Pan-cancer analysis of the tumorigenic role of Fanconi anemia complementation group D2 (FANCD2) in human tumors.

Monoubiquitination of FANCD2 is a central step in the activation of the Fanconi anemia (FA) pathway after DNA damage. Defects in the FA pathway centered around FANCD2 not only lead to genomic instability but also induce tumorigenesis. At present, few studies have investigated FANCD2 in tumors, and no pan-cancer research on FANCD2 has been conducted. We conducted a comprehensive analysis of the role of FANCD2 in cancer using public databases and other published studies. Moreover, we evaluated the role of FANCD2 in the proliferation, migration and invasion of lung adenocarcinoma cells through in vitro and in vivo experiments, and explored the role of FANCD2 in cisplatin chemoresistance. We investigated the regulatory effect of FANCD2 on the cell cycle of lung adenocarcinoma cells by flow cytometry, and verified this effect by western blotting. FANCD2 expression is elevated in most TCGA tumors and shows a strong positive correlation with poor prognosis in tumor patients. In addition, FANCD2 expression shows strong correlations with immune infiltration, immune checkpoints, the tumor mutation burden (TMB), and microsatellite instability (MSI), which are immune-related features, suggesting that it may be a potential target of tumor immunotherapy. We further found that FANCD2 significantly promotes the proliferation, invasion, and migration abilities of lung adenocarcinoma cells and that its ability to promote cancer cell proliferation may be achieved by modulating the cell cycle. The findings indicate that FANCD2 is a potential biomarker and therapeutic target in cancer treatment by analyzing the oncogenic role of FANCD2 in different tumors.

Prognostic Implications of Six Altered Genes in Asian Non-Surgical Esophageal Carcinoma Patients Treated with Chemoradiotherapy.

BACKGROUND: Esophageal cancer (EC), especially esophageal squamous cell carcinoma, remained as one of the most aggressive tumors in China with a five-year survival rate of around 40%. Molecular characteristics through next-generation sequencing are becoming an emerging method in identifying prognostic biomarkers for better treatment management for EC patients. METHODS: Targeted next-generation sequencing using a 422-gene pan-cancer panel was performed with tumor tissue samples from a total of 69 Asian non-surgical esophageal carcinoma patients (AEC) treated with chemoradiotherapy. A TCGA cohort of 143 EC patients and another Asian ESCC cohort of 47 patients were employed for validation. RESULTS: In the AEC cohort, alterations in TP53 (94.2%) and NOTCH1 (55.1%) were the two most frequently observed alterations, whereas in the TCGA cohort, only TP53 alterations were observed at a high ratio (85.3%). Co-amplifications of FGF19 and CCND1 were found at a similar ratio in both cohorts. Multiple alterations in the DNA damage pathway were identified but not associated with overall survival in AEC. Using univariate and multivariate Cox regression analyses, six gene alterations including YAP1 amplification, RB1 alteration, BAP1 mutation, MYC amplification, WRN mutation, and BRIP1 mutation were identified as adverse prognostic factors in the AEC cohort. A Cox proportional hazard model based on the six prognosis-related genes was constructed and showed the ability in distinguishing EC patients with poorer disease outcomes in AEC and two validation cohorts. CONCLUSION: Six gene alterations were found to be potential unfavorable prognostic markers that might provide guidance in the treatment management for EC patients.

CILP, a Putative Gene Associated With Immune Infiltration in Breast Cancer Brain Metastases.

Breast cancer (BC) is the second leading cause of brain metastases (BM), with high morbidity and mortality. The aim of our study was to explore the effect of the cartilage intermediate layer protein (CILP) on breast cancer brain metastases (BCBM). Using a weighted gene coexpression network analysis (WGCNA) in GSE100534 and GSE125989 datasets, we found that the yellow module was closely related to the occurrence of BCBM, and CILP was a hub gene in the yellow module. Low CILP expression was associated with a poor prognosis, and it was an independent prognostic factor for stage III-IV BC determined using Cox regression analysis. A nomogram model including CILP expression was established to predict the 5-, 7-, and 10-year overall survival (OS) probabilities of stage III-IV BC patients. We found that CILP mRNA expression was downregulated in BCBM through GSE100534, GSE125989, and GSE43837 datasets. In addition, we found that CILP mRNA expression was negatively correlated with vascular endothelial growth factor A (VEGFA), which is involved in regulating the development of BM. UALCAN analysis showed that CILP expression was downregulated in HER2-positive (HER2+) and triple-negative breast cancer (TNBC), which are more prone to BM. The vitro experiments demonstrated that CILP significantly inhibited BC cell proliferation and metastasis. Western blot (WB) results further showed that the mesenchymal protein marker vimentin was significantly downregulated following CILP overexpression, suggesting that CILP could participate in migration through epithelial-mesenchymal transition (EMT). A comparison of CILP expression using immunohistochemistry in BC and BCBM showed that CILP was significantly downregulated in BCBM. In addition, gene set variation analysis (GSVA) revealed that CILP was associated with the T-cell receptor signaling pathway in BCBM and BC, indicating that CILP may be involved in BCBM through immune effects. BCBM showed lower immune infiltration than BC. Moreover, CILP expression was positively correlated with HLA-II, T helper cells (CD4+ T cells), and Type II IFN Response in BCBM. Collectively, our study indicates that CILP is associated with immune infiltration and may be a putative gene involved in BCBM. CILP offers new insights into the pathogenesis of BCBM, which will facilitate the development of novel targets for BCBM patients.

Postoperative radiotherapy for resected pathological stage IIIA-N2 non-small cell lung cancer: a retrospective study of 221 cases from a single institution.

BACKGROUND: For patients with resected pathological stage IIIA-N2 non-small cell lung cancer (NSCLC), the role of postoperative radiotherapy (PORT) is not well defined. In this single-institutional study, we re-evaluated the effect of PORT on overall survival (OS) as well as tumor control in this subgroup of patients. METHODS: In 2003-2005, 221 consecutive patients with resected pathological stage IIIA-N2 NSCLC at our institution were retrospectively analyzed in an institutional review board-approved study. The effect of PORT on OS, cancer-specific survival (CSS), and disease-free survival (DFS) was evaluated using the Kaplan-Meier method and log-rank tests. The impact of PORT on locoregional control and distant metastasis was also analyzed. Results. Compared with the control, patients treated with PORT had a significantly longer OS time (χ2, 3.966; p = .046) and DFS interval (χ2, 6.891; p = .009), as well as a trend toward a longer CSS duration (χ2, 3.486; p = .062). Patients treated with PORT also had a significantly higher locoregional recurrence-free survival rate (χ2, 5.048; p = .025) as well as distant metastasis-free survival rate (χ2, 11.248; p = .001). Multivariate analyses showed that PORT was significantly associated with a longer OS duration (p = .000). CONCLUSIONS: PORT can significantly improve the survival of patients with resected pathological stage IIIA-N2 NSCLC. A prospective randomized multicenter clinical trial is ongoing.

TLR7 regulates dendritic cell-dependent B-cell responses through BlyS in immune thrombocytopenic purpura.

OBJECTIVES: Immune thrombocytopenic purpura (ITP) is an autoimmune disorder in which anti-platelet antibodies induce platelet destruction owing to an imbalanced immune response. Several studies have established that B cells play an important role in the production of anti-platelet antibodies and that dendritic cells (DC) are professional antigen-presenting cells of the immune system that may lead to the development of autoantibody through B cells. We aimed at investigating the role of B cells and DC in the pathogenesis of ITP through B-lymphocyte stimulator (BlyS) and toll-like receptor 7 (TLR7) signals. METHODS: Twenty-two patients with ITP and 20 healthy controls were enrolled in this study. Serum BlyS, its mRNA and TLR7 mRNA were measured using ELISA kits or RT-PCR, and CD14(+) or CD19(+) monocytes were investigated for the pathogenesis of ITP with in vitro culture systems. RESULTS: We demonstrated that serum BlyS levels in patients with ITP were significantly higher than those in healthy controls and that there was a positive correlation between serum BlyS levels and glycoprotein-specific antibody levels in patients with ITP. We found that TLR7 regulates dendritic cell-dependent B-cell responses through BlyS in patients with ITP. Dendritic cells stimulated with R848 (TLR7 ligand) are able to produce vast amounts of BlyS, which is crucial for B-cell survival, proliferation and differentiation, and increase anti-platelet antibodies production in in vitro coculture systems. CONCLUSIONS: These findings provide new insights into the pathogenesis of ITP by which TLR7 regulates DC-dependent B-cell responses through BlyS.

Radiomics Study for Predicting the Expression of PD-L1 and Tumor Mutation Burden in Non-Small Cell Lung Cancer Based on CT Images and Clinicopathological Features.

BACKGROUND: The present study compared the predictive performance of pretreatment computed tomography (CT)-based radiomics signatures and clinicopathological and CT morphological factors for ligand programmed death-ligand 1 (PD-L1) expression level and tumor mutation burden (TMB) status and further explored predictive models in patients with advanced-stage non-small cell lung cancer (NSCLC). METHODS: A total of 120 patients with advanced-stage NSCLC were enrolled in this retrospective study and randomly assigned to a training dataset or validation dataset. Here, 462 radiomics features were extracted from region-of-interest (ROI) segmentation based on pretreatment CT images. The least absolute shrinkage and selection operator (LASSO) and logistic regression were applied to select radiomics features and develop combined models with clinical and morphological factors for PD-L1 expression and TMB status prediction. Ten-fold cross-validation was used to evaluate the accuracy, and the predictive performance of these models was assessed using receiver operating characteristic (ROC) and area under the curve (AUC) analyses. RESULTS: The PD-L1-positive expression level correlated with differentiation degree (p = 0.005), tumor shape (p = 0.006), and vascular convergence (p = 0.007). Stage (p = 0.023), differentiation degree (p = 0.017), and vacuole sign (p = 0.016) were associated with TMB status. Radiomics signatures showed good performance for predicting PD-L1 and TMB with AUCs of 0.730 and 0.759, respectively. Predictive models that combined radiomics signatures with clinical and morphological factors dramatically improved the predictive efficacy for PD-L1 (AUC = 0.839) and TMB (p = 0.818). The results were verified in the validation datasets. CONCLUSIONS: Quantitative CT-based radiomics features have potential value in the classification of PD-L1 expression levels and TMB status. The combined model further improved the predictive performance and provided sufficient information for the guiding of immunotherapy in clinical practice, and it deserves further analysis.

Pathway-Based Analysis Revealed the Role of Keap1-Nrf2 Pathway and PI3K-Akt Pathway in Chinese Esophageal Squamous Cell Carcinoma Patients With Definitive Chemoradiotherapy.

Esophageal squamous cell carcinoma (ESCC) is the major type of EC in China. Chemoradiotherapy is a standard definitive treatment for early-stage EC and significantly improves local control and overall survival for late-stage patients. However, chemoradiotherapy resistance, which limits therapeutic efficacy and treatment-induced toxicity, is still a leading problem for treatment break. To optimize the selection of ESCC patients for chemoradiotherapy, we retrospectively analyzed the clinical features and genome landscape of a Chinese ESCC cohort of 58 patients. TP53 was the most frequent mutation gene, followed by NOTCH1. Frequently, copy number variants were found in MCL1 (24/58, 41.4%), FGF19 (23/58, 39.7%), CCND1 (22/58, 37.9%), and MYC (20/58, 34.5%). YAP1 and SOX2 amplifications were mutually exclusive in this cohort. Using univariate and multivariate analyses, the YAP1 variant and BRIP1 mutant were identified as adverse factors for OS. Patients with PI3K-Akt pathway alterations displayed longer PFS and OS than patients with an intact PI3K-Akt pathway. On the contrary, two patients with Keap1-Nrf2 pathway alterations displayed significantly shortened PFS and OS, which may be associated with dCRT resistance. Our data highlighted the prognostic value of aberrant cancer pathways in ESCC patients, which may provide guidance for better chemoradiotherapy management.

Pretreatment CT-Based Radiomics Signature as a Potential Imaging Biomarker for Predicting the Expression of PD-L1 and CD8+TILs in ESCC.

BACKGROUND: The present study constructed and validated models to predict PD-L1 and CD8+TILs expression levels in esophageal squamous cell carcinoma (ESCC) patients using radiomics features and clinical factors. PATIENTS AND METHODS: This retrospective study randomly assigned 220 ESCC patients to a discovery dataset (n= 160) and validation dataset (n= 60). A total of 462 radiomics features were extracted from the segmentation of regions of interest (ROIs) based on pretreatment CT images of each patient. The LASSO algorithm was applied to reduce the dimensionality of the data and select features. A multivariable logistic regression analysis was adopted to build radiomics signatures. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive accuracy of these models. RESULTS: There was no significant difference between the training and validation datasets for any clinical factors in patients with ESCC. The PD-L1 expression level correlated with the differentiation degree (p= 0.011) and tumor stage (p= 0.032). Smoking status (p= 0.043) and differentiation degree (p= 0.025) were associated with CD8+TILs expression levels. The radiomics signatures achieved good performance in predicting PD-L1 and CD8+TILs with AUCs= 0.784 and 0.764, respectively. The combined model showed a favorable predictive ability compared to radiomics signatures or clinical factors alone and improved the AUCs from 0.669 to 0.871 for PD-L1 and from 0.672 to 0.832 for CD8+TILs. These results were verified in the validation dataset with the AUCs of 0.817 and 0.795, respectively. CONCLUSION: CT-based radiomics features have a potential value for classifying patients according to PD-L1 and CD8+TILs expression levels. The combination of clinical factors and radiomics signatures significantly improved the predictive performance in ESCC.

YAP1 amplification as a prognostic factor of definitive chemoradiotherapy in nonsurgical esophageal squamous cell carcinoma.

BACKGROUND: Definitive chemoradiation therapy (dCRT) is the standard treatment for patients with nonsurgical esophageal squamous cell carcinoma (ESCC), yet patients have demonstrated great variations in their responses to dCRT and inevitably progressed following treatment. METHODS: To identify prognostic biomarkers, we performed targeted next-generation sequencing of 416 cancer-related genes on primary tumors from 47 nonsurgical ESCC patients prior to dCRT treatment. The association between genetic alterations and patients' local recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) was analyzed. RESULTS: TP53 (78% of patients), NOTCH1 (32%), ARID1A (13%), FAT1 (13%), and CDKN2A (13%) were commonly mutated in ESCC patients, while gene amplifications frequently occurred in MCL1 (36%), FGF19 (34%), MYC (32%), CCND1 (27%), ZNF217 (15%), CDKN2A (13%), and YAP1 (11%). Univariate and multivariate analyses of clinical factors and genetic alterations indicated that sex is an independent prognostic factor, with males tending to have better LRFS (hazard ratio [HR], 0.25; 95%CI, 0.08-0.77, P = .015) and progression-free survival (PFS) (HR, 0.35; 95%CI, 0.13-0.93, P = .030) following dCRT. Meanwhile, YAP1 amplification (n = 7) was an adverse prognostic factor, and patients with this alteration demonstrated a tendency toward worse outcomes with shorter LRFS (HR, 4.06; 95%CI, 1.26-13.14, P = .019) and OS (HR, 2.78; 95%CI, 0.95-8.17, P = .062). In a subgroup analysis, while sex and M-stage were controlled, a much stronger negative effect of YAP1 amplification vs wild-type in LRFS was observed (log-rank P = .0067). CONCLUSION: The results suggested that YAP1 amplification is a potentially useful biomarker for predicting treatment outcomes and identifying patients with a high risk of relapse who should be closely monitored.

18F-FDG uptake as a biologic factor predicting outcome in patients with resected non-small-cell lung cancer.

BACKGROUND: The outcome of surgical treatment of non-small-cell lung cancer (NSCLC) remains poor. In many patients the biological behavior of NSCLC does not follow a definite pattern, and can not be accurately predicted before treatment. (18)F-fluoro-2-deoxy-glucose ((18)F-FDG) uptake on positron-emission tomography (PET) is associated with the aggressiveness of NSCLC. The present study focused on the role of (18)F-FDG uptake in predicting the outcome of surgically treated patients with NSCLC. METHODS: A retrospective analysis was made of 82 patients who underwent complete resection and preoperative FDG PET. The maximum standardized uptake value (SUV(max)), in addition to five clinicopathological factors and three biomolecular factors, which could possibly influence survival, was compared for possible association with patients' recurrence and survival, by the Log-rank test in univariate analysis and the Cox proportional hazards model in multivariate analysis. The association between SUV(max) and other factors was also analyzed. RESULTS: Patients with SUV(max) more than 11 had a disease-free survival and overall survival shorter than patients with SUV(max) less than 11 in univariate analyses (P < 0.001, P = 0.002). In the multivariate analysis, SUV(max) (dichotomized by 11) was the only significant predictor for tumor recurrence. TNM stage and SUV(max) (dichotomized by 11) were independent predictors for the overall survival. Associations of SUV(max) with p53 overexpression, proliferating cell nuclear antigen (PCNA) labeling index and microvascular density of the tumor were significant in the entire group. CONCLUSIONS: (18)F-FDG uptake on PET may be used to noninvasively assess biological aggressiveness of NSCLC in vivo, identifying the surgically-treated patients with poor prognosis who could benefit from additional therapy.

Announcing the Genome Atlas of Bamboo and Rattan (GABR) project: promoting research in evolution and in economically and ecologically beneficial plants.

Bamboo and rattan are widely grown for manufacturing, horticulture, and agroforestry. Bamboo and rattan production might help reduce poverty, boost economic growth, mitigate climate change, and protect the natural environment. Despite progress in research, sufficient molecular and genomic resources to study these species are lacking. We launched the Genome Atlas of Bamboo and Rattan (GABR) project, a comprehensive, coordinated international effort to accelerate understanding of bamboo and rattan genetics through genome analysis. GABR includes 2 core subprojects: Bamboo-T1K (Transcriptomes of 1000 Bamboos) and Rattan-G5 (Genomes of 5 Rattans), and several other subprojects. Here we describe the organization, directions, and status of GABR.

Clinical observation of gene expression-guided chemoradiation therapy for nonsurgical esophageal squamous cell carcinoma patients: a retrospective analysis of 36 cases.

OBJECTIVE: To make an informed choice of chemotherapy drugs according to the oncogene mRNA expression and to explore whether it could increase the survival rate of patients. PATIENTS AND METHODS: The study retrospectively analyzed 36 cases of nonsurgical esophageal squamous cell carcinoma patients treated at the Center for Oncology of Shandong Provincial Hospital from December 1, 2010, to November 1, 2013. Intensity-modulated radiation therapy was used for the treatment with a conventional radiotherapy dose of 60-66 Gy. Chemotherapy started 1-5 weeks after radiation therapy. The selection of the chemotherapy drug was based on the mRNA expression levels of excision repair cross-complementation 1, thymidylate synthetase, ribonucleotide reductase M1, and ß-tubulin isotype III. The objective response rate, progression-free survival, and overall survival were observed. RESULTS: The reason for poor prognosis of patients with high expression of excision repair cross-complementation 1 was unknown. No correlation was observed between patient survival and expression of thymidylate synthetase, ribonucleotide reductase M1, and ß-tubulin isotype III. Complete response, partial response, stable disease, and progressive disease were observed in 25, five, three, and three patients, respectively. The objective response rate was 83.3%. The 1-year, 2-year, and 3-year progression-free survival rates were 79.8%, 58.9%, and 54.4%, respectively. The 1-year, 2-year, and 3-year overall survival rates were 83.3%, 68.1%, and 58.4%, respectively. CONCLUSION: Selecting the chemotherapy drug according to the oncogene expression, combined with radiation therapy, could increase the 3-year survival rate in nonsurgical esophageal squamous cell carcinoma patients. Such conclusion needs to be further confirmed using a larger sample size.

A Proposal for Combination of Lymph Node Ratio and Anatomic Location of Involved Lymph Nodes for Nodal Classification in Non-Small Cell Lung Cancer.

INTRODUCTION: The current pathologic nodal classification (pN) based on anatomic location of involved lymph nodes (LNs) is unsatisfactory in distinguishing heterogeneous pN1 or pN2 non-small cell lung cancer (NSCLC). For the first time we comprehensively compared the prognostic significance of the number of positive LNs (nN), the ratio of the number of positive to removed LNs (LN ratio [LNR]), the combination of pN and nN (pN-nN), the combination of pN and LNR (pN-LNR), and pN to identify a superior classification. METHODS: We identified 700 patients with pN1 (n = 203) or pN2 (n = 497) NSCLC. We classified the patients into four nN categories (nN1, nN2, nN3-6, and nN≥7), four pN-nN categories (pN1-nN1-2, pN1-nN≥3, pN2-nN1-6, and pN2-nN≥7); four LNR categories (LNR≤0.05, 0.1≥LNR>0.05, 0.4≥LNR>0.1, and LNR>0.4), and four pN-LNR categories (pN1-LNR<0.1, pN1-LNR≥0.1, pN2-LNR<0.4, and pN2-LNR≥0.4). The log-rank test was used to analyze differences among groups, and Cox regression was used to evaluate relationships between each classification and survival. RESULTS: In adjusted analyses, pN-LNR was an independent prognostic factor for patients with pN1 or pN2 NSCLC, as were pN-nN, LNR, nN, and pN. pN-LNR was prognostically superior to the other four classifications. Postoperative radiotherapy (PORT) was an independent prognostic factor for pN2 NSCLC. Analyses stratified by LNR showed that PORT did not improve survival in patients with pN2-LNR<0.14 NSCLC, whereas significantly improved survival times in pN2-LNR≥0.14 NSCLC. CONCLUSIONS: We propose a potential revised nodal classification, pN-LNR, to further stratify patients with pN1 or pN2 NSCLC into subgroups so as to more precisely predict survival and help tailor individualized postoperative treatment.

Selection of proper candidates with resected pathological stage IIIA-N2 non-small cell lung cancer for postoperative radiotherapy.

BACKGROUND: To establish a prediction model in selecting fit patients with resected pIIIA-N2 non-small cell lung cancer (NSCLC) for postoperative radiotherapy (PORT), and evaluate the model in clinical practice. METHODS: Between January 2003 and December 2005, 221 patients with resected pIIIA-N2 NSCLC were retrospectively analyzed. The effect of PORT on overall survival (OS) of patients with different clinicopathological factors was evaluated and the results were used to establish a prediction model to select patients fit for PORT. RESULTS: Compared with the control, PORT significantly improved the OS of patients with a smoking index ≤400 (P = 0.033), cN2 (P = 0.003), pT3 (P = 0.014), squamous cell carcinoma (SCC) (P = 0.013), or ≥4 positive nodes (P = 0.025). Patients were divided from zero to all five factors into low, middle, and high PORT index (PORT-I) groups (scored 0-1, 2, and 3-5, respectively). PORT did not improve OS (3-year, P = 0.531), disease free survival (DFS) (P = 0.358), or loco-regional recurrence free survival (LRFS) (P = 0.412) in the low PORT-I group. PORT significantly improved OS (P = 0.033), and tended to improve DFS (P = 0.064), but not LRFS (P = 0.287) in the middle PORT-I group. PORT could significantly improve OS (P = 0.000), DFS (P = 0.000), and LRFS (P = 0.006) in the high PORT-I group. CONCLUSION: The prediction model is valuable in selecting patients with resected pIIIA-N2 NSCLC fit for PORT. PORT is strongly recommended for patients with three or more of the five factors of smoking index ≤400, cN2, pT3, SCC, and ≥4 positive nodes.

EGFR mutations and clinical outcomes of chemotherapy for advanced non-small cell lung cancer: a meta-analysis.

BACKGROUND: This meta-analysis was performed to assess whether epidermal growth factor receptor (EGFR) mutation status was associated with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy. METHOD: We systematically identified eligible articles investigating the effects of chemotherapy in patients with NSCLC stratified by EGFR mutation status. The summary risk ratio (RR) for ORR and hazard ratios (HRs) for both PFS and OS were calculated using the inverse variance formula of meta-analysis. RESULTS: Identification for the current meta-analysis: 5 prospective studies (n=875) and 18 retrospective studies (n=1934) for ORR; 2 prospective studies (n=434) and 10 retrospective studies (n=947) for PFS; 2 prospective studies (n=438) and 7 retrospective studies (n=711) for OS. The ORR was significantly higher in patients with EGFR mutations in prospective studies (RR=1.42; 95% confidence interval [CI], 1.16-1.74; P=0.001), but not in retrospective studies (RR=1.12; 95% CI, 0.96-1.32; P=0.146). There was no obvious association between EGFR mutations and PFS both in prospective (HR=0.84; 95% CI: 0.65-1.09; P=0.197) and retrospective (HR=1.02; 95% CI: 0.87-1.18; P=0.838) studies. Association between EGFR mutations and OS was also not seen in prospective studies (HR=0.74; 95% CI: 0.27-2.05; P=0.566), but was seen in retrospective studies (HR=0.48; 95% CI: 0.33-0.72; P<0.001; I(2)=75.9%; P<0.001) with significant heterogeneity. CONCLUSION: EGFR mutations in advanced NSCLC may be associated with higher ORRs to chemotherapy, but may have nothing to do with PFS and OS. Further prospective studies are required to identify the influence of EGFR mutations on chemotherapy effects in advanced NSCLC.

Risk factors of brain metastases in completely resected pathological stage IIIA-N2 non-small cell lung cancer.

BACKGROUND: Brain metastases (BM) is one of the most common failures of locally advanced non-small cell lung cancer (LA-NSCLC) after combined-modality therapy. The outcome of trials on prophylactic cranial irradiation (PCI) has prompted us to identify the highest-risk subset most likely to benefit from PCI. Focusing on patients with completely resected pathological stage IIIA-N2 (pIIIA-N2) NSCLC, we aimed to assess risk factors of BM and to define the highest-risk subset. METHODS: Between 2003 and 2005, the records of 217 consecutive patients with pIIIA-N2 NSCLC in our institution were reviewed. The cumulative incidence of BM was estimated using the Kaplan-Meier method, and differences between the groups were analyzed using log-rank test. Multivariate Cox regression analysis was applied to assess risk factors of BM. RESULTS: Fifty-three (24.4 %) patients developed BM at some point during their clinical course. On multivariate analysis, non-squamous cell cancer (relative risk [RR]: 4.13, 95 % CI: 1.86-9.19; P = 0.001) and the ratio of metastatic to examined nodes or lymph node ratio (LNR) ≥ 30 % (RR: 3.33, 95 % CI: 1.79-6.18; P = 0.000) were found to be associated with an increased risk of BM. In patients with non-squamous cell cancer and LNR ≥ 30 %, the 5-year actuarial risk of BM was 57.3 %. CONCLUSIONS: In NSCLC, patients with completely resected pIIIA-N2 non-squamous cell cancer and LNR ≥ 30 % are at the highest risk for BM, and are most likely to benefit from PCI. Further studies are warranted to investigate the effect of PCI on this subset of patients.