Feifei Na

Primary Tumor Standardized Uptake Value Measured on F18-Fluorodeoxyglucose Positron Emission Tomography Is of Prediction Value for Survival and Local Control in Non–Small-Cell Lung Cancer Receiving Radiotherapy: Meta-Analysis

Introduction: The 2-[18F]-Fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) has become an imaging tool for clinical assessment of tumor, node, metastasis in non–small-cell lung cancer (NSCLC). Primary tumor maximum standardized uptake value (SUVmax) on 18F-FDG PET/CT before and after radiation therapy (RT) has been studied as a potential prognostic factor for NSCLC patients receiving radiotherapy. However, the sample sizes of most studies were small, and the results of the prediction value of SUVmax remained undetermined, which lead us to perform a meta-analysis to improve the precision in estimating its effect. Methods: We performed a meta-analysis of published literature for primary tumor SUVmax-based biomarkers of the outcome of NSCLC receiving radiotherapy. The required data for estimation of individual hazard ratios (HRs) to compare patients with a low and a high SUVmax were extracted from each publication. A combined HR was calculated by Stata statistical software (Version 11). All of the results were verified by two persons to ensure its accuracy. Results: Thirteen studies were finally included into this meta-analysis; data are available in 13 studies for pre-RT primary tumor SUVmax and in five studies for post-RT. For overall survival, the combined HR estimate was 1.05 (95% confidence interval [CI], 1.02–1.08) and 1.32 (95% CI, 1.15–1.51) for pre-RT SUVmax and post-RT SUVmax, respectively; 1.26 (95% CI, 1.05–1.52) and 2.01 (95% CI, 1.16–3.46) for local control (LC). In stereotactic body radiotherapy (SBRT) group, HR for LC was 1.11 (95% CI, 1.06–1.18) and 2.19 (95% CI, 1.34–3.60) for pre-SBRT SUVmax and post-SBRT SUVmax, respectively. Conclusion: Both pre-RT and post-RT primary tumor SUVmax can predict the outcome of patients with NSCLC treated with radiotherapy. Patients with high levels of pre-RT SUVmax seemed to have poorer overall survival and LC.

Enhanced radioresponse with a novel recombinant human endostatin protein via tumor vasculature remodeling: Experimental and clinical evidence

PURPOSE This study aimed to examine the effect of the novel recombinant human endostatin (rh-Endo) protein on tumor vasculature, and to explore and evaluate the optimal scheduling of rh-Endo and radiotherapy (RT). METHODS Tumor-perfusion parameters and hypoxia were monitored after rh-Endo treatment in 10 non-small cell lung-cancer (NSCLC) patients. Eight-week female C57BL/6J mice were randomized to receive rh-Endo or control (saline) once daily for 12 days when Lewis lung carcinoma (LLC) reached approximately 100-150 mm(3). On planned days, tumors were measured for cell apoptosis, microvessel density, pericytes, blood-vessel morphology, and tumor hypoxia. The tumor response under different combinations of rh-Endo and RT schedules was evaluated. RESULTS Tumor hypoxia was significantly reduced 5 days after rh-Endo in NSCLC patients, and a similar result was found in the LLC mouse model. The anti-tumor effect was markedly enhanced when RT was administered within the remodeling period compared to any other treatment schedule. rh-Endo treatment remodeled the tumor vasculature after 5 days by reducing microvessel density and increasing pericytic coverage of the vessel endothelium. CONCLUSION This study demonstrated decreased hypoxia in animals and patients upon rh-Endo treatment, which also enhanced the radioresponse within the vasculature-remodeling period. The optimal clinical combination of rh-Endo and RT warrants further investigation.

Association of PDCD1 and CTLA-4 Gene Expression with Clinicopathological Factors and Survival in Non–Small-Cell Lung Cancer: Results from a Large and Pooled Microarray Database

Introduction: Immune checkpoint blockade is being investigated in clinical trials and showed great potential in lung cancer. The prognostic roles of and clinicopathological factors associated with immune checkpoint gene expression, CTLA-4 and PDCD1 remain largely undefined, which encodes cytotoxic-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1), respectively. Methods: We used a lung cancer database of 1715 patients measured by Affymetrix microarrays to analyze the association of gene expression with clinicopathological factors and survival. Hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) were calculated. Cutoffs were determined by median across the entire database. Results: In 909 patients with histology information, significantly higher PDCD1 and CTLA-4 expression were found in squamous carcinoma than adenocarcinoma. In 848 patients with known smoking history, current/former smokers were found to have significantly elevated gene expression compared with nonsmokers. Significant higher expression of both genes were found in TNM stage II versus I. Higher expression of PDCD1 predicted worse OS in univariate analysis, but not in multivariate (HR: 1.22; 95% CI: 0.53–2.79). CTLA-4 was marginally significant in univariate analysis of the entire set (HR: 1.15; 95% CI: 0.99–1.34). In patients with information for multivariate analysis, higher expression of CTLA-4 was associated with worse OS (HR: 1.96; 95% CI: 1.18–3.31). Conclusions: In this study with large number of patients, PDCD1 and CTLA-4 expression is significantly higher in squamous carcinoma and current/former smokers. Higher expression of CTLA-4, but not PDCD1 predicts worse survival.

Prognostic Role of Hypoxic Inducible Factor Expression in Non-small Cell Lung Cancer: A Meta-analysis

INTRODUCTION Reported prognostic roles of hypoxic inducible factor (HIF) expression in non-small cell lung cancer (NSCLC) have varied. This meta-analysis aimed to examine the relationship between HIF expression and clinical outcome in NSCLC patients. METHODS PubMed were used to identify relevant literature with the last report up to December 20th, 2012. After careful review, survival data were collected from eligible studies. We completed the meta-analysis using Stata statistical software (Version 11) and combined hazard ratio (HR) for overall survival (OS). Subgroup specificity, heterogeneity and publication bias were also assessed. All of the results were verified by two persons to ensure accuracy. RESULTS Eight studies were finally stepped into this meta-analysis in which seven had available data for HIF-1α and three for HIF-2α. Combined HRs suggested that higher expression of HIF1α had a negative impact on NSCLC patient survival (HR=1.50; 95%CI =1.07-2.10; p=0.019). The expression of HIF-2α was also relative to a poorer survival (HR=2.02; 95%CI =1.47-2.77; p=0.000). No bias existed in either of the two groups. CONCLUSION This study suggests that elevations of HIF-1α and HIF- 2α expression are both associated with poor outcome for patients with NSCLC. The data support further and high quality investigation of HIF expression for predicting poor outcome in patients with NSCLC.

The Association between TGF-β1 Polymorphisms and Radiation Pneumonia in Lung Cancer Patients Treated with Definitive Radiotherapy: A Meta-Analysis

Background Previous studies investigating the association between TGF-β1 polymorphisms and Radiation Pneumonia (RP) risk have provided inconsistent results. The aim of our study was to assess the association between the TGF-β1 genes C509T, G915C and T869C polymorphisms and risk of RP in lung cancer patients treated with definitive radiotherapy. Methods Two investigators independently searched the Medline, Embase, CNKI, and Chinese Biomedicine Databases for studies published before September 2013. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for TGF-β1 polymorphisms and RP were calculated in a fixed-effects model or a random-effects model when appropriate. Results Ultimately, each 7 studies were found to be eligible for meta-analyses of C509T, G915C and T869C, respectively. Our analysis suggested that the variant genotypes of T869C were associated with a significantly increased RP risk in dominant model (OR = 0.59, 95% CI = 0.45–0.79) and CT vs. TT model (OR = 0.47, 95% CI = 0.32–0.69). In the subgroup analyses by ethnicity/country, a significantly increased risk was observed among Caucasians. For C509T and G915C polymorphism, no obvious associations were found for all genetic models. Conclusion This meta-analysis suggests that T869C polymorphism of TGF-β1 may be associated with RP risk only in Caucasians, and there may be no association between C509T and G915C polymorphism and RP risk.

Bevacizumab radiosensitizes non-small cell lung cancer xenografts by inhibiting DNA double-strand break repair in endothelial cells

The aims of this study were to evaluate the effects of biweekly bevacizumab administration on a tumor microenvironment and to investigate the mechanisms of radiosensitization that were induced by it. Briefly, bevacizumab was administered intravenously to Balb/c nude mice bearing non-small cell lung cancer (NSCLC) H1975 xenografts; in addition, bevacizumab was added to NSCLC or endothelial cells (ECs) in vitro, followed by irradiation (IR). The anti-tumor efficacy, anti-angiogenic efficacy and repair of DNA double-strand breaks (DSBs) were evaluated. The activation of signaling pathways was determined using immunoprecipitation (IP) and WB analyses. Finally, biweekly bevacizumab administration inhibited the growth of H1975 xenografts and induced vascular normalization periodically. Bevacizumab more significantly increased cellular DSB and EC apoptosis when administered 1 h prior to 12 Gy/1f IR than when administered 5 days prior to IR, thereby inhibiting tumor angiogenesis and growth. In vitro, bevacizumab more effectively increased DSBs and apoptosis prior to IR and inhibited the clonogenic survival of ECs but not NSCLC cells. Using IP and WB analyses, we confirmed that bevacizumab can directly inhibit the phosphorylation of components of the VEGR2/PI3K/Akt/DNA-PKcs signaling pathway that are induced by IR in ECs. In conclusion, bevacizumab radiosensitizes NSCLC xenografts mainly by inhibiting DSB repair in ECs rather than by inducing vascular normalization.

Ethyl pyruvate alleviates radiation-induced lung injury in mice

OBJECTIVE Radiation-induced lung injury (RILI) is a common complication of thoracic cancer radiation therapy. Ethyl pyruvate (EP) was reported to have an ameliorating effect on a variety of systemic inflammation reactions, including acute lung injury. However, the protective effect of EP on RILI has not been explored. MATERIALS/METHODS RILI was induced by a single thoracic irradiation of 16Gy X-rays in C57BL/6 mice. Mice were divided into four groups: control, radiation, 100mg/kg EP, and 200mg/kg dexamethasone. Inflammation and fibrosis grade of lung tissue were scored by H&E and Massons trichrome staining. Cytokines include IL-1β, IL-6, TNF-α, GM-CSF, M-CSF, TGF-β1, and HMGB1 were measured after irradiation. Colony formation assay was performed to determine the protective effect of EP in RAW264.7 and HBE cells. The effect of EP on HMGB1 was also explored in vitro. RESULT The cytoplasm of bronchial epithelium cells in mice was positive-stained of HMGB1 accompanying with an increase of HMGB1, IL-6, IL-1β, GM-CSF, M-CSF, TNF-α, and TGF-β1 after irradiation. EP prescription significantly reduced pulmonary inflammation infiltration of RILI, along with a decrease of HMGB1, IL-6, IL-1β, and GM-CSF at 4 weeks after irradiation. Furthermore, EP decreased radiation-induced collagen deposition at 20 weeks after irradiation. Pro-fibrotic cytokines including TGF-β1 and HMGB1 in irradiated lung tissue and plasma obviously decreased in EP administration group in the later stage. In vitro, EP administration protected HBE cells from radiation injury. EP also rescued radiation-induced release but not translocation of HMGB1 in RAW264.7 and HBE cells. CONCLUSION EP treatment ameliorates RILI, including radiation-induced fibrosis in mice. The inhibition of production and release of pro-inflammatory or fibrotic cytokines, especially HMGB1, may partly attribute to its attenuating RILI effect.

PDGFR-β inhibitor slows tumor growth but increases metastasis in combined radiotherapy and Endostar therapy

BACKGROUND Pericytes are pivotal mural cells of blood vessels and play an essential role in coordinating the function of endothelial cells. Previous studies demonstrated that Endostar, a novel endostatin targeting endothelial cells, can enhance the effect of radiotherapy (RT). The present study addressed whether inhibiting pericytes could potentially improve the efficacy of combined RT and Endostar therapy. METHODS Platelet-derived growth factor beta-receptor inhibitor (CP673451) was chosen to inhibit pericytes and RT (12 Gy) was delivered. Lewis lung carcinoma-bearing C57BL/6 mice were randomized into 3 groups: RT, RT + Endo, and RT + Endo + CP673451. Subsequently, tumor microvessel density (MVD), pericyte coverage, tumor hypoxia, and lung metastasis were monitored at different time points following different therapies. RESULTS Compared to the other two groups, RT + Endo + CP673451 treatment markedly inhibited tumor growth with no improvement in the overall survival. Further analyses clarified that in comparison to RT alone, RT + Endo significantly reduced the tumor MVD, with a greater decrease noted in the RT + Endo + CP673451 group. However, additional CP673451 accentuated tumor hypoxia and enhanced the pulmonary metastasis in the combined RT and Endostar treatment. CONCLUSIONS Tumor growth can be further suppressed by pericyte inhibitor; however, metastases are potentially enhanced. More in-depth studies are warranted to confirm the potential benefits and risks of anti-pericyte therapy.

Synergy between peroxisome proliferator-activated receptor γ agonist and radiotherapy in cancer

Angiogenesis and inflammation are crucial processes through which the tumor microenvironment (TME) influences tumor progression. In this study, we showed that peroxisome proliferator‐activated receptor γ (PPARγ) is not only expressed in CT26 and 4T1 tumor cell lines but also in cells of TME, including endothelial cells and tumor‐associated macrophages (TAM). In addition, we showed that rosiglitazone may induce tumor vessel normalization and reduce TAM infiltration. Additionally, 4T1 and CT26 tumor‐bearing mice treated with rosiglitazone in combination with radiotherapy showed a significant reduction in lesion size and lung metastasis. We reported that a single dose of 12 Gy irradiation strongly inhibits local tumor angiogenesis. Secretion of C‐C motif chemokine ligand 2 (CCL2) in response to local irradiation facilitates the recruitment of migrating CD11b+ myeloid monocytes and TAM to irradiated sites that initiate vasculogenesis and enable tumor recurrence after radiotherapy. We found that rosiglitazone partially decreases CCL2 secretion by tumor cells and reduces the infiltration of CD11b+ myeloid monocytes and TAM to irradiated tumors, thereby delaying tumor regrowth after radiotherapy. Therefore, combination of the PPARγ agonist rosiglitazone with radiotherapy enhances the effectiveness of radiotherapy to improve local tumor control, decrease distant metastasis risks and delay tumor recurrence.

Continuation of Tyrosine Kinase Inhibitor is Associated with Survival Benefit in NSCLC Patients with Exon 19 Deletion after Solitary Progression

Introduction: The benefit and selection criteria of continuing tyrosine kinase inhibitor (TKI) after secondary resistance in non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutation remain largely unknown. This study was designed to investigate the role and predictive factors of TKI continuation in patients with solitary progression. Methods: We retrospectively analyzed NSCLCs treated with first generation of TKI from June 2009 to October 2014 in our cancer center. Number of progressive lesions upon first progression was recorded per RECIST v1.1. Results: Sixty-one of 144 (42.4%) patients progressed with one lesion. Postprogression TKI use information was available in 58 patients. No brain metastases and stable disease compared to immediate prior scans were associated continued TKI. In the whole cohort, TKI as the first line treatment was found to be associated with longer postprogression survival, but TKI continuation was not. In patients with exon 19 deletion, TKI continuation compared to discontinuation was significantly associated with longer postprogression survival (32.0 months, 95% CI: 20.8 - 43.3 vs. 15.6 months, 95% CI: 7.3 - 23.8, p=0.013). This difference was not observed in L858R mutation. Exon 19 deletion patients had longer time to TKI cessation after progression (13.7 months, 95% CI: 4.5-22.9 vs. 5.6 months in L858R, 95% CI: 0.0-11.9, p = 0.047). Conclusions: TKI continuation may prolong survival of NSCLCs with exon 19 deletion rather than L858R. Further studies are required to validate this finding.