Lung Cancer Brain Metastases Research Articles

CCKAR is a biomarker for prognosis and asynchronous brain metastasis of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer, and brain metastasis (BM) is the most lethal complication of NSCLC. The predictive biomarkers and risk factors of asynchronous BM are still unknown. A total of 203 patients with NSCLC were enrolled into our cohort and followed up. The clinicopathological factors such as tumor size, T stage, lymphatic invasion, metastasis and asynchronous BM were investigated. CCKAR expression in NSCLC and resected BM was assessed by IHC, and CCKAR mRNAs in NSCLC and para-tumor tissues were estimated by qRT-PCR. The correlations between CCKAR expression, BM and other clinicopathological factors were assessed by chi-square test, and prognostic significance of CCKAR was estimated by univariate and multivariate analyses. CCKAR was highly expressed in NSCLC tissues compared with para-tumor tissues. CCKAR expression in NSCLC was significantly associated with asynchronous BM. The BM percentages for NSCLC patients with low and high CCKAR were surprisingly 5.2% and 66.6%, respectively. CCKAR expression and BM were unfavorable factors predicting unfavorable outcome of NSCLC. Moreover, CCKAR expression in NSCLC was an independent risk factor of asynchronous BM. CCKAR is a prognostic biomarker of NSCLC. CCKAR expression in NSCLC is positively associated with asynchronous BM, and is a risk factor of asynchronous BM from NSCLC.

Research progress in immune microenvironment and immunotherapy of brain metastasis in non-small cell lung cancer

In recent years, the rise of immunotherapy has comprehensively changed the treatment pattern of advanced non-small cell lung cancer(NSCLC). With the understanding of the immune microenvironment in brain metastasis, patients with advanced lung cancer with brain metastasis, who usually were previously excluded from clinical studies, gradually gained attention from researchers. The development from immune monotherapy to combination with chemotherapy significantly improved the survival prognosis of patients with brain metastases from lung cancer. This review aimed to briefly elucidate the mechanism of the immune microenvironment, and summarized the latest research progress of immunotherapy for NSCLC patients with brain metastasis.

The clinical application of 68Ga-PSMA PET/CT and regulating mechanism of PSMA expression in patients with brain metastases of lung cancer

Brain metastases (BMs) of lung cancer are common malignant intracranial tumours associated with severe neurological symptoms and an abysmal prognosis. Prostate-specific membrane antigen (PSMA) has been reported to express significantly in a variety of solid tumours. However, the clinical applications of 68Ga-PSMA PET/CT and the mechanism of PSMA expression in patients with BMs of lung cancer have rarely been reported. Experiments with 68Ga-PSMA PET/CT and immunohistochemical staining were conducted to evaluate the expression of PSMA from seven patients with BMs of lung cancer who accepted surgical treatment in Fudan University Shanghai Cancer Center between October 2020 and October 2021. The mechanism of PSMA expression in BMs of lung cancer was explored by using single-cell RNA sequencing. The median maximum standardized uptake value (SUVmax) in BMs was higher than that in primary lung cancer (8.6 ± 2.8 vs. 3.6 ± 1.3, P < 0.01). The mean SUVmax in BMs was 1.76-fold higher than that in the liver, which indicated the potential of PSMA radioligand therapy (PSMA-RLT) for BMs. BMs showed intense PSMA staining, while normal lung tissue had no PSMA staining and there was only faint primary lung cancer staining by immunohistochemistry (IHC). Single-cell RNA sequencing (scRNA-seq) analysis found that PSMA was mainly expressed in oligodendrocytes of BMs, whereas it was expressed at lower levels in solid cells of lung cancer. PSMA expression in oligodendrocytes might be regulated by the factors ATF3 and NR4A1, which were associated with ER stress.

C-C Motif Ligand 21/C-C Motif Chemokine Receptor 7 Modulated Tumor Properties for Non-Small Cell Lung Cancer Brain Metastasis Patients

The non-small cell lung cancer is a common malignancy with high metastasis capacity. The brain is the primary site for non-small cell lung cancer patients with unclear mechanism. Here, in this study, we hypothesized an innovative signaling cascade for the disorder and systematically investigated the underlying mechanism. Their differentially gene expression analysis was based on 13 conventional nonsmall cell lung cancer and 15 non-small cell lung cancer brain metastasis patients respectively. The nonsmall cell lung cancer cell line, adenocarcinomic human alveolar basal epithelial cells-A549 and human bronchial epithelial cell line-BEAS-2B were established for in vitro study. The syngeneic mouse tumor models injected with 5×105 cells of control, C-C motif ligand 21 overexpressing, C-C motif chemokine receptor 7 overexpressing A549 cells were generated for in vivo analysis. Compared with conventional non-small cell lung cancer patients, the non-small cell lung cancer brain metastasis patients showed 352 differentially expressed genes, as 212 down-regulated ones and 140 up-regulated ones. Moreover, the C-C motif ligand 21 and C-C motif chemokine receptor 7 were prominently inhibited in non-small cell lung cancer brain metastasis patients. In A549 cells, C-C motif ligand 21 overexpressing could inhibit epithelial-mesenchymal transition progression. C-C motif ligand 21 modulated epithelial-mesenchymal transition and migration plus invasion ability but not proliferation capacity of non-small cell lung cancer cells through C-C motif chemokine receptor 7 dependent signaling pathway, as Janus kinase 2/signal transducer and activator of transcription 3 was a potential downstream signaling pathway. Moreover, C-C motif ligand 21/C-C motif chemokine receptor 7 signaling axis could modulate tumor growth and survival time in vivo. Collectively, these data initiated a C-C motif ligand 21/C-C motif chemokine receptor 7-Janus kinase 2/signal transducer and activator of transcription 3 signaling for non-small cell lung cancer patients with brain metastasis, which shed various beneficial insights for future study.

Lung cancer presenting with central nervous system metastasis: Clinicopathological and molecular analysis of 171 cases

A subset of lung carcinoma presents initially with brain metastasis. Precise subtyping is mandatory for optimized treatment of these advanced aggressive carcinomas. We herein analyzed surgical biopsies from 171 Patients (99 males and 72 females aged 48–96; mean, 72), who presented with brain metastasis of lung cancer. In addition to conventional subtyping, we applied an extended immunohistochemistry (IHC) panel and performed several molecular tests looking for potential therapeutic targets other than EGFR mutations. Non-small cell carcinoma (NSCLC) comprised 157 (91.8 %) of cases: 109 (63.7 %) adenocarcinomas, 27 (15.8 %) squamous cell (SCC), 18 (10.5 %) large cell undifferentiated, 1 (0.6 %) adenosquamous and 2 (1.2 %) unclassified carcinomas. Of the adenocarcinomas, 81.7 % were TTF1+. Notably, 45 % of those TTF1-negative cases expressed HepPar1. SMARCA4 and SMARCA2 loss was observed in 13/171 (7.6 %) and 32/163 (19.6 %) cases, respectively; mainly TTF1- (40.0 %) and HepPar1+ (38.1 %) adenocarcinomas were affected by SMARCA2/4 loss. Loss of at least one mismatch repair (MMR) protein was observed in 3/156 (1.9 %) cases (2 adenocarcinomas and 1 large cell neuroendocrine carcinoma/LCNEC). Limited available data on mutation testing showed a frequency of EGFR mutations of 4.3% and of KRAS mutations of 57%. HER2 expression (2+/3+) was found in 45/166 (27.1 %) of cases with amplification verified by CISH in 18/38 (47.4 % of immunopositive cases and 10.5 % of the whole cohort); all but one were adenocarcinomas. Other genetic abnormalities detected included EML4::ALK rearrangements in 3 (1.8 %; 2 TTF1+ adenocarcinomas and 1 LCNEC) and RET rearrangements in one SCNEC. Variable subsets of tumors revealed amplifications of several potentially therapeutically targetable genes including MYC (30.0 %), MET (10.1 %), HER2 (10 %), FGFR1 (9.6 %), FGFR3 (4.6 %), and FGFR2 (3.4 %). This study highlights a highly heterogeneous molecular background in lung cancer presenting with CNS metastases. These findings highlight the need for individualized tumor testing strategies looking for potential therapeutic targets for this aggressive disease.

Iodine-125 brachytherapy treatment for newly diagnosed brain metastasis in non-small cell lung cancer: A biocentric analysis.

The aim of the present study is to evaluate the safety and efficacy of iodine-125 brachytherapy for newly diagnosed brain metastasis in patients with non-small cell lung cancer (NSCLC). The study included 158 NSCLC patients diagnosed with brain metastasis from December 2003 to August 2017. Ninety-nine patients underwent external beam radiotherapy (EBRT group), and 59 patients received iodine-125 brachytherapy (125I group). In addition, the 6- and 12-month progression-free survival (PFS) rates and the 12- and 24-month overall survival (OS) rates were compared between the EBRT group and the 125I group. Median OS and PFS were analyzed using the Kaplan-Meier method with a log-rank test. The 6-month PFS rate was significantly higher in the 125I group (p = 0.002) than in the EBRT group, while no differences were found in the 12-month PFS rate (p = 0.184). Additionally, the 12- (p = 0.839) and 24-month (p = 0.284) OS rates were not significantly different between the two groups. No significant differences in median OS (p = 0.525) or PFS (p = 0.425) were found between the two groups. Iodine-125 brachytherapy is an alternative therapy for patients unable to undergo surgical resection.

Heterogeneity and Clinical Effect of Epidermal Growth Factor Receptor in Primary Lung and Brain Metastases of Nonsmall Cell Lung Cancer

IntroductionThis study aimed to analyze the heterogeneity in epidermal growth factor receptor (EGFR) gene mutation and its impact on clinical outcomes in primary tumor and corresponding brain metastasis (BM) in nonsmall cell lung cancer (NSCLC). Materials and methodsPrimary pulmonary tumors and paired BMs of 27 NSCLC patients were surgically removed. All brain lesions were histologically confirmed as metastatic NSCLC. EGFR gene mutation status was detected by using amplification refraction mutation system. McNemar test was performed to compare EGFR mutation status between lung primary tumors and metastatic brain tumors and Kappa test was performed to quantify the agreement between the two. ResultsOf the 27 patients, nine cases were found to have EGFR mutations in BMs and 10 had a positive EGFR mutation status in primary lung tumor tissue. The rate of consistency of the matched tumor was 24/27 (88.9%). Among the three cases presenting EGFR mutational heterogeneity, two patients harbored an EGFR mutation in the primary tumor but not in the BMs; meanwhile, the last patient demonstrated the opposite pattern. Compared to patients with consistent EGFR mutations, patients with inconsistent mutations showed better outcomes. Further analysis revealed that the two patients whose EGFR mutant-type primary tumor progressed to wild-type cerebral metastatic tumor had longer overall survival than the patient whose EGFR wild-type primary tumor progressed to mutant-type brain metastatic tumor. ConclusionsHeterogeneity of EGFR mutation status was observed between primary NSCLC and paired BM. Patients possessing a wild-type EGFR mutation in BM might have better outcomes, especially those with transition from mutant to wild-type.

Clinical application of 3D-Slicer + 3D printing guide combined with transcranial neuroendoscopic in minimally invasive neurosurgery

To explore the clinical advantages of 3D-Slicer + 3D printing guide combined with transcranial neuroendoscopic in minimally invasive neurosurgery. By collecting the datum of patients who underwent craniotomy under 3D-Slicer + 3D printing guide plate positioning combined with transcranial neuroendoscopic in our hospital from October 2021 to February 2022, this paper introduces the accurate planning and positioning lesions of patients before operation and the minimally invasive operation of intraoperative neuroendoscopic and analyses clinical data such as lesion size and surgical bone window size. We collected the case datum of 16 patients who underwent craniocerebral surgery with 3D-Slicer + 3D printing guide combined with transcranial neuroendoscopic, including 5 males and 11 females, aged 46–76 years, including 6 brain tumors (3 meningiomas, 1 glioblastoma, 2 lung cancer brain metastases), 2 cavernous hemangioma, 7 hydrocephalus and 1 chronic subdural hematoma. The lesions of the 16 patients were located accurately before operation and the target areas were reached quickly during operation. Postoperative imaging datum confirmed that the lesions was removed fully, and the ventricular end of shunt tube was in good position. The technology of 3D-Slicer + 3D printing guide plate combined with transcranial neuroendoscopic is not difficult, which has many advantages such as inexpensive equipment, simple operation, easy learning, accurate positioning, and minimally invasive surgery. It is considered to be a practical technology that is feasible, reliable, convenient for diagnosis, preoperative planning and minimally invasive surgery. It is suitable for promotion in neurosurgery and other surgical departments of all medical institutions.

Treatment of brain metastases in lung cancer

Lung cancer is the most frequent oncological disorder and has been the main topic in most oncological congresses. There have been countless changes in diagnosis and treatment, improvements in the diagnostic methods, more effective and less invasive curative care and improvements in systemic treatments (new drugs and molecular targets). In the whole therapeutic spectrum, radiotherapy plays a significant role and at the brain metastasis level the changes are very relevant. Brain metastases are the most frequent neuro-oncologic complication in lung cancer patients. Managing this situation has become increasingly complex in recent years. The results have been improving, not only in terms of responses to treatment but also in terms of an increasing reduction in side effects. This paper reviews the latest advances and current management of patients with brain metastases from lung cancer.

NCOG-07. SURVIVAL BENEFIT OF RADIOTHERAPY AND SURGERY IN PATIENTS WITH LUNG CANCER BRAIN METASTASES WITH POOR PROGNOSIS FACTORS: A SINGLE-CENTER, RETROSPECTIVE, PROPENSITY SCORE MATCHING ANALYSIS

Abstract PURPOSE To investigate the effect of radiotherapy and surgery in patients with lung cancer brain metastases (BMs) with poor prognosis factors. METHODS We analyzed retrospectively 714 patients with lung cancer BMs. A 1:1 propensity score matching (PSM) was performed to balance potential confounders. Analyses of overall survival (OS) and risk factors for OS were assessed by log-rank test and Cox proportional hazard model. RESULTS Age ≥ 65 years, Karnofsky Performance Scale (KPS) score ≤ 70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, extracranial metastases, non-surgery and non-radiotherapy led to poor prognosis. Patients were stratified according to these factors. Radiotherapy and surgery showed no survival benefit in patients with aged ≥ 65 years and pretreatment KPS score ≤ 70 before and after PSM. Before PSM,whole brain radiotherapy (WBRT) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or extracranial metastases. WBRT also predicted good prognosis in patients with non-surgery. Stereotactic radiosurgery (SRS) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with extracranial metastases or non-surgery. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS and predicted good prognosis in patients with non-radiotherapy. After PSM, SRS improved the OS and predicted good prognosis in non-surgery patients. WBRT plus SRS improved the OS and predicted good prognosis in patients with non-surgery or extracranial metastases. WBRT plus SRS predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS of patients with non-radiotherapy. CONCLUSIONS Radiotherapy has significant survival benefit in patients with lung cancer BMs with poor prognosis factors, including patients with ALK/EGFR wild type or extracranial metastases or non-surgery. Surgery only has significant survival benefit in patients with non-radiotherapy.

NIMG-11. THE EXTENT OF NECROSIS IN BRAIN METASTASES MAY PREDICT SUBTYPES OF PRIMARY CANCER AND OVERALL SURVIVAL IN PATIENTS RECEIVING CRANIOTOMY

Abstract Although necrosis is common in brain metastasis (BM), its biological and clinical significances remain unknown. We evaluated necrosis extent differences by primary cancer subtype and correlated BM necrosis to overall survival post craniotomy. We analyzed 145 BM patients receiving craniotomy. Necrosis to tumor ratio (NTR) was measured. Patients were divided into two groups by NTR: BMs with sparse necrosis and with abundant necrosis. Clinical features were compared. To investigate factor relevance for BM necrosis, multivariate logistic regression, random forests, and gradient boosting machine analyses were performed. Kaplan–Meier analysis and log-rank tests were performed to evaluate the effect of BM necrosis on overall survival. Lung cancer was a more common origin for BMs with abundant necrosis (42/72, 58.33%) versus sparse necrosis (23/73, 31.51%, p&amp;lt; 0.01). Primary cancer subtype and tumor volume were the most relevant factors for BM necrosis (p&amp;lt; 0.01). BMs harboring moderately abundant necrosis showed longer survival, versus sparse or highly abundant necrosis (p=0.03). Lung cancer BM may carry larger necrosis than BMs from other cancers. Further, moderately abundant necrosis in BM may predict a good prognosis post craniotomy.

Single-cell RNA sequencing reveals cellular and molecular reprograming landscape of gliomas and lung cancer brain metastases.

Brain malignancies encompass gliomas and brain metastases originating from extracranial tumours including lung cancer. Approximately 50% of patients with lung adenocarcinoma (LUAD) will eventually develop brain metastases. However, the specific characteristics of gliomas and lung-to-brain metastases (LC) are largely unknown. We applied single-cell RNA sequencing to profile immune and nonimmune cells in 4 glioma and 10 LC samples. Our analysis revealed that tumour microenvironment (TME) cells are present in heterogeneous subpopulations. LC reprogramed cells into immune suppressed state, including microglia, macrophages, endothelial cells, and CD8+ T cells, with unique cell proportions and gene signatures. Particularly, we identified that a subset of macrophages was associated with poor prognosis. ROS (reactive oxygen species)-producing neutrophils was found to participant in angiogenesis. Furthermore, endothelial cells participated in active communication with fibroblasts. Metastatic epithelial cells exhibited high heterogeneity in chromosomal instability (CIN) and cell population. Our findings provide a comprehensive understanding of the heterogenicity of the tumor microenvironment and tumour cells and it will be crucial for successful immunotherapy development for brain metastasis of lung cancer.

An in silico comparative transcriptome analysis identifying hub lncRNAs and mRNAs in brain metastatic small cell lung cancer (SCLC)

Small cell lung cancer (SCLC) is a particularly lethal subtype of lung cancer. Metastatic lung tumours lead to most deaths from lung cancer. Predicting and preventing tumour metastasis is crucially essential for patient survivability. Hence, in the current study, we focused on a comprehensive analysis of lung cancer patients' differentially expressed genes (DEGs) on brain metastasis cell lines. DEGs are analysed through KEGG and GO databases for the most critical biological processes and pathways for enriched DEGs. Additionally, we performed protein–protein interaction (PPI), GeneMANIA, and Kaplan–Meier survival analyses on our DEGs. This article focused on mRNA and lncRNA DEGs for LC patients with brain metastasis and underlying molecular mechanisms. The expression data was gathered from the Gene Expression Omnibus database (GSE161968). We demonstrate that 30 distinct genes are up-expressed in brain metastatic SCLC patients, and 31 genes are down-expressed. All our analyses show that these genes are involved in metastatic SCLC. PPI analysis revealed two hub genes (CAT and APP). The results of this article present three lncRNAs, Including XLOC_l2_000941, LOC100507481, and XLOC_l2_007062, also notable mRNAs, have a close relation with brain metastasis in lung cancer and may have a role in the epithelial-mesenchymal transition (EMT) in tumour cells.

Metabolic and Textural Changes in the Brain of Lung Cancer Patients: A Total-Body PET/CT Study

<h3>Purpose/Objective(s)</h3> Brain metastases are frequent complications for lung cancer patients. The aim of this paper was to explore whether there were alterations in brain glucose uptake and brain texture in lung cancer patients, as well as to investigate possible associations between brain alterations and lung cancers via the state-of-the-art total-body PET/CT. <h3>Materials/Methods</h3> Forty-four subjects including 27 healthy controls and 17 lung cancer patients were enrolled in this study. Lung cancer patients were tested for serum lung cancer markers including carcinoembryonic antigen (CEA), neuron specific enolase (NSE), pro-gastrin-releasing peptide (ProGRP), cytokeratin-19-fragment (CYFRA21-1) and squamous cell carcinoma (SCC). 2-deoxy-2-[fluorine-18] fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) images were acquired using the uEXPLORER PET/CT system. Standardized uptake value normalized by lean body mass (SUL) was calculated as indicators of brain glucose uptake. Differences in brain SUL maps between lung cancer patients and healthy controls were assessed. Correlation analysis was conducted between aberrant brain glucose uptake, SUL values of cancer lesions, and serum concentrations of lung cancer markers. In addition, we performed PET/CT radiomics to investigate whether radiomic features from the regions with aberrant glucose uptake were predictive in distinguishing lung cancer from healthy controls. Specifically, we extracted 86 radiomic features from each brain regions using an open-source python package open-source software, including the intensity features and texture features. Recursive feature elimination was used to eliminate redundant features. The selected features were used by a linear support vector machine (SVM) classifier. <h3>Results</h3> Compared with healthy controls, lung cancer patients showed increased SUL values in the right middle temporal gyrus (MTG), left brainstem, bilateral lentiform nucleus and right putamen. Correlation analysis showed that the serum level of CYFRA21-1 was negatively correlated with SUL values of the right MTG, left brainstem and right putamen. Radiomic features extracted from the above four brain regions could accurately classify lung cancer patients and healthy controls with an accuracy of 100%. Furthermore, radiomic features extracted from brain regions with aberrant glucose uptake were more predictive than radiomic features from the entire brain. <h3>Conclusion</h3> Lung cancer patients experienced altered brain glucose uptake and changes in brain textures compared with healthy controls. These alterations may reflect possible lung-brain interactions and potential brain metastasis of lung cancer.

Impact of ATM Mutations on Brain Metastasis Control and Radionecrosis in Non-Small Cell Lung Cancer Patients Undergoing SRS

<h3>Purpose/Objective(s)</h3> While Ataxia Telangectasia Mutated gene (ATM) variants have been associated with improved local control after radiation, adverse radiation events have been reported following conventional radiotherapy for extracranial tumors. It remains unknown whether ATM variants affect rates of radiation necrosis (RN) and local intracranial progression (LIP) following stereotactic radiosurgery (SRS) for brain metastases. We questioned whether pathologic ATM variants increase rates of RN and/or decrease rates of LIP following SRS for brain metastasis in non-small cell lung cancer (NSCLC) patients. <h3>Materials/Methods</h3> Patients undergoing an initial course of SRS for NSCLC brain metastases between 1/2015 and 12/2020 were retrospectively identified at our institution. RN and LIP were determined by either biopsy or multi-disciplinary serial MRI review. Cumulative incidence of RN and LIP were estimated via the Kaplan Meier method. Cox proportional hazards testing was performed for variant classification (not detected [ND] vs variant of unknown significance [VUS] or pathogenic variant [PV]). A power analysis estimated that 34 events would need to be observed to detect a >4-fold hazard ratio for event. <h3>Results</h3> 541 patients completed SRS for brain metastasis secondary to NSCLC, of which 260 completed molecular profiling. Comprehensive Genomic Profiling (CGP) was performed on cell free circulating tumor DNA (61%), primary tumor (17%), extracranial metastasis (17%), and brain tumor (18%), including ≥2 sites for 33 (13%) patients. Availability of CGP data was significantly associated with more recent year of SRS completion (2018-20, 64% vs 2015-17, 25%; p<0.001), younger age at brain metastasis diagnosis (64.8 years [IQR 57.1-72.8] vs 67.8 years [IQR 59.6-72.8]; p=0.036), no prior tobacco use (22% vs 10%; p<0.001), adenocarcinoma histology (84% vs 73%; p=0.002), and metastatic disease at initial diagnosis (73% vs 63%; p=0.017). ATM variants were identified in 36 cases (13.8%; 13 PV, 23 VUS). For all patients with CPG, RN incidence was 4.9% (95% CI 1.6 – 8.2%) at 6 months and 9.9% (95% CI 4.8 - 15.0%) at 12 months and LIP was 5.4% (95% CI 2.4 – 8.4%) at 6 months and 9.8% (5.5 – 14.1%) at 12 months. For patients with ATM variants, RN incidence was 5.3% (0.0 - 15.3%) at both 6 and 12 months, with 2 total RN events at 5.7 months and 13.9 months following SRS, respectively; LIP was 3.1% (0.0 - 9.1%) at both 6 and 12 months, with one total LIP event at 2.0 months following SRS (P=0.46 and P=0.26 for RN and LIP, respectively). <h3>Conclusion</h3> We did not detect significant differences in RN or LIP risk following SRS for NSCLC brain metastases associated with ATM variants. These results suggest that at this time, ATM status should not inform SRS use when otherwise indicated for NSCLC brain metastases. This dataset additionally allowed us to estimate the number of patients needed to detect a given magnitude of relative risk for RN or LIP associated with a given variant. These data can inform future studies as CGP data accumulate.

The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis

Brain metastases (BrMs) are a common occurrence in lung cancer with a dismal outcome. To understand the mechanism of metastasis to inform prognosis and treatment, here we analyze primary and metastasized tumor specimens from 44 non-small cell lung cancer patients by spatial RNA sequencing, affording a whole transcriptome map of metastasis resolved with morphological markers for the tumor core, tumor immune microenvironment (TIME), and tumor brain microenvironment (TBME). Our data indicate that the tumor microenvironment (TME) in the brain, including the TIME and TBME, undergoes extensive remodeling to create an immunosuppressive and fibrogenic niche for the BrMs. Specifically, the brain TME is characterized with reduced antigen presentation and B/T cell function, increased neutrophils and M2-type macrophages, immature microglia, and reactive astrocytes. Differential gene expression and network analysis identify fibrosis and immune regulation as the major functional modules disrupted in both the lung and brain TME. Besides providing systems-level insights into the mechanism of lung cancer brain metastasis, our study uncovers potential prognostic biomarkers and suggests that therapeutic strategies should be tailored to the immune and fibrosis status of the BrMs.

MR imaging profile and histopathological characteristics of tumour vasculature, cell density and proliferation rate define two distinct growth patterns of human brain metastases from lung cancer

PurposeNon-invasive prediction of the tumour of origin giving rise to brain metastases (BMs) using MRI measurements obtained in radiological routine and elucidating the biological basis by matched histopathological analysis.MethodsPreoperative MRI and histological parameters of 95 BM patients (female, 50; mean age 59.6 ± 11.5 years) suffering from different primary tumours were retrospectively analysed. MR features were assessed by region of interest (ROI) measurements of signal intensities on unenhanced T1-, T2-, diffusion-weighted imaging and apparent diffusion coefficient (ADC) normalised to an internal reference ROI. Furthermore, we assessed BM size and oedema as well as cell density, proliferation rate, microvessel density and vessel area as histopathological parameters.ResultsApplying recursive partitioning conditional inference trees, only histopathological parameters could stratify the primary tumour entities. We identified two distinct BM growth patterns depending on their proliferative status: Ki67high BMs were larger (p = 0.02), showed less peritumoural oedema (p = 0.02) and showed a trend towards higher cell density (p = 0.05). Furthermore, Ki67high BMs were associated with higher DWI signals (p = 0.03) and reduced ADC values (p = 0.004). Vessel density was strongly reduced in Ki67high BM (p < 0.001). These features differentiated between lung cancer BM entities (p ≤ 0.03 for all features) with SCLCs representing predominantly the Ki67high group, while NSCLCs rather matching with Ki67low features.ConclusionInterpretable and easy to obtain MRI features may not be sufficient to predict directly the primary tumour entity of BM but seem to have the potential to aid differentiating high- and low-proliferative BMs, such as SCLC and NSCLC.

P11.75.B Survival benefit of radiotherapy and surgery in patients with lung cancer brain metastases with poor prognosis factors

Abstract Background Radiotherapy and surgery are the standard treatments for lung cancer brain metastases (BMs). However, limitted studies focused on the treatments for patients with lung cancer BMs with poor prognosis factors. The purpose of this study was to investigate the effects of radiotherapy and surgery in patients with lung cancer BMs with poor prognosis factors, providing reference for clinical strategies. Material and Methods We analyzed retrospectively 714 patients with lung cancer BMs. A 1:1 propensity score matching (PSM) was performed to balance potential confounders. Analyses of overall survival (OS) and risk factors for OS were assessed by log-rank test and Cox proportional hazard model. Results Age ≥65 years, Karnofsky Performance Scale (KPS) score ≤70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, extracranial metastases, non-surgery and non-radiotherapy led to poor prognosis. Patients were stratified according to these factors. Radiotherapy and surgery showed no survival benefit in patients with aged ≥65 years or pretreatment KPS score ≤70 before and after PSM. Before PSM, whole brain radiotherapy (WBRT) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or extracranial metastases. WBRT also predicted good prognosis in patients with non-surgery. Stereotactic radiosurgery (SRS) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with extracranial metastases or non-surgery. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS and predicted good prognosis in patients with non-radiotherapy. After PSM, SRS improved the OS and predicted good prognosis in patients with non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with non-surgery or extracranial metastases. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS of patients with non-radiotherapy. We defined that the treatment would provide significant survival benefit if it both prolonged the OS and predicted good prognosis. Meanwhile, the results after PSM were more convincing than the results before PSM. Conclusion Radiotherapy has significant survival benefit in patients with lung cancer BMs with poor prognosis factors, including patients with ALK/EGFR wild type or extracranial metastases or non-surgery. Surgery only has significant survival benefit in patients with non-radiotherapy.

P01.02.B Case Report: Disruption of Resting-State Networks and Cognitive Deficits After Whole Brain Irradiation for Singular Brain Metastasis

Abstract Background Long-term survivors of whole brain radiation (WBRT) are at significant risk for developing cognitive deficits, but knowledge about the underlying pathophysiological mechanisms is limited. Therefore, we here report a rare case with a singular brain metastasis treated by resection and WBRT that survived for more than 10 years where we investigated the integrity of brain networks using resting-state functional MRI. Material and Methods A female patient with a left frontal non-small cell lung cancer (NSCLC) brain metastasis had resection and postoperative WBRT (30.0 in 3.0Gy fractions) and stayed free from brain metastasis recurrence for a follow-up period of 11 years. Structural magnetic resonance imaging (MRI) and amino acid [O-(2-[18F]fluoroethyl)-L-tyrosine] positron emission tomography (FET PET) were repeatedly acquired. At the last follow up, neurocognitive functions and resting-state functional connectivity (RSFC) using resting-state fMRI were assessed. Within-network and inter-network connectivity of seven resting-state networks were computed from a connectivity matrix. All measures were compared to a matched group of 10 female healthy subjects. Results At the 11-year follow-up, T2/FLAIR MR images of the patient showed extended regions of hyper-intensities covering mainly the white matter of the bilateral dorsal frontal and parietal lobes while sparing most of the temporal lobes. Compared to the healthy subjects, the patient performed significantly worse in all cognitive domains that included executive functions, attention and processing speed, while verbal working memory, verbal episodic memory, and visual working memory were left mostly unaffected. The connectivity matrix showed a heavily disturbed pattern with a widely distributed, scattered loss of RSFC. The within-network RSFC revealed a significant loss of connectivity within all seven networks where the dorsal attention and fronto-parietal control networks were affected most severely. The inter-network RSFC was significantly reduced for the visual, somato-motor, and dorsal and ventral attention networks. Conclusion As demonstrated here in a patient with a metastatic NSCLC and long-term survival, WBRT may lead to extended white matter damage and cause severe disruption of the RSFC in multiple resting state networks. In consequence, executive functioning which is assumed to depend on the interaction of several networks may be severely impaired following WBRT apart from the well-recognized deficits in memory function.

Role of apparent diffusion coefficient measurement in differentiating histological subtypes of brain metastasis of lung cancer

SUMMARYOBJECTIVE:The aim of this study was to investigate the role of apparent diffusion coefficient of diffusion-weighted imaging in differentiating histological subtypes of brain metastasis of lung cancer.METHODS:Diffusion-weighted imaging of 158 patients (mean age: 61.2±10.68 years) with brain metastasis of lung cancer (36 small cell lung cancer and 122 non-small cell lung cancer) were retrospectively evaluated. The minimum and mean apparent diffusion coefficient values of the metastasis, apparent diffusion coefficient of edema around the metastasis, and apparent diffusion coefficient of contralateral brain parenchyma were measured. Normalized apparent diffusion coefficient was calculated by proportioning the mean apparent diffusion coefficient of the metastasis to the apparent diffusion coefficient of the contralateral brain parenchyma. Minimum and mean apparent diffusion coefficient of the metastasis, apparent diffusion coefficient of edema around metastasis, and normalized apparent diffusion coefficient were compared between small cell lung cancer and non-small cell lung cancer metastases.RESULTS:Minimum apparent diffusion coefficient, mean apparent diffusion coefficient, and normalized apparent diffusion coefficient values of small cell lung cancer metastases (0.43±0.19×10−3mm2/s, 0.63±0.20×10−3mm2/s, and 0.81 [0.55–1.44], respectively) were significantly lower than those of non-small cell lung cancer metastases (0.71±0.26×10−3mm2/s, 0.93±0.29×10−3mm2/s, and 1.30 [0.60–3.20], respectively; p<0.001). Mean apparent diffusion coefficient of edema of small cell lung cancer metastases (1.21±0.28×10−3mm2/s) was significantly lower than that of non-small cell lung cancer metastases (1.39±0.26×10−3mm2/s, p=0.020). The best cutoff values of minimum apparent diffusion coefficient, mean apparent diffusion coefficient, normalized apparent diffusion coefficient, and apparent diffusion coefficient of edema for the differentiation of small cell lung cancer and non-small cell lung cancer were found to be 0.56×10−3mm2/s, 0.82×10−3mm2/s, 1.085, and 1.21×10−3mm2/s, respectively. The area under the receiver operating characteristic curve, sensitivity, and specificity values were, respectively, 0.812, 80.6, and 73.8% for minimum apparent diffusion coefficient; 0.825, 91.7, and 61.5% for mean apparent diffusion coefficient; 0.845, 80.6, and 73.8% for normalized apparent diffusion coefficient; and 0.698, 75.0, and 67.7% for apparent diffusion coefficient of edema.CONCLUSIONS:Minimum apparent diffusion coefficient, mean apparent diffusion coefficient, normalized apparent diffusion coefficient, and apparent diffusion coefficient of edema around metastasis can differentiate histological subtypes of brain metastasis of lung cancer.