Analysis and Review of Downregulated Actin Cytoskeletal Proteins in Non-Small Cell Lung Cancer

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.

Efficacy and Safety of Primary Radiotherapy in Combination with EGFR-TKIs for Non-Small Cell Lung Cancer Harboring EGFR Mutation

Objective: To evaluate the efficacy and safety of EGFR-TKI with the radiotherapy in EGFR mutant metastatic NSCLC. Methods: Retrospective analysis of 72 patients with stage IV lung cancer with EGFR-sensitive mutation. Patients in the A group were treated with the first-generation EGFR-TKI (Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor) combined with radiotherapy for primary tumors (34 cases). The B group was treated with the first-generation EGFR-TKI alone until the disease progressed (38 cases). PFS, OS, pulmonary infection and hematological toxicity during treatment were commented in both groups. Results: The objective remission rate was 47.1% (16/34) in the A group and 21.1% (8/38) in the B group. There was a significant difference between the two groups. There was no significant difference in hematological toxicity between the A group and the B group. There were 10 patients (29.4%) with degree II pulmonary infection in the A group and 3 patients (7.9%) in the B group. The difference between the two groups was statistically significant, suggesting that the incidence of pneumonia in the A group was higher than that in the B group. The median PFS (Progression-Free Survival)) and OS (Overall Survival) of the A group were significantly longer than those of the B group (16.5 months vs 9 months) and the median OS (36 months vs 19 months). The PFS and OS in the A group were significantly longer than those in the B group. Conclusion: EGFR-TKI combined with primary radiotherapy can significantly prolong the drug resistance time of EGFR mutant metastatic NSCLC.

High plasma fibrinogen concentration and platelet count unfavorably impact survival in non–small cell lung cancer patients with brain metastases

High expression of fibrinogen and platelets are often observed in non–small cell lung cancer(NSCLC) patients with local regional or distant metastasis. However, the role of these factors remains unclear. The aims of this study were to evaluate the prognostic significance of plasma fibrinogen concentration and platelet count, as well as to determine the overall survival of NSCLC patients with brain metastases. A total of 275 NSCLC patients with brain metastasis were enrolled into this study. Univariate analysis showed that high plasma fibrinogen concentration was associated with age ≥ 65 years(P = 0.011), smoking status(P = 0.009), intracranial symptoms(P = 0.022), clinical T category(P = 0.010), clinical N category(P = 0.003), increased partial thromboplastin time(P < 0.001), and platelet count(P < 0.001). Patients with low plasma fibrinogen concentration demonstrated longer overall survival compared with those with high plasma fibrinogen concentration(median, 17.3 months versus 11.1 months; P ≤ 0.001). A similar result was observed for platelet counts(median, 16.3 months versus 11.4 months; P = 0.004). Multivariate analysis showed that both plasma fibrinogen concentration and platelet count were independent prognostic factors for NSCLC with brain metastases(R2 = 1.698, P < 0.001 and R2 = 1.699, P < 0.001, respectively). Our results suggest that high plasma fibrinogen concentration and platelet count indicate poor prognosis for NSCLC patients with brain metastases. Thus, these two biomarkers might be independent prognostic predictors for this subgroup of NSCLC patients.

Therapeutic management options for stage Ⅲ non-small cell lung cancer

Lung cancer is the leading cause of cancer death worldwide.Majority of newly diagnosed lung cancers are non-small cell lung cancer(NSCLC), of which up to half are considered locally advanced at the time of diagnosis.Patients with locally advanced stage Ⅲ NSCLC consists of a heterogeneous population, making management for these patients complex.Surgery has long been the preferred local treatment for patients with resectable disease.For select patients, multimodality therapy involving systemic and radiation therapies in addition to surgery improves treatment outcomes compared to surgery alone.For patients with unresectable disease, concurrent chemoradiation is the preferred treatment.More recently, research into different chemotherapy agents, targeted therapies, radiation fractionation schedules, intensity-modulated radiotherapy, and proton therapy have shown promise to improve treatment outcomes and quality of life.The array of treatment approaches for locally advanced NSCLC is large and constantly evolving.An updated review of past and current literature for the roles of surgery, chemotherapeutic agents, radiation therapy, and targeted therapy for stage Ⅲ NSCLC patients are presented.

Clinical characteristics and response to tyrosine kinase inhibitors of patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor mutations

Objective： To investigate the clinical features of patients with non-small cell lung cancer（NSCLC） harboring uncommon epidermal growth factor receptor（EGFR） mutations, and the treatment outcomes of EGFR tyrosine kinase inhibitors（TKIs） in these patients.Methods： We retrospectively analyzed the data of 128 NSCLC patients pathologically diagnosed with uncommon EGFR mutation in the Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences ＆ Peking Union Medical College and Beijing Hospital from January 2010 to December 2015, including 40 advanced patients who received EGFR-TKI.Results： Among the total 128 patients, 11 patients were non-adenocarcinoma, including squamous carcinoma（3.9%）, adenosquamous carcinoma（2.3%）, large cell carcinoma（0.8%）, and composite neuroendocrine carcinoma（1.6%）. Single mutations accounted for 75.0%（96/128）, including G719X（29.7%）, S768I（18.0%）, 20 exon insertion（13.3%）, L861Q（12.5%）, De novo T790M（0.8%）, and T725（0.8%）. Thirty-two patients harbored complex mutations. Forty advanced patients received EGFR-TKI, the objective response rate（ORR） was 20.0%,the disease control rate（DCR） was 85.0%, and the progression-free survival（PFS） was 6.4 [95% confidence interval（95% CI）, 4.8–7.9] months. The exploratory analysis of tumor response and PFS in 33 patients with G719X/S768I/L861 Q subtypes showed that ORR was 21.2%（7/33）, the DCR was 93.9%（31/33）, and PFS was 7.6（95% CI, 5.8–9.4） months. Patients with exon 20 insertion mutation and De novo T790 M experienced rapid disease progression with PFS no more than 2.7 months.Conclusions： Uncommon EGFR-mutant NSCLCs are heterogeneous, EGFR-TKIs can have different efficacy in this specific subtype, and thus further individual assessment is required for each case.

Nedaplatin/Gemcitabine Versus Carboplatin/Gemcitabine in Treatment of Advanced Non-small Cell Lung Cancer: A Randomized Clinical Trial

Objective： To evaluate the efficacy and safety of nedaplatin/gemcitabine （NG） and carboplatin/gemcitabine （CG） in the management of untreated advanced non-small cell lung cancer （NSCLC）. Methods： Sixty-two patients with previously untreated advanced NSCLC were recruited between June 2006 and November 2007. Subjects were randomly assigned to the NG arm （n=30） and the CG arm （n=32）. Only patients （24 and 25 in the NG and CG arms, respectively） who completed 〉2 chemotherapy cycles were included in the data analysis. The primary outcome measure was the objective response rate （ORR）. The secondary outcome measures included progression-free survival （PFS）, overall survival （OS） and adverse events. Results： There were no statistically significant differences in the efficacy measures （ORR, P=0.305; median PFS, P=0.298, median OS, P=0.961） or in the major adverse events （grade 3/4 neutropenia, P=0.666; grade 3/4 anemia, P=0.263; grade 3/4 thrombocytopenia, P=0.222） between the two treatment arms. However, there was a trend towards higher ORR （37.5% vs. 24.0%）, longer PFS （6.0 vs. 5.0 months）, and less adverse events in the NG arm. Conclusion： NG regimen seems to be superior over CG regimen for advance NSCLS, but further investigation is needed to validate this superiority.

Telomerase activity and expression of the telomerase catalytic subunit gene in non small cell lung cancer: correlation with decreased apoptosis and clinical prognosis

To investigate the level of telomerase activation (TA) and telomerase catalytic subunit (hEST 2) gene mRNA in patients with non small cell lung cancer, and determine whether they are associated with tumor cell apoptosis, stage, and clinical outcome Methods Primary tumor specimens from 58 patients untreated with chemotherapy and 10 cases of histologically benign and adjacent lung tissue were analyzed TA and hEST 2 were measured by means of a modified telomerase repeat amplification protocol (TRAP) assay and in situ hybridization (ISH), respectively Terminal deoxynucleotidyl transferase (TdT) mediated biotin dUTP nick end labeling (TUNEL) was used to evaluate apoptotic cells Reverse transcription polymerase chain reaction (RT PCR) was used to detect bcl 2 mRNA expression Results TA and hEST 2 were detected in 45 (77 6%) and 43 (74 1%) of 58 tumor specimens, respectively, and not detected in specimens of adjacent and benign lung tissue One case expressed hEST 2 as a weak positive Statistically significant positive association was found between the level of TA and hEST 2( r =0 85, P =0 001) TA and hEST 2 were associated with tumor stage, but not associated with tumor grade, gender and patient age Positive rate of bcl 2 mRNA was 38 (65 5%) of 58 tumor specimens The mean apoptotic index in the bcl 2 positive group (9 5±1 3) was lower than that in the bcl 2 negative one (19 8±2 1, P <0.05), suggesting that apoptotic index may be inversely associated with bcl 2 expression ( r =-0 48, P =0 041) Bcl 2 expression in the TA and hEST 2 positive group (92 1% and 89 4%) was higher than that in the negative one (50 0% and 45 0%, P =0 043 and P =0 032, respectively) The apoptotic index was lower in the TA or hEST 2 positive group (8 2±1 4, 10 7±1 1) than in the negative one (20 5±1 6, 24 2±2 1, P <0 05) A statistically significant inverse association was found between TA or hEST 2 and apoptotic index ( r =-0 45, P =0 02 and r = -0 51, P =0 001, respectively) Positive correlation was also detected between TA or hEST 2 and bcl 2 expression ( r =0 86, P =0 01 and r =0 73, P =0 024, respectively) The level of hEST 2 mRNA and apoptotic index were associated with clinical outcome in a multivariate cox regression analysis Conclusions High TA and hEST 2 were frequently detected in primary non small cell lung cancer untreated with chemotherapy, having high bcl 2 expression and a low tumor cell apoptotic rate This suggests that both TA and hEST 2 are correlated with the deregulation of apoptosis hEST 2 and apoptotic index have prognostic significance in patients with non small cell lung cancer

Expression of Maspin in Non-small Cell Lung Cancer and Its Relationship to Vasculogenic Mimicry

Maspin belongs to the serine protease inhibitor （serpin） family and has been proven to be a suppressor of tumor growth and metastasis in many types of tumors. The purpose of this study was to investigate the expression of maspin in non-small cell lung cancer （NSCLC） and its relationship to vasculogenic mimicry （VM）. A total of 160 specimens of NSCLC were involved in this study and 20 specimens of normal lung tissue served as controls. VM, microvessel density （MVD） and the expression of maspin were detected by using immunohistochemical staining. The results showed that the positive rates of maspin and VM in the NSCLC group were 48.1% （77/160） and 36.9% （59/160）, respectively, which were significantly different from those in the control group with the positive rates of maspin and VM being 100% and 0% respectively （P〈0.05）. VM, MVD and the expression level of maspin were significantly related to tumor differentiation, lymph node metastasis, clinical stages and postoperative survival time （all P〈0.05）. The maspin expression in patients with squamous cell carcinoma was significantly higher than that in those with adenocarcinoma （P〈0.05）. The maspin expression was negatively correlated with VM and MVD, and there was a positive correlation between VM and MVD. Maspin-negative expression, VM and high MVD score were negatively related to the 5-year-survival rate. PTNM stages, VM, MVD and maspin expression were independent prognostic factors for NSCLC （P〈0.05）. It was suggested that the loss of expression of maspin may participate in the invasion and metastasis of NSCLC and it has a positive relationship to VM in NSCLC. Combined detection of maspin, VM and MVD may help predict the progression and prognosis of NSCLC.

Efficacy and safety evaluation of icotinib in patients with advanced non-small cell lung cancer

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 icofinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.

A Preliminary Analysis of Non-small Cell Lung Cancer Biomarkers in Serum

To identify potential serum biomarkers that could be used to discriminate lung cancers from normal. Methods Proteomic spectra of twenty-eight serum samples from patients with non-small cell lung cancer and twelve from normal individuals were generated by SELDI (Surfaced Enhanced Laser Desorption/Ionization) Mass Spectrometry. Anion-exchange columns were used to fractionate the sera into 6 designated pH groups. Two different types of protein chip arrays, IMAC-Cu and WCX2, were employed. Samples were examined in PBSII Protein Chip Reader (Ciphergen Biosystem Inc) and the discriminatory profiling between cancer and normal samples was analyzed with Biomarker Pattern software. Results Five distinct potential lung cancer biomarkers with higher sensitivity and specificity were found, with four common biomarkers in both IMAC-Cu and WCX2 chip; the remaining biomarker occurred only in WCX2 chip. Two biomarkers were up-regulated while three biomarkers were down-regulated in the serum samples from patients with non-small cell lung cancer. The sensitivities provided by the individual biomarkers were 75%-96.43% and specificities were 75%-100%. Conclusions The preliminary results suggest that serum is a capable resource for detecting specific non-small cell lung cancer biomarkers. SELDI mass spectrometry is a useful tool for the detection and identification of new potential biomarker of non-small cell lung cancer in serum.

Radiomics-based predictive risk score: A scoring system for preoperatively predicting risk of lymph node metastasis in patients with resectable non-small cell lung cancer

Objective: To develop and validate a radiomics-based predictive risk score(RPRS) for preoperative prediction of lymph node(LN) metastasis in patients with resectable non-small cell lung cancer(NSCLC).Methods: We retrospectively analyzed 717 who underwent surgical resection for primary NSCLC with systematic mediastinal lymphadenectomy from October 2007 to July 2016. By using the method of radiomics analysis, 591 computed tomography(CT)-based radiomics features were extracted, and the radiomics-based classifier was constructed. Then, using multivariable logistic regression analysis, a weighted score RPRS was derived to identify LN metastasis. Apparent prediction performance of RPRS was assessed with its calibration,discrimination, and clinical usefulness.Results: The radiomics-based classifier was constructed, which consisted of 13 selected radiomics features.Multivariate models demonstrated that radiomics-based classifier, age group, tumor diameter, tumor location, and CT-based LN status were independent predictors. When we assigned the corresponding score to each variable,patients with RPRSs of 0-3, 4-5, 6, 7-8, and 9 had distinctly very low(0%-20%), low(21%-40%), intermediate(41%-60%), high(61%-80%), and very high(81%-100%) risks of LN involvement, respectively. The developed RPRS showed good discrimination and satisfactory calibration (C-index: 0.785, 95% confidence interval(95% CI):0.780-0.790)Additionally, RPRS outperformed the clinicopathologic-based characteristics model with net reclassification index(NRI) of 0.711(95% CI: 0.555-0.867).Conclusions: The novel clinical scoring system developed as RPRS can serve as an easy-to-use tool to facilitate the preoperatively individualized prediction of LN metastasis in patients with resectable NSCLC. This stratification of patients according to their LN status may provide a basis for individualized treatment.

Pharmacogenomics of EGFR-targeted therapies in non-small cell lung cancer:EGFR and beyond

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.

Nab-paclitaxel(abraxane)-based chemotherapy to treat elderly patients with advanced non-small-cell lung cancer:a single center,randomized and open-label clinical trial

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/m2, days 1, 8）; （B） abraxane ＋ nedaplatin （20 mg/m2 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.

Weekly albumin-bound paclitaxel/cisplatin versus gemcitabine/cisplatin as first-line therapy for patients with advanced non-small-cell lung cancer:A phase II open-label clinical study

Objective: The aim of this trial was to compare both the efficacy and the safety of a weekly nanoparticle albumin-bound paclitaxel(nab-paclitaxel) plus cisplatin vs. gemcitabine plus cisplatin in patients with advanced non-small-cell lung cancer(NSCLC).Methods: A total of 84 participants received either 100 mg/m^2 nab-paclitaxel each week on d 1, 8 and 15 of a 28 day cycle, as well as cisplatin 75 mg/m^2 on d 1 every three weeks(nab-TP arm); or gemcitabine 1,000 mg/m^2 on d 1 and 8, plus cisplatin 75 mg/m^2 on d 1 every three weeks(GP arm). The primary end point was progression-free survival(PFS). The secondary end points were overall response rate(ORR) and overall survival(OS).Results: According to our analysis, the median PFS was 4.8 months for the nab-TP arm vs. 5.2 months for the GP arm(P=0.55). Analysis showed the median OS was 14.6 months for participants who were in the nab-TP arm vs. 15.1 months for those in the GP arm(P=0.94). Besides, nab-TP showed OS advantages over GP in patients harboring epidermal growth factor receptor(EGFR) mutation(26.7 vs. 15.3 months, P=0.046) and patients with a performance status of 0(23.5 vs. 14.7 months, P=0.020). It was found that incidences of drug-related grade 3 or 4 toxicities were comparable between the two treatment arms.Conclusions: Therefore, it can be seen that weekly nab-TP treatment has a similar efficacy and tolerability to GP treatment for patients who are undergoing their first-line treatment for NSCLC. It could be that survival differences among platinum doublets in the context of both EGFR mutation and performance status have the potential to be the basis for our further clinical trials.

Survival and prognostic factors of non-small cell lung cancer patients with postoperative locoregional recurrence treated with radical radiotherapy

Background: Locoregional recurrence remains the challenge for long-term survival of non-small cell lung cancer(NSCLC) patients after radical surgery, and curative-intent radiotherapy could be a treatment choice. This study aimed to assess the survival and prognostic factors of patients with postoperative locoregionally recurrent NSCLC treated with radical radiotherapy.Methods: We reviewed medical records of 74 NSCLC patients with postoperative locoregional recurrence who received radical radiotherapy between April 2012 and February 2016 at Sun Yat-sen University Cancer Center(Guangzhou, China). The efficacy and safety of radical radiotherapy were analyzed. The probability of survival was estimated using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used to identify prognostic factors.Results: Grade 3/4 adverse events included neutropenia(8 cases, 10.8%), esophagitis(7 cases, 9.5%), pneumonitis(1 case, 1.4%), and vomiting(1 case, 1.4%).The 2-year overall survival, progression-free survival, local recurrencefree survival(LRFS), and distant metastasis-free survival(DMFS) rates of all patients were 84.2,42.5,70.0, and 50.9%,respectively. Univariate and multivariate analyses showed that a higher biological effective dose(BED) of radiation was associated with longer LRFS [hazard ratios(HR)=0.317,95% confidence interval(CI) = 0.112-0.899, P = 0.016] and that wild-type epidermal growth factor receptor(EGFR) was associated with longer DMFS compared with EGFR mutation(HR = 0.383,95% CI=0.171-0.855, P = 0.019).Conclusions: Radical radiotherapy is effective and well-tolerated in NSCLC patients with postoperative locoregional recurrence. High BED is a predictor for long LRFS, and the presence of wild-type EGFR is a predictor for long DMFS.

Autophagy Accompanied with Bisdemethoxycurcumin-induced Apoptosis in Non-small Cell Lung Cancer Cells

Objective To investigate the effects of bisdemethoxycurcumin （BDMC） on non-small cell lung cancer （NSCLC） cell line, A549, and the highly metastatic lung cancer 95D cells. Methods CCK-8 assay was used to assess the effect of BDMC on cytotoxicity. Flow cytometry was used to evaluate apoptosis. Western blot analysis, electron microscopy, and quantification of GFP-LC3 punctuates were used to test the effect of BDMC on autophagy and apoptosis of lung cancer cells. Results BDMC inhibited the viability of NSCLC cells, but had no cytotoxic effects on lung small airway epithelial cells （SAECs）. The apoptotic cell death induced by BDMC was accompanied with the induction of autophagy in NSCLC cells. Blockage of autophagy by the autophagy inhibitor 3-methyladenine （3-MA） repressed the growth inhibitory effects and induction of apoptosis by BDMC. In addition, BDMC treatment significantly decreased smoothened （SMO） and the transcription factor glioma-associated oncogene 1 （G1il） expression. Furthermore, depletion of Gill by siRNA and cyclopamine （a specific SMO inhibitor） induced autophagy. Conclusion Aberrant activation of Hedgehog （Hh） signaling has been implicated in several human cancers, including lung cancers. The present findings provide direct evidence that BDMC-induced autophagy plays a pro-death role in NSCLC, in part, by inhibiting Hedgehog signaling.

PTEN and Ki67 expression is associated with clinicopathologic features of non-small cell lung cancer

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.

Improvement of Quality of Life with Shenfu Injection (参附注射液) in Non Small Cell Lung Cancer Patients Treated with Gemcitabine plus Cisplatin Regimen

Objective： To observe the effect of Shenfu injection （参附注射液, SFI） in treating non small cell lung cancer （NSCLC） patients on quality of life with gemcitabine （GEM） plus cisplatin （GP） regimen. Methods： Thirty-four patients were ready to receive GP regimen chemotherapy for treating NSCLC disease, according to lot-drawing, they were divided into SFI pre-treatment group （18 cases） and SFI post-treatment group （ 16 cases）. SFI pre-treatment group： During the first treatment course, chemotherapy was begun with SFI 60 ml, intravenous dripping on the 3rd day, once daily, consecutively for 10 days; on the 1st day, GP regimen （GEM 1250 mg/m^2 , intravenous dripping, on the 1st and 8th day; cisplatin 70 mg/m^2 on the 2nd day; 21 days as one cycle） was carried out; in the second treatment course GP regimen was merely given to serve as the self-control. SFI post-treatment group： the medicament sequence order was reversed from that of pre-treatment group. Using dual international quality of life （QOL） scores, the effect of SFI on the patients＂ QOL was observed through randomized self pre- and post- crossover control. Results： The QOL in the 34 patients after being treated by SFI in combination with GP chemotherapy regimen in one group, and GP chemotherapy regimen alone in the other, was improved in different degrees, with significant difference （P〈0.01）; comparision of SFI combined with GP chemotherapy regimen with GP chemotherapy alone showed that QOL in patients was significantly different （P〈0.01）. Conclusion： SFI could improve QOL in patients with NSCLC who were treated with GP regimen.

SPARC expression and prognostic value in non-small cell lung cancer

Secreted protein,acidic and rich in cysteine(SPARC) is expressed in numerous types of tumors and is suggested to have prognostic value.Moreover,because of its strong affinity for albumin,and hence albumin-bound drugs,SPARC has increasingly become a focus for research.In this study,we aimed to determine SPARC expression in patients with non-small cell lung cancer(NSCLC) and investigate the association of SPARC with disease prognosis.Tissue microarrays were constructed with specimens from 105 patients with NSCLC treated at Sun Yat-sen University Cancer Center,and immunohistochemical analysis was performed on these tissue microarrays to assess SPARC expression.Our results showed that SPARC expression status did not significantly relate with age,gender,and tumor stage.However,SPARC was expressed more frequently in squamous cell carcinoma than in adenocarcinoma(75% vs.43.5%,P = 0.004).Patients with smoking history had higher SPARC expression than non-smokers(68.2% vs.33.3%,P = 0.002).In both univariate and multivariate analyses,SPARC was a prognostic factor of overall survival(HR = 0.32;95% CI:0.16-0.65) but not disease-free survival.Our study indicates that SPARC expression is higher in squamous cell carcinoma than in adenocarcinoma in NSCLC.Most notably,SPARC can be used as a prognostic factor for NSCLC.

Stereotactic body radiation therapy for non-small cell lung cancer:A review

Stereotactic body radiation therapy(SBRT) is the treatment of choice for medically inoperable patients with early stage non-small cell lung cancer(NSCLC). A literature search primarily based on PubMed electronic databases was completed in July 2018. Inclusion and exclusion criteria were determined prior to the search, and only prospective clinical trials were included. Nineteen trials from 2005 to 2018 met the inclusion criteria, reporting the outcomes of 1434 patients with central and peripheral early stage NSCLC. Patient eligibility,prescription dose and delivery, and follow up duration varied widely. Threeyears overall survival ranged from 43% to 95% with loco-regional control of up to 98% at 3 years. Up to 33% of patients failed distantly after SBRT at 3 years. SBRT was generally well tolerated with 10%-30% grade 3-4 toxicities and a few treatment-related deaths. No differences in outcomes were observed between conventionally fractionated radiation therapy and SBRT, central and peripheral lung tumors, or inoperable and operable patients. SBRT remains a reasonable treatment option for medically inoperable and select operable patients with early stage NSCLC. SBRT has shown excellent local and regional control with toxicity rates equivalent to surgery. Decreasing fractionation schedules have been consistently shown to be both safe and effective. Distant failure is common, and chemotherapy may be considered for select patients. However, the survival benefit of additional interventions, such as chemotherapy, for early stage NSCLC treated with SBRT remains unclear.