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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A not negligible proportion of NSCLC patients may be considered eligible for a third-line therapy with a palliative intent. Unfortunately, it is not uncommon to observe toxic side-effects with lack of efficacy. Aim of our study was to analyse clinical factors potentially influencing the global outcome of advanced NSCLC patients receiving third-line therapy. Patients with histologically proven inoperable (IIIB) or metastatic (IV) NSCLC, who received a second- and third-line treatment (either with EGFR-TKIs or chemotherapy), were eligible for our analysis. 143 patients received a second-line treatment after failing a first line cisplatin-based chemotherapy. 52 patients from this series were offered a third-line treatment. In the third-line setting, a better overall survival (months) was related to sex and to response to second-line. Globally, our findings seem to indicate that an improved overall survival in third-line is more strictly dependent on response to second-line, thus suggesting that when planning a third-line treatment, response to second-line should be considered as a relevant factor for the decision making process.
Lung Cancer 2010 Jun
PMID:Clinical predictive factors for advanced non-small cell lung cancer (NSCLC) patients receiving third-line therapy: Selecting the unselectable? 1966 42

The molecule of lidamycin that belongs to the chromoprotein family of antitumor antibiotics is composed of an apoprotein (LDP) and an enediyne chromophore. The enediyne moiety of the molecule is responsible for the potent cytotoxicity; however, the biological function of the apoprotein moiety, particularly its interaction with cancer cells, remains unclear. In present study, the binding capability of LDP to human tumors was detected for the first time by tissue microarray. LDP bound to various human tumors with significant difference from the corresponding normal tissues. Positive correlation between binding activity and the overexpression of VEGF and EGFR was confirmed by lung carcinoma tissue microarray. A fusion protein LG-LDP that consists of LDP and a ligand oligopeptide to EGFR was constructed by DNA recombination. LG-LDP showed augmented binding to EGFR-overexpressing cancer cells. Furthermore, an energized fusion protein LG-LDP-AE was prepared by integrating the active enediyne (AE) into LG-LDP molecule. By MTT assay, LG-LDP-AE displayed extremely potent cytotoxicity to cancer cells with IC50 approximate to 0.01nM. The results indicate that LDP binds to various human tumors and it might serve as a delivery carrier by integration of ligand oligopeptide to manufacture motif-based, targeted fusion proteins for cancer.
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PMID:Binding capability of the enediyne-associated apoprotein to human tumors and constitution of a ligand oligopeptide-integrated protein. 1973 85

The role of thromboxane receptor alpha (TPalpha) in tumor growth and angiogenesis was investigated in a nude mice model and in cell culture. Stable human lung cancer A549 cells over-expressing TPalpha (A549-TPalpha) was generated and used to inoculate athymic nude mice. A549-TPalpha cells induced greater tumor growth and increased vascularization in tumors than in the control A549 cells. Increased angiogenesis was further verified by studying the induction of vascular endothelial growth factor (VEGF) in A549-TPalpha cells. I-BOP, an agonist of TP, stimulated the expression of VEGF in this cell line as well as in another human lung cancer H157 cells in a time and dose dependent manner. The expression of VEGF was determined at both the mRNA and protein levels. The signaling pathways that are involved in I-BOP-induced VEGF expression were further examined by the use of inhibitors. Inhibition of the extracellular signal-regulated kinase (ERK) activation blocked the induction almost completely indicating that ERK activation was an essential step in the induction. Each of the three upstream kinases, protein kinase A, EGFR kinase and Src kinase, contributed partially to the overall induction. However, PI 3-kinase and protein kinase C had minimal contribution. These results indicate that activation of the TPalpha induces the expression of VEGF through multiple signaling pathways.
Lung Cancer 2010 Jul
PMID:Thromboxane receptor alpha mediates tumor growth and angiogenesis via induction of vascular endothelial growth factor expression in human lung cancer cells. 1985 59

Screening for EGFR and KRAS mutations in patients with lung adenocarcinomas can be used to predict the patient's response to EGFR tyrosine kinase inhibitors, but there is a lack of guidelines for testing in clinical practice. We analyzed the morphological and clinicopathological characteristics, including tumor stage, size, presence of scar, inflammatory response, angiolymphatic and pleural invasion, of 345 surgically treated primary lung adenocarcinomas with respect to their EGFR and KRAS mutational profile and EGFR FISH. EGFR and KRAS mutations were found in 33 (10%) and 78 (23%) of lung adenocarcinomas, respectively, whereas 226 (67%) cases were negative for both mutations. There was a large overlap in the analyzed clinicopathological characteristics among the three study groups. Statistically significant predictors for the presence of EGFR mutations included history of never smoking (OR 5.939; 95% Wald confidence limit 1.662-21.223, P=0.0149), mild lymphocytic host response (OR 4.724; 95% Wald confidence limit 1.33-1.776; P=0.0163), female gender (OR 2.571; 95% Wald confidence limit 1.015-6.511, P=0.0463) and absence of solid growth pattern. Statistically significant predictors for the presence of KRAS mutations included older age (OR 1.034; 95% Wald confidence limit 1.007-1.062, P=0.0132), history of smoking (OR 0.617, 95% Wald confidence limit 0.357-1.066, P=0.0412) and mucinous differentiation. EGFR FISH positivity as defined by the Colorado criteria was a significant predictor of EGFR mutations, with high polysomy as the strongest predictive criteria. Despite statistically significant differences among the study groups and because of the large overlap in the analyzed clinicopathological criteria, none of these could be implemented as the selection criteria for molecular testing in clinical practice. The cost-effectiveness of lung carcinoma mutational testing would be improved by initial determination of KRAS mutational status as negative predictor of the patient's response to EGFR tyrosine kinase inhibitors, followed by EGFR mutational analysis, if necessary.
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PMID:Clinicopathological predictors of EGFR/KRAS mutational status in primary lung adenocarcinomas. 1985 75

Lipid raft, a specialized membrane structure enriched with cholesterol and glycosphingolipid, contains molecules that convey environmental stimuli to the intracellular systems. Authors investigated the effects of raft cholesterol depletion on non-small cell lung cancer (NSCLC) cell migration. Incubation of NSCLC cells in media containing lovastatin resulted in inhibition of cell migration by 63.1-83.3%, whereas raft cholesterol depletion with successive treatment using methyl-beta cyclodextrin (MbetaCD) followed by lovastatin further suppressed their migration by 35.0-57.8%. Raft cholesterol depletion partially inhibited EGF-induced phosphorylation of EGFR and FAK, however, no change was observed in other molecules comprising focal adhesion complex. It resulted in disappearance of filopodia, inhibition of EGF-induced pY397 FAK aggregation, and its destabilization. Cholesterol depletion inhibited phosphorylation of Src on Y416 in the detergent-insoluble fraction followed by decreased localization of total and pY397 FAK in the detergent-insoluble fraction. Minimal changes in these molecules were observed in the detergent-soluble fraction and interactions between FAK and other molecules of the focal adhesion complex were not influenced. Immunocytochemical analysis confirmed translocation of Src from the raft into cytoplasm and disappearance of EGF-induced membrane ruffling by raft cholesterol depletion. In cholesterol-depleted cells, EGF-induced phosphorylation of Src, Akt, and p44/42 in the detergent-insoluble fraction were inhibited whereas phosphorylation of GSK-3beta was unaffected. We conclude that raft cholesterol depletion inhibited NSCLC migration through inhibition of phosphorylation of raft associated Src and dislocation of molecules comprising focal adhesion complexes from raft rather than by inhibiting their recruitment to Src and interaction.
Lung Cancer 2010 Aug
PMID:Lipid raft modulation inhibits NSCLC cell migration through delocalization of the focal adhesion complex. 1994 66

The activation status of signal transduction pathways involving receptor tyrosine kinases and its association with EGFR or KRAS mutations have been widely studied using cancer cell lines, although it is still uncertain in primary tumors. To study the activation status of main components of growth factor-induced pathways, phosphorylated Akt (pAkt), extracellular signal-regulated kinases 1 and 2 (pERK) and other downstream proteins were immunohistochemically examined using surgical samples of 193 primary lung adenocarcinomas. Also, thyroid transcription factor-1 (TTF-1) expression and mutation status of EGFR and KRAS were examined. Advanced tumor stages (p<0.001), negative TTF-1 expression (p<0.001) and Akt activation (p=0.015) were independent and significant poor prognostic markers. Akt activation related to advanced stage (p=0.021), invasiveness (p=0.004), and not to mutations. TTF-1 expression associated with never-smoker (p=0.013), pre- or minimally invasiveness (p<0.001) and EGFR mutations (p=0.017) as well as with pERK (p=0.039) expression. EGFR mutations did not correlated with pAkt and pERK expression, which was different from the results based on cultured cells, while KRAS mutations were solely and significantly linked to ERK activation (p=0.009). In lung adenocarcinoma, tumors with TTF-1 expression have distinct characteristics regarding mutations, signal protein activation and clinical issues. Moreover, this property was revealed to be important in outcome estimation at any tumor stage, whereas Akt activation is abnormally affected according to the tumor stage regardless of their cell origin. The signal proteins were differently related to mutation status from cultured cells.
Lung Cancer 2010 Oct
PMID:Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations. 2011 55

The low rate of approval of novel anti-cancer agents underscores the need for better preclinical models of therapeutic response as neither xenografts nor early-generation genetically engineered mouse models (GEMMs) reliably predict human clinical outcomes. Whereas recent, sporadic GEMMs emulate many aspects of their human disease counterpart more closely, their ability to predict clinical therapeutic responses has never been tested systematically. We evaluated the utility of two state-of-the-art, mutant Kras-driven GEMMs--one of non-small-cell lung carcinoma and another of pancreatic adenocarcinoma--by assessing responses to existing standard-of-care chemotherapeutics, and subsequently in combination with EGFR and VEGF inhibitors. Standard clinical endpoints were modeled to evaluate efficacy, including overall survival and progression-free survival using noninvasive imaging modalities. Comparisons with corresponding clinical trials indicate that these GEMMs model human responses well, and lay the foundation for the use of validated GEMMs in predicting outcome and interrogating mechanisms of therapeutic response and resistance.
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PMID:Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. 2053 33

The fusion gene EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) was recently identified as a novel genetic alteration in non-small-cell lung cancer. The clinicopathological features of EML4-ALK-positive adenocarcinoma are reported to include its high incidence in young, non-smoking patients, tumors that show distinct solid or acinar growth patterns with or without signet-ring cell histology, and its mutually exclusive occurrence with mutations in EGFR and KRAS. However, the clinical findings have not been well described. Here, we report a case of EML4-ALK-positive lung adenocarcinoma that showed multiple metachronous lesions on the pleura and pulmonary field, suspected to be a recurrence of lung adenocarcinoma after a 20-year disease-free interval. The slow clinical course may be characteristic of EML4-ALK-positive lung adenocarcinoma. Therefore, long-term observation of patients with EML4-ALK-positive lung adenocarcinomas is required after surgery.
Lung Cancer 2010 Sep
PMID:Recurrent EML4-ALK-associated lung adenocarcinoma with a slow clinical course. 2065 20

The potential differential effect of first-line treatment and molecular mechanisms on survival to second-line chemotherapy or EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) has not been fully investigated. In particular, CHFR is frequently methylated in NSCLC and may influence outcome. We analyzed the outcome of second-line chemotherapy or EGFR TKIs in 179 of 366 patients who had been treated in an ERCC1 mRNA-based customized cisplatin trial and correlated the results with CHFR methylation status. CHFR methylation in circulating DNA was examined by methylation-specific assay. A panel of seven human EGFR wild-type NSCLC cell lines was characterized for their sensitivity to sequential treatment with cisplatin and erlotinib, and the results were correlated with CHFR. Patients who had received first-line docetaxel/cisplatin attained an overall survival of 19.2 months when treated with second-line EGFR TKIs, in comparison with 10.7 months when treated with second-line chemotherapy (P = 0.0002). However, for patients who had received first-line docetaxel/gemcitabine, overall survival was 14.8 months with EGFR TKIs and 10.8 months with chemotherapy (P = 0.29). For patients with unmethylated CHFR overall survival to EGFR TKIs was 21.4 months, and 11.2 months for those with treated with chemotherapy (P = 0.0001). In the only lung tumor cell line not expressing CHFR, pretreatment with cisplatin was antagonistic to erlotinib, while it was synergistic in the other six lines. Second-line EGFR TKIs improved survival in patients receiving first-line cisplatin-based treatment. Unmethylated CHFR predicts increased survival to EGFR TKIs.
Lung Cancer 2011 Apr
PMID:First-line therapy and methylation status of CHFR in serum influence outcome to chemotherapy versus EGFR tyrosine kinase inhibitors as second-line therapy in stage IV non-small-cell lung cancer patients. 2070 57

Lung carcinoma is the most frequent cause of cancer death in Germany. It is characterized by a considerable morphological complexity that has been reduced by clinicians to the distinction between small cell (SCLC) and non-small cell carcinoma (NSCLC). Underpinned by the possibilities of more differentiated tumor therapy, the classification of lung cancer has undergone a re-evaluation, some essential developments of which are summarized in this article. SCLC and NSCLC do not only differ in gene expression and genetic alterations but also in the ploidy level: SCLC is typically hypodiploid, NSCLC often hyperdiploid/near-triploid. Immunohistochemical analysis is meanwhile standard and includes in particular the markers p63, TTF-1, CK5/6, CK7, CD56/NCAM, synaptophysin, chromogranin and Ki67. A new interdisciplinary classification of adenocarcinoma differentiates between preinvasive, minimally invasive and invasive lesions. Lending new weight to the predominantly histological growth patterns it includes information on molecular genetic alterations such as EGFR mutations.
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PMID:[Morphological and molecular pathology of lung cancer]. 2085 64


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