosis of NSCLC. The patients with both abnormal expression of p0071 and E-cadherin (cytoplasmic expression) had a statistically significant shorter survival than the patients without both abnormal expression (P  E-cadherin in NSCLC tissues. p0071 interacted with E-cadherin in the cytoplasm of A549 and SPC cell lines. Treatment with siRNA-p0071 inhibited the invasion and migration ability of NSCLC cells. Above results confirmed that p0071 interacted with E-cadherin in the cytoplasm so as to promote the invasion and metastasis of NSCLC. © 2017 Wiley Periodicals, Inc.

  20. Hesperidin suppresses the migration and invasion of non-small cell lung cancer cells by inhibiting the SDF-1/CXCR-4 pathway.

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    Xia, Rongmu; Xu, Gang; Huang, Yue; Sheng, Xin; Xu, Xianlin; Lu, Hongling

    2018-03-28

    of CXCR-4. Subsequent RT-qPCR and western blot analyses also confirmed that hesperidin had a significant effect on the expression of EMT-related proteins, including MMP-9, CK-19 and Vimentin, in A549 cells. In summary, we demonstrated that hesperidin inhibited the migratory and invasive capabilities of A549 human non-small cell lung cancer cells by the mediation of the SDF-1/CXCR-4 signaling cascade, thus providing the foundation for the development of hesperidin as a safer and more effective anticancer drug for non-small cell lung cancer. Copyright © 2017. Published by Elsevier Inc.

  1. Combined Effects of Suberoylanilide Hydroxamic Acid and Cisplatin on Radiation Sensitivity and Cancer Cell Invasion in Non-Small Cell Lung Cancer.

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    Feng, Jianguo; Zhang, Shirong; Wu, Kan; Wang, Bing; Wong, Jeffrey Y C; Jiang, Hong; Xu, Rujun; Ying, Lisha; Huang, Haixiu; Zheng, Xiaoliang; Chen, Xufeng; Ma, Shenglin

    2016-05-01

    Lung cancer is a leading cause of cancer-related mortality worldwide, and concurrent chemoradiotherapy has been explored as a therapeutic option. However, the chemotherapeutic agents cannot be administered for most patients at full doses safely with radical doses of thoracic radiation, and further optimizations of the chemotherapy regimen to be given with radiation are needed. In this study, we examined the effects of suberoylanilide hydroxamic acid (SAHA) and cisplatin on DNA damage repairs, and determined the combination effects of SAHA and cisplatin on human non-small cell lung cancer (NSCLC) cells in response to treatment of ionizing radiation (IR), and on tumor growth of lung cancer H460 xenografts receiving radiotherapy. We also investigated the potential differentiation effect of SAHA and its consequences on cancer cell invasion. Our results showed that SAHA and cisplatin compromise distinct DNA damage repair pathways, and treatment with SAHA enhanced synergistic radiosensitization effects of cisplatin in established NSCLC cell lines in a p53-independent manner, and decreased the DNA damage repair capability in cisplatin-treated primary NSCLC tumor tissues in response to IR. SAHA combined with cisplatin also significantly increased inhibitory effect of radiotherapy on tumor growth in the mouse xenograft model. In addition, SAHA can induce differentiation in stem cell-like cancer cell population, reduce tumorigenicity, and decrease invasiveness of human lung cancer cells. In conclusion, our data suggest a potential clinical impact for SAHA as a radiosensitizer and as a part of a chemoradiotherapy regimen for NSCLC. Mol Cancer Ther; 15(5); 842-53. ©2016 AACR. ©2016 American Association for Cancer Research.

  2. The HLJ1-targeting drug screening identified Chinese herb andrographolide that can suppress tumour growth and invasion in non-small-cell lung cancer.

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    Lai, Yi-Hua; Yu, Sung-Liang; Chen, Hsuan-Yu; Wang, Chi-Chung; Chen, Huei-Wen; Chen, Jeremy J W

    2013-05-01

    HLJ1 is a novel tumour suppressor and is a potential druggable target for non-small-cell lung cancer (NSCLC). In this report, using a promoter-containing enhancer region as the HLJ1-targeting drug-screening platform, we identified several herbal compounds from a Chinese herbal bank with the capacity to enhance HLJ1 promoter activity and suppress tumour growth and invasion of NSCLC. Among the herbal drugs identified, the andrographolide (from Andrographis paniculata [Burm. f.] Nees.) most significantly induced HLJ1 expression and suppressed tumorigenesis both in vitro and in vivo. The andrographolide upregulates HLJ1 via JunB activation, which modulates AP-2α binding at the MMP-2 promoter and represses the expression of MMP-2. In addition, silencing of HLJ1 partially reverses the inhibition of cancer-cell invasion by andrographolide. Microarray transcriptomic analysis was performed to comprehensively depict the andrographolide-regulated signalling pathways. We showed that andrographolide can affect 939 genes (analysis of variance, false discovery rate andrographolide on anticancer invasion and proliferation. In conclusion, the HLJ1-targeting drug-screening platform is useful for screening of novel anticancer compounds. Using this platform, we identified andrographolide is a promising new anticancer agent that could suppress tumour growth and invasion in NSCLC.

  3. Zinc finger protein 668 suppresses non-small cell lung cancer invasion and migration by downregulating Snail and upregulating E-cadherin and zonula occludens-1.

    Science.gov (United States)

    Zhang, Xiupeng; Jiang, Guiyang; Wu, Jingjing; Zhou, Haijing; Zhang, Yong; Miao, Yuan; Feng, Yangyang; Yu, Juanhan

    2018-03-01

    Zinc finger protein 668 (ZNF668) is a recently discovered protein and its expression levels, as well as its involvement in the invasion and metastasis of non-small cell lung cancer (NSCLC), are largely unknown. In the present study, immunohistochemical analysis demonstrated that ZNF668 protein expression was decreased in lung tumors (51/167, 30.5%) compared with adjacent normal lung tissues (43/62, 69.4%; P<0.001). Subsequent statistical analysis revealed that ZNF668 expression was negatively associated with increased tumor-node-metastasis stage (P=0.019) and lymph node metastasis (P=0.002). Following ZNF668 downregulation by transfection of a ZNF668 -expressing plasmid or small interfering RNA, it was demonstrated that ZNF668 inhibited the invasion and migration of NSCLC cells. Furthermore, restoration of ZNF668 expression downregulated the expression of Snail and increased the protein levels of epithelial (E-)cadherin and zonula occludens-1 (ZO-1). The results of the present study suggest that ZNF668 is downregulated in human NSCLC. Furthermore, restoration of ZNF668 expression was demonstrated to decrease the expression of Snail and increase the expression of E-cadherin and ZO-1, suppressing the invasion and migration of NSCLC cells.

  4. Role of MiR-3619-5p in β-Catenin-Mediated Non-Small Cell Lung Cancer Growth and Invasion

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    Xuecai Niu

    2015-10-01

    Full Text Available Background/Aims: The malignancy of non-small cell lung cancer (NSCLC is largely due to its fast growth and invasion. WNT/β-catenin signaling plays a critical role in regulating NSCLC carcinogenesis. Hence, suppression of β-catenin signal transduction in NSCLC cells may improve the therapeutic outcome. Methods: We analyzed the levels of β-catenin and miR-3619-5p in NSCLC specimens, compared to paired non-tumor normal lung tissue (NT. We did Bioinformatics analyses on the binding sites of 3'-UTR of β-catenin mRNA by miR-3619-5p. We modified the levels of miR-3619-5p in NSCLC cells and examined their effects on β-catenin levels, and on the growth and invasion of NSCLC cells in an MTT assay and a transwell cell migration assay, respectively. Results: NSCLC specimens had significant higher levels of β-catenin, and significantly lower levels of miR-3619-5p, compared to NT. The levels of β-catenin and miR-3619-5p were inversely correlated in NSCLC specimens. Bioinformatics analyses showed that miR-3619-5p bound to 3'-UTR of β-catenin mRNA in NSCLC cells to inhibit its translation. Overexpression of miR-3619-5p decreased β-catenin protein, while depletion of miR-3619-5p increased β-catenin protein in NSCLC cells, without altering β-catenin mRNA levels. Overexpression of miR-3619-5p in NSCLC cells inhibited cell growth and invasion, while depletion of miR-3619-5p in NSCLC lines increased cell growth and invasion. Conclusion: Our data demonstrate a previously unappreciated role for miR-3619-5p in suppression of β-catenin-mediated cancer growth and invasion in NSCLC cells, and highlight miR-3619-5p as a novel cancer suppressor in NSCLC.

  5. Residual tumor after laser ablation of human non-small-cell lung cancer demonstrated by ex vivo staining: correlation with invasive temperature measurements.

    Science.gov (United States)

    Hoffmann, Christian Oliver Martin; Rosenberg, Christian; Linder, Albert; Hosten, Norbert

    2012-02-01

    Histology is the gold standard for confirming thermally induced necrosis. Generally, however, no specimen is obtained from thermal ablation therapy for pathological examination. The aim of this study was to provide evidence for the relationship between temperatures reached and resulting tissue coagulation during laser ablation in a near-physiological ex vivo lung tumor model by combining viability staining and direct temperature measurement. In all, 17 human lung specimens with primary non-small-cell lung cancer (NSCLC) were examined in this study. Organs were resected with curative intent from patients of either gender (5 female, 12 male) with an average age of 65 years (51-78). Here, 11/17 specimens were subjected to interstitial laser thermal ablation in an ex vivo lung perfusion and ventilation model after surgery. A control group of 6/17 specimens was tested for viability without laser ablation. Tissue temperature was measured invasively in real-time during the ablation process using thermocouples. Afterwards, representative slices of all 17 specimens were tested for viability with triphenyltetrazolium chloride (TTC). Maximum tissue temperature Tmax[°C] measured at a distance of 10 and 20 mm from the laser tip and time of temperature exposure were correlated with the diameter of the induced coagulation as ascertained with viability staining. CH evaluated the results. Mean maximum temperature was 75.9°C ± 14.4°C at a distance of 10 mm from the laser tip and 50.3°C ± 14.6°C at a distance of 20 mm, respectively. The mean distance between the coagulation margin and the laser tip was 17.8 mm ± 7.3 mm. We found that coagulation size correlated positively with temperature. There was a clear trend towards the correlation of time over 44°C and ablation depth. Maximum temperatures did not significantly correlate with coagulation size. Laser ablation of lung tumors using the IHLP (isolated human lung perfusion) model represents a possible method for evaluating

  6. Hypoxia-inducible factor 1α (HIF-1α) and reactive oxygen species (ROS) mediates radiation-induced invasiveness through the SDF-1α/CXCR4 pathway in non-small cell lung carcinoma cells.

    Science.gov (United States)

    Gu, Qing; He, Yan; Ji, Jianfeng; Yao, Yifan; Shen, Wenhao; Luo, Jialin; Zhu, Wei; Cao, Han; Geng, Yangyang; Xu, Jing; Zhang, Shuyu; Cao, Jianping; Ding, Wei-Qun

    2015-05-10

    Radiotherapy is an important procedure for the treatment of inoperable non-small cell lung cancer (NSCLC). However, recent evidence has shown that irradiation can promote the invasion and metastasis of several types of cancer, and the underlying mechanisms are not fully understood. This study aimed to investigate the molecular mechanism by which radiation enhances the invasiveness of NSCLC cells. We found that after irradiation, hypoxia-inducible factor 1α (HIF-1α) was increased and translocated into the nucleus, where it bound to the hypoxia response element (HRE) in the CXCR4 promoter and promoted the transcription of CXCR4. Furthermore, reactive oxygen species (ROS) also plays a role in the radiation-induced expression of CXCR4. Our results revealed that 2 Gy X-ray irradiation promoted the metastasis and invasiveness of H1299, A549 and H460 cells, which were significantly enhanced by SDF-1α treatment. Blocking the SDF-1α/CXCR4 interaction could suppress the radiation-induced invasiveness of NSCLC cells. The PI3K/pAkt and MAPK/pERK1/2 pathways were found to be involved in radiation-induced matrix metalloproteinase (MMP) expression. In vivo, irradiation promoted the colonization of H1299 cells in the liver and lung, which was mediated by CXCR4. Altogether, our findings have elucidated the underlying mechanisms of the irradiation-enhanced invasiveness of NSCLC cells.

  7. MicroRNA-106b-25 cluster targets β-TRCP2, increases the expression of Snail and enhances cell migration and invasion in H1299 (non small cell lung cancer) cells

    Energy Technology Data Exchange (ETDEWEB)

    Savita, Udainiya; Karunagaran, Devarajan, E-mail: karuna@iitm.ac.in

    2013-05-17

    Highlights: •miR-106b-25 cluster directly targets the 3′UTR of the β-TRCP2 transcript. •β-TRCP2 mRNA was lower in H1299 cells stably expressing miR-106b-25 cluster. •miR-106b-25 cluster increased the expression of Snail. •miR-106b-25 cluster promoted the migration, colony formation and invasion. •miR-106b-25 cluster enhanced endothelial tube formation. -- Abstract: Lung cancer causes high mortality without a declining trend and non small cell lung cancer represents 85% of all pulmonary carcinomas. MicroRNAs (miRNAs) serve as fine regulators of proliferation, migration, invasion/metastasis and angiogenesis of normal and cancer cells. Using TargetScan6.2, we predicted that the ubiquitin ligase, β-TRCP2, could be a target for two of the constituent miRNAs of the miR-106b-25 cluster (miR-106b and miR-93). We generated a stable clone of miR-106b-25 cluster (CL) or the empty vector (EV) in H1299 (non small cell lung cancer) cells. The expression of β-TRCP2 mRNA was significantly lower in CL than that in EV cells. Transient expression of miR-93 but not antimiR-93 decreased the expression of β-TRCP2 mRNA in H1299 cells. β-TRCP2-3′UTR reporter assay revealed that its activity in CL cells was only 60% of that in EV cells. Snail protein expression was higher in CL than that in EV cells and H1299 cells exhibited an increase in the expression of Snail upon transient transfection with miR-93. miR-106b-25 cluster-induced migration of CL measured by scratch assay was more than that in EV cells and no significant difference in migration was observed between antimiR-93-transfected H1299 cells and the corresponding control-oligo-transfected cells. miR-106b-25 cluster-induced migration of CL cells was again confirmed in a Boyden chamber assay without the matrigel. CL cells were more invasive than EV cells when assessed using Boyden chambers with matrigel but there were no significant changes in the cell viabilities between EV and CL cells. Colony formation assay

  8. Gefitinib in Non Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Raffaele Costanzo

    2011-01-01

    Full Text Available Gefitinib is an oral, reversible, tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR that plays a key role in the biology of non small cell lung cancer (NSCLC. Phase I studies indicated that the recommended dose of gefitinib was 250 mg/day. Rash, diarrhea, and nausea were the most common adverse events. The positive results obtained in early phase 2 clinical trials with gefitinib were not confirmed in large phase 3 trials in unselected patients with advanced NSCLC. The subsequent discovery that the presence of somatic mutations in the kinase domain of EGFR strongly correlates with increased responsiveness to EGFR tyrosine kinase inhibitors prompted phase 2 and 3 trials with gefitinib in the first line-treatment of EGFR-mutated NSCLC. The results of these trials have demonstrated the efficacy of gefitinib that can be now considered as the standard first-line treatment of patients with advanced NSCLC harbouring activating EGFR mutations.

  9. Inhibitory Effects of Salinomycin on Cell Survival, Colony Growth, Migration, and Invasion of Human Non-Small Cell Lung Cancer A549 and LNM35: Involvement of NAG-1.

    Directory of Open Access Journals (Sweden)

    Kholoud Arafat

    Full Text Available A major challenge for oncologists and pharmacologists is to develop more potent and less toxic drugs that will decrease the tumor growth and improve the survival of lung cancer patients. Salinomycin is a polyether antibiotic used to kill gram-positive bacteria including mycobacteria, protozoans such as plasmodium falciparum, and the parasites responsible for the poultry disease coccidiosis. This old agent is now a serious anti-cancer drug candidate that selectively inhibits the growth of cancer stem cells. We investigated the impact of salinomycin on survival, colony growth, migration and invasion of the differentiated human non-small cell lung cancer lines LNM35 and A549. Salinomycin caused concentration- and time-dependent reduction in viability of LNM35 and A549 cells through a caspase 3/7-associated cell death pathway. Similarly, salinomycin (2.5-5 µM for 7 days significantly decreased the growth of LNM35 and A549 colonies in soft agar. Metastasis is the main cause of death related to lung cancer. In this context, salinomycin induced a time- and concentration-dependent inhibition of cell migration and invasion. We also demonstrated for the first time that salinomycin induced a marked increase in the expression of the pro-apoptotic protein NAG-1 leading to the inhibition of lung cancer cell invasion but not cell survival. These findings identify salinomycin as a promising novel therapeutic agent for lung cancer.

  10. Mediastinal staging of non-small-cell lung cancer among Australasian thoracic physicians: clinical practice and constraints on minimally invasive techniques.

    Science.gov (United States)

    Dabscheck, E J; Steinfort, D P; Irving, L B; Hew, M

    2012-06-01

    We determined current practice among Australasian thoracic physicians in the mediastinal staging of non-small-cell lung cancer (NSCLC). We focused on the availability of endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) and constraints to its use, as there has been no systematic analysis regarding the availability and uptake of this new technology among thoracic physicians. Physician members of the Thoracic Society of Australia and New Zealand were emailed a survey seeking their current approach to three scenarios requiring mediastinal staging of NSCLC. Respondents were also asked for their preferred investigation for each scenario if any current constraints were removed. Relevant demographic information was sought. We received 164 responses from 512 Australasian physicians (34%). Without constraints, EBUS-TBNA was the preferred investigation for all three clinical scenarios, but only 33% of respondents had access to EBUS-TBNA. Constraints included lack of availability and lack of expertise. Reduced EBUS-TBNA access was associated with a number of clinician factors. Australasian thoracic physicians prefer EBUS-TBNA for the mediastinal staging of NSCLC, but access to EBUS-TBNA services is limited. We recommend targeted measures to improve access to EBUS-TBNA use and optimise mediastinal staging of NSCLC. © 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.

  11. CD74-ROS1 G2032R mutation transcriptionally up-regulates Twist1 in non-small cell lung cancer cells leading to increased migration, invasion, and resistance to crizotinib.

    Science.gov (United States)

    Gou, Wenfeng; Zhou, Xuejiao; Liu, Zi; Wang, Lijing; Shen, Jiwei; Xu, Xiaobo; Li, Zengqiang; Zhai, Xin; Zuo, Daiying; Wu, Yingliang

    2018-02-23

    The c-ros oncogene 1 (ROS1) is a receptor tyrosine kinase, which has been identified as an oncogene driver of non-small-cell lung cancer (NSCLC). Although crizotinib has a prominent effect on ROS1, resistance is inevitable. Development of the acquired ROS1 G2032R mutation has been reported as a resistant mechanism to ROS1 inhibitors in ROS1-rearranged (ROS1 + ) NSCLC patients. To explore the mechanism of drug resistance, we constructed the crizotinib resistance cell line, A549-CD74-ROS1 G2032R mutation cells, by the methods of fusion polymerase chain reaction (PCR), plasmid construction and cell transfection in vitro. The results showed that the expression of CD74-ROS1 or CD74-ROS1 G2032R mutation in A549 cells induced epithelial-mesenchymal transition (EMT), dramatically enhanced the ability of invasion and migration, and increased expression of matrix metalloproteinase (MMP)-9 and Twist1 transcription factor. Moreover, we found that inhibition of Twist1 could reverse EMT induced by CD74-ROS1 G2032R mutation. Combination of Twist1 siRNA and crizotinib significantly reduced cell vitality, inhibited cell invasion and migration, and promoted apoptosis in A549-CD74-ROS1 G2032R mutation cells. Taken together, these results suggested that CD74-ROS1 G2032R mutation mediated EMT phenotype by increasing the expression of Twist1, resulting in drug resistance. Combination of Twist1 silence and ROS1 inhibitor may provide a potent strategy to treat the ROS1 + NSCLC patients with crizotinib resistance. Copyright © 2018 Elsevier B.V. All rights reserved.

  12. Erlotinib in previously treated non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Smrdel, U.; Kovac, V.

    2006-01-01

    Background. Erlotinib is a novel biological anti-tumour agent in the treatment of advanced non small cell lung cancer. It represents the molecularly-targeted therapy which has been studied extensively. Case report. We present a case of a patient who suffered from advanced non-small-cell lung cancer. After the progress of disease following a prior chemotherapy he was treated with erlotinib with remarkable effect which was shown at chest x ray and symptoms were quite reduced. Conclusions. In selected patients with advanced non-small-cell lung cancer Erlotinib improves survival and symptom control as it results in presented case. (author)

  13. MicroRNA-330-3p promotes cell invasion and metastasis in non-small cell lung cancer through GRIA3 by activating MAPK/ERK signaling pathway

    Directory of Open Access Journals (Sweden)

    Chun-Hua Wei

    2017-06-01

    Full Text Available Abstract Background Brain metastasis (BM is associated with poor prognosis in patients with non-small cell lung cancer (NSCLC. Recent studies demonstrated that microRNA-330-3p (miR-330-3p was involved in NSCLC brain metastasis (BM. However, the exact parts played by miR-330-3p in BM of NSCLC remain unknown. Discovery and development of biomarkers and elucidation of the mechanism underlying BM in NSCLC is critical for effective prophylactic interventions. Here, we evaluated the expression and biological effects of miR-330-3p in NSCLC cells and explored the underlying mechanism of miR-330-3p in promoting cell migration and invasion in NSCLC. Methods Stable over-expression and knockdown of miR-330-3p in NSCLC cells was constructed with lentivirus. Expression levels of miR-330-3p in NSCLC cells were quantified by quantitive real-time PCR (qRT-PCR. The effects of miR-330-3p on NSCLC cells were investigated using assays of cell viability, migration, invasion, cell cycle, apoptosis, western blotting, immunohistochemical, and immunofluorescence staining. A xenograft nude mouse model and in situ brain metastasis model were used to observe tumor growth and brain metastasis. The potential target of miR-330-3p in NSCLC cells was explored using the luciferase reporter assay, qRT-PCR, and western blotting. The miR-330-3p targets were identified using bioinformatics analysis and verified by luciferase reporter assay. The correlation between GRIA3 and DNA methyltransferase (DNMT 1 and DNMT3A was tested by RT-PCR, western blotting, and co-immunoprecipitation (IP. Results miR-330-3p was significantly up-regulated in NSCLC cell lines. MTT assay, transwell migration, and invasion assays showed that miR-330-3p promoted the growth, migration, and invasion of NSCLC cells in vitro and induced tumor growth and metastasis in vivo. Luciferase reporter assays showed that GRIA3 was a target of miR-330-3p. qRT-PCR and western blotting exhibited that miR-330-3p promoted the

  14. Long noncoding RNA HOTAIR, a hypoxia-inducible factor-1α activated driver of malignancy, enhances hypoxic cancer cell proliferation, migration, and invasion in non-small cell lung cancer.

    Science.gov (United States)

    Zhou, Chunxia; Ye, Lincai; Jiang, Chuan; Bai, Jie; Chi, Yongbin; Zhang, Haibo

    2015-12-01

    Despite the fact that great advances have been made in the management of non-small cell lung cancer (NSCLC), the prognosis of advanced NSCLC remains very poor. HOX transcript antisense intergenic RNA (HOTAIR) has been identified as an oncogenic long noncoding RNA (lncRNA) that is involved in the progression of a variety of carcinomas and acts as a negative prognostic biomarker. Yet, little is known about the effect of HOTAIR in the hypoxic microenvironment of NSCLC. The expression and promoter activity of HOTAIR were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and luciferase reporter assay. The function of the hypoxia-inducible factor-1α (HIF-1α) binding site to hypoxia-responsive elements (HREs) in the HOTAIR promoter region was tested by luciferase reporter assay with nucleotide substitutions. The binding of HIF-1α to the HOTAIR promoter in vivo was confirmed by chromatin immunoprecipitation assay (CHIP) and electrophoretic mobility shift assay (EMSA). The effect of HIF-1α suppression by small interference RNA or YC-1 on HOTAIR expression was also determined. In the present study, we demonstrated that HOTAIR was upregulated by hypoxia in NSCLC cells. HOTAIR is a direct target of HIF-1α through interaction with putative HREs in the upstream region of HOTAIR in NSCLC cells. Furthermore, HIF-1α knockdown or inhibition could prevent HOTAIR upregulation under hypoxic conditions. Under hypoxic conditions, HOTAIR enhanced cancer cell proliferation, migration, and invasion. These data suggested that suppression of HOTAIR upon hypoxia of NSCLC could be a novel therapeutic strategy.

  15. Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study

    OpenAIRE

    Morrow, C. J.; Trapani, F.; Metcalf, R. L.; Bertolini, G.; Hodgkinson, C. L.; Khandelwal, G.; Kelly, P.; Galvin, M.; Carter, L.; Simpson, K. L.; Williamson, S.; Wirth, C.; Simms, N.; Frankliln, L.; Frese, K. K.

    2016-01-01

    Background Over the past decade, numerous reports describe the generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling and preclinical drug testing, the requirement of a tissue biopsy limits the available patient population, particularly those with advanced oligometastatic disease. Conversely, ?liquid biopsies? such as circulating tumour cells (CTCs) are minimally invasive...

  16. Kaempferol modulates the metastasis of human non-small cell lung cancer cells by inhibiting epithelial-mesenchymal transition

    Directory of Open Access Journals (Sweden)

    Meng Hang

    2015-06-01

    Full Text Available The present study was done to determine whether kaempferol, a natural polyphenol of the flavonoid family, affects Epithelial-Mesenchymal Transition (EMT in non-small cell lung cancer cells. Kaempferol not only inhibited cancer cell proliferation and migration in a dose-dependent manner but also modulated the expression of EMT-related proteins E-cadherin and vimentin which are indispensible to cellular motility, invasiveness and metastasis. These results indicate that kaempferol suppresses non-small cell lung cancer migration by modulating the expression of EMT proteins. Therefore, kaempferol may be useful as a potential anticancer agent for non-small cell lung cancer.

  17. Results of surgical treatment of T4 non-small cell lung cancer

    NARCIS (Netherlands)

    Pitz, CCM; de la Riviere, AB; van Swieten, HA; Westermann, CJJ; Lammers, JWJ; van den Bosch, JMM

    2003-01-01

    Objective: Because of location and invasion of surrounding structures, the role of surgical treatment for T4 tumors remains unclear. Extended resections carry a high mortality and should be restricted for selected patients. This study clarifies the selection process in non-small cell T4 tumors with

  18. Tracking the Evolution of Non-Small-Cell Lung Cancer

    DEFF Research Database (Denmark)

    Jamal-Hanjani, Mariam; Wilson, Gareth A.; McGranahan, Nicholas

    2017-01-01

    Background Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the cl...

  19. Low-Dose Acetylsalicylic Acid in Treating Patients With Stage I-III Non-Small Cell Lung Cancer

    Science.gov (United States)

    2017-06-29

    Adenocarcinoma of the Lung; Recurrent Non-small Cell Lung Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  20. ICAM-3, radiation resistance gene, activates PI3K/Akt-CREB-MMPs pathway and promotes migration/invasion of the human non-small cell lung cancer cell NCI-H1299

    International Nuclear Information System (INIS)

    Park, Jong Kuk; Park, Seon Ho; Hong, Sung Hee; Um, Hong Duck; Yoo, Young Do

    2008-01-01

    Cancer cell is characterized by various distinctive functions difference from normal cell. The one of specific properties of cancer is invasion and metastasis. Invasion and metastasis is a multi-step process involving over-expression of proteolytic enzymes such as matrix metalloproteinases (MMPs) and critically dependent on the ability of cells to move away from the primary tumor to gain access to the vascular or lymphatic systems which disperses cells to distant sites, where they can grow in a permissive microenvironment at a secondary location. All of these processes are critically dependent upon the ability of cancer cells to breach the basement membrane and to migrate through neighboring tissues. Cancer cell invasion is an important, tightly regulated process that is related with development, immune response and wound healing. This invasive response is dependent on activation of signaling pathways that result in both short-term and long-term cellular responses. The gene expressions of the cancer cell invasion related-proteolytic enzymes are regulated at the transcriptional level (through AP-1 and NF-kB via mitogen activated protein kinases (MAPKs) and PI3K-Akt pathways) and post-transcriptional levels, and the protein level via their activators or inhibitors, and their cell surface localization. Therefore, the related proteins such as MMPs, MAPK, PI3K, Akt and their regulatory pathway have been considered as promising targets for anti-cancer drugs. In previous reports, Intercellular adherin molecule-3 (ICAM-3) showed increase of radio-resistance and proliferation. We have made ICAM-3 overexpressed cancer cells which shows elevated level of invasion compared with normal cancer cells and its invasion capacity was down regulated with treatment of specific inhibitor for PI3K. These results suggest that ICAM-3 related invasion is associated with PI3K signaling pathway

  1. Approach for oligometastasis in non-small cell lung cancer.

    Science.gov (United States)

    Suzuki, Hidemi; Yoshino, Ichiro

    2016-04-01

    Non-small cell lung cancer (NSCLC) harboring a limited number of distant metastases, referred to as the oligometastatic state, has been indicated for surgery for the past several decades. However, whether the strategy of surgical treatment results in a survival benefit for such patients remains controversial. Experientially, however, thoracic surgeons often encounter long-term survivors among surgically resected oligometastatic NSCLC patients. In this article, the current situation of surgical approach and potential future perspective for oligometastatic NSCLC are reviewed.

  2. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T. [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Aftab, Blake T. [Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Rudin, Charles M. [Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Tran, Phuoc T. [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Hales, Russell K., E-mail: rhales1@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

    2013-05-01

    Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras{sup G12D}-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.

  3. MiR-122 Induces Radiosensitization in Non-Small Cell Lung Cancer Cell Line

    Directory of Open Access Journals (Sweden)

    Debin Ma

    2015-09-01

    Full Text Available MiR-122 is a novel tumor suppresser and its expression induces cell cycle arrest, or apoptosis, and inhibits cell proliferation in multiple cancer cells, including non-small cell lung cancer (NSCLC cells. Radioresistance of cancer cell leads to the major drawback of radiotherapy for NSCLC and the induction of radiosensitization could be a useful strategy to fix this problem. The present work investigates the function of miR-122 in inducing radiosensitization in A549 cell, a type of NSCLC cells. MiR-122 induces the radiosensitization of A549 cells. MiR-122 also boosts the inhibitory activity of ionizing radiation (IR on cancer cell anchor-independent growth and invasion. Moreover, miR-122 reduced the expression of its targeted genes related to tumor-survival or cellular stress response. These results indicate that miR-122 would be a novel strategy for NSCLC radiation-therapy.

  4. Overexpression of SAMD9 suppresses tumorigenesis and progression during non small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Qing; Yu, Tao; Ren, Yao-Yao; Gong, Ting; Zhong, Dian-Sheng, E-mail: zhongdsyx@126.com

    2014-11-07

    Highlights: • SAMD9 is down-regulated in human non-small cell lung cancer (NSCLC). • Knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro. • Overexpression of SAMD9 suppressed proliferation and invasion in A549 cells in vitro. • Depletion of SAMD9 increases tumor formation in vivo. - Abstract: The Sterile Alpha Motif Domain-containing 9 (SAMD9) gene has been recently emphasized during the discovery that it is expressed at a lower level in aggressive fibromatosis and some cases of breast and colon cancer, however, the underlying mechanisms are poorly understood. Here, we found that SAMD9 is down-regulated in human non-small cell lung cancer (NSCLC). Furthermore, knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro and overexpression of SAMD9 suppressed proliferation and invasion in A549 cells. Finally, depletion of SAMD9 increases tumor formation in vivo. Our results may provide a strategy for blocking NSCLC tumorigenesis and progression.

  5. Oligometastatic non-small-cell lung cancer: current treatment strategies

    Directory of Open Access Journals (Sweden)

    Richard PJ

    2016-11-01

    Full Text Available Patrick J Richard, Ramesh Rengan Department of Radiation Oncology, University of Washington, Seattle, WA, USA Abstract: The oligometastatic disease theory was initially described in 1995 by Hellman and Weichselbaum. Since then, much work has been performed to investigate its existence in many solid tumors. This has led to subclassifications of stage IV cancer, which could redefine our treatment approaches and the therapeutic outcomes for this historically “incurable” entity. With a high incidence of stage IV disease, non-small-cell lung cancer (NSCLC remains a difficult cancer to treat and cure. Recent work has proven the existence of an oligometastatic state in NSCLC in terms of properly selecting patients who may benefit from aggressive therapy and experience long-term overall survival. This review discusses the current treatment approaches used in oligometastatic NSCLC and provides the evidence and rationale for each approach. The prognostic factors of many trials are discussed, which can be used to properly select patients for aggressive treatment regimens. Future advances in both molecular profiling of NSCLC to find targetable mutations and investigating patient selection may increase the number of patients diagnosed with oligometastatic NSCLC. As this disease entity increases, it is of utmost importance for oncologists treating NSCLC to be aware of the current treatment strategies that exist and the potential advantages/disadvantages of each. Keywords: oligometastatic, non-small-cell lung cancer, oligoprogressive, treatment

  6. Detection of circulating tumor cells in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Annkathrin eHanssen

    2015-09-01

    Full Text Available Lung Cancer is the most common cause of cancer related deaths that frequently metastasizes prior to disease diagnosis. Circulating tumor cells (CTCs are found in many different types of epithelial tumors and are of great clinical interest in terms of prognosis and therapy intervention. Here, we present and discuss EpCAM-dependent and -independent capture of CTCs in non-small cell lung cancer (NSCLC and the clinical relevance of CTC detection and characterization. Taking blood samples and analyzing CTCs as liquid biopsy might be a far less invasive diagnostic strategy than biopsies of lung tumors or metastases. Moreover, sequential blood sampling allows to study the dynamic changes of tumor cells during therapy, in particular the development of resistant tumor cell clones.

  7. Non-small-cell lung cancer in the elderly.

    Science.gov (United States)

    Meriggi, Fausto; Zaniboni, Alberto

    2006-02-01

    The world population is getting increasingly older. In Western countries, lung cancer in the most frequent cancer and more than 50% of patients who contract non-small-cell lung cancer (NSCLC) are close to 70 years old. It is therefore fundamentally important that we identify an overall strategy of screening, diagnosis and therapy designed specifically for elderly patients. NSCLC research still has relatively little material dedicated exclusively to the elderly, but recently interest has been growing, possibly due to the positive results of the most recent trials (Elderly Lung Cancer Vinorelbine Study Group (ELVIS), Southern Italy Cooperative Oncology Group (SICOG), Multicenter Italian Lung Cancer in the Elderly Study (MILES)). In particular, the integration of geriatric and oncological information has led to better recognition of elderly candidates for more aggressive therapy which is usually reserved for younger patients, while recognizing more fragile patients who need only support therapy.

  8. Progress in Immunotherapy for Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Yan XU

    2014-01-01

    Full Text Available In recent years, the five-year survival rate of patients with advanced stage non-small cell lung cancer (NSCLC remains low despite recent advances in surgery, irradiation, chemotherapy, and targeted therapy. Immunotherapy which utilizes the immune system to control and eradicate cancer is a viable treatment approach for malignancy. Immunotherapy in patients with lung cancer has made breakthrough progress recently. Novel immunotherapeutic agents, such as antigen-specific tumour vaccines, checkpoint inhibitors, etc, have all been evaluated in lung cancer, and some have shown prolonged survival time in phase II trials and III trails. The immune-related response criteria for the evaluation of antitumor responses with immunotherapeutic agents have been made. Now, immunotherapy will likely be a fundamentally new concept for the treatment of NSCLC.

  9. Management of non-small cell lung cancer with oligometastasis.

    Science.gov (United States)

    Villaruz, Liza C; Kubicek, Gregory J; Socinski, Mark A

    2012-08-01

    Patients with oligometastatic Non-Small Cell Lung Cancer (NSCLC) present a potential opportunity for curative therapy; however, the challenge remains the definitive treatment of their localized disease and ablation of their limited overt metastatic sites of disease. In selecting patients with oligometastatic NSCLC for definitive therapy, proper staging through radiographic studies, including PET and brain MRI, and the pathologic staging of the mediastinal lymph nodes and potential sites of metastatic disease, are critical. With that in mind, the available literature suggests that in highly selected patients with solitary metastases to the brain, adrenals and other organs, long term survival may be achieved with combined definitive therapy of both the primary lung tumor and the solitary metastatic site.

  10. Prognostic factors in resected satellite-nodule T4 non-small cell lung cancer.

    Science.gov (United States)

    Rao, Jagan; Sayeed, Rana A; Tomaszek, Sandra; Fischer, Stefan; Keshavjee, Shaf; Darling, Gail E

    2007-09-01

    The 1997 non-small cell lung cancer staging revisions assigned a T4 descriptor to satellite nodules in the primary tumor lobe. We reviewed our experience of satellite-nodule T4 non-small cell lung cancer following these revisions and evaluated prognostic factors for this group. All patients who underwent resection of non-small cell lung cancer between April 1997 and June 2005 with satellite nodule(s) confirmed at pathologic examination were identified from our institutional Lung Tumor Registry. Case notes and pathology reports were reviewed and data collected on possible prognostic factors. Survival was modeled using the Kaplan-Meier method, and survival differences between groups were analyzed using the log-rank test. From 1,276 non-small cell lung cancer patients who underwent resection, 137 were staged pT4, and 35 were T4-satellite nodules. Median follow-up was 25 months (range, 1 to 102 months). Median main tumor size was 3.0 cm (range, 1 to 9.8 cm). Adenocarcinoma or bronchioloalveolar carcinoma was the predominant histologic diagnosis (n = 28; 80%). One-, 3- and 5-year survival was 86%, 69%, and 57%, respectively; median survival was 68 months. During the same period, 137 patients undergoing resection for all T4 lesions had a 1-, 3-, and 5-year survival of 68%, 53%, and 18%, respectively. Adenocarcinoma or bronchioloalveolar carcinoma histologic diagnosis (adenocarcinoma or bronchioloalveolar carcinoma versus squamous, 75% versus 67% 3-year survival; p = 0.0026), female gender (66% versus 49% for males, 5-year survival; p = 0.041), and absence of vascular invasion (no invasion versus vascular invasion, 74% versus 20% 5-year survival; p = 0.0101) were significant predictors of better survival. Survival for resected T4 non-small cell lung cancer with satellite nodule(s) in the primary lobe is better than for other T4 lesions, and the T4 descriptor may unduly upstage these cases. The current T4 descriptor represents a heterogeneous population.

  11. Non-Small Cell Carcinoma Biomarker Testing: The Pathologist's Perspective.

    Directory of Open Access Journals (Sweden)

    Elisa eBrega

    2014-07-01

    Full Text Available Biomarker testing has become standard of care for patients diagnosed with non-small cell lung cancer. Although it can be successfully performed in circulating tu-mor cells, at present, the vast majority of investigations are carried out using di-rect tumor sampling, either through aspiration methods, which render most often isolated cells, or tissue sampling, that could range from minute biopsies to large resections. Consequently, pathologists play a central role in this process. Recent evidence suggests that refining NSCLC diagnosis might be clinically signifi-cant, particularly in cases of lung adenocarcinomas (ADC, which in turn, has prompted a new proposal for the histologic classification of such pulmonary neo-plasms. These changes, in conjunction with the mandatory incorporation of biomarker testing in routine NSCLC tissue processing, have directly affected the pathologist’s role in lung cancer work-up. This new role pathologists must play is complex and demanding, and requires a close interaction with surgeons, oncologists, radiologists and molecular pathologists. Pathologists often find themselves as the central figure in the coordination of a process, that involves assuring that the tumor samples are properly fixed, but without disruption of the DNA structure, obtaining the proper diagnosis with a minimum of tissue waste, providing pre-analytical evaluation of tumor samples selected for biomarker testing, which includes assessment of the proportion of tumor to normal tissues, as well as cell viability, and assuring that this entire pro-cess happens in a timely fashion. Therefore, it is part of the pathologist’s respon-sibilities to assure that the samples received in their laboratories, be processed in a manner that allows for optimal biomarker testing. This article goal is to discuss the essential role pathologists must play NSCLC bi-omarker testing, as well as to provide a summarized review of the main NSCLC bi-omarkers of

  12. [Non-small cell lung cancer irradiation in elderly].

    Science.gov (United States)

    Dupic, G; Bellière-Calandry, A

    2016-06-01

    People over the age of 65 are often excluded from participation in oncological clinical trials. However, more than half of patients diagnosed with non-small-cell lung cancer are older than 65 years. Any therapeutic strategy must be discussed in multidisciplinary meetings after adapted geriatric assessment. Patients who benefit from the comprehensive geriatric assessment (CGA) of Balducci and Extermann are those whose G8 screening tool score is less than or equal to 14. Age itself does not contraindicate a curative therapeutic approach. Stereotactic radiotherapy is an alternative to surgery for early stages in elderly patients who are medically inoperable or who refuse surgery, because it significantly increases overall survival. Mostly sequential (rarely concomitant) chemoradiotherapy can be proposed to elderly patients with locally advanced stages in good general state of health. For the others, an exclusive palliative radiotherapy, a single or dual agent of chemotherapy, a targeted drug or best supportive care only may be discussed. Copyright © 2016. Published by Elsevier SAS.

  13. Health state utilities for non small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Bhalla Shkun

    2008-10-01

    Full Text Available Abstract Background Existing reports of utility values for metastatic non-small cell lung cancer (NSCLC vary quite widely and are not all suitable for use in submissions in the UK. The aim of this study was to elicit UK societal based utility values for different stages of NSCLC and different grade III-IV toxicities commonly associated with chemotherapy treatments. Toxicities included neutropenia, febrile neutropenia, fatigue, diarrhoea, nausea and vomiting, rash and hair loss. Methods Existing health state descriptions of metastatic breast cancer were revised to make them suitable as descriptions of metastatic NSCLC patients on second-line treatment. The existing health states were used in cognitive debrief interviews with oncologists (n = 5 and oncology specialist nurses (n = 5. Changes were made as suggested by the clinical experts. The resulting health states (n = 17 were piloted and used in a societal based valuation study (n = 100. Participants rated half of the total health states in a standard gamble interview to derive health state utility scores. Data were analysed using a mixed model analysis. Results Each health state described the symptom burden of disease and impact on different levels of functioning (physical, emotional, sexual, and social. The disutility related to each disease state and toxicity was estimated and were combined to give health state values. All disease states and toxicities were independent significant predictors of utility (p Conclusion This study reflects the value that society place on the avoidance of disease progression and severe toxicities in NSCLC.

  14. Cetuximab and biomarkers in non-small-cell lung carcinoma

    Directory of Open Access Journals (Sweden)

    Patil N

    2012-07-01

    Full Text Available Nitin Patil, Mohammed Abba, Heike AllgayerDepartment of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg and Molecular Oncology of Solid Tumors Unit, German Cancer Research Center (DKFZ, Heidelberg, GermanyAbstract: Cancer progression is a highly complex process that is driven by a constellation of deregulated signaling pathways and key molecular events. In non-small-cell lung cancer (NSCLC, as in several other cancer types, the epidermal growth factor receptor (EGFR and its downstream signaling components represent a key axis that has been found not only to trigger cancer progression but also to support advanced disease leading to metastasis. Two major therapeutic approaches comprising monoclonal antibodies and small molecule tyrosine kinase inhibitors have so far been used to target this pathway, with a combination of positive, negative, and inconsequential results, as judged by patient survival indices. Since these drugs are expensive and not all patients derive benefits from taking them, it has become both pertinent and paramount to identify biomarkers that can predict not only beneficial response but also resistance. This review focuses on the chimeric monoclonal antibody, cetuximab, its application in the treatment of NSCLC, and the biomarkers that may guide its use in the clinical setting. A special emphasis is placed on the EGFR, including its structural and mechanistic attributes.Keywords: NSCLC, cetuximab, biomarker, cancer progression

  15. MEDI 4736 (durvalumab) in non-small cell lung cancer.

    Science.gov (United States)

    Jeanson, Arnaud; Barlesi, Fabrice

    2017-10-01

    Immune checkpoint inhibitors (ICI) are now a therapeutic option for advanced non-small cell lung cancer (NSCLC) patients. ICI, such as the PD-1 inhibitors nivolumab and pembrolizumab and the PD-L1 inhibitor atezolizumab, have already been marketed for the treatment of pretreated patients with advanced NSCLC. Other notable PD-L1 inhibitors under development include avelumab and durvalumab. Areas covered: This article reviews literature on durvalumab development, from the preclinical data to the results of phase III clinical trials, whether published or presented at international scientific conferences. Ongoing clinical trials were also reviewed. Expert opinion: Early phase trials of durvalumab monotherapy (and in combination) have demonstrated activity in advanced NSCLC patients and it has demonstrated a good safety profile. The authors believe that durvalumab will likely play an important role in future treatment strategies for NSCLC. The PACIFIC trial assessing durvalumab after standard chemoradiotherapy for locally advanced NSCLC has already met its primary endpoint and the potential of durvalumab will be reinforced if phase III randomized studies of first-line (MYSTIC trial) and second or subsequent (ARCTIC trial) lines of therapy demonstrate superiority over the current standard of care.

  16. [Computed tomography imaging of non-small cell lung cancer].

    Science.gov (United States)

    Chassagnon, G; Bennani, S; Revel, M P

    2016-10-01

    Computed tomography (CT) plays a key role in the initial evaluation of non-small cell lung cancer. It allows initial staging and helps targeting lesions for pathological analysis. The aim of initial imaging work-up is to differentiate between localized disease, eligible to a local treatment, and advanced disease requiring medical treatment. CT is very useful for the assessment of local extension but is less accurate than positron emission tomography (PET)-CT for the assessment of lymphatic and metastatic spread. However, initial staging should include CT examination of the brain and upper abdomen, and PET-CT should be only be performed in patients eligible to a local treatment after initial CT assessment. Propositions for the 8th edition of lung cancer TNM bring several changes for T staging. In particular, the weight of lesion size is increased. Similarly, N1 and N2 stages are now divided in subgroups according the number of involved stations. Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  17. Non small cell carcinoma of the lung: a retrospective study

    International Nuclear Information System (INIS)

    Stevens, G.; Firth, I.

    1992-01-01

    A retrospective study was undertaken in 1990 of 188 patients with the diagnosis of non small cell carcinoma of the lung referred to the Department of Radiation Oncology in 1984. Most patients (178 out of 188) received a course of radiotherapy. This was definitive in 23, palliative in 148 (primary site in 113, metastases in 16, primary plus metastases in 19) and postoperative in 7. This report is a 5 year follow-up of the 171 patients treated by radiation alone, to assess factors that influence survival. Palliative intent of treatment and poorer performance status were related significantly to increasing stage of disease. The effects of palliative treatment were recorded in 79 cases: in 71 there was a reduction in symptoms. The median survival from diagnosis was 8 months. Using univariate and multi-variate analyses, significant and independent prognostic factors for improved survival were good performance status, absence of systemic symptoms, lower tumour stage and curative intent of treatment (higher radiation dose). However the 5-year survival was only 2%. Long-term survival was associated predominantly with early stage disease but not with the type or intent of treatment. Age, sex, histology and apical site did not influence survival. These results are comparable to those found in the literature and emphasize the need to select patients carefully for either palliative or aggressive treatment. 29 refs., 4 tabs., 3 figs

  18. MEK inhibition in non-small cell lung cancer.

    Science.gov (United States)

    Stinchcombe, Thomas E; Johnson, Gary L

    2014-11-01

    KRAS mutations are the most common mutations in non-small cell lung cancer (NSCLC) with adenocarcinoma histology. KRAS mutations result in the activation of the RAF-MEK-ERK pathway, and agents that target RAF-MEK-ERK pathways have been investigated in KRAS mutant NSCLC. The two agents furthest in development are selumetinib and trametinib. Trametinib has greater binding for the MEK1/2 allosteric site, and generally has superior pharmacokinetics. A randomized phase II trial of docetaxel with and without selumetinib revealed that the combination resulted numerically superior overall survival, and a statistically significant improvement in progression-free survival and objective response rate. However, a concerning rate of hospital admission, grade 3 or 4 neutropenia, and febrile neutropenia was observed with the combination. Trials have investigated MEK inhibitors as single agents and in combination with erlotinib, and the data do not support the further development. The activity of MEK inhibitors appears to be similar in patients with KRAS mutant and wild-type NSCLC suggesting KRAS mutation status is not a reliable biomarker for efficacy. It is possible that mutations of genes in addition to KRAS mutations impact the activity of MEK inhibitors, or specific subsets of KRAS mutations may be resistant or susceptible to MEK inhibition. Other potential explanations are gene amplifications, alternative RNA splicing of genes resulting in activation of their protein products, and deregulation of noncoding RNAs and consequent altered protein expression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Epithelial mesenchymal transition of non-small-cell lung cancer cells A549 induced by SPHK1.

    Science.gov (United States)

    Ni, Min; Shi, Xiao-Lei; Qu, Zhi-Gang; Jiang, Hong; Chen, Zi-Qian; Hu, Jun

    2015-02-01

    To explore the effect and molecular mechanism of SPHK1 in the invasion and metastasis process of non-small-cell lung cancer cells (A549). Recombinant retrovirus was used to mediate the production of A549/vector, A549/SPHK1, A549/scramble, and A549/SPHKl/RNAi that stably expressed or silenced SPHK1. The invasion and migration capacities of A549 cells overexpressing or silencing SPHK1 were determined using Transwell invasion assay and scratch wound repair experiment. The protein and mRNA expression levels of E-cadherin, fibronectin, vimentin in A549/vector, A549/SPHK1, A549/scramble, A549/SPHK1/RNAi were detected with Western blot (WB) and quantitative PCR (QPCR) methods, respectively. Transwell invasion assay and scratch wound repair experiments showed that over-expression of SPHK1 obviously enhanced the invasion and migration capacities of A549 cells. WB and QPCR detection results showed that, the expression of E-cadherin (a molecular marker of epithelial cells) and fibronectin, vimentin (molecular markers of mesenchymal cells) in A549 cells was upregulated after overexpression of SPHK1; while SPHK1 silencing significantly reduced the invasion and metastasis capacities of A549 cells, upregulated the expression of molecular marker of epithelial cells, and downregulated the expression of molecular marker of mesenchymal cells. SPHK1 promotes epithelial mesenchymal transition of non-small-cell lung cancer cells and affects the invasion and metastasis capacities of these cells. Copyright © 2015 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

  20. Nivolumab and Plinabulin in Treating Patients With Stage IIIB-IV, Recurrent, or Metastatic Non-small Cell Lung Cancer

    Science.gov (United States)

    2017-08-29

    ALK Gene Translocation; EGFR Activating Mutation; Recurrent Non-Small Cell Lung Carcinoma; ROS1 Gene Translocation; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IV Non-Small Cell Lung Cancer AJCC v7

  1. Surgical management of oligometastatic non-small cell lung cancer.

    Science.gov (United States)

    Novoa, Nuria M; Varela, Gonzalo; Jiménez, Marcelo F

    2016-11-01

    The oligometastatic stage IV non-small cell lung cancer (NSCLC) offers a new surgical opportunity. New reported data is showing that surgery can offer a reasonable benefit, in terms of long-term survival, to some patients. The advantages of surgical treatment rely on a more adequate patient selection and a better understanding of the biology of these tumors. Currently, mediastinal involvement of the primary tumor can be identified as the most important prognostic variable after curative-intent of synchronous or metachronous metastasis. It seems clear that the routine use of combined FDG-PET and CT will help to detect the more favorable cohort of oligometastatic patients. As expected, pathological T staging of the primary tumor and the completeness of its resection are also crucial factors influencing final results. The real benefit of the local treatment over synchronous or metachronous metastasis is controversial with series showing better outcomes for metachronous lesions than for synchronous and others offering equal results. Also non conclusive results appear when analyzing different sites of metastasis. Retrospective series tend to show different outcomes depending on the affected organ while usually no differences are found in prospective ones. Most of the current evidence is based on retrospective studies on patients collected along extended periods of time. That represents a great limitation to the knowledge on this topic. Some prospective analyses have added some insight, but still the quality of the evidence is too low to allow drawing robust conclusions. As frequently concluded, prospective well designed investigation is requested to ascertain the value of surgery in this specific population of patients with extended NSCLC.

  2. Protein signature for non-small cell lung cancer prognosis

    Science.gov (United States)

    Liu, Wei; Wu, Yong; Wang, Libo; Gao, Ling; Wang, Yingping; Liu, Xiaoliang; Zhang, Kai; Song, Jena; Wang, Hongxia; Bayer, Thomas A; Glaser, Laurel; Sun, Yezhou; Zhang, Weijia; Cutaia, Michael; Zhang, David Y; Ye, Fei

    2014-01-01

    Background: Current histopathological classification and TNM staging have limited accuracy in predicting survival and stratifying patients for appropriate treatment. The goal of the study is to determine whether the expression pattern of functionally important regulatory proteins can add additional values for more accurate classification and prognostication of non-small lung cancer (NSCLC). Methods: The expression of 108 proteins and phosphoproteins in 30 paired NSCLC samples were assessed using Protein Pathway Array (PPA). The differentially expressed proteins were further confirmed using a tissue microarray (TMA) containing 94 NSCLC samples and were correlated with clinical data and survival. Results: Twelve of 108 proteins (p-CREB(Ser133), p-ERK1/2(Thr202/Tyr204), Cyclin B1, p-PDK1(Ser241), CDK4, CDK2, HSP90, CDC2p34, β-catenin, EGFR, XIAP and PCNA) were selected to build the predictor to classify normal and tumor samples with 97% accuracy. Five proteins (CDC2p34, HSP90, XIAP, CDK4 and CREB) were confirmed to be differentially expressed between NSCLC (n=94) and benign lung tumor (n=19). Over-expression of CDK4 and HSP90 in tumors correlated with a favorable overall survival in all NSCLC patients and the over-expression of p-CREB(Ser133) and CREB in NSCLC correlated with a favorable survival in smokers and those with squamous cell carcinoma, respectively. Finally, the four proteins (CDK4, HSP90, p-CREB and CREB) were used to calculate the risk score of each individual patient with NSCLC to predict survival. Conclusion: In summary, our data demonstrated a broad disturbance of functionally important regulatory proteins in NSCLC and some of these can be selected as clinically useful biomarkers for diagnosis, classification and prognosis. PMID:24959380

  3. Sirolimus and Gold Sodium Thiomalate in Treating Patients With Advanced Squamous Non-Small Cell Lung Cancer

    Science.gov (United States)

    2012-12-13

    Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  4. Prognostic Factors in Non-Small Cell Lung Cancer Less Than 3 Centimeters: Actuarial Analysis, Accumulative Incidence and Risk Groups.

    Science.gov (United States)

    Peñalver Cuesta, Juan C; Jordá Aragón, Carlos; Mancheño Franch, Nuria; Cerón Navarro, José A; de Aguiar Quevedo, Karol; Arrarás Martínez, Miguel; Vera Sempere, Francisco J; Padilla Alarcón, Jose D

    2015-09-01

    In TNM classification, factors determining the tumor (T) component in non-small cell lung cancer have scarcely changed over time and are still based solely on anatomical features. Our objective was to study the influence of these and other morphopathological factors on survival. A total of 263 patients undergoing lung resection due to stage I non-small cell lung cancer ≤3cm in diameter were studied. A survival analysis and competing-risk estimate study was made on the basis of clinical, surgical and pathological variables using actuarial analysis and accumulative incidence methods, respectively. A risk model was then generated from the results. Survival at 5 and 10 years was 79.8 and 74.3%, respectively. The best prognostic factors were presence of symptoms, smoking habit and FEV1>60%, number of resected nodes>7, squamous histology, absence of vascular invasion, absence of visceral pleural invasion and presence of invasion more proximal than the lobar bronchus. All these were statistically significant according to the actuarial method. The factor "age60%. Pleural invasion and vascular invasion determine survival or risk of death due to non-small cell lung cancer ≤3cm and can be used for generating a predictive risk model. Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.

  5. Urokinase receptor forms in serum from non-small cell lung cancer patients

    DEFF Research Database (Denmark)

    Almasi, Charlotte Elberling; Christensen, Ib Jarle; Høyer-Hansen, Gunilla

    2011-01-01

    To study the prognostic impact of the different forms of the receptor for urokinase plasminogen activator (uPAR) in serum from 171 non-small cell lung cancer (NSCLC) patients.......To study the prognostic impact of the different forms of the receptor for urokinase plasminogen activator (uPAR) in serum from 171 non-small cell lung cancer (NSCLC) patients....

  6. Radiation pneumonitis in non.small.cell lung cancer patients treated ...

    African Journals Online (AJOL)

    Radiation pneumonitis in non.small.cell lung cancer patients treated with helical tomotherapy. B Yao, YD Wang, QZ Liu. Abstract. Objective: In this study, we investigated the incidence of radiation pneumonitis (RP) in non.small.cell lung cancer (NSCLC) patients undergoing helical tomotherapy (HT) and the clinical and ...

  7. Bmi-1 expression modulates non-small cell lung cancer progression

    Science.gov (United States)

    Xiong, Dan; Ye, Yunlin; Fu, Yujie; Wang, Jinglong; Kuang, Bohua; Wang, Hongbo; Wang, Xiumin; Zu, Lidong; Xiao, Gang; Hao, Mingang; Wang, Jianhua

    2015-01-01

    Previous studies indicate that the role of B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is responsible for multiple cancer progression. However, Bmi-1 in controlling gene expression in non-small cell lung cancer (NSCLC) development is not well explored. Here we report that the Bmi-1 level is highly increased in primary NSCLC tissues compared to matched adjacent non-cancerous tissues and required for lung tumor growth in xenograft model. Furthermore, we also demonstrate that Bmi-1 level is lower in matched involved lymph node cancerous tissues than the respective primary NSCLC tissues. We find that Bmi-1 does not affect cell cycle and apoptosis in lung cancer cell lines as it does not affect the expression of p16/p19, Pten, AKT and P-AKT. Mechanistic analyses note that reduction of Bmi-1 expression inversely regulates invasion and metastasis of NSCLC cells in vitro and in vivo, followed by induction of epithelial-mesenchymal transition (EMT). Using genome microarray assays, we find that RNAi-mediated silence of Bmi-1 modulates some important molecular genetics or signaling pathways, potentially associated with NSCLC development. Taken together, our findings disclose for the first time that Bmi-1 level accumulates strongly in early stage and then declines in late stage, which is potentially important for NSCLC cell invasion and metastasis during progression. PMID:25880371

  8. Genetically Modified T Cells in Treating Patients With Stage III-IV Non-small Cell Lung Cancer or Mesothelioma

    Science.gov (United States)

    2018-01-12

    Advanced Pleural Malignant Mesothelioma; HLA-A*0201 Positive Cells Present; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Pleural Malignant Mesothelioma; Stage III Non-Small Cell Lung Cancer AJCC v7; Stage III Pleural Malignant Mesothelioma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IV Non-Small Cell Lung Cancer AJCC v7; Stage IV Pleural Malignant Mesothelioma AJCC v7; WT1 Positive

  9. Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yu-Chun Yin

    2015-02-01

    Full Text Available Background/Aims: Previous studies have shown that patients with schizophrenia have a lower incidence of cancer than the general population, and several antipsychotics have been demonstrated to have cytotoxic effects on cancer cells. However, the mechanisms underlying these results remain unclear. The present study aimed to investigate the effect of clozapine, which is often used to treat patients with refractory schizophrenia, on the growth of non-small cell lung carcinoma cell lines and to examine whether autophagy contributes to its effects. Methods: A549 and H1299 cells were treated with clozapine, and cell cytotoxicity, cell cycle and autophagy were then assessed. The autophagy inhibitor bafilomycin A1 and siRNA-targeted Atg7 were used to determine the role of autophagy in the effect of clozapine. Results: Clozapine inhibited A549 and H1299 proliferation and increased p21 and p27 expression levels, leading to cell cycle arrest. Clozapine also induced a high level of autophagy, but not apoptosis, in both cell lines, and the growth inhibitory effect of clozapine was blunted by treatment with the autophagy inhibitor bafilomycin A1 or with an siRNA targeting atg7. Conclusions: Clozapine inhibits cell proliferation by inducing autophagic cell death in two non-small cell lung carcinoma cell lines. These findings may provide insights into the relationship between clozapine use and the lower incidence of lung cancer among patients with schizophrenia.

  10. Nivolumab, Cisplatin, and Pemetrexed Disodium or Gemcitabine Hydrochloride in Treating Patients With Stage I-IIIA Non-small Cell Lung Cancer That Can Be Removed by Surgery

    Science.gov (United States)

    2018-03-02

    Non-Squamous Non-Small Cell Lung Carcinoma; Stage I Non-Small Cell Lung Cancer; Stage IA Non-Small Cell Lung Carcinoma; Stage IB Non-Small Cell Lung Carcinoma; Stage II Non-Small Cell Lung Cancer; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer

  11. Radiation Therapy, Chemotherapy, and Soy Isoflavones in Treating Patients With Stage IIIA-IIIB Non-Small Cell Lung Cancer

    Science.gov (United States)

    2017-05-23

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  12. PET-Adjusted Intensity Modulated Radiation Therapy and Combination Chemotherapy in Treating Patients With Stage II-IV Non-small Cell Lung Cancer

    Science.gov (United States)

    2018-03-22

    Metastatic Malignant Neoplasm in the Brain; Recurrent Non-Small Cell Lung Carcinoma; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer

  13. Palliative Care Intervention in Improving Symptom Control and Quality of Life in Patients With Stage II-IV Non-small Cell Lung Cancer and Their Family Caregivers

    Science.gov (United States)

    2017-10-16

    Caregiver; Psychological Impact of Cancer and Its Treatment; Recurrent Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  14. The effect of foxp3-overexpressing Treg cells on non-small cell lung cancer cells.

    Science.gov (United States)

    Peng, Jiangzhou; Yu, Zigang; Xue, Lei; Wang, Jiabin; Li, Jun; Liu, Degang; Yang, Qiang; Lin, Yihui

    2018-04-01

    The aim of the present study was to investigate the novel mechanisms of forkhead box protein P3 (foxp3) in T regulatory (Treg) cells in lung cancer behavior. Treg cells were isolated from the peripheral blood of healthy volunteers and then co‑cultured with 95D cells. A plasmid overexpressing foxp3 was constructed and transfected into Treg cells and an MTS assay was performed to assess cell viability. Flow cytometry was performed to evaluate cell apoptosis and reverse transcription‑quantitative polymerase chain reaction was used to measure mRNA expression. A Transwell assay was used to assess cell invasion. Treg cells were successfully isolated from peripheral blood with purity of 94.26%. Foxp3 expression in Treg cells was significantly increased following co‑culture with 95D cells, while matrix metalloproteinase‑9 expression was upregulated in 95D cells co‑cultured with Treg cells. The apoptosis, invasion and migration abilities of 95D cells were suppressed by co‑culture with Treg cells, whereas the adhesive ability was enhanced. Foxp3 overexpression in Treg cells enhanced the viability and invasiveness of 95D cells, whereas cell adhesion and migration were decreased. The results of the present study demonstrate that the viability and invasiveness of 95D cells are enhanced by foxp3 overexpression in Treg cells, indicating that increased levels of foxp3 in the tumor microenvironment may promote tumor cell growth.

  15. Anticancer and antimetastatic activities of Renieramycin M, a marine tetrahydroisoquinoline alkaloid, in human non-small cell lung cancer cells.

    Science.gov (United States)

    Halim, Hasseri; Chunhacha, Preedakorn; Suwanborirux, Khanit; Chanvorachote, Pithi

    2011-01-01

    Renieramycin M, has been shown to exhibit promising anticancer activity against some cancer cell lines; however, the underlying mechanism remains unknown. Renieramycin M was isolated from the blue sponge Xestospongia sp. Anticancer and antimetastatic activities of renieramycin M were investigated in human non-small cell lung cancer cells. Renieramycin M treatment caused p53 activation, which subsequently down-regulated anti-apoptotic MCL-1 and BCL-2 proteins, while the level of pro-apoptotic BAX protein was not altered. The subtoxic concentrations of renieramycin M significantly decreased invasion and migration abilities of cancer cells. In addition, this compound showed a strong inhibitory effect on anchorage-independent growth of the cells. These results reveal that renieramycin M induced lung cancer cells apoptosis through p53-dependent pathway and the compound may inhibit progression and metastasis of lung cancer cells.

  16. Radiosensitization of non-small cell lung cancer by kaempferol.

    Science.gov (United States)

    Kuo, Wei-Ting; Tsai, Yuan-Chung; Wu, His-Chin; Ho, Yung-Jen; Chen, Yueh-Sheng; Yao, Chen-Han; Yao, Chun-Hsu

    2015-11-01

    The aim of the present study was to determine whether kaempferol has a radiosensitization potential for lung cancer in vitro and in vivo. The in vitro radio-sensitization activity of kaempferol was elucidated in A-549 lung cancer cells by using an MTT (3-(4 5-dimethylthiazol-2-yl)-25-diphenyl-tetrazolium bromide) assay, cell cycle analysis and clonogenic assay. The in vivo activity was evaluated in the BALB/c nude mouse xenograft model of A-549 cells by hematoxylin and eosin staining and immunohistochemistry, and the tumor volume was recorded. Protein levels of the apoptotic pathway were detected by western blot analysis. Treatment with kaempferol inhibited the growth of A-549 cells through activation of apoptotic pathway. However, the same doses did not affect HFL1 normal lung cell growth. Kaempferol induced G2/M cell cycle arrest and the enhancement of radiation-induced death and clonogenic survival inhibition. The in vivo data showed that kaempferol increased tumor cell apoptosis and killing of radiation. In conclusion, the findings demonstrated that kaempferol increased tumor cell killing by radiation in vitro and in vivo through inhibition of the AKT/PI3K and ERK pathways and activation of the mitochondria apoptosis pathway. The results of the present study provided solid evidence that kaempferol is a safe and potential radiosensitizer.

  17. Inhibition of RalA signaling pathway in treatment of non-small cell lung cancer.

    Science.gov (United States)

    Male, Heather; Patel, Vijay; Jacob, Mark A; Borrego-Diaz, Emma; Wang, Kun; Young, Derek A; Wise, Amanda L; Huang, Chao; Van Veldhuizen, Peter; O'Brien-Ladner, Amy; Williamson, Stephen K; Taylor, Sarah A; Tawfik, Ossama; Esfandyari, Tuba; Farassati, Faris

    2012-08-01

    Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and relatively resistant to chemotherapy. The most prevalent molecular abnormality in NSCLC is the overactivation of K-Ras proto-oncogene; therefore, elucidating down-stream Ras signaling in NSCLC is significantly important in developing novel therapies against this malignancy. Our work indicates that RalA, an important effector of Ras, is activated in NSCLC cell lines. While RalA was also overactivated in fetal human broncho-epithelial cells, RalBP1 (Ral binding protein-1), an important down-stream effector of RalA, was expressed at higher levels in cancer cell lines. Aurora kinase-A (AKA), an upstream activator of RalA, was also found to be active only in malignant cells. The outcome of inhibition of RalA (by gene specific silencing using a lentivirus) on the malignant phenotype of A549 cells was also studied. While proliferation and invasiveness of A549 cells were reduced upon silencing RalA, apoptosis and necrosis were elevated in such conditions. Additionally, the in vivo tumorigenesis of A549 cells was reduced upon partial inhibition of RalA and AKA using pharmacological inhibitors. Finally, we were interested in evaluating the level of active RalA in the fraction of NSCLC cells expressing cancer stem cell markers. For this purpose cells with increased expression of CD44 were separated from A549 cells and compared with cells with low level of expression of this marker and an unsorted population. A significant enhancement of RalA activation in high CD44+ cells was found as potential evidence for involvement of RalA signaling in initiation of the neoplastic procedure and an important contributor for tumor maintenance in NSCLC. Further studies can reveal therapeutic, preventive and diagnostic value of RalA pathway in this deadly disease. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. Promoter Methylation Primarily Occurs in Tumor Cells of Patients with Non-small Cell Lung Cancer

    NARCIS (Netherlands)

    De Jong, Wouter K.; Verpooten, Gonda F.; Kramer, Henk; Louwagie, Joost; Groen, Harry J. M.

    Background: The distribution of promoter methylation throughout the lungs of patients with non-small cell lung cancer (NSCLC) is unknown. In this explorative study, we assessed the methylation status of the promoter region of 11 genes in brush samples of 3 well-defined endobronchial locations in

  19. Biomarkers for early diagnosis, prognosis, prediction, and recurrence monitoring of non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Tang Y

    2017-09-01

    Full Text Available Yong Tang,1,2,* Guibin Qiao,1,2,* Enwu Xu,2 Yiwen Xuan,2 Ming Liao,2 Guilin Yin1 1Southern Medical University, Guangzhou, Guangdong Province, China, 2Department of Thoracic Surgery, General Hospital of Guangzhou Military Command of PLA, Yuexiu District, Guangzhou City, Guangdong Province, China *These authors contributed equally to this work Abstract: Despite advances in the management of non-small cell lung cancer, it remains to be the leading cause of cancer-related deaths worldwide primarily because of diagnosis at a late stage with an overall 5-year survival rate of 17%. A reduction in mortality was achieved by low-dose computed tomography screening of high-risk patients. However, the benefit was later challenged by the high false positive rate, resulting in unnecessary follow-ups, thus entailing a burden on both the health care system and the individual. The diagnostic dilemma imposed by imaging modalities has created a need for the development of biomarkers capable of differentiating benign nodules from malignant ones. In the past decade, with the advancements in high-throughput profiling technologies, a huge amount of work has been done to derive biomarkers to supplement clinical diagnosis. However, only a few of them have efficient sensitivity and specificity to be utilized in clinical settings. Therefore, there is an urgent need for the development of sensitive and specific means to detect and diagnose lung cancers at an early stage, when curative interventions are still possible. Due to the invasiveness of tissue biopsies and inability to capture tumor heterogeneity, nowadays enormous efforts have been invested in the development of technologies and biomarkers that enable sensitive and cost-effective testing using substrates that can be obtained in a noninvasive manner. This review, primarily focusing on liquid biopsy, summarizes all documented potential biomarkers for diagnosis, monitoring recurrence treatment response. Keywords

  20. Genetic polymorphisms and non-small-cell lung cancer: future paradigms

    Energy Technology Data Exchange (ETDEWEB)

    Mello, Ramon Andrade Bezerra de [Serviço de Oncologia Médica, Instituto Português de Oncologia Francisco Gentil, Porto (Portugal); Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, Faro (Portugal)

    2014-07-01

    This article addresses some current issues about genetic polymorphisms studied in the non-small-cell lung cancer translational field. Furthermore, it discusses about new potential biomarkers regarding lung cancer risk and prognosis.

  1. Immune-based Therapies for Non-small Cell Lung Cancer.

    Science.gov (United States)

    Rafei, Hind; El-Bahesh, Ehab; Finianos, Antoine; Nassereddine, Samah; Tabbara, Imad

    2017-02-01

    Lung cancer is the leading cause of cancer-related death worldwide. Treatment of non-small cell lung cancer has evolved tremendously over the past decade. Specifically, immune checkpoint inhibitors have become an increasingly interesting target of pharmacological blockade. These immune inhibitors have shown promising results in front-line therapy and after failure of multiple lines, as well as in monotherapy and combination with other therapies. Vaccination in non-small cell lung cancer is also an emerging field of research that holds promising results for the future of immunotherapy in non-small cell lung cancer. This review presents a concise update on the most recent data regarding the role of checkpoint inhibitors as well as vaccination in non-small cell lung cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  2. Preoperative computed tomography of the brain in non-small cell bronchogenic carcinoma.

    OpenAIRE

    Kormas, P; Bradshaw, J R; Jeyasingham, K

    1992-01-01

    BACKGROUND: Computed tomography of the brain is the most accurate diagnostic investigation for detecting intracranial tumours. A prospective study was undertaken to try to maximise the cost effectiveness of computed tomography of the brain in the preoperative evaluation of non-small cell lung cancer. METHODS: All patients with non-small cell lung cancer who were free of neurological symptoms and were thought to be free of metastases from the results of routine investigations were subjected to...

  3. Liquid Biopsy in Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Molina-Vila, Miguel A; Mayo-de-Las-Casas, Clara; Giménez-Capitán, Ana; Jordana-Ariza, Núria; Garzón, Mónica; Balada, Ariadna; Villatoro, Sergi; Teixidó, Cristina; García-Peláez, Beatriz; Aguado, Cristina; Catalán, María José; Campos, Raquel; Pérez-Rosado, Ana; Bertran-Alamillo, Jordi; Martínez-Bueno, Alejandro; Gil, María-de-Los-Llanos; González-Cao, María; González, Xavier; Morales-Espinosa, Daniela; Viteri, Santiago; Karachaliou, Niki; Rosell, Rafael

    2016-01-01

    Liquid biopsy analyses are already incorporated in the routine clinical practice in many hospitals and oncology departments worldwide, improving the selection of treatments and monitoring of lung cancer patients. Although they have not yet reached its full potential, liquid biopsy-based tests will soon be as widespread as "standard" biopsies and imaging techniques, offering invaluable diagnostic, prognostic, and predictive information. This review summarizes the techniques available for the isolation and analysis of circulating free DNA and RNA, exosomes, tumor-educated platelets, and circulating tumor cells from the blood of cancer patients, presents the methodological challenges associated with each of these materials, and discusses the clinical applications of liquid biopsy testing in lung cancer.

  4. VILIP-1 downregulation in non-small cell lung carcinomas: mechanisms and prediction of survival.

    Directory of Open Access Journals (Sweden)

    Jian Fu

    2008-02-01

    Full Text Available VILIP-1, a member of the neuronal Ca++ sensor protein family, acts as a tumor suppressor gene in an experimental animal model by inhibiting cell proliferation, adhesion and invasiveness of squamous cell carcinoma cells. Western Blot analysis of human tumor cells showed that VILIP-1 expression was undetectable in several types of human tumor cells, including 11 out of 12 non-small cell lung carcinoma (NSCLC cell lines. The down-regulation of VILIP-1 was due to loss of VILIP-1 mRNA transcripts. Rearrangements, large gene deletions or mutations were not found. Hypermethylation of the VILIP-1 promoter played an important role in gene silencing. In most VILIP-1-silent cells the VILIP-1 promoter was methylated. In vitro methylation of the VILIP-1 promoter reduced its activity in a promoter-reporter assay. Transcriptional activity of endogenous VILIP-1 promoter was recovered by treatment with 5'-aza-2'-deoxycytidine (5'-Aza-dC. Trichostatin A (TSA, a histone deacetylase inhibitor, potently induced VILIP-1 expression, indicating that histone deacetylation is an additional mechanism of VILIP-1 silencing. TSA increased histone H3 and H4 acetylation in the region of the VILIP-1 promoter. Furthermore, statistical analysis of expression and promoter methylation (n = 150 primary NSCLC samples showed a significant relationship between promoter methylation and protein expression downregulation as well as between survival and decreased or absent VILIP-1 expression in lung cancer tissues (p<0.0001. VILIP-1 expression is silenced by promoter hypermethylation and histone deacetylation in aggressive NSCLC cell lines and primary tumors and its clinical evaluation could have a role as a predictor of short-term survival in lung cancer patients.

  5. Gefitinib: a pharmacoeconomic profile of its use in patients with Non Small Cell Lung Cancer EGFR+

    Directory of Open Access Journals (Sweden)

    Viola Sacchi

    2011-06-01

    Full Text Available Lung cancer is the most common form of cancer with the highest incidence worldwide. The mortality rates are highest in males and second highest in females, after breast cancer. The genetic predisposition to Non Small Cell Lung Cancer (NSCLC is still under investigation, however, studies have shown that the Epidermal Growth Factor Receptor (EGFR, a receptor tyrosine kinase is frequently over-expressed and activated to a phosphorylated state in NSCLC. The activity of EGFR in cancer cells results in the phosphorylation of downstream proteins that promote cell proliferation, invasion, metastasis, and inhibition of apoptosis. Targeting the EGFR pathway therefore constitutes a relevant strategy for cancer therapy. Gefitinib is a selective inhibitor of the EGFR tyrosine kinase and is indicated for the treatment of adult patients with locally advanced or metastatic NSCLC with activating mutations of EGFR-TK. From the pharmacoeconomic point of view gefitinib is dominant (more effective and less expensive compared to the alternatives. In conclusion, gefitinib is a treatment option for NSCLC tumors with a high clinical and economic value in the Italian setting.

  6. 76 FR 35450 - Draft Guidance for Industry on Clinical Trial Endpoints for the Approval of Non-Small Cell Lung...

    Science.gov (United States)

    2011-06-17

    ... the Approval of Non-Small Cell Lung Cancer Drugs and Biologics; Availability AGENCY: Food and Drug... draft guidance for industry entitled ``Clinical Trial Endpoints for the Approval of Non-Small Cell Lung... current thinking on clinical trial endpoints for the approval of non-small cell lung cancer drugs and...

  7. Epithelial-Mesenchymal Transition in Non Small-cell Lung Cancer.

    Science.gov (United States)

    Tsoukalas, Nikolaos; Aravantinou-Fatorou, Eleni; Tolia, Maria; Giaginis, Constantinos; Galanopoulos, Michail; Kiakou, Maria; Kostakis, Ioannis D; Dana, Eugene; Vamvakaris, Ioannis; Korogiannos, Athanasios; Tsiambas, Evangelos; Salemis, Nikolaos; Kyrgias, George; Karameris, Andreas; Theocharis, Stamatios

    2017-04-01

    Lung cancer is the first cause of cancer related deaths in both males and females. Epithelial-mesenchymal transition (EMT) is a reversible process by which epithelial cells transform to mesenchymal stem cells by losing their cell polarity and cell-to-cell adhesion, gaining migratory and invasive properties. High levels of E-cadherin are expressed in epithelial cells, whereas mesenchymal cells express high levels of N-cadherin, fibronectin and vimentin. The aim of this study was to evaluate the correlation between E-cadherin and vimentin expression and their clinical significance in non-small cell lung cancer (NSCLC). The immunohistochemical expression of E-cadherin, vimentin and Ki-67 was performed on tissue microarrays from NSCLC specimens obtained from 112 newly- diagnosed cases and were studied using classical pathological evaluation. Associations between E-cadherin, vimentin and Ki-67 expression, clinicopathological variables and survival were analyzed. In all cases, a value of p≤0.05 was considered significant. Low E-cadherin expression was significantly correlated with tumor necrosis (p=0.019). Moreover, there was a trend for correlation between high E-cadherin expression and better overall survival (hazard ratio=1.02, and 95% confidence interval=0.45-1.87, p=0.091). There was also a significant negative correlation between vimentin expression and overall survival (hazard ratio=1.13, and 95% confidence interval=0.78-1.65, p=0.026). Additionally, there was a significant negative correlation between vimentin expression and grade I tumors (p=0.031). Finally, a positive correlation trend between vimentin expression and Ki-67 was found (p=0.073). High E-cadherin and low vimentin expression correlate with better prognosis and overall survival. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  8. Detection of lymphangiogenesis in non-small cell lung cancer and its prognostic value

    Directory of Open Access Journals (Sweden)

    Liao Rong-xia

    2009-02-01

    Full Text Available Abstract Background Our aim was to detect lymphatic endothelial marker podoplanin, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1 and vascular endothelial growth factor receptor-3 (VEGFR-3 and study the prognostic relevance of lymphangiogenesis in non-small cell lung cancer (NSCLC. Materials 82 paraffin-embedded tissues and 40 fresh frozen tissues from patients with NSCLC were studied. Tumor samples were immunostained for the lymphatic endothelial markers. Lymphangiogenesis was assessed by immunohistochemical double stains for Podoplanin and Ki-67. The prognostic relevance of lymphangiogenesis-related clinicopathological parameters in NSCLC was evaluated. Results We found that the number of podoplanin positive vessels was correlated positively with the number of LYVE-1 positive vessels. Most of VEGFR-3 positive, few of LYVE-1 positive and none of podoplanin positive vessels were blood vessels. Peritumoral lymphatic vessel density (ptLVD, pathologic stage, lymph node status, lymphatic vessel invasion (LVI, vascular endothelial growth factor-C (VEGF-C expression and Ki-67 index of the endothelium cells of the micro lymphatic vessels (Ki67% were associated significantly with a higher risk of tumor progress. ptLVD, pathologic stage, lymph-node metastasis and Ki67% were independent prognostic parameters for overall survival. Conclusion Podoplanin positive ptLVD might play important roles in the lymphangiogenesis and progression of NSCLC. Patients with high podoplanin+ ptLVD have a poor prognosis.

  9. Breviscapine suppresses the growth of non-small cell lung cancer ...

    Indian Academy of Sciences (India)

    Breviscapine (BVP) has previously been shown to inhibit the proliferation of hepatocellular carcinoma cells.However, little is known about the effects of BVP on non-small cell lung cancer (NSCLC) growth. Here, we aimedto study the effects of BVP on human NSCLC growth. We employed A549, NCL-H460 and A549 cells ...

  10. Radiosensitization of C225 on human non-small cell lung cancer cell line H-520

    International Nuclear Information System (INIS)

    Zhang Yingdong; Wang Junjie; Liu Feng; Zhao Yong

    2008-01-01

    Objective: To investigate the efficacy of C225 (cetuximab), a chimeric human-mouse anti-epithelial growth factor receptor monoclonal antibody, combined with 60 Co gamma irradiation against human non-small cell lung cancer cell line H-520. Methods: H-520 cells were treated either with different dose of 60 Co irradiation (1,2,4,6,8 and 10 Gy)alone or together with C225 (100 nmol/L). Colony forming capacity was determined to create the survival curve 10 days after the treatment. Cells in different groups were harvested 72 hours after irradiation for apoptosis analysis or 48 hours after irradiation for cell cycle analysis by flow cytometry assay. Results: The clone number in combinational treatment group was less than that in irradiation only group, which suggested that the cell survival rate in the combinational treatment group was significantly decreased comparing with irradiation only group (F=6.36, P O + G 1 phases for C225 treatment, in G 2 + M phases for 60 Co irradiation, and in both G 0 + G 1 and G 2 + M phases for C225 in combination with 60 Co irradiation. Conclusions: C225 has radiosensitizing effects on H-520 cells, which may through the enhancement of 60 Co irradiation-induced cell death and cell cycle arrest. This study provides a supportive evidence for clinical treatment in non-small cell lung cancer. (authors)

  11. Clinical study on bevacizumab combined with carboplatin therapy for malignant pleural effusion of non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Li-Ping Yang1

    2017-06-01

    Full Text Available Objective: To investigate the effect of bevacizumab combined with carboplatin therapy for malignant pleural effusion of non-small cell lung cancer on tumor markers, angiogenesis molecules and invasive growth molecules. Methods: A total of 68 patients who were diagnosed with non-small cell lung cancer complicated by pleural effusion in the Affiliated T.C.M Hospital of Southwest Medical University between June 2013 and August 2016 were selected and randomly divided into two groups, the combined group received bevacizumab combined with carboplatin chemotherapy, and the carboplatin group received carboplatin chemotherapy. Before treatment as well as 3 cycles and 6 cycles after treatment, the contents of tumor markers, angiogenesis molecules and invasive growth molecules in pleural effusion were examined. Results: 3 cycles and 6 cycles after treatment, CEA, SCCAg, CYFRA21-1, sHLA-G, VEGF, VEGFR, PTN, MMP7 and MMP10 contents in pleural effusion of both groups of patients were significantly lower than those before treatment while TIMP1 and TIMP2 contents were significantly higher than those before treatment, and CEA, SCCAg, CYFRA21-1, sHLA-G, VEGF, VEGFR, PTN, MMP7 and MMP10 contents in pleural effusion of combined group were significantly lower than those of carboplatin group while TIMP1 and TIMP2 contents were significantly higher than those of carboplatin group. Conclusion: Bevacizumab combined with carboplatin therapy for malignant pleural effusion of non-small cell lung cancer can effectively kill cancer cells, and inhibit angiogenesis and cell invasion.

  12. Mast cells and histamine enhance the proliferation of non-small cell lung cancer cells.

    Science.gov (United States)

    Stoyanov, Evgeniy; Uddin, Mohib; Mankuta, David; Dubinett, Steven M; Levi-Schaffer, Francesca

    2012-01-01

    Non-small cell lung cancer (NSCLC) is the most common form of lung cancer with an extremely low survival rate. It is characterized by a chronic inflammatory process with intense mast cell infiltrate that is associated with reduced survival. The aim of this study was to test the hypothesis that mast cells have an enhancing effect on NSCLC proliferation. To assess the tumor-promoting potential of mast cells, we used the human alveolar basal adenocarcinoma (A549) and the mouse Lewis lung carcinoma (LLC) cell lines, umbilical cord blood-derived mast cells (CBMC) and the mast cell-deficient mouse Sash model. The proliferation rate of A549/LLC cells was markedly increased by mast cells and histamine. Histamine proliferating activity was mediated via H(1), H(2) and H(4) receptors and caused ERK phosphorylation. LLC induced in Sash mice or in wild-type mice treated with the mast cell stabilizer nedocromil sodium displayed an accelerated growth (number of metastic colonies in the lungs, total lung area and lung/total mice weight ratio). In summary, we have shown a significant effect of mast cells and histamine in enhancing NSCLC/LLCX growth in vitro, while in a mouse LLC model in vivo we have found that mast cells are important negative regulators of cancer development. Therefore our results would indicate a pro-tumorogenic effect of the mast cells in vitro on established lung tumor cell lines, and anti-tumorogenic effect in mice at lung cancer induction. In conclusion, mast cell/anti-histamine targeted therapies should carefully consider this dual effect. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  13. Downregulated TIPE2 is associated with poor prognosis and promotes cell proliferation in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yuexia [Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 (China); Li, Xiaohui [Department of Cardiovascular Surgery, Henan Provincial People’s Hospital, Zhengzhou, Henan 450003 (China); Liu, Gang; Sun, Rongqing; Wang, Lirui [Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 (China); Wang, Jing, E-mail: jing_wang1980@163.com [Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 (China); Wang, Hongmin, E-mail: hmwangzz@126.com [Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 (China)

    2015-01-30

    Highlights: • TIPE2 is down-regulated in NSCLC tissues. • TIPE2 inhibits NSCLC cell proliferation, colony formation and invasion. • TIPE2 reduces the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. - Abstract: The present study aims to investigate the expression pattern of TIPE2 protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of TIPE2 in 96 NSCLC tumor samples by immunohistochemistry and then analyzed its clinical significance. Furthermore, the role of TIPE2 on the biological properties of the NSCLC cell line H1299 and A549 was experimentally tested in vitro and in vivo. We found that the expression level of TIPE2 was significantly higher in normal lung tissues compared with NSCLC tissues (P < 0.001), and TIPE2 downregulation was significantly correlated with advanced TNM stage (P = 0.006). TIPE2 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TIPE2 plasmid was performed in H1299 and A549 cells. TIPE2 overexpression inhibited lung cancer cell proliferation, colony formation and cell invasive in vitro, and prevented lung tumor growth in vivo. In addition, TIPE2 transfection reduced the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. Taken together, our results demonstrate that TIPE2 might serve as a tumor suppressor in NSCLC progression.

  14. Downregulated TIPE2 is associated with poor prognosis and promotes cell proliferation in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Li, Yuexia; Li, Xiaohui; Liu, Gang; Sun, Rongqing; Wang, Lirui; Wang, Jing; Wang, Hongmin

    2015-01-01

    Highlights: • TIPE2 is down-regulated in NSCLC tissues. • TIPE2 inhibits NSCLC cell proliferation, colony formation and invasion. • TIPE2 reduces the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. - Abstract: The present study aims to investigate the expression pattern of TIPE2 protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of TIPE2 in 96 NSCLC tumor samples by immunohistochemistry and then analyzed its clinical significance. Furthermore, the role of TIPE2 on the biological properties of the NSCLC cell line H1299 and A549 was experimentally tested in vitro and in vivo. We found that the expression level of TIPE2 was significantly higher in normal lung tissues compared with NSCLC tissues (P < 0.001), and TIPE2 downregulation was significantly correlated with advanced TNM stage (P = 0.006). TIPE2 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TIPE2 plasmid was performed in H1299 and A549 cells. TIPE2 overexpression inhibited lung cancer cell proliferation, colony formation and cell invasive in vitro, and prevented lung tumor growth in vivo. In addition, TIPE2 transfection reduced the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. Taken together, our results demonstrate that TIPE2 might serve as a tumor suppressor in NSCLC progression

  15. L1CAM protein expression is associated with poor prognosis in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Weder Walter

    2011-10-01

    Full Text Available Abstract Background The L1 cell adhesion molecule (L1CAM is potentially involved in epithelial-mesenchymal transition (EMT. EMT marker expression is of prognostic significance in non-small cell lung cancer (NSCLC. The relevance of L1CAM for NSCLC is unclear. We investigated the protein expression of L1CAM in a cohort of NSCLC patients. L1CAM protein expression was correlated with clinico-pathological parameters including survival and markers of epithelial-mesenchymal transition. Results L1CAM protein expression was found in 25% of squamous cell carcinomas and 24% of adenocarcinomas and correlated with blood vessel invasion and metastasis (p Conclusions A subset of NSCLCs with vessel tropism and increased metastasis aberrantly expresses L1CAM. L1CAM is a novel prognostic marker for NSCLCs that is upregulated by EMT induction and appears to be instrumental for enhanced cell invasion.

  16. Vorinostat increases carboplatin and paclitaxel activity in non-small cell lung cancer cells

    OpenAIRE

    Owonikoko, Taofeek K.; Ramalingam, Suresh S.; Kanterewicz, Beatriz; Balius, Trent; Belani, Chandra P.; Hershberger, Pamela A.

    2010-01-01

    We observed a 53% response rate in non-small cell lung cancer (NSCLC) patients treated with vorinostat plus paclitaxel/carboplatin in a Phase I trial. Studies were undertaken to investigate the mechanism (s) underlying this activity. Growth inhibition was assessed in NSCLC cells by MTT assay after 72 h of continuous drug exposure. Vorinostat (1 µM) inhibited growth by: 17±7% in A549, 28±6% in 128-88T, 39±8% in Calu1, and 41±7% in 201T cells. Vorinostat addition to carboplatin or paclitaxel le...

  17. Cytoplasmic Kaiso is associated with poor prognosis in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Dai, Shun-Dong; Wang, Yan; Miao, Yuan; Zhao, Yue; Zhang, Yong; Jiang, Gui-Yang; Zhang, Peng-Xin; Yang, Zhi-Qiang; Wang, En-Hua

    2009-01-01

    Kaiso has been identified as a new member of the POZ-zinc finger family of transcription factors that are implicated in development and cancer. Although controversy still exists, Kaiso is supposed to be involved in human cancer. However, there is limited information regarding the clinical significance of cytoplasmic/nuclear Kaiso in human lung cancer. In this study, immunohistochemical studies were performed on 20 cases of normal lung tissues and 294 cases of non-small cell lung cancer (NSCLC), including 50 cases of paired lymph node metastases and 88 cases with complete follow-up records. Three lung cancer cell lines showing primarily nuclear localization of Kaiso were selected to examine whether roles of Kaiso in cytoplasm and in nucleus are identical. Nuclear Kaiso was down-regulated by shRNA technology or addition a specific Kaiso antibody in these cell lines. The proliferative and invasive abilities were evaluated by MTT and Matrigel invasive assay, transcription of Kaiso's target gene matrilysin was detected by RT-PCR. Kaiso was primarily expressed in the cytoplasm of lung cancer tissues. Overall positive cytoplasmic expression rate was 63.61% (187/294). The positive cytoplasmic expression of Kaiso was higher in advanced TNM stages (III+IV) of NSCLC, compared to lower stages (I+II) (p = 0.019). A correlation between cytoplasmic Kaiso expression and lymph node metastasis was found (p = 0.003). In 50 paired cases, cytoplasmic expression of Kaiso was 78.0% (41/50) in primary sites and 90.0% (45/50) in lymph node metastases (p = 0.001). The lung cancer-related 5-year survival rate was significantly lower in patients who were cytoplasmic Kaiso-positive (22.22%), compared to those with cytoplasmic Kaiso-negative tumors (64.00%) (p = 0.005). Nuclear Kaiso staining was seen in occasional cases with only a 5.10% (15/294) positive rate and was not associated with any clinicopathological features of NSCLC. Furthermore, after the down-regulation of the nuclear

  18. Melatonin as a potential anticarcinogen for non-small-cell lung cancer

    Science.gov (United States)

    Han, Jing; Wang, Dongjin; Di, Shouyin; Hu, Wei; Liu, Dong; Li, Xiaofei; Reiter, Russel J.; Yan, Xiaolong

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is a leading cause of death from cancer worldwide. Melatonin, an indoleamine discovered in the pineal gland, exerts pleiotropic anticancer effects against a variety of cancer types. In particular, melatonin may be an important anticancer drug in the treatment of NSCLC. Herein, we review the correlation between the disruption of the melatonin rhythm and NSCLC incidence; we also evaluate the evidence related to the effects of melatonin in inhibiting lung carcinogenesis. Special focus is placed on the oncostatic effects of melatonin, including anti-proliferation, induction of apoptosis, inhibition of invasion and metastasis, and enhancement of immunomodulation. We suggest the drug synergy of melatonin with radio- or chemotherapy for NSCLC could prove to be useful. Taken together, the information complied herein may serve as a comprehensive reference for the anticancer mechanisms of melatonin against NSCLC, and may be helpful for the design of future experimental research and for advancing melatonin as a therapeutic agent for NSCLC. PMID:27102150

  19. The emerging roles of NGS-based liquid biopsy in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Yi-Chen Zhang

    2017-10-01

    Full Text Available Abstract The treatment paradigm of non-small cell lung cancer (NSCLC has evolved into oncogene-directed precision medicine. Identifying actionable genomic alterations is the initial step towards precision medicine. An important scientific progress in molecular profiling of NSCLC over the past decade is the shift from the traditional piecemeal fashion to massively parallel sequencing with the use of next-generation sequencing (NGS. Another technical advance is the development of liquid biopsy with great potential in providing a dynamic and comprehensive genomic profiling of NSCLC in a minimally invasive manner. The integration of NGS with liquid biopsy has been demonstrated to play emerging roles in genomic profiling of NSCLC by increasing evidences. This review summarized the potential applications of NGS-based liquid biopsy in the diagnosis and treatment of NSCLC including identifying actionable genomic alterations, tracking spatiotemporal tumor evolution, dynamically monitoring response and resistance to targeted therapies, and diagnostic value in early-stage NSCLC, and discussed emerging challenges to overcome in order to facilitate clinical translation in future.

  20. Small nucleolar RNA signatures as biomarkers for non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Li Ruiyun

    2010-07-01

    Full Text Available Abstract Background Non-small-cell lung cancer (NSCLC is the leading cause of cancer death. Early detection of NSCLC will improve its outcome. The current techniques for NSCLC early detection are either invasive or have low accuracy. Molecular analyses of clinical specimens present promising diagnostic approaches. Non-coding RNAs (ncRNAs play an important role in tumorigenesis and could be developed as biomarkers for cancer. Here we aimed to develop small nucleolar RNAs (snoRNAs, a common class of ncRNAs, as biomarkers for NSCLC early detection. The study comprised three phases: (1 profiling snoRNA signatures in 22 NSCLC tissues and matched noncancerous lung tissues by GeneChip Array, (2 validating expressions of the signatures by RT-qPCR in the tissues, and (3 evaluating plasma expressions of the snoRNAs in 37 NSCLC patients, 26 patients with chronic obstructive pulmonary disease (COPD, and 22 healthy subjects. Results In the surgical tissues, six snoRNAs were identified, which were overexpressed in all tumour tissues compared with their normal counterparts. The overexpressions of the genes in tumors were confirmed by RT-qPCR. The snoRNAs were stably present and reliably detectable in plasma. Of the six genes, three (SNORD33, SNORD66 and SNORD76 displayed higher plasma expressions in NSCLC patients compared with the cancer-free individuals (All 0.05. Conclusions The identified snoRNAs provide potential markers for NSCLC early detection.

  1. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer

    NARCIS (Netherlands)

    Schaake-Koning, C.; van den Bogaert, W.; Dalesio, O.; Festen, J.; Hoogenhout, J.; van Houtte, P.; Kirkpatrick, A.; Koolen, M.; Maat, B.; Nijs, A.

    1992-01-01

    BACKGROUND AND METHODS: Cisplatin (cis-diamminedichloroplatinum) has been reported to enhance the cell-killing effect of radiation, an effect whose intensity varies with the schedule of administration. We randomly assigned 331 patients with nonmetastatic inoperable non-small-cell lung cancer to one

  2. Breviscapine suppresses the growth of non-small cell lung cancer ...

    Indian Academy of Sciences (India)

    2017-02-10

    Feb 10, 2017 ... Breviscapine (BVP) has previously been shown to inhibit the proliferation of hepatocellular carcinoma cells. However, little is known about the effects of BVP on non-small cell lung cancer (NSCLC) growth. Here, we aimed to study the effects of BVP on human NSCLC growth. We employed A549, NCL-H460 ...

  3. CD10/NEP in non-small cell lung carcinomas. Relationship to cellular proliferation.

    OpenAIRE

    Ganju, R K; Sunday, M; Tsarwhas, D G; Card, A; Shipp, M A

    1994-01-01

    The cell surface metalloproteinase CD10/neutral endopeptidase 24.11 (NEP) hydrolyzes a variety of peptide substrates and reduces cellular responses to specific peptide hormones. Because CD10/NEP modulates peptide-mediated proliferation of small cell carcinomas of the lung (SCLC) and normal fetal bronchial epithelium, we evaluated the enzyme's expression in non-small cell lung carcinomas (NSCLC). Bronchoalveolar and large cell carcinoma cell lines had low levels of CD10/NEP expression whereas ...

  4. Prognostic significance of CD44s expression in resected non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Ko Yoon

    2011-08-01

    Full Text Available Abstract Background CD44s is a cell adhesion molecule known to mediate cellular adhesion to the extracellular matrix, a prerequisite for tumor cell migration. CD44s plays an important role in invasion and metastasis of various cancers. In the present study, we sought to determine whether CD44s is involved in clinical outcomes of patients with resected non-small cell lung cancer (NSCLC. Methods Using immunohistochemical staining, we investigated CD44s protein expression using tissue array specimens from 159 patients with resected NSCLC (adenocarcinoma (AC; n = 82 and squamous cell carcinoma (SCC; n = 77. Additionally, the immunoreactivity of cyclooxygenase (COX-2 was also studied. The clinicopathological implications of these molecules were analyzed statistically. Results High CD44s expression was detected more frequently in NSCLC patients with SCC (66/72; 91.7% than in those with AC histology (P 0.001. Additionally, high CD44s expression was significant correlated with more advanced regional lymph node metastasis (P = 0.021. In multivariate analysis of survival in NSCLC patients with AC histology, significant predictors were lymph node metastasis status (P P = 0.046, and high CD44s expression (P = 0.014. For NSCLC patients with SCC histology, the significant predictor was a more advanced tumor stage (P = 0.015. No significant association was found between CD44s and clinical outcome (P = 0.311. Conclusions High CD44s expression was a negative prognostic marker with significance in patients with resected NSCLC, particularly those with AC histology, and was independent of tumor stage.

  5. Treatment and outcomes of non-small-cell lung cancer patients with high comorbidity

    Directory of Open Access Journals (Sweden)

    Rios J

    2018-01-01

    Full Text Available Jorge Rios,1 Rahul Gosain,1 Bernardo HL Goulart,2 Bin Huang,3 Margaret N Oechsli,1 Jaclyn K McDowell,4 Quan Chen,4 Thomas Tucker,4 Goetz H Kloecker1 1James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 2Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, 3Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, 4Markey Cancer Center, University of Kentucky, Lexington, KY, USA Background: The life expectancy of untreated non-small-cell lung cancer (NSCLC is dismal, while treatment for NSCLC improves survival. The presence of comorbidities is thought to play a significant role in the decision to treat or not treat a given patient. We aim to evaluate the association of comorbidities with the survival of patients treated for NSCLC.Methods: We performed a retrospective study of patients aged ≥66 years with invasive NSCLC between the years 2007 and 2011 in the Surveillance, Epidemiology, and End Results Kentucky Cancer Registry. Comorbidity was measured using the Klabunde Comorbidity Index (KCI, and univariate and multivariate logistic regression models were used to measure association between receiving treatment and comorbidity. Kaplan–Meier plots were constructed to estimate time-to-event outcomes.Results: A total of 4014 patients were identified; of this, 94.9% were white and 55.7% were male. The proportion of patients who did not receive any treatment was 8.7%, 3.9%, 19.1%, and 23.5% for stages I, II, III, and IV, respectively (p<0.0001. In multivariate analysis, older age, higher stage, and higher comorbidity (KCI ≥3 were associated with a lower likelihood of receiving any treatment. The median overall survival (OS for untreated and KCI=0 was 17.7 months for stages I and II, 2.3 months for stage III, and 1.3 months for stage IV. The median OS for treated and KCI=0 was 58.9 months for stages I and II, 16.8 months for stage III, and 5.8 months for stage

  6. Biologic Evaluation of Diabetes and Local Recurrence in Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Yang, Xuebin; Liu, Yongjun; Mani, Haresh; Olson, Jeffrey; Clawson, Gary; Caruso, Carla; Bruggeman, Richard; Varlotto, John M; Zander, Dani S; Rassaei, Negar

    2017-01-01

    A recent multicenter study led by our institution demonstrated that local recurrence of non-small cell lung cancer (NSCLC) was significantly more frequent in patients with diabetes, raising the possibility of different tumor biology in diabetics. Epithelial-to-mesenchymal transition (EMT) plays a key role in local tumor recurrence and metastasis. In the present study, we investigated differences of tumor microenvironment between patients with and without diabetes by examining expression of EMT markers. Seventy-nine NSCLC patients were selected from the cohort of our early multicenter study. These patients were classified into 4 groups: 39 with adenocarcinoma with (n = 19) and without (n = 20) diabetes, and 40 with squamous cell carcinoma with (n = 20) and without (n = 20) diabetes. Immunohistochemical expression of eight EMT markers was analyzed, including transforming growth factor-beta (TGF-β), epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF-1R), vimentin, E-cadherin, N-cadherin, HtrA1, and beta-catenin. Five markers (E-cadherin, HtrA1, TGF-β, IGF-1R and vimentin) demonstrated significantly higher expression in diabetics than in non-diabetics in both histology types. N-cadherin had higher expression in diabetics, though the difference did not reach statistical significance. EGFR showed a higher expression in diabetics in squamous cell carcinoma only. Beta-catenin was the only marker with no difference in expression between diabetics versus non-diabetics. Our findings suggest that diabetes is associated with enhanced EMT in NSCLC, which may contribute to growth and invasiveness of NSCLC.

  7. Genome-wide DNA methylation profiling of non-small cell lung carcinomas

    NARCIS (Netherlands)

    R.H. Carvalho (Rejane Hughes); V. Haberle (Vanja); J. Hou (Jun); T. van Gent (Teus); S. Thongjuea (Supat); W.F.J. van IJcken (Wilfred); C. Kockx (Christel); R.W.W. Brouwer (Rutger); E.J. Rijkers; A.M. Sieuwerts (Anieta); J.A. Foekens (John); M. van Vroonhoven (Mirjam); J.G.J.V. Aerts (Joachim); F.G. Grosveld (Frank); B. Lenhard (Boris); J.N.J. Philipsen (Sjaak)

    2012-01-01

    textabstractBackground: Non-small cell lung carcinoma (NSCLC) is a complex malignancy that owing to its heterogeneity and poor prognosis poses many challenges to diagnosis, prognosis and patient treatment. DNA methylation is an important mechanism of epigenetic regulation involved in normal

  8. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.

    NARCIS (Netherlands)

    Carbone, D.P.; Reck, M.; Paz-Ares, L.; Creelan, B.; Horn, L.; Steins, M.; Felip, E.; Heuvel, M. van den; Ciuleanu, T.E.; Badin, F.; Ready, N.; Hiltermann, T.J.N.; Nair, S.; Juergens, R.; Peters, S.; Minenza, E.; Wrangle, J.M.; Rodriguez-Abreu, D.; Borghaei, H.; umenschein GR, J.r. Bl; Villaruz, L.C.; Havel, L.; Krejci, J.; rral Jaime, J. Co; Chang, H.; Geese, W.J.; Bhagavatheeswaran, P.; Chen, A.C.; Socinski, M.A.

    2017-01-01

    BACKGROUND: Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1

  9. [Guideline on 'non-small cell lung carcinoma; staging and treatment'

    NARCIS (Netherlands)

    Meerbeeck, J.P. van; Koning, C.C.; Tjan-Heijnen, V.C.; Boekema, A.G.; Kaandorp, C.J.; Burgers, J.S.

    2005-01-01

    A national, evidence-based guideline on the staging and treatment of patients with non-small cell lung carcinoma (NSCLC) has been compiled by the various disciplines involved. The initial diagnostic measures in patients with suspected lung cancer include history taking, physical examination and

  10. Clinical impact of ki-67 labeling index in non-small cell lung cancer

    DEFF Research Database (Denmark)

    Jakobsen, Jan Nyrop; Sørensen, Jens Benn

    2013-01-01

    The ki-67 index is a marker of proliferation in malignant tumors. Studies from the period 2000 to 2012 on the prognostic and predictive value of ki-67 labeling index (LI) in non-small cell cancer (NSCLC) are reviewed. Twenty-eight studies reported on the prognostic value of ki-67 index with various...

  11. Drug development for breast, colorectal, and non-small cell lung cancers from 1979 to 2014.

    Science.gov (United States)

    Nixon, Nancy A; Khan, Omar F; Imam, Hasiba; Tang, Patricia A; Monzon, Jose; Li, Haocheng; Sun, Gavin; Ezeife, Doreen; Parimi, Sunil; Dowden, Scot; Tam, Vincent C

    2017-12-01

    Understanding the drug development pathway is critical for streamlining the development of effective cancer treatments. The objective of the current study was to delineate the drug development timeline and attrition rate of different drug classes for common cancer disease sites. Drugs entering clinical trials for breast, colorectal, and non-small cell lung cancer were identified using a pharmaceutical business intelligence database. Data regarding drug characteristics, clinical trials, and approval dates were obtained from the database, clinical trial registries, PubMed, and regulatory Web sites. A total of 411 drugs met the inclusion criteria for breast cancer, 246 drugs met the inclusion criteria for colorectal cancer, and 315 drugs met the inclusion criteria for non-small cell lung cancer. Attrition rates were 83.9% for breast cancer, 87.0% for colorectal cancer, and 92.0% for non-small cell lung cancer drugs. In the case of non-small cell lung cancer, there was a trend toward higher attrition rates for targeted monoclonal antibodies compared with other agents. No tumor site-specific differences were noted with regard to cytotoxic chemotherapy, immunomodulatory, or small molecule kinase inhibitor drugs. Drugs classified as "others" in breast cancer had lower attrition rates, primarily due to the higher success of hormonal medications. Mean drug development times were 8.9 years for breast cancer, 6.7 years for colorectal cancer, and 6.6 years for non-small cell lung cancer. Overall oncologic drug attrition rates remain high, and drugs are more likely to fail in later-stage clinical trials. The refinement of early-phase trial design may permit the selection of drugs that are more likely to succeed in the phase 3 setting. Cancer 2017;123:4672-4679. © 2017 American Cancer Society. © 2017 American Cancer Society.

  12. Treatment of stage I non-small cell lung cancer: What's trending?

    Science.gov (United States)

    McMurry, Timothy L; Shah, Puja M; Samson, Pamela; Robinson, Clifford G; Kozower, Benjamin D

    2017-09-01

    Stage I non-small cell lung cancer traditionally is treated with lobectomy. Sublobar resection and stereotactic body radiation therapy provide alternative treatments for higher-risk groups. The purpose of this study was to determine the national treatment trends for stage I lung cancer. The National Cancer Database was queried for patients with clinical stage I non-small cell lung cancer between 1998 and 2012. Patients were compared across treatment groups, and trends in treatment and disease were evaluated over the 15-year time period. The National Cancer Database contained 369,931 patients with clinical stage I non-small cell lung cancer. After removing patients who received chemotherapy as a first course of treatment and patients with pathologic stage IV, 357,490 patients were analyzed. The first recorded cases of stereotactic body radiation therapy are in 2003 and rapidly increased to 6.6% (2063) of all patients treated in 2012. The number of diagnoses of stage I non-small cell lung cancer steadily increased over the 15-year period, whereas the rate of lobectomy decreased from 55% in 1998 to 50% in 2012 (P lung cancer cases continues to increase, lobectomy rates are decreasing while sublobar resection and stereotactic body radiation therapy rates are increasing. Although the increasing popularity of alternative therapies to lobectomy for treatment of stage I non-small cell lung cancer should allow more patients to undergo treatment, we did not observe this trend in the data. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  13. Multifocal T4 non-small cell lung cancer: a subset with improved prognosis.

    Science.gov (United States)

    Trousse, Delphine; D'Journo, Xavier Benoît; Avaro, Jean-Philippe; Doddoli, Christophe; Giudicelli, Roger; Fuentes, Pierre Antoine; Thomas, Pascal Alexandre

    2008-01-01

    T4-disease for non-small cell lung cancer (NSCLC) includes different conditions: mediastinal invasion, neoplastic pleural cytology, and multifocal disease in the same lobe; regarding the last category, no strict criteria allow to differentiate satellite nodules from synchronous multiple primary tumours. Retrospective study of 56 patients who underwent a complete resection from 1985 to 2006 of a NSCLC graded pT4N0 due to multifocal disease. A small nodule (satellite nodule (pT4sn). Multiple tumours, sized more than 1cm, with an identical histology, located in the same lobe but in different segment were considered as synchronous cancers (pT4sc). There were 44 males and 12 females: 35 patients were graded T4sn and 21 patients T4sc. The median age was 62.5 years. The two groups were similar for sex, age, tobacco consumption, ASA score, NYHA, Charlson's index, spirometric parameters, cardiovascular comorbidity and history of previous extra-thoracic malignancies. All had a complete anatomic resection with mediastinal lymphadenectomy. Thirty-day mortality rate was 3.6%. Overall 5-year and 10-year survival rates were 48.2% and 29.9%, respectively. There was a non-significant trend for a worse survival in T4sn group patients when compared to that of T4sc group patients: 42.9% vs 52.3% at 5 years, and 25% vs 34.9% at 10 years (p=0.62). Multifocal T4 stage IIIB disease is a heterogeneous category where overall prognosis is far better than those of other T4 subgroups. Survival rates associated with pT4sn and pT4sc look roughly similar because of the small size of the subgroups usually submitted to comparison in most series. In the present experience, respective survival figures diverge, suggesting different biological behaviours.

  14. Effect of cryoablation sequential chemotherapy on patients with advanced non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Shu-Hui Yao

    2016-03-01

    Full Text Available Objective: To evaluate the effect of cryoablation sequential chemotherapy on patients with advanced non-small cell lung cancer. Methods: A total of 39 cases with advanced non-small cell lung cancer who received cryoablation sequential chemotherapy and 39 cases with advanced non-small cell lung cancer who received chemotherapy alone were selected and enrolled in sequential group and control group, disease progression and survival of two groups were followed up, and contents of tumor markers and angiogenesis molecules in serum as well as contents of T-lymphocyte subsets in peripheral blood were detected. Results: Progressionfree survival and median overall survival (mOS of sequential group were longer than those of control group, and cumulative cases of tumor progression at various points in time were significantly less than those of control group (P<0.05; 1 month after treatment, serum tumor markers CEA, CYFRA21-1 and NSE contents, serum angiogenesis molecules PCDGF, VEGF and HDGF contents as well as CD3+CD4-CD8+CD28-T cell content in peripheral blood of sequential group were significantly lower than those of control group (P<0.05, and contents of CD3+CD4+CD8-T cell and CD3+CD4-CD8+CD28+T cell in peripheral blood were higher than those of control group (P<0.05. Conclusions: Cryoablation sequential chemotherapy can improve the prognosis of patients with advanced non-small cell lung cancer, delay disease progression, prolong survival time, inhibit angiogenesis and improve immune function.

  15. PKC 412 sensitizes U1810 non-small cell lung cancer cells to DNA damage

    International Nuclear Information System (INIS)

    Hemstroem, Therese H.; Joseph, Bertrand; Schulte, Gunnar; Lewensohn, Rolf; Zhivotovsky, Boris

    2005-01-01

    Non-small cell lung carcinoma (NSCLC) is characterized by resistance to drug-induced apoptosis, which might explain the survival of lung cancer cells following treatment. Recently we have shown that the broad-range kinase inhibitor staurosporine (STS) reactivates the apoptotic machinery in U1810 NSCLC cells [Joseph et al., Oncogene 21 (2002) 65]. Lately, several STS analogs that are more specific in kinase inhibition have been suggested for tumor treatment. In this study the apoptosis-inducing ability of the STS analogs PKC 412 and Ro 31-8220 used alone or in combination with DNA-damaging agents in U1810 cells was investigated. In these cells Ro 31-8220 neither induced apoptosis when used alone, nor sensitized cells to etoposide treatment. PKC 412 as a single agent induced death of a small number of U1810 cells, whereas it efficiently triggered a dose- and time-dependent apoptosis in U1285 small cell lung carcinoma cells. In both cell types PKC 412 triggered release of mitochondrial proteins followed by caspase activation. However, concomitant activation of a caspase-independent pathway was essential to kill NSCLC cells. Importantly, PKC 412 was able to sensitize etoposide- and radiation-induced death of U1810 cells. The best sensitization was achieved when PKC 412 was administered 24 h after treatments. In U1810 cells, Ro 31-8220 decreased PMA-induced ERK phosphorylation as efficiently as PKC 412, indicating that the failure of Ro 31-8220 to induce apoptosis was not due to weaker inhibition of conventional and novel PKC isoforms. However, Ro 31-8220 increased the basal level of ERK and Akt phosphorylation in both cell lines, whereas Akt phosphorylation was suppressed in the U1810 cells, which might influence apoptosis. These results suggest that PKC 412 could be a useful tool in increasing the efficiency of therapy of NSCLC

  16. [Suppression of WIFI transcript and protein in non-small cell lung carcinomas].

    Science.gov (United States)

    Korobko, E V; Kalinichenko, S V; Shepelev, M V; Zborovskaia, I B; Allakhverdiev, A K; Zinov'eva, M V; Vinogradova, T V; Sverdlov, E D; Korobko, I V

    2007-01-01

    Changes in WIFI expression, an extracellular inhibitor of Wnt pathway, in non-small cell lung carcinomas were analyzed. Frequent (67% cases) suppression of WIFI transcript in non-small cell lung carcinomas were found. Our results, together with previously published data, suggest that inhibition of WIFI expression often occurs in squamous cell carcinomas and is less typical of adenocarcinomas. It was also found that a decrease in the WIFI transcript in tumors is parallel to concomitant suppression of the WIFI protein level. Our results provide further evidence that the WIFI suppression is a frequent event in the lung carcinogenesis, which might lead to disregulation of Wnt signaling pathway and contribute to tumor progression.

  17. Clinicopathological significance of fascin-1 expression in patients with non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Ling XL

    2015-06-01

    Full Text Available Xiao-Ling Ling,* Tao Zhang,* Xiao-Ming Hou, Da Zhao Department of Oncology, The First Hospital of Lanzhou University (The Branch Hospital of Donggang, Lanzhou, Gansu Province, People’s Republic of China *These authors contributed equally to this work Purpose: Fascin-1 promotes the formation of filopodia, lamellipodia, and microspikes of cell membrane after its cross-linking with F-actin, thereby enhancing the cell movement and metastasis and invasion of tumor cells. This study explored the fascin-1 protein’s expression in non-small cell lung cancer (NSCLC tissues and its relationship with clinical pathology and prognostic indicators.Methods: Immunohistochemical analysis was used to determine the expression of fascin-1 in NSCLC tissues. We used quantitative real-time polymerase chain reaction and western blot analysis to further verify the results. The fascin-1 expression and statistical method for clinical pathological parameters are examined by χ2. Kaplan–Meier method is used for survival analysis. Cox’s Proportional Hazard Model was used to conduct a combined-effect analysis for each covariate.Results: In 73 of the 128 cases, NSCLC cancer tissues (57.0% were found with high expression of fascin-1, which was significantly higher than the adjacent tissues (35/128, 27.3%. The results suggested that the high expression of fascin-1 was significantly correlated with lymph node metastasis (P=0.022 and TNM stage (P=0.042. The high fascin-1 expression patients survived shorter than those NSCLC patients with low fascin-1 expression (P<0.05. Univariate analysis revealed that lymph node metastasis, TNM stage, and fascin-1 expression status were correlated with the overall survival. Similarly, lymph node metastasis, TNM stage, and fascin-1 expression status were significantly associated with the overall survival in multivariate analyses by using the Cox regression model.Conclusion: The fascin-1 protein may be a useful prognostic indicator and

  18. Survival in Operated Early and Local Advanced-Stage (IA-IIIA Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Mahsuk Taylan

    2016-06-01

    Full Text Available Objective: The early and local advanced stages (IA-IIIA of non-small cell lung cancer (NSCLC warrant the curative treatment approach of surgery. However, despite the surgical approach, survival depends on a number of factors. The aim of the study was to examine the factors that affect survival in operated NSCLC patients with these stages. Methods: A cohort of 231 operated patients with IA, IB, IIA, IIB, and IIIA stages of NSCLC were analyzed. The effects of age, sex, comorbidity, performance status, histopathology of the tumor, T stage, N stage, pleural invasion, surgical resection type and postoperative resection margin invasion on the survival of the patients were examined with Kaplan-Meier and Cox Regression analyses. Results: Advanced age (OR=1.042 for every passing year, CI=1.020-1.064, adenocarcinoma histopathology (OR=1.676 CI=1.178-2.384, N2 invasion (OR=2.389 CI=1.46-4.239, pleural invasion (OR=2.403 CI=1.569-3.678, resection margin invasion (OR=2.401, CI=1.141-5.048 and pneumonectomy as the type of surgical operation (OR=2.313, CI=1.467-3.647 were found to be independent prognostic factors of mortality. Conclusion: Follow-up of the NSCLC cases with advanced age, an adenocarcinoma type, visceral pleural invasion, N2-lymph node invasion, a history of pneumonectomy, and a resection margin invasion should be undertaken more atten­tively during planning of surgical operation and postoperative period. J Clin Exp Invest 2016; 7 (2: 125-133

  19. Preoperative computed tomography of the brain in non-small cell bronchogenic carcinoma.

    Science.gov (United States)

    Kormas, P; Bradshaw, J R; Jeyasingham, K

    1992-01-01

    BACKGROUND: Computed tomography of the brain is the most accurate diagnostic investigation for detecting intracranial tumours. A prospective study was undertaken to try to maximise the cost effectiveness of computed tomography of the brain in the preoperative evaluation of non-small cell lung cancer. METHODS: All patients with non-small cell lung cancer who were free of neurological symptoms and were thought to be free of metastases from the results of routine investigations were subjected to computed tomography of the brain in the 12-24 hours immediately before surgery. RESULTS: Of 158 such patients, five showed positive evidence of metastases, confirmed on craniotomy and excision biopsy; one of these patients was found to have a non-metastatic tumour (false positive). Five patients with a negative scan who underwent lung resection returned within 12 months with neurological defects and positive findings on further computed tomography (false negative). The predominant cell type in patients with positive and false negative scans was adenocarcinoma or adenosquamous carcinoma (7/10); the majority had nodal state N2. CONCLUSIONS: Computed tomography of the brain should be carried out if mediastinal disease is suspected or confirmed in non-small cell lung cancer before proceeding to surgery. PMID:1549816

  20. Nrf2 mediates redox adaptation in NOX4-overexpressed non-small cell lung cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Qipeng; Yao, Bei; Li, Ning; Ma, Lei; Deng, Yanchao; Yang, Yang; Zeng, Cheng; Yang, Zhicheng [Department of Clinical Pharmacy, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006 (China); Liu, Bing, E-mail: liubing520@gdpu.edu.cn [Department of Clinical Pharmacy, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006 (China); Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou 510006 (China)

    2017-03-15

    The redox adaptation mechanisms in cancer cells are very complex and remain largely unclear. Our previous studies have confirmed that NADPH oxidase 4 (NOX4) is abundantly expressed in non-small cell lung cancer (NSCLC) and confers apoptosis resistance on NSCLC cells. However, the comprehensive mechanisms for NOX4-mediated oxidative resistance of cancer cells remain still undentified. The present study found that NOX4-derived H{sub 2}O{sub 2} enhanced the nuclear factor erythroid 2-related factor 2 (Nrf2) stability via disruption of redox-dependent proteasomal degradation and stimulated its activity through activation of PI3K signaling. Specifically, the results showed that ectopic NOX4 expression did not induce apoptosis of A549 cells; however, inhibition of Nrf2 resulted in obvious apoptotic death of NOX4-overexpressed A549 cells, accompanied by a significant increase in H{sub 2}O{sub 2} level and decrease in GSH content. Besides, inhibition of Nrf2 could suppress cell growth and efficiently reverse the enhancement effect of NOX4 on cell growth. The in vivo data confirmed that inhibition of Nrf2 could interfere apoptosis resistance in NOX4-overexpressed A549 tumors and led to cell growth inhibition. In conclusion, these results reveal that Nrf2 is critically involved in redox adaptation regulation in NOX4-overexpressed NSCLC cells. Therefore, NOX4 and Nrf2 may be promising combination targets against malignant progression of NSCLC. - Highlights: • NOX4-derived H{sub 2}O{sub 2} upregulates Nrf2 expression and activity in NSCLC. • Nrf2 confers apoptosis resistance in NOX4-overexpressed NSCLC cells. • Inhibition of Nrf2 reverses the enhancement effect of NOX4 on cell growth.

  1. Nrf2 mediates redox adaptation in NOX4-overexpressed non-small cell lung cancer cells

    International Nuclear Information System (INIS)

    Wu, Qipeng; Yao, Bei; Li, Ning; Ma, Lei; Deng, Yanchao; Yang, Yang; Zeng, Cheng; Yang, Zhicheng; Liu, Bing

    2017-01-01

    The redox adaptation mechanisms in cancer cells are very complex and remain largely unclear. Our previous studies have confirmed that NADPH oxidase 4 (NOX4) is abundantly expressed in non-small cell lung cancer (NSCLC) and confers apoptosis resistance on NSCLC cells. However, the comprehensive mechanisms for NOX4-mediated oxidative resistance of cancer cells remain still undentified. The present study found that NOX4-derived H 2 O 2 enhanced the nuclear factor erythroid 2-related factor 2 (Nrf2) stability via disruption of redox-dependent proteasomal degradation and stimulated its activity through activation of PI3K signaling. Specifically, the results showed that ectopic NOX4 expression did not induce apoptosis of A549 cells; however, inhibition of Nrf2 resulted in obvious apoptotic death of NOX4-overexpressed A549 cells, accompanied by a significant increase in H 2 O 2 level and decrease in GSH content. Besides, inhibition of Nrf2 could suppress cell growth and efficiently reverse the enhancement effect of NOX4 on cell growth. The in vivo data confirmed that inhibition of Nrf2 could interfere apoptosis resistance in NOX4-overexpressed A549 tumors and led to cell growth inhibition. In conclusion, these results reveal that Nrf2 is critically involved in redox adaptation regulation in NOX4-overexpressed NSCLC cells. Therefore, NOX4 and Nrf2 may be promising combination targets against malignant progression of NSCLC. - Highlights: • NOX4-derived H 2 O 2 upregulates Nrf2 expression and activity in NSCLC. • Nrf2 confers apoptosis resistance in NOX4-overexpressed NSCLC cells. • Inhibition of Nrf2 reverses the enhancement effect of NOX4 on cell growth.

  2. SSX2-4 expression in early-stage non-small cell lung cancer

    DEFF Research Database (Denmark)

    Greve, K B V; Pøhl, M; Olsen, K E

    2014-01-01

    The expression of cancer/testis antigens SSX2, SSX3, and SSX4 in non-small cell lung cancers (NSCLC) was examined, since they are considered promising targets for cancer immunotherapy due to their immunogenicity and testis-restricted normal tissue expression. We characterized three SSX antibodies...... was only detected in 5 of 143 early-stage NSCLCs, which is rare compared to other cancer/testis antigens (e.g. MAGE-A and GAGE). However, further studies are needed to determine whether SSX can be used as a prognostic or predictive biomarker in NSCLC.......The expression of cancer/testis antigens SSX2, SSX3, and SSX4 in non-small cell lung cancers (NSCLC) was examined, since they are considered promising targets for cancer immunotherapy due to their immunogenicity and testis-restricted normal tissue expression. We characterized three SSX antibodies...

  3. Longitudinal assessment of TUBB3 expression in non-small cell lung cancer patients

    DEFF Research Database (Denmark)

    Jakobsen, Jan Nyrop; Santoni-Rugiu, Eric; Sørensen, Jens Benn

    2014-01-01

    INTRODUCTION: Class-III-beta-tubulin (TUBB3) expression may be a potential predictive factor for treatment with microtubule interfering cytotoxic drugs in non-small cell lung cancer (NSCLC). Potential changes in TUBB3 expression during chemotherapy may be of interest if future choice of chemother......INTRODUCTION: Class-III-beta-tubulin (TUBB3) expression may be a potential predictive factor for treatment with microtubule interfering cytotoxic drugs in non-small cell lung cancer (NSCLC). Potential changes in TUBB3 expression during chemotherapy may be of interest if future choice...... of chemotherapy is to be based on TUBB3 expression. If the biomarker expression changes during chemotherapy, biopsies before initiation of chemotherapy beyond first line may be needed if treatment decision is to be based on TUBB3 expression. Thus, the aim was to explore TUBB3 expression heterogeneity and changes......, suggesting no need for rebiopsy in case second-line chemotherapy with microtubule interfering cytotoxic treatments is necessary....

  4. Challenges in optimizing chemoradiation in locally advanced non small-cell lung cancers in India

    Directory of Open Access Journals (Sweden)

    Sushma Agrawal

    2013-01-01

    Full Text Available Data supporting use of concurrent chemoradiation in locally advanced lung cancers comes from clinical trials from developed countries. Applicability and outcomes of such schedules in developing countries is not widely reported. There are various challenges in delivering chemoradiation in locally advanced non small cell lung cancer in developing countries which is highlighted by an audit of patients treated with chemoradiation in our center. This article deals with the challenges in the context of a developing country. We conclude that sequential chemoradiotherapy is better tolerated than concurrent chemoradiation in Indian patients with locally advanced non-small cell lung cancers. Patients with stage IIIa, normal weight or overweight, and adequate baseline pulmonary function should be offered concurrent chemoradiation.

  5. Living with a diagnosis of non-small cell lung cancer: patients' lived experiences.

    LENUS (Irish Health Repository)

    McCarthy, Ita

    2012-01-31

    The aim of this study was to explore patients\\' experience of living with non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC know that their treatment is not with curative intent and can expect distressing symptoms. In this phenomenological study, six adults with a diagnosis of NSCLC were interviewed. Data was analysed guided by van Manen\\'s six-step process. Four main themes were interpreted: \\'Maintaining my life\\'; \\'The enemy within\\'; \\'Staying on the train\\

  6. Optimal Therapeutic Strategy for Non-small Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor

    Directory of Open Access Journals (Sweden)

    Zhong SHI

    2015-02-01

    Full Text Available Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs have been widely used in non-small cell lung cancer (NSCLC patients, it is still controversial about how to combine EGFR-TKI with chemotherapy and other targeted drugs. We have made a summary on the current therapeutic models of EGFR-TKI combined with chemotherapy/bevacizumab in this review and aimed to find the optimal therapeutic strategy for NSCLC patients with EGFR mutation.

  7. Targeted Therapies in Non-Small Cell Lung Cancer?Beyond EGFR and ALK

    OpenAIRE

    Rothschild, Sacha I.

    2015-01-01

    Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations (so-called “driver mutations”) for their malignant phenotype. Personalized therapy encompasses the strategy of matching these subtypes with effective targeted therapies. EGFR mutations and ALK t...

  8. Targeted therapies in development for non-small cell lung cancer

    OpenAIRE

    Reungwetwattana, Thanyanan; Dy, Grace Kho

    2013-01-01

    The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC), the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2]), RAS (rat sarcoma gene), BRAF (v-raf murine sarcoma viral oncogene homolog B1), ...

  9. Current state of immunotherapy for non-small cell lung cancer

    OpenAIRE

    Malhotra, Jyoti; Jabbour, Salma K.; Aisner, Joseph

    2017-01-01

    Lung cancer is the leading cause of cancer mortality and non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancers. Platinum-based doublet chemotherapy is the standard first-line treatment for metastatic NSCLC when genomic testing reveals no targetable alteration such as epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) or ROS1 translocation/re-arrangements. But, chemotherapy produces response rates ranging only between 15–30%. For pat...

  10. Intratumour variation of biomarker expression by immunohistochemistry in resectable non-small cell lung cancer

    DEFF Research Database (Denmark)

    Jakobsen, Jan Nyrop; Santoni-Rugiu, Eric; Ravn, Jesper

    2013-01-01

    truly reflect the pattern of biomarker expression. It may also be an important factor in chemo resistance, as tumours with heterogeneous biomarker expression may potentially harbour chemo resistant tumour clones. MATERIALS AND METHODS: Immunohistochemical evaluation of the expression of excision repair...... intratumour heterogeneity in 33-87% of tumours examined. This heterogeneity may influence results in studies investigating the therapeutic impact of predictive biomarkers in non-small cell lung cancer (NSCLC)....

  11. Chemotherapy related toxicity in locally advanced non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Bahl Amit

    2006-01-01

    Full Text Available Background: For inoperable non-small cell lung cancer combined chemotherapy and radiotherapy plays an important role as a therapeutic modality. The aim of the present study was to analyze neoadjuvant chemotherapy related acute toxicity in locally advanced lung cancer (stage IIIA and IIIB in Indian patients using Cisplatin and Etoposide combination chemotherapy. Material and methods: Forty patients of locally advanced Non small cell lung cancer received three cycles neoadjuvant chemotherapy using Injection Cisplatin and Etoposide. The patients were taken for Radical radiotherapy to a dose of 60 Gray over 30 fractions in conventional fractionation after completing chemotherapy. Chemotherapy associated toxicity was assessed using common toxicity criteria (CTC v2.0 Results: Forty patients were available for final evaluation. Median age of presentation of patients was fifty-six years. Thirteen patients had Non small cell lung cancer stage IIIA while twenty-seven patients had Stage IIIB disease. Anemia was the most common hematological toxicity observed (seen in 81% of patients. Nausea and vomiting were the most common non -hematological toxicity seen. Sensory neuropathy was seen in 38%of patients. 88% patients developed alopecia. Seven patients developed febrile neutropenias. Conclusion: Neo-adjuvant chemotherapy using Cisplatin and Etoposide continues to be a basic regimen in the Indian set up despite availability of higher molecules, since it is cost effective, well tolerated and therapeutically effective. Blood transfusions, growth factors and supportive care can be used effectively to over come toxicity associated with this regimen.

  12. Photodynamic Therapy of Non-Small Cell Lung Cancer. Narrative Review and Future Directions.

    Science.gov (United States)

    Shafirstein, Gal; Battoo, Athar; Harris, Kassem; Baumann, Heinz; Gollnick, Sandra O; Lindenmann, Joerg; Nwogu, Chukwumere E

    2016-02-01

    Photodynamic therapy (PDT) is an established treatment modality for non-small cell lung cancer. Phototoxicity, the primary adverse event, is expected to be minimized with the introduction of new photosensitizers that have shown promising results in phase I and II clinical studies. Early-stage and superficial endobronchial lesions less than 1 cm in thickness can be effectively treated with external light sources. Thicker lesions and peripheral lesions may be amenable to interstitial PDT, where the light is delivered intratumorally. The addition of PDT to standard-of-care surgery and chemotherapy can improve survival and outcomes in patients with pleural disease. Intraoperative PDT has shown promise in the treatment of non-small cell lung cancer with pleural spread. Recent preclinical and clinical data suggest that PDT can increase antitumor immunity. Crosslinking of signal transducer and activator of transcription-3 molecules is a reliable biomarker to quantify the photoreaction induced by PDT. Randomized studies are required to test the prognosis value of this biomarker, obtain approval for the new photosensitizers, and test the potential efficacy of interstitial and intraoperative PDT in the treatment of patients with non-small cell lung cancer.

  13. A Rare Case of Non-Small Cell Carcinoma of Lung Presenting as Miliary Mottling

    Directory of Open Access Journals (Sweden)

    Ballaekere Jayaram Subhashchandra

    2013-03-01

    Full Text Available Miliary mottling on chest radiography is seen in miliary tuberculosis, certain fungal infections, sarcoidosis, coal miner’s pneumoconiosis, silicosis, hemosiderosis, fibrosing alveolitis, acute extrinsic allergic alveolitis, pulmonary eosinophilic syndrome, pulmonary alveolar proteinosis, and rarely in hematogenous metastases from the primary cancers of the thyroid, kidney, trophoblasts, and some sarcomas. Although very infrequent, miliary mottling can be seen in primary lung cancers. Herein, we report the case of a 28-year-old female with chest X-ray showing miliary mottling. Thoracic computed tomography (CT features were suggestive of tuberculoma with miliary tuberculosis. CT-guided fine needle aspiration cytology confirmed the diagnosis as lower-lobe, left lung non-small cell carcinoma (adenocarcinoma. It is rare for the non-small cell carcinoma of the lung to present as miliary mottling. The rarity of our case lies in the fact that a young, non-smoking female with miliary mottling was diagnosed with non-small cell carcinoma of the lung.

  14. Survival outcomes for oligometastasis in resected non-small cell lung cancer.

    Science.gov (United States)

    Shimada, Yoshihisa; Saji, Hisashi; Kakihana, Masatoshi; Kajiwara, Naohiro; Ohira, Tatsuo; Ikeda, Norihiko

    2015-10-01

    We investigated the factors associated with post-recurrence survival and the treatment for non-small-cell lung cancer patients with postoperative distant recurrence, especially oligometastasis. We reviewed the data of 272 patients with distant recurrence who underwent resection of non-small-cell lung cancer from January 2000 through December 2011. The type of distant recurrence was classified as oligometastasis (n = 76, 28%) or polymetastasis (n = 196, 72%). Forty-seven (62%) patients with oligometastasis received local therapy (surgery 5, radiotherapy 9, sequential local and systemic therapy 28, chemoradiotherapy 5). Multivariate analysis revealed older age, non-adenocarcinoma, shorter disease-free interval, no pulmonary metastasis, liver metastases, bone metastases, and polymetastasis had significant associations with unfavorable post-recurrence survival. Subgroup analysis of patients with oligometastasis showed histology and disease-free interval had a great impact on survival. Smoking history and histology were associated with survival in patients with lung oligometastasis, whereas systemic treatment and longer disease-free interval were related to increased post-recurrence survival in those with brain oligometastasis. This study showed that an oligometastatic state per se was a significant favorable factor. Optimization of personalized systemic treatment and adding local treatment are important in the management of patients with non-small-cell lung cancer and oligometastasis. © The Author(s) 2015.

  15. The clinical significance of the tumor cell D2-40 immunoreactivity in non-small cell lung cancer.

    Science.gov (United States)

    Kadota, Kyuichi; Huang, Cheng-Long; Liu, Dage; Nakashima, Nariyasu; Yokomise, Hiroyasu; Ueno, Masaki; Haba, Reiji

    2010-10-01

    A monoclonal antibody D2-40 has been widely used for tumor lymphangiogenesis and lymphatic vessel invasion (LVI) in human cancers. However, the clinical significance of the tumor cell D2-40 immunoreactivity has not been clearly understood. We evaluated the tumor cell D2-40 immunoreactivity in non-small cell lung cancer (NSCLC). One hundred and forty-seven NSCLC patients were investigated. Immunohistochemistry using D2-40 was performed to evaluate the tumor cell D2-40 immunoreactivity, micro-lymphatic vessel density (Micro-LVD) and LVI. The intratumoral microvessels density (MVD) was evaluated by the CD34-immunostaining, and tumor proliferation was evaluated by the Ki-67-immunostaining. The percentage of D2-40-positive tumor cells was significantly higher in squamous cell carcinomas than in adenocarcinomas (P<0.0001), and all D2-40-strong tumors were squamous cell carcinomas. The percentage of D2-40-strong tumors was significantly higher in moderately to poorly differentiated tumors than in well-differentiated tumors (P=0.0332). Furthermore, the Ki-67 proliferation index in D2-40-strong tumors was significantly the highest. However, the tumor cell D2-40 immunoreactivity was not associated with Micro-LVD, LVI, or MVD. Regarding the patient survival, the overall survival was significantly lower in patients with D2-40-strong tumors than in patients with D2-40-negative or D2-40-weak tumors (P=0.0005). Multivariate analyses also revealed the tumor cell D2-40 immunoreactivity to be a significant prognostic factor of poor prognosis for NSCLC patients (P=0.0007). The D2-40 immunostaining is useful to identify aggressive squamous cell carcinomas of the lung. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  16. p53-Independent thermosensitization by mitomycin C in human non-small cell lung carcinoma cells

    International Nuclear Information System (INIS)

    Jin, Z.-H.; Matsumoto, H.; Hayashi, S.; Shioura, H.; Kitai, R.; Kano, E.; Hatashita, M.

    2003-01-01

    The combined treatment with hyperthermia and chemotherapeutic drugs such as cisplatin (CDDP), doxorubicin (DOX) and mitomycin C (MMC) has been widely adopted as a strategy of interdisciplinary cancer therapy to obtain greater therapeutic benefits. However, the involved mechanisms of the interactive cytotoxic effects of hyperthermia and MMC remain unclear. To elucidate the relationship between p53 functions and the interactive effects of the combined treatment with mild-hyperthermia and MMC, we examined the potentiation of cytotoxic effects, the induction of apoptosis, the changes in cell cycles and the accumulation of Hsp72 after the combined treatment with hyperthermia at 42 degree C and MMC using human non-small cell lung carcinoma H1299 transfectants with either null, wild-type (wt) or mutant (m) p53 gene. H1299/null, H1299/wtp53 and H1299/mp53 cells showed similar sensitivities to either hyperthermia at 42 degree C alone or MMC alone. The combined treatment resulted in a synergistically enhanced cytotoxicity in H1299 transfectants in a p53-independent manner. The mechanisms involved an enhancement of heat-induced apoptosis and a modulation of the cell cycle distribution by the combined treatment. The accumulation of Hsp72 was not suppressed by the combined treatment, as is not the case of the combined treatment with hyperthermia and either CDDP (1) or bleomycin (2). Our findings demonstrate a p53-independent mechanism for a synergistically cytotoxic enhancement by the combined treatment with mild-hyperthermia and MMC

  17. Prognosis and Treatment Decision Making in Early Stage Non-Small Cell Lung Cancer

    OpenAIRE

    Mokhles, Sahar

    2017-01-01

    textabstractLung cancer is one of the leading causes of death worldwide, and it is the largest contributor to new cancer diagnoses (12% of total new cancer cases) and to death from cancer (18% of total cancer deaths). There are two major groups of lung cancer that arise from the cells of the respiratory epithelium: non-small-cell lung cancer (NSCLC) and small-cell lung cancer, accounting for approximately 85% and 15% of lung cancer cases, respectively. The 5 year survival rate is 70-85% for l...

  18. Radiotherapy in medically inoperable early stage non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Bo Kyoung; Park, Charn II [College of Medicine, Seoul National Univ., Seoul (Korea, Republic of)

    2000-12-01

    For early stage non-small-cell lung cancer, surgical resection is the treatment of choice. But when the patients are not able to tolerate it because of medical problem and when refuse surgery, radiation therapy is considered an acceptable alternative. We report on the treatment results and the effect of achieving local control of primary tumors on survival end points and analyze factors that may influence survival and local control. We reviewed the medical records of 32 patients with medically inoperable non--small cell lung cancer treated at our institution from June, 1987 through June, 1997. All patients had a pathologic diagnosis of non-small cell lung cancer and were not. candidate for surgical resection because of either patients refusal (4), old age (2), lung problem (21), chest wall invasion (3) and heart problems (3). In 8 patients, there were more than 2 problems. The median age of the patients was 68 years (ranging from 60 to 86 years). Histologic cell type included squamous (24), adenocarcinoma (6) and unclassified squamous cell (2). The clinical stages of the patients were T1 in 5. T2 in 25, T3 in 2 patients. Initial tumor size was {<=}3.0 cm in 11, between 3.0 cm and 5.0 cm in 13 and more than 5.0 em in 8 patients. All patients had taken chest x-rays, chest CT, abdomen USG and bone scan. Radiotherapy was delivered using 6 MV or 10 MV linear accelerators. The doses of primary tumor were the ranging from 54.0 Gy to 68.8 Gy (median; 61.2 Gy). The duration of treatment was from 37 days through 64 days (median; 48.5 days) and there was no treatment interruption except 1 patient due to poor general status. In 12 patients, concomitant boost technique was used. There were no neoadjuvant or adjuvant treatments such as surgery or chemotherapy. The period of follow-up was ranging from 2 months through 93 months (median; 23 months). Survival was measured from the date radiation therapy was initiated. The overall survival rate was 44.6% at 2 years and 24.5% at 5

  19. Illness perceptions and quality of life in Japanese and Dutch patients with non-small-cell lung cancer

    NARCIS (Netherlands)

    Kaptein, A.A.; Yamaoka, K.; Snoei, L.; Kobayashi, K.; Uchida, Y.; van der Kloot, W.A.; Tabei, T.; Kleijn, W.C.; Koster, M.; Wijnands, G.; Kaajan, H.; Tran, T.; Inoue, K.; van Klink, R.; van Dooren-Coppens, E.; Dik, H.; Hayashi, F.; Willems, L.; Annema-Schmidt, D.; Annema, J.; van der Maat, B.; van Kralingen, K.; Meirink, C.; Ogoshi, K.; Aaronson, N.; Nortier, H.; Rabe, K.

    2011-01-01

    This study examined quality of life (QOL) and illness perceptions in Dutch and Japanese patients with non-small-cell lung cancer, thereby extending the body of knowledge on cultural differences and psychosocial aspects of this illness. 24 Dutch and 22 Japanese patients with non-small-cell lung

  20. [Survival and prognostic factors in resected satellite-nodule T4 non-small cell lung cancer].

    Science.gov (United States)

    Ma, Kai; Wang, Tian-you; He, Bao-liang; Chang, Dong; Hu, Xiao-dan; Yin, Zhi-yi; Jiang, Hua; Cui, Yong; Gao, Zhi; Gong, Min

    2009-01-15

    To study the survival and prognostic implication in surgically resected satellite-nodule T4 (T4 satellite) non-small cell lung cancer (NSCLC). From January 1995 to March 2005, the complete resection was performed to 42 patients with NSCLC who were postoperatively identified as pathologic-stage T4 satellite. Survival and associations between clinicopathological parameters and prognosis were analyzed. Thirty-two patients with pathologic stage local-invasion T4 (T4 invasion) NSCLC who underwent resection at the same time were also analyzed. The 1-, 3- and 5-year survival was 76.2%, 57.1% and 46.0% for patients with T4 satellite, while 62.3%, 31.5% and 20.0% for patients with T4 invasion. There was a significant higher survival in T4 satellite group when compared to that in T4 invasion group (P satellite N0M0 got a better survival than those with T4 satellite N1-2M0, T4 invasion N0M0 and T4 invasion N1 -2M0 (P satellite, univariate analysis showed that histology, main tumor size, lymph node status and adjuvant chemotherapy were linked with survival, while main tumor size, lymph node status and adjuvant chemotherapy served as the independent prognostic factors with multivariate analysis. Patients with completely resected T4 satellite NSCLC have a better prognosis than those with T4 invasion. Main tumor size over 3 cm, lymph node metastasis or no adjuvant chemotherapy means an unfavorable prognosis.

  1. Ulmus davidiana Nakai induces apoptosis and autophagy on non-small cell lung cancer cells.

    Science.gov (United States)

    Hong, Soon-Oh; Choi, In Keun; Jeong, Wonsik; Lee, Se Ryeon; Sung, Hwa Jung; Hong, Seong Su; Seo, Jae Hong

    2017-04-18

    Ulmus davidiana Nakai (UDN) is frequently used in the treatment of cancer in traditional oriental medicine. Although several reports indicate that UDN has inhibitory effects in some cancers, there has been no report on the inhibitory effects of UDN via both autophagy and apoptosis. Cytotoxicity induced by UDN in human non-small cell lung cancer (NSCLC) H-1299 and H-460 cell lines was evaluated using the 2, 3-Bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt (XTT) assay and trypan blue exclusion assay. Induction of apoptosis was also investigated using Hoechst staining and annexin-V binding assay and was confirmed with western blot analysis. Induction of autophagy was investigated through observation of autophagy vacuoles under inverted phase-contrast microscopy and was confirmed by observing the formation of autophagy vacuoles under a fluorescence microscope using monodansylcadaverine (MDC) staining and western blot analysis. The in vivo anti-tumorigenic effect of UDN was investigated in an athymic nude mouse xenograft model using H-1299 NSCLC cells. UDN exhibited a marked inhibitory effect on cell growth in H-1299 and H-460 human NSCLC cell lines in a dose- and time-dependent manner in vitro and in vivo. It induced not only apoptosis, but also autophagy in both H-1299 and H-460 cells in a dose-dependent manner. UDN-mediated autophagy led to the accumulation of autophagosome, resulting in apoptosis induction and cell death. From our current knowledge, we are the first to demonstrate that UDN has the potential to induce both autophagy and apoptosis in H-1299 and H-460 human NSCLC cell lines. We suggest that UDN can be considered a potential candidate for lung cancer-specific chemotherapy with efficacy as a cytotoxic agent. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  2. LncRNA CCAT2 promotes tumorigenesis by over-expressed Pokemon in non-small cell lung cancer.

    Science.gov (United States)

    Zhao, Zhihong; Wang, Ju; Wang, Shengfa; Chang, Hao; Zhang, Tiewa; Qu, Junfeng

    2017-03-01

    Non-small cell lung cancer (NSCLC) remains one of the most important death-related diseases, with poor effective diagnosis and less therapeutic biomarkers. LncRNA colon cancer-associated transcript 2 (CCAT2) was identified as an oncogenic lncRNA and over-expressed in many tumor cells. The aims of this study were to detect the correlation between CCAT2 and its regulatory genes and then explore the potential mechanism between them in NSCLC. In this study, qRT-PCR was used to detect CCAT2, Pokemon and p21 expression. Western-blot was used to detect protein levels of Pokemon and p21. CCK-8 assay and Transwell chambers were used to assess cell viability and invasion. CCAT2 and Pokemon were over-expressed in NSCLC tissue and cells. In NSCLC cells, CCAT2 knockdown significantly decreased cell viability and invasion as well as Pokemon expression, but increased the expression of p21; then CCAT2 overexpression revealed an opposite result. In addition, over-expressed Pokemon reversed the results that induced by si-CCAT2, while down-regulation of Pokemon significantly reversed the results that induced by CCAT2 overexpression. The results indicated that CCAT2 promotes tumorigenesis by over-expression of Pokemon, and the potential mechanism might relate to the Pokemon related gene p21. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. ABCC4 is required for cell proliferation and tumorigenesis in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Zhao X

    2014-02-01

    Full Text Available Xiaoting Zhao, Yinan Guo, Wentao Yue, Lina Zhang, Meng Gu, Yue Wang Department of Cellular and Molecular Biology, Beijing TB and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, People's Republic of China Background: Multidrug resistance protein 4 (MRP4, also known as ATP-cassette binding protein 4 (ABCC4, is a member of the MRP/ABCC subfamily of ATP-binding cassette transporters, which are capable of pumping a wide variety of drugs out of the cell. However, little is known about the function of ABCC4 in the proliferation of lung cancer cells. Methods: ABCC4 mRNA and protein levels in lung cancer cell lines were measured by real-time polymerase chain reaction and Western blot, respectively. A lentivirus-mediated RNA interference technique was used to inhibit ABCC4 mRNA expression in A549 and 801D cells. The function of ABCC4 in cell growth was investigated by MTS and colony formation assays. The role of ABCC4 in cell cycle progression was evaluated by flow cytometry and Western blot analysis. ABCC4 mRNA levels in 30 pairs of tumors and corresponding matched adjacent normal tissues from non-small cell lung cancer patients were detected by real-time polymerase chain reaction. Results: ABCC4 was highly expressed in lung cancer cell lines. ABCC4 expression was markedly downregulated in A549 and 801D cells using the RNA interference technique. Suppression of ABCC4 expression inhibited cell growth. The percentage of cells in G1 phase was increased when ABCC4 expression was suppressed. Phosphorylation of retinoblastoma protein was weakened, originating in the downregulation of ABCC4. ABCC4 mRNA was highly expressed in lung cancer tissue and lung cancer cell lines. Conclusion: ABCC4 may play an important role in the control of A549 and 801D cell growth. ABCC4 is a potential target for lung cancer therapy. Keywords: ABCC4, cell proliferation, lung cancer, cell cycle

  4. NOX4 supports glycolysis and promotes glutamine metabolism in non-small cell lung cancer cells.

    Science.gov (United States)

    Zeng, Cheng; Wu, Qipeng; Wang, Jing; Yao, Bei; Ma, Lei; Yang, Zhicheng; Li, Juan; Liu, Bing

    2016-12-01

    Our previous studies have confirmed that NADPH oxidase 4 (NOX4) is abundantly expressed in non-small cell lung cancer (NSCLC) and contributes to cancer progression. Nevertheless, the comprehensive mechanisms for NOX4-mediated malignant progression and oxidative resistance of cancer cells remain largely unknown. This study found that NOX4 directed glucose metabolism not only to the glycolysis but also to pentose phosphate pathway (PPP) pathway for production of NADPH in NSCLC cell lines. Besides, we also found that NOX4 promoted glutaminolysis into total GSH synthesis. Specifically, the data showed that ectopic NOX4 expression did not induce apoptosis of NSCLC cells; however, inhibition of GSH production resulted in obvious apoptotic death of NOX4-overexpressed NSCLC cells. Furthermore, we demonstrated that NOX4-induced glycolysis probably via ROS/PI3K/Akt signaling-dependent c-Myc upregulation. The selective NOX4 inhibitor, GKT137831, significantly inhibited glucose and glutamine metabolic phenotypes both in vitro and in vivo, and itself or combination with 2-DG, a synthetic glycolytic inhibitor, suppressed cancer cell growth both in vivo and in vitro. Elimination of NOX4-derived H 2 O 2 effectively reversed NOX4 overexpression-mediated metabolic effects in NSCLC cells. NOX4 levels were significantly correlated with increased glucose and glutamine metabolism-related genes, as well as Akt phosphorylation and c-Myc expression in primary NSCLC specimens. In conclusion, these results reveal that NOX4 promotes glycolysis, contributing to NSCLC growth, and supports glutaminolysis for oxidative resistance. Therefore, NOX4 may be a promising target to reverse malignant progression of NSCLC. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Comparison between morphometry and immunostaining of malignant cells in non-small cell lung cancer.

    Science.gov (United States)

    Politi, Ekaterini N; Lazaris, Andreas C; Kavantzas, Nikolaos; Koutselini, Helen

    2003-06-01

    To investigate the morphometric properties of tumor cells in combination with the expression of 5 immunomarkers, quantitatively evaluated by image analysis, in a series of 60 non-small cell lung carcinomas (NSCLCs) and to assess their prognostic significance. Tissue sections from 60 NSCLCs were assessed for the expression of p53, Ki-67, bcl-2, bax and FasL using immunohistochemistry and antibodies. Correlations between morphometric features and clinicopathologic variables, including overall survival and the expression of the above markers, were statistically investigated. Major and minor axis nuclear values, as well as nuclear area and perimeter values, were positively interrelated. No statistically significant correlations were observed between nuclear morphometry and any of the clinicopathologic parameters. p53 Accumulation, when quantitatively estimated, displayed a positive correlation with major axis (P = .008), minor axis (P = .06), nuclear perimeter (P = .006) and mainly nuclear area values (P = .003). Bcl-2- and bax-quantified immunostaining demonstrated a weak negative correlation with shape factor values (P = .039 and P = .025, respectively). Univariate and multivariate analysis showed that stage was the only significant predictor of survival in all patients. In univariate statistical analysis there was a trend between worse survival and shape factor values < 0.8 (P = .0791); this trend almost reached statistical significance in the subgroup of squamous cell carcinomas (P = .0570). p53 Accumulation, when quantified, appears to be positively linked with nuclear morphometric values. The prognostic significance of shape factor in NSCLC warrants further investigation.

  6. Exosomal proteins as prognostic biomarkers in non-small cell lung cancer

    DEFF Research Database (Denmark)

    Sandfeld-Paulsen, B; Aggerholm-Pedersen, N; Bæk, R

    2016-01-01

    BACKGROUND: Use of exosomes as biomarkers in non-small cell lung cancer (NSCLC) is an intriguing approach in the liquid-biopsy era. Exosomes are nano-sized vesicles with membrane-bound proteins that reflect their originating cell. Prognostic biomarkers are needed to improve patient selection...... for optimal treatment. We here evaluate exosomes by protein phenotyping as a prognostic biomarker in NSCLC. METHODS: Exosomes from plasma of 276 NSCLC patients were phenotyped using the Extracellular Vesicle Array; 49 antibodies captured the proteins on the exosomes, and a cocktail of biotin...

  7. Intracellular calcium promotes radioresistance of non-small cell lung cancer A549 cells through activating Akt signaling.

    Science.gov (United States)

    Wang, Yiling; He, Jiantao; Zhang, Shenghui; Yang, Qingbo

    2017-03-01

    Radiotherapy is a major therapeutic approach in non-small cell lung cancer but is restricted by radioresistance. Although Akt signaling promotes radioresistance in non-small cell lung cancer, it is not well understood how Akt signaling is activated. Since intracellular calcium (Ca 2+ ) could activate Akt in A549 cells, we investigated the relationship between intracellular calcium (Ca 2+ ) and Akt signaling in radioresistant A549 cells by establishing radioresistant non-small cell lung cancer A549 cells. The radioresistant cell line A549 was generated by dose-gradient irradiation of the parental A549 cells. The cell viability, proliferation, and apoptosis were, respectively, assessed using the cell counting kit-8, EdU labeling, and flow cytometry analysis. The phosphorylation of Akt was evaluated by Western blotting, and the intracellular Ca 2+ concentration was assessed by Fluo 4-AM. The radioresistant A549 cells displayed mesenchymal morphology. After additional irradiation, the radioresistant A549 cells showed decreased cell viability and proliferation but increased apoptosis. Moreover, the intracellular Ca 2+ concentration and the phosphorylation level on the Akt473 site in radioresistant A549 cells were higher than those in original cells, whereas the percentage of apoptosis in radioresistant A549 cells was less. All these results could be reversed by verapamil. In conclusion, our study found that intracellular Ca 2+ could promote radioresistance of non-small cell lung cancer cells through phosphorylating of Akt on the 473 site, which contributes to a better understanding on the non-small cell lung cancer radioresistance, and may provide a new target for radioresistance management.

  8. Inhibitory Activity of (+-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility.

    Directory of Open Access Journals (Sweden)

    Yi Yang

    Full Text Available Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, β-catenin-mediated TOPFLASH activity and KITENIN-mediated AP-1 activity were decreased by (+-usnic acid treatment in a dose-dependent manner. The quantitative real-time PCR data showed that (+-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both β-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with (+-usnic acid. Interestingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+-usnic acid and cetuximab. These results implied that (+-usnic acid might have potential activity in inhibition of cancer cell metastasis, and (+-usnic acid could be used for anti-cancer therapy with a distinct mechanisms of action.

  9. Inhibitory Activity of (+)-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility

    Science.gov (United States)

    Yang, Yi; Nguyen, Thanh Thi; Jeong, Min-Hye; Crişan, Florin; Yu, Young Hyun; Ha, Hyung-Ho; Choi, Kyung Hee; Jeong, Hye Gwang; Jeong, Tae Cheon; Lee, Kwang Youl; Kim, Kyung Keun; Hur, Jae-Seoun; Kim, Hangun

    2016-01-01

    Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+)-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, β-catenin-mediated TOPFLASH activity and KITENIN-mediated AP-1 activity were decreased by (+)-usnic acid treatment in a dose-dependent manner. The quantitative real-time PCR data showed that (+)-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both β-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with (+)-usnic acid. Interestingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+)-usnic acid and cetuximab. These results implied that (+)-usnic acid might have potential activity in inhibition of cancer cell metastasis, and (+)-usnic acid could be used for anti-cancer therapy with a distinct mechanisms of action. PMID:26751081

  10. Swarm Intelligence-Enhanced Detection of Non-Small-Cell Lung Cancer Using Tumor-Educated Platelets.

    Science.gov (United States)

    Best, Myron G; Sol, Nik; In 't Veld, Sjors G J G; Vancura, Adrienne; Muller, Mirte; Niemeijer, Anna-Larissa N; Fejes, Aniko V; Tjon Kon Fat, Lee-Ann; Huis In 't Veld, Anna E; Leurs, Cyra; Le Large, Tessa Y; Meijer, Laura L; Kooi, Irsan E; Rustenburg, François; Schellen, Pepijn; Verschueren, Heleen; Post, Edward; Wedekind, Laurine E; Bracht, Jillian; Esenkbrink, Michelle; Wils, Leon; Favaro, Francesca; Schoonhoven, Jilian D; Tannous, Jihane; Meijers-Heijboer, Hanne; Kazemier, Geert; Giovannetti, Elisa; Reijneveld, Jaap C; Idema, Sander; Killestein, Joep; Heger, Michal; de Jager, Saskia C; Urbanus, Rolf T; Hoefer, Imo E; Pasterkamp, Gerard; Mannhalter, Christine; Gomez-Arroyo, Jose; Bogaard, Harm-Jan; Noske, David P; Vandertop, W Peter; van den Broek, Daan; Ylstra, Bauke; Nilsson, R Jonas A; Wesseling, Pieter; Karachaliou, Niki; Rosell, Rafael; Lee-Lewandrowski, Elizabeth; Lewandrowski, Kent B; Tannous, Bakhos A; de Langen, Adrianus J; Smit, Egbert F; van den Heuvel, Michel M; Wurdinger, Thomas

    2017-08-14

    Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92-0.96; p swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Radiation therapy alone for early stage non-small cell carcinoma of the lung

    International Nuclear Information System (INIS)

    Chun, Ha Chung; Lee, Myung Za

    2002-01-01

    To evaluate the outcome of early stage non-small cell lung cancer patients who were treated with radiation therapy along and define the optimal radiotherapeutic regimen for these patients. A retrospective review was performed on patients with sage I or II non-small cell carcinoma of the lung that were treated at our institution between June, 1987 and May, 2000. A total of 21 patients treated definitively with radiation therapy alone were included in this study. The age of the patients ranged from 53 to 81 years with a median of 66 years. All the patients were male. The medical reasons for inoperability were lack of pulmonary reserve, cardiovascular disease, poor performance status, old age, and patient refusal in the decreasing order. Pathological evidence was not adequate to characterize the non-small cell subtype in two patients. Of the remaining 19 patients, 16 had squamous cell carcinoma and 3 had adenocarcinoma. Treatment was given with conventional fractionation, once a day, five times a week. The doses to the primary site ranged from 56 Gy to 69 Gy. No patients were lost to follow-up. The overall survival rates for the entire group at 2, 3 and 5 years were 41, 30 and 21%, respectively. The cause specific survivals at 2, 3 and 5 years were 55, 36 and 25%, respectively. An intercurrent disease was the cause of death in two patients. The cumulative local failure rate at 5 years was 43%. Nine of the 21 patients had treatment failures after the curative radiotherapy was attempted. Local recurrences as the first site of failure were documented in 7 patients. Therefore, local failure alone represented 78% of the total failures. Those patients whose tumor sizes were less than 4 cm had a significantly better 5 year disease free survival than those with tumors greater than 4 cm (0% vs 36%). Those patients with a Karnofsky performance status less than 70 did not differ significantly with respect to actuarial survival when compared to those with a status greater than 70

  12. Proton Beam Therapy of Stage II and III Non-Small-Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Nakayama, Hidetsugu, E-mail: hnakayam@tokyo-med.ac.jp [Proton Medical Research Center, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, Tokyo Medical University, Shinjuku, Tokyo (Japan); Satoh, Hiroaki [Department of Respiratory Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki (Japan); Sugahara, Shinji [Proton Medical Research Center, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, Tokyo Medical University, Shinjuku, Tokyo (Japan); Kurishima, Koichi [Department of Respiratory Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki (Japan); Tsuboi, Koji; Sakurai, Hideyuki [Proton Medical Research Center, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki (Japan); Ishikawa, Shigemi [Department of Thoracic Surgery, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki (Japan); Tokuuye, Koichi [Proton Medical Research Center, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki (Japan); Department of Radiation Oncology, Tokyo Medical University, Shinjuku, Tokyo (Japan)

    2011-11-15

    Purpose: The present retrospective study assessed the role of proton beam therapy (PBT) in the treatment of patients with Stage II or III non-small-cell lung cancer who were inoperable or ineligible for chemotherapy because of co-existing disease or refusal. Patients and Methods: Between November 2001 and July 2008, PBT was given to 35 patients (5 patients with Stage II, 12 with Stage IIIA, and 18 with Stage IIIB) whose median age was 70.3 years (range, 47.4-85.4). The median proton dose given was 78.3 Gy (range, 67.1-91.3) (relative biologic effectiveness). Results: Local progression-free survival for Stage II-III patients was 93.3% at 1 year and 65.9% at 2 years during a median observation period of 16.9 months. Four patients (11.4%) developed local recurrence, 13 (37.1%) developed regional recurrence, and 7 (20.0%) developed distant metastases. The progression-free survival rate for Stage II-III patients was 59.6% at 1 year and 29.2% at 2 years. The overall survival rate of Stage II-III patients was 81.8% at 1 year and 58.9% at 2 years. Grade 3 or greater toxicity was not observed. A total of 15 patients (42.9%) developed Grade 1 and 6 (17.1%) Grade 2 toxicity. Conclusion: PBT for Stage II-III non-small-cell lung cancer without chemotherapy resulted in good local control and low toxicity. PBT has a definite role in the treatment of patients with Stage II-III non-small-cell lung cancer who are unsuitable for surgery or chemotherapy.

  13. [Non-small cell lung cancer: risk factors of radiation pneumonitis].

    Science.gov (United States)

    Giroux Leprieur, E; Fernandez, D; Chatellier, G; Klotz, S; Giraud, P; Durdux, C

    2012-01-01

    To evaluate the predictors of acute radiation pneumonitis after conformal thoracic radiotherapy in the treatment of locally advanced non-small cell lung cancer. Forty-seven consecutive patients were treated with conformal thoracic irradiation for locally advanced non-small cell lung cancer and retrospectively analysed. The mean total dose of radiotherapy was 65 Gy with respiratory gating in 19 cases. Neoadjuvant and concomitant chemotherapy was performed in 33 patients (70%) and 41 patients (87%) respectively. Eleven patients (23%) had an acute radiation pneumonitis, resulting in death for one patient. In univariate analysis, age, sex, pretherapeutic value of forced expiratory volume, non-gated radiotherapy and type of concomitant chemotherapy did not appear as contributing factors in contrast to the administration of neoadjuvant gemcitabine (P=0.03). The occurrence of acute radiation pneumonitis was significantly associated with non-tumour lung volumes irradiated to 13 Gy (V13, P=0.04), 20 Gy (V20, P=0.02) and 25 Gy (V25, P=0.006), the mean lung dose (P=0.008) and lung normal tissue complication probability (P=0.004). In multivariate logistic regression analysis, the occurrence of acute radiation pneumonitis was significantly associated with age above 75 years (odds ratio [OR]=16.72 ; P=0.02) and with administration of neoadjuvant gemcitabine (OR=18.08, P=0.04). Acute radiation pneumonitis is a common acute side effect of the conformal thoracic radiotherapy of locally advanced non-small cell lung cancer, requiring close post-treatment follow-up, particularly for elderly patients. The use of gemcitabine before radiation should be avoided. The benefits and risks of conformal thoracic radiotherapy must be carefully analyzed in view of the dosimetric parameters obtained. Copyright © 2012. Published by Elsevier SAS.

  14. A New Target in Non-small Cell Lung Cancer: EML4-ALK Fusion Gene

    Directory of Open Access Journals (Sweden)

    Huijuan WANG

    2011-06-01

    Full Text Available It was only 3 years ago that the fusion gene between echinoderm microtubule-associated protein-like4 (EML4 and anaplastic lymphoma kinase (ALK has been identified in a subset of non-small cell lung cancer (NSCLC. EML4-ALK is most often detected in never smokers with lung adenocarcinoma and has unique pathologic features. EML4-ALK fusion gene is oncogenic, which could be suppressed by ALK-inhibitor through blocking the downstream signaling passway of EML4-ALK. This review will focus on the molecular structure, function, biology, detection method and the diagnostic and therapeutic meaning of EML4-ALK of lung cancer.

  15. Significances of RET Fusion Gene in Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jingjing LIU

    2013-11-01

    Full Text Available Lung cancer is the leading cause of cancer-related death worldwide, molecular target therapy has become a hot research direction of non-small cell lung cancer (NSCLC treatment. RET fusion gene with an identifiable clinical pathological features, is present in some subsets of lung cancer, and its treatment is effective by RET inhibitor, suggesting that RET fusion gene may be a new target for individualized treatment to the subgroup of NSCLC. This article reviews the structural characteristics of RET fusion gene and expression model in clinical samples, and treatment of NSCLC.

  16. Peripheral intrapulmonary lymph node metastases of non-small-cell lung cancer.

    Science.gov (United States)

    Boubia, Souheil; Barthes, Françoise Lepimpec; Danel, Claire; Riquet, Marc

    2004-03-01

    Since the development and progress of computed tomographic imaging, peripheral intrapulmonary lymph nodes (IPLNs) have become increasingly described and well-known entities. Intrapulmonary lymph nodes may appear as a solitary pulmonary nodular shadow mimicking a non-small-cell lung cancer (NSCLC) or as multiple nodules masquerading as carcinoma metastases. We describe a case in which IPLNs presented as a clinical "nodular" T4 N0 NSCLC that finally proved to be a pathologic T2 N1 NSCLC, thus raising new questions on this entity.

  17. Learning From Trials on Radiation Dose in Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bradley, Jeffrey, E-mail: jbradley@wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Hu, Chen [Division of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

    2016-11-15

    In this issue of the International Journal of Radiation Oncology • Biology • Physics, Taylor et al present a meta-analysis of published data supporting 2 findings: (1) radiation dose escalation seems to benefit patients who receive radiation alone for non-small cell lung cancer; and (2) radiation dose escalation has a detrimental effect on overall survival in the setting of concurrent chemotherapy. The latter finding is supported by data but has perplexed the oncology community. Perhaps these findings are not perplexing at all. Perhaps it is simply another lesson in the major principle in radiation oncology, to minimize radiation dose to normal tissues.

  18. CIMAvax-EGF®: Therapeutic Vaccine Against Non-small Cell Lung Cancer in Advanced Stages

    Directory of Open Access Journals (Sweden)

    Diana Rosa Fernández Ruiz

    2017-02-01

    Full Text Available Biotechnology is one of the scientific activities deployed by the Cuban State, which shows greater results and impact on the of the Cuban population health. It has increased the therapeutic repertoire in dealing with oncological diseases with products such as CIMAvax-EGF®, the first therapeutic vaccine of its kind, from the Molecular Immunology Center, against non-small cell lung cancer in advanced stages IIIB IV. The application of this product already extends to Primary Health Care with encouraging results, by prolonging the survival of patients with higher quality of life.

  19. Low level of 5-Hydroxymethylcytosine predicts poor prognosis in non-small cell lung cancer

    OpenAIRE

    LIAO, YUNFEI; GU, JIE; WU, YONGBING; LONG, XIANG; GE, DI; XU, JIANJUN; DING, JIANYONG

    2016-01-01

    The loss of 5-hydroxymethylcytosine (5-hmC) has previously been demonstrated to be implicated in the initiation and progression of various tumors. However, its role in non-small cell lung cancer (NSCLC) remains unknown. The present study aimed to determine the level of 5-hmC in NSCLC and their adjacent normal lung tissues by immunohistochemistry and dot-blot analysis; then the relationship between 5-hmC level and the clinicopathological features of NSCLC and the prognostic significance of 5-h...

  20. Relationship between intercellular communication and adriamycin resistance in non-small cell lung cancer.

    Science.gov (United States)

    Bradley, C; Freshney, R I; Pitts, J

    1994-01-01

    The adriamycin chemosensitivity and extent of gap junctional intercellular communication were assessed in a panel of seven human non-small cell lung cancer (NSCLC) cell lines. Communication was assessed by autoradiographic detection of transfer of 3H uridine nucleotides between coupled cells. The strength of coupling varied widely between the cell lines and they could be separated into 3 groups: those which exhibited strong coupling, L-DAN and A549; those which exhibited weak coupling, SK-MES-1, Calu-3 and NCI-H125; and an intermediate group, WIL and NCI-H23. Adriamycin chemosensitivity was assessed by both clonogenic and MTT assays. The range of IC50 values as measured by either assay was extremely narrow, with no important differences between the lines. Thus, despite the wide spectrum of intercellular communication observed in these lines, this did not correlate with their adriamycin resistance.

  1. Metronomic Chemotherapy - A New Path to Treat Advanced Non-small Cell Lung Cancer

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    Shuang ZHANG

    2015-04-01

    Full Text Available Metronomic chemotherapy is an emerging strategy to fight cancer. Unlike traditional chemotherapy, metronomic chemotherapy is defined by the frequent, repetitive administration of chemotherapeutic drugs at relatively low doses, and without prolonged drug-free break. Initially thought to play a role inhibiting tumor angiogenesis by targeting activated endothelial cells in tumors, metronomic chemotherapy is a multi-targeted therapy,including activation of immunity, effect on tumour initiating cells, induction of tumor dormancy. It is from eradicateing tumor cells to improve effect, reduce the toxicity and improve quality of life for treatment of advanced non-small cell lung cancer (NSCLC. Metronomic chemotherapy which can avoid the toxicity of traditional chemotherapy and rebounding is explored in clinical studies of advanced NSCLC, as a promising treatment strategy.

  2. Src Promotes Metastasis of Human Non-Small Cell Lung Cancer Cells through Fn14-Mediated NF-κB Signaling.

    Science.gov (United States)

    Wang, Wei; Liu, Feiyu; Wang, Chaoyang; Wang, Chengde; Tang, Yijun; Jiang, Zhongmin

    2018-03-03

    BACKGROUND Src and Fn14 are implicated in the aggressiveness of non-small cell lung cancer (NSCLC) cells, yet the molecular mechanism is not fully understood. MATERIAL AND METHODS The proliferation, migration, and invasion of HCC827 cells with Src knockdown were examined in vitro. The expression of Fn14 and the activation of NF-κB signaling pathway in Src-silenced HCC827 cells were detected by western blot. The role of Fn14 in Src-regulated cell migration/invasion and activation of NF-κB signaling was investigated by overexpressing Fn14 in Src knockdown NSCLC cells. Furthermore, the pro-metastatic role of Src was validated in a NSCLC metastasis mouse model. RESULTS Knockdown of Src inhibited the proliferation, migration, and invasion of HCC827 cells, which was associated with reduced levels of Fn14, p-IκBα, p-IKKβ, and nuclear NF-κB p65. Overexpression of Fn14 restored the potential of migration and invasion as well as the activation of NF-κB signaling in Src-silenced NSCLC cells. In addition, silencing of Src suppressed lung metastasis of HCC827 cells in mice, and inhibited the expression of Fn14 and nuclear translocation of NF-κB p65 in vivo. CONCLUSIONS The data demonstrated that the Src/Fn14/NF-κB axis plays a critical role in NSCLC metastasis.

  3. [Role of PET/CT in primitive non-small cell bronchopulmonary cancer].

    Science.gov (United States)

    Soumia, Fdil; Leila, Achachi; Mohamed, Raoufi; Laila, Herrak; Mustapha, Elftouh

    2017-01-01

    Bronchopulmonary cancer is a real public health problem. Morphological imaging plays a central role in its diagnosis, staging as well as post-therapeutic assessment but it has some limitations. Metabolic imaging is a more recent technique which allows to significantly improve the overall imagery performance. We conducted a retrospective, descriptive and analytical study at the Ibn Sina Hospital and at the Military Hospital of instruction Mohammed V in Rabat over a period of 18 months, between September 2014 and February 2016, in order to evaluate the role of Fluorodeoxyglucose-PET/CT in the staging and restaging of non-small cell bronchopulmonary cancer. Initial staging showed a vast majority of locally advanced and metastatic stages: stage IV (40%), Stage IIIB (36%), Stage IIIA (16%), Stage II (8%). PET-CT allowed to detect new sites which were not initially seen on CT scan in 24 cases: 15 new ganglion sites, 8 new adrenal sites and 6 sites of bone lesions. PET/CT allowed to modify initial tumor stage in 60% of cases: upstaging in 23 patients (46%) and downstaging in 7 patients(14%). The initial stage remained unchanged in 40% of patients. Our study confirms the data from the literature concerning the superiority of PET-CT in comparison with CT scan, but only in the optimization of the non-small cell bronchopulmonary cancer management, in particular in locoregional and distant staging.

  4. Molecularly targeted approaches herald a new era of non-small-cell lung cancer treatment

    Directory of Open Access Journals (Sweden)

    Kaneda H

    2013-06-01

    Full Text Available Hiroyasu Kaneda,1 Takeshi Yoshida,1 Isamu Okamoto2 1Department of Medical Oncology, Kinki University, Osakasayama, Japan; 2Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan Abstract: The discovery of activating mutations in the epidermal growth-factor receptor (EGFR gene in 2004 opened a new era of personalized treatment for non-small-cell lung cancer (NSCLC. EGFR mutations are associated with a high sensitivity to EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib. Treatment with these agents in EGFR-mutant NSCLC patients results in dramatically high response rates and prolonged progression-free survival compared with conventional standard chemotherapy. Subsequently, echinoderm microtubule-associated protein-like 4 (EML4–anaplastic lymphoma kinase (ALK, a novel driver oncogene, has been found in 2007. Crizotinib, the first clinically available ALK tyrosine kinase inhibitor, appeared more effective compared with standard chemotherapy in NSCLC patients harboring EML4-ALK. The identification of EGFR mutations and ALK rearrangement in NSCLC has further accelerated the shift to personalized treatment based on the appropriate patient selection according to detailed molecular genetic characterization. This review summarizes these genetic biomarker-based approaches to NSCLC, which allow the instigation of individualized therapy to provide the desired clinical outcome. Keywords: non-small-cell lung cancer, epidermal growth factor receptor, ALK rearrangement, gefitinib, erlotinib, crizotinib

  5. Clinical outcome of stage III non-small-cell lung cancer patients after definitive radiotherapy.

    Science.gov (United States)

    Nakamura, Tatsuya; Fuwa, Nobukazu; Kodaira, Takeshi; Tachibana, Hiroyuki; Tomoda, Takuya; Nakahara, Rie; Inokuchi, Haruo

    2008-01-01

    Primarily combined radiotherapy and chemotherapy are used to treat unresectable non-small-cell lung cancer; however, the results are not satisfactory. In this study treatment results were retrospectively analyzed and the prognostic factors related to survival were identified. From March 1999 to January 2004, 102 patients with stage IIIA/IIIB non-small-cell lung cancer received definitive radiotherapy with or without chemotherapy. Radiotherapy involved a daily dose of 1.8-2.0 Gy five times a week; 60 Gy was set as the total dose. Maximal chemotherapy was given to patients with normal kidney, liver, and bone marrow functions. The 5-year overall survival rate was 22.2%; the median survival was 18 months. The median follow-up of surviving patients was 53 months. The complete or partial response rate was 85%. At the time of the last follow-up, 21 patients were alive and 81 patients had died, including 5 patients who had died due to radiation pneumonitis. There were significant differences in survival and in the fatal radiation pneumonitis rate between patients with superior lobe lesions and those with middle or inferior lobe lesions. Patients whose primary tumor is located in the superior lobe appear to have a better clinical outcome.

  6. Radiotherapy alone for elderly patients with stage III non-small cell lung cancer

    International Nuclear Information System (INIS)

    Nakano, Kikuo; Hiramoto, Takehiko; Kanehara, Masasi; Doi, Mihoko; Furonaka, Osamu; Miyazu, Yuka; Hada, Yosihiro

    1999-01-01

    We undertook a retrospective study of elderly patients with stage III non-small cell lung cancer who had been treated solely with radiotherapy during the period 1986 to 1995. Our study was designed to assess the influence of age on survival and malnutrition in patients aged 75 years or older (elderly group) and patients aged 74 years or younger (younger group). Radiotherapy alone resulted in a median survival period of 11.5 months in the younger group and 6.3 months in the elderly group (p=0.0043). With the Cox multivariate model, good performance status, age less than 75 years, and good response were significant favorable independent predictors. Furthermore, the elderly group patients more frequently died of respiratory infections and had lower prognostic nutritional indexes than the younger group patients before and after radiotherapy. These findings suggested elderly patients with stage III non-small cell lung cancer who had been treated with radiotherapy alone had a poor prognosis and that malnutrition caused by radiotherapy was a factor contributing to the risk of death from respiratory infection in such patients. (author)

  7. Natural History of Non-Small-Cell Lung Cancer with Bone Metastases

    Science.gov (United States)

    Daniele, Santini; Sandro, Barni; Salvatore, Intagliata; Alfredo, Falcone; Francesco, Ferraù; Domenico, Galetta; Luca, Moscetti; Nicla, La Verde; Toni, Ibrahim; Fausto, Petrelli; Enrico, Vasile; Laura, Ginocchi; Davide, Ottaviani; Flavia, Longo; Cinzia, Ortega; Antonio, Russo; Giuseppe, Badalamenti; Elena, Collovà; Gaetano, Lanzetta; Giovanni, Mansueto; Vincenzo, Adamo; Filippo, De Marinis; Satolli, Maria Antonietta; Flavia, Cantile; Andrea, Mancuso; Tanca, Francesca Maria; Raffaele, Addeo; Marco, Russano; Sterpi, M; Francesco, Pantano; Bruno, Vincenzi; Giuseppe, Tonini

    2015-01-01

    We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age >65 years, non-adenocarcinoma histology, ECOG Performance Status >2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival. PMID:26690845

  8. Quality of life assessment as a predictor of survival in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Staren Edgar D

    2011-08-01

    Full Text Available Abstract Background There are conflicting and inconsistent results in the literature on the prognostic role of quality of life (QoL in cancer. We investigated whether QoL at admission could predict survival in lung cancer patients. Methods The study population consisted of 1194 non-small cell lung cancer patients treated at our institution between Jan 2001 and Dec 2008. QoL was evaluated using EORTC-QLQ-C30 prior to initiation of treatment. Patient survival was defined as the time interval between the date of first patient visit and the date of death from any cause/date of last contact. Univariate and multivariate Cox regression evaluated the prognostic significance of QoL. Results Mean age at presentation was 58.3 years. There were 605 newly diagnosed and 589 previously treated patients; 601 males and 593 females. Stage of disease at diagnosis was I, 100; II, 63; III, 348; IV, 656; and 27 indeterminate. Upon multivariate analyses, global QoL as well as physical function predicted patient survival in the entire study population. Every 10-point increase in physical function was associated with a 10% increase in survival (95% CI = 6% to 14%, p Conclusions Baseline global QoL and physical function provide useful prognostic information in non-small cell lung cancer patients.

  9. Postoperative Radiation Therapy in Resected N2 Stage Non-Small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Lee, Chang Geol

    1993-01-01

    A total of forty patients with resected N2 stage non-small cell lung cancer treated with postoperative adjuvant radiation therapy between Jan. 1975 and Dec. 1990 at the Department of Radiation Oncology, Yonsei University College of Medicine, Yonsei Cancer Center were retrospectively analysed to evaluate whether postoperative radiation therapy improves survival. Patterns of failure and prognostic factors affecting survival were also analysed. The 5 year overall and disease free survival rate were 26.3%, 27.3% and median survival 23.5 months. The 5 year survival rates by T-stage were T1 66.7%, T2 25.6% and T3 12.5%. Loco-regional failure rate was 14.3% and distant metastasis rate was 42.9% and both 2.9%. Statistically significant factor affecting distant failure rate was number of positive lymph nodes(>= 4). This retrospective study suggests that postoperative radiation therapy in resected N2 stage non-small cell lung cancer can reduce loco-regional recurrence and may improve survival rate as compared with other studies which were treated by surgery alone. Further study of systemic control is also needed due to high rate of distant metastasis

  10. Outcome following radiotherapy for loco-regionally recurrent non-small cell lung cancer

    International Nuclear Information System (INIS)

    Foo, K.; Yeghiaian-Alvandi, R.; Foroudi, F.

    2005-01-01

    Local and regional recurrence of non-small cell lung cancer is reported to occur in 13-20% of treatment failures after resection. Reported post-recurrent median survival following radiotherapy ranges from 9 to 14 months. This study examines survival following radiotherapy alone for patients with loco-regionally recurring non-small cell lung cancer after initial surgery. Fifty-five patients, receiving radiotherapy at Westmead Hospital between 1979 and 1997, were eligible for study. Data were collected retrospectively by reviewing patient records. The end-point was overall survival. Symptom control was also recorded. Prognostic factors for analysis included age, sex, original presenting stage, disease-free interval (DFI), performance status, site of recurrence, treatment intent and dose. The median overall survival was 11.5 months (95% confidence interval: 8.1-13.0). Survival following treatment with radical intent was 26 months compared to 10.5 months for patients treated with palliative intent (P = 0.025). There was no significant difference in survival for short (<2 years) or long DFI, performance status, radiation dose, age, sex, site of recurrence or stage. Most patients (55%) had partial or complete resolution of symptoms. Radiotherapy results in overall post-recurrence median survival of nearly 1 year, consistent with previous published data. Radical treatment intent predicts better prognosis as a result of patient selection and higher dose. Radiotherapy is effective at palliating symptoms of this disease Copyright (2005) Blackwell Publishing Asia Pty Ltd

  11. Natural History of Non-Small-Cell Lung Cancer with Bone Metastases.

    Science.gov (United States)

    Santini, Daniele; Daniele, Santini; Barni, Sandro; Sandro, Barni; Intagliata, Salvatore; Salvatore, Intagliata; Falcone, Alfredo; Alfredo, Falcone; Ferraù, Francesco; Francesco, Ferraù; Galetta, Domenico; Domenico, Galetta; Moscetti, Luca; Luca, Moscetti; La Verde, Nicla; Nicla, La Verde; Ibrahim, Toni; Toni, Ibrahim; Petrelli, Fausto; Fausto, Petrelli; Vasile, Enrico; Enrico, Vasile; Ginocchi, Laura; Laura, Ginocchi; Ottaviani, Davide; Davide, Ottaviani; Longo, Flavia; Flavia, Longo; Ortega, Cinzia; Cinzia, Ortega; Russo, Antonio; Antonio, Russo; Badalamenti, Giuseppe; Giuseppe, Badalamenti; Collovà, Elena; Elena, Collovà; Lanzetta, Gaetano; Gaetano, Lanzetta; Mansueto, Giovanni; Giovanni, Mansueto; Adamo, Vincenzo; Vincenzo, Adamo; De Marinis, Filippo; Filippo, De Marinis; Satolli, Maria Antonietta; Cantile, Flavia; Flavia, Cantile; Mancuso, Andrea; Andrea, Mancuso; Tanca, Francesca Maria; Addeo, Raffaele; Raffaele, Addeo; Russano, Marco; Marco, Russano; Sterpi, Michelle; Sterpi, M; Pantano, Francesco; Francesco, Pantano; Vincenzi, Bruno; Bruno, Vincenzi; Tonini, Giuseppe; Giuseppe, Tonini

    2015-12-22

    We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age >65 years, non-adenocarcinoma histology, ECOG Performance Status >2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival.

  12. Patient-controlled intravenous analgesia for non-small cell lung cancer patient after thoracotomy.

    Science.gov (United States)

    Zhou, Yi; Huang, Jin-Xi; Lu, Xi-Hua; Zhang, Yun-Fei; Zhang, Wei

    2015-08-01

    The objective was to evaluate the effect of patient-controlled intravenous analgesia (PCIA) in non-small cell lung cancer patients (NSLCPs) after thoracotomy. From January 2014 to March 2015, 40 patients of non-small cell lung cancer were recruited in this study and divided into two groups, (PCIA) group and control group with 20 patients in each group. The patients in the PCIA group were connected to intravenous self-control analgesia pump which contains 2 μg/ml of sufentanil and 8 mg of ondansetron diluting to 100 ml of 0.9% saline after surgery. Initial loading dose was 2 ml, background dose was 2 ml/h, single PCIA dose was 0.5 ml, and locking time 15 min. 10 mg of morphine was intramuscular injected, if necessary. Patients in the control group use an intramuscular injection of morphine 10 mg singly. The visual analog scale (VAS) score of the two groups were recorded in the time point of 2 h, 4 h, 8 h, 12 h, and 24 h. The morphine consumption of the two groups was also compared. Patients in PCIA group after surgery, 2 h, 4 h, 8 h, 12 h, and 24 h VAS score were obviously lower than those in control group (P control group (P control group (P controlled intravenous analgesia can significantly decrease the VAS score without increasing the toxicity in NSLCP after thoracotomy.

  13. Profile of bavituximab and its potential in the treatment of non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Stasi I

    2014-08-01

    Full Text Available Irene Stasi, Federico Cappuzzo Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy Abstract: Bavituximab is a an unconjugated, chimeric immunoglobulin G1 (IgG1 monoclonal antibody directed against the phosphatidylserine (PS expressed on tumor endothelium, with a specific mechanism of action. PS is an anionic membrane phospholipid, physiologically restricted to the internal membrane leaflet; various pathophysiologic processes cause the exposure of PS on the external membrane leaflet. Bavituximab, once bound, starts up host effector activities, such as antibody dependent cellular cytotoxicity, causing vessel destruction and enhancing antitumor immunity. Phase I clinical trials of bavituximab administered as monotherapy or in combination with other chemotherapeutic agents in adults with pretreated solid tumors have been accomplished, indicating that bavituximab can be safely dispensed weekly, with a recommended dose of 1 and 3 mg/kg. A Phase II randomized, placebo-controlled trial of bavituximab plus docetaxel, in the second-line therapy setting of locally advanced or metastatic non-small-cell lung cancer, has been conducted and recently presented, suggesting a clinical benefit of the combination, with an overall response rate of 17% and median overall survival of more than 11 months. A Phase III trial is currently ongoing. Bavituximab has been studied in combination with platinum-based doublets with promising results. In the present paper we summarize the preclinical development and clinical experience with bavituximab in non-small-cell lung cancer. Keywords: bavituximab, NSCLC, targeted therapy, vascular disrupting agent, vascular targeting agent

  14. Profile of bavituximab and its potential in the treatment of non-small-cell lung cancer.

    Science.gov (United States)

    Stasi, Irene; Cappuzzo, Federico

    2014-01-01

    Bavituximab is a an unconjugated, chimeric immunoglobulin G1 (IgG1) monoclonal antibody directed against the phosphatidylserine (PS) expressed on tumor endothelium, with a specific mechanism of action. PS is an anionic membrane phospholipid, physiologically restricted to the internal membrane leaflet; various pathophysiologic processes cause the exposure of PS on the external membrane leaflet. Bavituximab, once bound, starts up host effector activities, such as antibody dependent cellular cytotoxicity, causing vessel destruction and enhancing antitumor immunity. Phase I clinical trials of bavituximab administered as monotherapy or in combination with other chemotherapeutic agents in adults with pretreated solid tumors have been accomplished, indicating that bavituximab can be safely dispensed weekly, with a recommended dose of 1 and 3 mg/kg. A Phase II randomized, placebo-controlled trial of bavituximab plus docetaxel, in the second-line therapy setting of locally advanced or metastatic non-small-cell lung cancer, has been conducted and recently presented, suggesting a clinical benefit of the combination, with an overall response rate of 17% and median overall survival of more than 11 months. A Phase III trial is currently ongoing. Bavituximab has been studied in combination with platinum-based doublets with promising results. In the present paper we summarize the preclinical development and clinical experience with bavituximab in non-small-cell lung cancer.

  15. Liquid biopsy in non-small cell lung cancer: a key role in the future of personalized medicine?

    Science.gov (United States)

    Pi, Can; Zhang, Ming-Feng; Peng, Xiao-Xiao; Zhang, Yi-Chen; Xu, Chong-Rui; Zhou, Qing

    2017-12-01

    Liquid biopsies, especially the analysis of circulating tumor DNA (ctDNA), as a novel and non-invasive method for the diagnosis and monitoring of non-small cell lung cancer (NSCLC) have already been implemented in clinical settings. The majority of ctDNA is released from apoptotic or necrotic tumor cells, thus reflecting the genetic profile of a tumor. Numerous studies have reported a high concordance in mutation profiles derived from liquid biopsy and tissue biopsy, especially in driver genes. Liquid biopsy could overcome the clonal heterogeneity of tumour biopsy, as it provides a single snapshot of a tumour tissue. Moreover, non-invasiveness is the biggest advantage for liquid biopsy, and the procedure can be repeatedly performed during the treatment for the purpose of monitoring. Therefore, ctDNA could act as a potential complementary method for tissue biopsies in diagnosis, prognostic, treatment response and resistance. Areas covered: This review summarizes the recent advancements in liquid biopsy with a focus on NSCLC, including its applications and technologies associated with assessing ctDNA. The authors conclude the review by discussing the challenges associated with liquid biopsy. Expert commentary: The analysis of ctDNA represents a promising method for liquid biopsy, which will be a novel and potentially complementary method in diagnosis, treatment and prognostic in NSCLC at all stages.

  16. Malignant Cardiac Tamponade from Non-Small Cell Lung Cancer: Case Series from the Era of Molecular Targeted Therapy

    Directory of Open Access Journals (Sweden)

    Bob T. Li

    2014-12-01

    Full Text Available Cardiac tamponade complicating malignant pericardial effusion from non-small cell lung cancer (NSCLC is generally associated with extremely poor prognosis. With improved systemic chemotherapy and molecular targeted therapy for NSCLC in recent years, the prognosis of such patients and the value of invasive cardiothoracic surgery in this setting have not been adequately examined. We report outcomes from a contemporary case series of eight patients who presented with malignant cardiac tamponade due to NSCLC to an Australian academic medical institution over an 18 months period. Two cases of cardiac tamponade were de novo presentations of NSCLC and six cases were presentations following previous therapy for NSCLC. The median survival was 4.5 months with a range between 9 days to alive beyond 17 months. The two longest survivors are still receiving active therapy at 17 and 15 months after invasive surgical pericardial window respectively. One survivor had a histological subtype of large cell neuroendocrine carcinoma and the other received targeted therapy for epidermal growth factor receptor mutation. These results support the consideration of active surgical palliation to treating this oncological emergency complicating NSCLC, including the use of urgent drainage, surgical creation of pericardial window followed by appropriate systemic therapy in suitably fit patients.

  17. PIAS1-FAK Interaction Promotes the Survival and Progression of Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jerfiz D. Constanzo

    2016-05-01

    Full Text Available The sequence of genomic alterations acquired by cancer cells during tumor progression and metastasis is poorly understood. Focal adhesion kinase (FAK is a non-receptor tyrosine kinase that integrates cytoskeleton remodeling, mitogenic signaling and cell survival. FAK has previously been reported to undergo nuclear localization during cell migration, cell differentiation and apoptosis. However, the mechanism behind FAK nuclear accumulation and its contribution to tumor progression has remained elusive. We report that amplification of FAK and the SUMO E3 ligase PIAS1 gene loci frequently co-occur in non-small cell lung cancer (NSCLC cells, and that both gene products are enriched in a subset of primary NSCLCs. We demonstrate that endogenous FAK and PIAS1 proteins interact in the cytoplasm and the cell nucleus of NSCLC cells. Ectopic expression of PIAS1 promotes proteolytic cleavage of the FAK C-terminus, focal adhesion maturation and FAK nuclear localization. Silencing of PIAS1 deregulates focal adhesion turnover, increases susceptibility to apoptosis in vitro and impairs tumor xenograft formation in vivo. Nuclear FAK in turn stimulates gene transcription favoring DNA repair, cell metabolism and cytoskeleton regulation. Consistently, ablation of FAK by CRISPR/Cas9 editing, results in basal DNA damage, susceptibility to ionizing radiation and impaired oxidative phosphorylation. Our findings provide insight into a mechanism regulating FAK cytoplasm-nuclear distribution and demonstrate that FAK activity in the nucleus promotes NSCLC survival and progression by increasing cell-ECM interaction and DNA repair regulation.

  18. Isolation and characterization of erlotinib-resistant human non-small cell lung cancer A549 cells

    OpenAIRE

    IKEDA, RYUJI; VERMEULEN, LEE C.; LAU, ELIM; JIANG, ZHISHENG; KAVANAUGH, SHANNON M.; YAMADA, KATSUSHI; KOLESAR, JILL M.

    2010-01-01

    Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is an effective therapy for non-small cell lung cancer (NSCLC). However, resistance to erlotinib reduces its efficacy. To investigate the basis of erlotinib resistance, we isolated erlotinib-resistant human NSCLC A549 cells, termed A549/ER cells. The A549/ER cells were found to be resistant to erlotinib, as well as paclitaxel and gemcitabine. We then performed a PCR array to investigate the resistance to erlotini...

  19. FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Jun-Hai; Zhao, Chun-Liu [Department of Respiratory Medicine, Luwan Branch of Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20020 (China); Ding, Lan-Bao [Department of Nuclear Medicine, Shanghai 10th People' s Hospital, Tongji University School of Medicine, Shanghai 200072 (China); Zhou, Xi, E-mail: modelmap@139.com [Department of Respiratory Medicine, Luwan Branch of Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20020 (China)

    2015-10-09

    The transcription factor forkhead box D3 (FOXD3), widely studied as a transcriptional repressor in embryogenesis, participates in the carcinogenesis of many cancers. However, the expression pattern and role of FOXD3 in non-small cell lung cancer (NSCLC) have not been well characterized. We report that FOXD3 is significantly downregulated in NSCLC cell lines and clinical tissues. FOXD3 overexpression significantly inhibits cell growth and results in G1 cell cycle arrest in NSCLC A549 and H1299 cells. In a xenograft tumor model, FOXD3 overexpression inhibits tumor growth and angiogenesis. Remarkably, expression of vascular endothelial growth factor (VEGF) was reduced in FOXD3 overexpression models both in vitro and in vivo. These findings suggest that FOXD3 plays a potential tumor suppressor role in NSCLC progression and represents a promising clinical prognostic marker and therapeutic target for this disease. - Highlights: • FOXD3 is downregulated in NSCLC cell lines and tissues. • FOXD3 overexpression inhibited cell proliferation in NSCLC cells. • FOXD3 overexpression led to decreased angiogenesis in NSCLC cells in vitro and in vivo.

  20. PED is overexpressed and mediates TRAIL resistance in human non-small cell lung cancer.

    Science.gov (United States)

    Zanca, Ciro; Garofalo, Michela; Quintavalle, Cristina; Romano, Giulia; Acunzo, Mario; Ragno, Pia; Montuori, Nunzia; Incoronato, Mariarosaria; Tornillo, Luigi; Baumhoer, Daniel; Briguori, Carlo; Terracciano, Luigi; Condorelli, Gerolama

    2008-12-01

    PED (phosphoprotein enriched in diabetes) is a death-effector domain (DED) family member with a broad anti-apoptotic action. PED inhibits the assembly of the death-inducing signalling complex (DISC) of death receptors following stimulation. Recently, we reported that the expression of PED is increased in breast cancer cells and determines the refractoriness of these cells to anticancer therapy. In the present study, we focused on the role of PED in non-small cell lung cancer (NSCLC), a tumour frequently characterized by evasion of apoptosis and drug resistance. Immunohistochemical analysis of a tissue microarray, containing 160 lung cancer samples, indicated that PED was strongly expressed in different lung tumour types. Western blotting performed with specimens from NSCLC-affected patients showed that PED was strongly up-regulated (>6 fold) in the areas of tumour compared to adjacent normal tissue. Furthermore, PED expression levels in NSCLC cell lines correlated with their resistance to tumour necrosis factor related apoptosis-inducing ligand (TRAIL)-induced cell death. The involvement of PED in the refractoriness to TRAIL-induced cell death was investigated by silencing PED expression in TRAIL-resistant NSCLC cells with small interfering (si) RNAs: transfection with PED siRNA, but not with cFLIP siRNA, sensitized cells to TRAIL-induced cell death. In conclusion, PED is specifically overexpressed in lung tumour tissue and contributes to TRAIL resistance.

  1. FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Yan, Jun-Hai; Zhao, Chun-Liu; Ding, Lan-Bao; Zhou, Xi

    2015-01-01

    The transcription factor forkhead box D3 (FOXD3), widely studied as a transcriptional repressor in embryogenesis, participates in the carcinogenesis of many cancers. However, the expression pattern and role of FOXD3 in non-small cell lung cancer (NSCLC) have not been well characterized. We report that FOXD3 is significantly downregulated in NSCLC cell lines and clinical tissues. FOXD3 overexpression significantly inhibits cell growth and results in G1 cell cycle arrest in NSCLC A549 and H1299 cells. In a xenograft tumor model, FOXD3 overexpression inhibits tumor growth and angiogenesis. Remarkably, expression of vascular endothelial growth factor (VEGF) was reduced in FOXD3 overexpression models both in vitro and in vivo. These findings suggest that FOXD3 plays a potential tumor suppressor role in NSCLC progression and represents a promising clinical prognostic marker and therapeutic target for this disease. - Highlights: • FOXD3 is downregulated in NSCLC cell lines and tissues. • FOXD3 overexpression inhibited cell proliferation in NSCLC cells. • FOXD3 overexpression led to decreased angiogenesis in NSCLC cells in vitro and in vivo.

  2. Progress in Tissue Specimens Alternative for the Driver Genes Testing of Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Yan SUN

    2015-06-01

    Full Text Available Target treatment based on driver genes in advanced non-small cell lung cancer is very important currently. Tumor tissues is the gold standard for driver genes testing. However, most of patients could not get the gene information for lack of enough tissues. To explore the tissue specimens alternatives is a hot spot in clinical work. This report reviews the tissue specimen alternatives of driver gene testing in non-small cell lung cancer.

  3. [Progress in Tissue Specimens Alternative for the Driver Genes Testing of Non-small Cell Lung Cancer].

    Science.gov (United States)

    Sun, Yan; Song, Zhengbo

    2015-06-01

    Target treatment based on driver genes in advanced non-small cell lung cancer is very important currently. Tumor tissues is the gold standard for driver genes testing. However, most of patients could not get the gene information for lack of enough tissues. To explore the tissue specimens alternatives is a hot spot in clinical work. This report reviews the tissue specimen alternatives of driver gene testing in non-small cell lung cancer.

  4. Recombinant Interleukin-15 in Treating Patients With Advanced Melanoma, Kidney Cancer, Non-small Cell Lung Cancer, or Squamous Cell Head and Neck Cancer

    Science.gov (United States)

    2017-09-14

    Head and Neck Squamous Cell Carcinoma; Recurrent Head and Neck Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Skin Carcinoma; Stage III Renal Cell Cancer; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Non-Small Cell Lung Cancer AJCC v7; Stage IV Renal Cell Cancer

  5. EML4-ALK induces epithelial–mesenchymal transition consistent with cancer stem cell properties in H1299 non-small cell lung cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Fuchun; Liu, Xiaoke, E-mail: liuxk57@163.com; Qing, Qin, E-mail: qinqingscu@126.com; Sang, Yaxiong, E-mail: yaxiongsang@gmail.com; Feng, Chengjun, E-mail: leymj@163.com; Li, Xiaoyu, E-mail: lixiaoyu2012huaxi@163.com; Jiang, Li, E-mail: summer.jl06@foxmail.com; Su, Pei, E-mail: keyanxiaozhu@163.com; Wang, Yongsheng, E-mail: wangys@scu.edu.cn

    2015-04-10

    The echinoderm microtubule-associated protein-like 4(EML4) – anaplastic lymphoma kinase (ALK) fusion gene has been identified as a driver mutation in non-small-cell lung cancer (NSCLC). However, the role of EML4-ALK in malignant transformation is not entirely clear. Here, for the first time, we showed that H1299 NSCLC cells stably expressing EML4-ALK acquire EMT phenotype, associated with enhanced invasive migration and increased expression of EMT-inducing transcription factors. H1299-EML4-ALK cells also displayed cancer stem cell-like properties with a concomitant up-regulation of CD133 and enhanced ability of mammospheres formation. Moreover, we found that inhibition of ERK1/2 reversed EMT induced by EML4-ALK in H1299 cells. Taken together, these results suggested that EML4-ALK induced ERK activation is mechanistically associated with EMT phenotype. Thus, inhibition of ERK signaling pathway could be a potential strategy in treatment of NSCLC patients with EML4-ALK translocation. - Highlights: • EML4-ALK induced epithelial–mesenchymal transition in H1299 cells. • Expression of EML4-ALK promotes invasion and migration in vitro. • EML4-ALK enhanced sphere formation and stem cell-like properties in H1299 cells. • Blockage of ERK1/2 reverse Epithelial–Mesenchymal transition induced by EML4-ALK.

  6. In vitro effects of nicotine on the non-small-cell lung cancer line A549.

    Science.gov (United States)

    Gao, Tao; Zhou, Xue-Liang; Liu, Sheng; Rao, Chang-Xiu; Shi, Wen; Liu, Ji-Chun

    2016-04-01

    To investigate in vitro effects of nicotine on the non-small-cell lung cancer line A549. The case-control study was conducted at the First Affiliated Hospital of Nanchang University from 1st January to 30th June, 2014 and comprised A549 cells which were treated with a series of concentrations of nicotine (0.01 µM, 0.1 µM, 1 µM and 10 µM) for 24 hours. Control cells were incubated under the same conditions without the addition of nicotine. Cell growth was detected by monotetrazolium salt [3-(4, 5-dimethyl-2-thiazolyl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. Cell apoptosis was detected by Haematoxylin and Eosin staining, immunofluorescence analysis of Filamentous actin and electron microscope observation. Nicotine had no significant effect on A549 cell growth at the dose of 0.01µM (p>0.05), but had significant growth inhibitory effects at the doses of 0.1µM, 1µM and 10µM (pA549 cells were found to be dose-dependent.

  7. Circumvention of drug resistance in human non-small cell lung cancer in vitro by verapamil.

    Science.gov (United States)

    Merry, S; Courtney, E R; Fetherston, C A; Kaye, S B; Freshney, R I

    1987-10-01

    The sensitivity of 7 human non-small cell lung cancer cell lines to each of 7 cytotoxic drugs was determined. None of the cell lines used in these experiments had been previously exposed to cytotoxic drugs in vitro. A pattern of cross-resistance (P less than 0.05) between the drugs adriamycin (ADR), vincristine (VC) and etoposide (VP16) was noted similar to that seen in other models. The calcium antagonist verapamil (6.6 microM) was shown to increase sensitivity (up to 29-fold) to ADR, VC or VP16 in 5 cell lines. For 2 of the cell lines (A549 and WIL) 2.2 microM verapamil increased VP16 cytotoxicity (up to 4-fold). Drug accumulation studies in 2 cell lines (A549 and SK-MES-1) showed that 6.6 microM verapamil increased intracellular levels of VC up to 4-fold with the greatest increase seen in the cell line (SK-MES-1) for which verapamil produced the greatest increase in cytotoxicity (10-fold). For ADR and VP16 increases in drug accumulation were smaller (up to 1.6-fold). Our data support a potential clinical role for verapamil in overcoming cytotoxic drug resistance in human lung cancer.

  8. High level of chromosomal instability in circulating tumor cells of ROS1-rearranged non-small-cell lung cancer

    OpenAIRE

    Pailler, E.; Auger, N.; Lindsay, C. R.; Vielh, P.; Islas-Morris-Hernandez, A.; Borget, I.; Ngo-Camus, M.; Planchard, D.; Soria, J.-C.; Besse, B.; Farace, F.

    2015-01-01

    Background Genetic aberrations affecting the c-ros oncogene 1 (ROS1) tyrosine kinase gene have been reported in a small subset of patients with non-small-cell lung cancer (NSCLC). We evaluated whether ROS1-chromosomal rearrangements could be detected in circulating tumor cells (CTCs) and examined tumor heterogeneity of CTCs and tumor biopsies in ROS1-rearranged NSCLC patients. Patients and methods Using isolation by size of epithelial tumor cells (ISET) filtration and filter-adapted-fluoresce...

  9. Neutrophils dominate the immune cell composition in non-small cell lung cancer. | Office of Cancer Genomics

    Science.gov (United States)

    The response rate to immune checkpoint inhibitor therapy for non-small-cell lung cancer (NSCLC) is just 20%. To improve this figure, several early phase clinical trials combining novel immunotherapeutics with immune checkpoint blockade have been initiated. Unfortunately, these trials have been designed without a strong foundational knowledge of the immune landscape present in NSCLC. Here, we use a flow cytometry panel capable of measuring 51 immune cell populations to comprehensively identify the immune cell composition and function in NSCLC.

  10. Radiation protective nursing intervene of 125I seed implantation in non-small cell lung carcinoma guided by CT

    International Nuclear Information System (INIS)

    Fu Li; Zhang Zuncheng; Yu Zhaochen; Zheng Guangjun; Tian Meirong

    2009-01-01

    Objective: To research radiation protective nursing intervene and important notice of 125 I seeds minimally invasive implantation in non-small cell lung carcinoma (NSCLC) by CT. Methods: Under the system of therapy planning system (TPS) and posologic validation, 125 I seeds were implanted in 89 cases of NSCLC patients. The consistent radiation protective nursing intervene was used in perioperative period management. The operative successful rate, therapeutic effect and complication rate, therapeutic effect and complication rate was observed. Results: The scientific radiation protective nursing intervene can ensure that the radioactive dose distribution of 125 I seed implantation brachytherapy is consistent with the principles of effective and minimally invasive. The operative successful rate was 100%. The local control rate and 1 year survival rate respectively was 97.4% and 92.2%. But the early and later incidence rate of radioactive damaging effect was 14.6% and 1.1% respectively. Leakage of radioactive contamination has not occurred. Conclusion: The consistent TPS and posologic validation 125 I seeds implantation integrated scientific radiation protective nursing intervene. It is very important to improve the therapeutic effect of NSCLC and reduce the incidence of complications. (authors)

  11. The clinical and pathological significance of RCAS1 expression as a prognostic biomarker in non-small cell lung cancer.

    Science.gov (United States)

    Tsoukalas, Nikolaos; Kostakis, Ioannis D; Siakavellas, Spyros; Giaginis, Constantinos; Bournakis, Evangelos; Sfiniadakis, Ioannis; Karameris, Andreas; Patsouris, Efstratios; Theocharis, Stamatios

    2014-01-01

    Lung cancer remains a major health problem due to its incidence and mortality. Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a protein that can be expressed in cancer cells and is involved in tumor cell escape from immune system surveillance. The aim of this study was to evaluate the clinical significance of immunohistochemical staining for RCAS1 in non-small cell lung cancer (NSCLC). Tissue microarrays of tumor specimens from 112 consecutive patients with newly diagnosed primary NSCLC were constructed. RCAS1 and Ki-67 immunohistochemistry were studied through computerized image analysis. Associations between RCAS1 and Ki-67 expression and clinico-pathological variables and survival were analyzed. RCAS1 expression was higher in grade III tumors (p=0.009), regardless of the histological type, and in adenocarcinomas with lymphovascular invasion (p=0.014). A positive correlation between RCAS1 and Ki-67 levels was observed (p=0.002). Moreover, there was an inverse correlation of overall survival with RCAS1 (hazard ratio=0.99, p<0.001) and Ki-67 (hazard ratio=1.05, p=0.003) levels. Particularly, patients with higher expression of RCAS1 or Ki-67 had a significantly shorter survival than those with lower expression. RCAS1 could be a useful immunohistochemical biomarker, indicating not only tumor aggressiveness but also a poorer prognosis for patients with NSCLC.

  12. Bystander effects in radiotherapy of non-small cell lung cancer

    International Nuclear Information System (INIS)

    McKenzie, D.R.

    2011-01-01

    Full text: School of Physics, The University of Sydney, Australia Objectives The bystander effect causes a response in unirradiated cells that are in communication with cells that receive a radiation dose. In recent work we have shown that there are 3 types bystander effect and that the expression of these effects follows a Ii course. The aim of this work is to identify the conditions for the three types of bystander effects in radiotherapy of non-small cell II cancer. A human non small cell lung cancer cell line (NCI-H460) was irradiated with a 6 MV photon beam produced from a Varian I i near accelerator to doses of 2, 4, 6 and 8 Gy. These cells v termed donor cells. At selected time intervals after exposure (5,15 and 60 min), the medium was transferred to receiver cells of the cell line in separate flasks. The clonogenic survival fraction of the receiver cells was determined following 5 days of incubation comparing cells receiving transfer of medium from exposed cells to cell receiving transfer from sham exposed cells. The experimental design controlled for the density of cells in the donor flask, the e of irradiation on the medium alone and on the donor cell metabolites. The results show a strong time course for the bystander signal expression, which is dependent on the density of cells in the donor receiver flasks. Sub lethal doses of radiation resulted in a proliferative response at short time intervals after exposure [15 min] but a toxic response when medium transfer was carried out after 60 min. A higher cell density in the donor flasks produces an increased response in the receiver flasks for the same volume of medium transferred. The latter response corresponds to Bystander Effect type 1 in which a reduced survival is observed in cells receiving medium from cells that receive a high but not lethal dose. The proliferative response, corresponding to Bystander Effect type 3 is more general and is not strongly dependent on dose. Following a lethal dose of

  13. Satellite pulmonary nodule in the same lobe (T4N0) should not be staged as IIIB non-small cell lung cancer.

    Science.gov (United States)

    Bryant, Ayesha S; Pereira, Sara J; Miller, Daniel L; Cerfolio, Robert James

    2006-11-01

    Treatment of non-small cell lung cancer depends on stage. Patients with T4 lesions represent a heterogeneous group. A case-control study of patients with pathologically proven, node-negative T4 lesions (T4 N0 M0) was conducted. Patients with T4 disease were stratified as T4 from a satellite nodule (T4-satellite) or T4 from local invasion (T4-invasion). T4-satellite patients were matched 1:4 for sex and histology with resected control patients with stage IA, IB, and IIA non-small cell lung cancer and matched 1:3 with stage II non-small cell lung cancer. Survival and the maximal standardized uptake value on F-18 fluorodeoxyglucose-positron emission tomography scans were compared. There were 337 patients, 26 patients with T4-satellite lesions, 25 with T4-invasion lesions, and 286 controls (104 patients with T1 N0 M0, 104 with T2 N0 M0, and 78 with T1 N1 M0 or T2 N1 M0 lesions). The two T4 groups were similar for age, race, sex, and neoadjuvant therapy rates. The 5-year survival was 80% for the T1 N0 M0 patients, 68% for T2 N0 M0, 57% for T4-satellite N0 M0, 45% for T1 N1 M0 or T2 N1 M0, and 30% for the T4-invasion N0 M0 patients (p = 0.016). Multivariate analysis showed that only the type of T4 impacted survival (p = 0.011). The median maximal standardized uptake values of the cancers were 4.2 for T1 N0 M0, 4.8 for T4-satellite, 5.4 for T2 N0 M0, 7.8 for T1 N1 M0 or T2 N1 M0, and 8.8 for the T4-invasion patients. Larger studies are needed; however, patients with T4-satellite non-small cell lung cancer who undergo complete resection have survival and maximal standardized uptake values similar to patients with stage IB and stage IIA lesions. Their survival is significantly better than those with T4-invasion. Patients with T4-satellite N0 M0 lesions should not be classified as stage IIIB and should not be grouped with patients with T4-invasion, and resection should be considered.

  14. Image-Guided Hypofractionated Radiation Therapy With Stereotactic Body Radiation Therapy Boost and Combination Chemotherapy in Treating Patients With Stage II-III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery

    Science.gov (United States)

    2017-06-12

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Large Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  15. Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer.

    Science.gov (United States)

    Tanino, Ryosuke; Tsubata, Yukari; Harashima, Nanae; Harada, Mamoru; Isobe, Takeshi

    2018-03-30

    Pemetrexed (PEM) improves the overall survival of patients with advanced non-small cell lung cancer (NSCLC) when administered as maintenance therapy. However, PEM resistance often appears during the therapy. Although thymidylate synthase is known to be responsible for PEM resistance, no other mechanisms have been investigated in detail. In this study, we explored new drug resistance mechanisms of PEM-treated NSCLC using two combinations of parental and PEM-resistant NSCLC cell lines from PC-9 and A549. PEM increased the apoptosis cells in parental PC-9 and the senescent cells in parental A549. However, such changes were not observed in the respective PEM-resistant cell lines. Quantitative RT-PCR analysis revealed that, besides an increased gene expression of thymidylate synthase in PEM-resistant PC-9 cells, the solute carrier family 19 member1 ( SLC19A1) gene expression was markedly decreased in PEM-resistant A549 cells. The siRNA-mediated knockdown of SLC19A1 endowed the parental cell lines with PEM resistance. Conversely, PEM-resistant PC-9 cells carrying an epidermal growth factor receptor (EGFR) mutation acquired resistance to a tyrosine kinase inhibitor erlotinib. Although erlotinib can inhibit the phosphorylation of EGFR and Erk, it is unable to suppress the phosphorylation of Akt in PEM-resistant PC-9 cells. Additionally, PEM-resistant PC-9 cells were less sensitive to the PI3K inhibitor LY294002 than parental PC-9 cells. These results indicate that SLC19A1 negatively regulates PEM resistance in NSCLC, and that EGFR-tyrosine-kinase-inhibitor resistance was acquired with PEM resistance through Akt activation in NSCLC harboring EGFR mutations.

  16. Advanced Research of Fibroblast Growth Factor Receptor 
in Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Dan PU

    2013-11-01

    Full Text Available Lung cancer is severely threatening human health. In recent years, the treatment for lung adenocarcinoma has made a great progress, targeted therapy has been widely applied in clinic, and benefits amount of patients. However, in squamous cell lung cancer, the incidence of epidermal growth factor receptor (EGFR gene mutant and ALK fusion gene are low,and targeted therapy like Tarceva and crizotinib, can hardly work. Since the fibroblast growth factors (fibroblast growth factor, FGF pathway is considered to be related to tumor cell proliferation, metastasis and angiogenesis, more and more researches proved the amplification of fibroblast growth factor receptor (FGFR in squamous cell lung cancer. Experiments in vivo and in vitro found that blocking FGF pathway could reduce the proliferation of tumor cells and inhibit metastasis. The FGF pathway might be a new target for treatment of squamous cell lung cancer. This article reviews the effect of FGFR in tumorigenesis,as well as the prospect as a therapeutic target in non-small cell lung cancer.

  17. The importance of multidisciplinary team management of patients with non-small-cell lung cancer.

    Science.gov (United States)

    Ellis, P M

    2012-06-01

    Historically, a simple approach to the treatment of non-small-cell lung cancer (nsclc) was applicable to nearly all patients. Recently, a more complex treatment algorithm has emerged, driven by both pathologic and molecular phenotype. This increasing complexity underscores the importance of a multidisciplinary team approach to the diagnosis, treatment, and supportive care of patients with nsclc. A team approach to management is important at all points: from diagnosis, through treatment, to end-of-life care. It also needs to be patient-centred and must involve the patient in decision-making concerning treatment. Multidisciplinary case conferencing is becoming an integral part of care. Early integration of palliative care into the team approach appears to contribute significantly to quality of life and potentially extends overall survival for these patients. Supportive approaches, including psychosocial and nutrition support, should be routinely incorporated into the team approach. Challenges to the implementation of multidisciplinary care require institutional commitment and support.

  18. Proton Beam Therapy for Non-Small Cell Lung Cancer: Current Clinical Evidence and Future Directions

    Energy Technology Data Exchange (ETDEWEB)

    Berman, Abigail T., E-mail: abigail.berman@uphs.upenn.edu [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104 (United States); James, Sara St.; Rengan, Ramesh [Department of Radiation Oncology, University of Washington Medical Center, Seattle, WA 98195 (United States)

    2015-07-02

    Lung cancer is the leading cancer cause of death in the United States. Radiotherapy is an essential component of the definitive treatment of early-stage and locally-advanced lung cancer, and the palliative treatment of metastatic lung cancer. Proton beam therapy (PBT), through its characteristic Bragg peak, has the potential to decrease the toxicity of radiotherapy, and, subsequently improve the therapeutic ratio. Herein, we provide a primer on the physics of proton beam therapy for lung cancer, present the existing data in early-stage and locally-advanced non-small cell lung cancer (NSCLC), as well as in special situations such as re-irradiation and post-operative radiation therapy. We then present the technical challenges, such as anatomic changes and motion management, and future directions for PBT in lung cancer, including pencil beam scanning.

  19. Clinical Application of 18F-FDG PET in Non-Small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Choi, Joon Young

    2008-01-01

    This review focuses on the clinical use of 18 F-FDG PET to evaluate solitary pulmonary nodule (SPN) and non-small cell lung cancer (NSCLC). When SPN or mass without calcification is found on chest X-ray or CT, 18 F-FDG PET is an effective modality to differentiate benign from malignant lesions. For initial staging of NSCLC, 18 F-FDG PET is useful, and proved to be cost-effective in several countries. 18 F-FDG PET is useful for detecting recurrence, restaging and evaluating residual tumor after curative therapy in NSCLC. For therapy response assessment, 18 F-FDG PET may be effective after chemotherapy or radiation therapy. 18 F-FDG PET is useful to predict pathological response after neoadjuvant therapy in NSCLC. For radiation therapy planning, 18 F-FDG PET may be helpful, but requires further investigations. PET/CT is better for evaluating NSCLC than conventional PET

  20. Novel treatment options in stage I non-small-cell lung cancer.

    Science.gov (United States)

    Tarasevych, Svitlana; Lauwers, Patrick; Vandaele, Frederik; van Meerbeeck, Jan P

    2014-09-01

    In the last 5 years, the current management of stage I non-small-cell lung cancer has been challenged due to novel surgical approaches and advances in radiation technology. The outcome after a sublobar resection is promising, especially for tumors less than 2 cm. Other treatment opportunities are available for high risk patients with comorbidity and impaired pulmonary function. Stereotactic ablative body radiotherapy is a good alternative treatment to surgery, especially in elderly and comorbid patients. However, randomized evidence comparing sublobar resection and stereotactic radiotherapy is presently lacking. The most recent development in radiotherapy is hadron therapy with a presumed reduced toxicity because of its peculiar physical and biological effects. Promising thermal and microwave ablative techniques are in development and have specific niche indications.

  1. Economic analysis of ALK testing and crizotinib therapy for advanced non-small-cell lung cancer.

    Science.gov (United States)

    Lu, Shun; Zhang, Jie; Ye, Ming; Wang, Baoai; Wu, Bin

    2016-06-01

    The economic outcome of crizotinib in advanced non-small-cell lung cancer harboring anaplastic lymphoma kinase rearrangement would be investigated. Based on a mathematical model, the economic outcome of three techniques for testing ALK gene rearrangement combing with crizotinib would be evaluated and compared with traditional regimen. The impact of the crizotinib patient assistance program (PAP) was assessed. Ventana immunohistochemistry, quantitative real-time reverse transcription-polymerase chain reaction and IHC testing plus fluorescent in situ hybridization confirmation for anaplastic lymphoma kinase testing following crizotinib treatment leaded to the incremental cost-effectiveness ratios of US$16,820 and US$223,242, US$24,424 and US$223,271, and US$16,850 and US$254,668 per quality-adjusted life-year gained with and without PAP, respectively. Gene-guided crizotinib therapy might be a cost-effective alternative comparing with the traditional regimen in the PAP setting.

  2. Proton Beam Therapy for Non-Small Cell Lung Cancer: Current Clinical Evidence and Future Directions

    Directory of Open Access Journals (Sweden)

    Abigail T. Berman

    2015-07-01

    Full Text Available Lung cancer is the leading cancer cause of death in the United States. Radiotherapy is an essential component of the definitive treatment of early-stage and locally-advanced lung cancer, and the palliative treatment of metastatic lung cancer. Proton beam therapy (PBT, through its characteristic Bragg peak, has the potential to decrease the toxicity of radiotherapy, and, subsequently improve the therapeutic ratio. Herein, we provide a primer on the physics of proton beam therapy for lung cancer, present the existing data in early-stage and locally-advanced non-small cell lung cancer (NSCLC, as well as in special situations such as re-irradiation and post-operative radiation therapy. We then present the technical challenges, such as anatomic changes and motion management, and future directions for PBT in lung cancer, including pencil beam scanning.

  3. The Conceptual Oligometastatic Non-small Cell Lung Cancer and Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Xiaozheng KANG

    2012-04-01

    Full Text Available Non-small cell lung cancer (NSCLC ranks among the most prevalent malignancies and is the major cause of cancer-related deaths worldwide. Nearly 20%-50% will accompany by metastatic disease and the most common extrapulmonary sites of distant metastases are the brain, bone, liver and adrenal gland. The oligometastatic state is a biologically mild tumor stage and a intermediate state in which spread may be limited to specific organs and metastases might be present in limited numbers. Oligometastases are thought to arise from micrometastases, which have been dormant for a period of time. Local control may be an crucial component of a curative therapeutic strategy in the following four clinical schemes: to prohibit metastases; to cure occult metastatic disease; to remedy oligometastases; and to deracinate any residual lesion after systemic therapy. This review aims to outline the concept of the oligometastatic NSCLC and its strategies of treatment.

  4. Radiotherapy of elderly patients with non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Nakano, Kikuo; Hiramoto, Takehiko; Kumagai, Kazuhiko; Tukamoto, Yuji; Furonaka, Makoto; Hayakawa, Masanobu; Nakamura, Kenji

    1996-01-01

    Treatment results of patients aged 75 years or older (elderly group) with non-small-cell lung cancer were compared with those of patients aged 74 years or younger (younger group). In patients with stage III disease, radiotherapy alone resulted in a median survival of 11.5 months in the younger group and 5.5 months in the elderly group. There was a significant difference in survival rate between the two groups (P=0.0008). Moreover, the elderly group patients more frequently died of pneumonia and radiation pneumonitis than the younger group patients. However, results of radiotherapy were similar in the two groups of patients with stage I and II disease. Accordingly, these findings suggested that radiotherapy is an appropriate treatment modality for elderly lung cancer patients, but that individualized radiotherapy is needed for those with locally advanced stage. (author)

  5. Prospective study on stereotactic radiotherapy of limited-stage non-small-cell lung cancer

    DEFF Research Database (Denmark)

    Høyer, Morten; Roed, Henrik; Hansen, Anders Traberg

    2006-01-01

    Purpose: To test the effect of stereotactic body radiotherapy (SBRT) in       the treatment of medically inoperable patients with limited-stage       non-small-cell lung cancer (NSCLC) in a Phase II trial. Methods and       Materials: Forty patients with Stage I NSCLC were treated with SBRT......%. At 2       years, 54% were without local or distant progression, and overall survival       was 47%. Within 6 months after treatment, one or more Grade >/=2 reactions       were observed in 48% of the patients. Conclusions: Stereotactic body       radiotherapy in patients with limited-stage NSCLC...

  6. Crizotinib in the treatment of non--small-cell lung cancer.

    Science.gov (United States)

    Rothschild, Sacha I; Gautschi, Oliver

    2013-09-01

    An anaplastic lymphoma kinase (ALK) translocation giving rise to activated ALK tyrosine kinase is present in approximately 5% of non-small-cell lung cancers (NSCLCs). Crizotinib is an oral tyrosine kinase inhibitor targeting ALK, met proto-oncogene, and c-ros oncogene 1 (ROS1). It was recently approved in several countries for the treatment of patients with advanced, ALK-rearranged NSCLC. In 2012, results from the first phase III trial showing superiority of crizotinib compared with standard chemotherapy in second-line treatment of ALK-positive NSCLC were presented. Furthermore, crizotinib was recently shown to be active in ROS1-rearranged NSCLC. Here, we give an overview of the molecular pathogenesis of ALK-rearranged NSCLC, the pharmacokinetic and pharmacodynamic properties of crizotinib, and clinical trials of crizotinib for ALK-rearranged NSCLC. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Immunohistochemistry for predictive biomarkers in non-small cell lung cancer.

    Science.gov (United States)

    Mino-Kenudson, Mari

    2017-10-01

    In the era of targeted therapy, predictive biomarker testing has become increasingly important for non-small cell lung cancer. Of multiple predictive biomarker testing methods, immunohistochemistry (IHC) is widely available and technically less challenging, can provide clinically meaningful results with a rapid turn-around-time and is more cost efficient than molecular platforms. In fact, several IHC assays for predictive biomarkers have already been implemented in routine pathology practice. In this review, we will discuss: (I) the details of anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) IHC assays including the performance of multiple antibody clones, pros and cons of IHC platforms and various scoring systems to design an optimal algorithm for predictive biomarker testing; (II) issues associated with programmed death-ligand 1 (PD-L1) IHC assays; (III) appropriate pre-analytical tissue handling and selection of optimal tissue samples for predictive biomarker IHC.

  8. Improved radiotherapy for locally advanced Non-Small Cell Lung Carcinoma (NSCLC) patients

    DEFF Research Database (Denmark)

    Ottosson, Wiviann

    be reduced by the DIBH method for the lung cancer patients. The overall aim of the clinical part of this thesis was to clarify the potential benefit of offering DIBH gating, compared to free-breathing (FB), for lung cancer patients. Particularly, the benefits for locally advanced non-small cell lung cancer......Lung cancer is worldwide one of the most common cancer diseases with a high mortality rate. There is thus an urgent need for improving radiotherapy for these patients. Radiotherapy for lung cancer patients is challenging because the tumor and organs at risk (OARs) move with the breathing motion....... Deep-Inspiration-Breath-Hold (DIBH) is a technique that potentially can improve the treatment for these patients. DIBH is frequently and routinely used for breast cancer treatments. However, it is still an experimental method for lung cancer patients e.g. due to preconceptions about their incapability...

  9. THE MANAGEMENT OF BRAIN METASTASES IN NON-SMALL CELL LUNG CANCER

    Directory of Open Access Journals (Sweden)

    Scott eOwen

    2014-09-01

    Full Text Available Brain metastases (BM are a common and lethal complication of non-small cell lung cancer (NSCLC which portend a poor prognosis. In addition, their management implies several challenges including preservation of neurological and neuro-cognitive function during surgery or radiation -therapy, minimizing iatrogenic complications of supportive medications, and optimizing drug delivery across the blood brain barrier (BBB. Despite these challenges, advancements in combined modality approaches can deliver hope of improved overall survival and quality of life for a subset of NSCLC patients with BM. Moreover, new drugs harnessing our greater understanding of tumour biology promise to build on this hope. In this mini-review, we revised the management of BM in NSCLC including advancements in neurosurgery, radiation therapy, as well as systemic and supportive therapy.

  10. Combination of immunotherapy with targeted therapies in advanced non-small cell lung cancer (NSCLC).

    Science.gov (United States)

    Moya-Horno, Irene; Viteri, Santiago; Karachaliou, Niki; Rosell, Rafael

    2018-01-01

    Treatment for advanced non-small cell lung cancer (NSCLC) has been significantly improved in recent years with the incorporation of drugs targeting antiangiogenesis and more specifically genomic alterations such as the EGFR mutations and ALK translocations. However, most patients invariably progress and die. The emergence of immune checkpoint inhibitors targeting the pathways involved in tumor-induced immunosuppression have redefined the management of the disease, achieving significant long-lasting responses with manageable safety profiles, regardless of histology. Still, response rates with immunotherapy are deemed suboptimal. Current efforts are focusing on new potential combination strategies with synergistic antitumor activity, using immune checkpoint blockade as a partner for targeted agents. Herein we discuss the available data on the combined use of immunotherapy, including PD-1/PD-L1 and CTLA-4 inhibitors, with EGFR and ALK inhibitors and comment on the current status of immunotherapy plus antiangiogenic drugs for molecularly unselected advanced NSCLC.

  11. CXCR4/CXCL12 in Non-Small-Cell Lung Cancer Metastasis to the Brain

    Directory of Open Access Journals (Sweden)

    Sebastiano Cavallaro

    2013-01-01

    Full Text Available Lung cancer represents the leading cause of cancer-related mortality throughout the world. Patients die of local progression, disseminated disease, or both. At least one third of the people with lung cancer develop brain metastases at some point during their disease, even often before the diagnosis of lung cancer is made. The high rate of brain metastasis makes lung cancer the most common type of tumor to spread to the brain. It is critical to understand the biologic basis of brain metastases to develop novel diagnostic and therapeutic approaches. This review will focus on the emerging data supporting the involvement of the chemokine CXCL12 and its receptor CXCR4 in the brain metastatic evolution of non-small-cell lung cancer (NSCLC and the pharmacological tools that may be used to interfere with this signaling axis.

  12. Current and future molecular diagnostics in non-small-cell lung cancer.

    Science.gov (United States)

    Li, Chun Man; Chu, Wing Ying; Wong, Di Lun; Tsang, Hin Fung; Tsui, Nancy Bo Yin; Chan, Charles Ming Lok; Xue, Vivian Wei Wen; Siu, Parco Ming Fai; Yung, Benjamin Yat Ming; Chan, Lawrence Wing Chi; Wong, Sze Chuen Cesar

    2015-01-01

    The molecular investigation of lung cancer has opened up an advanced area for the diagnosis and therapeutic management of lung cancer patients. Gene alterations in cancer initiation and progression provide not only information on molecular changes in lung cancer but also opportunities in advanced therapeutic regime by personalized targeted therapy. EGFR mutations and ALK rearrangement are important predictive biomarkers for the efficiency of tyrosine kinase inhibitor treatment in lung cancer patients. Moreover, epigenetic aberration and microRNA dysregulation are recent advances in the early detection and monitoring of lung cancer. Although a wide range of molecular tests are available, standardization and validation of assay protocols are essential for the quality of the test outcome. In this review, current and new advancements of molecular biomarkers for non-small-cell lung cancer will be discussed. Recommendations on future development of molecular diagnostic services will also be explored.

  13. Second generation tyrosine kinase inhibitors for the treatment of metastatic non-small-cell lung cancer.

    Science.gov (United States)

    Stasi, Irene; Cappuzzo, Federico

    2014-01-01

    Since their first description, activating epidermal growth factor receptor (EGFR) mutations identify a distinct clinical entity of patients with non-small-cell lung cancer (NSCLC). New targeted therapies for molecularly selected NSCLC are changing the natural history of the disease, with results superior to standard chemotherapy as demonstrated in large phase III studies with first generation EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, after an initial response, all patients inevitably progress and several mechanisms including a secondary mutation in exon 20 of the EGFR gene (T790M) or MET or HER2 amplifications are responsible for acquired resistance (AR). In clinical practice few options are available for patients with AR, and several new agents or strategies are currently under investigation, including second generation TKIs. Aim of the present review is to present available data on new EGFR-TKIs and to discuss how these agents could overcome AR to erlotinib or gefitinib.

  14. Expression of transcription factor Pokemon in non-small cell lung cancer and its clinical significance.

    Science.gov (United States)

    Zhao, Zhi-hong; Wang, Sheng-fa; Yu, Liang; Wang, Ju; Chang, Hao; Yan, Wei-li; Fu, Kai; Zhang, Jian

    2008-03-05

    Transcription factor Pokemon, a central regulation gene of the important tumor suppressor ARF gene, exerted its activity by acting upstream of many tumor-suppressing genes and proto-oncogenes. Its expression in non-small cell lung cancer (NSCLC) and its clinical significance remains unclear. The aim of this study was to investigate the expression of Pokemon in NSCLC and to explore its correlation with the clinical pathological characteristics and its influence on patients' prognosis. Fifty-five cases of NSCLC were involved in this study. The expression of Pokemon in the tumor tissue, the corresponding tumor adjacent tissue and the surrounding tissue was detected via reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, with the aim of investigating the correlation between the expression of Pokemon in tumor tissue of NSCLC and its clinical pathological characteristics. Moreover, a prognostic analysis was carried out based upon the immunohistochemical (IHC) detection of the expression of Pokemon gene in archival tumor specimens (5 years ago) of 62 cases of NSCLC. Statistical significance of the expression of Pokemon mRNA and protein was determined in the tumor tissue, the tumor adjacent tissue and the surrounding tissue (PPokemon was determined not to be associated with the patients' sex, age, smoking condition, tumor differentiation degree, histology and lymph node metastasis condition. However, its relationship with TNM staging was established (PPokemon expression was significantly higher than that of those with positive Pokemon expression (P=0.004), therefore, the expression of Pokemon is believed to be an independent factor affecting prognosis (P=0.034). Pokemon was over-expressed in NSCLC tissue and the expression of Pokemon might be of clinical significance in non-small cell lung cancer prognostic evaluation.

  15. First-line treatment of advanced ALK-positive non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Gandhi S

    2015-09-01

    Full Text Available Shipra Gandhi,1 Hongbin Chen,2 Yujie Zhao,2 Grace K Dy2 1Department of Internal Medicine, State University of New York, 2Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA Abstract: Non-small-cell lung cancer (NSCLC is one of the leading causes of cancer deaths, both within the US and worldwide. There have been major treatment advances in NSCLC over the past decade with the discovery of molecular drivers of NSCLC, which has ushered in an era of personalized medicine. There are several actionable genetic aberrations in NSCLC, such as epidermal growth factor receptor and anaplastic lymphoma kinase (ALK. In 3%–7% of NSCLC, a chromosomal inversion event in chromosome 2 leads to fusion of a portion of the ALK gene with the echinoderm microtubule–associated protein-like 4 (EML4 gene. The constitutive activation of the ALK fusion oncogene renders it vulnerable to therapeutic intervention. This review focuses on the first-line treatment of advanced ALK-positive NSCLC using ALK inhibitors. Crizotinib was the first agent proven to be efficacious as first-line treatment for ALK-positive NSCLC. However, acquired resistance inevitably develops. The central nervous system is a sanctuary site that represents a common site for disease progression as well. Hence, more potent, selective next-generation ALK inhibitors that are able to cross the blood–brain barrier have been developed for treatment against crizotinib-resistant ALK-positive NSCLC and are also currently being evaluated for first-line therapy as well. In this review, we provide summary of the clinical experience with these drugs in the treatment of ALK-positive NSCLC. Keywords: non-small-cell lung cancer, ALK, first line, crizotinib, pemetrexed

  16. CT-guided intratumoral gene therapy in non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Kauczor, H.U.; Heussel, C.P.; Thelen, M.; Schuler, M.; Huber, C.; Weymarn, A. von; Bongartz, G.; Rochlitz, C.

    1999-01-01

    The objective of this study was to prove the principle of CT-guided gene therapy by intratumoral injection of a tumor suppressor gene as an alternative treatment approach of incurable non-small-cell lung cancer. In a prospective clinical phase I trial six patients with non-small-cell lung cancer and a mutation of the tumor suppressor gene p53 were treated by CT-guided intratumoral gene therapy. Ten milliliters of a vector solution (replication-defective adenovirus with complete wild-type p53 cDNA) were injected under CT guidance. In four cases the vector solution was completely applied to the tumor center, whereas in two cases 2 ml aliquots were injected into different tumor areas. For the procedure the scan room had been approved as a biosafety cabinet. Gene transfer was assessed by reverse transcription and polymerase chain reaction in biopsy specimens obtained under CT guidance 24-48 h after therapy. Potential therapeutic efficacy was evaluated on day 28 after treatment using spiral CT. The CT-guided gene therapy was easily performed in all six patients without intervention-related complications. Besides flu-like symptoms, no significant adverse effects of gene therapy were noted. Three of the four patients with central injection exhibited gene transfer in the posttreatment biopsy. Gene transfer could not be proven in the two patients with multiple 2 ml injections. After 28 days, four of the six patients showed stable disease at the treated tumor site, whereas other tumor manifestations progressed. Computed tomography-guided injections are an adequate and easy-to-perform procedure for intratumoral gene therapy. (orig.)

  17. The clinical significance of CXCL5 in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Wu K

    2017-11-01

    Full Text Available Kongju Wu,1,* Shengnan Yu,2,* Qian Liu,2 Xianguang Bai,1 Xinhua Zheng,1 Kongming Wu2 1Medical School of Pingdingshan University, Pingdingshan, Henan, 2Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work Abstract: As a CXC-type chemokine, ENA78/CXCL5 is an important attractant for granulocytes by binding to its receptor CXCR2. Recent studies proved that CXCL5/CXCR2 axis plays an oncogenic role in many human cancers. However, the exact clinical significance of CXCL5 in lung cancer has not been well defined. Here, we found that the serum protein expression of CXCL5 was significantly increased in non-small cell lung cancer (NSCLC compared with that in healthy volunteers. Immunohistochemistry staining revealed that CXCL5 protein was higher in various lung cancer tissues compared with normal tissues. Moreover, CXCL5 expression correlated with histological grade, tumor size, and TNM stage in NSCLC. Elevated CXCL5 protein abundance predicted poor overall survival in adenocarcinoma patients. Further meta-analysis demonstrated that CXCL5 mRNA expression was also positively associated with tumor stage, lymph node metastasis, and worse survival. Kaplan–Meier plot analyses indicated high CXCL5 was associated with short overall survival and progression-free survival. Together, these results indicated that CXCL5 may be a potential biomarker for NSCLC. Keywords: non-small cell lung cancer, chemokine, CXCL5, migration, prognosis 

  18. Anaplastic lymphoma kinase inhibition in metastatic non-small cell lung cancer: clinical impact of alectinib

    Directory of Open Access Journals (Sweden)

    Muller IB

    2017-09-01

    Full Text Available Ittai B Muller,1 Adrianus J de Langen,2,3 Elisa Giovannetti,4,5 Godefridus J Peters4 1Department of Clinical Chemistry, 2Department of Pulmonology, VU University Medical Center, 3Department of Thoracic Oncology, Netherlands Cancer Institute, 4Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands; 5Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, Italy Abstract: A subset of non-small cell lung cancer (NSCLC tumors (5% harbors an anaplastic lymphoma kinase (ALK translocation that drives tumorigenesis. The clinically approved first-line treatment crizotinib specifically inhibits ALK and improves progression-free survival (PFS in treated and untreated patients by 4 months compared to standard chemotherapy. While some patients relapse after crizotinib treatment due to resistance mutations in ALK, second-generation ALK inhibitors effectively induce tumor response and prolong PFS. Alectinib, a second-generation ALK inhibitor, has recently been approved for ALK-rearranged NSCLC after patients progressed on crizotinib. Alectinib is able to inhibit several crizotinib- and ceritinib-resistant ALK mutations in vitro. Furthermore, alectinib is a more potent tyrosine kinase inhibitor (TKI, with favorable safety profile, and has increased penetration into the central nervous system, inhibiting crizotinib-resistant brain metastases. The discovery of effective personalized therapies to combat ALK-rearranged NSCLC such as alectinib is an example of the importance of genomic profiling of NSCLC and provides an excellent template for future discoveries in managing these tumors. Keywords: crizotinib, acquired resistance, alectinib, anaplastic lymphoma kinase, tyrosine kinase inhibitors, non-small cell lung cancer

  19. Curative radiotherapy in non-small cell carcinoma of the lung

    International Nuclear Information System (INIS)

    Talton, B.M.; Constable, W.C.; Kersh, C.R.

    1990-01-01

    Recent reports suggest radiotherapy administered to the 5000-6000 cGy level can result in significant long-term survival in non-small cell carcinoma of the lung. This is particularly true for many cases that are technically operable but for medical or other reasons thoracotomy cannot be performed. Such patients drawn from Southern Appalachia where the principal industry is coal mining are the subject of this report. In this region coal miners pneumoconiosis (black lung) is common as well as other chronic respiratory disorders resulting in poor tolerance for surgery. Three hundred and eleven cases of non-small cell carcinoma were irradiated during the 4 years of 1980 through 1983. This group consisted of 77 patients with clinical Stage T1, T2, T3 all N0, M0 tumors, the majority of which were technically operable but upon whom no thoracotomy was performed because of medical reasons or patient refusal. All are available for 5-year study. Each of these patients was uniformly irradiated to 6000 cGy target dose in 30 fractions over 6 weeks using standard techniques.Comparison with reported surgical series treated for cure show little difference in survival up to 2 years. Thereafter, the survival curves diverge with radiotherapy patients dying at a somewhat higher rate although by 4 years both survival curves slope similarly. A possible explanation for this difference is the advantage thoracotomy offers in early case selection allowing exclusion of advance cases from surgical reports whereas radiotherapy must include patients with occult local metastasis not identifiable on clinical grounds. This experience, among other reports include evidence that radiotherapy can result in long-term survival or cure with minimal morbidity in lung cancer patients in whom surgery carries excessive risk

  20. Difficulties encountered and solutions found when implementing stereotactic radiotherapy of non-small cell lung cancer

    International Nuclear Information System (INIS)

    Assouline, A.; Halley, A.; Belghith, B.; Mazeron, J.J.; Feuvret, L.

    2012-01-01

    The aim of this paper is to describe the difficulties encountered when implementing stereotactic radiotherapy of non-small cell lung cancer (T1-T2, N0, M0) using a voluntary breath-hold technique. From 25/03/2010 to 22/02/2011, eight patients with a non-small cell lung cancer were selected for treatment. CT images were obtained with the patient maintaining breath-hold using a spirometer. Treatment was delivered when the patient maintains this level of breath-hold. Treatment was performed with a 4 MV and 10 MV photon beams from a linear accelerator Varian 2100CS, equipped with a 120 leaves collimator. 60 Gy or 48 Gy were delivered, in four sessions, to the 80% isodose. The planning target volume (PTV) was defined by adding a 5 mm margin to the internal target volume (ITV), the ITV corresponding to the gross tumour volume (GTV) plus a 3 mm margin. CTV is considered equal to GTV. The non-understanding of the gating technique, the great number of beams and the limited breath-hold times led to the failure of some treatments. It can be explained by some patients insufficient respiratory abilities and the low dose rate of one of the beams used for treatment, thus forcing some radiation fields to be delivered in two or three times. Implementing such a technique can be limited by the patients' physical abilities and the materials used. Some solutions were found: a training phase more intense with a coaching of the breath-hold technique more precise, or the use of an abdominal compression device. (authors)

  1. Preoperative Chemotherapy Versus Preoperative Chemoradiotherapy for Stage III (N2) Non-Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Higgins, Kristin; Chino, Junzo P.; Marks, Lawrence B.; Ready, Neal; D'Amico, Thomas A.; Clough, Robert W.; Kelsey, Chris R.

    2009-01-01

    Purpose: To compare preoperative chemotherapy (ChT) and preoperative chemoradiotherapy (ChT-RT) in operable Stage III non-small-cell lung cancer. Methods and Materials: This retrospective study analyzed all patients with pathologically confirmed Stage III (N2) non-small-cell lung cancer who initiated preoperative ChT or ChT-RT at Duke University between 1995 and 2006. Mediastinal pathologic complete response (pCR) rates were compared using a chi-square test. The actuarial overall survival, disease-free survival, and local control were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox regression analysis was also performed. Results: A total of 101 patients who initiated preoperative therapy with planned resection were identified. The median follow-up was 20 months for all patients and 38 months for survivors. The mediastinal lymph nodes were reassessed after preoperative therapy in 88 patients (87%). Within this group, a mediastinal pCR was achieved in 35% after preoperative ChT vs. 65% after preoperative ChT-RT (p = 0.01). Resection was performed in 69% after ChT and 84% after ChT-RT (p = 0.1). For all patients, the overall survival, disease-free survival, and local control rate at 3 years was 40%, 27%, and 66%, respectively. No statistically significant differences were found in the clinical endpoints between the ChT and ChT-RT subgroups. On multivariate analysis, a mediastinal pCR was associated with improved disease-free survival (p = 0.03) and local control (p = 0.03), but not overall survival (p = 0.86). Conclusion: Preoperative ChT-RT was associated with higher mediastinal pCR rates but not improved survival.

  2. Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism

    Science.gov (United States)

    Chen, Xi; Xie, Chun; Fan, Xing-Xing; Jiang, Ze-Bo; Wong, Vincent Kam-Wai; Xu, Jia-Hui; Yao, Xiao-Jun; Liu, Liang; Leung, Elaine Lai-Han

    2017-01-01

    Drug resistance is becoming an obstacle in anti-cancer therapies. For target-based therapy of lung cancer, gefitinib, as the first generation of tyrosine kinase inhibitors (TKIs), demonstrated good initial response to the non-small cell lung cancer (NSCLC) patients whom harbors epidermal growth factor receptor (EGFR) mutation. However, within one year, additional EGFR mutation occurred, leading to eventual gefitinib-resistance. Therefore, it is urgently to discover novel effective small molecule inhibitors for those patients. Abnormal energy metabolism is accepted as new cancer hallmark. Recently, a metabolism rate-limiting enzyme 5’-adenosine menophosphate-activated protein kinase (AMPK) has become a promising anti-cancer target. In this study, we have identified a novel direct AMPK agonist, D561-0775 from a compound library by using molecular docking screening technique. We demonstrated that D561-0775 exhibited significant inhibitory effect on gefitinib-resistant NSCLC cell lines but less cytotoxicity on normal cells. Furthermore, D561-0775 demonstrated a remarkable in vitro AMPK enzyme activation effect. Taken together, D561-0775 showed potential anti-cancer activity via inducing apoptosis, cell cycle arrest, suppressing glycolysis and cholesterol synthesis after activation of AMPK in gefitinib-resistant H1975 cells. D561-0775 has provided a new chemical structure that could be developed as cancer drug for gefitinib-resistant NSCLC patients through inhibition lipid metabolism by directly targeting at AMPK directly. PMID:29221189

  3. Epigenetic Regulation of EMT in Non-Small Cell Lung Cancer.

    Science.gov (United States)

    O'Leary, Karen; Shia, Alice; Schmid, Peter

    2018-01-01

    Lung cancer remains the most diagnosed cancer in the world, with a high mortality rate and fewer therapeutic options. The most common lung cancer is non-small cell, consisting of adenocarcinoma, squamous cell carcinoma and large cell lung carcinoma. As per all solid tumours, the changes that occur for the initiation and metastasis of lung cancer can be described using the EMT (epithelial mesenchymal transition). Cells progressing through EMT lose their epithelial cell characteristics, expressing more mesenchymal markers and are phenotypically different. The transition can be controlled by changes in various pathways, such as TGF-β, PI3K, MAPK, Hedgehog and Wnt. The changes in those pathways can be controlled epigenetically, via DNA methylation, histone modifications or changes in small/non-coding RNA. We will describe the epigenetic changes that occur in these pathways and how we can consider novel methods to generate a synthetic lethality target in an epigenetically regulated pathway in EMT. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer.

    Science.gov (United States)

    Sears, Catherine R; Cooney, Sean A; Chin-Sinex, Helen; Mendonca, Marc S; Turchi, John J

    2016-04-01

    Non-small cell lung cancers (NSCLC) are commonly treated with a platinum-based chemotherapy such as cisplatin (CDDP) in combination with ionizing radiation (IR). Although clinical trials have demonstrated that the combination of CDDP and IR appear to be synergistic in terms of therapeutic efficacy, the mechanism of synergism remains largely uncharacterized. We investigated the role of the DNA damage response (DDR) in CDDP radiosensitization using two NSCLC cell lines. Using clonogenic survival assays, we determined that the cooperative cytotoxicity of CDDP and IR treatment is sequence dependent, requiring administration of CDDP prior to IR (CDDP-IR). We identified and interrogated the unique time and agent-dependent activation of the DDR in NSCLC cells treated with cisplatin-IR combination therapy. Compared to treatment with CDDP or IR alone, CDDP-IR combination treatment led to persistence of γH2Ax foci, a marker of DNA double-strand breaks (DSB), for up to 24h after treatment. Interestingly, pharmacologic inhibition of DDR sensor kinases revealed the persistence of γ-H2Ax foci in CDDP-IR treated cells is independent of kinase activation. Taken together, our data suggest that delayed repair of DSBs in NSCLC cells treated with CDDP-IR contributes to CDDP radiosensitization and that alterations of the DDR pathways by inhibition of specific DDR kinases can augment CDDP-IR cytotoxicity by a complementary mechanism. Published by Elsevier B.V.

  5. Immunotherapy for Non-small-cell Lung Cancer: Current Status and Future Obstacles.

    Science.gov (United States)

    Cho, Ju Hwan

    2017-12-01

    Lung cancer is one of the leading causes of death worldwide. There are 2 major subtypes of lung cancer, non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Studies show that NSCLC is the more prevalent type of lung cancer that accounts for approximately 80%-85% of cases. Although, various treatment methods, such as chemotherapy, surgery, and radiation therapy have been used to treat lung cancer patients, there is an emergent need to develop more effective approaches to deal with advanced stages of tumors. Recently, immunotherapy has emerged as a new approach to combat with such tumors. The development and success of programmed cell death 1 (PD-1)/program death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockades in treating metastatic cancers opens a new pavement for the future research. The current mini review discusses the significance of immune checkpoint inhibitors in promoting the death of tumor cells. Additionally, this review also addresses the importance of tumor-specific antigens (neoantigens) in the development of cancer vaccines and major challenges associated with this therapy. Immunotherapy can be a promising approach to treat NSCLC because it stimulates host's own immune system to recognize cancer cells. Therefore, future research should focus on the development of new methodologies to identify novel checkpoint inhibitors and potential neoantigens.

  6. MicroRNA-429 induces tumorigenesis of human non-small cell lung cancer cells and targets multiple tumor suppressor genes

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    Lang, Yaoguo; Xu, Shidong; Ma, Jianqun; Wu, Jun [Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang 150081 (China); Jin, Shi; Cao, Shoubo [Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang 150081 (China); Yu, Yan, E-mail: yuyan@hrbmu.edu.cn [Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang 150081 (China)

    2014-07-18

    Highlights: • MiR-429 expression is upregulated in non-small cell lung cancer (NSCLC). • MiR-429 inhibits PTEN, RASSF8 and TIMP2 expression. • MiR-429 promotes metastasis and proliferation. • We report important regulatory mechanisms involved in NSCLC progression. • MiR-429 is a potential therapeutic target and diagnostic marker. - Abstract: Lung cancer is the major cause of cancer death globally. MicroRNAs are evolutionally conserved small noncoding RNAs that are critical for the regulation of gene expression. Aberrant expression of microRNA (miRNA) has been implicated in cancer initiation and progression. In this study, we demonstrated that the expression of miR-429 are often upregulated in non-small cell lung cancer (NSCLC) compared with normal lung tissues, and its expression level is also increased in NSCLC cell lines compared with normal lung cells. Overexpression of miR-429 in A549 NSCLC cells significantly promoted cell proliferation, migration and invasion, whereas inhibition of miR-429 inhibits these effects. Furthermore, we demonstrated that miR-429 down-regulates PTEN, RASSF8 and TIMP2 expression by directly targeting the 3′-untranslated region of these target genes. Taken together, our results suggest that miR-429 plays an important role in promoting the proliferation and metastasis of NSCLC cells and is a potential target for NSCLC therapy.

  7. Green tea extract induces protective autophagy in A549 non-small lung cancer cell line

    Directory of Open Access Journals (Sweden)

    Magdalena Izdebska

    2015-12-01

    Full Text Available Background and objectives: For many decades, polyphenols, including green tea extract catechins, have been reported to exert multiple anti-tumor activities. However, to date the mechanisms of their action have not been completely elucidated. Thus, the aim of this study was to assess the effect of green tea extract on non-small lung cancer A549 cells. Material and methods: A549 cells following treatment with GTE were analyzed using the inverted light and fluorescence microscope. In order to evaluate cell sensitivity and cell death, the MTT assay and Tali image-based cytometer were used, respectively. Ultrastructural alterations were assessed using a transmission electron microscope.Results: The obtained data suggested that GTE, even at the highest dose employed (150 μM, was not toxic to A549 cells. Likewise, the treatment with GTE resulted in only a very small dose-dependent increase in the population of apoptotic cells. However, enhanced accumulation of vacuole-like structures in response to GTE was seen at the light and electron microscopic level. Furthermore, an increase in the acidic vesicular organelles and LC3-II puncta formation was observed under the fluorescence microscope, following GTE treatment. The analysis of the functional status of autophagy revealed that GTE-induced autophagy may provide self-protection against its own cytotoxicity, since we observed that the blockage of autophagy by bafilomycin A1 decreased the viability of A549 cells and potentiated necrotic cell death induction in response to GTE treatment.Conclusion: Collectively, our results revealed that A549 cells are insensitive to both low and high concentrations of the green tea extract, probably due to the induction of cytoprotective autophagy. These data suggest that a potential utility of GTE in lung cancer therapy may lie in its synergistic combinations with drugs or small molecules that target autophagy, rather than in monotherapy.

  8. MEK inhibitors against MET-amplified non-small cell lung cancer.

    Science.gov (United States)

    Chiba, Masato; Togashi, Yosuke; Tomida, Shuta; Mizuuchi, Hiroshi; Nakamura, Yu; Banno, Eri; Hayashi, Hidetoshi; Terashima, Masato; De Velasco, Marco A; Sakai, Kazuko; Fujita, Yoshihiko; Mitsudomi, Tetsuya; Nishio, Kazuto

    2016-12-01

    Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFR-mutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.

  9. The expression of GST isoenzymes and p53 in non-small cell lung cancer.

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    MĂźzeyyen Ozhavzali

    2010-06-01

    Full Text Available This study investigated the immunohistochemical staining characteristics of glutathione-S-transferase alpha, pi, mu, theta and p53 in non-small cell lung carcinoma and normal lung tissue from 50 patients. The relationships between expressions of the Glutathione-S-transferase isoenzymes and some clinicopathological features were also examined. Expression of glutathione-S-transferase pi, mu, alpha, theta and p53 was assessed by immunohistochemistry for primary lung carcinomas of 50 patients from the Sanitarium Education and Research Hospital, Ankara lung cancer collection. The relationships between expression of the glutathione-S-transferase isoenzymes, p53 in normal and tumor tissue by Student T test and the clinicopathological data were also examined by Spearman Rank tests. When the normal and tumor tissue of these cases were compared according to their staining intensity and percentage of positive staining, glutathione-S-transferase alpha, pi, mu, theta expressions in tumor cells was significantly higher than normal cells (p<0.05. There was no significant difference in the expression of p53 between normal and tumor cells (p>0.05. When the immunohistochemical results of glutathione-S-transferase isoenzymes and p53 were correlated with the clinical parameters, there were no significant associations between glutathione-S-transferases and p53 expressions and tumor stage, tumor grade and smoking status (p>0.05.

  10. A negative regulation loop of long noncoding RNA HOTAIR and p53 in non-small-cell lung cancer

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    Zhai N

    2016-09-01

    Full Text Available Nailiang Zhai,1 Yongfu Xia,1 Rui Yin,2 Jinping Liu,3 Fuquan Gao1 1Department of Respiratory Medicine, Affiliated Hospital of Binzhou Medical University, 2Department of Respiratory Medicine, People’s Hospital of Binzhou City, 3Department of Pharmacology, Binzhou Medical University, Binzhou, Shandong, People’s Republic of China Abstract: Non-small-cell lung cancer (NSCLC is one of the leading causes of cancer-related death worldwide, and the 5-year survival rate is still low despite advances in diagnosis and therapeutics. A long noncoding RNA (lncRNA HOX antisense intergenic RNA (HOTAIR has been revealed to play important roles in NSCLC carcinogenesis but the detailed mechanisms are still unclear. In the current study, we aimed to investigate the regulation between the lncRNA HOTAIR and p53 in the NSCLC patient samples and cell lines. Our results showed that HOTAIR expression was significantly higher in the cancer tissues than that in the adjacent normal tissue, and was negatively correlated with p53 functionality rather than expression. When p53 was overexpressed in A549 cells, the lncRNA HOTAIR expression was downregulated, and the cell proliferation rate and cell invasion capacity decreased as a consequence. We identified two binding sites of p53 on the promoter region of HOTAIR, where the p53 protein would bind to and suppress the HOTAIR mRNA transcription. Inversely, overexpression of lncRNA HOTAIR inhibited the expression of p53 in A549 cells. Mechanistic studies revealed that HOTAIR modified the promoter of p53 and enhanced histone H3 lysine 27 trimethylation (H3K27me3. These studies identified a specific negative regulation loop of lncRNA HOTAIR and p53 in NSCLC cells, which revealed a new understanding of tumorigenesis in p53 dysfunction NSCLC cells. Keywords: NSCLC, LncRNA HOTAIR, p53, negative loop

  11. MYC is a metastasis gene for non-small-cell lung cancer.

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    Ulf R Rapp

    Full Text Available BACKGROUND: Metastasis is a process by which cancer cells learn to form satellite tumors in distant organs and represents the principle cause of death of patients with solid tumors. NSCLC is the most lethal human cancer due to its high rate of metastasis. METHODOLOGY/PRINCIPAL FINDINGS: Lack of a suitable animal model has so far hampered analysis of metastatic progression. We have examined c-MYC for its ability to induce metastasis in a C-RAF-driven mouse model for non-small-cell lung cancer. c-MYC alone induced frank tumor growth only after long latency at which time secondary mutations in K-Ras or LKB1 were detected reminiscent of human NSCLC. Combination with C-RAF led to immediate acceleration of tumor growth, conversion to papillary epithelial cells and angiogenic switch induction. Moreover, addition of c-MYC was sufficient to induce macrometastasis in liver and lymph nodes with short latency associated with lineage switch events. Thus we have generated the first conditional model for metastasis of NSCLC and identified a gene, c-MYC that is able to orchestrate all steps of this process. CONCLUSIONS/SIGNIFICANCE: Potential markers for detection of metastasis were identified and validated for diagnosis of human biopsies. These markers may represent targets for future therapeutic intervention as they include genes such as Gata4 that are exclusively expressed during lung development.

  12. Cystatins in non-small cell lung cancer: tissue levels, localization and relation to prognosis.

    Science.gov (United States)

    Werle, Bernd; Schanzenbächer, Ulrike; Lah, Tamara Turensek; Ebert, Eileen; Jülke, Britta; Ebert, Werner; Fiehn, Werner; Kayser, Klaus; Spiess, Eberhard; Abrahamson, Magnus; Kos, Janko

    2006-10-01

    Cystatins regulate tumour-associated cysteine proteases, however, their role in tumour progression is not clear yet. To assess their relevance in the progression of non-small cell lung cancer (NSCLC) the protein level, cysteine protease activity (CPI) and localization of type I (stefins A and B) and type II (C, E/M and F) cystatins were defined in tumours and control lung counterparts from 165 patients. The medians of CPI activity, stefins A and B were significantly greater in tumour than in lung tissue (2.1-fold, 1.7-fold, 1.2-fold, respectively, all pcystatin C and cystatin E/M were lower in tumour tissue (0.9-fold, p=0.06; 0.6-fold, pcystatin F were below the detection limit. Immunohistochemical analysis revealed the presence of all cystatins in tumour cells and infiltrated inflammatory cells such as macrophages and neutrophils. In univariate survival analysis patients with high levels of stefin A, stefin B and CPI activity exhibited a better survival probability (p=0.05, p=0.05, pcystatins C and E/M provided no prognostic information. In multivariate analysis the most powerful predictor of survival was the pTNM stage (pcystatins, are up-regulated in lung tumours and thus able to counteract harmful tumour-associated proteolytic activity. As biological markers they may add independent prognostic information for better assessment of low- and high-risk patients with NSCLC.

  13. Loss of expression of BAP1 is very rare in non-small cell lung carcinoma.

    Science.gov (United States)

    Andrici, Juliana; Parkhill, Thomas R; Jung, Jason; Wardell, Kathryn L; Verdonk, Brandon; Singh, Arjun; Sioson, Loretta; Clarkson, Adele; Watson, Nicole; Sheen, Amy; Farzin, Mahtab; Toon, Christopher W; Gill, Anthony J

    2016-06-01

    Germline mutations of the BAP1 gene have been implicated in a cancer predisposition syndrome which includes mesothelioma, uveal melanoma, cutaneous melanocytic lesions, renal cell carcinoma, and possibly other malignancies. Double hit inactivation of BAP1 with subsequent loss of expression of the BAP1 protein also occurs in approximately 50% of mesotheliomas. The link between BAP1 mutation and lung cancer is yet to be fully explored. We sought to assess BAP1 expression in a large cohort of lung cancers undergoing surgery with curative intent. We searched the Anatomical Pathology database of our institution for lung cancer patients undergoing surgery with curative intent between 2000 and 2010. Immunohistochemistry for BAP1 was then performed in tissue microarray format. Our cohort included 257 lung cancer patients, of which 155 (60%) were adenocarcinomas and 72 (28%) were squamous cell carcinomas, with no other subtype comprising more than 3%. BAP1 loss of expression was found in only one lung cancer. We conclude that BAP1 mutation occurs very infrequently (0.4%) in non-small cell lung cancer. Given that the pathological differential diagnosis between lung carcinoma and mesothelioma may sometimes be difficult, this finding increases the specificity of loss of expression for BAP1 for the diagnosis of mesothelioma. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

  14. Pre-operative concurrent chemoradiotherapy for stage IIIA (N2) Non-Small cell lung cancer

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    Lee, Kyu Chan; Ahn, Yong Chan; Park, Keun Chil [College of Medicine, Sungkyunkwan Univ., Seoul (Korea, Republic of)] [and others

    1999-06-01

    This is to evaluate the acute complication, resection rate, and tumor down-staging after pre-operative concurrent chemoradiotherapy for stage IIIA (N2) non-small cell lung cancer. Fifteen patients with non-small cell lung cancer were enrolled in this study from May 1997 to June 1998 in Samsung Medical Center. The median age of the patients was 61 (range, 45-67) years and male to female ratio was 12:3. Pathologic types were squamous cell carcinoma (11) and adenocarcinoma (4). Pre-operative clinical tumor stages were cT1 in 2 patients, cT2 in 12, and cT3 in 1 and all were N2. Ten patients were proved to be N2 with mediastinoscopic biopsy and five had clinically evident mediastinal lymph node metastases on the chest CT scans. Pre-operative radiation therapy field included the primary tumor, the ipsilateral hilum, and the mediastinum. Total radiation dose was 45 Gy over 5 weeks with daily dose of 1.8 Gy. Pre-operative concurrent chemotherapy consisted of two cycles of intraventous cis-Platin (100 mg/m{sup 2}) on day 1 and oral Etoposide (50 mg/m{sup 2}/day) on days 1 through 14 with 4 weeks' interval. Surgery was followed after the pre-operative re-evaluation including chest CT scan in 3 weeks of the completion of the concurrent chemoradiotherapy if there was no evidence of disease progression. Full dose radiation therapy was administered to all the 15 patients. Planned two cycles of chemotherapy was completed in 11 patients and one cycle was given to four. One treatment related death of acute respiratory distress syndrome occurred in 15 days of surgery. Hospital admission was required in three patients including one with radiation pneumonitis and two with neutropenic fever. Hematologic complications and other acute complications including esophagitis were tolerable. Resection rate was 92.3% (12/13) in 13 patients excluding two patients who refused surgery. Pleural seeding was found in one patient after thoracotomy and tumor resection was not feasible. Post

  15. Survival Analysis of 1,742 Patients with Stage IV Non-small Cell Lung Cancer

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    Hong PENG

    2011-04-01

    Full Text Available Background and objective At present non-small cell lung cancer (NSCLC is still the leading cause of death induced by cancer. The aim of this study is to investigate the prognostic factors of advanced NSCLC. Methods Total 1,742 cases of stage IV NSCLC data from Jan 4, 2000 to Dec 25, 2008 in Shanghai Chest Hospital were collected, confirmed by pathological examinations. Analysis was made to observe the impact of treatment on prognosis in gender, age, smoking history, pathology, classification, clinical TNM stage. Survival rate, survival difference were evaluated by Kaplan-Meire method and Logrank test respectively. The prognosis were analyzed by Cox multivariate regression. Results The median survival time of 1,742 patients was 10.0 months (9.5 months-10.5 months. One, two, three, four, and five-year survival rates were 44%, 22%, 13%, 9%, 6% respectively. The median survivals of single or multiple metastasis were 11 months vs 7 months (P < 0.001. Survival time were different in metastasic organs, with the median survival time as follows: lung for about 12 months (11.0 months-12.9 months, bone for 9 months (8.3 months-9.6 months, brain for 8 months (6.8 months-9.1 months, liver, adrenal gland, distannt lymph node metastasis for 5 months (3.8 months-6.1 months, and subcutaneous for 3 months (1.7 months-4.3 months. The median survival times of adenocarcinoma (n=1,086, 62% and squamous cell carcinoma cases (n=305, 17.5% were 12 months vs 8 months (P < 0.001. The median survival time of chemotherapy and best supportive care were 11 months vs 6 months (P < 0.001; the median survival times of with and without radiotherapy were 11 months vs 9 months (P=0.017. Conclusion Gender, age, gross type, pathological type, clinical T stage, N stage, numbers of metastatic organ, smoking history, treatment of advanced non-small cell lung cancer were independent prognostic factors.

  16. Neuroendocrine differentiation as a survival prognostic factor in advanced non-small cell lung cancer

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    Petrović Marina

    2007-01-01

    Full Text Available Beckground/Aim. Neuroendrocine lung tumors are histologically heterogenous group of cancers with different clinical progression. In non-small cell lung cancer (NSCLC neuroendocrine differentiation exists in 10-30% of patients. The aim of this study was to determine the frequency and influence of neuroendocrine differentiation on survival of treated patients with advanced non-small cell lung cancer (NSCLC. Methods. A clinical trial included 158 patients (74% males and 26% females, with the diagnosis of NSCLC, determined by histological verification. The patients were treated by combined chemo - and X-ray therapy in stage III (without pleural effusion or chemotherapy only in stage III (with pleural effusion and stage IV. Chemotherapy was conducted until progression of the disease, but no more than six cycles. When the progression had been noted in stage III (without pleural effusion, the treatment was continued with X-ray therapy. Neuron specific enolase, chromogranin A, as well as synapthophysin expression in tissue examples were determined by immunohistochemical analysis with monoclonal mouse anti-human-bodies. Survival was assessed within a year and two years follow-up examination. Results. A total of 53 patients (34% had NSCLC with neuroendocrine differentiation, confirmed rather in large cell lung cancer and lung adenocarcinoma (66.7% and 40%, respectively. Neuron specific enolase, chromogranin A and synapthophysin expression was noted in 45 (28.5%, 34 (21.5% and 33 (20.1% patients, respectively. The one year and two years follow-up survival periods were confirmed in 39% and 17% of patients respectively. The median survival time in the patients with the neuroendocrine expression as compared to those without the expression was 15.6 vs 10.8 months; one year survival time with the expression compared to those without the expression achieved in 62% vs 27% of the patients, (p < 0.001; a two - year survival time noted in 30% of the patients (p = 0

  17. FBW7 loss promotes epithelial-to-mesenchymal transition in non-small cell lung cancer through the stabilization of Snail protein.

    Science.gov (United States)

    Zhang, Yong; Zhang, Xinxin; Ye, Mingxiang; Jing, Pengyu; Xiong, Jie; Han, Zhiping; Kong, Jing; Li, Mengyang; Lai, Xiaofeng; Chang, Ning; Zhang, Jian; Zhang, Jian

    2018-04-10

    The E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) functions as a putative tumor suppressor in non-small cell lung cancer (NSCLC) due to its regulation of a set of oncogenic proteins associated with cell proliferation and mitosis. Increasing efforts have been focused on the understanding of FBW7 in determining cell cycle progression and apoptosis induction, however, the correlation between FBW7 and tumor metastasis is not fully understood. In this study, we reported a potential anti-metastatic effect of FBW7 in non-small cell lung cancer (NSCLC). In this model, FBW7 inhibited cancer cell metastasis primarily by inducing ubiquitination and proteolysis of the transcriptional factor Snail, which suppressed E-cadherin cell tight junction protein expression. Loss of FBW7 would stabilize the Snail protein, thus, inhibit E-cadherin expression and promote metastasis in vitro and in vivo. Moreover, Snail ubiquitination and degradation were also achieved by pharmacological approach, in which the FBW7 agonist oridonin treatment led to Snail proteolysis. Furthermore, FBW7 silencing stabilized Snail protein and induced epithelial-to mesenchymal transition (EMT), and acquisition of migration and invasion properties in NSCLC. Overall, our study provides new insights into the FBW7-Snail axis in regulating cell migration and invasion, and suggests that targeting FBW7 may be a potent approach to inhibit metastasis in NSCLC. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

  18. MiR-138 Inhibits Tumor Growth Through Repression of EZH2 in Non-Small Cell Lung Cancer

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    Huijun Zhang

    2013-01-01

    Full Text Available Background/Aims: MicroRNAs (miRNAs play important roles in tumorigenesis. We investigated the roles and mechanisms of miR-138 in human non-small cell lung cancer (NSCLC. Methods: The expression of miR-138 was first examined in NSCLC cell lines and tumourtissues by real-time PCR The in vitro and in vivo functional effect of miR-138 was examined further. A luciferase reporter assay was conducted to confirm target association between miR-138 and the enhancer of zeste homolog 2 (EZH2. Results: miR-138 was frequently downregulated in NSCLC cells and tissues. Overexpression of miR-138 inhibited proliferation of NSCLC cells in vitro and tumor growth in vivo. The EZH2 oncogene, which is often overexpressed in various human cancers and acts as an important regulator of cell growth and tumor invasion, was identified as a novel target of miR-138. miR-138 can bind to the 3′ untranslated region (3′ UTR of EZH2 and suppress the expression of EZH2 at both mRNA and protein levels. Furthermore, knockdown of EZH2 phenocopied the tumor suppressive effects of miR-138 in cell models, whereas ectopic expression of EZH2 rescued the suppressive effects of miR-138. Conclusion: These findings define a tumor suppressor function for miR-138 in NSCLC and further suggest that miR-138 may represent a potential therapeutic target for NSCLC patients.

  19. [Expression and clinical significance of Pokemon in non-small cell lung cancer].

    Science.gov (United States)

    Zhao, Zhihong; Wang, Shengfa; Zhang, Tiewa

    2007-12-20

    Proto-oncogene Pokemon is the special transcription inhibitor of ARF,which can regulate cell growth and differentiation by ARF-P53 path.It may be the important monitoring target of tumor because of being upstream region of many tumor suppressor genes and proto-oncogenes.The aim of this study is to explore the clinical significance of Pokemon gene in non-small cell lung cancer(NSCLC). Immunohistochemistry was applied to detect the expression of Pokemon protein in 92 cases of NSCLC and 20 cases of paracancerous lung tissues.Correlation between abnormal expression of Pokemon with pathologic characteristics and prognosis of NSCLC was analyzed. Pokemon was not expressed in paracancerous lung tissues and was found in 66 of 92(71.7%) cases of lung cancer tissues.Expression of Pokemon was closely related to TNM stages(P=0.011).Survival rate of patients with negative Pokemon expression was significantly higher than that of those with positive Pokemon expression(P=0.0015).Pokemon expression was demonstrated as independent prognostic factor of NSCLC. Pokemon is expressed in NSCLC and it may be identified as a new diagnostic marker.High expression of Pokemon may indicate poor prognosis of patients with NSCLC.

  20. Re-188 Enhances the Inhibitory Effect of Bevacizumab in Non-Small-Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jie Xiao

    2016-09-01

    Full Text Available The malignant behaviors of solid tumors such as growth, infiltration and metastasis are mainly nourished by tumor neovascularization. Thus, anti-angiogenic therapy is key to controlling tumor progression. Bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF antibody, plus chemotherapy or biological therapy can prolong survival for cancer patients, but treatment-related mortality is a concern. To improve inhibitory effect and decrease side-effects on non-small-cell lung cancer (NSCLC, we used Re-188, which is a β emitting radionuclide, directly labeled with bevacizumab for radioimmunotherapy in a human A549 tumor model. Cytotoxic assay data showed that, after 188ReO4− or 188Re-bevacizumab at different concentration for 4 and 24 h, a time- and radioactivity does-dependent reduction in cell viability occurred. Also, an apoptosis assay conformed great apoptosis in the 188Re-bevacizumab group compared with controls and other treatment groups. In vivo, tumor volumes in the 188Re-bevacizumab (11.1 MBq/mice group were not reduced but growth was delayed compared with other groups. Thus, 188Re-bevacizumab enhanced the therapeutic effect of bevacizumab, suggesting a potential therapeutic strategy for NSCLC treatment.

  1. Profile of ramucirumab in the treatment of metastatic non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Cooper MR

    2016-04-01

    Full Text Available Maryann R Cooper,1 Chelsea Binkowski,2,3 Jessica Hartung,2,4 Jennifer Towle1 1Department of Pharmacy Practice, School of Pharmacy – Worcester/Manchester, MCPHS University, Manchester, NH, 2School of Pharmacy – Boston, MCPHS University, Boston, MA, 3North America Medical Affairs, 4Global Medical Affairs, Sanofi Oncology, Cambridge, MA, USA Abstract: The interaction between vascular endothelial growth factor and its receptor is an important therapeutic target due to the importance of this pathway in carcinogenesis. In particular, this pathway promotes and regulates angiogenesis as well as increases endothelial cell proliferation, permeability, and survival. Ramucirumab is a fully human monoclonal antibody that specifically targets the vascular endothelial growth factor receptor-2, the key receptor implicated in angiogenesis. Currently, ramucirumab is approved for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC in combination with docetaxel. In a Phase III clinical trial, ramucirumab was shown to improve the overall survival in patients with disease progression, despite platinum-based chemotherapy for advanced NSCLC. This review describes the pharmacology, pharmacokinetics and dynamics, adverse event profile, and the clinical activity of ramucirumab observed in Phase II and III trials in NSCLC. Keywords: NSCLC, antiangiogenesis, VEGF-targeted therapy

  2. Genetic and Biochemical Alterations in Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jackie L. Johnson

    2012-01-01

    Full Text Available Despite significant advances in the detection and treatment of lung cancer, it causes the highest number of cancer-related mortality. Recent advances in the detection of genetic alterations in patient samples along with physiologically relevant animal models has yielded a new understanding of the molecular etiology of lung cancer. This has facilitated the development of potent and specific targeted therapies, based on the genetic and biochemical alterations present in the tumor, especially non-small-cell lung cancer (NSCLC. It is now clear that heterogeneous cell signaling pathways are disrupted to promote NSCLC, including mutations in critical growth regulatory proteins (K-Ras, EGFR, B-RAF, MEK-1, HER2, MET, EML-4-ALK, KIF5B-RET, and NKX2.1 and inactivation of growth inhibitory pathways (TP53, PTEN, p16, and LKB-1. How these pathways differ between smokers and non-smokers is also important for clinical treatment strategies and development of targeted therapies. This paper describes these molecular targets in NSCLC, and describes the biological significance of each mutation and their potential to act as a therapeutic target.

  3. Recent developments in the use of immunotherapy in non-small cell lung cancer.

    Science.gov (United States)

    Santarpia, Mariacarmela; Giovannetti, Elisa; Rolfo, Christian; Karachaliou, Niki; González-Cao, Maria; Altavilla, Giuseppe; Rosell, Rafael

    2016-07-01

    Targeted therapies have significantly improved the prognosis of subsets of patients with advanced non-small-cell lung cancer (NSCLC) harboring somatically activated oncogenes, such as mutant EGFR and rearranged ALK. However, the efficacy of these agents is limited by the development of acquired resistance which occurs after variable periods of time. Therefore, there is an urgent need for novel therapeutic strategies to achieve long lasting disease control, as well as new therapies for those patients without targetable driver mutations. A deeper understanding of interactions between the immune system and tumor cells has led to the development of a number of immunotherapeutic agents. We review current data on immunotherapy for lung cancer treatment, with a focus on checkpoint inhibitors and therapeutic vaccines. References for this review were identified through searches of PubMed, congress proceedings and reference lists from key original and review papers. Expert commentary: While most vaccines have been unsuccessful, inhibitors of specific immune checkpoints, including CTLA-4 and PD-1/PD-L1 pathway, have shown significant clinical activity and manageable toxicities and recently, two anti-PD-1 monoclonal antibodies have been approved by the FDA for treatment of patients with advanced NSCLC. Identification of reliable predictive biomarkers for patient selection and novel rational combinations are currently active areas of research to further improve the efficacy of immunotherapy.

  4. Cost and effectiveness studies in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Pinar Yalcin-Balcik

    2015-02-01

    Full Text Available Lung cancer disease diagnosis and treatment is costly. As the numbers of inflicted rise so does the economic burden assumed for this cancer type. When the treatment expenditures are considered for all types of cancer, the lung cancer is thought to occupy a 20% share. The disease examined in two basic groups as small-cell lung cancer and non-small cell lung cancer (NSCLC is the most frequently encountered type of its kind nationally and in the World. This study considers the cost, effectiveness and cost effectiveness of platinum based chemotherapy medications with active ingredients pemetrexed and gemcitabine used for NSCLC. A review of studies relevant to the advanced stage NSCLC where majority of patients are positioned is foreseen to be useful to the decision makers since policy makers, regulating authorities and physicians require more information due to increased overall finance and costs, as well as treatment cost effectiveness. Furthermore, due to the entry attempt of pemetrexed active ingredient to the list of reimbursed medications for the first stage lung cancer treatment, it is assumed that a review of studies containing pemetrexed and gemcitabine will draw the attention of decision makers at the Social Security Instutition. [TAF Prev Med Bull 2015; 14(1.000: 55-64

  5. Evaluation of Irinotecan as a Third- or Fourth-line Treatment for Advanced Non-small Cell Lung Cancer

    OpenAIRE

    Keener, James

    2013-01-01

    Lung cancer is the leading cause of cancer-related deaths in the United States. There are two major types of lung cancer: non-small cell lung cancer (NSCLC), which comprises approximately 85% of all lung cancers, and small cell lung cancer. Currently, the most prevalent third- and fourth- line treatment for non-small cell lung cancer is cisplatin-based therapy. This form of therapy has been long established as the chief treatment for advanced NSCLC; however, cisplatin-based therapy also impai...

  6. Downregulation of Cyclophilin A by siRNA diminishes non-small cell lung cancer cell growth and metastasis via the regulation of matrix metallopeptidase 9

    Directory of Open Access Journals (Sweden)

    Qian Zhe

    2012-10-01

    Full Text Available Abstract Background Cyclophilin A (CypA is a cytosolic protein possessing peptidyl-prolyl isomerase activity that was recently reported to be overexpressed in several cancers. Here, we explored the biology and molecular mechanism of CypA in non-small cell lung cancer (NSCLC. Methods The expression of CypA in human NSCLC cell lines was detected by real-time reverse transcription PCR. The RNA interference-mediated knockdown of CypA was established in two NSCLC cell lines (95C and A549. 239836 CypA inhibitor was also used to suppress CypA activity. Tumorigenesis was assessed based on cellular proliferation, colony formation assays, and anchorage-independent growth assays; metastasis was assessed based on wound healing and transwell assays. Results Suppression of CypA expression inhibited the cell growth and colony formation of A549 and 95C cells. CypA knockdown resulted in the inhibition of cell motility and invasion. Significantly, we show for the first time that CypA increased NSCLC cell invasion by regulating the activity of secreted matrix metallopeptidase 9 (MMP9. Likewise, suppression of CypA with 239836 CypA inhibitor decreased cell proliferation and MMP9 activity. Conclusions The suppression of CypA expression was correlated with decreased NSCLC cell tumorigenesis and metastasis.

  7. Pemetrexed in maintenance treatment of advanced non-squamous non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Minami S

    2015-01-01

    Full Text Available Seigo Minami,1 Takashi Kijima2 1Department of Respiratory Medicine, Osaka Police Hospital, 2Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan Abstract: Pemetrexed, a multitargeting antifolate cytotoxic drug, plays a leading role in front-line chemotherapy for patients with advanced non-squamous non-small-cell lung cancer (NSCLC. Following its approval as second-line monotherapy for locally advanced or metastatic non-squamous NSCLC, pemetrexed has established itself as the first-line regimen in combination with cisplatin, and its powerful antitumor effects and less cumulative toxicities were then taken advantage of in the JMEN and PARAMOUNT trials, respectively, to pioneer a new treatment strategy of switch and continuation maintenance monotherapy. These developments have brought about a marked paradigm shift, and made pemetrexed indispensable in the treatment for non-squamous NSCLC. So far, only three drugs have been approved for maintenance therapy; pemetrexed both by switch and continuation maintenance, erlotinib by switch maintenance, and bevacizumab by continuation maintenance. Compared with observation alone after defined cycles of the first-line chemotherapy, subsequent pemetrexed maintenance therapy has provided significantly longer survival and infrequent severe adverse events. The cost-effectiveness of pemetrexed maintenance therapy is controversial, as well as the other two maintenance drugs, bevacizumab and erlotinib. The latest attractive attention is a combination maintenance therapy. We may have to consider epidermal growth factor receptor (EGFR mutation status for selection of a combination pattern. A combination maintenance therapy of pemetrexed plus bevacizumab is potential for patients with wild-type EGFR status, while a EGFR tyrosine kinase inhibitor-containing combination is promising for patients with active EGFR mutation status. Pemetrexed will be

  8. Cost analysis of adverse events associated with non-small cell lung cancer management in France

    Directory of Open Access Journals (Sweden)

    Chouaid C

    2017-07-01

    Full Text Available Christos Chouaid,1 Delphine Loirat,2 Emilie Clay,3 Aurélie Millier,3 Chloé Godard,4 Amira Fannan,4 Laurie Lévy-Bachelot,4 Eric Angevin5 1Chest Department, Centre Hospitalier Intercommunal Créteil, Créteil, France; 2Institut Curie, Paris, France; 3Creativ-Ceutical, Paris, France; 4MSD France, Courbevoie, France; 5Institut Gustave Roussy, Villejuif, France Background: Adverse events (AEs related to medical treatments in non-small cell lung cancer (NSCLC are frequent and need an appropriate costing in health economic models. Nevertheless, data on costs associated with AEs in NSCLC are scarce, particularly since the development of immunotherapy with specific immune-related AEs.Objective: To estimate the costs of grades 3 and 4 AEs related to NSCLC treatments including immunotherapy in France.Methods: Grades 3 and 4 AEs related to treatment and reported in at least 1% of patients in Phase III clinical trials for erlotinib, ramucirumab plus docetaxel, docetaxel, pemetrexed plus carboplatin plus bevacizumab, platinum-based chemotherapies, nivolumab and pembrolizumab were identified. When no cost evaluation was reported in literature, estimates on standard treatments and medical resource use for each AE were obtained thanks to an expert panel. Total cost per AE was calculated from a French national health insurance perspective and updated in 2017 Euros. Hospital stay costs were estimated based on public and private weighted tariffs and data from the French Medical Information System (Programme de Médicalisation des Systèmes d’Information. Costs of tests, consultations and treatments were calculated based on national reimbursement tariffs.Results: Overall, costs of grades 3 and 4 AEs related to treatment ranged from €46 per event to €7,742 per year. Fourteen out of 24 AEs identified had a mean estimated cost over €2,000. The highest mean costs were related to type 1 diabetes (€7,742 per year followed by pneumonitis (€5,786 per event

  9. Hormone and cytokine circadian alteration in non-small cell lung cancer patients.

    Science.gov (United States)

    Mazzoccoli, G; Sothern, R B; Francavilla, M; Giuliani, F; Carughi, S; Muscarella, L A; Fazio, V M; Parrella, P; Vinciguerra, M; Tarquini, R

    2012-01-01

    Alterations in hormone secretion and cytokine levels have been evidenced in many neoplastic diseases. In this study we have evaluated the circadian profile of growth hormone (GH), insulin-like growth factor-1 (IGF-1), interleukin-2 (IL2), melatonin (MEL) and cortisol (COR) serum levels in non-small cell lung cancer patients. Blood was sampled every 4 h for 24 h in 11 healthy (H) men (ages 35-53 years) and 9 men with stage 2, 3 or 4 non-small cell lung cancer (C) (ages 43-63 years). Serum GH, total IGF1, IL2, MEL and COR were measured and examined for group differences, trends, and rhythm characteristics. 24-h means were significantly higher in C234 vs H for GH, GH/IGF1, IL2 and COR, and lower for IGF1, but IL2 and COR were not different for C23 vs H. A linear regression across 4 groups (H, C2, C3, C4) found a positive trend for COR, GH, GH/IGF1 and IL2, and a negative trend for IGF1. A linear regression run between the 24-h mean levels of GH, IGF1, COR, MEL and IL2 in healthy subjects evidenced a statistically significant positive trend between MEL and GH (R = 0.281, p = 0.022) and in cancer patients showed a statistically significant negative trend between GH and IGF1 (R = 0.332, p = 0.01), COR and IGF1 (R=0.430, p=0.001), and a statistically significant positive trend between the 24-h mean of COR and GH (R = 0.304, p = 0.02). Rhythms in MEL and COR (peaks near 01:00h and 08:00h, respectively) indicated identical synchronization to the light-dark cycle for both groups. A circadian rhythm was detected in GH and GH/IGF1 for C23 and H, with IGF1 and IL2 non-rhythmic in any group. In conclusion, an increasing trend and progressive loss of circadian rhythmicity in GH and GH/IGF1, an increasing trend in cortisol and IL2, and a decreasing trend in IGF1 in C, reflect a complex chain of events that could be involved in progression of neoplastic disease. A therapeutic strategy needs to take into account circadian patterns and complex interactions of the multiple functions

  10. Crizotinib in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Removed by Surgery and ALK Fusion Mutations (An ALCHEMIST Treatment Trial)

    Science.gov (United States)

    2017-12-07

    ALK Gene Rearrangement; ALK Gene Translocation; ALK Positive; Stage IB Non-Small Cell Lung Carcinoma AJCC v7; Stage II Non-Small Cell Lung Cancer AJCC v7; Stage IIA Non-Small Cell Lung Carcinoma AJCC v7; Stage IIB Non-Small Cell Lung Carcinoma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7

  11. Carvacrol Targets AXL to Inhibit Cell Proliferation and Migration in Non-small Cell Lung Cancer Cells.

    Science.gov (United States)

    Jung, Chi Young; Kim, So-Young; Lee, Chuhee

    2018-01-01

    AXL has been reported to be overexpressed and highly activated in various cancer types. In this study, we demonstrated the effect of carvacrol on cell proliferation and migration in non-small cell lung cancer (NSCLC) cells by impeding the expression and activation of AXL. The levels of AXL protein, mRNA and promoter activity were evaluated by western blot, reverse transcription polymerase chain reaction (RT-PCR) and luciferase assay, respectively. AXL-overexpressing cells were established by ectopic expression of AXL cDNA. Cell viability, clonogenicity, and migration were measured in carvacrol-treated NSCLC cells. Carvacrol treatment of NSCLC cells caused down-regulation of AXL expression at the transcriptional level and also inhibited phosphorylation of AXL upon ligand stimulation. Carvacrol suppressed cell proliferation and migration and its inhibitory effect was attenuated in AXL-overexpressing NSCLC cells. Our data demonstrate that AXL is a crucial therapeutic target of carvacrol-induced inhibition of NSCLC cell proliferation and migration. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  12. Presence of urokinase plasminogen activator, its inhibitor and receptor in small cell lung cancer and non-small cell lung cancer

    DEFF Research Database (Denmark)

    Pappot, H.; Pfeiffer, P.; Grøndahl Hansen, J.

    1997-01-01

    Spreading of cancer cells is dependent on the combined action of several proteolytic enzymes, such as serine proteases, comprising the urokinase pathway of plasminogen activation. Previous studies of lung cancer indicate that expression, localization and prognostic impact of the components...... of the plasminogen activation system differ in the different non-small cell lung cancer (NSCLC) types, whereas the expression of the components in small cell lung cancer (SCLC) has only sparingly been investigated. In the present study we investigate the presence of the components of the plasminogen activation...... that the plasminogen activation system could play a role in this type of cancer during invasion. In addition a difference in the levels of the components of the plasminogen activation system in NSCLC and SCLC is found, which could contribute to the differences in biology....

  13. Targeted therapies for non-small-cell lung cancer: biology, rationale, and preclinical results from a radiation oncology perspective

    International Nuclear Information System (INIS)

    Raben, David; Helfrich, Barb; Bunn, Paul A.

    2004-01-01

    The epidermal growth factor receptor (EGFR) is overexpressed in the majority of non-small-cell lung cancers (NSCLCs). This presents an opportune target for new treatment strategies designed to selectively interfere with the cancer cell growth cycle. Recent investigations into the biology of the EGFR and its downstream signaling pathways have reminded us of the complexity of cancer cell communications from the cytoplasm to the nucleus. Multiple pathways are activated with stimulation of the autocrine and paracrine EGFR loop, from the ras-raf-MEK activation of ERK 1/2 to the P13K-Akt pathway, each playing an important role in cancer cell survival, invasion, and angiogenesis. Preclinical studies have demonstrated that molecules targeting the EGFR, either through extracellular blockade or intracellular interference with the EGFR-associated tyrosine kinase, reversibly or irreversibly, inhibit cancer cell growth. Potent antitumor effects have been observed in human tumor xenograft models. Preclinical studies have also demonstrated cooperative effects when anti-EGFR agents are combined with radiation or chemotherapy. Many of these agents have now entered into advanced human clinical trials with modest dose-related toxicity despite chronic administration. Encouraging response rates with single-agent targeted therapy have been reported in heavily pretreated patients with advanced NSCLC. In addition, agents targeting the angiogenic pathway, which plays a key role in the regulation of angiogenesis, may play an important role in enhancing the efficacy of anti-EGFR agents. This article will focus on the biology, rationale, and preclinical studies with targeted anti-EGFR and antiangiogenic therapies for the management of NSCLC

  14. Expression of Bim, Noxa, and Puma in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Sakakibara-Konishi, Jun; Oizumi, Satoshi; Kikuchi, Junko; Kikuchi, Eiki; Mizugaki, Hidenori; Kinoshita, Ichiro; Dosaka-Akita, Hirotoshi; Nishimura, Masaharu

    2012-01-01

    The BH3-only members of the Bcl-2 protein family have been proposed to play a key role in the control of apoptosis and in the initiation of the apoptotic pathways. In this study, we evaluated the expression of Bim, Noxa, and Puma in non-small cell lung cancer (NSCLC). A total of 135 surgically resected NSCLCs were immunohistochemically assessed for Bim, Noxa, and Puma expression. The immunoscores were determined, and then its correlation with either the clinicopathological variables or the survival outcomes were analyzed. Immunohistochemical reactivity for Bim, Noxa, and Puma was detected in the cytoplasm of the tumor cells. Bim expression was associated with several clinicopathological factors, including sex (p < 0.001), smoking habit (p = 0.03), pathological histology (p = 0.001), pathological T stage (p = 0.03), pathological disease stage (p = 0.02), and differentiation of tumor (p < 0.001). Multivariate logistic regression analysis showed a significant correlation between low Bim expression and squamous cell carcinoma (p = 0.04), in addition to a correlation between high Bim expression and well differentiated tumors (p = 0.02). Analysis of cellular biological expression demonstrated a link between low Bim expression and high Ki67. While Noxa expression was also shown to be correlated with both smoking habit (p = 0.02) and the pathological histology (p = 0.03), there was no strong association observed between the expression and the clinical features when they were examined by a multivariate logistic regression analysis. No correlations were noted between Puma expression and any of the variables. Our analyses also indicated that the expression levels of the BH3-only proteins were not pertinent to the survival outcome. The current analyses demonstrated that Bim expression in the NSCLCs was associated with both squamous cell carcinoma histology and tumor proliferation

  15. Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer

    DEFF Research Database (Denmark)

    Popat, Sanjay; Mellemgaard, Anders; Fahrbach, Kyle

    2015-01-01

    BACKGROUND: Nintedanib plus docetaxel has proven an overall survival benefit over docetaxel monotherapy in second-line treatment of non-small-cell lung cancer of adenocarcinoma histology in the LUME-Lung 1 pivotal trial. No published trials have previously compared nintedanib plus docetaxel...... with agents – other than docetaxel – that are approved second-line treatments for non-small-cell lung cancer. METHODS: The relative efficacy of nintedanib plus docetaxel versus second-line agents was evaluated by conducting a network meta-analysis of progression-free survival and overall survival. RESULTS...... with advanced non-small-cell lung cancer of adenocarcinoma histology, results suggest that nintedanib plus docetaxel offers clinical benefit compared with docetaxel alone, when used as second-line treatment, and suggests that this combination may also add clinical benefit compared with erlotinib in this patient...

  16. [What future for circulating tumor DNA? Current data and prospects in colorectal, non-small cell lung and pancreatic cancers].

    Science.gov (United States)

    Pietrasz, Daniel; Pécuchet, Nicolas; Fabre, Elizabeth; Blons, Hélène; Chevalier, Line; Taly, Valérie; Laurent-Puig, Pierre; Bachet, Jean-Baptiste

    2016-01-01

    Ten years after the discovery of the predictive value of KRAS status for anti-EGFR antibodies, other genes involved in oncogenesis and therapeutic responses were identified and are now systematically sought. Molecular diagnosis often requires invasive procedures, sometimes iatrogenic, and is limited by feasibility problems, quantity and quality of samples. Identifying these mutations from blood biomarkers would reduce costs and diagnostic delay. The circulating tumor DNA (ctDNA) is one of the most promising blood biomarkers. In this review, we report and discuss the latest results obtained with ctDNA in colorectal cancer, non-small cell lung cancer, and adenocarcinoma of the pancreas. If the methods highlighting appear very heterogeneous, the correlation between mutations found in tumor and those identified in the blood exceeds 95 % specificity in numerous studies. The detection sensitivity is in turn strongly related to tumor stage patients. The presence of ctDNA appears as a prognostic factor for progression-free survival and overall survival. Finally, recent studies have shown that the changing rate ctDNA during systemic treatments had a predictive value for therapeutic efficacy. These results allow to consider the use of ctDNA in monitoring patients to identify early recurrence or progression. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  17. Synchronous Oligometastatic Non-Small Cell Lung Cancer and Isolated Renal Cell Carcinoma: A Case Report and Literature Review.

    Science.gov (United States)

    Nguyen, Timothy K; Louie, Alexander V

    2015-10-27

    A 58-year-old gentleman presenting with a progressive headache, visual disturbance, decreased appetite, and weight loss was found to have a localized clear cell carcinoma of the kidney and synchronous Stage IV non-small cell lung cancer with a solitary brain metastasis. This case illustrates the challenges in distinguishing between primary and metastatic disease in a patient with both renal cell carcinoma and lung cancer. We highlight the uncertainties in the diagnosis and management of this unique clinical scenario and the potential implications on prognosis.

  18. Correlation between topoisomerase I and tyrosyl-DNA phosphodiesterase 1 activities in non-small cell lung cancer tissue

    DEFF Research Database (Denmark)

    Jakobsen, Ann-Katrine; Lauridsen, Kristina Lystlund; Samuel, Evelyn Benuja

    2015-01-01

    of the camptothecin family (CPT). TDP1 has in cell line based assays been shown to counteract the effect of CPT. We have quantified the enzymatic activities of TOP1 and TDP1 in paired (tumor and adjacent non-tumor) samples from non-small cell lung cancer (NSCLC) patients and show that in NSCLC TOP1 and TDP1...

  19. Proteasome-based mechanisms of intrinsic and acquired bortezomib resistance in non-small cell lung cancer

    NARCIS (Netherlands)

    de Wilt, Leonie H. A. M.; Jansen, Gerrit; Assaraf, Yehuda G.; van Meerloo, Johan; Cloos, Jacqueline; Schimmer, Aaron D.; Chan, Elena T.; Kirk, Christopher J.; Peters, Godefridus J.; Kruyt, Frank A. E.

    2012-01-01

    The proteasome inhibitor bortezomib, registered for Multiple Myeloma treatment, is currently explored for activity in solid tumors including non-small cell lung cancer (NSCLC). Here we studied the proteasome-based mechanisms underlying intrinsic and acquired bortezomib resistance in NSCLC cells.

  20. Local recurrence after surgery for non-small cell lung cancer: a recursive partitioning analysis of multi-institutional data.

    Science.gov (United States)

    Kelsey, Chris R; Higgins, Kristin A; Peterson, Bercedis L; Chino, Junzo P; Marks, Lawrence B; D'Amico, Thomas A; Varlotto, John M

    2013-10-01

    To define subgroups at high risk of local recurrence (LR) after surgery for non-small cell lung cancer using a recursive partitioning analysis (RPA). This Institutional Review Board-approved study included patients who underwent upfront surgery for I-IIIA non-small cell lung cancer at Duke Cancer Institute (primary set) or at other participating institutions (validation set). The 2 data sets were analyzed separately and identically. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered an LR. Recursive partitioning was used to build regression trees for the prediction of local recurrence-free survival (LRFS) from standard clinical and pathological factors. LRFS distributions were estimated with the Kaplan-Meier method. The 1411 patients in the primary set had a 5-year LRFS rate of 77% (95% confidence interval [CI], 0.74-0.81), and the 889 patients in the validation set had a 5-year LRFS rate of 76% (95% CI, 0.72-0.80). The RPA of the primary data set identified 3 terminal nodes based on stage and histology. These nodes and their 5-year LRFS rates were as follows: (1) stage I/adenocarcinoma, 87% (95% CI, 0.83-0.90); (2) stage I/squamous or large cell, 72% (95% CI, 0.65-0.79); and (3) stage II-IIIA, 62% (95% CI, 0.55-0.69). The validation RPA identified 3 terminal nodes based on lymphovascular invasion (LVI) and stage: (1) no LVI/stage IA, 82% (95% CI, 0.76-0.88); (2) no LVI/stage IB-IIIA, 73% (95% CI, 0.69-0.80); and (3) LVI, 58% (95% CI, 0.47-0.69). The risk of LR was similar in the primary and validation patient data sets. There was discordance between the 2 data sets regarding the clinical factors that best segregate patients into risk groups. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  1. Interpretation of NCCN Guidelines: General Therapies on Non-small Cell Lung Cancer (Version 6. 2015

    Directory of Open Access Journals (Sweden)

    Xin-en HUANG

    2015-06-01

    Full Text Available Lung cancer is one of the most common malignant tumors in China and ranks the first of cancer-related death. The major etiological agent of lung cancer is an industry-made and promoted addictive product, so lung cancer is considered to be a unique disease in all cancers. Effective policies for public health are required to prevent the smoking initiation so as to reduce the mortality of lung cancer, so Food and Drug Administration (FDA has introduced a series of measures to monitor the tobacco products. As to patients with strong suspicion of lung cancer in stage Ⅰ-Ⅱ, a preoperative biopsy is needed and intra-operative diagnosis is necessary before pneumonectomy, bilobectomy or lobectomy if the preoperative tissue diagnosis is not obtained. However, lung cancer still cannot be easily diagnosed and cured, so the annual improvement and update of new therapeutic protocols and the development of new agents is of great significance. Non-small cell lung cancer (NSCLC accounts for about 80% of all lung cancer, and above 75% NSCLC patients are in middle-advanced stage when diagnosed, so they have lost the optimal therapeutic opportunity and the 5-year survival rate is relatively low. Therefore, this study mainly interpreted the National Comprehensive Cancer Network (NCCN guidelines on the general therapies on NSCLC, hoping to provide references for the treatment of NSCLC patients and prolong their long-term survival.

  2. Treating advanced non-small-cell lung cancer in Chinese patients: focus on icotinib

    Directory of Open Access Journals (Sweden)

    Liang JL

    2014-05-01

    Full Text Available Jun-Li Liang,1 Xiao-Cang Ren,2 Qiang Lin2 1Department of Radiation Oncology, Hebei Medical University Fourth Hospital, Shijiazhuang, People’s Republic of China; 2Department of Oncology, North China Petroleum Bureau General Hospital of Hebei Medical University, Renqiu, Hebei Province, People’s Republic of China Abstract: Icotinib hydrochloride is an orally administered small-molecule reversible tyrosine kinase inhibitor that has been independently researched and developed and has independent intellectual property rights in the People’s Republic of China. Clinical trials have demonstrated that the response to icotinib among advanced non-small-cell lung cancer (NSCLC patients who received at least one platinum-based chemotherapy regimen was not inferior to gefitinib. Since being launched August 2011 in the People’s Republic of China, icotinib has been widely used in clinics, and has become an important treatment option for Chinese patients with advanced NSCLC. The present study presents the Phase I, II, and III clinical trials of icotinib and discusses current clinical applications in the People’s Republic of China and future research directions. Keywords: targeted therapy, EGFR-TKI, NSCLC

  3. Micrometastasis in non-small-cell lung cancer: Detection and staging

    Directory of Open Access Journals (Sweden)

    Gholamreza Mohajeri

    2012-01-01

    Full Text Available Background: The clinical relevance of bone marrow micrometastasis (BMM in non-small-cell lung cancer is undetermined, and the value of such analyses in advanced stage patients has not been clearly assessed previously. This study was conducted to estimate the accuracy of both polymerase chain reaction (PCR and immunohistochemistry (IHC in micrometastases detection and determine the best site for bone marrow biopsy in order to find micrometastasis. Methods: This prospective cross-sectional study was performed in the Department of Thoracic Surgery, Alzahra University Hospital from September 2008 to June 2009. To evaluate the bone marrow, a 3-cm rib segment and an aspirated specimen from the iliac bone prior to tumor resection were taken. PCR and IHC were performed for each specimen to find micrometastasis. Results: Of 41 patients, 14 (34% were positive for BMM by PCR compared with two positive IHC (4.8%. All BMMs were diagnosed in rib segments, and iliac specimens were all free from metastatic lesion. Our data showed no significant association between variables such as age, sex, histology, tumor location, side of tumor, involved lobe, smoking, or weight loss and presence of BMM. Conclusion: PCR could use as a promising method for BMM detection. BMM in a sanctuary site (rib is not associated with advanced stages of lung cancer. In addition, when predictor variables such as age, sex, histology, tumor location, smoking, or weight loss are analyzed, no correlation can be found between micrometastasis prevalence and any of those variables.

  4. Safety of Racotumomab in the treatment of patients with non-small cell lung cancer

    International Nuclear Information System (INIS)

    Perez, Leslie; Estevez, Daymys; Gaston, Yoisbel

    2013-01-01

    In Cuba, lung cancer ranks second in incidence and first in mortality. Therefore, it is necessary to identify new therapeutical options. Immunological approaches are interesting because of the potential activity without the toxicities of conventional chemotherapy. The Center of Molecular Immunology developed a vaccine called Racotumomab; it acts on the lung carcinoma inducing an increase in tumor apoptosis and a decrease in the number of tumor vessels. A expanded access, multicenter, open study was conducted in 86 patients with non-small cell lung cancer in order to assess its safety. The administered dose was 1 mg/mL intradermically. The first 5 doses were administered every 14 days and the remaining 10 every 28 days until completing the treatment. The follow-up re immunizations were every 28 days. The occurrence of adverse events (AE) was analyzed and they were classified according to CTC v4.02 criteria. Adverse events were reported by 58 patients (67.4%), making a total of 215 events. burning at the injection site was the most frequently reported event, 32 (14.9%). The use of the vaccine in the patients under study showed good safety and tolerance

  5. Radiofrequency ablation in primary non-small cell lung cancer: What a radiologist needs to know

    Science.gov (United States)

    Bhatia, Shivank; Pereira, Keith; Mohan, Prasoon; Narayanan, Govindarajan; Wangpaichitr, Medhi; Savaraj, Niramol

    2016-01-01

    Lung cancer continues to be one of the leading causes of death worldwide. In advanced cases of lung cancer, a multimodality approach is often applied, however with poor local control rates. In early non-small cell lung cancer (NSCLC), surgery is the standard of care. Only 15-30% of patients are eligible for surgical resection. Improvements in imaging and treatment delivery systems have provided new tools to better target these tumors. Stereotactic body radiation therapy (SBRT) has evolved as the next best option. The role of radiofrequency ablation (RFA) is also growing. Currently, it is a third-line option in stage 1 NSCLC, when SBRT cannot be performed. More recent studies have demonstrated usefulness in recurrent tumors and some authors have also suggested combination of RFA with other modalities in larger tumors. Following the National Lung Screening Trial (NLST), screening by low-dose computed tomography (CT) has demonstrated high rates of early-stage lung cancer detection in high-risk populations. Hence, even considering the current role of RFA as a third-line option, in view of increasing numbers of occurrences detected, the number of potential RFA candidates may see a steep uptrend. In view of all this, it is imperative that interventional radiologists be familiar with the techniques of lung ablation. The aim of this article is to discuss the procedural technique of RFA in the lung and review the current evidence regarding RFA for NSCLC. PMID:27081229

  6. Maintenance therapy in advanced non-small cell lung cancer: evolution, tolerability and outcomes

    Science.gov (United States)

    Coate, Linda E.; Shepherd, Frances A.

    2011-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the industrialized world. Despite significant progress in early stage disease, survival rates for advanced disease remain low. Maintenance therapy is a treatment strategy that has been investigated extensively in NSCLC and has been the subject of considerable recent debate. Options for maintenance include continuing the initial combination chemotherapy regimen, continuing only single agent chemotherapy (‘continuation maintenance’) or introducing a new agent (‘switch’ maintenance therapy). Therapies that have been studied in this setting in randomized trials to date include chemotherapy, molecularly targeted agents and immunotherapy approaches. Following the development of multiple new agents that show activity in NSCLC, and have a tolerable side-effect profile, there has been increasing interest in utilizing them to maintain response to initial therapy after treatment with platinum-based doublets. Despite considerable controversy, it has become an acceptable treatment paradigm. Here, we briefly outline the evolution of this treatment paradigm and examine which subgroups of patients are most likely to benefit. PMID:21904577

  7. Targeting brain metastases in ALK-rearranged non-small-cell lung cancer.

    Science.gov (United States)

    Zhang, Isabella; Zaorsky, Nicholas G; Palmer, Joshua D; Mehra, Ranee; Lu, Bo

    2015-10-01

    The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Time to Treatment in Patients With Stage III Non-Small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Wang Li; Correa, Candace R.; Hayman, James A.; Zhao Lujun; Cease, Kemp; Brenner, Dean; Arenberg, Doug; Curtis, Jeffery; Kalemkerian, Gregory P.; Kong, F.-M.

    2009-01-01

    Purpose: To determine whether time to treatment (TTT) has an effect on overall survival (OS) in patients with unresectable or medically inoperable Stage III non-small cell lung cancer (NSCLC) and whether patient or treatment factors are associated with TTT. Methods and Materials: Included in the study were 237 consecutive patients with Stage III NSCLC treated at University of Michigan Hospital (UM) or the Veterans Affairs Ann Arbor Healthcare System (VA). Patients were treated with either palliative or definitive radiotherapy and radiotherapy alone (n = 106) or either sequential (n = 69) or concurrent chemoradiation (n = 62). The primary endpoint was OS. Results: Median follow-up was 69 months, and median TTT was 57 days. On univariate analysis, the risk of death did not increase significantly with longer TTT (p = 0.093). However, subset analysis showed that there was a higher risk of death with longer TTT in patients who survived ≥ 5 years (p = 0.029). Younger age (p = 0.027), male sex (p = 0.013), lower Karnofsky Performance Score (KPS) (p = 0.002), and treatment at the VA (p = 0.001) were significantly associated with longer TTT. However, on multivariate analysis, only lower KPS remained significantly associated with longer TTT (p = 0.003). Conclusion: Time to treatment is significantly associated with OS in patients with Stage III NSCLC who lived longer than 5 years, although it is not a significant factor in Stage III patients as a whole. Lower KPS is associated with longer TTT.

  9. The prognostic value of KRAS mutated plasma DNA in advanced non-small cell lung cancer

    DEFF Research Database (Denmark)

    Nygaard, Anneli Dowler; Garm Spindler, Karen-Lise; Pallisgaard, Niels

    2013-01-01

    DNA) in the blood allows for tumour specific analyses, including KRAS-mutations, and the aim of the study was to investigate the possible prognostic value of plasma mutated KRAS (pmKRAS) in patients with non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Patients with newly diagnosed, advanced NSCLC eligible....... RESULTS: The study included 246 patients receiving a minimum of 1 treatment cycle, and all but four were evaluable for response according to RECIST. Forty-three patients (17.5%) presented with a KRAS mutation. OS was 8.9 months and PFS by intention to treat 5.4 months. Patients with a detectable plasma......-KRAS mutation had a significantly shorter OS and PFS compared to the wild type (WT) patients (median OS 4.8 months versus 9.5 months, HR 1.87, 95% CI 1.23-2.84, p=0.0002 and median PFS 3.0 months versus 5.6 months, HR 1.60, 95% CI 1.09-2.37, p=0.0043). A multivariate Cox regression analysis confirmed...

  10. The role of Gefitinib in patients with non-small-cell lung cancer in India

    Directory of Open Access Journals (Sweden)

    Asmita Anilkumar Mehta

    2013-01-01

    Full Text Available Background: Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor, represents a new treatment option for patients with advanced non-small-cell lung cancer (NSCLC. We analyzed the data of patients who received Gefitinib for NSCLC in a tertiary care center in South India. Materials and Methods: Sixty-three patients with advanced NSCLC who had received Gefitinib either after failure of conventional chemotherapy or were previously not treated as they were unfit or unwilling for conventional treatment were included in the analysis. Results: The median follow-up for the cohort was 311 days (range 11-1544 days. Median time to progression was 161 (range 9-883 days. Complete and partial remission was seen in 1 (2% and 6 (9% patients, respectively, with overall response rate of 11%. Twenty-four (38% patients had stable disease. Gefitinib was well tolerated with no significant side effects. Conclusion: Gefitinib shows anti-tumor activity in pretreated or previously untreated patients with advanced NSCLC. It has a favorable toxicity profile and is well tolerated. Gefitinib should be considered as a viable therapy in patients with NSCLC.

  11. Radiomics-based Prognosis Analysis for Non-Small Cell Lung Cancer

    Science.gov (United States)

    Zhang, Yucheng; Oikonomou, Anastasia; Wong, Alexander; Haider, Masoom A.; Khalvati, Farzad

    2017-04-01

    Radiomics characterizes tumor phenotypes by extracting large numbers of quantitative features from radiological images. Radiomic features have been shown to provide prognostic value in predicting clinical outcomes in several studies. However, several challenges including feature redundancy, unbalanced data, and small sample sizes have led to relatively low predictive accuracy. In this study, we explore different strategies for overcoming these challenges and improving predictive performance of radiomics-based prognosis for non-small cell lung cancer (NSCLC). CT images of 112 patients (mean age 75 years) with NSCLC who underwent stereotactic body radiotherapy were used to predict recurrence, death, and recurrence-free survival using a comprehensive radiomics analysis. Different feature selection and predictive modeling techniques were used to determine the optimal configuration of prognosis analysis. To address feature redundancy, comprehensive analysis indicated that Random Forest models and Principal Component Analysis were optimum predictive modeling and feature selection methods, respectively, for achieving high prognosis performance. To address unbalanced data, Synthetic Minority Over-sampling technique was found to significantly increase predictive accuracy. A full analysis of variance showed that data endpoints, feature selection techniques, and classifiers were significant factors in affecting predictive accuracy, suggesting that these factors must be investigated when building radiomics-based predictive models for cancer prognosis.

  12. Neoadjuvant and adjuvant therapy for Stage III non-small cell lung cancer.

    Science.gov (United States)

    Watanabe, Shun-Ichi; Nakagawa, Kazuo; Suzuki, Kenji; Takamochi, Kazuya; Ito, Hiroyuki; Okami, Jiro; Aokage, Keiju; Saji, Hisashi; Yoshioka, Hiroshige; Zenke, Yoshitaka; Aoki, Tadashi; Tsutani, Yasuhiro; Okada, Morihito

    2017-12-01

    The treatments for advanced non-small cell lung cancer (NSCLC) should control both local and microscopic systemic disease, because the 5-year survival of patients with Stage III NSCLC who underwent surgical resection alone has been dismal. One way to improve surgical outcome is the administration of chemotherapy before or after the surgical procedure. During the last two decades, many clinical studies have focused on developing optimal adjuvant or neoadjuvant chemotherapy regimens that can be combined with surgical treatment and/or radiotherapy. Based on the results of those clinical studies, multimodality therapy is considered to be an appropriate treatment approach for Stage IIIA NSCLC patients; although, optimal treatment strategies are still evolving. When N2 nodal involvement is discovered postoperatively, adjuvant cisplatin-based chemotherapy confers an overall survival benefit. The addition of postoperative radiotherapy might be considered for patients with nodal metastases. Although definitive chemoradiation remains a standard of care for cN2 NSCLC, alternative approaches such as induction chemotherapy or chemoradiotherapy and surgery can be considered for a selective group of patients. When surgical resection can be performed after induction therapy with low risk and a good chance of complete resection, the outcome may be optimal. The decision to proceed with resection after induction therapy must include a detailed preoperative pulmonary function evaluation as well as a critical intraoperative assessment of the feasibility of complete resection. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  13. Stereotactic radiotherapy for early stage non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ricardi, Umberto; Badellino, Serena; Filippi, Andrea Riccardo [Dept. of Oncology, Radiation Oncology, University of Torino, Torino (Italy)

    2015-06-15

    Stereotactic body radiotherapy (SBRT) represents a consolidated treatment option for patients with medically inoperable early stage non-small cell lung cancer (NSCLC). The clinical evidence accumulated in the past decade supports its use as an alternative to surgery with comparable survival outcomes. Due to its limited toxicity, SBRT is also applicable to elderly patients with very poor baseline pulmonary function or other severe comorbidities. Recent comparative studies in operable patients raised the issue of the possible use of SBRT also for this subgroup, with quite promising results that still should be fully confirmed by prospective trials with long-term follow-up. Aim of this review is to summarize and discuss the major studies conducted over the years on SBRT and to provide data on the efficacy and toxicity of this radiotherapy technique for stage I NSCLC. Technical aspects and quality of life related issues are also discussed, with the goal to provide information on the current role and limitations of SBRT in clinical practice.

  14. EGFR mutation positive stage IV non-small-cell lung cancer : Treatment beyond progression

    Directory of Open Access Journals (Sweden)

    Katrijn eVan Assche

    2014-12-01

    Full Text Available Non-small-cell lung cancer (NSCLC is the leading cause of death from cancer for both men en women. Chemotherapy is the mainstay of treatment in advanced disease, but is only marginally effective. In about 30% of patients with advanced NSCLC in East Asia and in 10-15% in Western countries, EGFR mutations are found. In this population, first-line treatment with the tyrosine kinase inhibitors (TKI erlotinib, gefitinib or afatinib is recommended. The treatment beyond progression is less well-defined. In this paper we present 3 patients, EGFR mutation positive, with local progression after an initial treatment with TKI. These patients were treated with local radiotherapy. TKI was temporarily stopped and restarted after radiotherapy. We give an overview of the literature and discuss the different treatment options in case of progression after TKI: TKI continuation with or without chemotherapy, TKI continuation with local therapy, alternative dosing or switch to next-generation TKI or combination therapy. There are different options for treatment beyond progression in EGFR mutation positive metastatic NSCLC, but the optimal strategy is still to be defined. Further research on this topic is ongoing.

  15. Neoadjuvant intratumoral immuno-gene therapy for non-small cell lung cancer.

    Science.gov (United States)

    Predina, Jarrod D; Keating, Jane; Venegas, Ollin; Nims, Sarah; Singhal, Sunil

    2016-04-01

    Non-small Cell Lung Cancer (NSCLC) remains a deadly disease despite aggressive treatment protocols which incorporate chemotherapy, radiation and surgery. These traditional approaches have reached a plateau in therapeutic benefit. There is emerging evidence suggesting that immunotherapy can serve as an alternative treatment modality for NSCLC. Our group has nearly two decades of experience involving immuno-gene therapy with Ad.hIFN-α and Ad.hIFN-β in human mesothelioma trials, and has observed both safety and efficacy in treatment of Thoracic malignancies. We have expanded the scope of our work and have obtained encouraging pre-clinical evidence suggesting a role for immunotherapy as a surgical adjuvant for NSCLC cancers. By combining immunotherapy with surgery, synergistic results have been observed. Based on these observations, we have prepared a Phase I Clinical Trial that pairs Ad.hIFN-α with surgery for patients with resectable NSCLC. Patient enrollment is likely to begin in the Summer of 2016. We hope that this trial will serve as a platform for future trials aimed at pairing immunotherapy with surgery for patients diagnosed with NSCLC.

  16. Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Hammerman, Peter S; Jänne, Pasi A; Johnson, Bruce E

    2009-12-15

    Gefitinib and erlotinib are ATP competitive inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase and are approved around the world for the treatment of patients with non-small cell lung cancer (NSCLC). Somatic mutations in the EGFR are found in 10 to 40% of patients with NSCLC. Patients with sensitizing somatic mutations of EGFR treated with gefitinib or erlotinib have an initial clinical response of 60 to 80%, approximately twice as high as the responses associated with the administration of conventional platinum-based chemotherapy. However, the efficacy of EGFR tyrosine kinase inhibitors (TKI) is limited by either primary (de novo) or acquired resistance after therapy and investigations to define the mechanisms of resistance are active areas of ongoing preclinical and clinical studies. Primary resistance is typically caused by other somatic mutations in genes such as KRAS, which also have an impact on the EGFR signaling pathway or by mutations in the EGFR gene that are not associated with sensitivity to EGFR-TKIs. Two established mechanisms of acquired resistance are caused by additional mutations in the EGFR gene acquired during the course of treatment that change the protein-coding sequence or by amplification of another oncogene signaling pathway driven by the MET oncogene. This review focuses on characterized mechanisms of resistance to the EGFR TKIs and efforts to overcome the problem of resistance aimed at improving the therapy of patients with NSCLC. (Clin Cancer Res 2009;15(24):7502-9).

  17. Prognosis in patients with non-small cell lung cancer and satellite tumors.

    Science.gov (United States)

    Kocaturk, C I; Gunluoglu, M Z; Cansever, L; Dincer, I S; Bedirhan, M A

    2011-09-01

    Aim of the study was to identify factors affecting survival in patients with lung cancer and satellite tumors (ST). Between 2001 and 2008, there were 102 patients with synchronous multiple lung cancers among the 1355 lung resections performed in lung cancer patients. Satellite tumors were found to be near the primary lung cancer (PLC) in 29 patients. Complete resection was achieved in all patients, and the 5-year survival rate was 52 %. The independent "T" stages of the PLCs and STs did not affect survival ( P = 0.98 and P = 0.54, respectively). A distance between the PLC and ST longer or shorter than 2, 3, or 4 cm also did not affect survival ( P = 0.78, P = 0.57, and P = 0.62, respectively). The survival of patients treated with adjuvant therapy was significantly higher than that of patients who did not receive adjuvant therapy ( P = 0.0043). Satisfactory survival was achieved after surgical therapy for non-small cell lung cancer associated with ST. While the PLC and ST characteristics and the distance between tumors did not affect survival rates, the introduction of adjuvant chemotherapy with/without radiotherapy positively affected survival. © Georg Thieme Verlag KG Stuttgart · New York.

  18. Results of concomitant cisplatin and radiotherapy in non-operable non small-cell lung cancer

    International Nuclear Information System (INIS)

    Antoine, E.; Mazeron, J.J.

    1993-01-01

    The Radiotherapy and Lung Cancer Cooperative Groups of the EORTC performed a randomized study in patients with non-metastatic inoperable non small-cell lung cancer to compare the results of radiotherapy alone (radiation was administered for two wk at a dose of 3 Gy given 10 times followed by a three-wk rest period and then radiotherapy for two more wk at a dose of 2.5 Gy given 10 times) with radiotherapy on the same schedule combined with cisplatin given either on the first day of each treatment week at a dose of 30 mg/m 2 , or daily before radiotherapy at a dose of 6 mg/m 2 . Preliminary results showed a significantly improved three-yr survival rate in the radiotherapy-daily cisplatin group as compared with the radiotherapy group (16% versus 2%; P = 0.009) and without major increase in toxicity. This survival benefit was due to improved control of local disease; survival without local recurrence was 31% at two yr in the radiotherapy-daily cisplatin group as compared with 19% in the radiotherapy (P = 0.003)

  19. Adjuvant chemotherapy for resected non-small-cell lung cancer: future perspectives for clinical research

    Directory of Open Access Journals (Sweden)

    Bonomi Maria

    2011-12-01

    Full Text Available Abstract Adjuvant chemotherapy for non-small-cell lung carcinoma (NSCLC is a debated issue in clinical oncology. Although it is considered a standard for resected stage II-IIIA patients according to the available guidelines, many questions are still open. Among them, it should be acknowledged that the treatment for stage IB disease has shown so far a limited (if sizable efficacy, the role of modern radiotherapies requires to be evaluated in large prospective randomized trials and the relative impact of age and comorbidities should be weighted to assess the reliability of the trials' evidences in the context of the everyday-practice. In addition, a conclusive evidence of the best partner for cisplatin is currently awaited as well as a deeper investigation of the fading effect of chemotherapy over time. The limited survival benefit since first studies were published and the lack of reliable prognostic and predictive factors beyond pathological stage, strongly call for the identification of bio-molecular markers and classifiers to identify which patients should be treated and which drugs should be used. Given the disappointing results of targeted therapy in this setting have obscured the initial promising perspectives, a biomarker-selection approach may represent the basis of future trials exploring adjuvant treatment for resected NSCLC.

  20. Dyspnea evolution after high-dose radiotherapy in patients with non-small cell lung cancer

    International Nuclear Information System (INIS)

    De Ruysscher, Dirk; Dehing, Cary; Yu, Shipeng; Wanders, Rinus; Ollers, Michel; Dingemans, Anne-Marie C.; Bootsma, Gerben; Hochstenbag, Monique; Geraedts, Wiel; Pitz, Cordula; Simons, Jean; Boersma, Liesbeth; Borger, Jacques; Dekker, Andre; Lambin, Philippe

    2009-01-01

    Purpose: To determine what the influence is of dyspnea (CTCAE3.0) before high-dose radiotherapy (RT) on the incidence and severity of subsequent lung toxicity in patients with non-small cell lung cancer (NSCLC). Methods: In 197 patients with stage I-III NSCLC maximal dyspnea scores (CTCAE3.0) were obtained prospectively at three time periods: before RT, the first 6 months post-RT and 6-9 months post-RT. Only patients who were clinically progression-free 12 months or more after RT were included, thus minimizing dyspnea due to tumor progression. Time-trends of dyspnea as a function of baseline dyspnea were investigated and correlated with gender, age, chemotherapy, mean lung dose (MLD), lung function parameters (FeV1 and DLCO), stage, PTV dose, overall treatment time and smoking habits. Results: The proportion developing less, the same or more dyspnea 6-9 months post-treatment according to their baseline dyspnea scores was: Grade 0: none, 82.9%, 17.1%; Grade 1: 21.2%, 51.9%, 26.9%; Grade 2: 27.3%, 54.5%, 18.2%, respectively. Only age was associated with increased dyspnea after RT. Conclusions: Patients with dyspnea before therapy have a realistic chance to improve after high-dose radiotherapy. Reporting only dyspnea at one time-point post-RT is insufficient to determine radiation-induced dyspnea.

  1. Assessment of metal contaminants in non-small cell lung cancer by EDX microanalysis

    Directory of Open Access Journals (Sweden)

    M. Scimeca

    2014-09-01

    Full Text Available Human cardio-respiratory diseases are strongly correlated to concentrations of atmospheric elements. Bioaccumulation of heavy metals is strictly monitored, because of its possible toxic effects. In this work, we utilized the EDX microanalysis in order to identify the potential heavy metal accumulation in the lung tissue.  To this aim, we enrolled 45 human lung biopsies: 15 non-small cell lung cancers, 15 lung benign lesions and 15 control biopsies. Lung samples were both paraffin embedded for light microscopy study and eponepoxid embedded for transmission electron microscopy. EDX microanalysis was performed on 100 nm thick unstained ultrathin-sections placed on specific copper grids. Our results demonstrated that the EDX technology was particularly efficient in the study of elemental composition of lung tissues, where we found heavy metals, such as Cobalt (Co, Chromium (Cr, Manganese (Mn and Lead (Pb. Furthermore, in malignant lesions we demonstrated the presence of multiple bio-accumulated elements. In fact, a high rate of lung cancers was associated with the presence of 3 or more bio-accumulated elements compared to benign lesions and control tissue (91.7%, 0%, 8.3%, respectively. The environmental impact on pulmonary carcinogenesis could be better clarified by demonstrating the presence of polluting agents in lung tissues. The application of EDX microanalysis on biological tissuescould shed new light in the study of the possible bioaccumulation of polluting agents in different human organs and systems.

  2. Non-small cell lung cancer therapy: safety and efficacy in the elderly

    Directory of Open Access Journals (Sweden)

    Glotzer OS

    2013-04-01

    Full Text Available Owen S Glotzer,1 Thomas Fabian,1 Anurag Chandra,2 Charles T Bakhos21Division of Thoracic Surgery, Albany Medical Center, Department of Surgery, Albany Medical College, Albany, New York, USA; 2Department of Radiation Oncology, Albany Medical Center, Albany Medical College, Albany, New York, USABackground: Our objective was to evaluate and review the current literature on the treatment of non-small cell lung cancer (NSCLC in the elderly.Methods: We selected recent peer-reviewed articles addressing ageing, cancer treatment in the elderly, and lung cancer treatment in the elderly. We defined elderly as over the age of 70.Results: The population is ageing dramatically throughout most of the world. Given that situation, clinicians are seeing and being asked to treat more elderly patients that have NSCLC. Elderly patients are less likely to participate or be allowed to participate in prospective or retrospective studies of treatments for NSCLC. Elderly patients are also less likely to be staged appropriately for their advanced tumors, and are less likely to be referred for surgery or adjuvant therapy after surgery. When treatment is tailored to patient comorbidities but not to age, the data support survival and outcomes comparable to those of younger patients.Conclusions: Data are limited on the treatment of elderly patients with NSCLC. No data exist to support limiting recommendations for treatment based on age alone. Treatments should be determined on an individual basis.Keywords: thoracic surgery, radiation therapy, chemotherapy, pulmonary, physiology, ageing, SBRT

  3. Intraoperative radioisotope sentinel lymph node mapping in non-small cell lung cancer

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    Sugi, Kazuro; Sudou, Manabu [National Sanyo Hospital, Ube, Yamaguchi (Japan); Kaneda, Yoshikazu; Hamano, Kimikazu [Yamaguchi Univ., Ube (Japan). School of Medicine

    2003-05-01

    We performed intraoperative Technetium (Tc) 99m sentinel lymph node (SN) mapping in patients with clinical T1N0M0 non-small cell lung cancer (NSCLC). Twenty patients with clinical T1N0M0 NSCLC were enrolled. Before thoracotomy, the primary tumor was injected with 2 mCi Tc-99m. After dissection, scintigraphic readings of lymph nodes were obtained ex vivo with a handheld gamma counter. The migration of the Tc solution was considered successful if any node registered five times or more count comared with background values. If lymph nodes were found to have the highest or more than 50% of the highest counts and measurements were greater than five times the intrathoracic background, those nodes were classified as sentinel nodes. Four of the 20 patients did not have NSCLC and were excluded. Eleven patients (68.8%) had SNs identified. No inaccurately identified SNs were encountered. Intraoperative SN mapping with Tc-99m is an accurate way to identify the first site of potential nodal metastases of NSCLC. Several technical problems still remain unresolved in this method, however. (author)

  4. Quality of life of inoperable non-small cell lung carcinoma

    International Nuclear Information System (INIS)

    Minet, P.; Chevalier, P.; Gras, A.; Dejardin-Closon, M.T.; Bartsch, P.; Raets, D.; Lennes, G.

    1987-01-01

    Eighty one patients with inoperable non-small cell lung carcinoma (NSCLC) were entered in a randomized phase II trial comparing split-dose irradiation alone to combined treatment radiotherapy and polychemotherapy (C.A.P. + V.D.S.). The quality of life and the survival of the patients were studied. The authors have defined three classes of quality of life responses based on the time elapsed before the performance status index drops. A higher quality of life failure rate was observed in the combined treatment group (p non-significant) but the time elapsed before the Karnofsky index drops is longer in the combined treatment group for the quality of life 'no change' subgroup (p = 0.15). Survival and quality adjusted survival are similar in both treatment groups. The same conclusion holds for retrospective stratified treatment groups. The authors conclude that as far as the quality of life is concerned, polychemotherapy combined with the particular split-dose irradiation schedule used is an effective treatment of inoperable NSCLC. (Auth.)

  5. Chemotherapy options for the elderly patient with advanced non-small cell lung cancer.

    LENUS (Irish Health Repository)

    Hennessy, B T

    2012-02-03

    Combination chemotherapy has been shown to improve overall survival compared with best supportive care in patients with advanced non-small cell lung cancer (NSCLC). The survival advantage is modest and was initially demonstrated with cisplatin-containing regimens in a large meta-analysis of randomized trials reported in 1995. Newer chemotherapy combinations have been shown to be better tolerated than older cisplatin-based combinations, and some trials have also shown greater efficacy and survival benefits with these newer combinations. Combination chemotherapy is, therefore, the currently accepted standard of care for patients with good performance statuses aged less than 70 years with advanced NSCLC. However, there are limited data from clinical trials to support the use of combination chemotherapy in elderly patients over 70 years of age with advanced NSCLC. Subgroup analyses of large randomized phase III trials suggest that elderly patients with good performance statuses do as well as younger patients treated with combination chemotherapy. There are few randomized trials reported that evaluate chemotherapy in patients aged greater than 70 years only. Based on data from trials performed by an Italian group, single-agent vinorelbine has been shown to have significant activity in elderly patients with advanced NSCLC and to be well tolerated by those patients with Eastern Cooperative Oncology Group performance statuses of two or less, with associated improvements in measures of global health.

  6. The End of Nihilism: Systemic Therapy of Advanced Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Ernani, Vinicius; Steuer, Conor E; Jahanzeb, Mohammad

    2017-01-14

    Lung cancer is the leading cause of cancer death in the United States and many other parts of the world. Non-small cell lung cancer (NSCLC) comprises 85-90% of lung cancers. Historically, the expected survival of patients with advanced disease has been estimated in months. In recent years, however, lung cancer has come to be seen as a treatable disease with multiple therapeutic options. Enormous advances in the understanding of its pathways and mechanisms have enabled personalized therapy in NSCLC. The evolving approach to therapy focuses on genomic profiling of the tumors to find molecular targets and develop specific agents for individualized therapy. In addition, maintenance therapy has emerged as a valid approach, and the choice of chemotherapy now varies by histology. Most recently, immunotherapy with checkpoint inhibitors has shown promising results, with impressive durations of response and a tolerable toxicity profile. Together, these discoveries have improved overall survival substantially in patient populations that have access to these advancements. We review the clinical data surrounding these impressive improvements.

  7. Tumor Immunology and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Jung, Chi Young; Antonia, Scott J

    2018-01-01

    Lung cancer is one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths worldwide. Although progress in the treatment of advanced non-small cell lung cancer (NSCLC) has been made over the past decade, the 5-year survival rate in patients with lung cancer remains only 10%-20%. Obviously, new therapeutic options are required for patients with advanced NSCLC and unmet medical needs. Cancer immunotherapy is an evolving treatment modality that uses a patient's own immune systems to fight cancer. Theoretically, cancer immunotherapy can result in long-term cancer remission and may not cause the same side effects as chemotherapy and radiation. Immuno-oncology has become an important focus of basic research as well as clinical trials for the treatment of NSCLC. Immune checkpoint inhibitors are the most promising approach for cancer immunotherapy and they have become the standard of care for patients with advanced NSCLC. This review summarizes basic tumor immunology and the relevant clinical data on immunotherapeutic approaches, especially immune checkpoint inhibitors in NSCLC. Copyright©2018. The Korean Academy of Tuberculosis and Respiratory Diseases.

  8. Sleeve lobectomy versus pneumonectomy for non-small cell lung cancer: a meta-analysis

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    Shi Woda

    2012-12-01

    Full Text Available Abstract Aim It is controversial that whether sleeve lobectomy (SL should be promoted more worthy than pneumonectomy (PN in suitable patients. Methods We searched all studies that had been published in English from PUBMED and Embase which compared the short-term and long-term outcomes of SL and pneumonectomy (PN in patients with non-small cell lung cancer (NSCLC. Results Nineteen studies met our criteria with a combined total of 3878 subjects, of which 1316 (33.9% underwent SL and 2562 (66.1% underwent PN. The odds ratio was 0.50 (95% CI: 0.34-0.72 for postoperative mortality, 1.17 (95% CI: 0.82-1.67 for postoperative complications, 0.78 (95% CI: 0.47-1.29 for locoregional recurrences. The risk difference for 1-, 3-, 5- year was 0.11 (95% CI: 0.07-0.14, 0.15 (95% CI: 0.06-0.24, 0.15 (95% CI: 0.09-0.20,respectively. The pooled hazard ratio was 0.63 (95% CI: 0.56-0.71 in favor of SL group. Conclusion SL is more worthy to be done than PN in suitable patients with less mortality and better long-term survival.

  9. Low level of 5-Hydroxymethylcytosine predicts poor prognosis in non-small cell lung cancer

    Science.gov (United States)

    LIAO, YUNFEI; GU, JIE; WU, YONGBING; LONG, XIANG; GE, DI; XU, JIANJUN; DING, JIANYONG

    2016-01-01

    The loss of 5-hydroxymethylcytosine (5-hmC) has previously been demonstrated to be implicated in the initiation and progression of various tumors. However, its role in non-small cell lung cancer (NSCLC) remains unknown. The present study aimed to determine the level of 5-hmC in NSCLC and their adjacent normal lung tissues by immunohistochemistry and dot-blot analysis; then the relationship between 5-hmC level and the clinicopathological features of NSCLC and the prognostic significance of 5-hmC level in NSCLC patients were analyzed. By employing the dot-blot analysis, a significant reduction of 5-hmC level in NSCLC tissues compared with the adjacent normal tissues was detected, which were further verified by the immunohistochemistry results on tissue microarrays. Further analyses demonstrated that 65.38% (136/208) presented with low 5-hmC level, and low 5-hmC level was significantly associated with lymph node metastasis (PhmC levels were significantly lower than patients with high 5-hmC levels (PhmC level was identified as independent prognostic factor in patients' overall survival. In conclusion, downregulation of 5-hmC may serve as a useful biomarker for NSCLC prognosis evaluation. PMID:27313688

  10. Low level of 5-Hydroxymethylcytosine predicts poor prognosis in non-small cell lung cancer.

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    Liao, Yunfei; Gu, Jie; Wu, Yongbing; Long, Xiang; Ge, D I; Xu, Jianjun; Ding, Jianyong

    2016-06-01

    The loss of 5-hydroxymethylcytosine (5-hmC) has previously been demonstrated to be implicated in the initiation and progression of various tumors. However, its role in non-small cell lung cancer (NSCLC) remains unknown. The present study aimed to determine the level of 5-hmC in NSCLC and their adjacent normal lung tissues by immunohistochemistry and dot-blot analysis; then the relationship between 5-hmC level and the clinicopathological features of NSCLC and the prognostic significance of 5-hmC level in NSCLC patients were analyzed. By employing the dot-blot analysis, a significant reduction of 5-hmC level in NSCLC tissues compared with the adjacent normal tissues was detected, which were further verified by the immunohistochemistry results on tissue microarrays. Further analyses demonstrated that 65.38% (136/208) presented with low 5-hmC level, and low 5-hmC level was significantly associated with lymph node metastasis (PhmC levels were significantly lower than patients with high 5-hmC levels (PhmC level was identified as independent prognostic factor in patients' overall survival. In conclusion, downregulation of 5-hmC may serve as a useful biomarker for NSCLC prognosis evaluation.

  11. Predictive factors of late radiation fibrosis: a prospective study in non-small cell lung cancer.

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    Mazeron, Renaud; Etienne-Mastroianni, Bénédicte; Pérol, David; Arpin, Dominique; Vincent, Michel; Falchero, Lionel; Martel-Lafay, Isabelle; Carrie, Christian; Claude, Line

    2010-05-01

    To determine predictive factors of late radiation fibrosis (RF) after conformal radiotherapy (3D-RT) in non-small cell lung cancer (NSCLC). Ninety-six patients with Stage IA-IIIB NSCLC were included in a prospective trial. Clinical evaluation, chest X-ray, and pulmonary functional tests including diffusion parameters were performed before and 6 months after radiotherapy. An independent panel of experts prospectively analyzed RF, using Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic scales classification. Logistic regression analysis was performed to identify relationships between clinical, functional, or treatment parameters and incidence of RF. Variations of circulating serum levels of pro-inflammatory (interleukin-6, tumor necrosis factor alpha, tumor growth factor beta1) and anti-inflammatory (interleukin-10) cytokines during 3D-RT were examined to identify correlations with RF. Of the 96 patients included, 72 were evaluable for RF at 6 months. Thirty-seven (51.4%) developed RF (Grade >or=1), including six severe RF (Grades 2-3; 8.3%). In univariate analysis, only poor Karnofsky Performance Status and previous acute radiation pneumonitis were associated with RF (p acute radiation pneumonitis and dosimetric parameters were significantly correlated with RF occurrence. It was not significantly correlated either with cytokines at baseline or with their variation during 3D-RT. This study confirms the importance of dosimetric parameters to limit the risk of RF. Contrary to acute radiation pneumonitis, RF was not correlated to cytokine variations during 3D-RT.

  12. Palliative radiotherapy in asymptomatic patients with locally advanced, unresectable, non-small cell lung cancer

    International Nuclear Information System (INIS)

    Reinfuss, M.; Skolyszewski, J.; Kowalska, T.; Rzepecki, W.; Kociolek, D.

    1993-01-01

    Between 1983 and 1990, 332 patients with non-small cell lung cancer (NSCLC) were referred to short-time, split-course palliative thoracic radiotherapy. The group consisted of patients with locally advanced (III o ), unresectable cancer, not suitable for curative radiotherapy, asymptomatic or having only minimal symptoms related to intrathoracic tumor. The therapeutic plan involved two series of irradiation. Tumor dose delivered in each series was 20 Gy given in five daily fractions over five treatment days. There were four weeks interval between series. Of 332 patients initially qualified to thoracic radiotherapy only 170 patients received the treatment; the other 162 patients were not irradiated because of treatment refusal or logistic problems concerning therapy. They made the control group of the study, receiving the best possible symptomatic care. Twelve-month survivals in the radiotherapy and control groups were 32.4% and 9.3%, respectively; 24-month survivals 11.2% and 0%, respectively. Improvement of survival after palliative thoracic radiotherapy was observed only in patients with clinical stage IIIA and Karnofsky's performance status (KPS) ≥ 70. (orig.) [de

  13. GEMCITABINE / PLATINUM VS. VINORELBINE- PLATINUM IN PATIENTS WITH ADVANCED NON- SMALL- CELL LUNG CANCER

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    Deyan Davidov

    2008-09-01

    Full Text Available Background: A platinum- based doublets with a third- generation agents /Gemcitabine, Vinorelbine/ represent the standard first- line treatment for advanced patients with non- small- cell lung cancer /NSCLC/ and good performance status. Aim: The aim of this study was to evaluate the two commonly used newer platinum- based regimes in response rate and survival. Methods: In the period 2005- 2007 ninety- four inoperable patients with NSCLC entered the study. The treatment schedule consist of Gemcitabine 1250 mg/m2 day 1 and 8 and cis- Platinum 80 mg/m2 with hydratation day 1- 46 patients /arm GP/ and Vinorelbine 30 mg/m2 day 1 and 8 and cis- Platinum 80 mg/m2 with hydratation day 1- 48 patients /arm VP/, every 21 days. Results: Overall response rate was 39% for GP and 32% for VP. Median survival was 10,3 and 9,8 months respectively. Neutropenia was significantly higher in arm VP as was thrombocytopenia on the GP arm. Conclusions: That data suggest that both regimes remain reasonable choices for patients with advanced NSCLC with slight prevalence of GP.

  14. MEK inhibitors under development for treatment of non-small-cell lung cancer.

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    Kim, Chul; Giaccone, Giuseppe

    2018-01-01

    The mitogen-activated protein kinase (MAPK) pathway is intimately implicated in the molecular pathogenesis of non-small-cell lung cancer (NSCLC). Aberrant MAPK signaling resulting from the upstream activating mutations converges on mitogen-activated protein kinase kinase 1/2 (MEK1/2), making MEK inhibition an attractive strategy for the treatment of NSCLC. Several MEK inhibitors have demonstrated anticancer activity in patients with NSCLC. Areas covered: In this article, we discuss the biological rationale for the use of MEK inhibitors and summarize the clinical experience with MEK1/2 inhibitors for the treatment of NSCLC, from initial phase I studies to phase II/III studies, both as monotherapy or in combination with other anticancer agents. Expert opinion: Trametinib in combination with the BRAF inhibitor dabrafenib represents the first MEK1/2 inhibitor containing regimen that is approved for advanced BRAF V600E -mutant NSCLC. Other MEK1/2 inhibitors that are also in advanced stages of clinical development include selumetinib, cobimetinib, and binimetinib. Several studies of MEK inhibitor combination therapies are underway, including trials using combined MEK inhibition and immune checkpoint blockade. Further research aimed at discovering biomarkers of response and resistance to MEK1/2 inhibitors will be needed to develop rational combination strategies for the treatment of NSCLC driven by aberrant MAPK signaling.

  15. Combined modality therapy for locally advanced non-small cell lung carcinoma

    International Nuclear Information System (INIS)

    Recine, D.; Rowland, K.; Reddy, S.; Lee, M.S.; Bonomi, P.; Taylor, S.; Faber, L.P.; Warren, W.; Kittle, C.F.; Hendrickson, F.R.

    1990-01-01

    Multi-modality treatment consisting of cisplatin, VP-16, and 5-fluorouracil chemotherapy given concomitantly with external beam radiation was used to treat 64 patients with locally advanced Stage III non-small cell lung carcinoma. This regimen was used in a preoperative fashion for four cycles in patients considered surgically resectable and with curative intent for six cycles in the remainder of patients. The clinical response rate for the entire group was 84% and the overall local control rate was 74%. The median survival was 13 months with a median follow-up for live patients of 19 months. The actuarial 3-year survival and disease-free survival rates were 30% and 23%, respectively. Histologic complete response was 39% and appeared to predict for survival. The 3-year actuarial survival and disease-free survival rates for 23 resected patients were 69% and 45%, respectively, with the complete histologic responders having a disease-free survival of 78%. The pattern of first recurrence did not appear to differ by histology or presence of lymph nodes in this subset of patients. The actuarial 3-year survival and disease-free survival rates for inoperable patients receiving six cycles of treatment were 18% and 23%, respectively. The local control was 67% with the majority of these patients having Stage IIIB disease. The Mountain International staging system appeared to predict for operability, local recurrence, and survival. This concomitant treatment regimen is feasible, with the major toxicities being leukopenia, nausea, and vomiting

  16. Optimal radiotherapy for non-small-cell lung cancer. Current progress and future challenges

    International Nuclear Information System (INIS)

    Ishikura, Satoshi

    2012-01-01

    Radiotherapy has a key role in treating lung cancer. Advances in physics and computer technology have improved radiation delivery systems. With innovations in the radiation therapy of non-small-cell lung cancer (NSCLC), new strategies have emerged, such as intensity-modulated radiation therapy, stereotactic body radiation therapy, and particle therapy. Compared with previous methods, these newer technologies can deliver even higher doses precisely to the tumor while minimizing doses to normal tissues, which should lead to better tumor control with less toxicity. In patients with stage I NSCLC, stereotactic body radiation therapy is highly effective and may achieve local control and survival equivalent to that achieved with surgery. In patients with stage III NSCLC, dose escalation has been investigated using three-dimensional conformal radiation therapy, intensity-modulated radiation therapy, and particle therapy. The results from ongoing randomized trials on both patient populations are awaited. It is important to generate new hypotheses and to explore newer radiotherapy approaches to overcome NSCLC. (author)

  17. Risk factors and management of oligometastatic non-small cell lung cancer.

    Science.gov (United States)

    Patel, Akshar N; Simone, Charles B; Jabbour, Salma K

    2016-08-01

    Non-small cell lung cancer (NSCLC) is an aggressive malignancy with close to half of all patients presenting with metastatic disease. A proportion of these patients with limited metastatic disease, termed oligometastatic disease, have been shown to benefit from a definitive treatment approach. Synchronous and metachronous presentation of oligometastatic disease have prognostic significance, with current belief that metachronous disease is more favorable. Surgical excision of intracranial and extracranial oligometastatic disease has been shown to improve survival, especially in patients with lymph node-negative disease, adenocarcinoma histology and smaller thoracic tumors. Definitive radiation to sites of oligometastatic disease and initial thoracic disease has also been shown to have a similar impact on survival for both intracranial and extracranial disease. Recent studies have reported on the use of targeted agents combined with ablative doses of radiation in the oligometastatic setting with promising outcomes. In this review, we present the historical and current literature describing surgical and radiation treatment options for patients with oligometastatic NSCLC. © The Author(s), 2016.

  18. Surgical treatment in non-small cell lung cancer with pulmonary oligometastasis.

    Science.gov (United States)

    He, Jinyuan; Li, Yun; An, Jun; Hu, Liu; Zhang, Junhang

    2017-02-02

    Previous studies have demonstrated survival benefits for local treatment in solitary metastatic non-small cell lung cancer (NSCLC).This study aimed to investigate the effect of local surgery for NSCLC with pulmonary oligometastasis. This study included 21 patients of NSCLC with pulmonary oligometastasis between January 2003 and December 2013, which were divided into two groups, group A (11 cases) for local surgery and group B (10 cases) for systematic chemotherapy, compared the median survival time (MST) and 5-year survival rate between the two groups, and analyzed the impact of the pathological types, the TNM and pN stage of primary tumor, the site, and the mode and number of oligometastatic nodule on group A. The MST of group A and B were 37 and 11.6 months respectively, 5-year survival rates were 18.2 and 9.1% respectively (p  0.05). Local surgery significantly prolonged the overall survival time and 5-year survival rate of primary NSCLC with pulmonary oligometastasis.

  19. Treatment outcomes in stage IIIA non-small-cell lung cancer in a community cancer center.

    Science.gov (United States)

    Hanson, Shaun; Persad, Kamleish; Qiao, Xian; Guarino, Michael; Petrelli, Nicholas

    2015-08-01

    Treatment outcomes for non-small-cell lung cancer (NSCLC) patients diagnosed at stage IIIA have been analyzed in many studies, which generally involve patients younger and healthier than the average patient with this disease. To analyze demographics and treatment outcomes in patients with stage IIIA NSCLC at a community cancer center. We reviewed charts of 226 patients diagnosed with stage IIIA NSCLC from January 2003 to December 2008 treated at our community cancer center. Results Median overall survival for all patients and sequentially and concurrently treated chemoradiation patients were 18 months, and 18 months, and 20 months, respectively. Median overall survival for women and men was 24 months and 16 months, respectively. Median overall survival for all patients and sequentially and concurrently treated chemoradiation patients were 18 months, and 18 months, and 20 months, respectively. Median overall survival for women and men was 24 months and 16 months, respectively. Study design was retrospective and some medical records were not available. However, this population is likely representative of patients treated in similar settings. In our population, advanced age and male gender were associated with lower median survival. Responses to concurrent and sequential chemoradiation seemed to differ based on age group, which may be useful as a prognostic guideline for similar populations. ©2015 Frontline Medical Communications.

  20. The impact of virtual simulation in palliative radiotherapy for non-small-cell lung cancer

    International Nuclear Information System (INIS)

    McJury, Mark; Fisher, Patricia M.; Pledge, Simon; Brown, Gillian; Anthony, Catherine; Hatton, Matthew Q.; Conway, John; Robinson, Martin H.

    2001-01-01

    Background and purpose: Radiotherapy is widely used to palliate local symptoms in non-small-cell lung cancer. Using conventional X-ray simulation, it is often difficult to accurately localize the extent of the tumour. We report a randomized, double blind trial comparing target localization with conventional and virtual simulation. Methods: Eighty-six patients underwent both conventional and virtual simulation. The conventional simulator films were compared with digitally reconstructed radiographs (DRRs) produced from the computed tomography (CT) data. The treatment fields defined by the clinicians using each modality were compared in terms of field area, position and the implications for target coverage. Results: Comparing fields defined by each study arm, there was a major mis-match in coverage between fields in 66.2% of cases, and a complete match in only 5.2% of cases. In 82.4% of cases, conventional simulator fields were larger (mean 24.5±5.1% (95% confidence interval)) than CT-localized fields, potentially contributing to a mean target under-coverage of 16.4±3.5% and normal tissue over-coverage of 25.4±4.2%. Conclusions: CT localization and virtual simulation allow more accurate definition of the target volume. This could enable a reduction in geographical misses, while also reducing treatment-related toxicity

  1. Genotyping non-small cell lung cancer (NSCLC) in Latin America.

    Science.gov (United States)

    Arrieta, Oscar; Cardona, Andrés Felipe; Federico Bramuglia, Guillermo; Gallo, Aly; Campos-Parra, Alma D; Serrano, Silvia; Castro, Marcelo; Avilés, Alejandro; Amorin, Edgar; Kirchuk, Ricardo; Cuello, Mauricio; Borbolla, José; Riemersma, Omar; Becerra, Henry; Rosell, Rafael

    2011-11-01

    Frequency of mutations in EGFR and KRAS in non-small cell lung cancer (NSCLC) is different between ethnic groups; however, there is no information in Latin-American population. A total of 1150 biopsies of NSCLC patients from Latin America (Argentina, Colombia, Peru, and Mexico) were used extracting genomic DNA to perform direct sequencing of EGFR gene (exons 18 and 21) and KRAS gene in 650 samples. In Mexico, Scorpions ARMS was also used to obtain a genetic profile. We report the frequency of mutations in EGFR and KRAS genes in four Latin-American countries (n = 1150). Frequency of EGFR mutations in NSCLC was 33.2% (95% confidence interval [CI] 30.5-35.9) (Argentina 19.3%, Colombia 24.8%, Mexico 31.2%, and Peru 67%). The frequency of KRAS mutations was 16.6% (95% CI 13.8-19.4). EGFR mutations were independently associated with adenocarcinoma histology, older age, nonsmokers, and absence of KRAS mutations. Overall response rate to tyrosine kinase inhibitors in EGFR-mutated patients (n = 56) was 62.5% (95% CI 50-75) with a median overall survival of 16.5 months (95% CI 12.4-20.6). Our findings suggest that the frequency of EGFR mutations in Latin America lies between that of Asian and Caucasian populations and therefore support the genetic heterogeneity of NSCLC around the world.

  2. Postoperative Radiation Therapy for Non-Small Cell Lung Cancer and Thymic Malignancies

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    Gomez, Daniel R., E-mail: dgomez@mdanderson.org; Komaki, Ritsuko [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1840 Old Spanish Trail, Houston, TX 77054 (United States)

    2012-03-14

    For many thoracic malignancies, surgery, when feasible, is the preferred upfront modality for local control. However, adjuvant radiation plays an important role in minimizing the risk of locoregional recurrence. Tumors in the thoracic category include certain subgroups of non-small cell lung cancer (NSCLC) as well as thymic malignancies. The indications, radiation doses, and treatment fields vary amongst subtypes of thoracic tumors, as does the level of data supporting the use of radiation. For example, in the setting of NSCLC, postoperative radiation is typically reserved for close/positive margins or N2/N3 disease, although such diseases as superior sulcus tumors present unique cases in which the role of neoadjuvant vs. adjuvant treatment is still being elucidated. In contrast, for thymic malignancies, postoperative radiation therapy is often used for initially resected Masaoka stage III or higher disease, with its use for stage II disease remaining controversial. This review provides an overview of postoperative radiation therapy for thoracic tumors, with a separate focus on superior sulcus tumors and thymoma, including a discussion of acceptable radiation approaches and an assessment of the current controversies involved in its use.

  3. Correlation between Pre-treatment Anemia and Prognosis in Non-small Cell Lung Cancer Patients

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    Qiuhua DENG

    2010-07-01

    Full Text Available Background and objective The patients with non-small cell lung cancer (NSCLC might contract anemia, however, whether anemia is one of the independent prognostic factors to the patients with NSCLC is still controversial. So the aim of this study is to investigate the correlation between anemia and overall survival (OS in patients with NSCLC. Methods 1 018 patients with operable NSCLC were retrospectively analyzed in our hospital from January 2000 to December 2008. Results The occurrence of anemia before operation was 252/1 018 (24.1%. The OS in NSCLC patients without anemia was (2 425.98±50.03 days, and the OS in patients with anemia was (2 107.15±93.86 days. There was significant difference in the OS between them (P=0.001. The patients with anemia in stage I had shorter survival time than those without anemia (P < 0.001. But there was no difference in other stage patients. TNM stage, gender, tumor size and lymph nodes metastasis were correlated with OS using Cox regression analysis. Conclusion Anemia is correlated with survival in operable NSCLC patients. Moreover, it is an independent prognostic factor in NSCLC patients with stage I.

  4. The value of positron emission tomography in patients with non-small cell lung cancer

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    Kee, Frank [Centre for Public Health, Queen' s University Belfast, Mulhouse Building, Royal Victoria Hospital Site, Grosvenor Road, Belfast BT12 6BJ, Northern Ireland (United Kingdom)], E-mail: f.kee@qub.ac.uk; Erridge, Sara [Edinburgh Cancer Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, Scotland (United Kingdom); Bradbury, Ian [Frontier Science (Scotland) Ltd., Grampian View, Kincraig, Inverness-shire PH21 1NA, Scotland (United Kingdom); Cairns, Karen [School of Maths and Physics, Queen' s University Belfast, David Bates Building, University Road, Belfast BT7 1NN, Northern Ireland (United Kingdom)

    2010-01-15

    Background: Pre-operative assessment of non-small cell lung cancer (NSCLC) is a major application of positron emission tomography (FDG-PET). Despite substantial evidence of diagnostic accuracy, relatively little attention has been paid to its effects on patient outcomes. This paper addresses this by extending an existing decision model to include patient-elicited utilities. Patients and methods: A decision-tree model of the effect of FDG-PET on pre-operative staging was converted to a Markov model. Utilities for futile and appropriate thoracotomy were elicited from 75 patients undergoing staging investigation for NSCLC. The decision model was then used to estimate the expected value of perfect information (EVPI) associated with three sources of uncertainty-the accuracy of PET, the accuracy of CT and the patient related utility of a futile thoracotomy. Results: The model confirmed the apparent cost-effectiveness of FDG-PET and indicated that the EVPI associated with the utility of futile thoracotomy considerably exceeds that associated with measures of accuracy. Conclusion: The study highlights the importance of patient related utilities in assessing the cost-effectiveness of diagnostic technologies. In the specific case of PET for pre-operative staging of NSCLC, future research effort should focus on such elicitation, rather than further refinement of accuracy estimates.

  5. Exploring hope and healing in patients living with advanced non-small cell lung cancer.

    Science.gov (United States)

    Eustache, Chloe; Jibb, Emily; Grossman, Mary

    2014-09-01

    To explore the experience and meaning of hope in relation to the healing process of patients living with stage IIIb or IV non-small cell lung cancer. Interpretative qualitative study design. Peter Brojde Lung Cancer Centre in the Jewish General Hospital in Montreal, Quebec, Canada. 12 English- and French-speaking patients, aged 36-78 years. One 60-90-minute semistructured interview per participant was conducted. An inductive approach to data analysis was taken, involving immersion in the data, coding, classifying, and creating linkages. Four main themes emerged: (a) the morass of shattered hope, (b) tentative steps toward a new hope paradigm, (c) reframing hope within the context of a life-threatening illness, and (d) strengthening the link between hope and wellness. Patients described a process where hope was diminished or lost entirely, regained, and reshaped as they learned to live and grow following their diagnosis. This study adds to the literature by describing the dynamic nature of hope as well as factors facilitating or hindering the hope process. It demonstrates how finding meaning, a structural component of healing, can be used to envision a new hopeful future. This study suggests hope and healing cannot exist in isolation, and highlights the importance of understanding the fluctuating nature of hope in patients with advanced lung cancer to foster it, therefore promoting healing.

  6. Expression of Rab25 in non-small cell lung cancer and its clinical significance

    Directory of Open Access Journals (Sweden)

    Pu ZHOU

    2014-03-01

    Full Text Available Objective To assess the expression of Rab25 protein in non-small cell lung cancer (NSCLC, and explore the correlation of its expression with tumor proliferation and metastasis. Methods Sixty-one cases of NSCLC specimens (31 cases of squamous cell carcinoma, 26 cases of adenocarcinoma, and 4 cases of adenosquamous carcinoma undergone surgical treatment, and 40 specimens of adjacent normal lung tissues were obtained from Jan. 2009 to Jun. 2010 at Xingqiao Hospital of Third Military Medical University. Immunochemistry method of MaxVision was used to detect the expression of Rab25 in the specimens, and then the correlation of the expression with the clinicopathological parameters (patients' sex, age, smoking history, tumor type, differentiation, volume, TNM stage, lymph metastasis, etc. was analyzed using statistical software SPSS 21.0. Results  Rab25 protein was mainly expressed in cytoplasm and cell membrane. The positive rate of Rab25 in NSCLC was 93.4%, which was significantly higher than that in adjacent normal tissues (27.5%, P<0.01. The expression of Rab25 protein was significantly associated with the TNM stage and tumor size (P<0.05. Conclusions The expression of Rab25 is obviously higher in NSCLC than in the adjacent normal tissues, and the expression is associated with TNM stage and tumor size. Moreover, the later of the NSCLC stage, the larger of tumor size, and the higher of Rab25 expression will be in the NSCLC tissue. DOI: 10.11855/j.issn.0577-7402.2014.02.16

  7. GP88 (Progranulin): A novel tissue and circulating biomarker for non-small cell lung carcinoma

    Science.gov (United States)

    Edelman, Martin J.; Feliciano, Josephine; Yue, Binbin; Bejarano, Pablo; Ioffe, Olga; Reisman, David; Hawkins, Douglas; Gai, Qiwei; Hicks, David; Serrero, Ginette

    2014-01-01

    GP88 (progranulin) is a growth and survival factor implicated in tumorigenesis and drug resistance. Previous studies showed that GP88 was expressed in breast cancer tissue in inverse correlation with survival. This study evaluates GP88 tissue expression in localized/locally advanced lung cancer and GP88 serum levels in advanced disease. GP88 expression was determined by immunohistochemistry in tumor tissue from non-small cell carcinoma (NSCLC) patients, 85 with localized (Stage I-II) and 40 with locally advanced disease (Stage IIIa) and correlated with clinical outcome. Serum GP88 levels from Stage IIIb/IV patients, quantified by Enzyme Immunoassay (EIA) were compared to GP88 levels from patients with Chronic Obstructive Pulmonary Disease (COPD) and healthy individuals. GP88 was expressed in >80% adenocarcinoma and squamous cell carcinoma in contrast to normal lung or small cell lung cancer. There was a statistically significant inverse association of GP88 expression (GP88 Immunohistochemistry score 3+ vs. <3+) with survival for patients with localized resected NSCLC with Hazard Ratio (HR)=2.28 (p=0.0076) for DFS and HR=2.17 (p=0.014) for OS. A statistically significant decrease in progression-free survival (HR=2.9, p=0.022) for GP88 scores of 3+ vs. <3+ was observed for Stage IIIa after chemoradiotherapy. In addition, serum GP88 was significantly elevated in Stage IIIb/IV NSCLC compared to control subjects (49.9ng/ml vs. 28.4ng/ml, p<0.0001). This is the first study demonstrating GP88 tissue and serum expression as a prognostic biomarker in localized and advanced disease. Future research will determine utility of monitoring GP88 and the potential of GP88 expression as a predictive marker for anti-GP88 therapeutics. PMID:25033727

  8. Non-small cell lung cancer is characterized by dramatic changes in phospholipid profiles.

    Science.gov (United States)

    Marien, Eyra; Meister, Michael; Muley, Thomas; Fieuws, Steffen; Bordel, Sergio; Derua, Rita; Spraggins, Jeffrey; Van de Plas, Raf; Dehairs, Jonas; Wouters, Jens; Bagadi, Muralidhararao; Dienemann, Hendrik; Thomas, Michael; Schnabel, Philipp A; Caprioli, Richard M; Waelkens, Etienne; Swinnen, Johannes V

    2015-10-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)-based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non-malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non-malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D-imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D-imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development. © 2015 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

  9. Expression of Transient Receptor Potential Canonical Channel Proteins in Human Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Qi ZHANG

    2010-06-01

    Full Text Available Background and objective Transient receptor potential canonical (TRPC proteins, a group of Ca2+ permeable nonselective cation channels, are thought to constitute store-operated calcium channels (SOCC and mediate store-operated calcium entry (SOCE in various cell types. Members of TRPC have been found to be involved in abnormal proliferation, differentiation, and growth of cancer cells. The aim of this study is to detect the mRNA and protein expression of TRPC in non-small cell lung cancer (NSCLC. Methods Real-time quantitative PCR was performed to screen the expression of TRPC mRNA in NSCLC tissue. Protein expression of TRPC was detected by Western blot. Results Among the seven family members of TRPC so far identified (TRPC1-7, we detected the expression of TRPC1, TRPC3, TRPC4, TRPC6 mRNA in 24 cases of NSCLC tissue; TRPC2, TRPC5 and TRPC7 mRNA were not detectable. The relative abundance of the expressed TRPC was TRPC1≈TRPC6>TRPC3>TRPC4. Western blot confirmed the protein expression of TRPC1, TRPC3, TRPC4 and TRPC6 in NSCLC tissue. Conclusion Out of the seven members of TRPC, we found TRPC1, TRPC3, TRPC4, TRPC6 mRNA and protein were selectively expressed in human NSCLC tissue. This study could provide a basis for future exploration of the individual role of these TRPC proteins in mediating SOCE and in the progression of lung cancer.

  10. Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer

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    Jang, Sang-Min; An, Joo-Hee; Kim, Chul-Hong; Kim, Jung-Woong, E-mail: jungkim@cau.ac.kr; Choi, Kyung-Hee, E-mail: khchoi@cau.ac.kr

    2015-08-07

    Lung cancer is the leading cause of cancer-mediated death. Although various therapeutic approaches are used for lung cancer treatment, these mainly target the tumor suppressor p53 transcription factor, which is involved in apoptosis and cell cycle arrest. However, p53-targeted therapies have limited application in lung cancer, since p53 is found to be mutated in more than half of lung cancers. In this study, we propose tumor suppressor FOXA2 as an alternative target protein for therapies against lung cancer and reveal a possible FOXA2-centered transcriptional regulation network by identifying new target genes and binding partners of FOXA2 by using various screening techniques. The genes encoding Glu/Asp-rich carboxy-terminal domain 2 (CITED2), nuclear receptor subfamily 0, group B, member 2 (NR0B2), cell adhesion molecule 1 (CADM1) and BCL2-associated X protein (BAX) were identified as putative target genes of FOXA2. Additionally, the proteins including highly similar to heat shock protein HSP 90-beta (HSP90A), heat shock 70 kDa protein 1A variant (HSPA1A), histone deacetylase 1 (HDAC1) and HDAC3 were identified as novel interacting partners of FOXA2. Moreover, we showed that FOXA2-dependent promoter activation of BAX and p21 genes is significantly reduced via physical interactions between the identified binding partners and FOXA2. These results provide opportunities to understand the FOXA2-centered transcriptional regulation network and novel therapeutic targets to modulate this network in p53-deficient lung cancer. - Highlights: • Identification of new target genes of FOXA2. • Identifications of novel interaction proteins of FOXA2. • Construction of FOXA2-centered transcriptional regulatory network in non-small cell lung cancer.

  11. Application of multifunctional targeting epirubicin liposomes in the treatment of non-small-cell lung cancer

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    Song X

    2017-10-01

    Full Text Available Xiao-li Song,1 Rui-jun Ju,2 Yao Xiao,1 Xin Wang,1 Shuang Liu,1 Min Fu,1 Jing-jing Liu,1 Li-yan Gu,1 Xue-tao Li,1 Lan Cheng1 1School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 2Department of Pharmaceutical Engineering, Beijing Institute of Petrochemical Technology, Beijing, China Abstract: Chemotherapy for aggressive non-small-cell lung cancer (NSCLC usually results in a poor prognosis due to tumor metastasis, vasculogenic mimicry (VM channels, limited killing of tumor cells, and severe systemic toxicity. Herein, we developed a kind of multifunctional targeting epirubicin liposomes to enhance antitumor efficacy for NSCLC. In the liposomes, octreotide was modified on liposomal surface for obtaining a receptor-mediated targeting effect, and honokiol was incorporated into the lipid bilayer for inhibiting tumor metastasis and eliminating VM channels. In vitro cellular assays showed that multifunctional targeting epirubicin liposomes not only exhibited the strongest cytotoxic effect on Lewis lung tumor cells but also showed the most efficient inhibition on VM channels. Action mechanism studies showed that multifunctional targeting epirubicin liposomes could downregulate PI3K, MMP-2, MMP-9, VE-Cadherin, and FAK and activate apoptotic enzyme caspase 3. In vivo results exhibited that multifunctional targeting epirubicin liposomes could accumulate selectively in tumor site and display an obvious antitumor efficacy. In addition, no significant toxicity of blood system and major organs was observed at a test dose. Therefore, multifunctional targeting epirubicin liposomes may provide a safe and efficient therapy strategy for NSCLC. Keywords: octreotide, honokiol, chemotherapy, vasculogenic mimicry, tumor metastasis, targeting drug delivery

  12. Small interfering RNA targeting S100A4 sensitizes non-small-cell lung cancer cells (A549) to radiation treatment.

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    Qi, Ruixue; Qiao, Tiankui; Zhuang, Xibing

    2016-01-01

    This study aimed to investigate the impact of S100A4-small interfering RNA (S100A4-siRNA) on apoptosis and enhanced radiosensitivity in non-small-cell lung cancer (A549) cells. We also explored the mechanisms of radiosensitization and identified a new target to enhance radiosensitivity and gene therapy for non-small-cell lung cancer. RNA interference is a powerful tool for gene silencing. In this study, we constructed an effective siRNA to knock down S100A4. A549 cells were randomly divided into three groups: blank, negative control, and S100A4-siRNA. To investigate the effect of S100A4-siRNA, the expression of S100A4, E-cadherin, and p53 proteins and their messenger RNA (mRNA) was detected by Western blot and quantitative real-time polymerase chain reaction. Transwell chambers were used to assess cell invasion. Cell cycle and apoptosis were analyzed by flow cytometry. Radiosensitivity was determined by colony formation ability. Our results demonstrate that S100A4-siRNA effectively silenced the S100A4 gene. When siRNA against S100A4 was used, S100A4 protein expression was downregulated, whereas the expressions of E-cadherin and p53 were upregulated. In addition, a clear reduction in S100A4 mRNA levels was noted compared with the blank and negative control groups, whereas E-cadherin and p53 mRNA levels increased. Transfection with S100A4-siRNA significantly reduced the invasiveness of A549 cells. S100A4 silencing induced immediate G2/M arrest in cell cycle studies and increased apoptosis rates in A549 cells. In clonogenic assays, we used a multitarget, single-hit model to detect radiosensitivity after S100A4 knockdown. All parameters (D0, Dq, α, β) indicated that the downregulation of S100A4 enhanced radiosensitivity in A549 cells. Furthermore, S100A4-siRNA upregulated p53 expression, suggesting that S100A4 may promote A549 cell proliferation, invasion, and metastasis by regulating the expression of other proteins. Therefore, siRNA-directed S100A4 knockdown may

  13. High-throughput qRT-PCR validation of blood microRNAs in non-small cell lung cancer.

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    Leidinger, Petra; Brefort, Thomas; Backes, Christina; Krapp, Medea; Galata, Valentina; Beier, Markus; Kohlhaas, Jochen; Huwer, Hanno; Meese, Eckart; Keller, Andreas

    2016-01-26

    Validation of biomarkers is essential to advance the translational process to clinical application. Although there exists an increasing number of reports on small non-coding RNAs (microRNAs) as minimally-invasive markers from blood, serum or plasma, just a limited number is verified in follow-up studies. We used qRT-PCR to evaluate a known miRNA signature measured from blood that allowed for separation between patients with non-small cell lung cancer (NSCLC), COPD and healthy controls.From the data of our previous microarray studies we selected a panel of 235 miRNAs related to lung cancer and COPD. We observed a high concordance between the AUC values of our initial microarray screening and the qRT-PCR data (correlation of 0.704, p < 10-16). Overall, 90.3% of markers were successfully validated. Among the top markers that were concordant between both studies we found hsa-miR-20b-5p, hsa-miR-20a-5p, hsa-miR-17-5p, and hsa-miR-106a-5p. The qRT-PCR analysis also confirmed that non-small cell lung cancer patients could be accurately differentiated from unaffected controls: a subset of five markers was sufficient to separate NSCLC patients from unaffected controls with accuracy of 94.5% (specificity and sensitivity of 98% and 91%). Beyond differentiation from controls, we also succeeded in separating NSCLC patients from patients with COPD. MiRNAs that were identified as relevant for the separation between lung cancer and COPD by both qRT-PCR and the array-based studies included hsa-miR-26a-5p, hsa-miR-328-3p and hsa-miR-1224-3p. Although for differentiation between NSCLC patients from COPD patients more markers were required, still high accuracy rates were obtained (5 markers: 78.8%; 10 markers: 83.9%; 50 markers: 87.6%).

  14. [Clinic significance of nm23, collage IV and PCNA expression in non-small cell lung cancer].

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    Yu, Q; Ma, L; Jing, S; Xu, Y; Geng, D

    2001-12-20

    To study the significance of nm23, collagen IV and PCNA expressions in non-small cell lung cancer. Expressions of the nm23, collagen IV and PCNA in 84 cases of non-small cell lung cancer were examined with SP immunohistochemical technique. Of the 84 cases, there were squamous cell carcinoma 42, adenocarcinoma 42, stage I 27, stage II 24, stage III 24, and stage IV 9. Statistical analysis was performed with Chi-Square test. Expressions of the nm23, collagen IV and PCNA in 84 cases of non-small cell lung cancer were 60. 7% ( 51/ 84) , 75. 0% ( 63/ 84) and 53. 6% ( 45/ 84) respectively. There was negative correlation between the lymph node metastasis and the expressions of nm23 and collagen IV in squamous cell carcinoma, and the expressions of collagen IV and PCNA were associated with tumor differentiation. No correlation was found between TNM stage and expressions of nm23, collagen IV and PCNA. The results indicate that nm23, collagen IV and PCNA participate the modulation of metastasis of non-small cell lung cancer and that they may be used to evaluate the potential of metastasis.

  15. TKTL1 is overexpressed in a large portion of non-small cell lung cancer specimens

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    Zabel Peter

    2008-08-01

    Full Text Available Abstract In several tumors the transketolase activity, controlled inter alia by enzymes of the pentose phosphate pathway which is an alternative, energy generating reaction-cascade to glycolysis, has been correlated with proliferation. The increase of thiamine-dependant transketolase enzyme reactions is induced especially through upregulated transketolase-like enzyme 1 (TKTL1-activity; that shows TKTL1 to be a causative enzyme for tumors enhanced, anaerobic glucose degradation. We investigated TKTL1-expression in 88 human, formalin-fixed non-small cell lung cancer tissues and 24 carcinomas of the breast by immunohistochemical stainings applying a 0 to 3 staining-score system (3 = strongest expression. For means of validation we additionally stained 40 NSCLC fixed and paraffin-embedded utilizing the HOPE-technique; showing comparable results to the formalin-fixed, paraffin-embedded specimens (not shown. Potential correlations with age, sex, TNM-classification parameters and tumor grading as well as tumor transcription factor 1 (TTF1 and surfactant protein A (SPA expression were investigated. 40.9% of the analyzed lung tumors expressed TKTL1 weakly (Score 1, 38.6% moderately (score 2 and 17.1% strongly (score 3. 3 tumors were diagnosed TKTL1-negative (3.4%; score 0. All Breast cancer specimen stainings were positive and scored 1: 32%; scored 2: 36%; scored 3: 32%. Alveolar macrophages and Alveolar Epithelial Cells Type II were also found to be TKTL1-positive. None of the listed clinical parameters could be found to show a significant correlation to TKTL1 signal appearance. Although we describe the expression of TKTL1 in lung cancers, we need to state that up till now there is no scientific indication for any treatment regimens based upon these findings.

  16. Exploring Boron Neutron Capture Therapy for non-small cell lung cancer.

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    Farías, Rubén O; Bortolussi, Silva; Menéndez, Pablo R; González, Sara J

    2014-12-01

    Boron Neutron Capture Therapy (BNCT) is a radiotherapy that combines biological targeting and high LET radiation. It consists in the enrichment of tumour with (10)B and in the successive irradiation of the target with low energy neutrons producing charged particles that mainly cause non-repairable damages to the cells. The feasibility to treat Non Small Cells Lung Cancer (NSCLC) with BNCT was explored. This paper proposes a new approach to determine treatment plans, introducing the possibility to choose the irradiation start and duration to maximize the tumour dose. A Tumour Control Probability (TCP) suited for lung BNCT as well as other high dose radiotherapy schemes was also introduced. Treatment plans were evaluated in localized and disseminated lung tumours. Semi-ideal and real energy spectra beams were employed to assess the best energy range and the performance of non-tailored neutron sources for lung tumour treatments. The optimal neutron energy is within [500 eV-3 keV], lower than the 10 keV suggested for the treatment of deep-seated tumours in the brain. TCPs higher than 0.6 and up to 0.95 are obtained for all cases. Conclusions drawn from [Suzuki et al., Int Canc Conf J 1 (4) (2012) 235-238] supporting the feasibility of BNCT for shallow lung tumours are confirmed, however discussions favouring the treatment of deeper lesions and disseminated disease are also opened. Since BNCT gives the possibility to deliver a safe and potentially effective treatment for NSCLC, it can be considered a suitable alternative for patients with few or no treatment options. Copyright © 2014 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

  17. Genome-wide DNA methylation profiling of non-small cell lung carcinomas.

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    Carvalho, Rejane Hughes; Haberle, Vanja; Hou, Jun; van Gent, Teus; Thongjuea, Supat; van Ijcken, Wilfred; Kockx, Christel; Brouwer, Rutger; Rijkers, Erikjan; Sieuwerts, Anieta; Foekens, John; van Vroonhoven, Mirjam; Aerts, Joachim; Grosveld, Frank; Lenhard, Boris; Philipsen, Sjaak

    2012-06-22

    Non-small cell lung carcinoma (NSCLC) is a complex malignancy that owing to its heterogeneity and poor prognosis poses many challenges to diagnosis, prognosis and patient treatment. DNA methylation is an important mechanism of epigenetic regulation involved in normal development and cancer. It is a very stable and specific modification and therefore in principle a very suitable marker for epigenetic phenotyping of tumors. Here we present a genome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, where we combine MethylCap and next generation sequencing (MethylCap-seq) to provide comprehensive DNA methylation maps of the tumor and paired lung samples. The MethylCap-seq data were validated by bisulfite sequencing and methyl-specific polymerase chain reaction of selected regions. Analysis of the MethylCap-seq data revealed a strong positive correlation between replicate experiments and between paired tumor/lung samples. We identified 57 differentially methylated regions (DMRs) present in all NSCLC tumors analyzed by MethylCap-seq. While hypomethylated DMRs did not correlate to any particular functional category of genes, the hypermethylated DMRs were strongly associated with genes encoding transcriptional regulators. Furthermore, subtelomeric regions and satellite repeats were hypomethylated in the NSCLC samples. We also identified DMRs that were specific to two of the major subtypes of NSCLC, adenocarcinomas and squamous cell carcinomas. Collectively, we provide a resource containing genome-wide DNA methylation maps of NSCLC and their paired lung tissues, and comprehensive lists of known and novel DMRs and associated genes in NSCLC.

  18. Genome-wide DNA methylation profiling of non-small cell lung carcinomas

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    Carvalho Rejane

    2012-06-01

    Full Text Available Abstract Background Non-small cell lung carcinoma (NSCLC is a complex malignancy that owing to its heterogeneity and poor prognosis poses many challenges to diagnosis, prognosis and patient treatment. DNA methylation is an important mechanism of epigenetic regulation involved in normal development and cancer. It is a very stable and specific modification and therefore in principle a very suitable marker for epigenetic phenotyping of tumors. Here we present a genome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, where we combine MethylCap and next generation sequencing (MethylCap-seq to provide comprehensive DNA methylation maps of the tumor and paired lung samples. The MethylCap-seq data were validated by bisulfite sequencing and methyl-specific polymerase chain reaction of selected regions. Results Analysis of the MethylCap-seq data revealed a strong positive correlation between replicate experiments and between paired tumor/lung samples. We identified 57 differentially methylated regions (DMRs present in all NSCLC tumors analyzed by MethylCap-seq. While hypomethylated DMRs did not correlate to any particular functional category of genes, the hypermethylated DMRs were strongly associated with genes encoding transcriptional regulators. Furthermore, subtelomeric regions and satellite repeats were hypomethylated in the NSCLC samples. We also identified DMRs that were specific to two of the major subtypes of NSCLC, adenocarcinomas and squamous cell carcinomas. Conclusions Collectively, we provide a resource containing genome-wide DNA methylation maps of NSCLC and their paired lung tissues, and comprehensive lists of known and novel DMRs and associated genes in NSCLC.

  19. MicroRNA-dependent regulation of transcription in non-small cell lung cancer.

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    Sonia Molina-Pinelo

    Full Text Available Squamous cell lung cancer (SCC and adenocarcinoma are the most common histological subtypes of non-small cell lung cancer (NSCLC, and have been traditionally managed in the clinic as a single entity. Increasing evidence, however, illustrates the biological diversity of these two histological subgroups of lung cancer, and supports the need to improve our understanding of the molecular basis beyond the different phenotypes if we aim to develop more specific and individualized targeted therapy. The purpose of this study was to identify microRNA (miRNA-dependent transcriptional regulation differences between SCC and adenocarcinoma histological lung cancer subtypes. In this work, paired miRNA (667 miRNAs by TaqMan Low Density Arrays (TLDA and mRNA profiling (Whole Genome 44 K array G112A, Agilent was performed in tumor samples of 44 NSCLC patients. Nine miRNAs and 56 mRNAs were found to be differentially expressed in SCC versus adenocarcinoma samples. Eleven of these 56 mRNA were predicted as targets of the miRNAs identified to be differently expressed in these two histological conditions. Of them, 6 miRNAs (miR-149, miR-205, miR-375, miR-378, miR-422a and miR-708 and 9 target genes (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1 were validated by quantitative PCR in an independent cohort of 41 lung cancer patients. Furthermore, the inverse correlation between mRNAs and microRNAs expression was also validated. These results suggest miRNA-dependent transcriptional regulation differences play an important role in determining key hallmarks of NSCLC, and may provide new biomarkers for personalized treatment strategies.

  20. Prognostic impact of cytological fluid tumor markers in non-small cell lung cancer.

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    Cho, Arthur; Hur, Jin; Hong, Yoo Jin; Lee, Hye-Jeong; Kim, Young Jin; Hong, Sae Rom; Suh, Young Joo; Im, Dong Jin; Kim, Yun Jung; Lee, Jae Seok; Shim, Hyo Sup; Choi, Byoung Wook

    2016-03-01

    The serum tumor markers CYFRA 21-1, carcinoembryonic antigen (CEA), and squamous cell carcinoma antigen (SCCA) are useful in diagnosis and prognosis of non-small cell lung cancer (NSCLC). Cytologic tumor markers obtained during needle aspiration biopsies (NAB) of lung lesions are useful for NSCLC diagnosis. This study investigated the incremental prognostic value of cytologic tumor markers compared to serum tumor markers. This prospective study included 253 patients diagnosed with NSCLC by NAB with cytologic tumor marker analysis. Levels of cytologic CYFRA 21-1, CEA, SCCA, and their serum counterparts were followed up for survival analysis. Optimal cutoff values for each tumor marker were obtained for overall survival (OS) and progression-free survival (PFS) analyses. All patients were followed up for a median of 22.8 months. Using cutoff values of 0.44 ng/ml for C-SCCA, 2.0 ng/ml for S-SCCA, and 3.3 ng/ml for S-CYFRA, a multivariate analysis revealed that high S-SCCA (hazard ratio, HR, 1.84) and high C-SCCA (HR, 1.63) were independent predictive factors of OS. The 3-year overall survival rate was 55 vs. 80 % for high and low C-SCCA, respectively. Cytologic tumor marker level detection is easily obtainable and provides prognostic information for NSCLC. Cytologic tumor markers provide comparable prognostic information relative to serum tumor markers, with C-SCCA acting as a strong prognostic factor of overall survival and PFS.

  1. Non-Small Cell Lung Cancer Cells Expressing CD44 Are Enriched for Stem Cell-Like Properties

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    Leung, Elaine Lai-Han; Fiscus, Ronald R.; Tung, James W.; Tin, Vicky Pui-Chi; Cheng, Lik Cheung; Sihoe, Alan Dart-Loon; Fink, Louis M.; Ma, Yupo; Wong, Maria Pik

    2010-01-01

    Background The cancer stem cell theory hypothesizes that cancers are perpetuated by cancer stem cells (CSC) or tumor initiating cells (TIC) possessing self-renewal and other stem cell-like properties while differentiated non-stem/initiating cells have a finite life span. To investigate whether the hypothesis is applicable to lung cancer, identification of lung CSC and demonstration of these capacities is essential. Methodology/Principal Finding The expression profiles of five stem cell markers (CD34, CD44, CD133, BMI1 and OCT4) were screened by flow cytometry in 10 lung cancer cell lines. CD44 was further investigated by testing for in vitro and in vivo tumorigenecity. Formation of spheroid bodies and in vivo tumor initiation ability were demonstrated in CD44+ cells of 4 cell lines. Serial in vivo tumor transplantability in nude mice was demonstrated using H1299 cell line. The primary xenografts initiated from CD44+ cells consisted of mixed CD44+ and CD44− cells in similar ratio as the parental H1299 cell line, supporting in vivo differentiation. Semi-quantitative Real-Time PCR (RT-PCR) showed that both freshly sorted CD44+ and CD44+ cells derived from CD44+-initiated tumors expressed the pluripotency genes OCT4/POU5F1, NANOG, SOX2. These stemness markers were not expressed by CD44− cells. Furthermore, freshly sorted CD44+ cells were more resistant to cisplatin treatment with lower apoptosis levels than CD44− cells. Immunohistochemical analysis of 141 resected non-small cell lung cancers showed tumor cell expression of CD44 in 50.4% of tumors while no CD34, and CD133 expression was observed in tumor cells. CD44 expression was associated with squamous cell carcinoma but unexpectedly, a longer survival was observed in CD44-expressing adenocarcinomas. Conclusion/Significance Overall, our results demonstrated that stem cell-like properties are enriched in CD44-expressing subpopulations of some lung cancer cell lines. Further investigation is required to clarify

  2. Prognostic significance of MCM2, Ki-67 and gelsolin in non-small cell lung cancer

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    Yang, Jun; Tan, Dongfeng; Ramnath, Nithya; Moysich, Kirsten B; Asch, Harold L; Swede, Helen; Alrawi, Sadir J; Huberman, Joel; Geradts, Joseph; Brooks, John SJ

    2006-01-01

    Uncontrolled proliferation and increased motility are hallmarks of neoplastic cells, therefore markers of proliferation and motility may be valuable in assessing tumor progression and prognosis. MCM2 is a member of the minichromosome maintenance (MCM) protein family. It plays critical roles in the initiation of DNA replication and in replication fork movement, and is intimately related to cell proliferation. Ki-67 is a proliferation antigen that is expressed during all but G 0 phases of the cell cycle. Gelsolin is an actin-binding protein that regulates the integrity of the actin cytoskeletal structure and facilitates cell motility. In this study, we assessed the prognostic significance of MCM2 and Ki-67, two markers of proliferation, and gelsolin, a marker of motility, in non-small cell lung cancer (NSCLC). 128 patients with pathologically confirmed, resectable NSCLC (stage I-IIIA) were included. Immunohistochemistry was utilized to measure the expressions of these markers in formalin-fixed, paraffin-embedded tumor tissues. Staining and scoring of MCM2, Ki-67 and gelsolin was independently performed. Analyses were performed to evaluate the prognostic significance of single expression of each marker, as well as the prognostic significance of composite expressions of MCM2 and gelsolin. Cox regression and Kaplan-Meier survival analysis were used for statistical analysis. Of the three markers, higher levels of gelsolin were significantly associated with an increased risk of death (adjusted RR = 1.89, 95% CI = 1.17–3.05, p = 0.01), and higher levels of MCM2 were associated with a non-significant increased risk of death (adjusted RR = 1.36, 95% CI = 0.84–2.20, p = 0.22). Combined, adjusted analyses revealed a significantly poor prognostic effect for higher expression of MCM2 and gelsolin compared to low expression of both biomarkers (RR = 2.32, 95% CI = 1.21–4.45, p = 0.01). Ki-67 did not display apparent prognostic effect in this study sample. The results suggest

  3. MYC expression correlates with PD-L1 expression in non-small cell lung cancer.

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    Kim, Eun Young; Kim, Arum; Kim, Se Kyu; Chang, Yoon Soo

    2017-08-01

    Objectives Programmed death-ligand 1 (PD-L1) is a widely used biomarker for predicting immune checkpoint inhibitors, but is of limited usefulness in the prediction of drug response. MYC, a transcription factor that is overexpressed in cancers, is involved in preventing immune cells from attacking tumor cells through inducing PD-L1 expression. This study evaluated the relationship between MYC and PD-L1 expression in 84 non-small cell lung cancer (NSCLC) patients who underwent curative surgical resection. Materials and Methods The relationship between MYC and PD-L1 was investigated by introducing pcDNA3-cMYC into A549 and H1299 cells with low PD-L1 expression and siRNA against MYC into H60 and H2009 cells with high PD-L1 expression. Expression of PD-L1 in NSCLC tissues was analyzed by immunostaining using a PD-L1 (22C3) PharmDx protocol using the Dako Automated Link 48 platform and expression of MYC was determined using anti-c-MYC (Y69) (ab320720). Results Of 84 patients, PD-L1 was expressed in 14 (16.7%) and MYC was overexpressed in 30 (35.7%). We investigated the relationship between PD-L1 and MYC expression. There were 49 (58.3%) double-negative patients and 9 (10.7%) double-positive patients. Significant positive correlation was observed between PD-L1 and MYC expression (γ=0.210, P=0.029). Double-negative patients showed better disease free (31.1 vs. 7.1 months, P=0.011) and overall survival (56.1 vs. 14.4 months, P=0.032) than double-positive patients. Conclusion Taken together, MYC expression significantly correlated with PD-L1 expression in NSCLC. The usefulness of MYC expression as a surrogate marker of treatment response assessment is worth evaluating for immune checkpoint inhibitor therapy and special interest are required for the subgroup of NSCLC patients, whose tumor expresses PD-L1 and MYC double positive. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. A new in vitro screening system for anticancer drugs for the treatment of non-small cell lung cancer

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    Hanauske, U.; Hanauske, A.R.; Clark, G.M.; Tsen, D.; Buchok, J.; Hoff, D.D. von

    1989-01-01

    We have evaluated a semiautomated radiometric assay (BACTEC 460 system) for screening of activity of anticancer drugs against human non-small cell lung cancer cell lines. Cells from seven cell lines were exposed to standard antineoplastic agents at four different concentrations using a 1-h incubation. Alpha 2-interferon was tested using a continuous incubation. In vitro drug activity was analyzed as a function of the clinically achievable serum concentration. Our results indicate that two cell lines (CALU-3, SK-MES-1) exhibit in vitro drug sensitivity patterns closest to those observed in clinical studies. These two cell lines might therefore be most useful for screening new anticancer compounds for activity against non-small cell lung cancer. The radiometric assay is a semiautomated system which has advantages over other, more time-consuming screening systems

  5. miR-126 inhibits non-small cell lung cancer cells proliferation by targeting EGFL7

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    Sun, Yanqin; Bai, Yifeng; Zhang, Fan; Wang, Yu [Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou (China); Guo, Ying, E-mail: guohanjing001@163.com [Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou (China); Guo, Linlang, E-mail: linlangg@yahoo.com [Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou (China)

    2010-01-15

    MicroRNAs (miRNAs) represent an abundant group of small non-coding RNAs that regulate gene expression, and have been demonstrated to play roles as tumor suppressor genes (oncogenes), and affect homeostatic processes such as development, cell proliferation, and cell death. Subsequently, epidermal growth factor-like domain 7 (EGFL7), which is confirmed to be involved in cellular responses such as cell migration and blood vessel formation, is identified as a potential miR-126 target by bioinformatics. However, there is still no evidence showing EGFL7's relationship with miR-126 and the proliferation of lung cancer cells. The aim of this work is to investigate whether miR-126, together with EGFL7, have an effect on non-small cell lung cancer (NSCLC) cells' proliferation. Therefore, we constructed overexpressed miR-126 plasmid to target EGFL7 and transfected them into NSCLC cell line A549 cells. Then, we used methods like quantitative RT-PCR, Western blot, flow cytometry assay, and immunohistochemistry staining to confirm our findings. The result was that overexpression of miR-126 in A549 cells could increase EGFL7 expression. Furthermore, the most notable finding by cell proliferation related assays is that miR-126 can inhibit A549 cells proliferation in vitro and inhibit tumor growth in vivo by targeting EGFL7. As a result, our study demonstrates that miR-126 can inhibit proliferation of non-small cell lung cancer cells through one of its targets, EGFL7.

  6. Prognostic biomarker study in pathologically staged N1 non-small cell lung cancer

    International Nuclear Information System (INIS)

    Komaki, Ritsuko; Milas, Luka; Ro, Jae Y.; Fujii, Takashi; Perkins, Penny; Allen, Pamela; Sikes, Charles R.; Mountain, Clifton F.; Ordonez, Nelson G.

    1998-01-01

    Purpose: The prognostic influence of 6 biomarkers correlated to histologic subtypes of non-small cell lung cancer (NSCLC) on loco-regional control, overall survival, disease-free survival (DFS), and distant disease control (DDC) rates, all measured at 5 years, were examined. Materials and Methods: Cell blocks from the primary tumors of 137 patients with pathologically staged N1 NSCLC at MDACC were analyzed by 6-biomarker status correlated to histological subtypes and their outcomes. Results: The ranges of biomarker values were as follows: apoptotic index, 0.2-2.8%; mitotic index, 0-1.8%; the proportion of cells in S+G2M, 3-36%; p53 status, 0-100%; Ki-67, 0-9.3%; DNA index, 1.0-2.74. Subtypes of 137 cases from the postoperative pathology specimen showed that 74 patients had squamous carcinoma and 63 patients had adenocarcinoma. Mean and median lengths of follow-up were 4.21 years and 2.43 years, respectively. Patients with squamous cell carcinoma (SCC) had a better 5-year survival (p = 0.006), DFS (pp = 0.002) than patients with adenocarcinoma (AC). Among patients with AC, the DNA index was a significant predictor of 5-year DFS (p = 0.02), DDC rate (p = 0.04), and local-regional control (p < 0.05). Higher apoptosis (p 0.03) and mitosis indices (p = 0.03) were also univariate predictors of increased distant disease among patients with AC. Multivariate analysis of patients with AC revealed that the DNA index and Ki-67 were the only significant independent predictors of distant metastasis (p < 0.04 and p < 0.02, respectively) and DFS (p < 0.04 for both). Among patients with SCC, univariate analysis showed that S+G2M proportion (p < 0.05) and Ki-67 levels (p < 0.02) were significant predictors for local-regional control; for SC, multivariate analysis showed that only mitosis was a significant predictor in this case for overall survival (p < 0.04). Conclusion: Spontaneous apoptotic index and Ki-67 were significantly higher in SC than in AC. Patients with SC had less

  7. Dose escalation for non-small cell lung cancer: Analysis and modelling of published literature

    International Nuclear Information System (INIS)

    Partridge, Mike; Ramos, Monica; Sardaro, Angela; Brada, Michael

    2011-01-01

    Purpose: To review the published clinical data on non-small cell lung cancer treated with radical radiotherapy to confirm a dose-response relationship as a basis for further dose-escalation trials. Methods: Twenty-four published clinical trials were identified, 16 of which - with 29 different standard, hyper- and hypofractionated treatment schedules - were analysed. Prescription doses were converted to biologically-equivalent dose (BED), with a correction for repopulation. Disease-free survival data were corrected for the stage profile of each cohort to allow better comparison of results. We also analysed moderate (grade II and III) lung and oesophageal acute toxicity related to the corrected BED delivered to the tumour. Results: The clinical data analysed showed good agreement between the observed and modelled disease-free survival at 2 years when compared to the published models of Fenwick (correlation coefficient 0.525, p = 0.003) and Martel (correlation coefficient 0.492, p = 0.007), indicating a clear tumour dose-response. In the normally fractionated treatments (∼2 Gy per fraction), improved disease-free survival was generally observed in the shorter schedules (maximum around 6 weeks). However, the best outcomes were obtained for the hypofractionated schedules. No systematic relationship was seen between prescribed dose and lung or oesophageal acute toxicity, possibly due to dose selection depending on V 20 or MLD in some studies and the diversity of the patients analysed. Conclusions: We have demonstrated a dose-response relationship for NSCLC based on clinical data. The clinical data provide a rational basis for selection of dose escalation schedules to be tested in future randomised trials.

  8. Coexistent Autoimmune Autonomic Ganglionopathy and Myasthenia Gravis Associated with Non-Small Cell Lung Cancer

    Science.gov (United States)

    Peltier, Amanda C.; Black, Bonnie K.; Raj, Satish R.; Donofrio, Peter; Robertson, David; Biaggioni, Italo

    2014-01-01

    We report a case of a 55 year old man with non-small cell lung cancer who underwent radiation, chemotherapy with carbotaxol and paclitaxel, and left upper lobe removal two years prior to evaluation. He was referred for disabling orthostatic hypotension (113/69 supine, 66/47 mmHg standing after 10 minutes without a compensatory heart rate increase (57 to 59 bpm), fatigue, and constipation with episodes of ileus. Clinical examination showed mild ptosis bilaterally, fatiguable neck flexor weakness and hip flexor weakness. Blood pressure response to Valsalva maneuver was abnormal with absence of phase 4 overshoot and a Valsalva heart rate ratio of 1.04, The plasma norepinephrine level was low (79 pg/ml supine to 330 pg/ml standing). Single fiber EMG of the right extensor digitorum communis revealed normal mean MCD (jitter) but several pairs exceeded a jitter of 100 µs. Antibodies against muscle acetylcholine receptor [(AChR) 0.66 nmol/L, normal <0.02] and ganglionic AChR (0.34 nmol/L, normal <0.02) were present. Treatment with plasma exchange normalized responses to standing posture (105/68 supine to 118/82 mmHg standing, 66 to 79 bpm), to Valsalva (normal blood pressure overshoot, HR ratio 1.47), norepinephrine (194 pg/ml supine, 763 standing), and jitter measurements. We conclude that autoimmune autonomic ganglionopathy and myasthenia gravis can coexist and suggest that the latter should be excluded in patients with autoimmune autonomic ganglionopathy who complain of fatigue that is improved with non-supine rest. PMID:19882640

  9. Indigenous Australians with non-small cell lung cancer or cervical cancer receive suboptimal treatment.

    Science.gov (United States)

    Whop, Lisa J; Bernardes, Christina M; Kondalsamy-Chennakesavan, Srinivas; Darshan, Deepak; Chetty, Naven; Moore, Suzanne P; Garvey, Gail; Walpole, Euan; Baade, Peter; Valery, Patricia C

    2017-10-01

    Lung cancer and cervical cancer are higher in incidence for Indigenous Australians and survival is worse compared with non-Indigenous Australians. Here we aim to determine if being Indigenous and/or other factors are associated with patients receiving "suboptimal treatment" compared to "optimal treatment" according to clinical guidelines for two cancer types. Data were collected from hospital medical records for Indigenous adults diagnosed with cervical cancer and non-small cell lung cancer (NSCLC) and a frequency-matched comparison group of non-Indigenous patients in the Queensland Cancer Registry between January 1998 and December 2004. The two cancer types were analyzed separately. A total of 105 women with cervical cancer were included in the study, 56 of whom were Indigenous. Indigenous women had higher odds of not receiving optimal treatment according to clinical guidelines (unadjusted OR 7.1; 95% CI, 1.5-33.3), even after adjusting for stage (OR 5.7; 95% CI, 1.2-27.3). Of 225 patients with NSCLC, 198 patients (56% Indigenous) had sufficient information available to be analyzed. The odds of receiving suboptimal treatment were significantly higher for Indigenous compared to non-Indigenous NSCLC patients (unadjusted OR 1.9; 95% CI, 1.0-3.6) and remained significant after adjusting for stage, comorbidity and age (adjusted OR 2.1; 95% CI, 1.1-4.1). The monitoring of treatment patterns and appraisal against guidelines can provide valuable evidence of inequity in cancer treatment. We found that Indigenous people with lung cancer or cervical cancer received suboptimal treatment, reinforcing the need for urgent action to reduce the impact of these two cancer types on Indigenous people. © 2016 John Wiley & Sons Australia, Ltd.

  10. Osteopontin is a prognostic biomarker in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Rud, Ane Kongsgaard; Mælandsmo, Gunhild M; Boye, Kjetil; Øijordsbakken, Miriam; Lund-Iversen, Marius; Halvorsen, Ann Rita; Solberg, Steinar K; Berge, Gisle; Helland, Åslaug; Brustugun, Odd Terje

    2013-01-01

    In a previously published report we characterized the expression of the metastasis-associated proteins S100A4, osteopontin (OPN) and ephrin-A1 in a prospectively collected panel of non-small cell lung cancer (NSCLC) tumors. The aim of the present follow-up study was to investigate the prognostic impact of these potential biomarkers in the same patient cohort. In addition, circulating serum levels of OPN were measured and single nucleotide polymorphisms (SNP) in the -443 position of the OPN promoter were analyzed. Associations between immunohistochemical expression of S100A4, OPN and ephrin-A1 and relapse free and overall survival were examined using univariate and multivariate analyses. Serum OPN was measured by ELISA, polymorphisms in the -443 position of the tumor OPN promoter were analyzed by PCR, and associations between OPN levels and promoter polymorphisms and clinicopathological parameters and patient outcome were investigated. High expression of OPN in NSCLC tumors was associated with poor patient outcome, and OPN was a strong, independent prognostic factor for both relapse free and overall survival. Serum OPN levels increased according to tumor pT classification and tumor size, and patients with OPN-expressing tumors had higher serum levels than patients with OPN-negative tumors. S100A4 was a negative prognostic factor in several subgroups of adenocarcinoma patients, but not in the overall patient cohort. There was no association between ephrin-A1 expression and patient outcome. OPN is a promising prognostic biomarker in NSCLC, and should be further explored in the selection of patients for adjuvant treatment following surgical resection

  11. Long term outcomes after salvage radiotherapy for postoperative locoregionally recurrent non-small-cell lung cancer

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    Kim, Eun Ji; Song, Chang Hoon; Kim, Jae Sung [Dept. of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Kim, Mi Young [Dept. of Radiation Oncology, Kyungpook National University Medical Center, Daegu (Korea, Republic of)

    2017-03-15

    The outcomes and toxicities of locoregionally recurrent non-small-cell lung cancer (NSCLC) patients treated with curative radiotherapy were evaluated in the modern era. Fifty-seven patients receiving radical radiotherapy for locoregionally recurrent NSCLC without distant metastasis after surgery from 2004 to 2014 were reviewed. Forty-two patients were treated with concurrent chemoradiotherapy (CCRT), and 15 patients with radiotherapy alone. The median radiation dose was 66 Gy (range, 45 to 70 Gy). Lung function change after radiotherapy was evaluated by comparing pulmonary function tests before and at 1, 6, and 12 months after radiotherapy. Median follow-up was 53.6 months (range, 12.0 to 107.5 months) among the survivors. The median overall survival (OS) and progression-free survival (PFS) were 54.8 months (range, 3.0 to 116.9 months) and 12.2 months (range, 0.8 to 100.2 months), respectively. Multivariate analyses revealed that single locoregional recurrence focus and use of concurrent chemotherapy were significant prognostic factors for OS (p = 0.048 and p = 0.001, respectively) and PFS (p = 0.002 and p = 0.026, respectively). There was no significant change in predicted forced expiratory volume in one second after radiotherapy. Although diffusing lung capacity for carbon monoxide decreased significantly at 1 month after radiotherapy (p < 0.001), it recovered to pretreatment levels within 12 months. Acute grade 3 radiation pneumonitis and esophagitis were observed in 3 and 2 patients, respectively. There was no chronic complication observed in all patients. Salvage radiotherapy showed good survival outcomes without severe complications in postoperative locoregionally recurrent NSCLC patients. A single locoregional recurrent focus and the use of CCRT chemotherapy were associated with improved survival. CCRT should be considered as a salvage treatment in patients with good prognostic factors.

  12. Definitive Primary Therapy in Patients Presenting With Oligometastatic Non-Small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Parikh, Ravi B.; Cronin, Angel M.; Kozono, David E.; Oxnard, Geoffrey R.; Mak, Raymond H.; Jackman, David M.; Lo, Peter C.; Baldini, Elizabeth H.; Johnson, Bruce E.; Chen, Aileen B.

    2014-01-01

    Purpose: Although palliative chemotherapy is the standard of care for patients with diagnoses of stage IV non-small cell lung cancer (NSCLC), patients with a small metastatic burden, “oligometastatic” disease, may benefit from more aggressive local therapy. Methods and Materials: We identified 186 patients (26% of stage IV patients) prospectively enrolled in our institutional database from 2002 to 2012 with oligometastatic disease, which we defined as 5 or fewer distant metastatic lesions at diagnosis. Univariate and multivariable Cox proportional hazards models were used to identify patient and disease factors associated with improved survival. Using propensity score methods, we investigated the effect of definitive local therapy to the primary tumor on overall survival. Results: Median age at diagnosis was 61 years of age; 51% of patients were female; 12% had squamous histology; and 33% had N0-1 disease. On multivariable analysis, Eastern Cooperate Oncology Group performance status ≥2 (hazard ratio [HR], 2.43), nodal status, N2-3 (HR, 2.16), squamous pathology, and metastases to multiple organs (HR, 2.11) were associated with a greater hazard of death (all P<.01). The number of metastatic lesions and radiologic size of the primary tumor were not significantly associated with overall survival. Definitive local therapy to the primary tumor was associated with prolonged survival (HR, 0.65, P=.043). Conclusions: Definitive local therapy to the primary tumor appears to be associated with improved survival in patients with oligometastatic NSCLC. Select patient and tumor characteristics, including good performance status, nonsquamous histology, and limited nodal disease, may predict for improved survival in these patients

  13. Metagenes Associated with Survival in Non-Small Cell Lung Cancer

    Science.gov (United States)

    Urgard, Egon; Vooder, Tõnu; Võsa, Urmo; Välk, Kristjan; Liu, Mingming; Luo, Cheng; Hoti, Fabian; Roosipuu, Retlav; Annilo, Tarmo; Laine, Jukka; Frenz, Christopher M.; Zhang, Liqing; Metspalu, Andres

    2011-01-01

    NSCLC (non-small cell lung cancer) comprises about 80% of all lung cancer cases worldwide. Surgery is most effective treatment for patients with early-stage disease. However, 30%–55% of these patients develop recurrence within 5 years. Therefore, markers that can be used to accurately classify early-stage NSCLC patients into different prognostic groups may be helpful in selecting patients who should receive specific therapies. A previously published dataset was used to evaluate gene expression profiles of different NSCLC subtypes. A moderated two-sample t-test was used to identify differentially expressed genes between all tumor samples and cancer-free control tissue, between SCC samples and AC/BC samples and between stage I tumor samples and all other tumor samples. Gene expression microarray measurements were validated using qRT-PCR. Bayesian regression analysis and Kaplan-Meier survival analysis were performed to determine metagenes associated with survival. We identified 599 genes which were down-regulated and 402 genes which were up-regulated in NSCLC compared to the normal lung tissue and 112 genes which were up-regulated and 101 genes which were down-regulated in AC/BC compared to the SCC. Further, for stage Ib patients the metagenes potentially associated with survival were identified. Genes that expressed differently between normal lung tissue and cancer showed enrichment in gene ontology terms which were associated with mitosis and proliferation. Bayesian regression and Kaplan-Meier analysis showed that gene-expression patterns and metagene profiles can be applied to predict the probability of different survival outcomes in NSCLC patients. PMID:21695068

  14. Respiration-averaged CT for attenuation correction in non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Cheng, Nai-Ming; Ho, Kung-Chu; Yen, Tzu-Chen; Yu, Chih-Teng; Wu, Yi-Cheng; Liu, Yuan-Chang; Wang, Chih-Wei

    2009-01-01

    Breathing causes artefacts on PET/CT images. Cine CT has been used to reduce respiratory artefacts by acquiring multiple images during a single breathing cycle. The aim of this prospective study in non-small-cell lung cancer (NSCLC) patients was twofold. Firstly, we sought to compare the motion artefacts in PET/CT images attenuation-corrected with helical CT (HCT) and with averaged CT (ACT), which provides an average of cine CT images. Secondly, we wanted to evaluate the differences in maximum standardized uptake values (SUV max ) between HCT and ACT. Enrolled in the study were 80 patients with NSCLC. PET images attenuation-corrected with HCT (PET/HCT) and with ACT (PET/ACT) were obtained in all patients. Misregistration was evaluated by measurement of the curved photopenic area in the lower thorax of the PET images for all patients and direct measurement of misregistration for selected lesions. SUV max was measured separately at the primary tumours, regional lymph nodes, and background. A total of 80 patients with NSCLC were included. Significantly lower misregistrations were observed in PET/ACT images than in PET/HCT images (below-thoracic misregistration 0.25±0.58 cm vs. 1.17±1.17 cm, p max were noted in PET/ACT images than in PET/HCT images in the primary tumour (p max in PET/ACT images was higher by 0.35 for the main tumours and 0.34 for lymph nodes. Due to its significantly reduced misregistration, PET/ACT provided more reliable SUV max and may be useful in treatment planning and monitoring the therapeutic response in patients with NSCLC. (orig.)

  15. Non-small-cell lung cancer resectability: diagnostic value of PET/MR

    International Nuclear Information System (INIS)

    Fraioli, Francesco; Menezes, Leon; Kayani, Irfan; Syed, Rizwan; O'Meara, Celia; Barnes, Anna; Bomanji, Jamshed B.; Punwani, Shonit; Groves, Ashley M.; Screaton, Nicholas J.; Janes, Samuel M.; Win, Thida; Zaccagna, Fulvio

    2015-01-01

    To assess the diagnostic performance of PET/MR in patients with non-small-cell lung cancer. Fifty consecutive consenting patients who underwent routine 18 F-FDG PET/CT for potentially radically treatable lung cancer following a staging CT scan were recruited for PET/MR imaging on the same day. Two experienced readers, unaware of the results with the other modalities, interpreted the PET/MR images independently. Discordances were resolved in consensus. PET/MR TNM staging was compared to surgical staging from thoracotomy as the reference standard in 33 patients. In the remaining 17 nonsurgical patients, TNM was determined based on histology from biopsy, imaging results (CT and PET/CT) and follow-up. ROC curve analysis was used to assess accuracy, sensitivity and specificity of the PET/MR in assessing the surgical resectability of primary tumour. The kappa statistic was used to assess interobserver agreement in the PET/MR TNM staging. Two different readers, without knowledge of the PET/MR findings, subsequently separately reviewed the PET/CT images for TNM staging. The generalized kappa statistic was used to determine intermodality agreement between PET/CT and PET/MR for TNM staging. ROC curve analysis showed that PET/MR had a specificity of 92.3 % and a sensitivity of 97.3 % in the determination of resectability with an AUC of 0.95. Interobserver agreement in PET/MR reading ranged from substantial to perfect between the two readers (Cohen's kappa 0.646 - 1) for T stage, N stage and M stage. Intermodality agreement between PET/CT and PET/MR ranged from substantial to almost perfect for T stage, N stage and M stage (Cohen's kappa 0.627 - 0.823). In lung cancer patients PET/MR appears to be a robust technique for preoperative staging. (orig.)

  16. A prognostic DNA methylation signature for stage I non-small-cell lung cancer.

    Science.gov (United States)

    Sandoval, Juan; Mendez-Gonzalez, Jesus; Nadal, Ernest; Chen, Guoan; Carmona, F Javier; Sayols, Sergi; Moran, Sebastian; Heyn, Holger; Vizoso, Miguel; Gomez, Antonio; Sanchez-Cespedes, Montse; Assenov, Yassen; Müller, Fabian; Bock, Christoph; Taron, Miquel; Mora, Josefina; Muscarella, Lucia A; Liloglou, Triantafillos; Davies, Michael; Pollan, Marina; Pajares, Maria J; Torre, Wenceslao; Montuenga, Luis M; Brambilla, Elisabeth; Field, John K; Roz, Luca; Lo Iacono, Marco; Scagliotti, Giorgio V; Rosell, Rafael; Beer, David G; Esteller, Manel

    2013-11-10

    Non-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard. A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC. Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high- and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001). The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.

  17. Tumor biomarker testing in non-small-cell lung cancer: A decade of change.

    Science.gov (United States)

    VanderLaan, Paul A; Rangachari, Deepa; Majid, Adnan; Parikh, Mihir S; Gangadharan, Sidharta P; Kent, Michael S; McDonald, Danielle C; Huberman, Mark S; Kobayashi, Susumu S; Costa, Daniel B

    2018-02-01

    Although a growing list of essential genomic/immune-based biomarkers are linked to approved non-small-cell lung cancer (NSCLC) therapies worldwide, few reports have detailed the evolution of NSCLC predictive biomarker assessment in routine clinical practice. We retrospectively reviewed the first one thousand plus NSCLC patient specimens from our institution analyzed for predictive biomarkers from 2004 to 2017 and evaluated patterns of testing as well as correlation with clinical-pathologic characteristics. The majority of 1009 NSCLC patients had advanced stages of adenocarcinoma with most tissues obtained from the lung, mediastinal/hilar nodes, or pleura. The majority of testing was performed on cytology or small biopsy specimens. All were tested for EGFR mutations, 895 for ALK rearrangement, 841 for KRAS mutation, 537 for ROS1 rearrangement, and 179 using comprehensive genomic profiling. Implementation of near-universal genomic biomarker testing at our institution for EGFR, ALK, ROS1 and PD-L1 all occurred within the first year following evidence of clinical activity or regulatory body approval of an associated inhibitor. The overall testing failure rate after use of the best specimen for the most common tests was ≤5.5%. A quarter of tumors had a driver oncogene identified (EGFR/ALK/ROS1/BRAF V600E) with an approved oral targeted therapy, with the highest prevalence in those patients with no or light (≤15 pack-years) history of tobacco use. Tumor biomarker testing using clinical NSCLC specimens in routine oncologic care evolves rapidly following approval of targeted therapies linked to diagnostic assays. Our practice's decade plus experience highlights the rapid evolution of biomarker testing and confirms the therapeutic relevance of such testing in all patients-particularly those patients with light/no history of tobacco use. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Comparative effectiveness of surgery and radiosurgery for stage I non-small cell lung cancer.

    Science.gov (United States)

    Yu, James B; Soulos, Pamela R; Cramer, Laura D; Decker, Roy H; Kim, Anthony W; Gross, Cary P

    2015-07-15

    Although surgery is the standard treatment for early-stage non-small cell lung cancer (NSCLC), stereotactic body radiotherapy (SBRT) has been disseminated as an alternative therapy. The comparative mortalities and toxicities of these treatments for patients of different life expectancies are unknown. The Surveillance, Epidemiology, and End Results-Medicare linked database was used to identify patients who were 67 years old or older and underwent SBRT or surgery for stage I NSCLC from 2007 to 2009. Matched patients were stratified into short life expectancies (treatment, there was no difference (69.7% vs 73.9%, P = .31). The incidence rate ratio (IRR) for toxicity from SBRT versus surgery was 0.74 (95% confidence interval [CI], 0.64-0.87). Overall mortality was lower with SBRT versus surgery at 3 months (2.2% vs 6.1%, P = .005), but by 24 months, overall mortality was higher with SBRT (40.1% vs 22.3%, P lung cancer mortality (IRR, 1.01; 95% CI, 0.40-2.56). However, for patients with long life expectancies, there was greater overall mortality (IRR, 1.49; 95% CI, 1.11-2.01) as well as a trend toward greater lung cancer mortality (IRR, 1.63; 95% CI, 0.95-2.79) with SBRT versus surgery. SBRT was associated with lower immediate mortality and toxicity in comparison with surgery. However, for patients with long life expectancies, there appears to be a relative benefit from surgery versus SBRT. © 2015 American Cancer Society.

  19. Role of anaplastic lymphoma kinase inhibition in the treatment of non-small-cell lung cancer.

    Science.gov (United States)

    Croegaert, Katie; Kolesar, Jill M

    2015-09-01

    Published data on the clinical efficacy, safety, dosage and administration, and costs of the anaplastic lymphoma kinase (ALK) inhibitors crizotinib and ceritinib in the treatment of non-small-cell lung cancer (NSCLC) are reviewed and compared. The ALK protein functions as a transmembrane receptor tyrosine kinase; rearrangements of the ALK gene are associated with the development of NSCLC with adenocarcinoma histology. Crizotinib is an oral tyrosine kinase inhibitor approved in 2011 as a first-line therapy for patients with metastatic ALK mutation-driven NSCLC. Significantly improved response rates and progression-free survival (PFS) have been reported with the use of crizotinib therapy versus standard chemotherapy, but mutations conferring resistance to treatment develop in most cases. The second-generation ALK inhibitor ceritinib was approved in 2014 for the treatment of ALK-mutated NSCLC in patients who are intolerant or develop resistance to crizotinib. In a clinical trial of ceritinib involving 130 patients with ALK-positive NSCLC, the majority of whom had experienced disease progression during crizotinib use, patients receiving at least 400 mg of ceritinib daily had an overall response rate of 56% and median PFS of seven months. Adverse effects commonly reported with the use of either drug include visual disturbances, gastrointestinal disorders (e.g., diarrhea), and liver enzyme abnormalities. The tyrosine kinase inhibitors crizotinib and ceritinib provide an effective treatment approach for patients with ALK-mutated NSCLC. Efficacy data for both crizotinib and ceritinib indicate improved response rates and PFS with the use of either drug as an alternative to standard chemotherapy. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  20. Detection of ROS1 rearrangement in non-small cell lung cancer: current and future perspectives

    Directory of Open Access Journals (Sweden)

    Rossi G

    2017-07-01

    Full Text Available Giulio Rossi,1 Genny Jocollé,2 Antonia Conti,3 Marcello Tiseo,4 Federica Zito Marino,5,6 Giovanni Donati,7 Renato Franco,5,6 Francesca Bono,8 Francesca Barbisan,9 Francesco Facchinetti4,10 1Pathology Unit, 2Oncology Unit, Azienda USL Valle d’Aosta, Regional Hospital “Parini”, Aosta, 3Medical Illustrator, Riccione, 4Medical Oncology Unit, University Hospital of Parma, Parma, 5Pathology Unit, Istituto Nazionale Tumori Fondazione G. Pascale, 6Pathology Unit, Luigi Vanvitelli University of Campania, Naples, 7Unit of Thoracic and Senology Surgery, Azienda USL Valle d’Aosta, Regional Hospital “Parini”, Aosta, 8Unit of Pathologic Anatomy, San Gerardo Hospital, IRCCS, Monza, 9Pathology Unit, University Hospital, Azienda Ospedali Riuniti, Ancona, Italy; 10INSERM, U981, Gustave Roussy Cancer Campus, Villejuif, France Abstract: ROS1 rearrangement characterizes a small subset (1%–2% of non-small cell lung cancer and is associated with slight/never smoking patients and adenocarcinoma histology. Identification of ROS1 rearrangement is mandatory to permit targeted therapy with specific inhibitors, demonstrating a significantly better survival when compared with conventional chemotherapy. Detection of ROS1 rearrangement is based on in situ (immunohistochemistry, fluorescence in situ hybridization and extractive non-in situ assays. While fluorescence in situ hybridization still represents the gold standard in clinical trials, this technique may fail to recognize rearrangements of ROS1 with some gene fusion partner. On the other hand, immunohistochemistry is the most cost-effective screening technique, but it seems to be characterized by low specificity. Extractive molecular assays are expensive and laborious methods, but they specifically recognize almost all ROS1 fusions using a limited amount of mRNA even from formalin-fixed, paraffin-embedded tumor tissues. This review is a discussion on the present and futuristic diagnostic scenario of ROS1

  1. Quality of life after palliative radiotherapy in non-small cell lung cancer: a prospective study

    International Nuclear Information System (INIS)

    Langendijk, J.A.; Velde, G.P.M. ten; Aaronson, N.K.; Jong, J.M.A. de; Muller, M.J.; Wouters, E.F.M.

    2000-01-01

    Purpose: The purpose of this study was to investigate changes in respiratory symptoms and quality of life (QoL) in patients with locally advanced and metastatic non-small cell lung cancer (NSCLC) receiving thoracic radiotherapy. Additionally, the correlation between the level of symptom relief and objective tumor response was investigated. Methods and Materials: Sixty-five patients were entered in this prospective study. The EORTC QLQ-C30 and EORTC QLQ-LC13 were used to investigate changes in QoL. Assessments were performed before radiotherapy and 2 weeks, 6 weeks, and 3 months after radiotherapy. Results: The QoL response rates were excellent for hemoptysis (79%); good for arm/shoulder pain (56%), chest wall pain (53%), and cough (49%); moderate for dyspnea (39%); and minimal for the general symptoms fatigue (22%) and appetite loss (11%). The QoL response rates for the five functioning scales of the QLQ-C30 varied from 35% for role functioning to 57% for emotional functioning. Global QoL improved in 37% of the cases. In general, there was a tendency for better palliation of symptoms and improvement of QoL among patients with an objective tumor response than among those without objective tumor response, which was statistically significant for dyspnea (p = 0.02) and social functioning (p = 0.04). Conclusions: This study confirms that conventional thoracic radiotherapy offers palliation of respiratory symptoms and improved QoL in a substantial proportion of patients with locally advanced and metastatic NSCLC. Tumor reduction is only one of the mechanisms by which palliation of symptoms and improvement of QoL is achieved

  2. Does Lymph Node Count Influence Survival in Surgically Resected Non-Small Cell Lung Cancer?

    Science.gov (United States)

    David, Elizabeth A; Cooke, David T; Chen, Yingjia; Nijar, Kieranjeet; Canter, Robert J; Cress, Rosemary D

    2017-01-01

    The prognostic significance of the number of lymph nodes sampled (NLNS) during resection for non-small cell lung cancer (NSCLC) is unclear. The NLNS is influenced by many factors, and some have argued that it should be a surrogate for quality. We sought to determine the influence of the NLNS on overall survival and cancer-specific survival for surgically resected NSCLC. The California Cancer Registry was queried from 2004 to 2011 for cases of stage I to III NSCLC treated with surgical resection, identifying 16,393 patients. Kaplan-Meier and Cox proportional hazards modeling were used to determine the influence of NLNS on overall survival and cancer-specific survival. In all, 15,195 patients had information regarding nodal sampling. Eighty percent (13,167 of 15,195) were treated with lobectomy. Patients who were younger, male, non-Hispanic white, highest socioeconomic status, higher stage, or larger size tumor had more nodes removed. Sampling fewer than 10 nodes was associated with poorer overall survival when compared with sampling 10 or more nodes after adjustment for demographic and clinical factors for stage I: overall survival hazard ratio 1.78 (95% confidence interval: 1.54 to 2.05, p < 0.0001), hazard ratio 1.43 (95% confidence interval: 1.27 to 1.59, p < 0.0001), and hazard ratio 1.16 (95% confidence interval: 1.05 to 1.28, p = 0.004), for 0, 1 to 3, and 4 to 10 nodes, respectively. Of patients who underwent sublobar resection, 43.8% had no nodes sampled. For NSCLC, the NLNS influenced both overall survival and cancer-specific survival, but the influence is dependent on stage. Surgeons should perform mediastinal lymphadenectomy to maximize patient survival, but the optimal NLNS remains unclear. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  3. Analysis of Prognostic Factors in 541 Female Patients with Advanced Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Meina WU

    2011-03-01

    Full Text Available Background and objective As there is a sharp increase in the incidence of lung cancer in women in recent years, it has brought broad concerns with its unique clinical and epidemiological characteristics and better prognosis. The aim of this study is to analyze the clinical data of women with advanced non-small cell lung cancer (NSCLC retrospectively to explore the prognostic factors. Methods Clinical data of 541 female patients with advanced NSCLC were collected and followed up till death. The primary endpoint is overall survival (OS. SPSS 11.0 statistical analysis software was used for univariate and multivariate analysis. Results The mean age is 59 years (20 years-86 years, adenocarcinoma account for 80.2% (434/541. The median OS was 15 months (95%CI: 13.87-16.13, and 1, 2, 5-year survival rates were 58.8%, 23.7% and 3.20% respectively. Univariate analysis showed that clinical stage, ECOG score, weight loss, clinical symptoms, liver/bone/brain metastasis and received more than one chemotherapy regimen, good response to the first-line chemotherapy, EGFR-TKI targeted therapy and radiotherapy treatment were significantly correlated with the OS and survival rate (P < 0.05. Combined with multivariate analysis, weight loss before treatment, ECOG score, received EGFR-TKI targeted therapy and response to first-line chemotherapy were independent prognostic factor for survival (P < 0.05. Conclusion There is a higher percentage of adenocarcinoma in female NSCLC. Weight loss before treatment, ECOG score, EGFR-TKI targeted therapy and response to first-line chemotherapy may become independent prognostic factors for survival of female patients with advanced NSCLC.

  4. Advances in the Development of Molecularly Targeted Agents in Non-Small-Cell Lung Cancer.

    Science.gov (United States)

    Dolly, Saoirse O; Collins, Dearbhaile C; Sundar, Raghav; Popat, Sanjay; Yap, Timothy A

    2017-05-01

    Non-small-cell lung cancer (NSCLC) remains a significant global health challenge and the leading cause of cancer-related mortality. The traditional 'one-size-fits-all' treatment approach has now evolved into one that involves personalized strategies based on histological and molecular subtypes. The molecular era has revolutionized the treatment of patients harboring epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and ROS1 gene aberrations. In the appropriately selected population, anti-tumor agents against these molecular targets can significantly improve progression-free survival. However, the emergence of acquired resistance is inevitable. Novel potent compounds with much improved and rational selectivity profiles, such as third-generation EGFR T790M resistance mutation-specific inhibitors, have been developed and added to the NSCLC armamentarium. To date, attempts to overcome resistance bypass pathways through downstream signaling blockade has had limited success. Furthermore, the majority of patients still do not harbor known driver genetic or epigenetic alterations and/or have no new available treatment options, with chemotherapy remaining their standard of care. Several potentially actionable driver aberrations have recently been identified, with the early clinical development of multiple inhibitors against these promising targets currently in progress. The advent of immune checkpoint inhibitors has led to significant benefit for advanced NSCLC patients with durable responses observed. Further interrogation of the underlying biology of NSCLC, coupled with modern clinical trial designs, is now required to develop novel targeted therapeutics rationally matched with predictive biomarkers of response, so as to further advance NSCLC therapeutics through the next decade.

  5. Quality of Life After Stereotactic Radiotherapy for Stage I Non-Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Voort van Zyp, Noelle C. van der; Prevost, Jean-Briac; Holt, Bronno van der; Braat, Cora; Klaveren, Robertus J. van; Pattynama, Peter M.; Levendag, Peter C.; Nuyttens, Joost J.

    2010-01-01

    Purpose: To determine the impact of stereotactic radiotherapy on the quality of life of patients with inoperable early-stage non-small-cell lung cancer (NSCLC). Overall survival, local tumor control, and toxicity were also evaluated in this prospective study. Methods and Materials: From January 2006 to February 2008, quality of life, overall survival, and local tumor control were assessed in 39 patients with pathologically confirmed T1 to 2N0M0 NSCLC. These patients were treated with stereotactic radiotherapy. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 and the QLQ LC13 lung cancer-specific questionnaire were used to investigate changes in quality of life. Assessments were done before treatment, at 3 weeks, and at 2, 4, 6, 9, and 12 months after treatment, until death or progressive disease. Toxicity was evaluated using common terminology criteria for adverse events version 3.0. Results: Emotional functioning improved significantly after treatment. Other function scores and QLQ C30 and QLQ LC13 lung symptoms (such as dyspnea and coughing) showed no significant changes. The overall 2-year survival rate was 62%. After a median follow-up of 17 months, 1 patient had a local recurrence (3%). No grade 4 or 5 treatment-related toxicity occurred. Grade 3 toxicity consisted of thoracic pain, which occurred in 1 patient within 4 months of treatment, while it occurred thereafter in 2 patients. Conclusions: Quality of life was maintained, and emotional functioning improved significantly after stereotactic radiotherapy for stage I NSCLC, while survival was acceptable, local tumor control was high, and toxicity was low.

  6. Gene Polymorphisms and Chemotherapy in Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Kayo OSAWA

    2009-08-01

    Full Text Available The phamacogenetics is being used to predict whether the selected chemotherapy will be really effective and tolerable to the patient. Irinotecan, oxidized by CYP3A4 to produce inactive compounds, is used for treatment of various cancers including advanced non small cell lung cancer (NSCLC patients. CYP3A4*16B polymorphism was associated with decreased metabolism of irrinotecan. Irinotecan is also metabolized by carboxylesterase to its principal active metabolite, SN-38, which is subsequently glucuronidated by UGT1As to form the inactive compound SN-38G. UGT1A1*28 and UGT1A1*6 polymorphisms were useful for predicting severe toxicity with NSCLC patients treated with irinotecan-based chemotherapy. Platinum-based compounds (cisplatin, carboplatin are being used in combination with new cytotoxic drugs such as gemcitabine, paclitaxel, docetaxel, or vinorelbine in the treatment of advanced NSCLC. Cisplatin activity is mediated through the formation of cisplatin-DNA adducts. Gene polymorphisms of DNA repair factors are therefore obvious candidates for determinants of repair capacity and chemotherapy efficacy. ERCC1, XRCC1 and XRCC3 gene polymorphisms were a useful marker for predicting better survival in advanced NSCLC patients treated with platinum-based chemotherapy. XPA and XPD polymorphisms significantly increased response to platinum-based chemotherapy. These DNA repair gene polymorphisms were useful as a predictor of clinical outcome to the platinum-based chemotherapy. EGFR kinase inhibitors induce dramatic clinical responses in NSCLC patients with advanced disease. EGFR gene polymorphism in intron 1 contains a polymorphic single sequence dinucleotide repeat (CA-SSR showed a statistically significant correlation with the gefitinib response and was appeared to be a useful predictive marker of the development of clinical outcome containing skin rashes with gefitinib treatment. The other polymorphisms of EGFR were also associated with increased EGFR

  7. Impact of symptom burden in post-surgical non-small cell lung cancer survivors.

    Science.gov (United States)

    Lowery, Amy E; Krebs, Paul; Coups, Elliot J; Feinstein, Marc B; Burkhalter, Jack E; Park, Bernard J; Ostroff, Jamie S

    2014-01-01

    Pain, fatigue, dyspnea, and distress are commonly reported cancer-related symptoms, but few studies have examined the effects of multiple concurrent symptoms in longer-term cancer survivors. We examined the impact of varying degrees of symptom burden on health-related quality of life (HRQOL) and performance status in surgically treated non-small cell lung cancer (NSCLC) survivors. A sample of 183 NSCLC survivors 1-6 years post-surgical treatment completed questionnaires assessing five specific symptoms (pain, fatigue, dyspnea, depression, and anxiety), HRQOL, and performance status. The number of concurrent clinically significant symptoms was calculated as an indicator of symptom burden. Most survivors (79.8 %) had some degree of symptom burden, with 30.6 % reporting one clinically significant symptom, 27.9 % reporting two symptoms, and 21.3 % reporting three or more symptoms. Physical HRQOL significantly decreased as the degree of symptom burden increased, but mental HRQOL was only significantly decreased in those with three or more symptoms. Receiver-operating characteristic (ROC) curves showed that having multiple concurrent symptoms (two or more) was most likely associated with limitations in functioning (area under a ROC curve = 0.75, sensitivity = 0.81, specificity = 0.54). Two or more clinically significant symptoms are identified as the "tipping point" for showing adverse effects on HRQOL and functioning. This highlights the need for incorporating multiple-symptom assessment into routine clinical practice. Comprehensive symptom management remains an important target of intervention for improved post-treatment HRQOL and functioning among lung cancer survivors.

  8. Rapid Disease Progression With Delay in Treatment of Non-Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Mohammed, Nasiruddin; Kestin, Larry Llyn; Grills, Inga Siiner; Battu, Madhu; Fitch, Dwight Lamar; Wong, Ching-yee Oliver; Margolis, Jeffrey Harold; Chmielewski, Gary William; Welsh, Robert James

    2011-01-01

    Purpose: To assess rate of disease progression from diagnosis to initiation of treatment for Stage I-IIIB non-small-cell lung cancer (NSCLC). Methods and Materials: Forty patients with NSCLC underwent at least two sets of computed tomography (CT) and 18-fluorodeoxyglucose positron emission tomography (PET) scans at various time intervals before treatment. Progression was defined as development of any new lymph node involvement, site of disease, or stage change. Results: Median time interval between first and second CT scans was 13.4 weeks, and between first and second PET scans was 9.0 weeks. Median initial primary maximum tumor dimension (MTD) was 3.5 cm (0.6-8.5 cm) with a median standardized uptake value (SUV) of 13.0 (1.7-38.5). The median MTD increased by a median of 1.0 cm (mean, 1.6 cm) between scans for a median relative MTD increase of 35% (mean, 59%). Nineteen patients (48%) progressed between scans. Rate of any progression was 13%, 31%, and 46% at 4, 8, and 16 weeks, respectively. Upstaging occurred in 3%, 13%, and 21% at these intervals. Distant metastasis became evident in 3%, 13%, and 13% after 4, 8, and 16 weeks, respectively. T and N stage were associated with progression, whereas histology, grade, sex, age, and maximum SUV were not. At 3 years, overall survival for Stage III patients with vs. without progression was 18% vs. 67%, p = 0.05. Conclusions: With NSCLC, treatment delay can lead to disease progression. Diagnosis, staging, and treatment initiation should be expedited. After 4-8 weeks of delay, complete restaging should be strongly considered.

  9. Percutaneous cryoablation for the treatment of medically inoperable stage I non-small cell lung cancer.

    Directory of Open Access Journals (Sweden)

    Yoshikane Yamauchi

    Full Text Available BACKGROUND: To evaluate the midterm results of percutaneous cryoablation for medically inoperable stage I non-small cell lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: Between January 2004 and June 2010, 160 patients underwent computer tomography guided percutaneous cryoablation for lung tumors at our institution. Of these patients, histologically proven stage I lung cancer patients with more than one year of follow-up, were retrospectively reviewed. All of these patients were considered to be medically inoperable with Charlson comorbidity index of 3 or greater. Follow-up was based primarily on computed tomography. There were 22 patients with 34 tumors who underwent 25 sessions of cryoablation treatment. Complications were pneumothoraces in 7 treatments (28%, chest tube required in one treatment, and pleural effusions in 8 treatments (31%. The observation period ranged from 12-68 months, average 29±19 months, median 23 months. Local tumor progression was observed in one tumor (3%. Mean local tumor progression-free interval was 69±2 months. One patient died of lung cancer progression at 68 months. Two patients died of acute exacerbations of idiopathic pulmonary fibrosis which were not considered to be directly associated with cryoablation, at 12 and 18 months, respectively. The overall 2- and 3-year survivals were 88% and 88%, respectively. Mean overall survival was 62±4 months. Median overall survival was 68 months. The disease-free 2- and 3-year survivals were 78% and 67%, respectively. Mean disease-free survival was 46±6 months. Pulmonary function tests were done in 16 patients (18 treatments before and after cryoablation. Percentage of predicted vital capacity, and percentage of predicted forced expiratory volume in 1 second, did not differ significantly before and after cryoablation (93±23 versus 90±21, and 70±11 versus 70±12, respectively. CONCLUSIONS/SIGNIFICANCE: Although further accumulation of data is necessary regarding efficacy

  10. Lungscape: resected non-small-cell lung cancer outcome by clinical and pathological parameters.

    Science.gov (United States)

    Peters, Solange; Weder, Walter; Dafni, Urania; Kerr, Keith M; Bubendorf, Lukas; Meldgaard, Peter; O'Byrne, Kenneth J; Wrona, Anna; Vansteenkiste, Johan; Felip, Enriqueta; Marchetti, Antonio; Savic, Spasenija; Lu, Shun; Smit, Egbert; Dingemans, Anne-Marie; Blackhall, Fiona H; Baas, Paul; Camps, Carlos; Rosell, Rafael; Stahel, Rolf A

    2014-11-01

    The Lungscape project was designed to address the impact of clinical, pathological, and molecular characteristics on outcome in resected non-small- cell lung cancer (NSCLC). A decentralized biobank with fully annotated tissue samples was established. Selection criteria for participating centers included sufficient number of cases, tissue microarray building capability, and documented ethical approval. Patient selection was based on availability of comprehensive clinical data, radical resection between 2003 and 2009 with adequate follow-up, and adequate quantity and quality of formalin-fixed tissue. Fifteen centers contributed 2449 cases. The 5-year overall survival (OS) was 69.6% and 63.6% for stages IA and IB, 51.6% and 47.7% for stages IIA and IIB, and 29.0% and 13.0% for stages IIIA and IIIB, respectively (p < 0.001). Median and 5-year relapse-free survival (RFS) were 52.8 months and 47.3%, respectively. Distant relapse was recorded for 44.4%, local for 26.0%, and both for 16.9% of patients. Based on multivariate analysis for the OS, RFS, and time to relapse, the factors significantly associated with all of them are performance status and pathological stage. The aim of this report is to present the results from Lungscape, the first large series reporting on NSCLC surgical outcome measured not only by OS but also by RFS and time to relapse and including multivariate analysis by significant clinical and pathological prognostic parameters. As tissue from all patients is preserved locally and is available for detailed molecular investigations, Lungscape provides an excellent basis to evaluate the influence of molecular parameters on the disease outcome after radical resection, besides providing an overview of the molecular landscape of stage I to III NSCLC.

  11. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer.

    Science.gov (United States)

    Cardarella, Stephanie; Ogino, Atsuko; Nishino, Mizuki; Butaney, Mohit; Shen, Jeanne; Lydon, Christine; Yeap, Beow Y; Sholl, Lynette M; Johnson, Bruce E; Jänne, Pasi A

    2013-08-15

    BRAF mutations are found in a subset of non-small cell lung cancers (NSCLC). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations. Using DNA sequencing, we successfully screened 883 patients with NSCLC for BRAF mutations between July 1, 2009 and July 16, 2012. Baseline characteristics and treatment outcomes were compared between patients with and without BRAF mutations. Wild-type controls consisted of patients with NSCLC without a somatic alteration in BRAF, KRAS, EGFR, and ALK. In vitro studies assessed the biologic properties of selected non-V600E BRAF mutations identified from patients with NSCLC. Of 883 tumors screened, 36 (4%) harbored BRAF mutations (V600E, 18; non-V600E, 18) and 257 were wild-type for BRAF, EGFR, KRAS, and ALK negative. Twenty-nine of 36 patients with BRAF mutations were smokers. There were no distinguishing clinical features between BRAF-mutant and wild-type patients. Patients with advanced NSCLC with BRAF mutations and wild-type tumors showed similar response rates and progression-free survival (PFS) to platinum-based combination chemotherapy and no difference in overall survival. Within the BRAF cohort, patients with V600E-mutated tumors had a shorter PFS to platinum-based chemotherapy compared with those with non-V600E mutations, although this did not reach statistical significance (4.1 vs. 8.9 months; P = 0.297). We identified five BRAF mutations not previously reported in NSCLC; two of five were associated with increased BRAF kinase activity. BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC. ©2013 AACR.

  12. Treatment of advanced non small cell lung cancer with erlotinib. Two clinical cases.

    Science.gov (United States)

    Parente, Bárbara; Gomes, Joana; Nogueira, Carla; Ferreira, Diva; Neves, Sofia; Barroso, Ana; Conde, Sara; Machado, José Carlos

    2008-10-01

    Early studies with tirosine kinase inhibitors (TKI), namely Erlotinib and Gefitinib, in patients with non small cell lung cancer (NSCLC), showed that although most patients did not respond radiologically, a small percentage of those patients (about 10%) had an excellent response to treatment, with radiological regression and clinical response duration. Four patient populations are known as having better response to TKI as opposed to other patients: adenocarcinoma patients, non-smokers, women and asians. Nevertheless, a good general status remains a predictive factor for treatment response. The discovery of the EGFR mutation in NSCLC patients' tumors and its association with clinical response to Erlotinib and Gefitinib, confirmed by a considerable number of retrospective and prospective studies, showed that response rates are between 75-80% in patients carrying this mutation. Although several mutations have been identified, the two commonest (approximately 90%) are located in exons 19 and 21. The authors present two patients studied and treated at the Pulmonology Department's Lung Oncology Unit of CHVNGaia, where Erlotinib was used as 3(rd) line treatment: in one patient, which was part of the population with good response to TKI, a classic exon 19 was identified, and was treated with Erlotinib for twenty months with clinical stability; the other patient did not belong to the above mentioned population and an Exon 20 mutation was identified (a mutation not yet described in literature, being not clear its association with response to treatment with TKI) - treatment was stopped after 7.4months due to disease progression. Rev Port Pneumol 2008; XIV (Supl 3): S43-S51. © 2008 Sociedade Portuguesa de Pneumologia/SPP.

  13. Radiation therapy for elderly patients with limited non-small cell lung cancer

    International Nuclear Information System (INIS)

    Hayakawa, Kazushige; Mitsuhashi, Norio; Katano, Susumu

    1998-01-01

    The treatment results for 93 patients aged 75 years or older (elderly group) with limited non-small cell lung cancer (NSCLC) were retrospectively analyzed and compared with those for 193 patients younger than 75-years old (younger group). The elderly patients were classified into two groups: 64 patients aged 75-79 years (the elderly A) and 29 patients aged 80 years or older (the elderly B). All patients were treated with 10 MV X-rays using 2 Gy daily standard fractionation between 1976 and 1994. The total dose ranged from 60 Gy to 80 Gy. The overall two and five year survival rates were 31% and 12% for the elderly A group, and 28% and 6% for the elderly B group, respectively, compared with 34% and 12% for the younger group. In stage I-II NSCLC patients, the 2-year and 5-year disease-specific survival rates were 61% and 43% for the elderly A group, and 55% and 17% for the elderly B group, respectively, while the corresponding rates for younger group were 56% and 22%, respectively. In patients with stage III disease, however, the survival curves of the elderly B were inferior to those of the younger group and the elderly A group, although the difference was not statistically significant. Only two elderly patients died of late pulmonary insufficiency associated with high-dose irradiation of 80 Gy to the proximal bronchus. No other treatment-related event was observed except for mild acceptable acute complications in the elderly groups. The condition of two patients aged more than 80 years, however, deteriorated in mentality during hospitalization. Definitive radiation therapy is recommended to the elderly aged 75 years or older with limited NSCLC, especially early stage disease, as an acceptable choice or treatment. (K.H.)

  14. Pemetrexed in maintenance treatment of advanced non-squamous non-small-cell lung cancer.

    Science.gov (United States)

    Minami, Seigo; Kijima, Takashi

    2015-01-01

    Pemetrexed, a multitargeting antifolate cytotoxic drug, plays a leading role in front-line chemotherapy for patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Following its approval as second-line monotherapy for locally advanced or metastatic non-squamous NSCLC, pemetrexed has established itself as the first-line regimen in combination with cisplatin, and its powerful antitumor effects and less cumulative toxicities were then taken advantage of in the JMEN and PARAMOUNT trials, respectively, to pioneer a new treatment strategy of switch and continuation maintenance monotherapy. These developments have brought about a marked paradigm shift, and made pemetrexed indispensable in the treatment for non-squamous NSCLC. So far, only three drugs have been approved for maintenance therapy; pemetrexed both by switch and continuation maintenance, erlotinib by switch maintenance, and bevacizumab by continuation maintenance. Compared with observation alone after defined cycles of the first-line chemotherapy, subsequent pemetrexed maintenance therapy has provided significantly longer survival and infrequent severe adverse events. The cost-effectiveness of pemetrexed maintenance therapy is controversial, as well as the other two maintenance drugs, bevacizumab and erlotinib. The latest attractive attention is a combination maintenance therapy. We may have to consider epidermal growth factor receptor (EGFR) mutation status for selection of a combination pattern. A combination maintenance therapy of pemetrexed plus bevacizumab is potential for patients with wild-type EGFR status, while a EGFR tyrosine kinase inhibitor-containing combination is promising for patients with active EGFR mutation status. Pemetrexed will be a pivotal drug when a combination maintenance therapy is used in practice. For future maintenance therapy, we need to explore reliable predictive selection or exclusion markers that can predict who will really benefit from maintenance therapy.

  15. EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis.

    Science.gov (United States)

    Liu, Haidan; Li, Wei; Yu, Xinfang; Gao, Feng; Duan, Zhi; Ma, Xiaolong; Tan, Shiming; Yuan, Yunchang; Liu, Lijun; Wang, Jian; Zhou, Xinmin; Yang, Yifeng

    2016-08-30

    Polycomb group (PcG) proteins are highly conserved epigenetic effectors that maintain the silenced state of genes. EZH2 is the catalytic core and one of the most important components of the polycomb repressive complex 2 (PRC2). In non-small cell lung cancer (NSCLC) cells and primary lung tumors, we found that PRC2 components, including EZH2, are overexpressed. High levels of EZH2 protein were associated with worse overall survival rate in NSCLC patients. RNA interference mediated attenuation of EZH2 expression blunted the malignant phenotype in this setting, exerting inhibitory effects on cell proliferation, anchorage-independent growth, and tumor development in a xenograft mouse model. Unexpectedly, we discovered that, in the suppression of EZH2, p53 upregulated modulator of apoptosis (PUMA) expression was concomitantly induced. This is achieved through EZH2 directly binds to the Puma promoter thus epigenetic repression of PUMA expression. Furthermore, cisplatin-induced apoptosis of EZH2-knocking down NSCLC cells was elevated as a consequence of increased PUMA expression. Our work reveals a novel epigenetic regulatory mechanism controlling PUMA expression and suggests that EZH2 offers a candidate molecular target for NSCLC therapy and EZH2-regulated PUMA induction would synergistically increase the sensitivity to platinum agents in non-small cell lung cancers.

  16. Iron deficiency anemia as initial presentation of a non-small cell lung carcinoma: A case report

    NARCIS (Netherlands)

    P.V.M. Linsen (Philip V.M.); V.M.J. Linsen (Victor M.J.); G. Buunk (Gerba); D.E. Arnold (Dorothee E.); J.G.J.V. Aerts (Joachim)

    2015-01-01

    textabstractDuodenal metastases secondary to lung cancer are very rare and most of the time asymptomatic. When symptomatic they usually present with bowel obstruction or perforation. We here describe the case of a 68 year-old man with a solitary metastasis in the duodenum from a non-small cell lung

  17. Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer

    DEFF Research Database (Denmark)

    Rossi, Antonio; Chiodini, Paolo; Sun, Jong-Mu

    2014-01-01

    BACKGROUND: Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer. However, the optimum number of treatment cycles remains controversial. Therefore, we did a systematic review and meta-analysis of individual patient data to compare ...

  18. Long-Term Excess Mortality for Survivors of Non-small Cell Lung Cancer in the Netherlands

    NARCIS (Netherlands)

    Janssen-Heijnen, Maryska L.; van Steenbergen, Liza N.; Steyerberg, Ewout; Visser, Otto; De Ruysscher, Dirk K.; Groen, Harry J.

    Introduction: Most patients diagnosed with non-small cell lung cancer (NSCLC) die within the first few years after diagnosis. However, only little is known about those who have survived these first years. We aimed to study conditional 5-year relative survival rates for NSCLC patients during

  19. Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer

    DEFF Research Database (Denmark)

    Kim, Dong-Wan; Tiseo, Marcello; Ahn, Myung-Ju

    2017-01-01

    Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refra...

  20. Platinum based doublet cross over therapy for advanced stage non small cell lung cancer? A better survival option

    Directory of Open Access Journals (Sweden)

    Rajiv Garg

    2012-01-01

    Full Text Available Platinum based doublet chemotherapy namely the cisplatin/carboplatin based etopiside or gemcitabine therapy forms the therapy of choice, for patients with advanced non small cell carcinoma of the lung. Here we report two cases were unusual cross over was done from gemcitabine-to cisplatin-doublet chemotherapy resulting in unexpectedly better clinical and radiological response.

  1. Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop

    DEFF Research Database (Denmark)

    Pirker, Robert; Herth, Felix J F; Kerr, Keith M

    2010-01-01

    Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have recently been characterized in a subset of patients with advanced non-small cell lung cancer (NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyros...

  2. Concurrent versus Sequential Chemoradiotherapy with Cisplatin and Vinorelbine in Locally Advanced Non-Small Cell Lung Cancer: A Randomized Study

    Czech Academy of Sciences Publication Activity Database

    Zatloukal, P.; Petruželka, L.; Zemanová, M.; Havel, L.; Janků, F.; Judas, L.; Kubík, A.; Křepela, E.; Fiala, P.; Pecen, Ladislav

    2004-01-01

    Roč. 46, - (2004), s. 87-98 ISSN 0169-5002 Institutional research plan: CEZ:AV0Z1030915 Keywords : concurrent chemoradiotherapy * sequential chemoradiotherapy * locally advanced non-small cell lung cancer * cisplatin * vinorelbine Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 2.914, year: 2004

  3. A phase I study of gemcitabine with concurrent radiotherapy in stage III, locally advanced non-small cell lung cancer

    NARCIS (Netherlands)

    van Putten, JWG; Price, A; van der Leest, AHD; Gregor, A; Little, FA; Groen, HJM

    Purpose: Our goal was to find the maximum tolerated dose of gemcitabine administered concurrently with thoracic radiotherapy in locally advanced non-small cell lung cancer (NSCLC). Patients and Methods: Patients with stage III NSCLC and a radiation planning volume less than 2000 cm(3) were included.

  4. Feasibility of escalating daily doses of cisplatin in combination with accelerated radiotherapy in non-small cell lung cancer

    NARCIS (Netherlands)

    Schuster-Uitterhoeve, A. L.; van de Vaart, P. J.; Schaake-Koning, C. C.; Benraadt, J.; Koolen, M. G.; González González, D.; Bartelink, H.

    1996-01-01

    The aim of this study was to determine whether it is feasible to reduce the overall treatment time from 7 to 4 weeks in patients with non-small cell lung cancer (NSCLC) receiving radiotherapy with cisplatin. This follows an EORTC phase III randomised trial (08844) in which cisplatin given before

  5. 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...

  6. Intratumor heterogeneity and chemotherapy-induced changes in EGFR status in non-small cell lung cancer

    DEFF Research Database (Denmark)

    Jakobsen, Jan Nyrop; Sørensen, Jens Benn

    2012-01-01

    Biomarker expression is increasingly being used to customize treatment in non-small cell lung cancer (NSCLC). The choice of systemic treatment usually depends on biomarker expression in the initial diagnostic biopsy taken before initiation of first-line treatment. Chemotherapy induces DNA damages...

  7. Significance of plasma transforming growth factor-beta levels in radiotherapy for non-small-cell lung cancer

    NARCIS (Netherlands)

    De Jaeger, K; Seppenwoolde, Y; Kampinga, HH; Belderbos, JSA; Lebesque, JV

    2004-01-01

    Purpose: In dose-escalation studies of radiotherapy (RT) for non-small-cell lung cancer (NSCLC), radiation pneumonitis (RP) is the most important dose-limiting complication. Transforming growth factor-beta1 (TGF-beta1) has been reported to be associated with the incidence of RP. It has been proposed

  8. Management of crizotinib therapy for ALK-rearranged non-small cell lung carcinoma : An expert consensus

    NARCIS (Netherlands)

    Cappuzzo, Federico; Moro-Sibilot, Denis; Gautschi, Oliver; Boleti, Ekaterini; Felip, Enriqueta; Groen, Harry J. M.; Germonpre, Paul; Meldgaard, Peter; Arriola, Edurne; Steele, Nicola; Fox, Jesme; Schnell, Patrick; Engelsberg, Arne; Wolf, Juergen

    Within 4 years of the discovery of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC), the ALK inhibitor crizotinib gained US and European approval for the treatment of advanced ALK-positive NSCLC. This was due to the striking response data observed with crizotinib

  9. [Expression and significance of E-cadherin, CD44v6, and proliferating cell nuclear antigen in non-small cell lung cancer].

    Science.gov (United States)

    Weng, Mi-Xia; Wu, Cui-Huan; Yang, Xiu-Ping

    2008-02-01

    E-cadherin (E-cad), CD44v6 and proliferating cell nuclear antigen (PCNA) play important roles in invasion and metastasis of cancers. This study was to investigate the correlations of the expression of E-cad, CD44v6, and PCNA to the invasion, metastasis, and prognosis of non-small cell lung cancer (NSCLC). The expression of E-cad, CD44v6 and PCNA in 86 specimens of NSCLC and 40 specimens of adjacent normal tissues were detected by EnVision immunohistochemistry. The high expression rate of E-cad was significantly lower in NSCLC than in adjacent normal tissues (53.5% vs. 80.0%, Pcad staining in NSCLC tissues was correlated to differentiation, lymph node metastasis and TNM stage (Pcad expression (r=-0.554, Pcad, CD44v6, and PCNA were prognostic factors of NSCLC. Multivariate analysis showed that E-cad and TNM stage were independent prognostic indicators (Pcad, CD44v6 and PCNA play important roles in invasion and metastasis of NSCLC. The expression of E-cad, CD44v6 and PCNA may be of prognostic value in patients with NSCLC.

  10. Pembrolizumab in the treatment of metastatic non-small-cell lung cancer: patient selection and perspectives

    Directory of Open Access Journals (Sweden)

    Somasundaram A

    2017-01-01

    Full Text Available Ashwin Somasundaram, Timothy F Burns Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA Abstract: Lung cancer is the leading killer of both men and women in the US, and the 5-year survival remains poor. However, the approval of checkpoint blockade immunotherapy has shifted the treatment paradigm and provides hope for improved survival. The ability of non-small-cell lung cancer (NSCLC to evade the host immune system can be overcome by agents such as pembrolizumab (MK-3475/lambrolizumab, which is a monoclonal antibody targeting the programmed death 1 (PD-1 receptor. In early studies, treatment with pembrolizumab led to dramatic and durable responses in select patients (PD-L1+ tumors. This remarkable efficacy lead to approval of pembrolizumab in the second-line setting as response rates were almost doubled compared to standard of care (SOC chemotherapy. Most recently, data in the first-line setting from the KEYNOTE-024 study have redefined the SOC therapy for a selected subset of patients. In patients with ≥50% PD-L1+ tumors, pembrolizumab had a clear progression-free survival and overall survival benefit. Toxicity was mostly immune related and similar to checkpoint blockade toxicities observed in previous studies. The initial approval and subsequent studies of pembrolizumab required and utilized a companion diagnostic test, Dako’s IHC 22C3, to assess PD-L1 status of patients. The evaluation and scoring system of this assay has been used by other companies as a reference to develop their own assays, which may complicate selection of patients. Finally, the impact of pembrolizumab in NSCLC is growing as evidenced by the numerous, ongoing trials open for combinations with chemotherapy, chemoradiation, other immunotherapeutics, immunomodulators, tyrosine kinase inhibitors, PI3K inhibitors, MEK inhibitors, hypomethylating agents, and histone deacetylase inhibitors. Further studies

  11. [Role of SOX4 on DDP Resistance in Non-small Cell Lung Cancer Cell of A549].

    Science.gov (United States)

    Li, Wei; Liu, Xu; Zhang, Guoqian; Zhang, Linlin

    2017-05-20

    Lung cancer is one of the most serious disease and the incidence of non-small cell lung cancer (NSCLC) is the highest in lung cancer. The main reason for the failure of chemotherapy is the tolerance to cisplatin. Transcriptional regulator SOX4 plays an important role in the occurrence and development of many tumors, and regulates Wnt signaling pathway by regulating the expression of β-catenin. We aimed to investigate the role of SOX4 on cisplatin-resistance in NSCLC cell A549 cell. The cisplatin-resistance lung cancer cell line A549/DDP was constructed by induction method in vitro, and cisplatin-resistance detected by CCK8 assay. Growth curves of A549 and A549/DDP was calculated. The expression level of SOX4 in A549 and A549/DDP cells were detected by Western blot. A549/DDP were knockdown of SOX4 by siRNA transfection, and the cisplatin-resistance of detected by CCK-8 assay, the expression level of β-catenin and Survivin were detected by real-time PCR and Western blot. The cisplatin-resistance cell line A549/DDP was constructed successfully, and its cisplatin-resistance is 13.7 times higher than in A549. There was no significance difference between A549 and A549/DDP in cell proliferation. The expression level of SOX4 is higher in A549/DDP than in A549. The cisplatin-resistance significantly decreased in A549/DDP cells after knockdown of SOX4 by siRNA transfection. The expression level of β-catenin and Survivin significantly decreased in A549/DDP cells after knockdown of SOX4. SOX4 can strengthen cisplatin-resistance of non-small cell lung cancer cell A549.
.

  12. Role of SOX4 on DDP Resistance in Non-small Cell Lung Cancer Cell of A549

    OpenAIRE

    Wei LI; Xu LIU; Guoqian ZHANG; Linlin ZHANG

    2017-01-01

    Background and objective Lung cancer is one of the most serious disease and the incidence of non-small cell lung cancer (NSCLC) is the highest in lung cancer. The main reason for the failure of chemotherapy is the tolerance to cisplatin. Transcriptional regulator SOX4 plays an important role in the occurrence and development of many tumors, and regulates Wnt signaling pathway by regulating the expression of β-catenin. We aimed to investigate the role of SOX4 on cisplatin-resistance in NSCLC c...

  13. Immune modulations during chemoimmunotherapy & novel vaccine strategies - In metastatic melanoma and non small-cell lung cancer

    DEFF Research Database (Denmark)

    Iversen, Trine Zeeberg

    2013-01-01

    This thesis describes the treatment of metastatic melanoma (MM) and non small-cell lung cancer (NSCLC) from an immunotherapeutic approach. The purpose of the first part of the thesis was to assess how treatment with Temozolomide (TMZ) chemotherapy affects the immune system in patients with metast......This thesis describes the treatment of metastatic melanoma (MM) and non small-cell lung cancer (NSCLC) from an immunotherapeutic approach. The purpose of the first part of the thesis was to assess how treatment with Temozolomide (TMZ) chemotherapy affects the immune system in patients...... of the vaccine IDO-specific CD8+ T cells at pre-treatment was significanctly increased. Moreover, low-frequent IDO positive tetramer CD8+ T cells were detected and led to effective killing of an IDO+ HLA-A2 positive cancer cell line (SW480) in 1 patient. Moreover, flow cytometry was performed and in general...

  14. BRCA1: a novel prognostic factor in resected non-small-cell lung cancer.

    Science.gov (United States)

    Rosell, Rafael; Skrzypski, Marcin; Jassem, Ewa; Taron, Miquel; Bartolucci, Roberta; Sanchez, Jose Javier; Mendez, Pedro; Chaib, Imane; Perez-Roca, Laia; Szymanowska, Amelia; Rzyman, Witold; Puma, Francesco; Kobierska-Gulida, Grazyna; Farabi, Raffaele; Jassem, Jacek

    2007-11-07

    Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1). We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04). Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy

  15. Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Mattsson, Johanna S. M.; Brunnström, Hans; Jabs, Verena; Edlund, Karolina; Jirström, Karin; Mindus, Stephanie; Fleur, Linnéa la; Pontén, Fredrik; Karlsson, Mats G.; Karlsson, Christina; Koyi, Hirsh; Brandén, Eva; Botling, Johan; Helenius, Gisela; Micke, Patrick; Svensson, Maria A.

    2016-01-01

    Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data. ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients. ALK rearrangements were detected in 1.7 % in the complete cohort and 2.0 % in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.8 and 1.4 % when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (> 98 %), while the sensitivity was between 69 % (Ventana) and 62 % (in house Dako protocol). Furthermore, only 67 % of the ALK IHC positive cases were positive with both IHC assays. Gene expression analysis revealed that 6/194 (3 %) tumors showed high ALK gene expression (≥ 6 AU) and of them only three were positive by either FISH or IHC. The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC. The online version of this article (doi:10.1186/s12885-016-2646-x) contains

  16. A Systematic Overview of Radiation Therapy Effects in Non-Small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Sirzen, Florin; Kjellen, Elisabeth; Soerenson, Sverre; Cavallin-Staahl, Eva

    2003-01-01

    A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately. This synthesis of the literature on radiation therapy for non-small cell lung cancer (NSCLC) is based on data from 4 meta-analyses and 31 randomized trials. Moreover, data from 12 prospective studies, 12 retrospective studies and 6 other articles were used. In total, 65 scientific articles are included, involving 18,310 patients. The results were compared with those of a similar overview from 1996 including 28,172 patients. The conclusions reached can be summarized as follows: Extensive clinical experience indicates that radiotherapy for medically inoperable patients or patients refusing surgery with NSCLC stage I/II prolongs survival, 15-20% of these patients reaching long-term (5-year) survival. However, no randomized trials have addressed this issue. There is strong evidence that postoperative radiotherapy in radically resected stage I/II NSCLC does not prolong survival compared with observation alone. There is some evidence that continuous hyperfractionated accelerated radiotherapy (CHART) is associated with increased survival compared to conventional radiotherapy in locally advanced NSCLC and also in medically unfit patients with stage I/II NSCLC. However, the benefit is limited to squamous cell histology. There is strong evidence that combined modality treatment with platinum-based chemotherapy and radiotherapy, either neoadjuvant or concomitant, is superior to radiotherapy alone in terms of survival in locally advanced unresectable NSCLC and should be the standard of care in patients with good performance status. There is some evidence that concomitant chemo-radiotherapy is associated with increased survival compared with sequential chemo-radiotherapy, albeit at the price of increased toxicity. Comment: Combined chemo

  17. A Systematic Overview of Radiation Therapy Effects in Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Sirzen, Florin [Karolinska Hospital, Stockholm (Sweden). Dept. of Oncology; Kjellen, Elisabeth; Soerenson, Sverre; Cavallin-Staahl, Eva

    2003-09-01

    A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately. This synthesis of the literature on radiation therapy for non-small cell lung cancer (NSCLC) is based on data from 4 meta-analyses and 31 randomized trials. Moreover, data from 12 prospective studies, 12 retrospective studies and 6 other articles were used. In total, 65 scientific articles are included, involving 18,310 patients. The results were compared with those of a similar overview from 1996 including 28,172 patients. The conclusions reached can be summarized as follows: Extensive clinical experience indicates that radiotherapy for medically inoperable patients or patients refusing surgery with NSCLC stage I/II prolongs survival, 15-20% of these patients reaching long-term (5-year) survival. However, no randomized trials have addressed this issue. There is strong evidence that postoperative radiotherapy in radically resected stage I/II NSCLC does not prolong survival compared with observation alone. There is some evidence that continuous hyperfractionated accelerated radiotherapy (CHART) is associated with increased survival compared to conventional radiotherapy in locally advanced NSCLC and also in medically unfit patients with stage I/II NSCLC. However, the benefit is limited to squamous cell histology. There is strong evidence that combined modality treatment with platinum-based chemotherapy and radiotherapy, either neoadjuvant or concomitant, is superior to radiotherapy alone in terms of survival in locally advanced unresectable NSCLC and should be the standard of care in patients with good performance status. There is some evidence that concomitant chemo-radiotherapy is associated with increased survival compared with sequential chemo-radiotherapy, albeit at the price of increased toxicity. Comment: Combined chemo

  18. Assessment of the efficacy and safety of bronchial artery perfusion chemotherapy combined with high-frequency hyperthermia for advanced non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Jia-Cheng Zhang

    2017-06-01

    Full Text Available Objective: To study the efficacy and safety of bronchial artery perfusion chemotherapy combined with high-frequency hyperthermia for advanced non-small cell lung cancer. Methods: Patients with advanced non-small cell lung cancer who were treated in Navy General Hospital between May 2014 and October 2016 were selected and randomly divided into two groups, the observation group received bronchial arterial infusion chemotherapy combined with high-frequency hyperthermia, and the control group received bronchial arterial infusion chemotherapy. Before and after treatment, the expression of tumor activity indexes and liver and kidney function indexes in serum as well as and proliferation and invasion genes in tumor lesions were detected respectively. Results: 5 d and 7 d after treatment, serum CEA, MIF, CYFRA21-1 and HE4 levels of both groups of patients were significantly lower than those before treatment and serum CEA, MIF, CYFRA21-1 and HE4 levels of observation group were significantly lower than those of control group; 7 d after treatment, MEF2D, c-myc, Survivin, Bcl-2, Vimentin, N-cadherin and Slug expression in tumor lesions of both groups of patients were significantly lower than those before treatment and MEF2D, c-myc, Survivin, Bcl-2, Vimentin, N-cadherin and Slug expression in tumor lesions of observation group were significantly lower than those of control group; serum Scr, BUN, ALT and AST levels were not significantly different between two groups of patients before and after treatment. Conclusion: Bronchial artery perfusion chemotherapy combined with high-frequency hyperthermia for advanced non-small cell lung cancer can significantly inhibit the tumor proliferation and invasion and is with ideal safety.

  19. Over-expressed RPL34 promotes malignant proliferation of non-small cell lung cancer cells.

    Science.gov (United States)

    Yang, Shaoxing; Cui, Jian; Yang, Yingshun; Liu, Zhaoping; Yan, Haiying; Tang, Chuanhao; Wang, Hong; Qin, Haifeng; Li, Xiaoyan; Li, Jianjie; Wang, Weixia; Huang, Yuqing; Gao, Hongjun

    2016-01-15

    Ribosomal protein L34 (RPL34) was reported to be involved in the regulation of cell proliferation of prokaryotes, plant and animal cells. In the present study, we analyze the expression and function of RPL34 in NSCLC. Immunohistochemical analysis, qPCR and Western blot were used to detect the expression of RPL34 in NSCLC tissues and cells lines. Flow cytometry was used to detect cell activity of NSCLC cell line H1299 under lentivirus-mediated RNAi on RPL34. Cell proliferation and colony formation assays were used to analyze the role of RPL34 in NSCLC cell proliferation. We found that expression of ribosomal protein RPL34 was significantly up-regulated in NSCLC tissues compared to adjacent normal tissues. Lentivirus-mediated shRNA knockdown of RPL34 in NSCLC cell line H1299 resulted in a strong decrease of proliferation, and a moderate but significant increase of apoptosis and S-phase arrest. These data indicate that over-expressed RPL34 may promote malignant proliferation of NSCLC cells, thus playing an important role in development and progress of NSCLC. Copyright © 2015. Published by Elsevier B.V.

  20. Possible application of circulating free tumor DNA in non-small cell lung cancer patients.

    Science.gov (United States)

    Karachaliou, Niki; Sosa, Aaron E; Molina, Miguel Angel; Centelles Ruiz, Margarita; Rosell, Rafael

    2017-10-01

    Liquid biopsies have been heralded as a game changer in cancer management. Blood tests offer a minimally invasive, safe and sensitive complementary (or even alternative) approach for tissue biopsies. With lung cancer being the second most commonly diagnosed cancer and the leading cause of cancer deaths worldwide, due to the limitations of tissue sampling, liquid biopsies must urgently materialize in the clinic. In this short review, we will present the current applications of cell-free DNA (cfDNA) in lung cancer management, emphasizing on our own experience and previous work. We will also shortly comment on the challenges and need for a coordinated collaboration combining disciplines and sectors (from academia to health economies) in order to accelerate liquid biopsy development in lung cancer and other cancers.

  1. Etoposide (VP-16) sensitizes p53-deficient human non-small cell lung cancer cells to caspase-7-mediated apoptosis.

    Science.gov (United States)

    Chiu, C-C; Lin, C-H M Y; Fang, K

    2005-05-01

    Human non-small-cell-lung-cancer (NSCLC) cells of (p)53-null genotype were exposed to low-dosage topoisomearse II inhibitor etoposide (VP-16). The cellular proliferation rate could be effectively inhibited by VP-16 in dose-dependent manner. The effective drug concentration for growth inhibition could be as low as 0.5 microM and the apoptotic phenotype became evident 48 h later. In H1299 cells, VP-16-induced cytotoxic effect was demonstrated associated with apoptosis that disappeared when restored with wild-type p53. Cell cycle analysis revealed that, upon VP-16 induction, cell death began with growth arrest by accumulating cells at the G(2)-M phase. The cells at sub-G(1) phase increased at the expense of those at G(2)-M transition state. To assess the regulation of cell cycle modulators, western blot analysis of H1299 cell lysates showed the release of apoptosis initiator, cytochrome c and apaf-1 hours following drug induction. The cleavage of downstream effectors, procaspase-9 and procaspase-7, but not procaspase-3, was accompanied with proteolysis of poly-(ADP-ribose) polymerase (PARP). VP-16-activated procaspase-7 cleavage was abrogated in cells with ectopically expressed p53. On the other hand, the inhibited procaspase-7 fragmentation by caspase-specific inhibitor reversed apoptotic phenotype caused by drug induction. Thus, VP-16-induced apoptotic cell death was contributed by caspase-7 activation in(p)53-deficient human NSCLC cells.

  2. Prognostic indices in stereotactic radiotherapy of brain metastases of non-small cell lung cancer.

    Science.gov (United States)

    Kaul, David; Angelidis, Alexander; Budach, Volker; Ghadjar, Pirus; Kufeld, Markus; Badakhshi, Harun

    2015-11-26

    Our purpose was to analyze the long-term clinical outcome and to identify prognostic factors after Linac-based stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) on patients with brain metastases (BM) from non-small cell lung cancer (NSCLC). We performed a retrospective analysis of survival on 90 patients who underwent SRS or FSRT of intracranial NSCLC metastases between 04/2004 and 05/2014 that had not undergone prior surgery or whole brain radiotherapy (WBRT) for BM. Follow-up data was analyzed until May 2015. Potential prognostic factors were examined in univariable and multivariable analyses. The Golden Grading System (GGS), the disease-specific graded prognostic assessment (DS-GPA), the RADES II prognostic index as well as the NSCLC-specific index proposed by Rades et al. in 2013 (NSCLC-RADES) were calculated and their predictive values were tested in univariable analysis. The median follow-up time of the surviving patients was 14 months. The overall survival (OS) rate was 51 % after 6 months and 29.9 % after 12 months. Statistically significant factors of better OS after univariable analysis were lower International Union Against Cancer (UICC) stage at first diagnosis, histology of adenocarcinoma, prior surgery of the primary tumor and lower total BM volume. After multivariable analysis adenocarcinoma histology remained a significant factor; higher Karnofsky Performance Score (KPS) and the presence of extracranial metastases (ECM) were also significant. The RADES II and the NSCLC-RADES indices were significant predictors of OS. However, the NSCLC-RADES failed to differentiate between intermediate- and low-risk patients. The DS-GPA and GGS were not statistically significant predictors of survival in univariable analysis. The ideal prognostic index has not been defined yet. We believe that more specific indices will be developed in the future. Our results indicate that the histologic subtype of NSCLC could add to the prognostic

  3. Serum proteomic patterns of patients with non-small cell lung cancer treated by radiochemotherapy

    International Nuclear Information System (INIS)

    Li Xianglan; You Qingshan; Yang Yanmei; Ma Yuyan; Tang Yali; Cai Huilong

    2007-01-01

    Objective:To detect the serum proteomic patterns of patients with non-small cell lung (NSCLC) treated with radiochemotherapy by surface enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF-MS) protein chip array techniques, and to screen differential expression protein and observe the changes between the patterns before and after the treatment. Methods: SELDI-TOF-MS and CM-10 protein chips were used to detect the serum proteomic patterns of 35 healthy persons (normal control) and 35 patients with NSCLC before radiochemotherapy. Twenty-six out of the 35 patients after the treatment were also studied. BioMarker Wizard 3.01 and BioMarker Pattern System 5. 01 were used in combination to analyze the data and to develop diagnostic models. Results: Sixteen differential expression protein peaks from a total of 251 protein peaks were automatically chosen, including 8 high expressions and 8 low expressions in patients with NSCLC. Of the 16 protein peaks, 6 protein peak patterns ( M 2 572.1, M 2 885.8, M 3 870.4, M 4 161.4, M 5 739.7 and M 8 164.3 mass/charge ratio [ m/z] ) were observed in model that could be used to distinguish lung cancer' from non-cancer diseases. The sensitivity and specificity results were 91% (32/35)and 83% (29/35). When the SELDI marker pattern was tested with the blinded test set, the sensitivity and specificity were 80% (28/35) and 71% (25/35). The 16 differential expression protein peaks of patients before and after the treatment were obviously different. But the peaks of patients after the treatment trended to those of the normal control. Of the 16 protein peaks, M 2 572.1, M 2 885.8, M 4 664.78, M 9 228.39 and M 9 396.42 were significantly changed. Conclusions: SELDI-TOF-MS is possibly significant for screening differential expression proteins and assessing the treatment efficacy and prognosis of patients, which needs to be demonstrated by further study. (authors)

  4. Targeted therapies in development for non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Thanyanan Reungwetwattana

    2013-01-01

    Full Text Available The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC, the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2], RAS (rat sarcoma gene, BRAF (v-raf murine sarcoma viral oncogene homolog B1, MAPK (mitogen-activated protein kinase c-MET (c-mesenchymal-epithelial transition, FGFR (fibroblast growth factor receptor, DDR2 (discoidin domain receptor 2, PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha, PTEN (phosphatase and tensin homolog, AKT (protein kinase B, ALK (anaplastic lym phoma kinase, RET (rearranged during transfection, ROS1 (reactive oxygen species 1 and EPH (erythropoietin-producing hepatoma are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and

  5. Quality of life in patients with non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Šarac Sanja

    2017-01-01

    Full Text Available Background/Aim. As lung cancer is considered the greatest contributor to death among all cancer types any help might be valuable in the assessment of treatment effects. The aim of this study was for assess the quality of life (QoL in patients with non-small cell lung cancer (NSCLC treated with gemcitabine- cisplatin regimen as the first line of chemotherapy. Methods. The QoL was assessed using certified Serbian translations of the European Organization for Research and Treatment of Cancer Quality Life Questionnaire Core 30 (EORTC QLQ-C30 and Lung Cancer Module (QLQ-LC13 - version 3. The questionnaire was used before starting treatment and after the completion of the 2nd and the 4th cycle of chemotherapy. The questionnaire scales and single items were compared in order to assess the impact of treatment on the QoL. Results. A total of 60 patients started and 51 completed all questionnaires. There were no changes in the global health status score between the baseline, the 2nd and the 4th cycle of chemotherapy (42.78 ± 15.76, 45.56 ± 17.59, 48.20 ± 19.24, respectively; p = 0.1. Social function score, symptom scores: nausea and vomiting, pain, appetite loss, constipation, diarrhea and financial difficulties score differed significantly among chemotherapy cycles, indicating improved or worsened the QoL. In the lung cancer symptom score a significant difference between measurements was observed in cough, alopecia, chest pain and in using analgesics. Conclusion. Monitoring of changes in the QoL among patients with locally advanced and metastatic NSCLC showed that chemotherapy did not decrease the global health status but led to significant changes in the social and financial functioning of patients. Some symptoms associated with the disease reduced in the intensity but some new occurred as a result of chemotherapy. Using questionnaires to assess the QoL helped in easier identification of adverse effects and specific problems for adequate treatment.

  6. Potential clinical predictors of outcome after postoperative radiotherapy of non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Buetof, R. [Medical Faculty and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Department of Radiation Oncology, Dresden (Germany); Medical Faculty and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, OncoRay National Center for Radiation Research in Oncology, Dresden (Germany); Kirchner, K.; Appold, S. [Medical Faculty and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Department of Radiation Oncology, Dresden (Germany); Loeck, S. [Medical Faculty and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, OncoRay National Center for Radiation Research in Oncology, Dresden (Germany); Rolle, A. [Lungenfachklinik Coswig, Department of Thoracic and Vascular Surgery, Coswig (Germany); Hoeffken, G. [Lungenfachklinik Coswig, Department of Pneumology, Coswig (Germany); Krause, M.; Baumann, M. [Medical Faculty and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Department of Radiation Oncology, Dresden (Germany); Medical Faculty and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, OncoRay National Center for Radiation Research in Oncology, Dresden (Germany); German Cancer Consortium (DKTK), Dresden (Germany); German Cancer Research Center (DKFZ), Heidelberg (Germany); Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany)

    2014-03-15

    The aim of this analysis was to investigate the impact of tumour-, treatment- and patient-related cofactors on local control and survival after postoperative adjuvant radiotherapy in patients with non-small cell lung cancer (NSCLC), with special focus on waiting and overall treatment times. For 100 NSCLC patients who had received postoperative radiotherapy, overall, relapse-free and metastases-free survival was retrospectively analysed using Kaplan-Meier methods. The impact of tumour-, treatment- and patient-related cofactors on treatment outcome was evaluated in uni- and multivariate Cox regression analysis. No statistically significant difference between the survival curves of the groups with a short versus a long time interval between surgery and radiotherapy could be shown in uni- or multivariate analysis. Multivariate analysis revealed a significant decrease in overall survival times for patients with prolonged overall radiotherapy treatment times exceeding 42 days (16 vs. 36 months) and for patients with radiation-induced pneumonitis (8 vs. 29 months). Radiation-induced pneumonitis and prolonged radiation treatment times significantly reduced overall survival after adjuvant radiotherapy in NSCLC patients. The negative impact of a longer radiotherapy treatment time could be shown for the first time in an adjuvant setting. The hypothesis of a negative impact of longer waiting times prior to commencement of adjuvant radiotherapy could not be confirmed. (orig.) [German] Das Ziel der vorliegenden Analyse war, den Einfluss von tumor-, patienten- und therapieabhaengigen Kofaktoren auf die lokoregionale Tumorkontrolle und das Ueberleben nach postoperativer adjuvanter Strahlentherapie bei Patienten mit einem nicht-kleinzelligen Bronchialkarzinom (NSCLC) zu untersuchen. Ein spezieller Fokus lag dabei auf der Wartezeit zwischen Operation und Beginn der Strahlentherapie sowie der Gesamtbehandlungszeit der Strahlentherapie. Fuer 100 Patienten, die eine postoperative

  7. Induction chemotherapy followed by concurrent chemoradiotherapy in stage III unresectable non-small cell lung cancer

    International Nuclear Information System (INIS)

    Tan, E.H.; Ang, P.T.; Leong, S.S.; Khoo, K.S.; Wee, J.; Fong, K.W.; Tan, T.; Lee, K.S.; Chua, E.J.; Eng, P.; Hsu, A.; Tan, Y.K.; Ong, Y.Y.

    1999-01-01

    che favourable experience with the combination regimen of vinorelbine, ifosfamide and cisplatin (NIP) in patients with metastatic non-small cell lung cancer (NSCLC) has led to a protocol assessing this regimen as an induction treatment in patients with stage III unresectable NSCLC, followed by thoracic radiotherapy with concurrent daily cisplatin as a radiosensitizer. Two cycles of NIP were administered 21 days apart; each cycle comprised i.v. vinorelbine 25 mg/m 2 on days 1 and 8, i.v. ifosfamide 3 g/m 2 on day 1 with MESNA as uroprotection, and i.v. cisplatin 50 mg/m 2 on day 1. Radical thoracic radiotherapy commenced on day 43 to a total dose of 64 Gy and i.v. cisplatin 6 mg/m 2 was given concurrently prior to each fraction of radiation as a sensitiser. Two more cycles of NIP were given to patients who responded favourably to the induction treatment about 2 weeks after completion of radiation. Between July 1995 and July 1997, 44 patients were treated with this protocol. This treatment schedule was generally well tolerated. Grade 3-4 neutropenia occurred in 50% of the patients and neutropenic sepsis was seen in 8. Grade 3-4 oesophagitis was uncommon. Most of the patients were able to complete the induction and concurrent chemoradiotherapy phase. Major response occurred in 75% of the patients with 2 (4.5%) complete responses (CR). A total of 6 patients achieved CR after chemoradiotherapy. At a median follow-up of 35 months, the median overall survival for all patients was 15 months with a 3-year survival rate of 24%. The median overall survival for stage IIIA patients was 19 months with a 3-year survival rate of 39% in contrast to 13 months' median overall survival and only 15% 3-year survival rate for stage IIIB. The NIP regimen results in a high response rate in NSCLC and this treatment programme seems to benefit selected patients with stage III disease. (orig.)

  8. Quality of life after curative radiotherapy in Stage I non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Langendijk, Johannes A.; Aaronson, Neil K.; Jong, Jos M.A. de; Velde, Guul P.M. ten; Muller, Martin J.; Slotman, Ben J.; Wouters, Emiel F.M.

    2002-01-01

    Purpose: The aim of this study was to investigate changes in quality of life (QOL) among medically inoperable Stage I non-small-cell lung cancer (NSCLC) patients treated with curative radiotherapy. Patients and Methods: The study sample was composed of 46 patients irradiated for Stage I NSCLC. Quality of life was assessed before, during, and after radiotherapy using the European Organization for the Research and Treatment of Cancer QLQ-C30 and QLQ-LC13. Changes in symptom and QOL scores over time were evaluated with a repeated measurement analysis of variance using the mixed effect modeling procedure, SAS Proc Mixed. Twenty-seven patients were treated only at the primary site, whereas for 19 patients, the regional lymph nodes were included in the target volume as well. Results: The median follow-up time of patients alive was 34 months. The median survival was 19.0 months. None of the locally treated patients developed regional recurrence. A significant, gradual increase over time was observed for dyspnea, fatigue, and appetite loss. A significant, gradual deterioration was observed also for role functioning. No significant changes were noted for the other symptoms or the functioning scales. Significantly higher levels of dysphagia, which persisted up to 12 months, were observed in those in which the regional lymph nodes were treated, as compared to the locally treated patients. Radiation-induced pulmonary changes assessed with chest radiograph were more pronounced in the group treated with locoregional radiotherapy. Conclusions: After curative radiotherapy for Stage I medically inoperable NSCLC, a gradual increase in dyspnea, fatigue, and appetite loss, together with a significant deterioration of role functioning, was observed, possibly because of pre-existing, slowly progressive chronic obstructive pulmonary disease and radiation-induced pulmonary changes. Taking into account the low incidence of regional recurrences after local irradiation, the higher incidence

  9. Patients' preferences: a discrete-choice experiment for treatment of non-small-cell lung cancer.

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    Mühlbacher, Axel C; Bethge, Susanne

    2015-07-01

    Lung cancer is a major cause of cancer-related deaths and thus represents a global health problem. According to World Health Organization (WHO) estimates, approximately 1.37 million people die each year from lung cancer. Different therapeutic approaches as well as several treatment options exist. To date decisions on which therapies to use have largely been made by clinical experts. Comparative preference studies show that underlying weighting of treatment goals by experts is not necessarily congruent with the preferences of affected patients. The aim of this empirical study was to ascertain patient preferences in relation to treatment of non-small-cell lung cancer (NSCLC). After identification of patient-relevant treatment attributes via literature review and qualitative interviews(ten) a discrete-choice experiment including seven patient-relevant attributes was conducted using a fractional factorial NGene-design. Statistical data analysis was performed using latent class models. The qualitative part of this study identified outcome measures related to efficacy, side effects and mode of administration. A total of 211 NSCLC patients (N = 211) participated in the computer-assisted personal interview. A clear preference for an increase in "progression-free survival" (coef.: 1.087) and a reduction of "tumor-associated symptoms"(cough, shortness of breath and pain); coef.: 1.090) was demonstrated, followed by the reduction of side effects: "nausea and vomiting" (coef.: 0.605); "rash" (coef.: 0.432); "diarrhea" (coef.: 0.427); and, "tiredness and fatigue" (coef.: 0.423). The "mode of administration" was less important for participants (coef.: 0.141). Preference measurement showed "progression-free survival" and "tumor-associated symptoms" had a significant influence on the treatment decision. Subgroup analysis revealed that the importance of "progression-free survival" increases with increased therapy experience. Based on the presented results therapies can be

  10. Assessing tumor treatment response and prognosis in non-small cell lung cancer with perfusion CT

    International Nuclear Information System (INIS)

    Wang Jianwei; Wu Ning; Song Ying

    2010-01-01

    Objective: To prospectively investigate whether any of the perfusion parameters would predict early tumor response to chemotherapy and/or radiotherapy and prognosis in non-small cell lung cancer (NSCLC). Methods: In a prospective series, Perfusion CT were performed in 152 patients suspected lung cancer with 16-slice or 8-slice multislice CT. Contrast medium (50 ml) was injected at a rate of 4 ml/s with a power injector. The scanning delay was 10 seconds and the scanning time was 50 seconds. Among 152 patients, 123 patients were proved lung cancer by pathology. With the perfusion 3.0 software, the parameters including blood flow (BF), blood volume (BV), mean transit time (MTT) and capillary permeability surface area product (PS) were calculated. The perfusion image quality was evaluated on a 4-1eveal scale. The treatment response after chemotherapy and (or) radiotherapy was assessed with Response Evaluation Criteria in Solid Tumors (RECIST), and then the relationship between perfusion parameters with early tumor response to chemotherapy and (or) radiotherapy was evaluated. Student t test and Kaplan-Meier estimates were used for data analysis. Results: In 84 patients (68.3%), the perfusion image quality was staged level 2 (moderate) and level 3 (good). Among them, 35 patients with NSCLC were assessed with RECIST after chemotherapy and (or) radiotherapy. In these 35 patients, The BF of responders and nonresponders was (81.0 ± 33.6)and (56.3 ± 23.1) ml · min -1 ·100 g -1 , respectively, which was significantly different(t=2.393, P=0.023). The median PFS of low-BF group (BF ≤ 80 ml · min -1 · 100 g -1 ) and high-BF group (BF>80 ml · min -1 · 100 g -1 ) was 11.8 and 8.0 months respectively (P>0.05), and the median PFS of low-BV group (BF ≤ 6 ml/100 g -1 ) and high-BV group (BF>6 ml/100 g -1 ) was 9.2 and 8.0 months respectively(P>0.05), both of them were not significantly different. Conclusion: NSCLC in high perfusion are relatively sensitive to chemotherapy

  11. Determination of EGFR and KRAS mutational status in Greek non-small-cell lung cancer patients.

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    Papadopoulou, Eirini; Tsoulos, Nikolaos; Tsirigoti, Angeliki; Apessos, Angela; Agiannitopoulos, Konstantinos; Metaxa-Mariatou, Vasiliki; Zarogoulidis, Konstantinos; Zarogoulidis, Pavlos; Kasarakis, Dimitrios; Kakolyris, Stylianos; Dahabreh, Jubrail; Vlastos, Fotis; Zoublios, Charalampos; Rapti, Aggeliki; Papageorgiou, Niki Georgatou; Veldekis, Dimitrios; Gaga, Mina; Aravantinos, Gerasimos; Karavasilis, Vasileios; Karagiannidis, Napoleon; Nasioulas, George

    2015-10-01

    It has been reported that certain patients with non-small-cell lung cancer (NSCLC) that harbor activating somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor ( EGFR ) gene may be effectively treated using targeted therapy. The use of EGFR inhibitors in patient therapy has been demonstrated to improve response and survival rates; therefore, it was suggested that clinical screening for EGFR mutations should be performed for all patients. Numerous clinicopathological factors have been associated with EGFR and Kirsten-rat sarcoma oncogene homolog (KRAS) mutational status including gender, smoking history and histology. In addition, it was reported that EGFR mutation frequency in NSCLC patients was ethnicity-dependent, with an incidence rate of ~30% in Asian populations and ~15% in Caucasian populations. However, limited data has been reported on intra-ethnic differences throughout Europe. The present study aimed to investigate the frequency and spectrum of EGFR mutations in 1,472 Greek NSCLC patients. In addition, KRAS mutation analysis was performed in patients with known smoking history in order to determine the correlation of type and mutation frequency with smoking. High-resolution melting curve (HRM) analysis followed by Sanger sequencing was used to identify mutations in exons 18-21 of the EGFR gene and in exon 2 of the KRAS gene. A sensitive next-generation sequencing (NGS) technology was also employed to classify samples with equivocal results. The use of sensitive mutation detection techniques in a large study population of Greek NSCLC patients in routine diagnostic practice revealed an overall EGFR mutation frequency of 15.83%. This mutation frequency was comparable to that previously reported in other European populations. Of note, there was a 99.8% concordance between the HRM method and Sanger sequencing. NGS was found to be the most sensitive method. In addition, female non-smokers demonstrated a high prevalence of

  12. Prognostic predictors for non-small cell lung cancer patients with brain metastasis after radiotherapy

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    Qiuhong FAN

    2008-06-01

    Full Text Available Background and objective Brain metastasis (BM is often found in the patients with lung cancer. Radiotherapy is regular and effective means of therapy and it aims at palliating symptoms and prolonging survival time. However, now there are different viewpoints on protocols of radiotherapy and prognostic factors. A retrospective analysis is used to evaluate the results of treatment for 82 cases with brain metastasis from non-small cell lung cancer (NSCLC and explore the prognostic factors to establish a prognostic index (PI model. Methods From Feb.1995 to Oct. 2006, 82 patients irradiated for BM from NSCLC, with both complete medical charts and follow-up data available, were eligible for this retrospective analysis. A number of potential factors which might affect prognosis after irradiation were evaluated. The significance of prognostic variables in the survival resulted from both univariate analysis by Kaplan-Meier combining with log-rank test and multivariate Cox regression model. The prognostic index (PI was established based on Cox regression analysis and subgrouping values. Results The follow-up time was 1-120 months. For the entire cohort, the median survival from the start of radiation for BM was 10.5 months, and the actuarial overall survival rate was 50.8%, 23.7% and 5.1% at 0.5, 1 and 2 years respectively. Univariate analysis showed KPS, control of primary tumor, interval from the beginning of diagnostic to BM, extracranial systemic metastasis, counts of lymphocyte and solitary BM were predictors of prognosis. However, in the Cox multivariate analysis, only KPS, control of primary tumor, interval from the beginning of diagnostic to BM and solitary BM were significant prognostic factors. The prognostic index was established based on Cox regression analysis and 82 patients were stratified good, intermediate and poor prognostic sub-groups. The difference of survival rate among 3 subgroups is significant (P<0.001. Conclusion Radiotherapy is

  13. Improvement of pulmonary function after lobectomy for non-small cell lung cancer in emphysematous patients.

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    Carretta, A; Zannini, P; Puglisi, A; Chiesa, G; Vanzulli, A; Bianchi, A; Fumagalli, A; Bianco, S

    1999-05-01

    Pulmonary emphysema is frequently associated with lung cancer and, because of the impaired pulmonary function involved, it may contraindicate surgical treatment. However, improvement of pulmonary function has been observed after surgical resection in patients with advanced emphysema. The aim of this study was to evaluate whether pulmonary emphysema, as assessed by pulmonary function tests and radiological evaluation, can influence postoperative respiratory function after lobectomy for non-small cell lung cancer (NSCLC). Respiratory function was evaluated before and after lobectomy for NSCLC. Radiological evaluation of emphysema was performed on chest X-ray and CT scan. Patients that had undergone chemo- or radiotherapy or had segmental or lobar atelectasis were excluded from the study. Thirty-five patients entered the study. A decrease in static lung volumes was observed after surgery. Total lung capacity (TLC) decreased from 6.58+/-0.92 to 5.46+/-0.77 l; functional residual capacity (FRC) from 3.70+/-0.88 to 2.96+/-0.73 1 and residual volume (RV) from 2.93+/-0.78 to 2.2+/-0.53 l. However, in a subgroup of 10 patients (Group 1), dynamic volumes after surgery were unchanged or slightly increased (forced vital capacity (FVC) from 3.23+/-0.65 to 3.3+/-0.68 l; forced expiratory volume in 1 s (FEV1) from 2.14+/-0.51 to 2.25+/-0.54 l), and airway resistances (sRaw) decreased from 15.58+/-5.18 to 11.42+/-5.25 cm H2O/s. Preoperative data showed that these patients had a greater obstruction, with FEV1 changing from 69+/-12.42 to 72.70+/-13.72% of predicted, as compared with a change from 87+/-12.7 to 72.08+/-13.10% in the other group of 25 patients (Group 2). Correlation analysis reached statistical significance between FEV1% variation (deltaFEV1%) and preoperative FEV1 and FVC% (r = -0.49, P = 0.002 and r = -0.5, P = 0.001, respectively) and between delta (FEV1)% and radiological scores for 3-level CT (r = 0.39, P = 0.04) and the sum of chest X-ray, single and 3-level CT

  14. Association between MGMT promoter methylation and non-small cell lung cancer: a meta-analysis.

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    Changmei Gu

    Full Text Available BACKGROUND: O(6-methylguanine-DNA methyltransferase (MGMT is one of most important DNA repair enzyme against common carcinogens such as alkylate and tobacco. Aberrant promoter methylation of the gene is frequently observed in non-small cell lung cancer (NSCLC. However, the importance of epigenetic inactivation of the gene in NSCLC published in the literature showed inconsistence. We quantified the association between MGMT promoter methylation and NSCLC using a meta-analysis method. METHODS: We systematically reviewed studies of MGMT promoter methylation and NSCLC in PubMed, EMBASE, Ovid, ISI Web of Science, Elsevier and CNKI databases and quantified the association between MGMT promoter methylation and NSCLC using meta-analysis method. Odds ratio (OR and corresponding 95% confidence interval (CI were calculated to evaluate the strength of association. Potential sources of heterogeneity were assessed by subgroup analysis and meta-regression. RESULTS: A total of 18 studies from 2001 to 2011, with 1, 160 tumor tissues and 970 controls, were involved in the meta-analysis. The frequencies of MGMT promote methylation ranged from 1.5% to 70.0% (median, 26.1% in NSCLC tissue and 0.0% to 55.0% (median, 2.4% in non-cancerous control, respectively. The summary of OR was 4.43 (95% CI: 2.85, 6.89 in the random-effects model. With stratification by potential source of heterogeneity, the OR was 20.45 (95% CI: 5.83, 71.73 in heterogeneous control subgroup, while it was 4.16 (95% CI: 3.02, 5.72 in the autologous control subgroup. The OR was 5.31 (95% CI: 3.00, 9.41 in MSP subgroup and 3.06 (95% CI: 1.75, 5.33 in Q-MSP subgroup. CONCLUSION: This meta-analysis identified a strong association between methylation of MGMT gene and NSCLC. Prospective studies should be required to confirm the results in the future.

  15. Prophylactic cranial irradiation in non-small cell lung cancer patients: who might be the candidates?

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    Dimitropoulos C

    2011-08-01

    Full Text Available Charalampos Dimitropoulos1, Georgios Hillas2, Sofia Nikolakopoulou2, Ioanna Kostara2, Konstantinos Sagris2, Fotis Vlastos2, Manos Alchanatis319th Respiratory Medicine Department; 2Department of Respiratory and Critical Care Medicine, Research Unit; 3University of Athens, 1st Respiratory Medicine Department, University of Athens Medical School, “Sotiria” Chest Diseases Hospital, Athens, GreeceObjectives: Brain metastases (BMs often advance the course of non-small cell lung cancer (NSCLC. We performed an observational study in order to investigate the possible correlation of selected clinical and epidemiological factors with BM appearance in patients suffering from different histological subtypes of NSCLC stage I–IV.Methods: The study included 161 consecutive patients with NSCLC. Analyzed data included patient- and tumor-related characteristics.Results: Thirty-nine patients (24.2% presented BMs within 12 (0–36 weeks of diagnosis. BMs decreased the mean overall survival significantly (15.6 versus 50.7 weeks, P < 0.001, with hazard ratio (95% confidence interval 3.60 (2.42–5.35. The age of the patients with BM was significantly lower than that of the patients without BM (60.8 ± 8.9 versus 66.5 ± 8.5, P < 0.001. Patients with BM had significantly higher pack-years consumption (75.9 ± 23.9 versus 58.9 ± 31.9, P = 0.003 and larger tumor size compared with patients without BM (size in mm: 55.1 ± 20.1 versus 45.9 ± 19.3, P = 0.012. The presence of BM was also correlated with the absence of lung (P < 0.001, bone (P = 0.005, and adrenal (P = 0.046 metastases.Conclusion: Younger NSCLC patients with high tobacco consumption, large tumor size, and absence of metastases in other organs (lung, bones, adrenal metastases are at high risk of BM appearance during the course of NSCLC and are candidates for prophylactic cranial irradiation early in the course of the disease.Keywords: NSCLC, brain metastases, clinical and epidemiological factors, PCI

  16. Targeted therapies in development for non-small cell lung cancer.

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    Reungwetwattana, Thanyanan; Dy, Grace Kho

    2013-01-01

    The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC), the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2]), RAS (rat sarcoma gene), BRAF (v-raf murine sarcoma viral oncogene homolog B1), MAPK (mitogen-activated protein kinase) c-MET (c-mesenchymal-epithelial transition), FGFR (fibroblast growth factor receptor), DDR2 (discoidin domain receptor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha)), PTEN (phosphatase and tensin homolog), AKT (protein kinase B), ALK (anaplastic lym phoma kinase), RET (rearranged during transfection), ROS1 (reactive oxygen species 1) and EPH (erythropoietin-producing hepatoma) are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4)-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and

  17. Associations between abnormal vitamin D metabolism pathway function and non-small cell lung cancer.

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    Ge, Nan; Chu, Xiu-Mei; Xuan, Yun-Peng; Ren, Dun-Qiang; Wang, Yongjie; Ma, Kai; Gao, Hui-Jiang; Jiao, Wen-Jie

    2017-12-01

    Lung cancer is a type of malignant tumor derived from the respiratory system, which is the leading cause of cancer-associated mortality worldwide, of which ~80% of cases are attributable to non-small cell lung cancer (NSCLC). A previous study demonstrated that 1α,25-Dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ), derived from the vitamin D metabolic pathway contributes an antitumor effect. Aberrant expression of the essential enzyme encoding genes, Cytochrome P450 Family 27 Subfamily A Member 1 ( CYP27A1 ), Cytochrome P450 Family 27 Subfamily B Member 1 ( CYP27B1 ), and Cytochrome P450 Family 24 Subfamily A Member 1 ( CYP24A1 ) may be associated with lung cancer. However, a lack of evidence exists concerning the association between CYP27A1 , CYP27B1 , CYP24A1 expression and NSCLC. The aim of the present study was to investigate the functions of CYP27A1, CYP27B1 and CYP24A1 expression in NSCLC. Lung cancer tissue and para-carcinoma control tissue were collected from patients with NSCLC. Reverse transcription-quantitative polymerase chain reaction was applied to analyze CYP27A1, CYP27B1 and CYP24A1 mRNA expression in lung cancer tissues. An association analysis was performed between the aforementioned metabolic enzymes and patients with NSCLC age, gender, tumor node metastasis (TNM) stage, pathological type, differentiation and prognosis. CYP27B1 and CYP24A1 mRNA were upregulated in NSCLC compared with controls (PCYP27A1 expression were observed between NSCLC and control. In addition, CYP24A1 expression was not associated with age, sex, smoking or TNM stage, but was associated with pathological type, differentiation and prognosis (P<0.05). CYP27B1 expression was significantly associated with TNM stage, differentiation, and prognosis, but not age, sex, smoking or pathological type. In conclusion, CYP27B1 and CYP24A1 may be considered as independent prognostic factors of NSCLC and may be novel therapeutic targets to assist clinical diagnosis, treatment and prognosis of the

  18. Development of the Fibulin-3 protein therapeutics of non small cell lung cancer stem cells

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    Kim, In Gyu; Kim, Kugchan; Jung, Il Lae; Kim, Seo Yeon; Choi, Su Im; Lee, Jae Ha

    2013-09-15

    This study focuses on developing an efficient bioprocess for large-scale production of fibulin-3 using Chinese Hamster Ovary cell expression system and evaluating its therapeutic potential for the treatment of cancer. The specific aims are as follows: Isolation and establishment of CSCs using FACS based on cell surface markers and high ALDH1 activity. Identification and characterization of lung cancer stem cells that acquire features of CSC upon exposure to ionizing radiation. Evaluation of the fibulin-3 effects on the stem traits and signaling pathways required for the generation and maintenance of CSCs. In vivo validation of fivulin-3 for tumor prognosis and therapeutic efficacy against lung cancer using animal model.

  19. Serum cathepsin K and cystatin C concentration in patients with advanced non-small-cell lung cancer during chemotherapy.

    Directory of Open Access Journals (Sweden)

    Elzbieta Chyczewska

    2009-12-01

    Full Text Available A pathogenic implication of cathepsin K (Cath K and its inhibitor - cystatin C (Cyst C occur to be of growing importance in the mechanisms of tumor invasiveness in lung cancer. This study was conducted to investigate the prognostic role and the effects of chemotherapy on serum Cath K and Cyst C (ELISA in patients with advanced stage non-small cell lung cancer (NSCLC. The study entered 40 patients (32 men and 15 healthy volunteers (control group. Peripheral blood samples were taken before and after four cycles of chemotherapy. The mean serum Cyst C levels were significantly higher in patients with advanced NSCLC than in controls (p=0.003. The levels of Cath K in serum of NSCLC are comparable to those in controls. No correlation was found between Cath K and Cyst C concentrations and the histological type and staging of lung cancer. Patients with T4-stage had a lower level of Cyst C, than those with T2 (p=0.033. No correlation was found between the concentrations of Cath K, Cyst C and the effect of chemotherapy. However, Cyst C level positively correlated with serum creatinine concentration (R=0.535; p=0.005 in patients who responded to chemotherapy and with patient's age (R=0.456; p=0.018 in whole group. When the cut-off values of serum Cath K and Cyst C (23.35 pmol/l, 1.29 mg/l, respectively were used, the prognoses of high and low groups were not different. Concluding, patients with lung cancer have a higher serum concentration of Cyst C compared to healthy people. In our opinion, determination of Cath K and Cyst C concentrations has no clinical significance in the prognosis of the survival time in lung cancer.

  20. Percutaneous microwave ablation for early-stage non-small cell lung cancer (NSCLC) in the elderly: a promising outlook

    International Nuclear Information System (INIS)

    Acksteiner, Christian; Steinke, Karin

    2015-01-01

    Microwave ablation (MWA) is a relatively new minimally invasive treatment option for lung cancer with substantially lower morbidity and mortality than surgery. This retrospective study was performed to evaluate the safety, effectiveness and follow-up imaging of MWA in the elderly aged 75 years and above. Eleven percutaneous computed tomography (CT)-guided MWA of early-stage non-small cell lung cancer (NSCLC) were performed in 10 patients aged 75 years and older. All but one patient were treated with a high-powered MWA system delivering maximally 140 W. Follow-up with CT and fluorodeoxyglucose-positron emission tomography (FDG-PET) was carried out over a maximum period of 30 months and a median period of 12 months. There were no peri-procedural deaths or major complications. Seven patients were disease free at the time of manuscript submission. Three patients showed growth of the treated lesions, one patient aged 90 years deceased due to unknown cause after approximately 18 months. One patient presented with local progression and disseminated metastatic disease at 12 months; he is still alive. One patient showed increasing soft tissue at the ablation site 15 months post-treatment. Three consecutive core biopsies over 2 months failed to confirm tumour recurrence. MWA therapy is a promising option of treating early-stage NSCLC in the elderly with good treatment outcome and negligible morbidity. Determining successful treatment outcome may be challenging at times as local tissue increase and PET-CT positivity do not seem to necessarily correlate with recurrence of malignancy.

  1. Quantitative proteomics identifies central players in erlotinib resistance of the non-small cell lung cancer cell line HCC827

    DEFF Research Database (Denmark)

    Jacobsen, Kirstine; Lund, Rikke Raaen; Beck, Hans Christian

    Background: Erlotinib (Tarceva®, Roche) has significantly changed the treatment of non-small cell lung cancer (NSCLC) as 70% of patients show significant tumor regression when treated. However, all patients relapse due to development of acquired resistance, which in 43-50% of cases are caused...... by a secondary mutation (T790M) in EGFR. Importantly, a majority of resistance cases are still unexplained. Our aim is to identify novel resistance mechanisms in erlotinib-resistant subclones of the NSCLC cell line HCC827. Materials & Methods: We established 3 erlotinib-resistant subclones (resistant to 10, 20...... or other EGFR or KRAS mutations, potentiating the identification of novel resistance mechanisms. We identified 2875 cytoplasmic proteins present in all 4 cell lines. Of these 87, 56 and 23 are upregulated >1.5 fold; and 117, 72 and 32 are downregulated >1.5 fold, respectively, in the 3 resistant clones...

  2. Reversal of cisplatin resistance in non-small cell lung cancer stem cells by Taxus chinensis var.

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    Jiang, Y Q; Xu, X P; Guo, Q M; Xu, X C; Liu, Q Y; An, S H; Xu, J L; Su, F; Tai, J B

    2016-09-02

    Drug resistance in cells is a major impedance to successful treatment of lung cancer. Taxus chinensis var. inhibits the growth of tumor cells and promotes the synthesis of interleukins 1 and 2 and tumor necrosis factor, enhancing immune function. In this study, T. chinensis var.-induced cell death was analyzed in lung cancer cells (H460) enriched for stem cell growth in a defined serum-free medium. Taxus-treated stem cells were also analyzed for Rhodamine 123 (Rh-123) expression by flow cytometry, and used as a standard functional indicator of MDR. The molecular basis of T. chinensis var.-mediated drug resistance was established by real-time PCR analysis of ABCC1, ABCB1, and lung resistance-related protein (LRP) mRNA, and western blot analysis of MRP1, MDR1, and LRP. Our results revealed that stem cells treated with higher doses of T. chinensis var. showed significantly lower growth inhibition rates than did H460 cells (P var. and cisplatin was also significantly inhibited (P var. (P var.-treated stem cells showed significant downregulation of the ABCC1, ABCB1, and LRP mRNA and MRP1, MDR1, and LRP (P var.-mediated downregulation of MRP1, MDR1, and LRP might contribute to the reversal of drug resistance in non-small cell lung cancer stem cells.

  3. BeyondALKandROS1: RET, NTRK, EGFRandBRAFgene rearrangements in non-small cell lung cancer.

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    Farago, Anna F; Azzoli, Christopher G

    2017-10-01

    The discovery of gene rearrangements involving the receptor tyrosine kinase genes ALK and ROS1 has revolutionized management of the subset of non-small cell lung cancers characterized by these alterations. The oncogenic fusion proteins expressed in these tumors drive cancer cell growth and survival, and targeted inhibition of this signaling can lead to dramatic and durable responses in patients. While the best characterized gene fusions in non-small cell lung cancer (NSCLC) involve ALK and ROS1 , fusions involving other kinases including RET , NTRK , EGFR and BRAF are now established as additional targetable drivers. Here we review data supporting the roles of these fusions as oncogenic drivers, and the potential for targeting these fusions for improved clinical outcomes. These discoveries should encourage multiplexed molecular profiling of lung cancers using next-generation platforms which identify these gene fusions in order to expand treatment options for patients.

  4. Molecular prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)-validation in two independent cohorts

    DEFF Research Database (Denmark)

    Buhl, Ida Kappel; Santoni-Rugiu, Eric; Ravn, Jesper

    2018-01-01

    INTRODUCTION: Effective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts are presen......INTRODUCTION: Effective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts...... are presented. METHODS: The profiles are correlations between in vitro sensitivity to cisplatin and vinorelbine and baseline mRNA expression of the 60 cell lines in the National Cancer Institute panel. An applied clinical samples filter focused the profiles to clinically relevant genes. The profiles were tested...

  5. MiR-1244 sensitizes the resistance of non-small cell lung cancer A549 cell to cisplatin.

    Science.gov (United States)

    Li, Weili; Wang, Wenzhe; Ding, Mingjian; Zheng, Xiaoliang; Ma, Shenglin; Wang, Xiaoju

    2016-01-01

    Cisplatin (DDP)-based chemotherapy is the mainstay of first-line therapy for lung cancer. However, their efficacy is often limited by the existence or development of chemoresistance. The aim of this study was to find and investigate the function of miRNAs in cisplatin (DDP)-resistant non-small cell lung cancer (NSCLC) A549 cell. Quantitative real-time PCR assay was employed to compare the differences of miRNA expression in both cisplatin-resistant A549 (A549/DDP) cell and the parental A549 cell. The dysregulated miRNAs were then corrected by transfecting oligonucleotides into A549/DDP cells. The cellular sensitivity to cisplatin, cell apoptosis and migration were conducted by MTT, flow cytometry and cell wound healing assay, respectively. Both miR-589 and miR-1244 were significantly down-regulated in A549/DDP cell compared to the parental A549, while the expression of miR-182 and miR-224 were increased in A549/DDP cell (P A549/DDP cell. The study indicates a crucial role of miR-1244 in the progress of cisplatin resistance of A549. Further understanding of miR-1244-mediated signaling pathways may promote the clinical use of miR-1244 in lung cancer therapy.

  6. Effects of miR-424 on Proliferation and Migration Abilities in Non-small Cell Lung Cancer A549 Cells and Its Molecular Mechanism

    Directory of Open Access Journals (Sweden)

    Hongmin LI

    2016-09-01

    Full Text Available Background and objective The inhibitory ability of miR-424 on the proliferation of renal carcinoma cell and the migration and invasion of cancer cells has been widely explored and demonstrated. However, the effects of miR-424 on non-small cell lung cancer (NSCLC have not been systematically examined. In this study, detected the growth and invasion effect of miR-424 in NSCLC A549 cell. The migration and molecular mechanism of this cell are also detected. Methods NSCLC A549 cell was transfected with miR-424 and its inhibitor. After transfection, the proliferation ability of A549 cell was detectedby CCK8 assay. Then, the migration ability in A549 cell was detected by migration assays. Furthermore, the expression level of MMP2 and MMP9 in A549 was detected by Western blot and immune fluorescence. The 3'UTR of E2F6 was cloned into luciferase reporter vector and its enzymatic activitywas detected to verify whether miR-424 can target E2F6. The expression level of E2F6 in a549 cell after transfecing with miR-424 was detected by Western blot. Results After transfection of miR-424, the proliferation and migration abilities were remarkably decreased and the expression level of MMP-2 and MMP-9 were down-regulated in A549. Moreover, MiR-424 inhibited the enzymatic activity of luviferase reporter vector of E2F6. Specifically, the expression level of E2F6 was down-regulated in A549. Conclusion miR-424 can inhibit the proliferation and migration abilities of A549 by negatively regulating the expression of E2F6.

  7. [Effects of miR-424 on Proliferation and Migration Abilities in Non-small Cell Lung Cancer A549 Cells and Its Molecular Mechanism].

    Science.gov (United States)

    Li, Hongmin; Lan, Haitao; Zhang, Ming; An, Ning; Yu, Ruilian; He, Yangke; Gan, Chongzhi

    2016-09-20

    The inhibitory ability of miR-424 on the proliferation of renal carcinoma cell and the migration and invasion of cancer cells has been widely explored and demonstrated. However, the effects of miR-424 on non-small cell lung cancer (NSCLC) have not been systematically examined. In this study, detected the growth and invasion effect of miR-424 in NSCLC A549 cell. The migration and molecular mechanism of this cell are also detected. NSCLC A549 cell was transfected with miR-424 and its inhibitor. After transfection, the proliferation ability of A549 cell was detectedby CCK8 assay. Then, the migration ability in A549 cell was detected by migration assays. Furthermore, the expression level of MMP2 and MMP9 in A549 was detected by Western blot and immune fluorescence. The 3'UTR of E2F6 was cloned into luciferase reporter vector and its enzymatic activitywas detected to verify whether miR-424 can target E2F6. The expression level of E2F6 in a549 cell after transfecing with miR-424 was detected by Western blot. After transfection of miR-424, the proliferation and migration abilities were remarkably decreased and the expression level of MMP-2 and MMP-9 were down-regulated in A549. Moreover, MiR-424 inhibited the enzymatic activity of luviferase reporter vector of E2F6. Specifically, the expression level of E2F6 was down-regulated in A549. miR-424 can inhibit the proliferation and migration abilities of A549 by negatively regulating the expression of E2F6.
.

  8. Nodal Stage of Surgically Resected Non-Small Cell Lung Cancer and Its Effect on Recurrence Patterns and Overall Survival

    Energy Technology Data Exchange (ETDEWEB)

    Varlotto, John M., E-mail: john.varlotto@umassmemorial.org [Department of Radiation Oncology, University of Massachusetts Medical Center, Worcester, Massachusetts (United States); Yao, Aaron N. [Department of Healthcare Policy and Research, Virginia Commonwealth University, Richmond, Virginia (United States); DeCamp, Malcolm M. [Division of Thoracic Surgery, Department of Surgery, Northwestern Memorial Hospital, Chicago, Illinois (United States); Northwestern University School of Medicine, Chicago, Illinois (United States); Ramakrishna, Satvik [Northwestern University School of Medicine, Chicago, Illinois (United States); Recht, Abe [Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (United States); Flickinger, John [Department of Radiation Oncology, Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States); Andrei, Adin [Northwestern University, Chicago, Illinois (United States); Reed, Michael F. [Pennsylvania State University College of Medicine, Hershey, Pennsylvania (United States); Heart and Vascular Institute, Pennsylvania State University-Hershey, Hershey, Pennsylvania (United States); Toth, Jennifer W. [Pennsylvania State University College of Medicine, Hershey, Pennsylvania (United States); Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Pennsylvania State University-Hershey, Hershey, Pennsylvania (United States); Fizgerald, Thomas J. [Department of Radiation Oncology, University of Massachusetts Medical Center, Worcester, Massachusetts (United States); Higgins, Kristin [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Zheng, Xiao [Department of Healthcare Policy and Research, Virginia Commonwealth University, Richmond, Virginia (United States); Shelkey, Julie [Department of Anesthesiology, Columbia University, New York, New York (United States); and others

    2015-03-15

    Purpose: Current National Comprehensive Cancer Network guidelines recommend postoperative radiation therapy (PORT) for patients with resected non-small cell lung cancer (NSCLC) with N2 involvement. We investigated the relationship between nodal stage and local-regional recurrence (LR), distant recurrence (DR) and overall survival (OS) for patients having an R0 resection. Methods and Materials: A multi-institutional database of consecutive patients undergoing R0 resection for stage I-IIIA NSCLC from 1995 to 2008 was used. Patients receiving any radiation therapy before relapse were excluded. A total of 1241, 202, and 125 patients were identified with N0, N1, and N2 involvement, respectively; 161 patients received chemotherapy. Cumulative incidence rates were calculated for LR and DR as first sites of failure, and Kaplan-Meier estimates were made for OS. Competing risk analysis and proportional hazards models were used to examine LR, DR, and OS. Independent variables included age, sex, surgical procedure, extent of lymph node sampling, histology, lymphatic or vascular invasion, tumor size, tumor grade, chemotherapy, nodal stage, and visceral pleural invasion. Results: The median follow-up time was 28.7 months. Patients with N1 or N2 nodal stage had rates of LR similar to those of patients with N0 disease, but were at significantly increased risk for both DR (N1, hazard ratio [HR] = 1.84, 95% confidence interval [CI]: 1.30-2.59; P=.001; N2, HR = 2.32, 95% CI: 1.55-3.48; P<.001) and death (N1, HR = 1.46, 95% CI: 1.18-1.81; P<.001; N2, HR = 2.33, 95% CI: 1.78-3.04; P<.001). LR was associated with squamous histology, visceral pleural involvement, tumor size, age, wedge resection, and segmentectomy. The most frequent site of LR was the mediastinum. Conclusions: Our investigation demonstrated that nodal stage is directly associated with DR and OS but not with LR. Thus, even some patients with, N0-N1 disease are at relatively high risk of local recurrence. Prospective

  9. Percentages of NKT cells in the tissues of patients with non-small cell lung cancer who underwent surgical treatment.

    Science.gov (United States)

    Pyszniak, Maria; Rybojad, Paweł; Pogoda, Katarzyna; Jabłonka, Andrzej; Bojarska-Junak, Agnieszka; Tabarkiewicz, Jacek

    2014-03-01

    Natural killer T (NKT) cells are involved in the antitumor response by direct cytotoxicity and indirectly through activation of effector cells. Recent studies have shown a relationship between the number and function of NKT cells and clinical outcomes. NKT cells seem to represent a promising tool for immunotherapy of cancer. The aim of the study was to evaluate the distribution of NKT cells in peripheral blood, lymph nodes and tumor tissue of non-small cell lung cancer (NSCLC) patients, as well as development of the most efficient set of cytokines stimulating differentiation of NKT cells. We evaluated the percentage of iNKT+CD3+ cells in the tissues collected from patients with NSCLC. For the generation of NKT cells, we cultured cells isolated from the blood of 20 healthy donors and from the tissues of 4 NSCLC patients. Cells were stimulated with α-GalCer in combinations with cytokines. We noted significant differences in the percentages of NKT cells in the patients' tissues. The highest percentage of these cells was observed in the tumor tissue and the lowest in the lymph nodes. In vitro, in healthy donors all α-GalCer-cytokine combinations were effective in stimulation of NKT cells' proliferation. NKT cells' proliferation was the most efficiently stimulated by α-GalCer+IL-2+IL-7 and α-GalCer+IL-2+IFN-γ. Our results suggest that in the course of NSCLC, NKT cells migrate to the primary tumor and accumulate therein. All tested combinations of α-GalCer and cytokines were capable of generation of NKT cells in vitro.

  10. Cathepsin B mediates caspase-independent cell death induced by microtubule stabilizing agents in non-small cell lung cancer cells.

    NARCIS (Netherlands)

    Broker, L.E.; Huisman, C.; Span, SW; Rodriguez, J.A.; Kruyt, F.A.E.; Giaccone, G.

    2004-01-01

    We have previously reported that the microtubule stabilizing agents (MSAs) paclitaxel, epothilone B and discodermolide induce caspase-independent cell death in non-small cell lung cancer (NSCLC) cells. Here we present two lines of evidence indicating a central role for the lysosomal protease

  11. Coxsackie-adenovirus receptor as a novel marker of stem cells in treatment-resistant non-small cell lung cancer.

    Science.gov (United States)

    Zhang, Xiaochun; Fang, Bingliang; Mohan, Radhe; Chang, Joe Y

    2012-11-01

    Treatment resistance resulting from the presence of cancer stem cells (CSCs) remains a challenge in cancer treatment. Little is known about possible markers of CSCs in treatment-resistant non-small cell lung cancer (NSCLC). We explored the coxsackie-adenovirus receptor (CAR) as one such marker of CSCs in models of treatment-resistant NSCLC. Resistant H460 and A549 cell lines were established by repeated exposure to paclitaxel or fractionated radiation. CSC markers were measured by Western blotting and flow cytometry. We also established stable CAR-overexpressing and stable shRNA-CAR-knockdown cell lines and assessed their survival, invasiveness, and tumorigenic capabilities with clonogenic, telomerase, Matrigel, and tumor formation assays. CAR expression was associated with CSC phenotype both in vitro and in vivo. CAR-overexpressing cells were more treatment-resistant, self-renewing, and tumorigenic than were parental cells, and shRNA-mediated knockdown of CAR expression was sufficient to inhibit these functions. CAR expression also correlated with the epithelial-mesenchymal transition. We showed for the first time that CAR is a marker of CSCs and may affect the activities of CSCs in treatment-resistant NSCLC. CAR may prove to be a target for CSC treatment and a predictor of treatment response in patients with NSCLC. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  12. Coxsackie- and adenovirus receptor as a novel marker of stem cells in treatment-resistant non-small cell lung cancer

    Science.gov (United States)

    Zhang, Xiaochun; Fang, Bingliang; Mohan, Radhe; Chang, Joe Y.

    2013-01-01

    Background Treatment resistance resulting from the presence of cancer stem cells (CSCs) remains a challenge in cancer treatment. Little is known about possible markers of CSCs in treatment-resistant non-small cell lung cancer (NSCLC). We explored the coxsackie- and adenovirus receptor (CAR) as one such marker of CSCs in models of treatment-resistant NSCLC. Materials and methods Resistant H460 and A549 cell lines were established by repeated exposure to paclitaxel or fractionated radiation. CSC markers were measured by western blotting and flow cytometry. We also established stable CAR-overexpressing and stable shRNA-CAR-knockdown cell lines and assessed their survival, invasiveness, and tumorigenic capabilities with clonogenic, telomerase, Matrigel, and tumor formation assays. Results CAR expression was associated with CSC phenotype both in vitro and in vivo. CAR-overexpressing cells were more treatment-resistant, self-renewing, and tumorigenic than were parental cells, and shRNA-mediated knockdown of CAR expression was sufficient to inhibit these functions. CAR expression also correlated with the epithelial-mesenchymal transition. Conclusions We showed for the first time that CAR is a marker of CSCs and may affect the activities of CSCs in treatment-resistant NSCLC. CAR may prove to be a target for CSC treatment and a predictor of treatment response in patients with NSCLC. PMID:23022172

  13. Clinical application of radiofrequency ablation combined with bronchial artery infusion of docetaxel in treating non-small cell lung cancer

    International Nuclear Information System (INIS)

    Lu Xiong; Chen Fang; Lin Yun; Tan Taikang; Wei Wei

    2010-01-01

    Objective: To discuss the clinical application of radiofrequency ablation combined with bronchial artery infusion of docetaxel in treating non-small cell lung cancer and to summarize the experience of using this therapy in clinical practice. Methods: Radiofrequency ablation was performed in twenty-one patients with lung cancer. The diagnosis was confirmed by CT-guided percutaneous needle biopsy or bronchoscopic biopsy in all patients. One week after radiofrequency ablation treatment, bronchial artery infusion of docetaxel was conducted. The therapeutic results were observed and evaluated. Results: After the treatment, the lesion's size was markedly reduced and the clinical symptoms were dramatically improved in all patients. Conclusion: Radiofrequency ablation combined with bronchial artery infusion of docetaxel is a safe, effective and simple technique with excellent therapeutic results for the treatment of non-small cell lung cancer. It is really worth popularizing this technique in clinical practice. (authors)

  14. Factors associated with disease-specific survival of patients with non-small cell lung cancer.

    Science.gov (United States)

    Souza, Mirian Carvalho de; Cruz, Oswaldo Gonçalves; Vasconcelos, Ana Glória Godoi

    2016-01-01

    Lung cancer is a global public health problem and is associated with high mortality. Lung cancer could be largely avoided by reducing the prevalence of smoking. The objective of this study was to analyze the effects of social, behavioral, and clinical factors on the survival time of patients with non-small cell lung cancer treated at Cancer Hospital I of the José Alencar Gomes da Silva National Cancer Institute, located in the city of Rio de Janeiro, Brazil, between 2000 and 2003. This was a retrospective hospital cohort study involving 1,194 patients. The 60-month disease-specific survival probabilities were calculated with the Kaplan-Meier method for three stage groups. The importance of the studied factors was assessed with a hierarchical theoretical model after adjustment by Cox multiple regression. The estimated 60-month specific-disease lethality rate was 86.0%. The 60-month disease-specific survival probability ranged from 25.0% (stages I/II) to 2.5% (stage IV). The performance status, the intention to treat, and the initial treatment modality were the major prognostic factors identified in the study population. In this cohort of patients, the disease-specific survival probabilities were extremely low. We identified no factors that could be modified after the diagnosis in order to improve survival. Primary prevention, such as reducing the prevalence of smoking, is still the best method to reduce the number of people who will suffer the consequences of lung cancer. O câncer de pulmão é um problema de saúde pública global e é associado a elevada mortalidade. Ele poderia ser evitado em grande parte com a redução da prevalência do tabagismo. O objetivo deste estudo foi analisar os efeitos de fatores sociais, comportamentais e clínicos sobre o tempo de sobrevida de pacientes com câncer de pulmão de células não pequenas atendidos, entre 2000 e 2003, no Hospital do Câncer I do Instituto Nacional de Câncer José Alencar Gomes da Silva, localizado na

  15. Gemcitabine, cisplatin, and hyperfractionated accelerated radiotherapy for locally advanced non-small cell lung cancer.

    Science.gov (United States)

    Zwitter, Matjaz; Kovac, Viljem; Smrdel, Uros; Strojan, Primoz

    2006-09-01

    Due to potent radiosensitization and potential serious or fatal toxicity, concurrent gemcitabine and irradiation should only be applied within clinical trials. We here present experience from a phase I-II clinical trial for patients with locally advanced non-small cell lung cancer (NSCLC) treated with hyperfractionated accelerated radiotherapy and concurrent low-dose gemcitabine. Eligible patients had locally advanced inoperable NSCLC without pleural effusion, Eastern Cooperative Oncology Group performance status 0-1, were chemotherapy naïve and had no previous radiotherapy to the chest, and had adequate hematopoietic, liver, and kidney function. Routine brain computed tomography was not performed, and positron emission tomography/computed tomography was not available. Treatment consisted of three parts: induction chemotherapy with gemcitabine and cisplatin in standard doses, local treatment with concurrent chemotherapy and radiotherapy, and consolidation chemotherapy. Patients were irradiated with opposed AP-PA and oblique fields, using 2.5-D treatment planning. Although corrections for inhomogeneous tissue were made, volume of total lung receiving > or =20 Gy (V20) could not be determined. The trial started as phase I, aimed to determine the dose-limiting toxicity and maximal tolerated dose (MTD) for concurrent hyperfractionated radiotherapy (1.4 Gy twice daily) and gemcitabine 55 mg/m twice weekly as a radiosensitizer. Phase II of the trial then continued at the level of MTD. Twenty-eight patients with NSCLC, nine patients with stage IIIA, 16 patients with IIIB, and three patients with an inoperable recurrence after previous surgery, entered the trial. The first 12 patients entered Phase I of the trial at the initial level of 42 Gy in 30 fractions in 3 weeks. Dose-limiting toxicity was acute esophagitis; 47.6 Gy in 34 fractions in 3.5 weeks was the MTD for this regimen of concurrent chemotherapy and radiotherapy. In phase II of the trial, this dose was applied

  16. Evaluation of adaptive treatment planning for patients with non-small cell lung cancer

    Science.gov (United States)

    Zhong, Hualiang; Siddiqui, Salim M.; Movsas, Benjamin; Chetty, Indrin J.

    2017-06-01

    The purpose of this study was to develop metrics to evaluate uncertainties in deformable dose accumulation for patients with non-small cell lung cancer (NSCLC). Initial treatment plans (primary) and cone-beam CT (CBCT) images were retrospectively processed for seven NSCLC patients, who showed significant tumor regression during the course of treatment. Each plan was developed with IMRT for 2 Gy  ×  33 fractions. A B-spline-based DIR algorithm was used to register weekly CBCT images to a reference image acquired at fraction 21 and the resultant displacement vector fields (DVFs) were then modified using a finite element method (FEM). The doses were calculated on each of these CBCT images and mapped to the reference image using a tri-linear dose interpolation method, based on the B-spline and FEM-generated DVFs. Contours propagated from the planning image were adjusted to the residual tumor and OARs on the reference image to develop a secondary plan. For iso-prescription adaptive plans (relative to initial plans), mean lung dose (MLD) was reduced, on average from 17.3 Gy (initial plan) to 15.2, 14.5 and 14.8 Gy for the plans adapted using the rigid, B-Spline and FEM-based registrations. Similarly, for iso-toxic adaptive plans (considering MLD relative to initial plans) using the rigid, B-Spline and FEM-based registrations, the average doses were 69.9  ±  6.8, 65.7  ±  5.1 and 67.2  ±  5.6 Gy in the initial volume (PTV1), and 81.5  ±  25.8, 77.7  ±  21.6, and 78.9  ±  22.5 Gy in the residual volume (PTV21), respectively. Tumor volume reduction was correlated with dose escalation (for isotoxic plans, correlation coefficient  =  0.92), and with MLD reduction (for iso-fractional plans, correlation coefficient  =  0.85). For the case of the iso-toxic dose escalation, plans adapted with the B-Spline and FEM DVFs differed from the primary plan adapted with rigid registration by 2.8  ±  1

  17. Prognostic value of tumor-to-blood standardized uptake ratio in patients with resectable non-small-cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Seung Hyeon; Pak, Kyoung June; Kim, In Joo [Dept. of Nuclear Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan(Korea, Republic of); Kim, Bum Soo; Kim, Seong Jang [Dept. of Nuclear Medicine and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan (Korea, Republic of)

    2017-09-15

    Previously published studies showed that the standard tumor-to-blood standardized uptake value (SUV) ratio (SUR) was a more accurate prognostic method than tumor maximum standardized uptake value (SUVmax). This study evaluated and compared prognostic value of positron emission tomography (PET) parameters and normalized value of PET parameters by blood pool SUV in non-small-cell lung cancer (NSCLC) patients who received curative surgery.

  18. Systemic disease-induced salivary biomarker profiles in mouse models of melanoma and non-small cell lung cancer.

    OpenAIRE

    Kai Gao; Hui Zhou; Lei Zhang; Jin Wook Lee; Qing Zhou; Shen Hu; Lawrence E Wolinsky; James Farrell; Guido Eibl; David T Wong

    2009-01-01

    Background Saliva (oral fluids) is an emerging biofluid poised for detection of clinical diseases. Although the rationale for oral diseases applications (e.g. oral cancer) is intuitive, the rationale and relationship between systemic diseases and saliva biomarkers are unclear. Methodology/Principal Findings In this study, we used mouse models of melanoma and non-small cell lung cancer and compared the transcriptome biomarker profiles of tumor-bearing mice to those of control mice. Microarray ...

  19. Computed tomography of the brain, chest, and abdomen in the preoperative assessment of non-small cell lung cancer.

    OpenAIRE

    Grant, D; Edwards, D; Goldstraw, P

    1988-01-01

    The benefit to be gained from carrying out computed tomography of brain and abdomen in addition to the chest has been evaluated retrospectively in 114 consecutive patients with non-small cell lung cancer who, on the basis of history, clinical examination, chest radiography, and bronchoscopy had been considered potentially operable. Computed tomography of the chest showed potentially inoperable tumour in 37 patients, of whom 25 had tumour confined to the chest. Three patients were shown to hav...

  20. Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) of Yunnan in southwestern China

    OpenAIRE

    Zhou, Yongchun; Yang, Yanlong; Yang, Chenggang; Chen, Yunlan; Yang, Changshao; Du, Yaxi; Zhao, Guangqiang; Ye, Lianhua; Huang, Yunchao

    2017-01-01

    To investigate the Epidermal Growth Factor Receptor (EGFR) mutation status in non-small cell lung cancer (NSCLC) in Yunnan province in southwestern China, we detected EGFR mutation by Amplification Refractory Mutation System (ARMS) polymerase chain reaction (PCR) using DNA samples from 447 pathologically confirmed NSCLC specimens (175 tissue, 256 plasma and 16 cytologic samples). The relationship between EGFR mutations and demographic and clinical factors were further explored. Subgroup analy...

  1. Is stereotactic ablative radiotherapy an alternative to surgery in operable stage I non-small cell lung cancer?

    OpenAIRE

    Filippi, Andrea Riccardo; Franco, Pierfrancesco; Ricardi, Umberto

    2013-01-01

    Surgery is the gold therapeutic standard for patients affected with stage I non-small cell lung cancer. Stereotactic ablative radiotherapy is currently considered the preferred treatment option for inoperable patients, representing approximately 25%. Limited data are available directly comparing surgery and SABR in operable patients, none of them prospective. Preliminary results are encouraging, showing that the two treatment modalities are equally effective in terms of tumour control, with e...

  2. Value of window technique in diagnosis of the ground glass opacities in patients with non-small cell pulmonary cancer

    OpenAIRE

    Yao, Gang

    2016-01-01

    The aim of the present study was to examine the value of window technique in qualitative diagnosis of the ground glass opacities (GGO) in patients with non-small cell pulmonary cancer. A total of 124 clinically suspected pulmonary cancer patients were analyzed retrospectively. The lesions were affirmed by puncture biopsy, and were GGO on pulmonary window while were invisible on mediastinal window. Sixty-four multi-detector spiral computed tomography with the window width and window level of 1...

  3. Patients with ROS1 rearrangement?positive non?small?cell lung cancer benefit from pemetrexed?based chemotherapy

    OpenAIRE

    Song, Zhengbo; Su, Haiyan; Zhang, Yiping

    2016-01-01

    Abstract ROS1 gene?rearrangement in non?small?cell lung cancer (NSCLC) patients has recently been identified as a driver gene and benefited from crizotinib treatment. However, no data are available for ROS1?positive NSCLC about chemotherapeutic options and prognostic data. We investigated pemetrexed?based treatment efficacy in ROS1 translocation NSCLC patients and determined the expression of thymidylate synthetase (TS) to provide a rationale for the efficacy results. We determined the ROS1 s...

  4. Activity of crizotinib over choroidal metastases in Non-Small-Cell Lung Cancer (NSCLC)-ALK rearranged: a case report

    OpenAIRE

    Bearz, Alessandra; Santarossa, Sandra; Manfrè, Antonio; Beltrame, Giorgio; Urbani, Martina; Sartor, Ivana; Da Ros, Valentina; Tirelli, Umberto

    2014-01-01

    Background Adenocarcinoma of the lung with EML4-ALK translocation is a rare subtype of Non Small-Cell Lung Cancer (NSCLC) that has recently shown to benefit from treatment with crizotinib. Despite the concerns about the efficacy of crizotinib over cerebral metastases, some reports have described its activity, although always after local treatment with radiotherapy. Recently it has been reported activity of crizotinib over choroidal metastases, again after radiotherapy. Case presentation Herei...

  5. Induction chemotherapy followed by concurrent radiotherapy and chemotherapy in stage III non-small cell lung cancer

    International Nuclear Information System (INIS)

    Bouillet, T.; MOrere, J.F.; Piperno-Neuman, S.; Boaziz, C.; Breau, J.L.; Mazeron, J.J.; Haddad, E.

    1997-01-01

    The purpose was to determine the efficacy and safety of induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of stage III non-small cell lung cancer and whether the response to induction chemotherapy can predict the response to subsequent chemoradiotherapy and survival. In conclusion, there is a statistically significant relationship not only between the response to ICT and the response to CCrt, but also between the response to ICT and the local outcome and survival. (authors)

  6. Non-Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases.

    Science.gov (United States)

    Isozaki, Hideko; Ichihara, Eiki; Takigawa, Nagio; Ohashi, Kadoaki; Ochi, Nobuaki; Yasugi, Masayuki; Ninomiya, Takashi; Yamane, Hiromichi; Hotta, Katsuyuki; Sakai, Katsuya; Matsumoto, Kunio; Hosokawa, Shinobu; Bessho, Akihiro; Sendo, Toshiaki; Tanimoto, Mitsune; Kiura, Katsuyuki

    2016-03-15

    Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult. ©2015 American Association for Cancer Research.

  7. Ceritinib (LDK378): a potent alternative to crizotinib for ALK-rearranged non-small-cell lung cancer.

    Science.gov (United States)

    Li, Sen; Qi, Xiaolong; Huang, Yufeng; Liu, Dingfeng; Zhou, Fangyu; Zhou, Caicun

    2015-03-01

    The success in identifying the chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) as an oncogenic driver has thoroughly changed the treatment of non-small-cell lung cancer. In the past decade, targeted drugs have emerged as an efficient personalized strategy for ALK-rearranged non-small-cell lung cancer. The accelerated approval of potent ALK inhibitors, such as crizotinib and more recently ceritinib (LDK378), based on the well designed phase I/II trials has been a landmark success in clinical cancer research and contributes a new era of oncogenic targeted therapy characterized by elegant clinical trial design. In this review, we aim to present the current knowledge on acquired resistance of crizotinib known as a first-in-class ALK inhibitor and potential solutions to improve the cost-effectiveness, and to review the difference between ceritinib and crizotinib; preclinical data and results of the elegant early clinical trial of ceritinib which promoted its accelerated approval, pharmacokinetics, safety profile, and tolerability, the updated results (eg, efficacy on brain metastases), and robust design of ongoing phase II/III trials, and future directions of ceritinib to be a potent alternative to crizotinib for ALK-rearranged non-small-cell lung cancer are also presented. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Serum long non coding RNA MALAT-1 protected by exosomes is up-regulated and promotes cell proliferation and migration in non-small cell lung cancer.

    Science.gov (United States)

    Zhang, Rui; Xia, Yuhong; Wang, Zhixin; Zheng, Jie; Chen, Yafei; Li, Xiaoli; Wang, Yu; Ming, Huaikun

    2017-08-19

    Circulating lncRNAs have been defined as a novel biomarker for non-small cell lung cancer (NSCLC), MALAT-1 was first identified lncRNA that was related to lung cancer metastasis. However, the relationship between exosomal lncRNAs and the diagnosis and prognosis of NSCLC was poorly understood. The aim of this study is to evaluate the clinical significance of serum exosomal MALAT-1 as a biomarker in the metastasis of NSCLC. In this study, we firstly isolated the exosomes from healthy subjects and NSCLC patients. Then we measured the expression levels of MALAT-1 contained in exosomes, and found that exosomal MALAT-1 was highly expressed in NSCLC patients, more importantly, the levels of exosomal MALAT-1 were positively associated with tumor stage and lymphatic metastasis. In addition, we decreased MALAT-1 expression by short hairpin RNA and conducted a series of assays including MTT, cell cycle, colony formation, wound-healing scratch and Annexin/V PI by flow cytometry in human lung cancer cell lines. These in vitro studies demonstrated that serum exosome-derived long noncoding RNA MALAT-1 promoted the tumor growth and migration, and prevented tumor cells from apoptosis in lung cancer cell lines. Taken together, this study shed a light on utilizing MALAT-1 in exosomes as a non-invasive serum-based tumor biomarker for diagnosis and prognosis of NSCLC. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Cisplatin sensitivity is enhanced in non-small cell lung cancer cells by regulating epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2.

    Science.gov (United States)

    Xu, Guodong; Yu, Hui; Shi, Xinbao; Sun, Lebo; Zhou, Qingyun; Zheng, Dawei; Shi, Huoshun; Li, Ni; Zhang, Xianning; Shao, Guofeng

    2014-11-07

    Epithelial-mesenchymal transition (EMT) has been believed to be related with chemotherapy resistance in non-small cell lung cancer (NSCLC). Recent studies have suggested eIF5A-2 may function as a proliferation-related oncogene in tumorigenic processes. We used cell viability assays, western blotting, immunofluorescence, transwell-matrigel invasion assay, wound-healing assay combined with GC7 (a novel eIF5A-2 inhibitor) treatment or siRNA interference to investigate the role of eIF5A-2 playing in NSCLC chemotherapy. We found low concentrations of GC7 have little effect on NSCLC viability, but could enhance cisplatin cytotoxicity in NSCLC cells. GC7 also could reverse mesenchymal phenotype in NCI-H1299 and prevented A549 cells undergoing EMT after TGF-β1 inducement. eIF5A-2 knockdown resulted in EMT inhibition. Our data indicated GC7 enhances cisplatin cytotoxicity and prevents the EMT in NSCLC cells by inhibiting eIF5A-2.

  10. Gefitinib (Iressa) in metastatic patients with non-small cell lung cancer: preliminary experience in a Brazilian center.

    Science.gov (United States)

    del Giglio, Auro; Ito, Cristina

    2004-05-06

    Patients with metastatic non-small cell lung cancer are deemed incurable, but they may derive some benefit from systemic palliative chemotherapy. Recently, with the introduction of epidermal growth factor receptor (EGFR) antagonists such as gefitinib (Iressa), an effective and less toxic option is now available for the treatment of such patients. To assess the activity and toxicity of gefitinib in a group of Brazilian patients. Prospective, open label, non-randomized and non-controlled. Clínica de Oncologia e Hematologia (CLIOH), São Paulo, Brazil. From June 2002 to April 2003 we treated five patients with metastatic previously-treated non-small cell lung cancer (median of two previous chemotherapy regimens), using gefitinib at a dose of 250 mg orally on a daily basis, within a compassionate protocol sponsored by AstraZeneca. The patients' median age was 65 years and two of them were male. Three had a performance status of 1, one of 2 and one of 3, on the ECOG (Eastern Cooperative Oncology Group) scale. We observed skin rash in two patients, diarrhea in three and arthralgia in two. One patient had a partial response and another had stabilization of her disease, as measured via imaging studies (which have lasted for more than 11 and 4 months, respectively), which were accompanied by significant decrease in tumor markers, whereas three patients worsened during treatment. New options of chemotherapy agents with favorable toxicity profiles are urgently needed for the treatment of metastatic non-small lung cancer patients who usually have short life expectancies. In our small series of five patients, we observed stabilization of the disease in two of them and the skin and gastrointestinal reactions often described in the literature in all of them. Two had arthralgia, not reported before. We concluded that gefitinib is an important addition to the therapeutic armamentarium for patients with metastatic non-small cell lung cancer.

  11. [A Paired Case Controlled Study Comparing the Short-term Outcomes of Da Vinci RATS and VATS Approach for Non-small Cell Lung Cancer].

    Science.gov (United States)

    Dai, Feng; Xu, Shiguang; Xu, Wei; Ding, Renquan; Liu, Bo; Meng, Hao; Kang, Yunteng; Meng, Xiangrui; Lin, Jie; Wang, Shumin

    2018-03-20

    Da Vinci Surgical System is one of the greatest inventions of the 20th century, which represents the development direction of the precise minimally invasive surgical techniques, the aim of this study was to comparing the short-term outcomes between da Vinci robot-assisted lobectomy and video-assisted thoracic surgery (VATS) lobectomy for non-small cell lung cancer. 45 pairs of non-small cell lung cancer patients underwent pulmonary lobectomy with da Vinci Robotic assisted thoracoscopic (RATS) and VATS approach during the same period from January 2014 to January 2017. The operative time, estimated blood loss (EBL), total number and total groups of dissected lymph nodes, postoperative duration of drainage, the first day volume of drainage, total volume of drainage were compared. No perioperative death and convertion to thoracotomy occured in both groups. There were significant difference between RATS group and VATS group in EBL [(50.30±32.33) mL vs (208.60±132.63) mL], the first day volume of drainage [(275.00±145.42) mL vs (347.60±125.80) mL], the dissected total number [(22.67±9.67) vs (15.51±5.41)] and total team [(6.31±1.43) vs (4.91±1.04)] of lymph node. There were no significant difference in other outcomes. RATS is safe and effective and took better short-outcomes than VATS in non-small cell lung cancer.

  12. Analysis of the Factors Associated with Abnormal Coagulation and Prognosis
in Patients with Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Yanhua LI

    2014-11-01

    Full Text Available Background and objective The activation of coagulation and fibrinolysis is frequently encountered among cancer patients. Such tumors are associated with high risk of invasion, metastases, and negative final outcomes. Non-small cell lung cancer (NSCLC accounts for approximately 80% to 85% of all lung malignancies. This study aims to investigate the prognostic value of blood coagulation tests for NSCLC and provide a reference to patients on the prevention and treatment of thrombophilia. Methods Data were collected from 604 cases of hospitalized patients with histologically confirmed NSCLC from January 2009 to December 2012 at the Fourth Hospital of Hebei Medical University. Data included the related indexes of coagulation function in patients before treatment [(i.e., prothrombin time (PT, prothrombin time activity (PTA, international normalized ratio (INR, activated partial thromboplastin time (APTT, fibrinogen (Fib, D-dimer, and platelet count], as well as sex, age, pathological type, TNM stage, and lymph node status. Fifty control subjects without cancer were included in the analysis. Statistical analysis was conducted by using SPSS 13.0 software. Results The plasma level of all coagulation tests including D-dimer, Fib, PT, APTT, INR, and platelet counts revealed statistically significant differences between the patient and control group (P<0.001 for all variables; P=0.001,5 and P=0.004,5 for Fib and platelet counts, respectively. The squamous subtype exhibited high plasma Fib levels (P<0.001 compared with adenocarcinoma cell lung cancer patients. Fib and PLT levels increased (P<0.001 and P=0.014, respectively, and aPTT decreased (P<0.001 in patients at stages III and IV compared with those in patients at stages I and II. aPTT decreased significantly (P<0.001, and Fib and D-dimer levels increased (P<0.001 and P=0.048, respectively in N1-3 patients with NSCLC compared with those of N0 patients. Prolonged PT and INR, high plasma Fib levels, and

  13. Lipoteichoic acids from Staphylococcus aureus stimulate proliferation of human non-small-cell lung cancer cells in vitro.

    Science.gov (United States)

    Hattar, Katja; Reinert, Christian P; Sibelius, Ulf; Gökyildirim, Mira Y; Subtil, Florentine S B; Wilhelm, Jochen; Eul, Bastian; Dahlem, Gabriele; Grimminger, Friedrich; Seeger, Werner; Grandel, Ulrich

    2017-06-01

    Pulmonary infections are frequent complications in lung cancer and may worsen its outcome and survival. Inflammatory mediators are suspected to promote tumor growth in non-small-cell lung cancer (NSCLC). Hence, bacterial pathogens may affect lung cancer growth by activation of inflammatory signalling. Against this background, we investigated the effect of purified lipoteichoic acids (LTA) of Staphylococcus aureus (S. aureus) on cellular proliferation and liberation of interleukin (IL)-8 in the NSCLC cell lines A549 and H226. A549 as well as H226 cells constitutively expressed TLR-2 mRNA. Even in low concentrations, LTA induced a prominent increase in cellular proliferation of A549 cells as quantified by automatic cell counting. In parallel, metabolic activity of A549 cells was enhanced. The increase in proliferation was accompanied by an increase in IL-8 mRNA expression and a dose- and time-dependent release of IL-8. Cellular proliferation as well as the release of IL-8 was dependent on specific ligation of TLR-2. Interestingly, targeting IL-8 by neutralizing antibodies completely abolished the LTA-induced proliferation of A549 cells. The pro-proliferative effect of LTA could also be reproduced in the squamous NSCLC cell line H226. In summary, LTA of S. aureus induced proliferation of NSCLC cell lines of adeno- and squamous cell carcinoma origin. Ligation of TLR-2 followed by auto- or paracrine signalling by endogenously synthesized IL-8 is centrally involved in LTA-induced tumor cell proliferation. Therefore, pulmonary infections may exert a direct pro-proliferative effect on lung cancer growth.

  14. Function and regulation of LAG3 on CD4+CD25- T cells in non-small cell lung cancer.

    Science.gov (United States)

    Ma, Qin-Yun; Huang, Da-Yu; Zhang, Hui-Jun; Wang, Shaohua; Chen, Xiao-Feng

    2017-11-15

    LAG3 is a surface molecule found on a subset of immune cells. The precise function of LAG3 appears to be context-dependent. In this study, we investigated the effect of LAG3 on CD4 + CD25 - T cells from non-small cell lung cancer (NSCLC) patients. We found that in the peripheral blood mononuclear cells of NSCLC patients, LAG3 was significantly increased in CD4 + T cells directly ex vivo and primarily in the CD4 + CD25 - fraction, which was regulated by prolonged TCR stimulation and the presence of IL-27. TCR stimulation also increased CD25 expression, but not Foxp3 expression, in LAG3-expressing CD4 + CD25 - cells Compared to LAG3-nonexpressing CD4 + CD25 - cells, LAG3-expressing CD4 + CD25 - cells presented significantly higher levels of PD1 and TIM3, two inhibitory receptors best described in exhausted CD8 + T effector cells. LAG3-expressing CD4 + CD25 - cells also presented impaired proliferation compared with LAG3-nonexpressing CD4 + CD25 - cells but could be partially rescued by inhibiting both PD1 and TIM3. Interestingly, CD8 + T cells co-incubated with LAG3-expressing CD4 + CD25 - cells at equal cell numbers demonstrated significantly lower proliferation than CD8 + T cells incubated alone. Co-culture with CD8 + T cell and LAG3-expressing CD4 + CD25 - T cell also upregulated soluble IL-10 level in the supernatant, of which the concentration was positively correlated with the number of LAG3-expressing CD4 + CD25 - T cells. In addition, we found that LAG3-expressing CD4 + CD25 - T cells infiltrated the resected tumors and were present at higher frequencies of in metastases than in primary tumors. Taken together, these data suggest that LAG3-expressing CD4 + CD25 - T cells represent another regulatory immune cell type with potential to interfere with anti-tumor immunity. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ting; Han, Shuai; Wu, Zhipeng; Han, Zhitao; Yan, Wangjun; Liu, Tielong; Wei, Haifeng; Song, Dianwen; Zhou, Wang, E-mail: brilliant212@163.com; Yang, Xinghai, E-mail: cnspineyang@163.com; Xiao, Jianru, E-mail: jianruxiao83@163.com

    2015-08-21

    Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1.

  16. Albendazole inhibits HIF-1α-dependent glycolysis and VEGF expression in non-small cell lung cancer cells.

    Science.gov (United States)

    Zhou, Fang; Du, Jin; Wang, Jianjun

    2017-04-01

    Albendazole (ABZ) has an anti-tumor ability and inhibits HIF-1α activity. HIF-1α is associated with glycolysis and vascular endothelial cell growth factor (VEGF) expression, which plays an important role in cancer progression. These clues indicate that ABZ exerts an anti-cancer effect by regulating glycolysis and VEGF expression. The aim of this study is to clarify the effects of ABZ on non-small cell lung cancer (NSCLC) cells and explore the underlying molecular mechanisms. The expression levels of HIF-1α and VEGF were detected using western blot analysis, and the effect of ABZ on glycolysis was evaluated by measuring the relative activities of hexokinase (HK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) and detecting the production of lactate in A549 and H1299 cells. The results showed that ABZ decreased the expression levels of HIF-1α and VEGF and suppressed glycolysis in under hypoxia, but not normoxic condition. Inhibiting HIF-1α also suppressed glycolysis and VEGF expression. Additionally, ABZ inhibited the volume and weight, decreased the relative activities of HK, PK, and LDH, and reduced the levels of HIF-1α and VEGF of A549 xenografts in mouse models. In conclusion, ABZ inhibited growth of NSCLC cells by suppressing HIF-1α-dependent glycolysis and VEGF expression.

  17. Upregulation of miR-146a increases cisplatin sensitivity of the non-small cell lung cancer A549 cell line by targeting JNK-2.

    Science.gov (United States)

    Pang, Linrong; Lu, Jinger; Huang, Jia; Xu, Caihong; Li, Hui; Yuan, Guangbo; Cheng, Xiaochun; Chen, Jun

    2017-12-01

    The aim of the present study was to investigate the effects of microRNA (miR-)146a on the cisplatin sensitivity of the non-small cell lung cancer (NSCLC) A549 cell line and study the underlying molecular mechanism. The differences in expression of miRNAs between A549 and A549/cisplatin (A549/DDP) cells were determined, and miR-146a was selected to study its effect on cisplatin sensitivity of A549/DDP cells. miR-146a mimic and inhibitor transient transfection systems were constructed using vectors, and A549/DDP cells were infected with miR-146a mimic and inhibitor to investigate growth, apoptosis and migration. The directed target of miR-146a was determined and the underlying molecular mechanism was validated in the present study. The results of the present study demonstrated that miR-146a was downregulated in NSCLC A549/DDP cells, compared with A549 cells. The overexpression of miR-146a induced apoptosis and inhibited the growth and invasion of A549/DDP cells, which resulted in increased cisplatin sensitivity in NSCLC cells. The JNK2 gene was determined as the direct target of miR-146a, and may be activated by the overexpression of miR-146a. Additionally, JNK2 activated the expression of p53 and inhibited B cell lymphoma 2. The upregulation of miR-146a increased cisplatin sensitivity of the A549 cell line by targeting JNK2, which may provide a novel method for treating NSCLC cisplatin resistance.

  18. TRAIL-coated lipid-nanoparticles overcome resistance to soluble recombinant TRAIL in non-small cell lung cancer cells

    Science.gov (United States)

    De Miguel, Diego; Gallego-Lleyda, Ana; María Ayuso, José; Erviti-Ardanaz, Sandra; Pazo-Cid, Roberto; del Agua, Celia; José Fernández, Luis; Ochoa, Ignacio; Anel, Alberto; Martinez-Lostao, Luis

    2016-05-01

    Purpose. Non-small cell lung cancer (NSCLC) is one the types of cancer with higher prevalence and mortality. Apo2-Ligand/TRAIL is a TNF family member able to induce apoptosis in tumor cells but not in normal cells. It has been tested in clinical trials against different types of human cancer including NSCLC. However, results of clinical trials have shown a limited efficacy of TRAIL-based therapies. Recently we have demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) greatly improved TRAIL cytotoxic ability being capable of killing chemoresistant hematological cancer cells. In the present work we have extended the study to NSCLC. Methods/patients. LUV-TRAIL-induced cytotoxicity was assessed on different NSCLC cell lines with different sensitivity to soluble TRAIL and on primary human tumor cells from three patients suffering from NSCLC cancer. We also tested LUV-TRAIL-cytotoxic ability in combination with several anti-tumor agents. Results. LUV-TRAIL exhibited a greater cytotoxic effect compared to soluble TRAIL both in A549 cells and primary human NSCLC cells. LUV-TRAIL-induced cell death was dependent on caspase-8 and caspase-3 activation. Moreover, combination of LUV-TRAIL with other anti-tumor agents such as flavopiridol, and SNS-032 clearly enhanced LUV-TRAIL-induced cytotoxicity against NSCLC cancer cells. Conclusion. The novel formulation of TRAIL based on displaying it on the surface of lipid nanoparticles greatly increases its anti-tumor activity and has clinical potential in cancer treatment.

  19. TRAIL-coated lipid-nanoparticles overcome resistance to soluble recombinant TRAIL in non-small cell lung cancer cells

    International Nuclear Information System (INIS)

    De Miguel, Diego; Gallego-Lleyda, Ana; Erviti-Ardanaz, Sandra; Anel, Alberto; Martinez-Lostao, Luis; Ayuso, José María; Fernández, Luis José; Ochoa, Ignacio; Pazo-Cid, Roberto; Del Agua, Celia

    2016-01-01

    Purpose. Non-small cell lung cancer (NSCLC) is one the types of cancer with higher prevalence and mortality. Apo2-Ligand/TRAIL is a TNF family member able to induce apoptosis in tumor cells but not in normal cells. It has been tested in clinical trials against different types of human cancer including NSCLC. However, results of clinical trials have shown a limited efficacy of TRAIL-based therapies. Recently we have demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) greatly improved TRAIL cytotoxic ability being capable of killing chemoresistant hematological cancer cells. In the present work we have extended the study to NSCLC. Methods/patients. LUV-TRAIL-induced cytotoxicity was assessed on different NSCLC cell lines with different sensitivity to soluble TRAIL and on primary human tumor cells from three patients suffering from NSCLC cancer. We also tested LUV-TRAIL-cytotoxic ability in combination with several anti-tumor agents. Results. LUV-TRAIL exhibited a greater cytotoxic effect compared to soluble TRAIL both in A549 cells and primary human NSCLC cells. LUV-TRAIL-induced cell death was dependent on caspase-8 and caspase-3 activation. Moreover, combination of LUV-TRAIL with other anti-tumor agents such as flavopiridol, and SNS-032 clearly enhanced LUV-TRAIL-induced cytotoxicity against NSCLC cancer cells. Conclusion. The novel formulation of TRAIL based on displaying it on the surface of lipid nanoparticles greatly increases its anti-tumor activity and has clinical potential in cancer treatment. (paper)

  20. Chemotherapy for advanced non-small cell lung cancer in the elderly population

    Directory of Open Access Journals (Sweden)

    Fábio Nasser Santos

    Full Text Available ABSTRACT BACKGROUND: Approximately 50% of patients with newly diagnosed non-small cell lung cancer (NSCLC are over 70 years of age at diagnosis. Despite this fact, these patients are underrepresented in randomized controlled trials (RCTs. As a consequence, the most appropriate regimens for these patients are controversial, and the role of single-agent or combination therapy is unclear. In this setting, a critical systematic review of RCTs in this group of patients is warranted. OBJECTIVES: To assess the effectiveness and safety of different cytotoxic chemotherapy regimens for previously untreated elderly patients with advanced (stage IIIB and IV NSCLC. To also assess the impact of cytotoxic chemotherapy on quality of life. METHODS: Search methods: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 10, MEDLINE (1966 to 31 October 2014, EMBASE (1974 to 31 October 2014, and Latin American Caribbean Health Sciences Literature (LILACS (1982 to 31 October 2014. In addition, we handsearched the proceedings of major conferences, reference lists from relevant resources, and the ClinicalTrial.gov database. Selection criteria: We included only RCTs that compared non-platinum single-agent therapy versus non-platinum combination therapy, or non-platinum therapy versus platinum combination therapy in patients over 70 years of age with advanced NSCLC. We allowed inclusion of RCTs specifically designed for the elderly population and those designed for elderly subgroup analyses. Data collection and analysis: Two review authors independently assessed search results, and a third review author resolved disagreements. We analyzed the following endpoints: overall survival (OS, one-year survival rate (1yOS, progression-free survival (PFS, objective response rate (ORR, major adverse events, and quality of life (QoL. MAIN RESULTS: We included 51 trials in the review: non-platinum single-agent therapy

  1. Phenotypic modification of human glioma and non-small cell lung carcinoma by glucocorticoids and other agents.

    Science.gov (United States)

    McLean, J S; Frame, M C; Freshney, R I; Vaughan, P F; Mackie, A E; Singer, I

    1986-01-01

    Glucocorticoids are cytostatic for human glioma grown at a high cell density in cell culture. The effect is not cytotoxic, appears to involve a modification of the cell surface, and has been detected with methyl prednisolone, dexamethasone, and beta-methasone. Glucocorticoids were also found to reduce malignancy-associated properties (plasminogen activator and endothelial mitogenesis) and enhance differentiation (glutamyl synthetase activity and high affinity GABA uptake). Cytostasis was also seen at high cell densities in non-small cell lung carcinoma with a concomitant reduction in plasminogen activator activity and endothelial mitogenesis. Preliminary data on surfactant production in A549 cells suggests that the repression of malignancy-associated properties is accompanied by an increase in cell differentiation. Treatment of the WIL adenocarcinoma gown as a xenograft in nude mice caused total cessation of growth and massive central necrosis in the tumor.

  2. Molecular, biological characterization and drug sensitivity of chidamide-resistant non-small cell lung cancer cells

    Science.gov (United States)

    Luo, Song'e; Ma, Kai; Zhu, Hongxia; Wang, Shuren; Liu, Mei; Zhang, Weina; Liang, Shufang; Xu, Ningzhi

    2017-01-01

    Chidamide, a histone deacetylase (HDAC) inhibitor, has been applied in clinical trials for various types of hematological and solid tumors. Although acquired resistance is common in chemotherapy, the mechanism of resistance to chidamide is poorly characterized. The goal of the present study was to explore, in detail, the mechanism for the induced resistance to chidamide, and investigate a potential cross-resistance to other chemotherapeutic drugs. A549 cells were exposed to gradually increasing chidamide concentrations to establish a chidamide-resistant non-small cell lung cancer cell line (A549-CHI-R). The IC50 for chidamide, the proliferation inhibition rate, the total HDAC activity and the HDAC protein level were determined by an MTT assay, colony formation, a fluorometric HDAC activity assay and western blotting, respectively. Overexpression of the HDAC1 gene and HDAC1 gene-knockdown were achieved via plasmid transfection. A549-CHI-R cells demonstrated increased resistance to chidamide (8.6-fold). HDAC1 protein degradation was inhibited and HDAC activity was significantly higher in the A549-CHI-R cells relative to the parental A549 cells. A549-CHI-R cells demonstrated cross-resistance to paclitaxel, vinorelbine and gemcitabine, but not to cisplatin (CDDP) or 5-fluorouracil (5-FU). These results indicated that HDAC1 may be associated with resistance to chidamide, and HDAC1 may therefore be a predictive marker for chidamide sensitivity in cancer. In addition, A549-CHI-R cells remained sensitive to 5-FU and CDDP, indicating a potential strategy for cancer therapy. PMID:29344124

  3. Detection of E2A-PBX1 fusion transcripts in human non-small-cell lung cancer

    OpenAIRE

    Mo, Min-Li; Chen, Zhao; Zhou, Hai-Meng; Li, Hui; Hirata, Tomomi; Jablons, David M; He, Biao

    2013-01-01

    Background E2A-PBX1 fusion gene caused by t(1;19)(q23;p13), has been well characterized in acute lymphoid leukemia (ALL). There is no report on E2A-PBX1 fusion transcripts in non-small-cell lung cancer (NSCLC). Methods We used polymerase chain reaction (PCR) to detect E2A-PBX1 fusion transcripts in human NSCLC tissue specimens and cell lines. We analyzed correlation of E2A-PBX1 fusion transcripts with clinical outcomes in 76 patients with adenocarcinoma in situ (AIS) and other subgroups. We c...

  4. Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population

    DEFF Research Database (Denmark)

    Li, Yafang; Xiao, Xiangjun; Han, Younghun

    2018-01-01

    Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between SNPs and smoking status (never vs ever smokers) in a European-descent population. We...... of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and p-value of 8.12x10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung...

  5. Heterogeneous resistance mechanisms in an EGFR exon 19-mutated non-small cell lung cancer patient treated with erlotinib

    DEFF Research Database (Denmark)

    Santoni-Rugiu, Eric; Grauslund, Morten; Melchior, Linea C

    2017-01-01

    Patients with epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer (NSCLC) obtain substantial clinical benefit from EGFR tyrosine-kinase inhibitors (TKIs), but will ultimately develop TKI-resistance resulting in median progression-free survival of 9-15 months during first-line...... an alternative pathway to EGFR-signaling. The patient received first-line erlotinib but after only 7 weeks showed metastatic pleural effusion, in which transformation to small cell lung cancer (SCLC) that retained the EGFR- and FGFR3-mutations was identified. Consequently, standard carboplatin-etoposide regimen...

  6. Peroxisome Proliferator-Activated Receptor-γ Inhibits Transformed Growth of Non-Small Cell Lung Cancer Cells through Selective Suppression of Snail

    Directory of Open Access Journals (Sweden)

    Rashmi Choudhary

    2010-03-01

    Full Text Available Work from our laboratory and others has demonstrated that activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ inhibits transformed growth of non-small cell lung cancer (NSCLC cell lines in vitro and in vivo. We have demonstrated that activation of PPARγ promotes epithelial differentiation of NSCLC by increasing expression of E-cadherin, as well as inhibiting expression of COX-2 and nuclear factor-κB. The Snail family of transcription factors, which includes Snail (Snail1, Slug (Snail2, and ZEB1, is an important regulator of epithelial-mesenchymal transition, as well as cell survival. The goal of this study was to determine whether the biological responses to rosiglitazone, a member of the thiazolidinedione family of PPARγ activators, are mediated through the regulation of Snail family members. Our results indicate that, in two independent NSCLC cell lines, rosiglitazone specifically decreased expression of Snail, with no significant effect on either Slug or ZEB1. Suppression of Snail using short hairpin RNA silencing mimicked the effects of PPARγ activation, in inhibiting anchorage-independent growth, promoting acinar formation in three-dimensional culture, and inhibiting invasiveness. This was associated with the increased expression of E-cadherin and decreased expression of COX-2 and matrix metaloproteinases. Conversely, overexpression of Snail blocked the biological responses to rosiglitazone, increasing anchorage-independent growth, invasiveness, and promoting epithelial-mesenchymal transition. The suppression of Snail expression by rosiglitazone seemed to be independent of GSK-3 signaling but was rather mediated through suppression of extracellular signal-regulated kinase activity. These findings suggest that selective regulation of Snail may be critical in mediating the antitumorigenic effects of PPARγ activators.

  7. Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer

    Science.gov (United States)

    Nilsson, R. Jonas A.; Karachaliou, Niki; Berenguer, Jordi; Gimenez-Capitan, Ana; Schellen, Pepijn; Teixido, Cristina; Tannous, Jihane; Kuiper, Justine L.; Drees, Esther; Grabowska, Magda; van Keulen, Marte; Heideman, Danielle A.M.; Thunnissen, Erik; Dingemans, Anne-Marie C.; Viteri, Santiago; Tannous, Bakhos A.; Drozdowskyj, Ana; Rosell, Rafael; Smit, Egbert F.; Wurdinger, Thomas

    2016-01-01

    Purpose: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers. Platelets can sequester RNA released by tumor cells and are thus an attractive source for the non-invasive assessment of biomarkers. Methods: EML4-ALK rearrangements were analyzed by RT-PCR in platelets and plasma isolated from blood obtained from 77 patients with non-small-cell lung cancer, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, EML4-ALK rearrangements in platelets were correlated with progression-free and overall survival. Results: RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets. In the subset of 29 patients treated with crizotinib, progression-free survival was 3.7 months for patients with EML4-ALK+ platelets and 16 months for those with EML4-ALK− platelets (hazard ratio, 3.5; P = 0.02). Monitoring of EML4-ALK rearrangements in the platelets of one patient over a period of 30 months revealed crizotinib resistance two months prior to radiographic disease progression. Conclusions: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone. PMID:26544515

  8. MiR-424 Promotes Non-Small Cell Lung Cancer Progression and Metastasis through Regulating the Tumor Suppressor Gene TNFAIP1

    Directory of Open Access Journals (Sweden)

    Ming Zhang

    2017-05-01

    Full Text Available Background/Aims: This study aimed to investigate the potential roles of miR-424 expression in non-small cell lung cancer (NSCLC metastasis and growth and its underlying mechanism. Methods: The expression of miR-424 in two NSCLC cell lines (A549 and H1975 was altered by transfection with miR-424 mimic and inhibitor. Effects of miR-424 overexpression and suppression on cells migration, invasion and colony formation were analyzed. Target genes for miR-424 were predicted using bioinformatics method and then verified using luciferase assay. Effects of miR-424 expression on cell migration, invasion and proliferation were reanalyzed on the condition of TNFAIP1 was silenced. Moreover, TNFAIP1 silencing and miR-424 modified A549 cells were subcutaneous injected into node BALB/c mice to confirm the regulation of miR-424 on TNFAIP1 in regulating tumor growth. Results: Compared with the control, miR-424 overexpression significantly increased the migrated and invaded cells, as well as the proliferated colonies. TNFAIP1 was a predicted target gene for miR-424, and was negatively regulated by miR-424. TNFAIP1 silence significantly increased the migrated and invaded cells compared to that in control, while these increases were abolished by miR-424 suppression. Animal experiment further evidenced miR-424 affected tumor growth by regulating TNFAIP1. Conclusions: These data demonstrate that miR-424 may be a contributor for NSCLC progression and metastasis through involving in cell migration, invasion and proliferation via inhibiting TNFAIP1. This study may provide theoretical basis for miR-424 in NSCLC target therapeutic treatment.

  9. The long non-coding RNA HOTAIR indicates a poor prognosis and promotes metastasis in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Liu, Xiang-hua; Liu, Zhi-li; Sun, Ming; Liu, Jing; Wang, Zhao-xia; De, Wei

    2013-01-01

    The identification of cancer-associated long non-coding RNAs and the investigation of their molecular and biological functions are important for understanding the molecular biology and progression of cancer. HOTAIR (HOX transcript antisense intergenic RNA) has been implicated in several cancers; however, its role in non-small cell lung cancer (NSCLC) is unknown. The aim of the present study was to examine the expression pattern of HOTAIR in NSCLC and to evaluate its biological role and clinical significance in tumor progression. Expression of HOTAIR was analyzed in 42 NSCLC tissues and four NSCLC cell lines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Over-expression and RNA interference (RNAi) approaches were used to investigate the biological functions of HOTAIR. The effect of HOTAIR on proliferation was evaluated by MTT and colony formation assays, and cell migration and invasion were evaluated by transwell assays. Tail vein injection of cells was used to study metastasis in nude mice. Protein levels of HOTAIR targets were determined by western blot analysis. Differences between groups were tested for significance using Student’s t-test (two-tailed). HOTAIR was highly expressed both in NSCLC samples and cell lines compared with corresponding normal counterparts. HOTAIR upregulation was correlated with NSCLC advanced pathological stage and lymph-node metastasis. Moreover, patients with high levels of HOTAIR expression had a relatively poor prognosis. Inhibition of HOTAIR by RNAi decreased the migration and invasion of NSCLC cells in vitro and impeded cell metastasis in vivo. HOXA5 levels were affected by HOTAIR knockdown or over-expression in vitro. Our findings indicate that HOTAIR is significantly up-regulated in NSCLC tissues, and regulates NSCLC cell invasion and metastasis, partially via the down-regulation of HOXA5. Thus, HOTAIR may represent a new marker of poor prognosis and is a potential therapeutic target for NSCLC

  10. Ascorbic acid and a cytostatic inhibitor of glycolysis synergistically induce apoptosis in non-small cell lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Saleha B Vuyyuri

    Full Text Available Ascorbic acid (AA exhibits significant anticancer activity at pharmacologic doses achievable by parenteral administration that have minimal effects on normal cells. Thus, AA has potential uses as a chemotherapeutic agent alone or in combination with other therapeutics that specifically target cancer-cell metabolism. We compared the effects of AA and combinations of AA with the glycolysis inhibitor 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3-PO on the viability of three non-small cell lung cancer (NSCLC cell lines to the effects on an immortalized lung epithelial cell line. AA concentrations of 0.5 to 5 mM caused a complete loss of viability in all NSCLC lines compared to a <10% loss of viability in the lung epithelial cell line. Combinations of AA and 3-PO synergistically enhanced cell death in all NSCLC cell lines at concentrations well below the IC50 concentrations for each compound alone. A synergistic interaction was not observed in combination treatments of lung epithelial cells and combination treatments that caused a complete loss of viability in NSCLC cells had modest effects on normal lung cell viability and reactive oxygen species (ROS levels. Combination treatments induced dramatically higher ROS levels compared to treatment with AA and 3-PO alone in NSCLC cells and combination-induced cell death was inhibited by addition of catalase to the medium. Analyses of DNA fragmentation, poly (ADP-ribose polymerase cleavage, annexin V-binding, and caspase activity demonstrated that AA-induced cell death is caused via the activation of apoptosis and that the combination treatments caused a synergistic induction of apoptosis. These results demonstrate the effectiveness of AA against NSCLC cells and that combinations of AA with 3-PO synergistically induce apoptosis via a ROS-dependent mechanism. These results support further evaluation of pharmacologic concentrations of AA as an adjuvant treatment for NSCLC and that combination of AA with

  11. Tivantinib (ARQ 197) efficacy is independent of MET inhibition in non-small-cell lung cancer cell lines.

    Science.gov (United States)

    Calles, Antonio; Kwiatkowski, Nicholas; Cammarata, Bernard K; Ercan, Dalia; Gray, Nathanael S; Jänne, Pasi A

    2015-01-01

    MET targeted therapies are under clinical evaluation for non-small-cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKI) against MET have varying degrees of specificity. Tivantinib (ARQ 197) is reported to be a non-ATP competitive selective MET inhibitor. We aimed to compare the activity of tivantinib to established MET TKIs in a panel of NSCLC cell lines characterized by their MET dependency and by different relevant genotypes. A549, H3122, PC9 and HCC827, their respective resistant clones PC9 GR4 and HCC827 GR6 and the MET amplified cell lines H1993 and EBC-1 were treated in vitro with tivantinib, crizotinib or PHA-665752. Crizotinib and PHA-665752 showed growth inhibition restricted to MET dependent cell lines. The pattern of activity was related to MET inhibition and downstream signaling inhibition of AKT and ERK1/2, resulting in G0/G1 cycle arrest and apoptosis. In contrast, tivantinib possessed more potent anti-proliferative activity that was not restricted to only MET dependent cell lines. Tivantinib did not inhibit cellular MET activity or phosphorylation of downstream signaling proteins AKT or ERK1/2 in either MET dependent or independent cell lines. Cell cycle analysis demonstrated that tivantinib induced a G2/M arrest and induced apoptosis. Tivantinib but not crizotinib effected microtubule dynamics, disrupting mitotic spindles by a mechanism consistent with it functioning as a microtubule depolymerizer. Tivantinib activity is independent of MET signaling in NSCLC and suggests alternative mechanisms of action that should be considered when interpreting the results from on-going clinical studies. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  12. DKK1 is a potential novel mediator of cisplatin-refractoriness in non-small cell lung cancer cell lines

    International Nuclear Information System (INIS)

    Salim, Hogir; Zong, Dali; Hååg, Petra; Novak, Metka; Mörk, Birgitta; Lewensohn, Rolf; Lundholm, Lovisa; Viktorsson, Kristina

    2015-01-01

    Platinum compounds are the mainstay of chemotherapy for lung cancer. Unfortunately treatment failure remains a critical issue since about 60 % of all non-small cell lung cancer (NSCLC) patients display intrinsic platinum resistance. We analyzed global gene expression profiles of NSCLC clones surviving a pulse treatment with cisplatin and mapped deregulated signaling networks in silico by Ingenuity Pathway Analysis (IPA). Further validation was done using siRNA. The pooled cisplatin-surviving NSCLC clones from each of the biological replicates demonstrated heterogeneous gene expression patterns both in terms of the number and the identity of the altered genes. Genes involved in Wnt signaling pathway (Dickkopf-1, DKK1), DNA repair machinery (XRCC2) and cell-cell/cell-matrix interaction (FMN1, LGALS9) were among the top deregulated genes by microarray in these replicates and were validated by q-RT-PCR. We focused on DKK1 which previously was reported to be overexpressed in NSCLC patients. IPA network analysis revealed coordinate up-regulation of several DKK1 transcriptional regulators (TCF4, EZH2, DNAJB6 and HDAC2) in cisplatin-surviving clones from that biological replicate. Knockdown of DKK1 by siRNA sensitized for cisplatin in two different NSCLC cell lines and in ovarian A2780 cells, but not in the A2780 cis subline made resistant to cisplatin by chronic exposure, suggesting a role of DKK1 in intrinsic but not acquired platinum refractoriness. We identified DKK1 as a possible marker of a cisplatin-refractory phenotype and as a potential novel therapeutic target to improve platinum response of NSCLC cells. The online version of this article (doi:10.1186/s12885-015-1635-9) contains supplementary material, which is available to authorized users

  13. Prognostic factors for patients with inoperable non-small cell lung cancer, limited disease

    International Nuclear Information System (INIS)

    Kaasa, S.; Mastekaasa, A.; Lund, E.

    1989-01-01

    In a prospective controlled clinical trial, 102 patients with inoperable non-small lung cancer (NSCLC), limited disease, stage II and III were treated with combination chemotherapy, cisplatin 70 mg/m 2 i.v. on day one and etoposide 100 mg/m 2 i.v. on day one, and etoposide 200 mg/m 2 orally on days 2 and 3, or radiotherapy given in 15 fractions of 2.8 Gy with two anterior/posterior fields during a period of three weeks. The patients completed a validated self-administered questionnaire before the start of treatment that assessed their psychosocial well-being, disease-related symptoms, personal functioning, and every day activity. These subjective varibles were evaluated together with treatment modality, WHO performance status, weight loss, and stage of disease, with regard to their value in predicting survival. Univariate survival analyses were undertaken for each individual factor, median survival was calculated according to life-table analyses. A step-wise multiple regression analysis was used to measure the prognostic value of the various factors. In the univariate analysis, general symptons (p=0.0006) psychosocial well-being (p=0.0002) and stage of disease (p=0.007) were the best predictive factors. In the multiple regression analyses the subjective variables, general symptons (p<0.01) and psychosocial well-being (p<0.05) were shown to have the best predictive value for the patients' survival. (author). 20 refs.; 4 figs.; 3 tabs

  14. Personalized medicine for non-small-cell lung cancer: implications of recent advances in tissue acquisition for molecular and histologic testing.

    Science.gov (United States)

    Moreira, Andre L; Thornton, Raymond H

    2012-09-01

    In light of recent advances in individualized therapy for non-small-cell lung cancer (NSCLC), molecular and histologic profiling is essential for guiding therapeutic decisions. Results of these analyses may have implications for both response (eg, molecular testing for EGFR [epidermal growth factor receptor] mutations) and safety (eg, contraindications for squamous histology) in NSCLC. Most patients with NSCLC present with unresectable advanced disease; therefore, greater emphasis is being placed on minimally invasive tissue acquisition techniques, such as small biopsy and cytology specimens. Due to the need for increasing histologic and molecular information and increasingly smaller tissue sample sizes, efforts must be focused on optimizing tissue acquisition and the development of more sensitive molecular assays. Recent advances in tissue acquisition techniques and specimen preservation may help to address this challenge and lead to enhanced personalized treatment in NSCLC. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Identification of I1171N resistance mutation in ALK-positive non-small-cell lung cancer tumor sample and circulating tumor DNA.

    Science.gov (United States)

    Johnson, Alison C; Dô, Pascal; Richard, Nicolas; Dubos, Catherine; Michels, Jean Jacques; Bonneau, Jessica; Gervais, Radj

    2016-09-01

    Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is sensitive to ALK inhibitor therapy, but resistance invariably develops and can be mediated by certain secondary mutations. The detection of these mutations is useful to guide treatment decisions, but tumors are not always easily accessible to re-biopsy. We report the case of a patient with ALK-rearranged NSCLC who presented acquired resistance to crizotinib and then alectinib. Sequencing analyses of DNA from a liver metastasis biopsy sample and circulating tumor DNA both found the same I1171N ALK kinase domain mutation, known to confer resistance to certain ALK inhibitors. However, the patient then received ceritinib, a 2nd generation ALK inhibitor, and achieved another partial response. This case underlines how ALK resistance mutation detection in peripheral blood could be a reliable, safer, and less invasive alternative to tissue-based samples in NSCLC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L)

    International Nuclear Information System (INIS)

    Nakamura, Kenichi; Shibata, Taro; Saji, Hisashi; Nakajima, Ryu; Tada, Hirohito; Okada, Morihito; Asamura, Hisao; Nakamura, Shinichiro; Tsuboi, Masahiro

    2010-01-01

    A Phase III study was started in Japan to evaluate the non-inferiority in overall survival of segmentectomy compared with lobectomy in patients with small-sized (diameter ≤2 cm) peripheral non-small cell lung cancer, excluding radiologically determined non-invasive cancer. This study began in August 2009, and a total of 1100 patients will be accrued from 71 institutions within 3 years. The primary endpoint is overall survival. The secondary endpoints are post-operative respiratory function, relapse-free survival, proportion of local recurrence, adverse events, proportion of patients who complete segmentectomy, duration of hospitalization, duration of chest tube placement, operation time, blood loss and number of auto-sutures used. This study is one of the first intergroup studies in Japan between the Japan Clinical Oncology Group and the West Japan Oncology Group. (author)

  17. Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells

    Directory of Open Access Journals (Sweden)

    Coffey Matthew C

    2009-07-01

    Full Text Available Abstract Background Reovirus type 3 Dearing strain (ReoT3D has an inherent propensity to preferentially infect and destroy cancer cells. The oncolytic activity of ReoT3D as a single agent has been demonstrated in vitro and in vivo against various cancers, including colon, pancreatic, ovarian and breast cancers