Qiuhua Deng

Development and validation of a nomogram for predicting survival in patients with resected non-small-cell lung cancer.

PURPOSEnA nomogram is a useful and convenient tool for individualized cancer prognoses. We sought to develop a clinical nomogram for predicting survival of patients with resected non-small-cell lung cancer (NSCLC).nnnPATIENTS AND METHODSnOn the basis of data from a multi-institutional registry of 6,111 patients with resected NSCLC in China, we identified and integrated significant prognostic factors for survival to build a nomogram. The model was subjected to bootstrap internal validation and to external validation with a separate cohort of 2,148 patients from the International Association for the Study of Lung Cancer (IASLC) database. The predictive accuracy and discriminative ability were measured by concordance index (C-index) and risk group stratification.nnnRESULTSnA total of 5,261 patients were included for analysis. Six independent prognostic factors were identified and entered into the nomogram. The calibration curves for probability of 1-, 3-, and 5-year overall survival (OS) showed optimal agreement between nomogram prediction and actual observation. The C-index of the nomogram was higher than that of the seventh edition American Joint Committee on Cancer TNM staging system for predicting OS (primary cohort, 0.71 v 0.68, respectively; P < .01; IASLC cohort, 0.67 v 0.64, respectively; P = .06). The stratification into different risk groups allowed significant distinction between survival curves within respective TNM categories.nnnCONCLUSIONnWe established and validated a novel nomogram that can provide individual prediction of OS for patients with resected NSCLC. This practical prognostic model may help clinicians in decision making and design of clinical studies.

MicroRNA-26a/b Regulate DNA Replication Licensing, Tumorigenesis, and Prognosis by Targeting CDC6 in Lung Cancer

Cancer is characterized by mutations, genome rearrangements, epigenetic changes, and altered gene expression that enhance cell proliferation, invasion, and metastasis. To accommodate deregulated cellular proliferation, many DNA replication-initiation proteins are overexpressed in human cancers. However, the mechanism that represses the expression of these proteins in normal cells and the cellular changes that result in their overexpression are largely unknown. One possible mechanism is through miRNA expression differences. Here, it is demonstrated that miR26a and miR26b inhibit replication licensing and the proliferation, migration, and invasion of lung cancer cells by targeting CDC6. Importantly, miR26a/b expression is significantly decreased in human lung cancer tissue specimens compared with the paired adjacent normal tissues, and miR26a/b downregulation and the consequential upregulation of CDC6 are associated with poorer prognosis of patients with lung cancer. These results indicate that miR26a/b repress replication licensing and tumorigenesis by targeting CDC6. Implications: The current study suggests that miR26a, miR26b, and CDC6 and factors regulating their expression represent potential cancer diagnostic and prognostic markers as well as anticancer targets. Visual Overview: http://mcr.aacrjournals.org/content/12/11/1535/F1.large.jpg. Mol Cancer Res; 12(11); 1535–46. ©2014 AACR. Visual Overview

Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas

The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.

The expression of p33 ING1 , p53, and autophagy-related gene Beclin1 in patients with non-small cell lung cancer

The purpose of this study was to investigate the expressions of tumor inhibitor of growth (ING1) gene p33ING1, p53, and autophagy-related gene Beclin1 in human non-small cell lung cancer (NSCLC), and the correlation between their expressions with clinical pathological features and clinical significance. The research can provide new ideas and experimental evidence for early diagnosis and biotherapy for NSCLC in the future. The human NSCLC tissues and surrounding non-cancerous tissues were collected from surgical operation. The expressions of mRNA or protein of p33ING1, p53, and Beclin1 were detected by using of reverse transcription polymerase chain reaction or Western blot in these tissues. The results were used to analyze the relationships between these gene expressions with the developing of NSCLC and clinical pathological features. The expressions of mRNA or protein of p33ING1 and Beclin1 in NSCLC tissues were significantly lower than that in surrounding noncancerous tissues (pu2009<u20090.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in well- and middle-differentiated NSCLC tissues were lower than those in poor-differentiated NSCLC tissues (pu2009<u20090.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in presence of lymph nodes metastasis were lower than those in absence of lymph nodes metastasis (pu2009<u20090.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in patients of pathological stage (stages I–II) were higher than those in pathological stage (stages III–IV) (pu2009<u20090.05). But the expression of protein of mutant-type p53 in NSCLC tissues was significantly higher than that in surrounding non-cancerous tissues (pu2009<u20090.05). The expressions of protein of mutant-type p53 in well- and middle-differentiated NSCLC tissues were higher than those in poor-differentiated NSCLC tissues (pu2009<u20090.05). The expressions of protein of mutant-type p53 in presence of lymph nodes metastasis were higher than those in absence of lymph nodes metastasis (pu2009<u20090.05). The expressions of protein of mutant-type p53 in patients of pathological stage (stages I–II) were lower than those in pathological stage (stages III–IV) (pu2009<u20090.05). These expression changes of p33ING1, p53, and autophagy-related Beclin1 genes were associated with tumor cell differentiation, lymph nodes metastasis, and pathological stage of NSCLC. But these expression changes of these three genes were not associated with gender, age, size of primary carcinoma, histological type of NSCLC (pu2009>u20090.05). The expression of mRNA of p53 and Beclin1 were correlated with p33ING1 mRNA expression in NSCLC tissues (pu2009<u20090.05). The activity changes of tumor inhibitor of growth, autophagy, and apoptosis may be related to the emergence and the development of NSCLC. The combined detection of p33ING1, p53, and Beclin1 genes and proteins will be helpful for early diagnosis and prognosis judgment for NSCLC, and can provide experimental evidence for biotherapy of NSCLC.

Heat shock protein-60 expression was significantly correlated with the prognosis of lung adenocarcinoma.

The purpose of this study was to investigate the role of heat shock protein 60 (HSP60) in the clinical pathology of lung adenocarcinoma, and to explore whether the expression of HSP60 can act as an independent predictor for tumor relapse and prognosis after radical resection of lung adenocarcinoma.

Erlotinib in combination with pemetrexed/cisplatin for leptomeningeal metastases and cerebrospinal fluid drug concentrations in lung adenocarcinoma patients after gefitinib faliure

Limited treatment options are available for lung cancer with brain metastases. Recent reports indicated that erlotinib and pemetrexed had synergistic effects in lung adenocarcinoma. Thus, we speculated that erlotinib plus pemetrexed/cisplatin may be more effective for the treatment of refractory central nervous system metastases in patients after gefitinib failure. Six lung adenocarcinoma patients with leptomeningeal metastasis (LM) who showed initial good response to gefitinib and subsequent gefitinib resistance were enrolled in this retrospective study. Five of the six patients had an epidermal growth factor receptor (EGFR) mutation in the primary tumor tissues or plasma. One patient showed complete remission, two patients showed a partial response, and two patients had stable disease. Performance and symptoms improved in the six patients. The survival time after the combination therapy was from 8 to 15xa0months (median, 9xa0months). There was no significant difference in cerebrospinal fluid (CSF) penetration rates of erlotinib between the erlotinib-only and the combination groups (Pu2009=u20090.44). Erlotinib combined with pemetrexed/cisplatin may be effective in the treatment of LM in EGFR mutation patients after gefitinib failure. Small but measurable penetration of erlotinib and pemetrexed into the CSF was observed.

High expression levels of class III β‑tubulin in resected non‑small cell lung cancer patients are predictive of improved patient survival after vinorelbine‑based adjuvant chemotherapy

The aim of the present study was to determine the frequency and predictive value of the expression of tumor microtubule components in patients with resected non-small cell lung cancer (R-NSCLC) subsequently treated with vinorelbine-based adjuvant chemotherapy. The expression of the microtubule components was evaluated in 85 R-NSCLC tumor samples using immunohistochemistry. All patients received vinorelbine-based chemotherapy. The predictive value of microtubule protein expression for disease-free survival (DFS) and overall survival (OS) was assessed. The expression of the microtubule components was not associated with any baseline clinicopathological factors in the R-NSCLC patients. High tumor expression levels of class III β-tubulin were correlated with an improved DFS (P=0.033) and a trend towards a longer OS (P=0.226). Class II and IV β-tubulins were not correlated with patient outcome. Multivariate analysis of factors, including gender, age, histology, stage and class II, III and IV β-tubulin expression demonstrated that high levels of class III β-tubulin expression were correlated independently with DFS (P= 0.031). These findings suggest that high class III β-tubulin expression levels in resected tumors are predictive of improved DFS in R-NSCLC patients receiving vinorelbine-based chemotherapy.

Prognostic value of ERCC1, RRM1, and TS proteins in patients with resected non‑small cell lung cancer

AbstractPurposenRecent clinical trials showed that expression of excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and thymidylate synthase (TS) proteins was able to predict the effects of non-small cell lung cancer (NSCLC) to chemotherapy. However, it remains unknown whether the adjuvant chemotherapy based on expression of the three proteins has survival significance in Chinese NSCLC patients.MethodsWe investigated 128 Chinese patients receiving chemotherapy after tumor resection for expression of these proteins using immunohistochemistry. Based on protein expression, patients were assigned to two groups for different adjuvant chemotherapy regimes. The disease-free survival (DFS) data were collected and analyzed using Kaplan–Meier curves and Cox models.ResultsWe found that DFS of these patients with carboplatin and a third-generation agent (gemcitabine or pemetrexed) stratified by protein expression showed no statistical difference between individual treatment versus non-individuation treatment analyzed using Kaplan–Meier method (Pxa0=xa00.143, median 23.9 vs. 30.8xa0months). Furthermore, the multivariate analysis showed that histology and tumor stages were independent predictors for DFS in these patients.ConclusionsnThe results suggest that chemotherapy based on ERCC1, RRM1, and TS expression did not have significant impact on DFS of patients with resection of NSCLC.

Establishment and characterization of a new drug surviving cell line Am1010, derived directly from muscle metastases of a human lung adenocarcinoma patient with multi-drug-resistance to cisplatin, taxol, and gefitinib

AbstractAim:To Characterize a new human lung cancer cell line Am1010, derived from drug-surviving cells (DSCs).Methods:The Am1010 cell line was established after 4 cycles of chemotherapy from an arm muscle metastasic tumor of a patient diagnosed with lung adenocarcinoma. The cell line has been remained in continuous culture for more than one year during this study.Results:The Am1010 cell line demonstrated in vitro multi-drug-resistance to cisplatin, taxol, and gefitinib. The Am1010 cell doubling time without drug treatment was 42.395 h. The IC50 value of cisplatin was 4.299 μmol/L and >10 μmol/L for the Am1010 and P0318 (a cell line derived from non-DSCs) cells, respectively. The IC50 value of taxol was 0.067 μmol/L and >1 μmol/L for the Am1010 and P0318 cells, respectively. The IC50 value of gefitinib was 15.233 μmol/L and >70 μmol/L for Am1010 and P0318 cells, respectively. 11 genes involved in the focal adhesion and cell adhesion pathways were found to be differentially expressed. The cells of Am1010 have a significantly larger chromosome number than most lung cancer cell lines.Conclusion:This novel DSCs derived lung cancer cell line will be a valuable in vitro tool for the investigation of lung cancer drug resistance and metastasis.

Comprehensive genomic profiling of lung cancer using a validated panel to explore therapeutic targets in East Asian patients

People of East Asian ethnicity have a different prevalence of and show unique clinical characteristics and tumor histology of oncogenic mutations. However, only limited studies have explored the landscape of genomic alterations in lung adenocarcinoma derived from Asian patients thus far. In this single‐center study, with an aim to elucidate the mutational profile of lung cancer in people of Chinese ethnicity and to use the obtained information to guide decision‐making for treatment, we employed a well‐validated assay to perform comprehensive genomic characterization of tumor specimens from 306 Chinese lung cancer patients. A total of 845 individual genomic alterations were found in 145 tumor‐related genes with a median of 2.8 alterations (range: 1–18) per sample. The most frequently mutated genes were EGFR (46.7%), TP53 (21.2%), ALK (12.1%; 8.8% of mutation and 3.3% of rearrangement) and KRAS (10.1%). Upon comparison with the Cancer Genome Atlas dataset, we found that EGFR was mutated at a much higher frequency in our cohort than in Caucasians, whereas KRAS was only found in 10.1% of our Chinese patients. Clinically relevant genomic alterations were identified in 185 (60.5%) patients, including 50% in adenocarcinoma patients and 14% in squamous cell carcinoma patients. Our findings suggest that the Asian ethnicity is significantly different from the Caucasian ethnicity with regard to the presence of somatic driver mutations. Furthermore, we showed that the use of a comprehensive genotyping approach could help identify actionable genomic alterations that have potential impact on therapeutic decisions.