Clinical Studies And Prognostic Analysis Of Leptomeningeal Metastases From Lung Cancer And Adenosquamous Lung Carcinoma

Chapter 1:Clinicopathologic Features and Prognostic Factors in Patients with Leptomeningeal Metastases from Lung CancerBackground and objective:Leptomeningeal metastases(LM)is a serious complication of lung cancer,and few effective therapeutic options are available.Here we investigated the clinicopathologic characteristics and potential prognostic factors of lung cancer with LM.Methods:We retrospectively analyzed a series of 155 lung cancer patients with LM between 2014 and 2018.Data of clinical features,image examinations,treatment and outcome were collected.Results:Median overall survival for the entire cohort was 12months.The gene mutation status was evaluated in 136 patients,65(47.8%)harbored a mutation in epidermal growth factor receptor tyrosine kinase inhibitor(EGFR)exon 21(L858R),36(26.5%)had exon 19 deletions,15(11.0%)had wild type.Female,non-smoking history,adenocarcinoma,LM at initial diagnosis,EGFR-TKIs and whole brain radiotherapy revealed significant prolonged survival(all P<0.05).The multivariate analysis showed that LM at initial diagnosis(P=0.019),EGFR-TKIs treatment(P=0.003)and whole brain radiotherapy(P=0.004)were significantly associated with a better prognosis.Conclusion:Lung cancer patients with LM had poor prognosis.However,LM at initial diagnosis were associated with prolonged survival.EGFR-TKIs and whole brain radiotherapy might confer a survival benefit.Chapter 2:Analysis of Treatment Outcomes of Intrathecal Chemotherapy with Methotrexate for Leptomeningeal Metastases from Lung CancerObjective:The purpose of this study is to investigate the efficacy,security and analyze prognostic factors of intrathecal methotrexate(MTX)for treatment of leptomeningeal metastasis(LM)from lung cancer.Methods:We retrospectively evaluated the clinical and pathological features of 108 patients who underwent intrathecal chemotherapy with MTX after a diagnosis of LM from lung cancer between 2014 and 2018.The treatment methods,efficacy and adverse reactions were collected.Results:Median overall survival was 14 months.After intrathecal chemotherapy,nervous system symptoms improved in 56 patients(51.9%).As compared with the biochemical level of cerebrospinal fluid(CSF)before intrathecal chemotherapy,CSF protein decreased significantly(P=0.011),CSF glucose increased significantly(P=0.003),but there was no significant difference in the change of CSF chlorine(P=0.725).Cox multivariate analysis showed that Kamofsky performance score,brain parenchymal metastasis,and EGFR-TKIs treatment were independent prognostic factors for LM patients with lung cancer(all P<0.05).Conclusion:Intrathecal chemotherapy with MTX for patients with LM from lung cancer could palliate clinical symptoms.KPS>60 or without brain metastasis was associated with prolonged patient’s survival.Combination of EGFR-TKIs treatment could improve the prognosis of lung cancer with LM patients who received MTX intrathecal chemotherapy.Chapter 3:Application of Cerebrospinal Fluid Cell-free DNA Sequencing in Leptomeningeal Metastasis from Non-Small Cell Lung CancerObjective:The purpose of this study was to detect the cell-free DNA(cfDNA)in cerebrospinal fluid(CSF)from non-small cell lung cancer(NSCLC)patients with leptomeningeal metastasis(LM),and to explore the whole genome and chromosomal alterations information of tumors.Methods:From 2016 October to 2019 February,a total of 46 lung adenocarcinoma patients were enrolled,42 cases with LM and 4 cases with only brain parenchymal metastasis(BPM).Paired 10 ml CSF and 10 ml blood samples were collected before intrathecal chemotherapy.Gene mutations of cfDNA in plasma and CSF were detected by second-generation sequencing(NGS).Three cases of NSCLC-LM CSF cfDNA were sequenced by whole genome sequencing(WGS)to screen chromosome instability(CIN).Results:Driver genes were detected much higher in CSF cfDNA than plasma cfDNA(95.5%vs 54.5%).237 specific genetic mutations were captured in CSF cfDNA,while only 48 specific mutations were detected in plasma.Copy number variations(CNV)were totally identified in CSF cfDNA,however,no CNV was detected in plasma.The three NSCLC-LM CSF cfDNA samples had either short arm deletion on chromosome 8 or short arm amplification on chromosome 5.Conclusion:Compared with plasma cfDNA,CSF cfDNA was more sensitive to the detection of LM genomic alterations.Our study suggests that CSF cfDNA could dynamically monitor the disease progression and guide precision therapies.Whether genome wide doubling(WGD)and CIN can predict overall survival or recurrence risk needs further exploration.Background and objective: Adenosquamous carcinoma(ASC)is a rare subtype of lung cancer,it is mixed glandular and squamous cell carcinoma Mdth a more aggressive behavior and poor prognosis than the other histologic subtypes.The aim of the study is to explore the clinicopathological characteristics and prognostic factors of ASC.Methods : A total of 72 patients were enrolled.We investigated clinicalpathological features and prognostic factors retrospectively.Results : The overall 72 ASC patients5 median age was 34.7months,5-year survival rates were 14.9%.The influence of tumor size,M stage,TNM pathological stage,gene mutation and surgery on the prognosis of patients show statistical significance.Conclusion: ASC is characterized by both histologic aggressiveness and adverse prognosis.We suggest the comprehensive therapy based on surgery,and given small molecule tyrosine kinase inhibitors(TKI)treatment may prolong patients’ overall survival.