Objective:Various nanoparticles have been designed and tested in order to select optimal carriers for the inhalation delivery of anticancer drugs to the lungs.
Methods:hTe following nanocarriers were studied:micelles, liposomes, mesoporous silica nanoparticles (MSNs), poly propyleneimine (PPI) dendrimer-siRNA complexes nanoparticles, quantum dots (QDs), and poly (ethylene glycol) polymers. All particles were characterized using the following methods:dynamic light scattering, zeta potential, atomic force microscopy, in vitro cyto-and genotoxicity. In vivo organ distribution of all nanoparticles, retention in the lungs, and anticancer effects of liposomes loaded with doxorubicin were examined in nude mice atfer the pulmonary or intravenous delivery.
Results:Signiifcant differences in lung uptake were found atfer the inhalation delivery of lipid-based and non-lipid-based nanoparticles. hTe accumulation of liposomes and micelles in lungs remained relatively high even 24 h atfer inhalation when compared with MSNs, QDs, and PPI dendrimers. hTere were notable differences between nanoparticle accumulation in the lungs and other organs 1 and 3 h atfer inhalation or intravenous administrations, but 24 h atfer intravenous injection all nanoparticles were mainly accumulated in the liver, kidneys, and spleen. Inhalation delivery of doxorubicin by liposomes signiifcantly enhanced its anticancer effect and prevented severe adverse side effects of the treatment in mice bearing the orthotopic model of lung cancer.
Conclusion:hTe results of the study demonstrate that lipid-based nanocarriers had considerably higher accumulation and longer retention time in the lungs when compared with non-lipid-based carriers atfer the inhalation delivery. hTese particles are most suitable for effective inhalation treatment of lung cancer.

HPV16 E6/E7 Negatively Affect Radiosensitivity of Lung Cancer Cells

Objective Lung cancer cells associated with radioresistance are likely to give rise to local recurrence and distant metastatic relapse,but little is known about its underlying mechanisms.In the present paper,the effects of the HPV16 E6 and HPV16 E7 oncoprotein on the radiosensitivity of lung cancer cell lines were investigated.Methods The HPV16 E6 or HPV16 E7 oncoprotein was expressed by a transient transfection with pcDNA3-HPV16 E6 or pcDNA3-HPV16 E7 expression vector.Human lung cancer H2179 cells and mouse lung cancer Lewis cells were exposed to a γ-ray radiation source,cellular survival was evaluated by using a colony formation assay.The expression of HPV16 oncoproteins E6/E7,extracellular signal-regulated kinases 1/2(ERK1/2) and AKT signaling was determined by Western blot assay.VEGF secretion was determined by ELISA.Results Both HPV16 oncoproteins E6 and E7 significantly decreased radiosensitivity of H2179 cells,associated with a promotion of the ERK1/2 and AKT phosphorylation.A decrease of reactive oxygen species(ROS) and an increase of VEGF levels were observed in the cells expressing the HPV16 oncoproteins E6 and E7.Furthermore,a similar reduction of radiosensitivity mediated by the HPV16 oncoproteins E6 and E7 was also observed in a mouse lung cancer Lewis cells.Conclusion The findings indicate that the HPV16 oncoproteins E6 and E7 negatively affects susceptibility of lung cancer cells to radiotherapy via regulation of the ERK1/2 and Akt signaling pathway and VEGF expression.

Epidemiological Evolution of Lung Cancer in the South of Spain from 1990 to 2010

Background: Changes in lung cancer has been characterized by the increase of cases among women and the increase in adenocarcinomas among other histological subtypes.Methods: Descriptive analysis of cases diagnosed with lung cancer in Hospital Virgen de las Nieves (Spain) from 1990 to 2010,based on five variables (age, sex, smoking, histology and pathological anatomy). The study establishes associations between these variables and compares the results with the literature.Results: 2,026 patients were diagnosed with lung cancer in this period; 1,838 were males (90.7％) and 188 women (9.3％); 1,892patients (93.4％) were smokers or ex-smokers and 134 (6.6％) had never smoked; the most frequent non-small cell histology types were squamous cell carcinoma and adenocarcinoma and it was the most frequent neoplasia in women and were associated with a lower tobacco consumption.Conclusion: The large majority of lung cancer cases is associated with a history of smoking tobacco and there are histopathological differences according to gender and cumulative tobacco smoke load.

Paraneoplastic Leukocytosis and Thrombocytosis as Prognostic Biomarkers in Non-small Cell Lung Cancer

Menstrual Factors,Reproductive Factors and Lung Cancer Risk:A Meta-analysis

Heparanase Expression Correlates with Angiogenesis and Lymphangiogenesis in Human Lung Cancer

Background and objective Heparanase has been thought to be a good molecular marker of tumor, and the heparanase expression level was correlated closely with tumor metastasis. In this study, we investigate the effects of heparanase on angiogenesis and lymphangiogenesis of lung cancer and the relationship between heparanase expression and vascular endothelial growth factor (VEGF), vascular endothelial growth factor-C (VEGF-C).Methods Immunohistochemistry was used to detect the expression of heparanase, VEGF, VEGF-C protein and microvascular density (MVD), lymphatic vessel density (LVD) in 115 cases of non-small cell lung cancer (NSCLC) and 45 cases of adjacent normal tissue samples.Results Our results showed that heparanase expression was significantly increased in 91 (79.13%) of the 115 cases and correlated with lymph node metastasis (node positive rate 87.0%; node negative rate 36.8%; P=0.003). Heparanase positive expression cases have significantly higher concentration of microvascular density (MVD) and lymphatic vessd density (LVD) as compared with heparanase negative expression cases (P<0.01, P<0.01, respectively), heparanase expression was significantly correlated with VEGF, VEGF-C expression in NSCLC.Conclusion Heparanase overexpression was associated with angiogenesis and lymphangiogenesis of lung cancer, targeting ofheparanase may represent a significant therapeutic potential for lung cancer.

Background and objective Recent studies have showed that combination of chemotherapy and radiotherapy might result in better outcome for locally advanced non-small cell lung cancer (NSCLC). The aim of this study is to determine the maximal tolerance dose (MTD) and efficacy of full-dose gemcitabine and oxaliplatin when given concurrently with 3-dimentional radiation therapy (3D-RT) for locally advanced NSCLC. Methods Oxaliplatin was administered at a fixed dose of 130 mg/m2, and gemcitabine was administered at a starting dose of 800 mg/m2 with an incremental dose gradient of 200 mg/m2 for 3 dose levels. MTD was defined as the immediate dose level lower than the dose at which dose-limiting toxicity (DLT) occurred in more than one-third of the patients. The chemotherapy was administered at 3-week cycle. The RT was given as 3-D conformal manner at a single daily dose of 2 Gy for 5 days per week. Results Twenty-two patients were evaluable and distributed to three different dose levels: 6 at level 1, 8 at level 2 and 8 at level 3. Pulmonary toxicity, esophageal and hematologic toxicity were the main DLT. Grade Ⅲ acute pulmonary toxicity occurred in one patient each at level 2 and level 3, both with V20＞20%, and grade Ⅲ esophagitis in two patients at level 3. The MTD of gemcitabine in this study was 1000 mg/m2. The overall response rate was 75.0% (9/12). The 1- and 2-year survival rate was 70.0% and 30.5% respectively. The median time to progression was 8.7 months (range 5--11.8 months). Conclusion With reduced radiation volume, gemcitabine of 1000 mg/m2 in combination with oxaliplatin of 130 mg/m2 was effective and could be safely administered for NSCLC.

Lung Cancer:MicroRNA and Target Database

MicroRNAs (miRNAs) are a class of non-coding RNAs that hybridize to mRNAs and induce either translation repression or mRNA cleavage.Recently,it has been reported that miRNAs could possibly play a critical role in cellular processes like regulation of cell growth,differentiation,and apoptosis,emphasizing their role in tumorigenesis.Likewise,several miRNA's are involved in lung cancer tumorigenesis.The present review puts forth a database of human miRNA's involved in lung cancer along with their target genes.It also provides sequences of miRNA's and their chromosomal locations retrieved from different databases like microCosm (218 microRNAs),PhenomiR (293 microRNAs),and mir2Disease (90 microRNAs) and target gene information such as the pathways like cell cycle regulation,angiogenesis,apoptosis etc.Though miRNA's are still to be explored,they hold a promise as therapeutic targets and diagnostic markers of cancer.

Background and objectiveMaintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. PR-Set7 (also known as Set8) is a cell cycle regulated enzyme that catalyses monomethylation of histone 4 at Lys20 (H4K20me1) to promote chromosome condensation and prevent DNA damage. Recent studies show that CRL4CDT2-mediated ubiquitylation of PR-Set7 leads to its degradation during S phase and atfer DNA damage. hTis might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity atfer DNA damage.Methods We developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. We have therefore used a mouse model to demonstrate for the ifrst time that Cul4A is oncogenicin vivo. With this model, staining of PR-Set7 in the preneoplastic and tumor lesions in AdenoCre-induced mouse lungs was performed. Meanwhile we identiifed higher protein level changes of γ-tubulin and pericentrin by IHC.Results hTe level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identiifed higher levels of the proteins pericentrin and γ-tubulin in Cul4A mouse lungs induced by AdenoCre.Conclusion PR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model.

Background and Objectives:Lung cancer is the most common cancer and cancer related cause of death worldwide. However, the association between sleep duration and incident lung cancer has not been investigated in a prospective cohort study. Methods:We prospectively examined the association between sleep duration and incident lung cancer in a cohort of 21,026 United States (US) male physicians. Self-reported sleep duration was ascertained during 2002 annual follow-up questionnaire. Incident lung cancer was ascertained through yearly follow-up questionnaires. Cox regression was used to estimate relative risk of incident lung cancer. Results:hTe average age at baseline was 68.3±8.8 yr. During a mean follow up of 7.5 (±2.2) yr, 150 cases of lung cancer occurred. Using 7 h of sleep as the reference group, multivariable adjusted hazard ratios (95%CI) for lung cancer were 1.18 (0.77-1.82), 1.0 (ref), and 0.97 (0.67-1.41) from lowest to the highest category of sleep duration (P for quadratic trend 0.697), respectively. In a secondary analysis, smoking status did not modify the sleep duration-lung cancer association (P=0.78). hTere was no evidence for an interaction between sleep duration and sleep apnea on the risk of lung cancer either (P=0.65). Conclusions:Our data failed to show a higher risk of lung cancer in association with altered sleep duration among US male physicians.

Surgical Therapeutic Strategy for Non-small Cell Lung Cancer with Mediastinal Lymph Node Metastasis(N2)

Background and objective Approximately 30% of patients who are diagnosed with non-small cell lung cancer(NSCLC)are classified as N2 on the basis of metastasis to the mediastinal lymph nodes.The effectiveness of surgery for these patients remainscontroversial.Although surgeries in recent years are proved to be effective to some extent,yet due to many reasons,5-yearsurvival rate after surgery varies greatly from patient to patient.Thus it is necessary to select patients who have ahigh probability of being be cured through an operation,who are suitable to receive surgery and the best surgical methods so as to figure out the conditions under which surgical treatment can be chosen and the factors that may influence prognosis.Methods 165 out of l73 patients with N2NSCLC were treated with surgery in our department from January 1999 to May 2003,among whom 130 were male,43 female and the sex ratio was 3:1,aver age age 53,ranging from 29 to 79.The database covers the patients'complete medical history including the information of their age,sex,location and size of tumor date of operation,surgical methods,histologic diagnosis,clinical stage,post-operative TNM stage,neoadjuvant treatment and chemoradiotherapy.The methods of clinical stage verification include chest X-ray,chest CT,PET,mediastinoscopy,bronchoscope(+?),brain CT or MRI,abdominal B ultrasound (or CT),and bone ECT.The pathological classification was based on the international standard for lungcancer(UICC1997).Survival time was analyzed from the opemtion date to May 2008 with the aid of SPSS(Statistical Package forthe Social Sciences)program.Kaplan-Meier survival analysis,Log-rank test and Cox multiplicity were adopted respectively to obtain patients'slLrvival curve,survival rate and the impact possible factors may have on their survival rate.Results The median survival tinle was 22 months.with 3-year survival rate reaching 28.1%and 5-year survival rate reaching 19.0%.Age,sex.different histological classification and postoperative chemoradiotherapy seem to have no correlation with 5-yearsurvival rate.In all N2 subtypes,5-year survival rate is remarkably higher for unexpected N2 discovered at thoractomy and proven N2 stage before preoperative work-up and receive a mediastinal down-staging after induction therapy (P<0.01),reaching 30.4%and 27.3%respectively.5-year survival rate for single station lymph node metastasis were 27.8%.much higher compared with 9.3% for multiple stations(P<0.001).Induction therapy which downstages proven N2 in 73.3%patients gains them the opportunity of surgery.The 5-year survival rate were 23.6%and 13.0%for patients who had complete resection and those who had incomplete resection(P<0.001).Patients who underwent lobectomy(23.2%)have higher survival rate,less incidence rate of complication and mortality rate,compared with pneumonectomy(14.8%)(P<0.01).T4patients has a 5-year survival rateaslow as 11.1%,much less than T1(31.s%)and T2(24.3%)patients(P=0.01).It is noted through Cox analysis that completeness of resection,number ofpositive lymph node stations and pnmary T status have significant correlativity with 5-year survival rate.Conclusion It is suggested that surgery(lobectomy preferentially)is the best solution for T1 and T2 with primary tumor have not invaded pleura or the distance to carina of trachea no less than 2 cm,unexpected N2 discovered at thoractomy when a complete resection can be applied,and proven N2 discovered during preoperative work-up and is down-staged after induction therapy.Surgical treatment is the best option,lobectomy should be prioritized in operational methods since ite rate of complication and morality are lower than that of pneumonectomy.Patients'survival time will not benefit from surgery if they are with lymph nodes metastasis of multiple stations(Bulky N2 included)and T4 which can be Partially removed.Neoadjuvant chemotherapy increases long-term survival rate of those with N2 proven prior to surgery.However,postoperative radiotherapy decreases local recurrence rate but does not contribute to patients'long-term survival rate.

Diagnostic Value of Sialic Acid in Pleural Effusion

The present study was conducted in 30 patients of malignant pleural effusion and 30 patients of non malignant pleural effusion.Pleural fluid and blood samples were taken at the time of admission,before starting any treatment.Sialic acid levels were estimated in seruln and pleural fluid by Warren'S TBA method.In the present study,serum sialic acid levels were higherin group II as compared to group I.In the present study, pleural fluid sialic acid levels and PF/S ratio was higher in malignant pleural effusion(though difference was not statistically significant).Smokers in group II had higher serum sialic acid as compared to group 1(p<0.05).The sensitivity and specificity of pleural fluid/serum sialic acid ratio with cut off value of 0.7 were 76.67%and 20%respectively,while taking the cut of value of 70 mg/dL for pleural fluid sialic acid in malignant pleural effusions,the sensitivity was 63.33%, specificity 60%and positive predictive value 46.34%.These findings indicate that determination ofsialicacid levels in pleural fluid has diagnostic value as a cheap,simple and reliable marker for malignant pleural effusion.

Tracheal Carinal Reconstruction and Bronchovasculoplasty in Central Type Bronchogenic Carcinoma

Background and objective Because ndical resection for lung cancer invading the initial borderline of different lobes and carina is difficult,we tried to analyse the variables of successful tracheal carinoplasty and bronchovasculoplasty to discover a proper approach for appropriate early and long term results.Methods of 1399 lung resections for primary lung cancer performed in our hospital from April 1985 to December 2006,133 underwent bronchoplastic surgeries, including 15 carinoplasty,cases and 118 sleeve lobectomy(SL)cases,and 118pneumoectomy(PN) cases were compared at the same time.Results Complications occurredin 18 cases, with no operative related mortaliW.For all patients,the l year,3 year,and 5 year survival rateswere 79.8%,56.7%and31.2%,respectively.The 5 year survival rate by cancer stage was 69.2%for Ib,40.6%for IIb,19.6%for IIIa,and 16.6%for IIIa(N2).Conclusion Selection of cases~clearance of lymph nodesJ disposal of the bronchus and pulmonary vessel and replacement or restoration of the superior vena cava are the main factors influencing prognosis.

Helicobacter Pylori Infection and Lung Cancer:New Insights and Future Challenges

Helicobacter pylori (H. pylori) is the causative agent of chronic gastritis and peptic ulcer diseases and is an important risk factor for the development functional dyspepsia, peptic ulceration, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. H. pylori has very high rates of infection in human populations, and it is estimated that over 50％ of the world population is infected. Recently, certain extra-gastric manifestations, linked to H. pylori infection, have been widely investigated. Noteworthy, a growing body of evidences supports an association between H. pylori infection with lung cancer. The present review intend to highlight not only the most recent evidences supporting this association, but also some missed points, which must be considered to validate this emerging association.

RAGE in Cancer Lung:the End of a Long and Winding Road is in Sight

IntroductionThe receptor of advanced glycation end-products (RAGE), is a type Ⅰ single-pass transmembrane protein, member of the multi-ligand immunoglobulin superfamily molecule, which was discovered in 1992, on account of its ability to bind the advanced glycation end-products (AGEs)[1].

Gene Polymorphisms and Chemotherapy in Non-small Cell Lung Cancer

The phamacogenetics is being used to predict whether the selected chemotherapy will be really effective and tolerable to the patient. Irinotecan, oxidized by CYP3A4 to produce inactive compounds, is used for treatment of various cancers including advanced non small cell lung cancer (NSCLC) patients. CYP3A4*16B polymorphism was associated with decreased metabolism ofirrinotecan. Irinotecan is also metabolized by carboxylesterase to its principal active metabolite, SN-38, which is subsequently glucuronidated by UGT1As to form the inactive compound SN-38G. UGT1A1*28 and UGT1A1*6 polymorphisms were useful for predicting severe toxicity with NSCLC patients treated with irinotecan-based chemotherapy. Platinum-based compounds (cisplatin, carboplatin) are being used in combination with new cytotoxic drugs such as gemcitabine, paclitaxel, docetaxel, or vinorelbine in the treatment of advanced NSCLC. Cisplatin activity is mediated through the formation of cisplatin-DNA adducts. Gene polymorphisms of DNA repair factors are therefore obvious candidates for determinants of repair capacity and chemotherapy efficacy. ERCC1, XRCC1 and XRCC3 gene polymorphisms were a useful marker for predicting better survival in advanced NSCLC patients treated with platinum-based chemotherapy. XPA and XPD polymorphisms significantly increased response to platinum-based chemotherapy. These DNA repair gene polymorphisms were useful as a predictor of clinical outcome to the platinum-based chemotherapy. EGFR kinase inhibitors induce dramatic clinical responses in NSCLC patients with advanced disease. EGFR gene polymorphism in intron 1 contains a polymorphic single sequence dinudeotide repeat (CA-SSR) showed a statistically significant correlation with the gefitinib response and was appeared to be a useful predictive marker of the development of clinical outcome containing skin rashes with gefitinib treatment. The other polymorphisms of EGFR were also associated with increased EGFR promoter activity. EGFR gene mutations and polymorphisms were also associated with EGFR kinase inhibitors response and toxicity.