Research Of Clinical Prognostic Factors,Pathological Subtypes And Molecular Biomarkers In Stage ? Non-small Cell Lung Cancer Patients

BackgroundLung cancer is the most common malignancy in the world and represents as the leading cause of cancer-related mortalities.There are two types of lung cancer:small cell lung cancer(SCLC)and non-small cell lung cancer(NSCLC).There are four subtypes of NSCLC:adenocarcinoma,squamous cell carcinoma,large cell(undifferentiated)carcinoma and other subtypes.The International Association for the Study of Lung Cancer(IASLC),the American Thoracic Society(ATS)and the European Respiratory Society(ERS)further proposed a classification system for lung adenocarcinoma which demon-strated to be significantly prognostic factors for death and recurrence for resected lung adenocarcinomapatients in 2011.Although efficacy andsafety of VATS lobectomy have been established,long-termoutcomes and survival benefits are still uncertain.An earlier meta-analysis showed that there was no statistically significant difference insurvival between the two techniques.Morerecent meta-analysessuggested that 5-year survival was higher after VATS lobectomy.Reports of favorable outcomes in patients undergoing VATS lobectomy in non-randomized studies,lack of clinical equipoise on the part of most surgeons performing VATS lobectomy,and prohibitive patient numbers that would be necessary all contrive to make a randomized controlled trial comparing long-term outcomes of VATS and open lobectomy.Previous studies have demonstrated that pathological nodal stage is the strongest predictor of long-term survival of early-stage resected NSCLC.Patients who harbor multiple lymph node metastases have a worse prognosis.Other studies invoke lymph node ratio(LNR number of positive lymph nodes divided by RNS)as a predictor of poor survival in resected,node-positive NSCLC.Because RNS may be confounded by fragmentation,the total number of lymph node stations sampled(LNS)may be another impact factor for prognosis.Therefor,sampling lymph nodes(LNS)may be an indicator of prognosis as same as the number of lymph nodes in the surgery.There was no significant difference in VATS resection of lymph nodes and thoracotomy,but the relationship between RNS,LNR and LNS in VATS and the prognosis were still unknowed.The relationship between these lymph node-related prognostic indicators and the prognosis of early NSCLC VATS surgery should be investigated.EGFR mutation plays animportant role in progression or prognosis in NSCLC.But EGFR-TKI is invalid for patients withKirsten rat sarcoma(KRAS)mutation.EGFR and KRAS mutations impact on prognosis is not yet clear in early stage NSCLC.Most KRAS mutations involve codon 12 and 13.The most common amino acid specific mutations are G12C and G12V.Furthermore,there is controversy on the predictive role of KRAS mutations to chemotherapy.Shepherd observed that mutations in codon 13had a poor prognosis.The prognostic role of codon and amino acid specific mutation in resected stage I NSCLC has not been sufficiently investigated.This study will investigate the prognostic value of EFGR/KRAS mutations in stage I(IA and IB)resected lung adenocarcinoma including the specific codon and aminoacid mutations of KRAS mutationIn stage IA adenocarcinoma the tumor size is not a decisive predictor of recurrence.VirendraKumar(Magnetic Resonance Imaging,2012)presents the concept of radiomic to establish a prognosis prediction model of cancer patients.The pure ground glass opacity(pGGO),mixed GGO(mGGO)and solid GGO(sGGO)were classified by CT imaging.The rate malignant of pGGO is about 18%,and malignancy mGGO is about 64%.This study attended to combine computed tomography featureswith EGFR/KRAS mutations and pathological subtypes and tried to establish a preliminary early stage lung cancer prognosis prediction model.Objectives?.This retrospective study seeks to compare nodal sampling and long-term outcomes in VATS versus open lobectomy in patients with stage I NSCLC.?.The retrospective study was to evaluate the influence of RNS?LNR?LNS and lymph node status on prognosis in patients with early stage NSCLC treated with video-assisted thoracoscopic surgery resection of pulmonary lobe or segment?.To explore the prognostic value of KRAS mutational status in resected stage I lung adenocarcinoma and the effects of KRAS specific codons and amino acid mutations on prognosis;?.To combined chest computed tomography appearance with EGFR/KRAS mutations and pathological subtypes and analysis the relationship between multiple factors and the prognosis of resected patients with stage I lung adenocarcinoma.Methods?.VATS versus Open Lobectomy for Stage I NSCLC patients:Analysis of Long Term Outcomes and effect of survivalRetrospective review of 724 patients with pathologic T1a-2aN0 NSCLC treated with VATS or open lobectomy between 2006 and 2012.The total number of dissected lymph nodes(RNs),and number of lymph node stations sampled(LNS)were recorded.Primary end-points were disease-free survival(DFS)and overall survival(OS).Multivariate analysis incorporated variables of interest to assess the effect of surgical approach on primary end-points.?.Lymph Node Assessment and Impact on Survival in Video-Assisted Thoracoscopic Lobectomy or Segment ectomy for I Stage NSCLCFive hundred and fifty patients who underwent VATS lobectomy or segmentectomy for clinical I stage NSCLC were retrospectively reviewed from 2006 to 2012.Primary end-points were disease-free survival(DFS)and overall survival(OS).Multivariate analysis incorporated variables of interest to assess the effect of surgical approach on primary end-points in RNs,LNR and LNS in clinical stage I NSCLC with video-assisted thoracoscopic lobectomy/segmentectomy.?.The prognostic impact of EGFR/KRAS mutation in patients with stage ? lung adenocarcinoma,and the prognostic significance of KRAS codon and amino acid specific mutations on prognosis.Mutation status was tested in patients who had complete resection of stage ? lung adenocarcinoma without any adjuvant therapy,using a multiplex PCR-based assay.Disease free survival(DFS)and overall survival(OS)were compared between patients with KRAS-mutant(KRAS-MUT),KRAS-MUT subtypes and KRAS wild-type(KRAS-WT)tumors.?.The relationship between radiographic CT findings and EGFR/KRAS mutation and pathological subtypes in the prognostic impact of stage I lung adenocarcinoma.Retrospective review from 2008 to 2012 for lung resection surgery in patients with stage I lung adenocarcinoma,174 cases of lung adenocarcinoma(AJCC 7th)gene mutations in patients with lung tissue samples,subtype analysis of three complete data CT data and pathological imaging,using the Kaplan-Meier analysis method and Cox proportional risk model to compare the different characteristics of CT expression and mutation of EGFR/KRAS gene and pathological subtypes and DFS patients and the overall survival time.The predictive accuracy and discriminative ability of the nomogram were determined by a concordance index(C-index)and calibration curve and were compared with clinical facgors,radiographic CT findings,EGFR/KRAS mutation and pathological subtypes in the prognostic impact of stage I lung adenocarcinoma.Results?.Disease-free survival and overall survival were compared for VATS versus Open Lobectomy on complete resection of pathological stage I NSCLC patientsVATS lobectomy was employed in 402(55.5%).Baseline characteristics were similar between groups;five-year recurrence rate,DFS and OS in the VATS group were 19%,74%and 75%versus 22%,73%and 61%for the open group,respectively.On multivariate analysis,the VATS approach was associated with better OS(HR:1.68[1.02-2.77],p=0.042),and show trend worse DFS(HR:1.45[0.97-2.18],p=0.02)in only the tumor size?2cm cohort but not for the tumor size>2cm cohort..? Lymph Node Assessment and Impact on Survival in Video-Assisted Thoracoscopic Lobectomy or Segmentectomy for I Stage NSCLCThere were 32 patients(5.8%)with postoperative pathologic diagnosis of N1 patients,24 patients(4.1%)with N2 were diagnosed by postoperative pathology and clinical evaluation.Postoperative pathological diagnosis of N2 from N1 patients was found in 3 cases(0.5%).Multivariate analysis identified lymph node stations>3 as a negative independent predictor for DFS(p=0.003)and OS(p=0.046).?.The influence of KRAS mutation on survival of pneumonectomy stage ?NSCLC and the effect of KRAS-specific codon and amino acid mutation on prognosis312 patients were included in this analysis;127 with KRAS mutations and 185 had KRAS-WT tumors.Compared to KRAS-WT,KRAS-MUTwas associated with significantly shorter OS(p=0.004)and DFS(p=0.005).Patients with codon 12 mutations had superior DFS(p=0.0314),but there were no differences in OS compared to mutations found in codons 13 and 61(p=0.177).Multivariate analysis identified KRAS mutation as independent predictorofworse OS and DFS.?.The Relationship between radiographic CT findings,EGFR/KRAS Mutation and Pathological Subtype on Prognosis of Stage ? Lung Adenocarcinoma174 patients who underwent curative resection for stage ? lung adenocarcinoma were analyzed.Multivariate analysis showed that KRAS-mutated tumors(p=0.004),and pathological subtype MPAP/Solid(p=0.006)were associated with worse DFS.KRAS mutation(p=0.002),Solid-component>80%(p=0.044),pathological subtype MPAP/Solid(p=0.014)were associated with worse OS.MPAP/Solid,Lepidic/papilary/Acina combined with KRAS gene mutation,real solid component>80%may be worse prognosis factors for pathological stage ? lung adenocarcinoma(DFS:p=0.0001;OS:p=0.001).Conclusions?.VATS versus Open Lobectomy for Stage I NSCLC:Analysis of Long Term Outcomes and Oncologic EquivalencyDFSandOS were comparable between groups suggested oncologic equivalency between open versus VATS lobectomy.VATS lobectomy was associated with better OS and trend improved DFS compared withopen technique in pathologic stage T1aN0 NSCLC.?.Lymph Node Assessment and Impact on Survival in Video-Assisted Thoracoscopic Lobectomy or Segmentectomy for I Stage NSCLCSampling>3 lymph node stations of early non-small cell lung cancer patients underwent thoracoscopic lobectomy or segmentectomy after disease-free survival and overall survival of the independent prognostic factors.LNS>3 and LNS<3 were 15%and 5%respectively,and the difference was statistically significant.In multivariate analyses,Only LNS>3 was found to be an independent predictor of DFS and OS in VATS lobectomy and segmentectomy in clinical early stage NSCLC.Lymph node escalation was associated with overall survival time.?.The influence of KRAS mutation on survival of resected stage I NSCLC and the impact of specific codon and amino acid mutations on prognosisKRAS is an independent prognostic marker in resected stage I lung adenocarcinoma.Differential outcomes are associated with codon and amino acid specific KRAS mutations.Compared to KRAS-WT,KRAS-MUT was associated with significantly shorter OS and DFS.When stratifying KRAS-WT patients based on EGFR status,KRAS-MUT patients had worse OS and DFS than patients with EGFR-MUT and EGFR-WT/KRAS-WT(WT/WT).Better DFS associated with G12C/G12V mutations compared to other amino acid specific KRAS mutations with a trend towards improved OS.Multivariate analysis identified KRAS mutation as independent predictor of worse OS and DFS.?.Driver mutation status in resected stage ? lung adenocarcinoma:correlation with radiographic CT findingsTumor size,KRAS mutation state,pathologic subtype MPAP/Solid may be an independent predictor of DFS in pathologic stage I lung adenocarcinoma,whereas KRAS mutation state,imaging solid component more than 80%and pathologic subtype(MPAP/Solid)may be the independent predictor for pathologic stage ? lung adenocarcinoma.MPAP/Solid,Lepidic/papilary/Acina combined with KRAS gene mutation,imaging of real solid component>80%may be the high risk factors for pathological stage ? lung adenocarcinoma.Compared with clinical facgors,radiographic CT findings,EGFR/KRAS mutation and pathological subtypes,the predictive accuracy and discriminative ability of the nomogram were determined by a concordance index(C-index)for the prognostic impact of stage I lung adenocarcinoma.