Actin, a highly conserved protein, plays a dominant role in Non-small cell lung cancer (NSCLC). Late diagnosis and the aggressive nature of NSCLC pose a significant threat. Studying the clinic pathological properties ...Actin, a highly conserved protein, plays a dominant role in Non-small cell lung cancer (NSCLC). Late diagnosis and the aggressive nature of NSCLC pose a significant threat. Studying the clinic pathological properties of NSCLC proteins is a potential alternative for developing treatment strategies. Towards this, 35 downregulated actin cytoskeletal proteins on NSCLC prognosis and treatment were studied by examining their protein-protein interactions, gene ontology enrichment terms, and signaling pathways. Using PubMed, various proteins in NSCLC were identified. The protein-protein interactions and functional associations of these proteins were examined using the STRING database. The focal adhesion signaling pathway was selected from all available KEGG and Wiki pathways because of its role in regulating gene expression, facilitating cell movement and reproduction, and significantly impacting NSCLC. The protein-protein interaction network of the 35 downregulated actin cytoskeleton proteins revealed that ACTG1, ACTR2, ACTR3, ANXA2, ARPC4, FLNA, TLN1, CALD1, MYL6, MYH9, MYH10, TPM1, TPM3, TPM4, PFN1, IQGAP1, MSN, and ZXY exhibited the highest number of interactions. Whereas HSPB1, CTNNA1, KRT17, KRT7, FLNB, SEPT2, and TUBA1B displayed medium interactions, while UTRN, TUBA1B, and DUSP23 had relatively fewer interactions. It was discovered that focal adhesions are critical in connecting membrane receptors with the actin cytoskeleton. In addition, protein kinases, phosphatases, and adapter proteins were identified as key signaling molecules in this process, greatly influencing cell shape, motility, and gene expression. Our analysis shows that the focal adhesion pathway plays a crucial role in NSCLC and is essential for developing effective treatment strategies and improving patient outcomes.展开更多
Introduction: Lung cancer is the leading cause of cancer death worldwide with poor survival rates. However, the prognostic factors for survival of patients with lung cancer are not well-established. In this study, we ...Introduction: Lung cancer is the leading cause of cancer death worldwide with poor survival rates. However, the prognostic factors for survival of patients with lung cancer are not well-established. In this study, we examined the impact of routine laboratory biomarkers and traditional factors on survival of patients with non-small cell lung cancer (NSCLC). Method: Secondary data analysis was conducted from a retrospective study of 404 patients with newly diag-nosed lung cancer in 2005-2007 in Taiwan. There were eight routine laboratory biomarkers and eight traditional factors investigated in the analyses. Cox proportional hazards model was used to assess the hazard ratios for the association between risk factors and patient overall survival. The Kaplan-Meier method was used to compare survival curves for each prognostic indicator. Results: High WBC counts (HR = 1.798, 95%CI: 1.225 - 2.639), low Hgb level (HR = 1.437, 95%CI: 1.085 - 1.903), and low serum albumin level (HR = 2.049, 95%CI: 1.376 - 3.052) were significant laboratory prognostic biomarkers for poor NSCLC survival. Additionally we confirmed the traditional prognostic factors for poor overall survival among NSCLC patients, including older age, comorbidity conditions, advanced cancer stage, and non-surgical treatment. Conclusions: This study identified three available laboratory biomarkers, high WBC counts, low Hgb level, and low serum albumin level, to be significant prognostic factors for poorer overall survival in NSCLC patients. Further prognostic evaluation studies are warranted to compare different ethnic groups on the prognostic values of these clinical parameters in NSCLC survival outcomes. These identified prognostic biomarkers should be included in early risk screening of hospitalized lung cancer patient population.展开更多
Background: Available study revealed advanced tumors have a higher expression rate of MAGE-A3 gene which has a lot of single nucleotide polymorphism(SNP) loci with polymorphisms. This study aimed to analyze the allele...Background: Available study revealed advanced tumors have a higher expression rate of MAGE-A3 gene which has a lot of single nucleotide polymorphism(SNP) loci with polymorphisms. This study aimed to analyze the allele frequency of SNP loci in MAGE-A3 gene and investigate the relationship between MAGE-A3 gene polymorphisms and clinical factors.Methods: Tumor samples of a cohort of 191 NSCLC patients were collected. EGFR m RNA expression were detected by q RT-PCR. SNPs in whole length of MAGE-A3 gene were detected by direct sequencing. Frequencies of the SNPs were correlated to gene expression, mutation status of EGFR and clinical factors.Results: Sequencing analysis confirmed that allele frequencies of genotypes on SNP loci rs5970360, rs5925210, rs5970361, rs5925211 and rs35123853 were CC(0.681)/CT(0.319), CC(0.660)/CG(0.340), CC(0.681)/CA(0.319), AA(0.984)/AT(0.016) and GG(1.000)/GA(0.000), respectively, which were different from the frequencies and genotypes of MAGE-A3 in SNP database. Chi-square tests showed the EGFR mR NA expression level had significant correlation with the genotypes of SNP loci rs5970360 and rs5925210. But all frequencies of each MAGE-A3 SNPs were not found significantly different between EGFR mutant and wild type patients. MAGE-A3 gene polymorphisms had no significant effects on survival of NSCLC patients.Conclusions: Chinese patients with NSCLC had different SNP patterns of MAGE-A3 in comparison with those in international SNP database. These MAGE-A3 SNP loci might have not prognostic significance. MAGE-A3 SNP loci rs5970360 and rs5925210 might be predictive for EGFR m RNA expression levels and helpful to the selection of patients for epidermal growth factor receptor(EGFR) targeted immunotherapy.展开更多
Objective: To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 89 patients with stage ⅢB or IV NSCLC received icotinib at a ...Objective: To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 89 patients with stage ⅢB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity. Results: A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate (RR) was 36.0% (32/89), and the disease control rate (DCR) was 69.7% (62/89). RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma (P<0.05). The symptom improvement rate was 57.3% (51/89), and the main symptoms improved were cough, pain, chest distress, dyspnea, and Eastern Cooperative Oncology Group performance status. The main toxic effects were rash [30/89 (33.7%)] and diarrhea [15/89 (16.9%)]. The level of toxicity was typically low. Conclusions: The use of icotinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.展开更多
Background:The purpose of this study is to evaluate the clinical efficacy and safety of abraxane-based chemotherapy with/without nedaplatin in elderly patients with non-small-cell lung cancer(NSCLC).Materials and meth...Background:The purpose of this study is to evaluate the clinical efficacy and safety of abraxane-based chemotherapy with/without nedaplatin in elderly patients with non-small-cell lung cancer(NSCLC).Materials and methods:From October 2009 to January 2013,48 elderly patients(>65 years) with NSCLC were investigated in this clinical trial.The patients were randomized and equally allocated into arms A and AP:(A) abraxane(130 mg/m^2,days 1,8);(B) abraxane + nedaplatin(20 mg/m^2 days 1-3,q3w).The parameters of objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),overall survival(OS) and side effects were evaluated between two arms.Results:Over 80%of the patients completed four cycles of chemotherapy.The total ORR was 21.3%,DCR was 55.3%,PFS 4.5 months and OS 12.6 months.No significant difference was found between arms A and AP in terms of ORR(16.7%vs.26.1%,P=0.665) or DCR(55.3%vs.56.5%,P=0.871).The median PFS in arm A was 3.3 months[25-75%confidence interval(CI):3.1-7.2]and 5.5 months(25-75%CI:3.2-7.0) in arm AP with no statistical significance(P=0.640).The median OS in arm A was 12.6 months(25-75%CI:5.7-26.2) and 15.1 months(25-75%CI:6.4-35.3) in arm AP with no statistical significance(P=0.770).The side effects were mainly grade 1-2.The incidence of grade 3-4 toxicities was 29.1%in arm A and 62.5%in arm AP with a statistical significance(P=0.020).Conclusions:Compared with combined therapy,abraxane alone chemotherapy was beneficial for elderly NSCLC patients with better tolerability and less adverse events,whereas did not significantly differ in terms of ORR,DCR,PFS or OS.展开更多
Phosphatase and tensin homolog deleted on chromosome 10(PTEN) and the proliferating antigen Ki67 have been widely studied in several tumors.However,their role as indicator in non-small cell lung cancer(NSCLC)remains u...Phosphatase and tensin homolog deleted on chromosome 10(PTEN) and the proliferating antigen Ki67 have been widely studied in several tumors.However,their role as indicator in non-small cell lung cancer(NSCLC)remains unknown.Here,we investigated the expression of PTEN and Ki67 in NSCLC tissues and paired normal lung tissues to identify whether these proteins are associated with lung cancer development and survival.Immunohistochemistry for PTEN and Ki67 was performed on 67 lung cancer tissues and 41 paired adjacent normal lung tissues to detect the expression of these two proteins.The expression of PTEN in NSCLC tissues(32.8%) was significantly lower than that in normal tissues(82.9%,P < 0.05).In contrast,the expression of Ki67 in NSCLC tissues(76.1%) was significantly higher than that in normal tissues(27.3%,P < 0.05).Expression of both PTEN and Ki67 were strongly associated with tumor histology,clinical stage,lymph node metastasis,differentiation and4-year postoperative survival rate(P < 0.05).However,PTEN expression was negatively correlated with Ki67 expression(r =-0.279,P < 0.05).In conclusion,low PTEN expression and Ki67 overexpression are associated with malignant invasion and lymph node metastasis of NSCLC.These proteins may serve as diagnostic and prognostic biomarkers of NSCLC.展开更多
Objective: Vascular-targeted therapy is gradually becoming more appealing for patients with lung cancer. It is unclear whether vascular endothelial growth factor receptor 2(VEGFR2) and neuropilin-1(NRP-1) can be bioma...Objective: Vascular-targeted therapy is gradually becoming more appealing for patients with lung cancer. It is unclear whether vascular endothelial growth factor receptor 2(VEGFR2) and neuropilin-1(NRP-1) can be biomarkers for clinical treatment. We aimed to investigate the expression levels of VEGFR2 and NRP-1 in human non-small cell lung cancer(NSCLC) and their clinical significance by observing patient prognosis. Methods: VEGFR2 and NRP-1 were assessed by immunohistochemistry(IHC) in 40 patients with NSCLC and in 10 patients with benign lesions of lung; kinase insert domain receptor(KDR) and NRP-1 copy number gain(CNG) was assessed by fluorescence in situ hybridization(FISH). The distributions of overall survival(OS) and progression-free survival(PFS) were estimated using the Kaplan-Meier method and compared between groups by log-rank test.Results: Rates of positive immunostaining for VEGFR2 and NRP-1 were 58% and 55%, respectively. KDR and NRP-1 CNG(+) were detected in 32.5% and 30% of tumors, respectively. Levels of both VEGFR2 and NRP-1 in lung tumors were significantly different than in the control tissue(χ2=11.22, P=0.001; χ2=9.82, P=0.001, respectively); similar results were obtained using CNGs(χ2=4.39, P=0.036; χ2=3.95, P=0.046, respectively). Statistically significant correlations were observed with histological grade, clinical TNM stage and the lymph node status(P<0.05), but not age, gender or pathology type(P>0.05). VEGFR2 showed a strong correlation with NRP-1(Rs=0.68, P=0.00); similar results were observed with KDR and NRP-1 CNG(Rs=0.32, P=0.04). Significant differences in OS and PFS were observed between the groups with higher VEGFR2 and NRP-1 and those with lower expression(P<0.05). Conclusions: According to these data, VEGFR2 and NRP-1 are highly expressed in NSCLC. We can conclude that they play a key role in NSCLC occurrence, development and metastasis and are associated with patient prognosis(P<0.05 for OS and PFS). This information will be beneficial for clinical antiangiogenic treatment in NSCLC.展开更多
Apoptosis plays a key role in inhibiting tumor growth, progression and resistance to anti-tumor therapy. We hypothesized that genetic variants in apoptotic genes may affect the prognosis of lung cancer. To test this h...Apoptosis plays a key role in inhibiting tumor growth, progression and resistance to anti-tumor therapy. We hypothesized that genetic variants in apoptotic genes may affect the prognosis of lung cancer. To test this hypothesis, we selected 38 potentially functional single nucleotide polymorphisms (SNPs) from 12 genes (BAX, BCL2, BID, CASP3, CASP6, CASP7, CASP8, CASP9, CASP10, FAS, FASLG and MCL1) involved in apoptosis to assess their prognostic significance in lung cancer in a Chinese case cohort with 568 non-small cell lung cancer (NSCLC) patients. Thirty-five SNPs passing quality control underwent association analyses, 11 of which were shown to be significantly associated with NSCLC survival (P<0.05). After Cox stepwise regression analyses, 3 SNPs were independently associated with the outcome of NSCLC (BID rs8190315: P=0.003; CASP9 rs4645981: P=0.007 and FAS rs1800682: P=0.016). A favorable survival of NSCLC was significantly associated with the genotypes of BID rs8190315 AG/GG (adjusted HR=0.65, 95% CI: 0.49-0.88), CASP9 rs4645981 AA (HR=0.22, 95% CI: 0.07-0.69) and FAS rs1800682 GG (adjusted HR=0.67, 95% CI: 0.46-0.97). Time-dependent receptor operation curve (ROC) analysis revealed that the area under curve (AUC) at year 5 was significantly increased from 0.762 to 0.819 after adding the risk score of these 3 SNPs to the clinical risk score. The remaining 32 SNPs were not significantly associated with NSCLC prognosis after adjustment for these 3 SNPs. These findings indicate that BID rs8190315, CASP9 rs4645981 and FAS rs1800682 polymorphisms in the apoptotic pathway may be involved in the prognosis of NSCLC in the Chinese population.展开更多
Commonly observed aberrations in epidermal growth factor receptor(EGFR) signaling have led to the development of EGFR-targeted therapies for various cancers,including non-small cell lung cancer(NSCLC).EGFR mutations a...Commonly observed aberrations in epidermal growth factor receptor(EGFR) signaling have led to the development of EGFR-targeted therapies for various cancers,including non-small cell lung cancer(NSCLC).EGFR mutations and overexpression have further been shown to modulate sensitivity to these EGFR-targeted therapies in NSCLC and several other types of cancers.However,it is clear that mutations and/or genetic variations in EGFR alone cannot explain all of the variability in the responses of patients with NSCLC to EGFR-targeted therapies.For instance,in addition to EGFR genotype,genetic variations in other members of the signaling pathway downstream of EGFR or variations in parallel receptor tyrosine kinase(RTK) pathways are now recognized to have a significant impact on the efficacy of certain EGFR-targeted therapies.In this review,we highlight the mutations and genetic variations in such genes downstream of EGFR and in parallel RTK pathways.Specifically,the directional effects of these pharmacogenetic factors are discussed with a focus on two commonly prescribed EGFR inhibitors:cetuximab and erlotinib.The results of this comprehensive review can be used to optimize the treatment of NSCLC with EGFR inhibitors.Furthermore,they may provide the rationale for the design of subsequent combination therapies that involve the inhibition of EGFR.展开更多
Background:Inflammation is often linked with the progress and poor outcome of lung cancer.The understanding of the relationship between tumor-associated macrophages(TAMs) and lung cancer cells involves in the underlyi...Background:Inflammation is often linked with the progress and poor outcome of lung cancer.The understanding of the relationship between tumor-associated macrophages(TAMs) and lung cancer cells involves in the underlying mechanism of inflammatory cytokine production.Toll-like receptors(TLRs) are engaged in promoting the production of pro-inflammatory cytokines and play an important role in tumor immunology.Methods:To investigate the mechanisms by which TAMs influence the production of pro-inflammatory cytokines in lung cancer cells,we established an in vitro coculture system using TAMs and human nonsmall cell lung cancer(NSCLC) cell line SPC-A1.Levels of interleukin(IL)-1β,IL-6 and IL-8 in SPC-A1 were evaluated by RT-PCR and cytometric bead array assay after being cocultured with TAMs.Expression changes of TLRs and TLRs signaling pathway proteins in SPC-A1 were further confirmed by RT-PCR and western blot.The level changes of IL-1β,IL-6 and IL-8 in SPC-A1 were also detected after the stimulation of TLRs agonists.Results:We found that the phenotype markers of TAMs were highly expressed after stimulating human monocyte cell line THP-1 by phorbol-12-myristate-13-acetate(PMA).Higher mRNA and supernate secretion levels of IL-1β,IL-6 and IL-8 were detected in SPC-A1 after being cocultured with TAMs.We also found that TLR1,TLR6 and TLR7 were up-regulated in SPC-A1 in the coculture system with TAMs.Meanwhile,TLRs signaling pathway proteins were also significantly activated.Moreover,pre-treatment with agonist ligands for TLR1,TLR6 and TLR7 could dramatically promote inductions of IL-1β,IL-6 and IL-8.Conclusions:These findings demonstrated that TAMs may enhance IL-1β,IL-6 and IL-8 expressions via TLRs signaling pathway.We conclude that TAMs contribute to maintain the inflammation microenvironment and ultimately promote the development and progression of lung cancer.展开更多
Objective: A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase(PI3K) and mitogen-activated protein kinase(MAPK) pathways on the clinic...Objective: A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase(PI3K) and mitogen-activated protein kinase(MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) treatment of non-small cell lung cancer(NSCLC) patients.Methods: Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3 CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios(ORs) for objective response rate(ORR) and hazard ratios(HRs) for progression-free survival(PFS) and overall survival(OS) were calculated.Results: Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval(CI), 0.13-0.35], shorter PFS(HR =1.56; 95% CI, 1.27-1.92), and shorter OS(HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3 CA significantly predicted shorter OS(HR =1.83; 95% CI, 1.05-3.20), showed poor ORR(OR =0.70; 95% CI, 0.22-2.18), and shorter PFS(HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs.Conclusion: K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFRTKIs. PIK3 CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3 CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.展开更多
Background: Video-assisted thoracic surgery(VATS) has been shown to be a safe alternative to conventional thoracotomy for patients with non-small cell lung cancer(NSCLC). However, popularization of this relatively nov...Background: Video-assisted thoracic surgery(VATS) has been shown to be a safe alternative to conventional thoracotomy for patients with non-small cell lung cancer(NSCLC). However, popularization of this relatively novel technique has been slow, partly due to concerns about its long-term outcomes. The present study aimed to evaluate the long-term survival outcomes of patients with NSCLC after VATS, and to determine the significant prognostic factors on overall survival.Methods: Consecutive patients diagnosed with NSCLC referred to one institution for VATS were identified from a central database. Patients were treated by either complete-VATS or assisted-VATS, as described in previous studies. A number of baseline patient characteristics, clinicopathologic data and treatment-related factors were analyzed as potential prognostic factors on overall survival.Results: Between January 2000 and December 2007, 1,139 patients with NSCLC who underwent VATS and fulfilled a set of predetermined inclusion criteria were included for analysis. The median age of the entire group was 60 years, with 791 male patients(69%). The median 5-year overall survival for Stage I, II, III and IV disease according to the recently updated TNM classification system were 72.2%, 47.5%, 29.8% and 28.6%, respectively. Female gender, TNM stage, pT status, and type of resection were found to be significant prognostic factors on multivariate analysis.Conclusions: VATS offers a viable alternative to conventional open thoracotomy for selected patients with clinically resectable NSCLC.展开更多
Background: Epidermal growth factor receptor(EGFR) mutation is the key predictor of EGFR tyrosine kinase inhibitors(TKIs) efficacy in non-small cell lung cancer(NSCLC). We conducted this study to verify the feasibilit...Background: Epidermal growth factor receptor(EGFR) mutation is the key predictor of EGFR tyrosine kinase inhibitors(TKIs) efficacy in non-small cell lung cancer(NSCLC). We conducted this study to verify the feasibility of EGFR mutation analysis in cytological specimens and investigate the responsiveness to gefitinib treatment in patients carrying EGFR mutations.Methods: A total of 210 cytological specimens were collected for EGFR mutation detection by both direct sequencing and amplification refractory mutation system(ARMS). We analyzed EGFR mutation status by both methods and evaluated the responsiveness to gefitinib treatment in patients harboring EGFR mutations by overall response rate(ORR), disease control rate(DCR) and progression free survival(PFS).Results: Of all patients, EGFR mutation rate was 28.6%(60/210) by direct sequencing and 45.2%(95/210) by ARMS(P<0.001) respectively. Among the EGFR wild type patients tested by direct sequencing, 26.7% of them were positive by ARMS. For the 72 EGFR mutation positive patients treated with gefitinib, the ORR, DCR and median PFS were 69.4%, 90.2% and 9.3 months respectively. The patients whose EGFR mutation status was negative by direct sequencing but positive by ARMS had lower ORR(48.0% vs. 80.9%, P=0.004) and shorter median PFS(7.4 vs. 10.5 months, P=0.009) as compared with that of EGFR mutation positive patients by both detection methods. Conclusions: Our study verified the feasibility of EGFR analysis in cytological specimens in advanced NSCLC. ARMS is more sensitive than direct sequencing in EGFR mutation detection. EGFR Mutation status tested on cytological samples is applicable for predicting the response to gefitinib. Abundance of EGFR mutations might have an influence on TKIs efficacy.展开更多
Objective:To assess prognostic factors and validate the effectiveness of recursive partitioning analysis (RPA) classes and graded prognostic assessment (GPA) in 290 non-small cell lung cancer (NSCLC) patients with bra...Objective:To assess prognostic factors and validate the effectiveness of recursive partitioning analysis (RPA) classes and graded prognostic assessment (GPA) in 290 non-small cell lung cancer (NSCLC) patients with brain metastasis (BM).Methods:From Jan 2008 to Dec 2009,the clinical data of 290 NSCLC cases with BM treated with multiple modalities including brain irradiation,systemic chemotherapy and tyrosine kinase inhibitors (TKIs) in two institutes were analyzed.Survival was estimated by Kaplan-Meier method.The differences of survival rates in subgroups were assayed using log-rank test.Multivariate Cox's regression method was used to analyze the impact of prognostic factors on survival.Two prognostic indexes models (RPA and GPA) were validated respectively.Results:All patients were followed up for 1-44 months,the median survival time after brain irradiation and its corresponding 95% confidence interval (95% CI) was 14 (12.3-15.8) months.1-,2-and 3-year survival rates in the whole group were 56.0%,28.3%,and 12.0%,respectively.The survival curves of subgroups,stratified by both RPA and GPA,were significantly different (P<0.001).In the multivariate analysis as RPA and GPA entered Cox's regression model,Karnofsky performance status (KPS) ≥ 70,adenocarcinoma subtype,longer administration of TKIs remained their prognostic significance,RPA classes and GPA also appeared in the prognostic model.Conclusion:KPS ≥70,adenocarcinoma subtype,longer treatment of molecular targeted drug,and RPA classes and GPA are the independent prognostic factors affecting the survival rates of NSCLC patients with BM.展开更多
Background: To determine the safety and therapeutic efficacy of nimotuzumab(h-R3) combined with docetaxel in advanced non-small-cell lung cancer(NSCLC) patients who have failed to respond to prior first-line chemother...Background: To determine the safety and therapeutic efficacy of nimotuzumab(h-R3) combined with docetaxel in advanced non-small-cell lung cancer(NSCLC) patients who have failed to respond to prior first-line chemotherapy.Methods: In this single-center, open-label, dose-escalating phase I trial, patients with epidermal growth factor receptor(EGFR)-expressing stage IV NSCLC were treated with nimotuzumab plus docetaxel according to a dose escalation schedule. The safety and efficacy of the combination treatment were observed and analyzed.Results: There were 12 patients with EGFR-expressing stage IV NSCLC enrolled. The dose of nimotuzumab was escalated from 200 to 600 mg/week. The longest administration of study drug was 40 weeks at the 600 mg/week dose level. Grade III–IV toxicities included neutropenia and fatigue, and other toxicities included rash. Dose-limiting toxicity occurred with Grade 3 fatigue at the 200 mg dose level of nimotuzumab and Grade 4 neutropenia with pneumonia at the 600 mg dose level of nimotuzumab. No objective responses were observed, and stable disease was observed in eight patients(66.7%). The median progression-free survival(PFS) was 4.4 months in all patients, 1.3 months in patients with the EGFR mutation, and 4.4 months in those with wild type EGFR(EGFR WT). The median survival time(MST) was 21.1 months in all patients, 21.1 months in patients with EGFR mutation, and 26.4 months in patients with EGFR WT.Conclusions: Nimotuzumab and docetaxel combination therapy was found to be well tolerated and efficacious. Further study of nimotuzumab is warranted in advanced NSCLC patients.展开更多
The aim of this study was to analyze the correlation of the expression of MET and cyclin D1 and MET gene copy number in non-small cell lung cancer (NSCLC) tissues and patient clinicopathologic characteristics and surv...The aim of this study was to analyze the correlation of the expression of MET and cyclin D1 and MET gene copy number in non-small cell lung cancer (NSCLC) tissues and patient clinicopathologic characteristics and survival. Sixty-one NSCLC tissue specimens were included in the study. The expression of MET and cyclin D1 was evaluated by immunohistochemistry and MET gene copy number was assessed by quantitative real-time polymerase chain reaction (Q-PCR). Positive expression of MET and cyclin D1 protein and increased MET gene copy number occurred in 59.0%, 59.0% and 18.0% of 61 NSCLC tissues, respectively. MET-positivity correlated with poor differentiation (P=0.009). Increased MET gene copy number was significantly associated with lymph node metastasis (P=0.004) and advanced tumor stage (P=0.048), while the expression of cyclin D1 was not associated with any clinicopathologic parameters. There was a significant correlation between the expression of MET and MET gene copy number (P=0.002). Additionally, the expression of cyclin D1 had a significant association with the expression of MET as well as MET gene copy number (P=0.002 and P=0.017, respectively). MET-positivity and increased MET gene copy number were significantly associated with poor overall survival (P=0.003 and P<0.001, respectively) in univariate analysis. Multivariate Cox proportional hazard analysis confirmed that the expression of MET and MET gene copy number were prognostic indicators of NSCLC (P=0.003 and P=0.001, respectively). The overexpression of MET and the increased MET gene copy number might be adverse prognostic factors for NSCLC patients. The activation of the MET/cyclin D1 signaling pathway may contribute to carcino- genesis and the development of NSCLC, and may represent a target for therapy.展开更多
Objective:Epidermal growth factor receptor (EGFR) mutations are strong determinants of tumor response to EGFR tyrosine kinase inhibitors in non-small-cell lung cancer (NSCLC) patients. The aim of this study was to eva...Objective:Epidermal growth factor receptor (EGFR) mutations are strong determinants of tumor response to EGFR tyrosine kinase inhibitors in non-small-cell lung cancer (NSCLC) patients. The aim of this study was to evaluate the correspondence between EGFR mutations in non-small-cell lung cancer tissues and in circulating DNA. Methods:The research was conducted in 50 non-small-cell lung cancer patients who had undergone curative surgery,and in whom both serum and neoplastic tissues were available. Meanwhile sera of 33 cases of advanced NSCLC patients were also analyzed. DNA were extracted from each sample. Mutations of EGFR in exon18-21 were examined by PCR amplification method and direct sequencing. Results:EGFR mutations were detected in 15 (30%) of 50 neoplastic tissue samples,6 cases were in-frame deletion del E746-A750 in exon19,9 cases were substitution in exon 21 (all were L858R except one was L861Q),but no mutated DNA resulted in paired serum circulating DNA samples of 50 resectable patients. As the 33 advanced NSCLC patients,EGFR mutations were detected in only 2 serum circulating DNA samples,all were L858R mutation in exon 21. Conclusion:These data indicated that it was difficult to identify EGFR mutations in circulating DNA of NSCLC patients. The use of EGFR mutation in serum as a clinical method for decision making of TKI therapy is unsatisfactory.展开更多
Objective Anlotinib,an oral vascular endothelial growth factor receptor 2(VEGFR2)inhibitor,has confirmed antitumor activity in lung cancer in both in vitro and in vivo assays,and has been recommended as third-line tre...Objective Anlotinib,an oral vascular endothelial growth factor receptor 2(VEGFR2)inhibitor,has confirmed antitumor activity in lung cancer in both in vitro and in vivo assays,and has been recommended as third-line treatment agent in non-oncogene driven non-small cell lung cancer(NSCLC).This prospective study aimed to investigate the efficacy and safety of anlotinib plus S-1 for third-or later-line treatment in patients with advanced NSCLC.Methods Patients with histologically or cytologically confirmed NSCLC,and documented disease progression following second-line chemotherapy,and/or epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI)treatment were enrolled in this study.The patients were treated anlotinib(8 mg daily d 1–14)and S-1(60 mg/m^2 d 1–14)and the treatment was repeated every 3 weeks.Treatment was continued until disease progression or unacceptable toxicity occurred.The objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),and adverse events(AEs)were reviewed and evaluated.Results Forty-one patients were enrolled in the study between June 2018 and December 2018.The total ORR and DCR were 26.8%and 80.5%,respectively.The median PFS was 5.2 months[95%confidence interval(CI),3.9 to 6.6 months].In the univariate analysis,there was a significant difference in the median PFS between patients with brain metastases and those without brain metastases(4.8 months vs 5.9 months,respectively;P=0.039).The Eastern Cooperative Oncology Group(ECOG)performance status(P=0.002),lines of therapy(P=0.015),and therapeutic evaluation(P=0.014)were independent factors that influenced PFS.The most common AEs were hypertension,proteinuria,myelosuppression,gastrointestinal reactions,fatigue,and mucositis.Conclusion Anlotinib plus S-1 is an effective and safe regimen for advanced NSCLC as third-or later-line therapy.展开更多
Lobectomy with partial removal of the pulmonary artery in video-assisted thoracic surgery (VATS) currently remains a challenge for thoracic surgeons. We were interested in introducing pulmonary vessel blocking techniq...Lobectomy with partial removal of the pulmonary artery in video-assisted thoracic surgery (VATS) currently remains a challenge for thoracic surgeons. We were interested in introducing pulmonary vessel blocking techniques in open thoracic surgery into video-assisted thoracic surgery (VATS) procedures. In this study, we reported a surgical technique simultaneously blocking the pulmonary artery and the pulmonary vein for partial removal of the pulmonary artery under VATS. Seven patients with non-small-cell lung cancer (NSCLC) received lobectomy with partial removal of the pulmonary artery using the technique between December 2007 and March 2012. Briefly, rather than using a small clamp on the distal pulmonary artery to the area of invading cancer, we replaced a vascular clamp with a ribbon and Hem-o-lock clip to block the preserved pulmonary veins so as to prevent back bleeding and yield a better view for surgeons. The mean occlusion time of the pulmonary artery and pulmonary veins were 44.0±10.0 and 41.3±9.7 minutes, respectively. The mean repair time of the pulmonary artery was 25.3±13.7 minutes. No complications occurred. No patients showed abnormal blood flow through the reconstructed vessel. There were no local recurrences on the pulmonary artery. In conclusion, the technique for blocking the pulmonary artery and veins is feasible and safe in VATS and reduces the risk of abrupt intraoperative bleeding and the chance of converting to open thoracotomy, and extends the indications of VATS lobectomy.展开更多
文摘Actin, a highly conserved protein, plays a dominant role in Non-small cell lung cancer (NSCLC). Late diagnosis and the aggressive nature of NSCLC pose a significant threat. Studying the clinic pathological properties of NSCLC proteins is a potential alternative for developing treatment strategies. Towards this, 35 downregulated actin cytoskeletal proteins on NSCLC prognosis and treatment were studied by examining their protein-protein interactions, gene ontology enrichment terms, and signaling pathways. Using PubMed, various proteins in NSCLC were identified. The protein-protein interactions and functional associations of these proteins were examined using the STRING database. The focal adhesion signaling pathway was selected from all available KEGG and Wiki pathways because of its role in regulating gene expression, facilitating cell movement and reproduction, and significantly impacting NSCLC. The protein-protein interaction network of the 35 downregulated actin cytoskeleton proteins revealed that ACTG1, ACTR2, ACTR3, ANXA2, ARPC4, FLNA, TLN1, CALD1, MYL6, MYH9, MYH10, TPM1, TPM3, TPM4, PFN1, IQGAP1, MSN, and ZXY exhibited the highest number of interactions. Whereas HSPB1, CTNNA1, KRT17, KRT7, FLNB, SEPT2, and TUBA1B displayed medium interactions, while UTRN, TUBA1B, and DUSP23 had relatively fewer interactions. It was discovered that focal adhesions are critical in connecting membrane receptors with the actin cytoskeleton. In addition, protein kinases, phosphatases, and adapter proteins were identified as key signaling molecules in this process, greatly influencing cell shape, motility, and gene expression. Our analysis shows that the focal adhesion pathway plays a crucial role in NSCLC and is essential for developing effective treatment strategies and improving patient outcomes.
文摘Introduction: Lung cancer is the leading cause of cancer death worldwide with poor survival rates. However, the prognostic factors for survival of patients with lung cancer are not well-established. In this study, we examined the impact of routine laboratory biomarkers and traditional factors on survival of patients with non-small cell lung cancer (NSCLC). Method: Secondary data analysis was conducted from a retrospective study of 404 patients with newly diag-nosed lung cancer in 2005-2007 in Taiwan. There were eight routine laboratory biomarkers and eight traditional factors investigated in the analyses. Cox proportional hazards model was used to assess the hazard ratios for the association between risk factors and patient overall survival. The Kaplan-Meier method was used to compare survival curves for each prognostic indicator. Results: High WBC counts (HR = 1.798, 95%CI: 1.225 - 2.639), low Hgb level (HR = 1.437, 95%CI: 1.085 - 1.903), and low serum albumin level (HR = 2.049, 95%CI: 1.376 - 3.052) were significant laboratory prognostic biomarkers for poor NSCLC survival. Additionally we confirmed the traditional prognostic factors for poor overall survival among NSCLC patients, including older age, comorbidity conditions, advanced cancer stage, and non-surgical treatment. Conclusions: This study identified three available laboratory biomarkers, high WBC counts, low Hgb level, and low serum albumin level, to be significant prognostic factors for poorer overall survival in NSCLC patients. Further prognostic evaluation studies are warranted to compare different ethnic groups on the prognostic values of these clinical parameters in NSCLC survival outcomes. These identified prognostic biomarkers should be included in early risk screening of hospitalized lung cancer patient population.
基金supported by grants from the Foundation of Guangdong Science and Technology Department(Grant No.2010B031600158,XN Yang)Key Lab System Project of Guangdong Science and Technology Department(Grant No.2012A061400006,YL WU)
文摘Background: Available study revealed advanced tumors have a higher expression rate of MAGE-A3 gene which has a lot of single nucleotide polymorphism(SNP) loci with polymorphisms. This study aimed to analyze the allele frequency of SNP loci in MAGE-A3 gene and investigate the relationship between MAGE-A3 gene polymorphisms and clinical factors.Methods: Tumor samples of a cohort of 191 NSCLC patients were collected. EGFR m RNA expression were detected by q RT-PCR. SNPs in whole length of MAGE-A3 gene were detected by direct sequencing. Frequencies of the SNPs were correlated to gene expression, mutation status of EGFR and clinical factors.Results: Sequencing analysis confirmed that allele frequencies of genotypes on SNP loci rs5970360, rs5925210, rs5970361, rs5925211 and rs35123853 were CC(0.681)/CT(0.319), CC(0.660)/CG(0.340), CC(0.681)/CA(0.319), AA(0.984)/AT(0.016) and GG(1.000)/GA(0.000), respectively, which were different from the frequencies and genotypes of MAGE-A3 in SNP database. Chi-square tests showed the EGFR mR NA expression level had significant correlation with the genotypes of SNP loci rs5970360 and rs5925210. But all frequencies of each MAGE-A3 SNPs were not found significantly different between EGFR mutant and wild type patients. MAGE-A3 gene polymorphisms had no significant effects on survival of NSCLC patients.Conclusions: Chinese patients with NSCLC had different SNP patterns of MAGE-A3 in comparison with those in international SNP database. These MAGE-A3 SNP loci might have not prognostic significance. MAGE-A3 SNP loci rs5970360 and rs5925210 might be predictive for EGFR m RNA expression levels and helpful to the selection of patients for epidermal growth factor receptor(EGFR) targeted immunotherapy.
文摘Objective: To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 89 patients with stage ⅢB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity. Results: A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate (RR) was 36.0% (32/89), and the disease control rate (DCR) was 69.7% (62/89). RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma (P<0.05). The symptom improvement rate was 57.3% (51/89), and the main symptoms improved were cough, pain, chest distress, dyspnea, and Eastern Cooperative Oncology Group performance status. The main toxic effects were rash [30/89 (33.7%)] and diarrhea [15/89 (16.9%)]. The level of toxicity was typically low. Conclusions: The use of icotinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.
文摘Background:The purpose of this study is to evaluate the clinical efficacy and safety of abraxane-based chemotherapy with/without nedaplatin in elderly patients with non-small-cell lung cancer(NSCLC).Materials and methods:From October 2009 to January 2013,48 elderly patients(>65 years) with NSCLC were investigated in this clinical trial.The patients were randomized and equally allocated into arms A and AP:(A) abraxane(130 mg/m^2,days 1,8);(B) abraxane + nedaplatin(20 mg/m^2 days 1-3,q3w).The parameters of objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),overall survival(OS) and side effects were evaluated between two arms.Results:Over 80%of the patients completed four cycles of chemotherapy.The total ORR was 21.3%,DCR was 55.3%,PFS 4.5 months and OS 12.6 months.No significant difference was found between arms A and AP in terms of ORR(16.7%vs.26.1%,P=0.665) or DCR(55.3%vs.56.5%,P=0.871).The median PFS in arm A was 3.3 months[25-75%confidence interval(CI):3.1-7.2]and 5.5 months(25-75%CI:3.2-7.0) in arm AP with no statistical significance(P=0.640).The median OS in arm A was 12.6 months(25-75%CI:5.7-26.2) and 15.1 months(25-75%CI:6.4-35.3) in arm AP with no statistical significance(P=0.770).The side effects were mainly grade 1-2.The incidence of grade 3-4 toxicities was 29.1%in arm A and 62.5%in arm AP with a statistical significance(P=0.020).Conclusions:Compared with combined therapy,abraxane alone chemotherapy was beneficial for elderly NSCLC patients with better tolerability and less adverse events,whereas did not significantly differ in terms of ORR,DCR,PFS or OS.
基金supported by Nanjing Medical University Focus Development and Natural Science Foundation of China
文摘Phosphatase and tensin homolog deleted on chromosome 10(PTEN) and the proliferating antigen Ki67 have been widely studied in several tumors.However,their role as indicator in non-small cell lung cancer(NSCLC)remains unknown.Here,we investigated the expression of PTEN and Ki67 in NSCLC tissues and paired normal lung tissues to identify whether these proteins are associated with lung cancer development and survival.Immunohistochemistry for PTEN and Ki67 was performed on 67 lung cancer tissues and 41 paired adjacent normal lung tissues to detect the expression of these two proteins.The expression of PTEN in NSCLC tissues(32.8%) was significantly lower than that in normal tissues(82.9%,P < 0.05).In contrast,the expression of Ki67 in NSCLC tissues(76.1%) was significantly higher than that in normal tissues(27.3%,P < 0.05).Expression of both PTEN and Ki67 were strongly associated with tumor histology,clinical stage,lymph node metastasis,differentiation and4-year postoperative survival rate(P < 0.05).However,PTEN expression was negatively correlated with Ki67 expression(r =-0.279,P < 0.05).In conclusion,low PTEN expression and Ki67 overexpression are associated with malignant invasion and lymph node metastasis of NSCLC.These proteins may serve as diagnostic and prognostic biomarkers of NSCLC.
基金supported by National Natural Science Foundation of China [81472792]Ministry of Health of China (W201210)Jiangsu Natural Science Foundation of China (BK2012661)
文摘Objective: Vascular-targeted therapy is gradually becoming more appealing for patients with lung cancer. It is unclear whether vascular endothelial growth factor receptor 2(VEGFR2) and neuropilin-1(NRP-1) can be biomarkers for clinical treatment. We aimed to investigate the expression levels of VEGFR2 and NRP-1 in human non-small cell lung cancer(NSCLC) and their clinical significance by observing patient prognosis. Methods: VEGFR2 and NRP-1 were assessed by immunohistochemistry(IHC) in 40 patients with NSCLC and in 10 patients with benign lesions of lung; kinase insert domain receptor(KDR) and NRP-1 copy number gain(CNG) was assessed by fluorescence in situ hybridization(FISH). The distributions of overall survival(OS) and progression-free survival(PFS) were estimated using the Kaplan-Meier method and compared between groups by log-rank test.Results: Rates of positive immunostaining for VEGFR2 and NRP-1 were 58% and 55%, respectively. KDR and NRP-1 CNG(+) were detected in 32.5% and 30% of tumors, respectively. Levels of both VEGFR2 and NRP-1 in lung tumors were significantly different than in the control tissue(χ2=11.22, P=0.001; χ2=9.82, P=0.001, respectively); similar results were obtained using CNGs(χ2=4.39, P=0.036; χ2=3.95, P=0.046, respectively). Statistically significant correlations were observed with histological grade, clinical TNM stage and the lymph node status(P<0.05), but not age, gender or pathology type(P>0.05). VEGFR2 showed a strong correlation with NRP-1(Rs=0.68, P=0.00); similar results were observed with KDR and NRP-1 CNG(Rs=0.32, P=0.04). Significant differences in OS and PFS were observed between the groups with higher VEGFR2 and NRP-1 and those with lower expression(P<0.05). Conclusions: According to these data, VEGFR2 and NRP-1 are highly expressed in NSCLC. We can conclude that they play a key role in NSCLC occurrence, development and metastasis and are associated with patient prognosis(P<0.05 for OS and PFS). This information will be beneficial for clinical antiangiogenic treatment in NSCLC.
基金supported in part by the National Natural Science Foundation of China (81270044,30972541,30901233)the Doctoral Fund of Ministry of Education of China (20093234110001)A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institution
文摘Apoptosis plays a key role in inhibiting tumor growth, progression and resistance to anti-tumor therapy. We hypothesized that genetic variants in apoptotic genes may affect the prognosis of lung cancer. To test this hypothesis, we selected 38 potentially functional single nucleotide polymorphisms (SNPs) from 12 genes (BAX, BCL2, BID, CASP3, CASP6, CASP7, CASP8, CASP9, CASP10, FAS, FASLG and MCL1) involved in apoptosis to assess their prognostic significance in lung cancer in a Chinese case cohort with 568 non-small cell lung cancer (NSCLC) patients. Thirty-five SNPs passing quality control underwent association analyses, 11 of which were shown to be significantly associated with NSCLC survival (P<0.05). After Cox stepwise regression analyses, 3 SNPs were independently associated with the outcome of NSCLC (BID rs8190315: P=0.003; CASP9 rs4645981: P=0.007 and FAS rs1800682: P=0.016). A favorable survival of NSCLC was significantly associated with the genotypes of BID rs8190315 AG/GG (adjusted HR=0.65, 95% CI: 0.49-0.88), CASP9 rs4645981 AA (HR=0.22, 95% CI: 0.07-0.69) and FAS rs1800682 GG (adjusted HR=0.67, 95% CI: 0.46-0.97). Time-dependent receptor operation curve (ROC) analysis revealed that the area under curve (AUC) at year 5 was significantly increased from 0.762 to 0.819 after adding the risk score of these 3 SNPs to the clinical risk score. The remaining 32 SNPs were not significantly associated with NSCLC prognosis after adjustment for these 3 SNPs. These findings indicate that BID rs8190315, CASP9 rs4645981 and FAS rs1800682 polymorphisms in the apoptotic pathway may be involved in the prognosis of NSCLC in the Chinese population.
基金supported by two NIH/NIGMS grants(No.U01GM61393 and No.K08GM089941)a NIH/NCI grant(No.R21 CA139278)+2 种基金the University of Chicago Cancer Center Support Grant(No.#P30 CA14599)the Breast Cancer SPORE Career Development Award(No.CA125183)a grant from the National Center for Advancing Translational Sciences of the NIH(No.UL1 RR024999)
文摘Commonly observed aberrations in epidermal growth factor receptor(EGFR) signaling have led to the development of EGFR-targeted therapies for various cancers,including non-small cell lung cancer(NSCLC).EGFR mutations and overexpression have further been shown to modulate sensitivity to these EGFR-targeted therapies in NSCLC and several other types of cancers.However,it is clear that mutations and/or genetic variations in EGFR alone cannot explain all of the variability in the responses of patients with NSCLC to EGFR-targeted therapies.For instance,in addition to EGFR genotype,genetic variations in other members of the signaling pathway downstream of EGFR or variations in parallel receptor tyrosine kinase(RTK) pathways are now recognized to have a significant impact on the efficacy of certain EGFR-targeted therapies.In this review,we highlight the mutations and genetic variations in such genes downstream of EGFR and in parallel RTK pathways.Specifically,the directional effects of these pharmacogenetic factors are discussed with a focus on two commonly prescribed EGFR inhibitors:cetuximab and erlotinib.The results of this comprehensive review can be used to optimize the treatment of NSCLC with EGFR inhibitors.Furthermore,they may provide the rationale for the design of subsequent combination therapies that involve the inhibition of EGFR.
基金the technical support from National Key Clinical Department of Laboratory Medicine of Jiangsu Province Hospitalsupported by National Natural Science Foundation of China(No. 81272324,81371894)+1 种基金Key Laboratory for Medicine of Jiangsu Province of China(No.XK201114)project funded by the Priority Academic Program Development ofJiangsu Higher Education Institutions
文摘Background:Inflammation is often linked with the progress and poor outcome of lung cancer.The understanding of the relationship between tumor-associated macrophages(TAMs) and lung cancer cells involves in the underlying mechanism of inflammatory cytokine production.Toll-like receptors(TLRs) are engaged in promoting the production of pro-inflammatory cytokines and play an important role in tumor immunology.Methods:To investigate the mechanisms by which TAMs influence the production of pro-inflammatory cytokines in lung cancer cells,we established an in vitro coculture system using TAMs and human nonsmall cell lung cancer(NSCLC) cell line SPC-A1.Levels of interleukin(IL)-1β,IL-6 and IL-8 in SPC-A1 were evaluated by RT-PCR and cytometric bead array assay after being cocultured with TAMs.Expression changes of TLRs and TLRs signaling pathway proteins in SPC-A1 were further confirmed by RT-PCR and western blot.The level changes of IL-1β,IL-6 and IL-8 in SPC-A1 were also detected after the stimulation of TLRs agonists.Results:We found that the phenotype markers of TAMs were highly expressed after stimulating human monocyte cell line THP-1 by phorbol-12-myristate-13-acetate(PMA).Higher mRNA and supernate secretion levels of IL-1β,IL-6 and IL-8 were detected in SPC-A1 after being cocultured with TAMs.We also found that TLR1,TLR6 and TLR7 were up-regulated in SPC-A1 in the coculture system with TAMs.Meanwhile,TLRs signaling pathway proteins were also significantly activated.Moreover,pre-treatment with agonist ligands for TLR1,TLR6 and TLR7 could dramatically promote inductions of IL-1β,IL-6 and IL-8.Conclusions:These findings demonstrated that TAMs may enhance IL-1β,IL-6 and IL-8 expressions via TLRs signaling pathway.We conclude that TAMs contribute to maintain the inflammation microenvironment and ultimately promote the development and progression of lung cancer.
基金supported by Key Projects in the National Science & Technology Pillar Program (Grant No. 2013ZX09303001, 2015BAI12B12, and 2015BAI12B15)National Natural Science Foundation of China (Grant No. 81472473 and 81272360)Tianjin Municipal Commission of Science & Technology Key Research Program (Grant No.13ZCZCSY20300)
文摘Objective: A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase(PI3K) and mitogen-activated protein kinase(MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) treatment of non-small cell lung cancer(NSCLC) patients.Methods: Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3 CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios(ORs) for objective response rate(ORR) and hazard ratios(HRs) for progression-free survival(PFS) and overall survival(OS) were calculated.Results: Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval(CI), 0.13-0.35], shorter PFS(HR =1.56; 95% CI, 1.27-1.92), and shorter OS(HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3 CA significantly predicted shorter OS(HR =1.83; 95% CI, 1.05-3.20), showed poor ORR(OR =0.70; 95% CI, 0.22-2.18), and shorter PFS(HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs.Conclusion: K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFRTKIs. PIK3 CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3 CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.
文摘Background: Video-assisted thoracic surgery(VATS) has been shown to be a safe alternative to conventional thoracotomy for patients with non-small cell lung cancer(NSCLC). However, popularization of this relatively novel technique has been slow, partly due to concerns about its long-term outcomes. The present study aimed to evaluate the long-term survival outcomes of patients with NSCLC after VATS, and to determine the significant prognostic factors on overall survival.Methods: Consecutive patients diagnosed with NSCLC referred to one institution for VATS were identified from a central database. Patients were treated by either complete-VATS or assisted-VATS, as described in previous studies. A number of baseline patient characteristics, clinicopathologic data and treatment-related factors were analyzed as potential prognostic factors on overall survival.Results: Between January 2000 and December 2007, 1,139 patients with NSCLC who underwent VATS and fulfilled a set of predetermined inclusion criteria were included for analysis. The median age of the entire group was 60 years, with 791 male patients(69%). The median 5-year overall survival for Stage I, II, III and IV disease according to the recently updated TNM classification system were 72.2%, 47.5%, 29.8% and 28.6%, respectively. Female gender, TNM stage, pT status, and type of resection were found to be significant prognostic factors on multivariate analysis.Conclusions: VATS offers a viable alternative to conventional open thoracotomy for selected patients with clinically resectable NSCLC.
文摘Background: Epidermal growth factor receptor(EGFR) mutation is the key predictor of EGFR tyrosine kinase inhibitors(TKIs) efficacy in non-small cell lung cancer(NSCLC). We conducted this study to verify the feasibility of EGFR mutation analysis in cytological specimens and investigate the responsiveness to gefitinib treatment in patients carrying EGFR mutations.Methods: A total of 210 cytological specimens were collected for EGFR mutation detection by both direct sequencing and amplification refractory mutation system(ARMS). We analyzed EGFR mutation status by both methods and evaluated the responsiveness to gefitinib treatment in patients harboring EGFR mutations by overall response rate(ORR), disease control rate(DCR) and progression free survival(PFS).Results: Of all patients, EGFR mutation rate was 28.6%(60/210) by direct sequencing and 45.2%(95/210) by ARMS(P<0.001) respectively. Among the EGFR wild type patients tested by direct sequencing, 26.7% of them were positive by ARMS. For the 72 EGFR mutation positive patients treated with gefitinib, the ORR, DCR and median PFS were 69.4%, 90.2% and 9.3 months respectively. The patients whose EGFR mutation status was negative by direct sequencing but positive by ARMS had lower ORR(48.0% vs. 80.9%, P=0.004) and shorter median PFS(7.4 vs. 10.5 months, P=0.009) as compared with that of EGFR mutation positive patients by both detection methods. Conclusions: Our study verified the feasibility of EGFR analysis in cytological specimens in advanced NSCLC. ARMS is more sensitive than direct sequencing in EGFR mutation detection. EGFR Mutation status tested on cytological samples is applicable for predicting the response to gefitinib. Abundance of EGFR mutations might have an influence on TKIs efficacy.
文摘Objective:To assess prognostic factors and validate the effectiveness of recursive partitioning analysis (RPA) classes and graded prognostic assessment (GPA) in 290 non-small cell lung cancer (NSCLC) patients with brain metastasis (BM).Methods:From Jan 2008 to Dec 2009,the clinical data of 290 NSCLC cases with BM treated with multiple modalities including brain irradiation,systemic chemotherapy and tyrosine kinase inhibitors (TKIs) in two institutes were analyzed.Survival was estimated by Kaplan-Meier method.The differences of survival rates in subgroups were assayed using log-rank test.Multivariate Cox's regression method was used to analyze the impact of prognostic factors on survival.Two prognostic indexes models (RPA and GPA) were validated respectively.Results:All patients were followed up for 1-44 months,the median survival time after brain irradiation and its corresponding 95% confidence interval (95% CI) was 14 (12.3-15.8) months.1-,2-and 3-year survival rates in the whole group were 56.0%,28.3%,and 12.0%,respectively.The survival curves of subgroups,stratified by both RPA and GPA,were significantly different (P<0.001).In the multivariate analysis as RPA and GPA entered Cox's regression model,Karnofsky performance status (KPS) ≥ 70,adenocarcinoma subtype,longer administration of TKIs remained their prognostic significance,RPA classes and GPA also appeared in the prognostic model.Conclusion:KPS ≥70,adenocarcinoma subtype,longer treatment of molecular targeted drug,and RPA classes and GPA are the independent prognostic factors affecting the survival rates of NSCLC patients with BM.
文摘Background: To determine the safety and therapeutic efficacy of nimotuzumab(h-R3) combined with docetaxel in advanced non-small-cell lung cancer(NSCLC) patients who have failed to respond to prior first-line chemotherapy.Methods: In this single-center, open-label, dose-escalating phase I trial, patients with epidermal growth factor receptor(EGFR)-expressing stage IV NSCLC were treated with nimotuzumab plus docetaxel according to a dose escalation schedule. The safety and efficacy of the combination treatment were observed and analyzed.Results: There were 12 patients with EGFR-expressing stage IV NSCLC enrolled. The dose of nimotuzumab was escalated from 200 to 600 mg/week. The longest administration of study drug was 40 weeks at the 600 mg/week dose level. Grade III–IV toxicities included neutropenia and fatigue, and other toxicities included rash. Dose-limiting toxicity occurred with Grade 3 fatigue at the 200 mg dose level of nimotuzumab and Grade 4 neutropenia with pneumonia at the 600 mg dose level of nimotuzumab. No objective responses were observed, and stable disease was observed in eight patients(66.7%). The median progression-free survival(PFS) was 4.4 months in all patients, 1.3 months in patients with the EGFR mutation, and 4.4 months in those with wild type EGFR(EGFR WT). The median survival time(MST) was 21.1 months in all patients, 21.1 months in patients with EGFR mutation, and 26.4 months in patients with EGFR WT.Conclusions: Nimotuzumab and docetaxel combination therapy was found to be well tolerated and efficacious. Further study of nimotuzumab is warranted in advanced NSCLC patients.
基金supported in part by a grant from the Nature Science Foundation of Health Bureau of Shaanxi Province(#08D28)
文摘The aim of this study was to analyze the correlation of the expression of MET and cyclin D1 and MET gene copy number in non-small cell lung cancer (NSCLC) tissues and patient clinicopathologic characteristics and survival. Sixty-one NSCLC tissue specimens were included in the study. The expression of MET and cyclin D1 was evaluated by immunohistochemistry and MET gene copy number was assessed by quantitative real-time polymerase chain reaction (Q-PCR). Positive expression of MET and cyclin D1 protein and increased MET gene copy number occurred in 59.0%, 59.0% and 18.0% of 61 NSCLC tissues, respectively. MET-positivity correlated with poor differentiation (P=0.009). Increased MET gene copy number was significantly associated with lymph node metastasis (P=0.004) and advanced tumor stage (P=0.048), while the expression of cyclin D1 was not associated with any clinicopathologic parameters. There was a significant correlation between the expression of MET and MET gene copy number (P=0.002). Additionally, the expression of cyclin D1 had a significant association with the expression of MET as well as MET gene copy number (P=0.002 and P=0.017, respectively). MET-positivity and increased MET gene copy number were significantly associated with poor overall survival (P=0.003 and P<0.001, respectively) in univariate analysis. Multivariate Cox proportional hazard analysis confirmed that the expression of MET and MET gene copy number were prognostic indicators of NSCLC (P=0.003 and P=0.001, respectively). The overexpression of MET and the increased MET gene copy number might be adverse prognostic factors for NSCLC patients. The activation of the MET/cyclin D1 signaling pathway may contribute to carcino- genesis and the development of NSCLC, and may represent a target for therapy.
文摘Objective:Epidermal growth factor receptor (EGFR) mutations are strong determinants of tumor response to EGFR tyrosine kinase inhibitors in non-small-cell lung cancer (NSCLC) patients. The aim of this study was to evaluate the correspondence between EGFR mutations in non-small-cell lung cancer tissues and in circulating DNA. Methods:The research was conducted in 50 non-small-cell lung cancer patients who had undergone curative surgery,and in whom both serum and neoplastic tissues were available. Meanwhile sera of 33 cases of advanced NSCLC patients were also analyzed. DNA were extracted from each sample. Mutations of EGFR in exon18-21 were examined by PCR amplification method and direct sequencing. Results:EGFR mutations were detected in 15 (30%) of 50 neoplastic tissue samples,6 cases were in-frame deletion del E746-A750 in exon19,9 cases were substitution in exon 21 (all were L858R except one was L861Q),but no mutated DNA resulted in paired serum circulating DNA samples of 50 resectable patients. As the 33 advanced NSCLC patients,EGFR mutations were detected in only 2 serum circulating DNA samples,all were L858R mutation in exon 21. Conclusion:These data indicated that it was difficult to identify EGFR mutations in circulating DNA of NSCLC patients. The use of EGFR mutation in serum as a clinical method for decision making of TKI therapy is unsatisfactory.
基金Supported by a grant from the Youth National Science Foundation of China(No.61702164)。
文摘Objective Anlotinib,an oral vascular endothelial growth factor receptor 2(VEGFR2)inhibitor,has confirmed antitumor activity in lung cancer in both in vitro and in vivo assays,and has been recommended as third-line treatment agent in non-oncogene driven non-small cell lung cancer(NSCLC).This prospective study aimed to investigate the efficacy and safety of anlotinib plus S-1 for third-or later-line treatment in patients with advanced NSCLC.Methods Patients with histologically or cytologically confirmed NSCLC,and documented disease progression following second-line chemotherapy,and/or epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI)treatment were enrolled in this study.The patients were treated anlotinib(8 mg daily d 1–14)and S-1(60 mg/m^2 d 1–14)and the treatment was repeated every 3 weeks.Treatment was continued until disease progression or unacceptable toxicity occurred.The objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),and adverse events(AEs)were reviewed and evaluated.Results Forty-one patients were enrolled in the study between June 2018 and December 2018.The total ORR and DCR were 26.8%and 80.5%,respectively.The median PFS was 5.2 months[95%confidence interval(CI),3.9 to 6.6 months].In the univariate analysis,there was a significant difference in the median PFS between patients with brain metastases and those without brain metastases(4.8 months vs 5.9 months,respectively;P=0.039).The Eastern Cooperative Oncology Group(ECOG)performance status(P=0.002),lines of therapy(P=0.015),and therapeutic evaluation(P=0.014)were independent factors that influenced PFS.The most common AEs were hypertension,proteinuria,myelosuppression,gastrointestinal reactions,fatigue,and mucositis.Conclusion Anlotinib plus S-1 is an effective and safe regimen for advanced NSCLC as third-or later-line therapy.
文摘Lobectomy with partial removal of the pulmonary artery in video-assisted thoracic surgery (VATS) currently remains a challenge for thoracic surgeons. We were interested in introducing pulmonary vessel blocking techniques in open thoracic surgery into video-assisted thoracic surgery (VATS) procedures. In this study, we reported a surgical technique simultaneously blocking the pulmonary artery and the pulmonary vein for partial removal of the pulmonary artery under VATS. Seven patients with non-small-cell lung cancer (NSCLC) received lobectomy with partial removal of the pulmonary artery using the technique between December 2007 and March 2012. Briefly, rather than using a small clamp on the distal pulmonary artery to the area of invading cancer, we replaced a vascular clamp with a ribbon and Hem-o-lock clip to block the preserved pulmonary veins so as to prevent back bleeding and yield a better view for surgeons. The mean occlusion time of the pulmonary artery and pulmonary veins were 44.0±10.0 and 41.3±9.7 minutes, respectively. The mean repair time of the pulmonary artery was 25.3±13.7 minutes. No complications occurred. No patients showed abnormal blood flow through the reconstructed vessel. There were no local recurrences on the pulmonary artery. In conclusion, the technique for blocking the pulmonary artery and veins is feasible and safe in VATS and reduces the risk of abrupt intraoperative bleeding and the chance of converting to open thoracotomy, and extends the indications of VATS lobectomy.
