Treatment and survival of analysis in patients with leptomeningeal metastasis from lung cancer

Treatment and survival of analysis in patients with leptomeningeal metastasis from lung cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Treatment and survival of analysis in patients with leptomeningeal metastasis from lung cancer Zhiqin Lu, Tao Zhou, Congying Zhong, Chen Hong, Duanyang Peng, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4014067/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives: Leptomeningeal metastasis (LM) is a severe complication of advanced non-small cell lung cancer (NSCLC) and portends a grim prognosis. This study aimed to retrospectively analyzed the diagnosis, treatment, and survival analysis of 173 patients with LM from NSCLC. Materials and methods: We reviewed charts of 173 patients with diagnoses of LM from lung cancer (LC-LM) between May 2016 and May 2021. 173 patients who had unequivocal radiographic evidence comprised our “LM MRI+” cohort. Radiographic involvement (n=136) was scored by number of gadolinium-enhancing sites in 8 locations. Genetic testing of paired cerebrospinal fluid (CSF) and plasma samples from 22 patients at the time of LM diagnosis using second-generation sequencing (NGS). Clinical outcomes were compared with Kaplan-Meier log-rank test and Cox proportional hazards methodologies. Results: The median overall survival (OS) was 9.33 months (95% CI: 6.35‒12.31) with 77.5% maturity. 107 (61.8%) patients harbored a targetable mutation. Those with clinically actionable mutations were significantly longer OS than those without (6.30 vs 12.17 months; HR:0.63; 95% CI: 0.45-0.90; p=0.009). In the “LM MRI+” cohort, MRI site extent of radiographic involvement 3-4 sites was significantly shorter OS than that those involved 1-2 sites (3.77 vs 10.07 months; HR: 1.84; 95% CI: 1.02–3.31; p = 0.034). CSF was more sensitive than plasma and indicated the unique genetic profiles of LM. Multivariate analysis revealed that targetable mutations, PS, LM treat, and LM tyrosine kinase inhibitor (TKI) therapy were independent prognostic factors for LM. Conclusions: Our study provides real-world clinical evidence that patients with MRI site extent of radiographic involvement 3-4 sites was significantly shorter OS than that those involved 1-2 sites and those with clinically actionable mutations were significantly longer OS than those without. Leptomeningeal metastasis non-small-cell lung cancer overall survival Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Lung cancer (LC) remains a leading cause of death worldwide, and most patients of non‐small-cell lung cancer (NSCLC) are diagnosed at an advanced stage[1]. Leptomeningeal metastasis (LM) is a devastating complication of advanced NSCLC and portends a grim prognosis, LM develops in 3–5% of patients with advanced NSCLC, and its incidence has increased in subgroups of patients with targetable mutations, being more frequent in the adenocarcinoma subtype, and one‐third of patients have concomitant brain metastasis[2-6]. The median survival after diagnosis of LM from lung cancer (LC-LM) is only 2-4 months despite therapy, and 4-6 weeks if untreated[7, 8]. While the presence of a clinically actionable mutation, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangement, has altered disease management and improved prognosis [7-9]. A positive CSF cytology, radiologic findings with associated clinical findings, and/or signs and symptoms indicative of CSF involvement in a patient with known cancer are used to formally establish a diagnosis[6, 10]. Plasma is less sensitive than CSF, a medium obtained by a mini-invasive biopsy, which reveals the particular gene features of LM[11]. The Response Assessment in Neuro-Oncology (RANO) group and its Leptomeningeal Assessment in Neuro-Oncology (LANO) score, as well as the European Association of Neuro-Oncology- European Society of Medical Oncology (EANO-ESMO) group, are trying to standardize diagnostic workup and interpretation[6, 12, 13]. The two systems have still not each been validated[14]. The prognosis for patients with LM at the time of diagnosis still needs to be better predicted. According to a research, LC-LM patients may be managed clinically and given a good prognosis utilizing molecular characterization and CNS staging (using MRI to identify disease locations and quantify CSF liquid biopsy results) [15]. Seeking therapies that actually control LM has proven to be quite difficult. Due to leptomeningeal lesions' broad subarachnoid distribution and the rarity of surgical excision, systemic and radiation treatments continue to be the gold standard of care for LM[16]. Classifying patients into groups based on their level of risk (good or poor) and recommending best supportive care (BSC) for those in the poor risk category are recommendations from the National Comprehensive Cancer Network (NCCN) guideline[17]. Radiotherapy and systemic therapy with or without intrathecal chemotherapy are the mainstays of treatment for patients with a better prognosis[6, 17]. Systemic pembrolizumab was evaluated in a phase II single-arm trial (NCT02886585) for the treatment of LM in 2020, mostly in breast cancer patients, and it was shown to have tolerable tolerability and potential efficacy[18]. While receiving therapy, individuals without a targetable molecular mutation have a median overall survival (OS) of 1-3 months and those with one have an OS of up to 12 months [2, 19]. Osimertinib, a third-generation mutant EGFR inhibitor, has recently demonstrated significant efficacy in managing LM from EGFR mutant lung cancer[20]. Its efficacy is mostly attributable to better CNS penetration compared to first-generation EGFR inhibitors (gefitinib and erlotinib)[21]. Comparable to crizotinib, emerging ALK inhibitor drugs (ceritinib, alectinib, and lorlatinib) that are successful in treating individuals with ALK-translocated NSCLC have better CNS penetration [22-25]. Therefore, this study retrospectively analyzed the diagnosis, treatment and survival analysis of 173 patients with LM from NSCLC and provided reference for clinical practice. 2. Materials and methods 2.1 Patients This single-center, retrospective study was approved by Institutional Ethics Committee of Second Affiliated Hospital of Nanchang University with waiver of written informed consent. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). From the clinical records database of our center, we reviewed charts of 173 patients with diagnoses of LC-LM between May 2016 and May 2021 with adequate follow-up data. The eligibility criteria included the following: age older than 18 years; histological diagnosis of NSCLC; LM defined by CSF positivity for malignant cells and/or focal or diffuse enhancement of leptomeninges, nerve roots or the ependymal surface diagnosed by magnetic resonance imaging (MRI) with gadolinium contrast. Patients who did not meet these criteria were excluded. Date of LC-LM diagnosis was defined as date of first CSF cytology revealing malignant cells or date of first contrast-enhanced MRI demonstrating LM. If both MRI and CSF were positive for LC-LM, the date of the first test demonstrating LC-LM was used as the date of LC-LM diagnosis. 2.2 MRI Scoring All patients underwent magnetic resonance imaging (MRI) brain with gadolinium contrast enhancement, and/or MRI spine with gadolinium contrast enhancement. Unequivocal radiographic evidence includes linear leptomeningeal disease (type A), nodular leptomeningeal disease (type B), and both (type C)[6]. Patients who had unequivocal radiographic evidence comprised our “LM MRI+” cohort. Radiographic involvement was scored by number of gadolinium-enhancing sites in 8 predetermined locations[15], cerebrum, ventricle, brainstem (pons and medulla included in this category), cerebellum, cranial nerves, cervical spinal cord, thoracic spinal cord, lumbosacral spinal cord. Patients received one point per location of radiographically evident LM. Number of MRI sites of disease for each patient was determined based on the original radiology report and confirmed by two independent radiologists. 2.3 CSF findings CSF samples were obtained by lumbar puncture. CSF data including protein, glucose, chloride and cytology. We identified a cohort of 22 patients with CSF cytology confirmed LM who had CSF next-generation sequencing (NGS) results, matched plasma was also obtained. Approximately 10 mL of CSF was collected via lumbar puncture for NGS, and meanwhile 8 mL of plasma was collected for NGS. The NGS genetic testing process included DNA extraction, NGS library preparation and sequencing data analysis. 2.4 Data collection and statistical Analysis Patient demographics, clinical data, laboratory results, imaging findings, and survival information were collected from the clinical records database of our center. Follow-up of all the patients was carried out until February 2022. Overall survival of LM (LM­_OS) was defined as the period from diagnosis of LM to death or last follow‐up (censored). The data are presented as the median (range) and n (%). Survival analysis was performed using Kaplan-Meier method with log-rank p values and 95% confidence intervals (CIs) reported. The p values were two-sided and considered significant if less than 0.05. Multivariate analysis was performed using interactive Cox proportional hazard regression with inclusion of variables significant on univariate regression. Statistical analysis and figure plotting were performed in RStudio with implemented R (v. 4.1.2, CRAN). 3. Results 3.1 Patient Characteristics We identified 173 patients with LM evaluated at our center between June 2011 and June 2021 (Table 1). median age at LM diagnosis was 59 years (range, 32-84). Ever-smokers accounted for 49.1% of the patients (n = 85). There was a preponderance of adenocarcinoma. A prominent majority (107, 61.8%) of patients had targetable mutations identified from primary or metastatic malignant pathology specimens: there were 95 cases with EGFR mutations, eight with ALK rearrangement and four with ROS proto-oncogene 1(ROS-1). 58.4% (101/173) received targeted therapy before they were diagnosed as LM. Most patients (127/173; 73.4%) had brain metastasis (BM) before or simultaneously with LM diagnosis. Before LM diagnosis, 48 patients had history of brain radiotherapy (BRT) (27.7%). The median time from NSCLC diagnosis to LM diagnosis was 11.1 months (range: 0-23.9). The ECOG PS was 0–2 for 67.1% of patients. Regarding treatments modalities for LM, 23 (13.3%) patients received supportive care alone after they were diagnosed as LM, 102 (59.0%) patients received TKI therapy, there were 22.5% (23/102) received first/second generation TKI therapy, and 77.5% (79/102) received third generation TKI therapy, 22 (12.7%) patients received whole brain radiotherapy, 51 (29.5%) patients received chemotherapy, and 40 (23.1%) patients received intrathecal chemotherapy (ITC). Table 1 Patient Characteristics Characteristics group N=173 (n, %) Median age, years (range) 59 (32-84) Sex (%) male 95 (54.9) female 78 (45.1) Age1 (%) ＜60 87 (50.3) ≥60 86 (49.7) Smoking status (%) Never 88 (50.9) Former 85 (49.1) Pulmonary lesion (%) Unknown 5 ( 2.9) Left 81 (46.8) Right 87 (50.3) Histological type (%) LUAD 145 (83.8) Non-LUAD 28 (16.2) Targetable mutations (%) No 66 (38.2) Yes 107 (61.8) Specific mutation (%) EGFR 95 (88.8) ALK 8 ( 7.5) ROS-1 4 ( 3.7) Initial diagnosis with BM (%) No 93 (53.8) Yes 80 (46.2) Initial diagnosis with LM (%) No 119 (68.8) Yes 54 (31.2) TKI therapy before LM (%) No 72 (41.6) Yes 101 (58.4) BRT before LM (%) No 125 (72.3) Yes 48 (27.7) CNS symptoms (%) No 20 (11.6) Yes 153 (88.4) ECOG PS (%) ≤2 116 (67.1) ＞2 57 (32.9) LM and BM (%) No 46 (26.6) Yes 127 (73.4) LM Treat (%) No 23 (13.3) Yes 150 (86.7) WBRT (%) No 151 (87.3) Yes 22 (12.7) LM Chemotherapy therapy (%) No 122 (70.5) Yes 51 (29.5) ITC (%) No 133 (76.9) Yes 40 (23.1) LM_ TKI therapy (%) No 71 (41.0) Yes 102 (59.0) TKI therapy _drugs (%) 1/2 generation 23 (22.5) 3 generation 79 (77.5) Death (%) Yes 134 (77.5) Lost follow-up 5 ( 2.9) No 34 (19.6) Notes: LUAD, lung adenocarcinoma; BM, brain metastasis; LM, leptomeningeal metastasis; TKI, tyrosine kinase inhibitor; BRT, brain radiotherapy; CNS, central nervous system; ECOG PS: Eastern Cooperative Oncology Group Performance Status; WBRT, whole brain radiotherapy; ITC, Intrathecal chemotherapy. 3.2 Radiographic Burden of Disease There are 136 patients in the “LM MRI+” cohort, A prominent majority (103, 75.7%) of patients were linear leptomeningeal disease (Table2), Cerebrum and cerebellum were the most vulnerable sites involvement of LM (Fig. 1). MRI site extent of radiographic involvement at LC-LM diagnosis ranged from 0 to 4 sites involved (Table2); median was 1 site and mean were 1.21 sites. In the “LM MRI+” cohort (n = 136), MRI site extent of radiographic involvement 3-4 sites was significantly shorter than that those who involved 1-2 sites (3.77 vs 10.07months; HR: 1.84; 95% CI: 1.02–3.31; P = 0.034; Fig. 2), but there was no association between number of sites involved and overall survival (HR: 1.13; 95% CI: 0.94–1.35; P = 0.208). There was no association between anatomic location of LM and survival. Table 2 Diagnostic of LM Characteristics lever N=173 (n, %) Cytological examination No 53 (30.6) Yes 120 (69.4) Positive cytology No 32 (26.7) Yes 88 (73.3) Radiographic evidence equivocal 37 unequivocal 136 MRI type linear 103 nodular 30 linear and nodular 3 Number of MRI sites 1 79 2 43 3 11 4 3 3.3 CSF Findings 120 (69.4%) individuals had CSF cytology data available at the time of LC-LM diagnosis. Using the criterion of positive CSF cytology as cytology that conclusively revealed malignant cells or cells suspected of malignancy in a patient with acceptable clinical signs and symptoms, we found that 73.3% (88/120) of patients had positive CSF cytology. When this cohort was studied, a positive CSF cytology at the time of diagnosis was not linked to an elevated risk of mortality (p = 0.159). In 102 individuals, the CSF protein levels at the time of the LC-LM diagnosis were available; the presence of CSF proteins over the upper limit of normal was not significantly related to survival (p = 0.311). Low CSF chloride, however, was linked to a higher probability of passing away from the time of LC-LM diagnosis (HR: 2.15; 95% CI: 1.34-3.44; p = 0.002). Cell-free DNA (cfDNA) was extracted from a subset of 19 patients who had CSF collected at time of LC-LM diagnosis. cfDNA concentration ranged from 0.720ng to 47.300ng, with a median of 4.840 ng and mean of 14.486 ng. Using the median cutpoint, there was no increased risk of death associated with the above median value of cfDNA concentration (HR: 1.43; 95% CI: 0.43-4.73; p = 0.554), due to impacted by small sample size. 3.4 Mutation Profiling of Paired CSF and Plasma There are 22 patients those tumor tissue detected EGFR mutations underwent NGS with paired CSF and plasma. 21 (95.5%) CSF samples and 8(36.4%) plasma samples were detected drive genes, of which EGFR-sensitive mutations were detected in 9 CSF and plasma samples and 1 No EGFR-sensitive mutations were detected in both CSF and plasma samples, the concordance was 45.5%. TP53 was detected in 18 CSF and 4 plasma samples. The detection rate of CSF TP53 was higher (81.8%) than plasma (18.2%; χ²= 17.82, p＜0.001), We also found that the exons where the TP53 mutation site located were different. In our study, exons 5 and 8 of the TP53 frequent mutation (Fig. 3) and related to poor prognosis. T790M mutations were detected in 3 samples, including 1 in CSF and 2 in plasma. MET amplification was detected in 5 CSF samples, and no MET amplification was detected in plasma samples. In addition, EGFR amplification (7 cases), IKZF1 (7 cases), CDKN2A/B (6 cases), RICTOR amplification (6 cases), PIK3CA mutation (4 case), MAP2K4 (4 cases), ERBB2 amplification (3 cases), CDK4 (3 cases), STK11 (3cases), RB1 (2cases), PTEN mutation (2 cases), and ATM (2 cases) and PMS2 (2 cases) were also detected in CSF. 3.5 Presence of a Targetable Mutation 107 (61.8%) patients harbored a targetable mutation, which included mutations in EGFR, ALK, and ROS-1. Those with a clinically actionable mutation were significantly longer overall survival than those without (6.30 vs 12.17 months; HR:0.63; 95% CI: 0.45-0.90; p=0.009; Fig. 4). Due to the limited number of patients with each specific targetable mutation (other than EGFR mutations, which dominated the cohort), the potential prognostic importance of each individual mutation was unable to be determined. 3.6 Survival After Diagnosis with LM The median follow-up time was 34.1 months, the median OS of the entire cohort (173 patients) was 9.33 months (95% CI: 6.35‒12.31) with 77.5% maturity (134/173). Univariate analysis revealed that sex, smoking status, histological type, targetable mutations, TKI therapy before LM, PS, LM treat and LM TKI therapy were potential prognostic factors for LM (Table 3). Among these, targetable mutations, PS, LM treat and LM TKI therapy were independent prognostic factors for LM in the multivariate analysis (Fig. 5). Table 3 Univariate analysis for LC-LM Univariate analysis (N = 173) Variable name HR (95%CI) p-value Sex (male vs. female) 0.63 (0.45-0.89) 0.01* age1(＜60 vs ≥60) 1.08 (0.77-1.52) 0.659 Smoking status (never vs former) 1.64 (1.16-2.33) 0.005* Histological type (non-LUAD vs LUAD) 0.52 (0.331-0.830) 0.006* Targetable mutations (no vs yes) 0.63 (0.45-0.9) 0.010* Initial diagnosis with BM (no vs yes) 1.05 (0.75-1.47) 0.789 Initial diagnosis with LM (no vs yes) 0.80 (0.55-1.15) 0.225 TKI therapy before LM (no vs yes) 0.59 (0.416-0.824) 0.002* BRT before LM (no vs yes) 1.31 (0.91-1.89) 0.142 CNS symptoms (no vs yes) 1.33 (0.78-2.28) 0.299 ECOG PS (≤2 vs＞2) 3.08 (2.1-4.51) ＜ 0.001* LM and BM (no vs yes) 1.5 (1-2.26) 0.053 LM Treat (no vs yes) 0.27 (0.17-0.43) ＜ 0.001* WBRT (no vs yes) 1.45 (0.9-2.34) 0.125 LM Chemotherapy therapy (no vs yes) 1.27 (0.88-1.84) 0.195 ITC (no vs yes) 1.04 (0.67-1.6) 0.865 LM_ TKI therapy (no vs yes) 0.39 (0.28-0.55) ＜ 0.001* 4. Discussion LM involves cancer cells reaching the subarachnoid space, surviving in the CSF, and frequently adhering to the leptomeninges, as evidenced by linear or nodular enhancement on MRI [26, 27]. A study suggested that patients harboring LM diagnosed with CSF disease alone succumbed to the disease earlier than patients with adherent (MRI-positive) disease[27]. Wang et al focused on 86 patients with cytologically confirmed LM, the patients were divided into MRI-positive and MRI-negative groups according to the presence of leptomeningeal enhancement on initial contrast MRI, showed that MRI- positive of the neuroaxis has been proposed as a risk factor for the prognosis of LM from lung adenocarcinoma. These studies indicated that the visibility of leptomeningeal enhancement is likely to represent a larger tumor burden compared with invisible lesions on MRI[28]. Adrienne Boire et.al showed that extent of radiographic involvement correlated with risk of death (HR: 1.16; 95% CI: 1.02–1.33; p = 0.03)[15]. Our study found MRI site extent of radiographic involvement 3-4 sites was significantly shorter OS than that those involved 1-2 sites (3.77 vs 10.07 months; HR: 1.84; 95% CI: 1.02–3.31; p = 0.034) and was consistent with other similar studies. In our study, 107 (61.8%) patients harbored a targetable mutation, and OS was considerably longer in individuals with clinically actionable mutations than in those without (6.30 vs. 12.17 months; HR:0.63; 95% CI: 0.45-0.90; p=0.009). Patients with LC-LM and clinically actionable mutations survive longer than patients without targetable mutations, and those who get targeted treatment survive even longer, attributable to the exponential growth in research and drug development of targeted therapies for these diseases since the discovery of molecular targets in NSCLC more than a decade ago[8, 9, 15, 29]. In our study, individuals with malignancies who included a clinically actionable mutation showed enhanced OS; therapy with medications that targeted that mutation also increased survival. Prior to receiving a diagnosis of LC-LM, participants in our research who underwent targeted treatment had a shorter OS (HR: 0.59; 95%CI: 0.416-0.824; p=0.002). This is in line with a theory in which past exposure to a targeted medicine breeds resistance, leaving less room for treatment alternatives than for a patient with LC-LM who has never received a targeted therapy. According to certain research, liquid biopsies of the CSF are more sensitive than those of the plasma to find targetable mutations[30, 31]. In our study, we collected and sequenced 22 paired CSF and plasma samples of LC-LM. We demonstrated that CSF is concordant with tumor to detect drive genes for NSCLC, our study found 21 (95.5%) CSF samples and 8(36.4%) plasma samples were detected drive genes; we showed the unique molecular feature of CSF in LM (MET amplification, EGFR amplification, IKZF1, CDKN2A/B, RICTOR amplification, PIK3CA mutation et.al were detected only in CSF), indicating screening of CSF is a suitable liquid biopsy for LM. In our study, TP53 is the first and co-occurring of EGFR and TP53 in 18 cases, and TP53, we also found that the exons where the TP53 mutation site located were different, exons 5 and 8 of the TP53 frequent mutation. Recent studies have found that baseline TP53 mutation significantly associated with shorter survival in EGFR mutant patients treated with EGFR-TKI[32], TP53 may contributes to poor prognosis for LM, and a large number of clinical and preclinical studies are needed for verification in the future. In addition to correlating outcome with clinically actionable mutations and MRI- positive, certain characteristics have been found to influence patient survival. A study[33] showed that LM with active anti-tumor therapy improved OS (6.0 vs. 1.9 months; p<0.001). For example, PS and active anti-tumor therapy had been explored as predictors of survival[33, 34]; lower PS typically leads to better prognosis, in our study population, lower PS and active anti-tumor therapy were associated with longer survival times, as might be expected. Our research has certain limitations. Firstly, because our study only used a limited sample size from a single institution, sample bias may have been introduced; Secondly, because this was a retrospective cohort study and the dataset included a heterogeneous population of patients with respect to the number and types of treatments received prior to LC-LM diagnosis, sites of systemic disease, and treatments received after LC-LM diagnosis, we were unable to control for or evaluate for a potential impact of treatment regimen on the outcome; Thus, to continue evaluating clinical effectiveness, future research must continue to overcome these methodological obstacles. In conclusion, our study provides real-world clinical evidence that patients with MRI site extent of radiographic involvement 3-4 sites was significantly shorter than that those involved 1-2 sites and those with clinically actionable mutations were significantly longer overall survival than those without. Our findings also suggest that CSF indicated the unique genetic profiles of LM. Declarations Ethics approval and consent to participate This study was approved by the Institutional Ethics Committee of Second Affiliated Hospital of Nanchang University (Review [2016] NO.002), Nanchang, China. All procedures performed in this study using human data were in accordance with the Declaration of Helsinki (as revised in 2013). Informed consent was waived by the Institutional Ethics Committee of Second Affiliated Hospital of Nanchang University because of the retrospective nature of this study. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding No funding Author Contributions ZQL and TZ performed the statistical analysis and participated in drafting and wrote the manuscript; XW and DYP made useful comments and participated in revising the manuscript; CYZ and CH collected the clinical data; AWL and ZMZ was the principal investigator for this study and was involved in project oversight and organization. All authors approved the final version of the manuscript. Acknowledgements We kindly thank the editor and reviewers for their careful review and valuable comments, which have significantly improved the manuscript. References Siegel RL, Miller KD, Jemal A: Cancer statistics, 2020 . CA: a cancer journal for clinicians 2020, 70 (1):7-30. Cheng H, Perez-Soler R: Leptomeningeal metastases in non-small-cell lung cancer . The Lancet Oncology 2018, 19 (1):e43-e55. 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Brastianos PK, Lee EQ, Cohen JV, Tolaney SM, Lin NU, Wang N, Chukwueke U, White MD, Nayyar N, Kim A et al : Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis . Nat Med 2020, 26 (8):1280-1284. Umemura S, Tsubouchi K, Yoshioka H, Hotta K, Takigawa N, Fujiwara K, Horita N, Segawa Y, Hamada N, Takata I et al : Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group . Lung cancer (Amsterdam, Netherlands) 2012, 77 (1):134-139. Yang JCH, Kim SW, Kim DW, Lee JS, Cho BC, Ahn JS, Lee DH, Kim TM, Goldman JW, Natale RB et al : Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study . Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2020, 38 (6):538-547. Nosaki K, Yamanaka T, Hamada A, Shiraishi Y, Harada T, Himeji D, Kitazaki T, Ebi N, Shimose T, Seto T et al : Erlotinib for Non-Small Cell Lung Cancer with Leptomeningeal Metastases: A Phase II Study (LOGIK1101) . The oncologist 2020, 25 (12):e1869-e1878. LQ C, F B, EM B, F B, M S: Results of the ASCEND-7 phase II study evaluating ALK inhibitor ceritinib in patients with ALK+ non-small cell lung cancer metastatic to the brain . ESMO Congress 2019, Abstract 1478O . Remon J, Rhun EL, Besse B: Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era Cancer treatment reviews 2016. Khozin S, Blumenthal GM, Zhang L, Tang S, Brower M, Fox E, Helms W, Leong R, Song P, Pan Y et al : FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer . Clinical cancer research : an official journal of the American Association for Cancer Research 2015, 21 (11):2436-2439. Larkins E, Blumenthal GM, Chen H, He K, Agarwal R, Gieser G, Stephens O, Zahalka E, Ringgold K, Helms W et al : FDA Approval: Alectinib for the Treatment of Metastatic, ALK-Positive Non-Small Cell Lung Cancer Following Crizotinib . Clinical cancer research : an official journal of the American Association for Cancer Research 2016, 22 (21):5171-5176. Graber JJ, Kesari S: Leptomeningeal Metastases . Current treatment options in oncology 2018, 19 (1):3. Remsik J, Chi Y, Tong X, Sener U, Derderian C, Park A, Saadeh F, Bale T, Boire A: Leptomeningeal metastatic cells adopt two phenotypic states . Cancer Rep (Hoboken) 2020:e1236. Gao X, Pan R, Chen M, Zhao J, Zhong W, Wang H, Si X, Zhang X, Zhang L, Xu Y et al : Leptomeningeal enhancement in magnetic resonance imaging predicts poor prognosis in lung adenocarcinoma patients with leptomeningeal metastasis . Thoracic cancer 2022. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T et al : Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer . The New England journal of medicine 2018, 378 (2):113-125. Zheng MM, Li YS, Jiang BY, Tu HY, Tang WF, Yang JJ, Zhang XC, Ye JY, Yan HH, Su J et al : Clinical Utility of Cerebrospinal Fluid Cell-Free DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC . J Thorac Oncol 2019, 14 (5):924-932. Ying S, Ke H, Ding Y, Liu Y, Tang X, Yang D, Li M, Liu J, Yu B, Xiang J et al : Unique genomic profiles obtained from cerebrospinal fluid cell-free DNA of non-small cell lung cancer patients with leptomeningeal metastases . Cancer biology & therapy 2019, 20 (4):562-570. Canale M, Petracci E, Delmonte A, Chiadini E, Dazzi C, Papi M, Capelli L, Casanova C, De Luigi N, Mariotti M et al : Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors . Clinical cancer research : an official journal of the American Association for Cancer Research 2017, 23 (9):2195-2202. Wu YL, Zhao Q, Deng L, Zhang Y, Zhou XJ, Li YY, Yu M, Zhou L, Zou BW, Lu Y et al : Leptomeningeal metastasis after effective first-generation EGFR TKI treatment of advanced non-small cell lung cancer . Lung cancer (Amsterdam, Netherlands) 2019, 127 :1-5. Herrlinger U, Förschler H, Küker W, Meyermann R, Bamberg M, Dichgans J, Weller M: Leptomeningeal metastasis: survival and prognostic factors in 155 patients . Journal of the neurological sciences 2004, 223 (2):167-178. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4014067","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":280079096,"identity":"6fc45a9f-1deb-4330-acaa-f80713a52c2c","order_by":0,"name":"Zhiqin Lu","email":"","orcid":"","institution":"The Second Affiliated Hospital of Nanchang University","correspondingAuthor":false,"prefix":"","firstName":"Zhiqin","middleName":"","lastName":"Lu","suffix":""},{"id":280079097,"identity":"043cc7fe-8504-4522-b7eb-a58d011862eb","order_by":1,"name":"Tao Zhou","email":"","orcid":"","institution":"The First Affiliated Hospital of Nanchang Medical College","correspondingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Zhou","suffix":""},{"id":280079098,"identity":"d198e0a2-4a91-42b3-9ee8-b1e990a4a82b","order_by":2,"name":"Congying Zhong","email":"","orcid":"","institution":"The First Affiliated Hospital of Nanchang Medical College","correspondingAuthor":false,"prefix":"","firstName":"Congying","middleName":"","lastName":"Zhong","suffix":""},{"id":280079099,"identity":"ad7eceab-a448-4946-a790-5ed69d3ffd53","order_by":3,"name":"Chen Hong","email":"","orcid":"","institution":"The Second Affiliated Hospital of Nanchang University","correspondingAuthor":false,"prefix":"","firstName":"Chen","middleName":"","lastName":"Hong","suffix":""},{"id":280079100,"identity":"629feea1-3897-43e2-a0cd-eccc684e1b79","order_by":4,"name":"Duanyang Peng","email":"","orcid":"","institution":"The Second Affiliated Hospital of Nanchang University","correspondingAuthor":false,"prefix":"","firstName":"Duanyang","middleName":"","lastName":"Peng","suffix":""},{"id":280079101,"identity":"0cadffaf-b6fd-4992-a011-1e60321b222c","order_by":5,"name":"Xia Wang","email":"","orcid":"","institution":"The Second Affiliated Hospital of Nanchang University","correspondingAuthor":false,"prefix":"","firstName":"Xia","middleName":"","lastName":"Wang","suffix":""},{"id":280079102,"identity":"cecaf32f-751f-4370-a7aa-6ff550e987ec","order_by":6,"name":"Zhimin Zeng","email":"","orcid":"","institution":"The Second Affiliated Hospital of Nanchang University","correspondingAuthor":false,"prefix":"","firstName":"Zhimin","middleName":"","lastName":"Zeng","suffix":""},{"id":280079103,"identity":"884915df-3cdd-4d75-89a6-bf5152461fbc","order_by":7,"name":"Anwen Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvElEQVRIiWNgGAWjYFAC5oYDDBU2cvzMzIcfEKmFEajlTJqxZDtbmgHRWhgYWw4lGpznUZAgSgP/jMTGw7wNBxKMD/MwGDDU2EQT1CJxI7HhMO+OO3lmh3kPPGA4lpbbQFDPbZCWM8+KzQ7zJRgwNhwmrEUerKXtcOLmZh4DCaK0GMC0bGAmVovh/YcNB+cAA1niMDCQE4jxi9yZw4c/vAFFZf/hww8+1NgQ4X0UkECa8lEwCkbBKBgFuAAA11VHHdLxglkAAAAASUVORK5CYII=","orcid":"","institution":"The Second Affiliated Hospital of Nanchang University","correspondingAuthor":true,"prefix":"","firstName":"Anwen","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-03-04 18:55:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4014067/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4014067/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53009596,"identity":"4515aca4-26a0-4e3b-a2c6-191de99c8430","added_by":"auto","created_at":"2024-03-19 15:23:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":51171,"visible":true,"origin":"","legend":"\u003cp\u003eBar graph of eight defined sites of radiographic involvement of LC-LM, cerebrum and cerebellum were the most vulnerable sites involvement of LM.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4014067/v1/a629d13085753eef4d86a01a.png"},{"id":53010878,"identity":"19e3fae6-009b-403e-8504-a6ab29efe967","added_by":"auto","created_at":"2024-03-19 15:31:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":51360,"visible":true,"origin":"","legend":"\u003cp\u003eIn the “LM MRI+” cohort, MRI site extent of radiographic involvement 3-4 sites was significantly shorter than that those who involved 1-2 sites(3.77 vs 10.07months; HR: 1.84; 95% CI: 1.02–3.31; P = 0.034).\u003c/p\u003e","description":"","filename":"fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-4014067/v1/9a183397a3b6125d334d3e8c.png"},{"id":53009599,"identity":"6e3197cf-853b-496e-8e7b-96b5d98b49f5","added_by":"auto","created_at":"2024-03-19 15:23:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":23809,"visible":true,"origin":"","legend":"\u003cp\u003eBar graph of the exons where the TP53 mutation site located, exons 5 and 8 of the TP53 frequent mutation.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-4014067/v1/0f471008343a3ff41c47aa3a.png"},{"id":53009598,"identity":"6aaa100d-f84e-4d51-bfa6-4a0b5c252ca7","added_by":"auto","created_at":"2024-03-19 15:23:07","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":77097,"visible":true,"origin":"","legend":"\u003cp\u003e107 of 171 patients (61.8%) harbored a targetable mutation. Those with a clinically actionable mutation were significantly longer overall survival than those without (6.30 vs 12.17 months; HR:0.63; 95% CI: 0.45-0.90; p=0.009).\u003c/p\u003e","description":"","filename":"fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-4014067/v1/be3a0032c304e8bd733b77fa.png"},{"id":53009600,"identity":"0433b31f-53a1-493f-b051-d75ee67423e5","added_by":"auto","created_at":"2024-03-19 15:23:07","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":141978,"visible":true,"origin":"","legend":"\u003cp\u003eCoxmultivariate regression model forest plot of 173 patients. Among these, targetable mutations, PS, LM treat and LM TKI therapy were independent prognostic factors for LM in the multivariate analysis.\u003c/p\u003e","description":"","filename":"fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-4014067/v1/fc1cbb2eeca37980f3277950.png"},{"id":64162048,"identity":"6fbf0a91-5b4f-4a8a-a376-db7ae9fd37b7","added_by":"auto","created_at":"2024-09-09 08:07:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1788107,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4014067/v1/ce3e9e22-757e-421b-a34c-a22215c90dad.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Treatment and survival of analysis in patients with leptomeningeal metastasis from lung cancer","fulltext":[{"header":"1.\tIntroduction","content":"\u003cp\u003eLung cancer (LC) remains a leading cause of death worldwide, and most patients of non‐small-cell lung cancer (NSCLC) are diagnosed at an advanced stage[1]. Leptomeningeal metastasis (LM) is a devastating complication of advanced NSCLC and portends a grim prognosis,\u0026nbsp;LM develops in 3\u0026ndash;5% of patients with advanced NSCLC, and\u0026nbsp;its incidence has increased in subgroups of patients with targetable mutations,\u0026nbsp;being more frequent in the adenocarcinoma subtype, and one‐third of patients have concomitant brain metastasis[2-6]. The median survival after diagnosis of LM from lung cancer (LC-LM) is only 2-4 months despite therapy, and 4-6 weeks if untreated[7, 8]. While the presence of a clinically actionable mutation, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangement, has altered disease management and improved prognosis\u0026nbsp;[7-9].\u003c/p\u003e\n\u003cp\u003eA positive CSF cytology, radiologic findings with associated clinical findings, and/or signs and symptoms indicative of CSF involvement in a patient with known cancer are used to formally establish a diagnosis[6, 10]. Plasma is less sensitive than CSF, a medium obtained by a mini-invasive biopsy, which reveals the particular gene features of LM[11].\u0026nbsp;The Response Assessment in Neuro-Oncology (RANO) group and its Leptomeningeal Assessment in Neuro-Oncology (LANO) score, as well as the European Association of Neuro-Oncology- European Society of Medical Oncology (EANO-ESMO) group, are trying to standardize diagnostic workup and interpretation[6, 12, 13]. The two systems have still not each been validated[14]. The prognosis for patients with LM at the time of diagnosis still needs to be better predicted. According to a research, LC-LM patients may be managed clinically and given a good prognosis utilizing molecular characterization and CNS staging (using MRI to identify disease locations and quantify CSF liquid biopsy results)\u0026nbsp;[15].\u003c/p\u003e\n\u003cp\u003eSeeking therapies that actually control LM has proven to be quite difficult. Due to leptomeningeal lesions\u0026apos; broad subarachnoid distribution and the rarity of surgical excision, systemic and radiation treatments continue to be the gold standard of care for LM[16]. Classifying patients into groups based on their level of risk (good or poor) and recommending best supportive care (BSC) for those in the poor risk category are recommendations from the National Comprehensive Cancer Network (NCCN) guideline[17]. Radiotherapy and systemic therapy with or without intrathecal chemotherapy are the mainstays of treatment for patients with a better prognosis[6, 17]. Systemic pembrolizumab was evaluated in a phase II single-arm trial (NCT02886585) for the treatment of LM in 2020, mostly in breast cancer patients, and it was shown to have tolerable tolerability and potential efficacy[18]. While receiving therapy, individuals without a targetable molecular mutation have a median overall survival (OS) of 1-3 months and those with one have an OS of up to 12 months [2, 19]. Osimertinib, a third-generation mutant EGFR inhibitor, has recently demonstrated significant efficacy in managing LM from EGFR mutant lung cancer[20]. Its efficacy is mostly attributable to better CNS penetration compared to first-generation EGFR inhibitors (gefitinib and erlotinib)[21]. Comparable to crizotinib, emerging ALK inhibitor drugs (ceritinib, alectinib, and lorlatinib) that are successful in treating individuals with ALK-translocated NSCLC have better CNS penetration [22-25]. Therefore, this study retrospectively analyzed the diagnosis, treatment and survival analysis of 173 patients with LM from NSCLC and provided reference for clinical practice.\u003c/p\u003e"},{"header":"2.\tMaterials and methods ","content":"\u003cp\u003e\u003cstrong\u003e2.1 Patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis single-center, retrospective study was approved by Institutional Ethics Committee of Second Affiliated Hospital of Nanchang University with waiver of written informed consent.\u0026nbsp;The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). From the clinical records database of our center, we reviewed charts of 173 patients with diagnoses of LC-LM between May 2016 and May 2021 with adequate follow-up data.\u0026nbsp;The eligibility criteria included the following: age older than 18\u0026thinsp;years; histological diagnosis of\u0026nbsp;NSCLC;\u0026nbsp;LM defined by CSF positivity for malignant cells and/or focal or diffuse enhancement of leptomeninges, nerve roots or the ependymal surface diagnosed by magnetic resonance imaging (MRI) with gadolinium contrast. Patients who did not meet these criteria were excluded. Date of LC-LM diagnosis was defined as date of first CSF cytology revealing malignant cells or date of first contrast-enhanced MRI demonstrating LM. If both MRI and CSF were positive for LC-LM, the date of the first test demonstrating LC-LM was used as the date of LC-LM diagnosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2\u0026nbsp;MRI Scoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients underwent magnetic resonance imaging (MRI) brain with gadolinium contrast enhancement, and/or MRI spine with gadolinium contrast enhancement. Unequivocal radiographic evidence includes linear leptomeningeal disease (type A), nodular leptomeningeal disease (type B), and both (type C)[6]. Patients who had unequivocal radiographic evidence comprised our \u0026ldquo;LM MRI+\u0026rdquo; cohort. Radiographic involvement was scored by number of gadolinium-enhancing sites in 8 predetermined locations[15], cerebrum, ventricle, brainstem (pons and medulla included in this category), cerebellum, cranial nerves, cervical spinal cord, thoracic spinal cord, lumbosacral spinal cord. Patients received one point per location of radiographically evident LM. Number of MRI sites of disease for each patient was determined based on the original radiology report and confirmed by two independent radiologists.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 CSF findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCSF samples were obtained by lumbar puncture. CSF data including protein, glucose,\u0026nbsp;chloride and cytology.\u0026nbsp;We identified a cohort of 22 patients with CSF cytology confirmed LM who had CSF next-generation sequencing (NGS) results, matched plasma was also obtained. Approximately 10 mL of CSF was collected via lumbar puncture for NGS, and meanwhile 8 mL of plasma was collected for NGS. The NGS genetic testing process included DNA extraction, NGS library preparation and sequencing data analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Data collection and statistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient demographics, clinical data, laboratory results, imaging findings, and survival information were collected from the clinical records database of our center. Follow-up of all the patients was carried out until February 2022. Overall survival of LM (LM\u0026shy;_OS) was defined as the period from diagnosis of LM to death or last follow‐up\u0026nbsp;(censored).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe data are presented as the median (range) and n (%). Survival analysis was performed using Kaplan-Meier method with log-rank p values and 95% confidence intervals (CIs) reported. The p values were two-sided and considered significant if less than 0.05. Multivariate analysis was performed using interactive Cox proportional hazard regression with inclusion of variables significant on univariate regression. Statistical analysis and figure plotting were performed in RStudio with implemented R (v. 4.1.2, CRAN).\u003c/p\u003e"},{"header":"3.\tResults","content":"\u003cp\u003e\u003cstrong\u003e3.1 Patient Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe identified 173 patients with LM evaluated at our center between June 2011 and June 2021 (Table 1). median age at LM diagnosis was 59 years (range,\u0026nbsp;32-84). Ever-smokers accounted for\u0026nbsp;49.1% of the patients (n = 85). There was a preponderance of adenocarcinoma. A prominent majority (107, 61.8%) of patients had targetable mutations identified from primary or metastatic malignant pathology specimens: there were 95 cases with EGFR mutations, eight with ALK rearrangement and four with ROS proto-oncogene 1(ROS-1).\u0026nbsp;58.4% (101/173) received targeted therapy before they were diagnosed as LM. Most patients (127/173;\u0026nbsp;73.4%) had brain metastasis (BM) before or simultaneously with LM diagnosis. Before LM diagnosis, 48 patients had history of brain radiotherapy (BRT) (27.7%). The median time from NSCLC diagnosis to LM diagnosis was 11.1 months (range: 0-23.9). The ECOG PS was 0\u0026ndash;2 for\u0026nbsp;67.1% of patients. Regarding treatments modalities for LM, 23 (13.3%) patients received supportive care alone after they were diagnosed as LM, 102 (59.0%) patients received TKI therapy, there were\u0026nbsp;22.5%\u0026nbsp;(23/102) received first/second\u0026nbsp;generation\u0026nbsp;TKI therapy, and\u0026nbsp;77.5%\u0026nbsp;(79/102) received third\u0026nbsp;generation\u0026nbsp;TKI therapy, 22 (12.7%) patients received whole brain radiotherapy, 51 (29.5%) patients received chemotherapy, and 40 (23.1%) patients received\u0026nbsp;intrathecal chemotherapy (ITC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1 Patient Characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"557\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003egroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003eN=173 (n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eMedian age, years (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e59 (32-84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eSex (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e95 (54.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003efemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e78 (45.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eAge1 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003e＜60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e87 (50.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e86 (49.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eSmoking status (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e88 (50.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eFormer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e85 (49.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003ePulmonary lesion (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e5 ( 2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e81 (46.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e87 (50.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eHistological type (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eLUAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e145 (83.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNon-LUAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e28 (16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eTargetable mutations (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e66 (38.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e107 (61.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eSpecific mutation (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eEGFR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e95 (88.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eALK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e8 ( 7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eROS-1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e4 ( 3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eInitial diagnosis with BM (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e93 (53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e80 (46.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eInitial diagnosis with LM (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e119 (68.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e54 (31.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eTKI therapy before LM (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e72 (41.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e101 (58.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eBRT before LM (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e125 (72.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e48 (27.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eCNS symptoms (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e20 (11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e153 (88.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eECOG PS (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026le;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e116 (67.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003e＞2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e57 (32.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eLM and BM (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e46 (26.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e127 (73.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eLM Treat (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e23 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e150 (86.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eWBRT (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e151 (87.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e22 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eLM Chemotherapy therapy (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e122 (70.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e51 (29.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eITC (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e133 (76.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e40 (23.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eLM_\u0026nbsp;TKI therapy (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e71 (41.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e102 (59.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eTKI therapy _drugs (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003e1/2 generation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e23 (22.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003e3 generation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e79 (77.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003eDeath (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e134 (77.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eLost follow-up\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e5 ( 2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.526032315978455%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.211849192100537%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.262118491921004%\"\u003e\n \u003cp\u003e34 (19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNotes: LUAD, lung adenocarcinoma; BM, brain metastasis; LM, leptomeningeal metastasis; TKI, tyrosine kinase inhibitor; BRT, brain radiotherapy; CNS, central nervous system; ECOG PS: Eastern Cooperative Oncology Group Performance Status; WBRT, whole brain radiotherapy; ITC, Intrathecal chemotherapy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eRadiographic Burden of Disease\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are 136 patients in the \u0026ldquo;LM MRI+\u0026rdquo;\u0026nbsp;cohort, A prominent majority (103, 75.7%) of patients were linear leptomeningeal disease (Table2), Cerebrum and cerebellum were the most vulnerable sites involvement of LM (Fig. 1). MRI site extent of radiographic involvement at LC-LM diagnosis ranged from 0 to 4 sites involved (Table2); median was 1 site and mean were 1.21 sites. In the \u0026ldquo;LM MRI+\u0026rdquo; cohort (n = 136), MRI site extent of radiographic involvement 3-4 sites was significantly shorter than that those who involved 1-2 sites (3.77 vs 10.07months; HR: 1.84; 95% CI: 1.02\u0026ndash;3.31; P = 0.034;\u0026nbsp;Fig. 2), but there was no association between number of sites involved and overall survival (HR: 1.13; 95% CI: 0.94\u0026ndash;1.35; P = 0.208). There was no association between anatomic location of LM and survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 Diagnostic of LM\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003elever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eN=173 (n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eCytological examination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e53 (30.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e120 (69.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003ePositive cytology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e32 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e88 (73.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eRadiographic evidence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eequivocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eunequivocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e136\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eMRI type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003elinear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003enodular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003elinear and nodular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of MRI sites\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e3.3\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCSF Findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e120 (69.4%) individuals had CSF cytology data available at the time of LC-LM diagnosis.\u0026nbsp;Using the criterion of positive CSF cytology as cytology that conclusively revealed malignant cells or cells suspected of malignancy in a patient with acceptable clinical signs and symptoms, we found that 73.3% (88/120) of patients had positive CSF cytology.\u0026nbsp;When this cohort was studied, a positive CSF cytology at the time of diagnosis was not linked to an elevated risk of mortality (p = 0.159). In 102 individuals, the CSF protein levels at the time of the LC-LM diagnosis were available; the presence of CSF proteins over the upper limit of normal was not significantly related to survival (p = 0.311). Low CSF chloride, however, was linked to a higher probability of passing away from the time of LC-LM diagnosis (HR: 2.15; 95% CI: 1.34-3.44; p = 0.002).\u003c/p\u003e\n\u003cp\u003eCell-free DNA (cfDNA) was extracted from a subset of 19 patients who had CSF collected at time of LC-LM diagnosis. cfDNA concentration ranged from 0.720ng to 47.300ng, with a median of 4.840 ng and mean of 14.486 ng.\u0026nbsp;Using the median cutpoint, there was no increased risk of death associated with the above median value of cfDNA concentration (HR: 1.43; 95% CI: 0.43-4.73; p = 0.554), due to impacted by small sample size.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Mutation Profiling of Paired CSF and Plasma\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are 22 patients those\u0026nbsp;tumor tissue detected EGFR mutations underwent NGS\u0026nbsp;with paired CSF and plasma.\u0026nbsp;21 (95.5%) CSF samples and 8(36.4%) plasma samples were detected\u0026nbsp;drive genes, of which EGFR-sensitive mutations were detected in 9 CSF and plasma samples and 1 No EGFR-sensitive mutations were detected in both CSF and plasma samples, the concordance was 45.5%. TP53 was detected in 18 CSF and 4 plasma samples. The detection rate of CSF TP53 was higher (81.8%) than plasma (18.2%; \u0026chi;\u0026sup2;= 17.82, p＜0.001), We also found that the exons where the TP53 mutation site located were different. In our study, exons 5 and 8 of the TP53 frequent mutation (Fig. 3) and related to poor prognosis. T790M mutations were detected in 3 samples, including 1 in CSF and 2 in plasma. MET amplification was detected in 5 CSF samples, and no MET amplification was detected in plasma samples. In addition, EGFR amplification (7 cases), IKZF1 (7 cases), CDKN2A/B (6 cases), RICTOR amplification (6 cases), PIK3CA mutation (4 case), MAP2K4 (4 cases), ERBB2 amplification (3 cases), CDK4 (3 cases), STK11 (3cases), RB1 (2cases), PTEN mutation (2 cases), and ATM (2 cases) and PMS2 (2 cases) were also detected in CSF.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Presence of a Targetable Mutation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e107 (61.8%) patients harbored a targetable mutation, which included mutations in EGFR, ALK, and ROS-1.\u0026nbsp;Those with a clinically actionable mutation were significantly longer overall survival than those without (6.30 vs 12.17 months; HR:0.63; 95% CI: 0.45-0.90; p=0.009; Fig. 4). Due to the limited number of patients with each specific targetable mutation (other than EGFR mutations, which dominated the cohort), the potential prognostic importance of each individual mutation was unable to be determined.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.6 Survival After Diagnosis with LM\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median follow-up time was 34.1 months, the median OS of the entire cohort\u0026nbsp;(173 patients) was 9.33 months (95% CI: 6.35‒12.31) with 77.5% maturity (134/173). Univariate analysis revealed that sex, smoking status, histological type, targetable mutations, TKI therapy before LM, PS, LM treat and LM TKI therapy were potential prognostic factors for LM (Table 3). Among these, targetable mutations, PS, LM treat and LM TKI therapy were independent prognostic factors for LM in the multivariate analysis (Fig. 5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3 Univariate analysis for LC-LM\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"564\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariate analysis (N = 173)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable name\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\" valign=\"top\"\u003e\n \u003cp\u003eSex\u0026nbsp;(male vs. female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e0.63 (0.45-0.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eage1(＜60 vs \u0026ge;60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e1.08 (0.77-1.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e0.659\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eSmoking status\u0026nbsp;(never vs former)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e1.64 (1.16-2.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\" valign=\"top\"\u003e\n \u003cp\u003eHistological type\u0026nbsp;(non-LUAD vs LUAD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\" valign=\"top\"\u003e\n \u003cp\u003e0.52 (0.331-0.830)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.006*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\" valign=\"top\"\u003e\n \u003cp\u003eTargetable mutations\u0026nbsp;(no vs yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e0.63 (0.45-0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.010*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\" valign=\"top\"\u003e\n \u003cp\u003eInitial diagnosis with BM (no vs yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e1.05 (0.75-1.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e0.789\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eInitial diagnosis with LM (no vs yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e0.80 (0.55-1.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e0.225\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eTKI therapy before LM\u0026nbsp;(no vs yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\" valign=\"top\"\u003e\n \u003cp\u003e0.59 (0.416-0.824)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eBRT before LM (no vs yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\" valign=\"top\"\u003e\n \u003cp\u003e1.31 (0.91-1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\" valign=\"top\"\u003e\n \u003cp\u003e0.142\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eCNS symptoms (no vs yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e1.33 (0.78-2.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e0.299\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eECOG PS (\u0026le;2 vs＞2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e3.08 (2.1-4.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e\u003cstrong\u003e＜\u003c/strong\u003e\u003cstrong\u003e0.001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eLM and BM (no vs yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e1.5 (1-2.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eLM Treat\u0026nbsp;(no vs yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e0.27 (0.17-0.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e\u003cstrong\u003e＜\u003c/strong\u003e\u003cstrong\u003e0.001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eWBRT (no vs yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e1.45 (0.9-2.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e0.125\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eLM Chemotherapy therapy (no vs yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e1.27 (0.88-1.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e0.195\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eITC (no vs yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e1.04 (0.67-1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e0.865\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.808510638297875%\"\u003e\n \u003cp\u003eLM_\u0026nbsp;TKI therapy\u0026nbsp;(no vs yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\"\u003e\n \u003cp\u003e0.39 (0.28-0.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.27659574468085%\"\u003e\n \u003cp\u003e\u003cstrong\u003e＜\u003c/strong\u003e\u003cstrong\u003e0.001*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"4.\tDiscussion","content":"\u003cp\u003eLM involves cancer cells reaching the subarachnoid space, surviving in the CSF, and frequently adhering to the leptomeninges, as evidenced by linear or nodular enhancement on MRI\u0026nbsp;[26, 27].\u0026nbsp;A study suggested that patients harboring LM diagnosed with CSF disease alone succumbed to the disease earlier than patients with adherent (MRI-positive) disease[27]. Wang \u003cem\u003eet al\u003c/em\u003e focused on 86 patients with cytologically confirmed LM, the patients were divided into MRI-positive and MRI-negative groups according to the presence of leptomeningeal enhancement on initial contrast MRI, showed that MRI- positive of the neuroaxis has been proposed as a risk factor for the prognosis of LM\u0026nbsp;from lung adenocarcinoma. These studies indicated that the visibility of leptomeningeal enhancement is likely to represent a larger tumor burden compared with invisible lesions on MRI[28]. Adrienne Boire et.al showed that extent of radiographic involvement correlated with risk of death (HR: 1.16; 95% CI: 1.02\u0026ndash;1.33; p = 0.03)[15]. Our study found MRI site extent of radiographic involvement 3-4 sites was significantly shorter OS than that those involved 1-2 sites (3.77 vs 10.07 months; HR: 1.84; 95% CI: 1.02\u0026ndash;3.31; p = 0.034) and was consistent with other similar studies.\u003c/p\u003e\n\u003cp\u003eIn our study, 107 (61.8%) patients harbored a targetable mutation, and OS was considerably longer in individuals with clinically actionable mutations than in those without (6.30 vs. 12.17 months; HR:0.63; 95% CI: 0.45-0.90; p=0.009).\u0026nbsp;Patients with LC-LM and clinically actionable mutations survive longer than patients without targetable mutations, and those who get targeted treatment survive even longer, attributable to the exponential growth in research and drug development of targeted therapies for these diseases since the discovery of molecular targets in NSCLC more than a decade ago[8, 9, 15, 29]. In our study, individuals with malignancies who included a clinically actionable mutation showed enhanced OS; therapy with medications that targeted that mutation also increased survival. Prior to receiving a diagnosis of LC-LM, participants in our research who underwent targeted treatment had a shorter OS (HR: 0.59; 95%CI: 0.416-0.824; p=0.002). This is in line with a theory in which past exposure to a targeted medicine breeds resistance, leaving less room for treatment alternatives than for a patient with LC-LM who has never received a targeted therapy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAccording to certain research, liquid biopsies of the CSF are more sensitive than those of the plasma to find targetable mutations[30, 31].\u0026nbsp;In our study, we collected and sequenced 22\u0026nbsp;paired CSF and plasma samples of LC-LM. We demonstrated that CSF is concordant with tumor to detect drive genes for NSCLC, our study found 21 (95.5%) CSF samples and 8(36.4%) plasma samples were detected drive genes; we showed the unique molecular feature of CSF in LM (MET amplification, EGFR amplification, IKZF1, CDKN2A/B, RICTOR amplification, PIK3CA mutation et.al were detected only in CSF), indicating screening of CSF is a suitable liquid biopsy for LM. In our study, TP53 is the first and co-occurring of EGFR and TP53 in 18 cases, and TP53, we also found that the exons where the TP53 mutation site located were different, exons 5 and 8 of the TP53 frequent mutation. Recent studies have found that baseline TP53 mutation significantly associated with shorter survival in EGFR mutant patients treated with EGFR-TKI[32], TP53 may contributes to poor prognosis for LM, and a large number of clinical and preclinical studies are needed for verification in the future.\u003c/p\u003e\n\u003cp\u003eIn addition to correlating outcome with\u0026nbsp;clinically actionable mutations and\u0026nbsp;MRI- positive, certain characteristics have been found to influence patient survival. A study[33]\u0026nbsp;showed that LM with active anti-tumor therapy improved OS (6.0 vs. 1.9 months; p\u0026lt;0.001). For example, PS and active anti-tumor therapy had been explored as predictors of survival[33, 34]; lower PS typically leads to better prognosis, in our study population, lower PS and active anti-tumor therapy were associated with longer survival times, as might be expected.\u003c/p\u003e\n\u003cp\u003eOur research has certain limitations. Firstly, because our study only used a limited sample size from a single institution, sample bias may have been introduced; Secondly, because this was a retrospective cohort study and the dataset included a heterogeneous population of patients with respect to the number and types of treatments received prior to LC-LM diagnosis, sites of systemic disease, and treatments received after LC-LM diagnosis, we were unable to control for or evaluate for a potential impact of treatment regimen on the outcome;\u0026nbsp;Thus, to continue evaluating clinical effectiveness, future research must continue to overcome these methodological obstacles.\u003c/p\u003e\n\u003cp\u003eIn conclusion, our study provides real-world clinical evidence that patients with MRI site extent of radiographic involvement 3-4 sites was significantly shorter than that those involved 1-2 sites and those with clinically actionable mutations were significantly longer overall survival than those without. Our findings also suggest that CSF indicated the unique genetic profiles of LM.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Ethics Committee of Second Affiliated Hospital of Nanchang University (Review [2016] NO.002), Nanchang, China. All procedures performed in this study using human data were in accordance with the Declaration of Helsinki (as revised in 2013). Informed consent was waived by the Institutional Ethics Committee of Second Affiliated Hospital of Nanchang University because of the retrospective nature of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZQL and TZ performed the statistical analysis and participated in drafting and wrote the manuscript; XW and DYP made useful comments and participated in revising the manuscript; CYZ and CH collected the clinical data; AWL and ZMZ was the principal investigator for this study and was involved in project oversight and organization. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe kindly thank the editor and reviewers for their careful review and valuable comments, which have significantly improved the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Jemal A: \u003cstrong\u003eCancer statistics, 2020\u003c/strong\u003e. \u003cem\u003eCA: a cancer journal for clinicians \u003c/em\u003e2020, \u003cstrong\u003e70\u003c/strong\u003e(1):7-30.\u003c/li\u003e\n\u003cli\u003eCheng H, Perez-Soler R: \u003cstrong\u003eLeptomeningeal metastases in non-small-cell lung cancer\u003c/strong\u003e. \u003cem\u003eThe Lancet Oncology \u003c/em\u003e2018, \u003cstrong\u003e19\u003c/strong\u003e(1):e43-e55.\u003c/li\u003e\n\u003cli\u003eIuchi T, Shingyoji M, Itakura M, Yokoi S, Moriya Y, Tamura H, Yoshida Y, Ashinuma H, Kawasaki K, Hasegawa 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cancer\u003c/strong\u003e. \u003cem\u003eLung cancer (Amsterdam, Netherlands) \u003c/em\u003e2019, \u003cstrong\u003e127\u003c/strong\u003e:1-5.\u003c/li\u003e\n\u003cli\u003eHerrlinger U, F\u0026ouml;rschler H, K\u0026uuml;ker W, Meyermann R, Bamberg M, Dichgans J, Weller M: \u003cstrong\u003eLeptomeningeal metastasis: survival and prognostic factors in 155 patients\u003c/strong\u003e. \u003cem\u003eJournal of the neurological sciences \u003c/em\u003e2004, \u003cstrong\u003e223\u003c/strong\u003e(2):167-178.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Leptomeningeal metastasis, non-small-cell lung cancer, overall survival","lastPublishedDoi":"10.21203/rs.3.rs-4014067/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4014067/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives: \u003c/strong\u003eLeptomeningeal metastasis (LM) is a severe complication of advanced non-small cell lung cancer (NSCLC) and portends a grim prognosis. This study aimed to retrospectively analyzed the diagnosis, treatment, and survival analysis of 173 patients with LM from NSCLC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and methods:\u003c/strong\u003e We reviewed charts of 173 patients with diagnoses of LM from lung cancer (LC-LM) between May 2016 and May 2021. 173 patients who had unequivocal radiographic evidence comprised our “LM MRI+” cohort. Radiographic involvement (n=136) was scored by number of gadolinium-enhancing sites in 8 locations. Genetic testing of paired cerebrospinal fluid (CSF) and plasma samples from 22 patients at the time of LM diagnosis using second-generation sequencing (NGS). Clinical outcomes were compared with Kaplan-Meier log-rank test and Cox proportional hazards methodologies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe median overall survival (OS) was 9.33 months (95% CI: 6.35‒12.31) with 77.5% maturity. 107 (61.8%) patients harbored a targetable mutation. Those with clinically actionable mutations were significantly longer OS than those without (6.30 vs 12.17 months; HR:0.63; 95% CI: 0.45-0.90; p=0.009). In the “LM MRI+” cohort, MRI site extent of radiographic involvement 3-4 sites was significantly shorter OS than that those involved 1-2 sites (3.77 vs 10.07 months; HR: 1.84; 95% CI: 1.02–3.31; p = 0.034). CSF was more sensitive than plasma and indicated the unique genetic profiles of LM. Multivariate analysis revealed that targetable mutations, PS, LM treat, and LM tyrosine kinase inhibitor (TKI) therapy were independent prognostic factors for LM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eOur study provides real-world clinical evidence that patients with MRI site extent of radiographic involvement 3-4 sites was significantly shorter OS than that those involved 1-2 sites and those with clinically actionable mutations were significantly longer OS than those without.\u003c/p\u003e","manuscriptTitle":"Treatment and survival of analysis in patients with leptomeningeal metastasis from lung cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-19 15:23:02","doi":"10.21203/rs.3.rs-4014067/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"16d418e1-a31e-452e-b04d-5a5d2f7319cc","owner":[],"postedDate":"March 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-09T07:59:36+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-19 15:23:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4014067","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4014067","identity":"rs-4014067","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}