Platelet inhibition delays cerebral metastasis in non-small cell lung cancer

Platelet inhibition delays cerebral metastasis in non-small cell 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 Platelet inhibition delays cerebral metastasis in non-small cell lung cancer David Wasilewski, Julia Onken, Sae-Yeon Won, Artem Rafaelian, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6194346/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 Purpose: An inverse association between the use of platelet inhibitors and the risk of cancer has been reported by numerous epidemiological studies in the past. The effects of antiplatelet agents on the cerebral metastasis formation of non-small cell lung cancer (NSCLC) are largely unknown. We therefore, investigated the effect of platelet inhibition in NSCLC patients at the time of the first diagnosis of cerebral metastases. Methods: We investigated the clinical course of 417 NSCLC patients with cerebral metastases who underwent craniotomy for metastasis resection during the course of their disease. The presence of platelet inhibition prior to cerebral metastases diagnosis was used to dichotomize the cohort. Relevant clinical parameters, including time to cerebral metastasis formation, overall survival, and the incidence of intracranial hemorrhage or hemorrhagic transformation of metastases, were compared between the two groups Results: The presence of platelet inhibitor intake significantly prolonged time to cerebral metastasis in non-small cell lung cancer 63 vs. 47 months; (p = 0.001). Furthermore, platelet inhibitor intake was also associated with an increased overall survival of 12 vs. 10 months (p=0.02). Statistically, no increased risk of hemorrhagic transformation of the metastasis or intracranial hemorrhage was found (p= 0.635 and p=1.000), respectively. Conclusion: While the use of platelet inhibitors did not show an increased risk of intracranial hemorrhage, the use of platelet inhibitors resulted in delayed cerebral metastasis and better survival in NSCLC patients. Aspirin platelet function cerebral metastases survival analysis cerebral metastasis prevention Figures Figure 1 Introduction Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancer cases, and approximately 65% of patients present with locally advanced or metastatic disease at the time of diagnosis.[1, 2] Among those, approximately 20% will have cerebral metastases at presentation and around 30% will develop cerebral metastases during the course of their disease. The pathomechanism of how NSCLC cerebral metastasis occurs and what influences the timing is currently undetermined.[3] NSCLC cells were shown to induce platelet activation and aggregation leading to a coating process that protects circulating tumor cells from harmful effects of shear forces, shields tumor cells from the immune system, and provides growth factors. [4, 5] More specificallys, platelets have been found to promote tumor cell growth and metastasis by secreting multiple growth factors and inducing an epithelial-mesenchymal-like transition (EMT) and evade the immune surveillance by impairing NK cell cytotoxicity and inhibiting T cell immunity.[6] Platelet inhibition on the other hand has gained momentum because of its potential anti-cancer effects supported by both in vitro and in vivo studies. Observational epidemiologic studies showed that aspirin, a nonselective cyclooxygenase (COX) inhibitor, commonly used in patients with cardiovascular disease prolongs survival in various cancers including NSCLC.[7] The primary objective of this study is to investigate whether platelet inhibition can delay the onset of cerebral metastasis in NSCLC patients. Methods Patient selection All patients who underwent surgical resection for brain metastasis at the neurosurgical department at the University Hospital Rostock and Charité-Universitätsmedizin Berlin between 2016 and 2022 were eligible to be included in the analysis. Indication for craniotomy were neurological deficit, metastasis size unsuitable for radiotherapy and tumor size >3cm in diameter. The indication for surgical treatment was confirmed in advance at an interdisciplinary tumour conference for all cases. 417 patients were included in the study. Patient characteristics and medical data were collected via the institution’s electronic database. For this retrospective analysis, ethical approval was obtained from the Ethics Committee of the University Medicine Rostock, Germany (Identification number: A 2021-0112); as a non-interventional bicentric, retrospective study, patient consent was waived. Clinical and radiological data Patient medical charts were analysed by two neurosurgeons (D.W. and A.R.). Metastasis and edema volume were analysed by semi-automatic segmentation with IPlannet 3 (Cranial planning software, Brainlab AG, Feldkirchen, Germany). All metastasis segmentation was done semi-automatically with the ‘Smartbrush’ tool of the Brainlab Elements software. A two-dimensional segmentation was drawn in the axial image and a second two-dimensional segmentation was drawn in a coronal slide. These two segmentations automatically generated a three-dimensional graphic of the tumor. The three-dimensional graphic was then manually corrected by adding or erasing certain areas. Platelet inhibitors included Acetylsalicylic acid (Aspirinâ), Clopidogrel (Plavixâ), Prasugrel (Effientâ), Ticagrelor (Brilintaâ) und Cangrelor (Kengrealâ). Intracranial hemorrhage was defined as ≥ 10 ml in volume, required surgical intervention, or was associated with clinical symptoms, such as nausea and vomiting, or focal neurologic deficit. To estimate the survival rates and cerebral metastasis rates, the Kaplan-Meier analysis was used. The differences between curves were assessed using the log-rank test. Time to cerebral metastasis was defined as the time from NSCLC diagnosis to first neurosurgical intervention for metastasis resection. Overall survival (OS) was defined as the time of first presentation to death. Statistics Kaplan–Meier survival curve analysis and the log-rank test were conducted to obtain the median OS of the groups. Univariate and multivariate analyses were performed using a Cox proportional regression model. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Visualization was performed with Biorender. Multivariate analysis was performed on variates with p values < 0.2, and p values < 0.05 were considered to indicate statistical significance. All statistical analyses were conducted using the GraphPad Prism 10 (GraphPad Software, California, USA). For patient characteristics, descriptive statistics were used. Results Cohort characteristics The study group consisted of 417 patients, the average age was 64.4 years old (IQR 53–81) and 176 (42%) of the patients were female. Medical record of platelet inhibition showed a total of 74 patients (42%) cases. Singular cerebral metastasis was seen in 357 cases (85%) and multiple cerebral metastasis in 60 (15%) accordingly. The median volume of cerebral metastasis was 12 ml (IQR 8–15)) and 67.1 (IQR 57–73) for median volume of perilesional edema. Hydrocephalus was seen in 24 patients (6%). Hemorrhagic metastasis transformation was recorded for 87 patients (21%) and intracranial hemorrhage for 7 patients (2%). The median Karnofsky performance status (KPS) was 80 (IQR 70–90) and median Graded Prognostic Assessment (GPA) 2 (IQR 1–3). Table 1 . Table 1 Clinical features of NSCLC patients at the time of diagnosis of cerebral metastases. GPD: Graded Prognostic Assessment, KPS: Karnofsky performance status scale. Patient characteristics ( n = 417) Female, n (%) 176 (42) Age, median (IQR) 64.9 (53–81) Platelet inhibitor yes, n (%) 74 (18) Singular cerebral metastasis, n (%) 357 (85) Multiple cerebral metastasis, n (%) 60 (15) Volume of cerebral metastasis in ml, median (IQR) 12 (8–15) Volume of perilesional edema in ml, median (IQR) 67.1 (57–73) Hydrocephalus, n (%) 24 (6) Hemorrhagic transformation, n (%) 87 (21) Intracranial hemorrhage, n (%) 7 (2) KPS, median (IQR) 80 (70–90) GPA, median (IQR) 2 (1–3) Time to cerebral metastasis in months, median 55 Overall survival in months, median 11.5 Table 2 Univariate analysis of juxtaposed characteristics according to platelet inhibitor intake in NSCLC patients at the time of cerebral metastases diagnosis. Abbreviations: OR: odds ratio, IQR: interquartile range, GPD: Graded Prognostic Assessment, KPS: Karnofsky performance status scale. Patient characteristics (n = 417) platelet inhibitor (n = 74) no platelet inhibitor (n = 343) Univariable OR 95% CI p-Value Female, n (%) 26 (6,2) 150 (36) 0.6 0.41–1.17 0.195 Age, median (IQR) 65.4 (10.9) 64.5 (10.7) 1.80–3.60 0.513 Singular cerebral metastasis, n (%) 63 (85) 294 (86) 0.9 0.47–1.93 1 Multiple cerebral metastasis, n (%) 11 (15) 49 (14) 1.0 0.51–2.12 1 Volume of cerebral metastasis in ml, median(IQR) 12 (21.2) 12.1 (19.9) 4.97–5.17 0.969 Volume of perilesional edema in ml, median (IQR) 65.7 (60.2) 67.7 (61.3) 14.74–18.74 0.814 Hydrocephalus, n (%) 13 (17) 33 (10) 2.0 0.99–4.02 0.061 Hemorrhagic transformation, n (%) 20 (27) 84 (24.5) 1.1 0.64–2.01 0.635 Intracranial hemorrhage, n (%) 1 (1) 6 (2) 0.7 0.09–6.48 1 Median KPS (SD) 80 (15.4) 80 (14.8) 3.75–3.75 1 Median GPA (SD) 2 (0.8) 2 (0.8) 0.30–0.30 1 Time to cerebral metastasis in months, median 63 47 1.3 1.01–1.75 0.001 Overall survival in months, median 12 10 1.2 0.82–1.46 0.020 The univariate analysis showed no significant association between patients’ sex or age and platelet inhibitor intake, p = 0.195 and 0.513 respectively. The presence of a singular or multiple cerebral metastasis was also non-significant, p = 1 and 1.000 respectively. The volumetric analysis of metastasis and its perilesional edema showed no significant association with platelet inhibitor intake (p = 0.969 and 0.814). The presence of a hydrocephalus was borderline non-significant according to platelet inhibitor intake (p = 0.061). Neither the hemorrhagic transformation nor the hemorrhage were statistically significant p = 0.635 and 1.000 respectively. The median KPS was 80 in both the platelet inhibitor cohort and also 80 in patients without platelet inhibitor intake. Furthermore, time to cerebral metastasis showed a strong association with platelet inhibitor intake with 63 months for intake and 47 months for patients without platelet inhibition, p = 0.001. In addition, patients with platelet inhibition had an overall survival of 12 months in comparison to 10 months (95% CI 0.82–1.46) in patients without platelet inhibition which was also statistically significant, p = 0.020. Table 2 and Fig. 1 . A multivariate analysis confirmed the non-significance of the above analysed parameters. Discussion This study investigated the retrospective effect of the use of platelet inhibitors on the occurrence of cerebral metastases and the risk of intracerebral hemorrhage complications in patients with NSCLC. The most important finding of our study was a significant association between platelet inhibition and the delayed onset of cerebral metastases as well as prolonged survival. The clinically significant effect of delayed onset of cerebral metastases in NSCLC is intriguing and the underlying mechanisms are complex. A prerequisite for cerebral metastasis formation is the disruption of the blood-brain-barrier (BBB). The tight junction complex of the BBB is composed of different junctional molecules, including occludin, claudins, and junctional adhesion molecules. [8] Recently, Wei et al., demonstrated their basic research analysis where aspirin was shown to upregulate the expression of tight junction proteins via the TNF-α/HSP70 signaling pathway in a time-dependent manner.[9] This mechanism could in part explain the phenomena observed in our study and aligns with our hypothesis. In addition, several studies confirmed that coculturing NSCLC cells with human platelets led to the induction of mesenchymal-like cancer cells characterized by downregulation of adhesion proteins, that enhanced cell mobility and a pro aggregatory action on platelets.[9] This effect leads to a coating process that protects circulating tumor cells from the deleterious effects of shear forces.[10, 11] Therefore, platelet inhibition hypothetically prevents this effect supporting the observed delayed cerebral metastasis formation in our cohort. Another mechanism that may explain the improved overall survival in our cohort, could be the direct anti-tumor effectiveness of platelet inhibitors. Several epidemiologic studies have reported an inverse association between aspirin use and the risk of cancer.[12] The anti-neoplastic effect of platelet inhibitors includes the inhibition of COX enzymes that promote carcinogenesis through the synthesis of prostaglandins.[13] Platelet inhibitors have also been shown to upregulate tumor-suppression genes and inhibit NF-kB activation, thus illustrating its anti-cancer activities in a COX independent pathway.[14] On the other hand, mounting preclinical evidence suggests, that platelet inhibitors may exhibit anti-neoplastic effects by inducing apoptosis suppressing angiogenesis, and inhibiting the proliferation of tumor cells.[15–17] Another clinically relevant finding is the that the use of platelet inhibitors in patients with NSCLC did not cause increased intracranial hemorrhage or hemorrhagic metastasis transformation. This result suggests that the use of platelet inhibitors is safe in patients with NSCLC. This finding is consistent with a recent analysis of Miller et al., where the use of antiplatelet agents was not associated with an increase in the incidence, size, or severity of intracranial hemorrhage in the setting of cerebral metastases.[18, 19] Although not the subject of this study, we must assume that the use of antiplatelets had an underlying cardiovascular indication and that survival was nevertheless better in NSCLC patients with platelet inhibitors. This means that the use of platelet inhibitors in patients with NSCLC can have a positive effect on the prognosis, even if the patients already have a poorer state of health. A prospective study with intake of platelet inhibitors in NSCLC patients without an underlying medical indication could clarify the effect. While our analysis demonstrates the benefits of platelet inhibition in a sizable cohort of NSCLC patients, our study faces some limitations. The retrospective analysis prohibited the evaluation of prospective aspects of this effect. Furthermore, as this was a retrospective observational study, confounding, selection bias, and uncontrolled statistical error risk cannot be excluded. Hence, further prospective randomized trials with large cohorts must validate our findings. Conclusions Our study shows that the use of platelet inhibitors in patients with NSCLC is associated with a delay in the formation of cerebral metastases and improved overall survival, without a relevant risk of bleeding. Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contributions Daniel Dubinski, David Wasilewski and Florian Gessler had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the University Medicine Rostock, Germany (Identification number: A 2021-0112); References Kahraman S, Karakaya S, Kaplan MA, et al (2024) Treatment outcomes and prognostic factors in patients with driver mutant non-small cell lung cancer and de novo brain metastases. Sci Reports 2024 141 14:1–13. https://doi.org/10.1038/s41598-024-56046-w Wang H, Ou Q, Li D, et al (2019) Genes associated with increased brain metastasis risk in non-small cell lung cancer: Comprehensive genomic profiling of 61 resected brain metastases versus primary non-small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036). Cancer 125:3535–3544. https://doi.org/10.1002/cncr.32372 Singh R, Stoltzfus KC, Chen H, et al (2020) Epidemiology of synchronous brain metastases. Neuro-oncology Adv 2:vdaa041. https://doi.org/10.1093/NOAJNL/VDAA041 Hinterleitner C, Strähle J, Malenke E, et al (2021) Platelet PD-L1 reflects collective intratumoral PD-L1 expression and predicts immunotherapy response in non-small cell lung cancer. Nat Commun 2021 121 12:1–16. https://doi.org/10.1038/s41467-021-27303-7 Li S, Lu Z, Wu S, et al (2023) The dynamic role of platelets in cancer progression and their therapeutic implications. Nat Rev Cancer 2023 241 24:72–87. https://doi.org/10.1038/s41568-023-00639-6 Hu X, Wu LW, Weng XU, et al (2018) Synergistic antitumor activity of aspirin and erlotinib: Inhibition of p38 enhanced aspirin plus erlotinib-induced suppression of metastasis and promoted cancer cell apoptosis. Oncol Lett 16:2715. https://doi.org/10.3892/OL.2018.8956 Chuang MC, Yang YH, Hsieh MJ, et al (2021) The association of aspirin use with overall survival of patients with inoperable non-small cell lung cancer: a retrospective study. BMC Cancer 21:1257. https://doi.org/10.1186/S12885-021-08999-8 Blanchette M, Daneman R (2015) Formation and maintenance of the BBB. Mech Dev 138:8–16. https://doi.org/10.1016/j.mod.2015.07.007 Wei D, Tang M, Gong W, et al (2023) Aspirin Inhibits Brain Metastasis of Lung Cancer via Upregulation of Tight Junction Protein Expression in Microvascular Endothelial Cells. Front Biosci (Landmark Ed 28:. https://doi.org/10.31083/J.FBL2811320 Del Zoppo GJ, Gu YH (2021) Hemostasis and cerebral metastases in a model system. Blood 137:1139–1140. https://doi.org/10.1182/blood.2020010130 Feinauer MJ, Schneider SW, Berghoff AS, et al (2021) Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model. Blood 137:1219–1232. https://doi.org/10.1182/BLOOD.2020005710 Chubak J, Whitlock EP, Williams SB, et al (2016) Aspirin for the prevention of cancer incidence and mortality: Systematic evidence reviews for the U.S. preventive services task force. Ann Intern Med 164:814–825. https://doi.org/10.7326/M15-2117 Chan AT, Ogino S, Fuchs CS (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356:2131–2142. https://doi.org/10.1056/NEJMOA067208 Khuder SA, Herial NA, Mutgi AB, Federman DJ (2005) Nonsteroidal antiinflammatory drug use and lung cancer: a metaanalysis. Chest 127:748–754. https://doi.org/10.1378/CHEST.127.3.748 Kaduševičius E (2021) Novel applications of nsaids: Insight and future perspectives in cardiovascular, neurodegenerative, diabetes and cancer disease therapy. Int J Mol Sci 22:. https://doi.org/10.3390/ijms22126637 Kashfi K, Rigas B (2005) Non-COX-2 targets and cancer: expanding the molecular target repertoire of chemoprevention. Biochem Pharmacol 70:969–986. https://doi.org/10.1016/J.BCP.2005.05.004 Kolawole OR, Kashfi K (2022) NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase. Int J Mol Sci 23:. https://doi.org/10.3390/ijms23031432 Miller EJ, Patell R, Uhlmann EJ, et al (2022) Antiplatelet medications and risk of intracranial hemorrhage in patients with metastatic brain tumors. Blood Adv 6:1559–1565. https://doi.org/10.1182/BLOODADVANCES.2021006470 Antiplatelet medications and risk of intracranial hemorrhage in patients with metastatic brain tumors - PubMed. https://pubmed.ncbi.nlm.nih.gov/35086145/. Accessed 18 Nov 2024 Additional Declarations No competing interests reported. Supplementary Files VisualAbstract.png Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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The pathomechanism of how NSCLC cerebral metastasis occurs and what influences the timing is currently undetermined.[3]\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNSCLC cells were shown to induce platelet activation and aggregation leading to a coating process that protects circulating tumor cells from harmful effects of shear forces, shields tumor cells from the immune system, and provides growth factors. [4, 5] More specificallys, platelets have been found to promote tumor cell growth and metastasis by secreting multiple growth factors and inducing an epithelial-mesenchymal-like transition (EMT) and evade the immune surveillance by impairing NK cell cytotoxicity and inhibiting T cell immunity.[6]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePlatelet inhibition on the other hand \u0026nbsp; has \u0026nbsp;gained \u0026nbsp; momentum \u0026nbsp; \u0026nbsp;because \u0026nbsp; of \u0026nbsp; its \u0026nbsp; \u0026nbsp;potential \u0026nbsp; anti-cancer \u0026nbsp;effects supported \u0026nbsp;by both \u0026nbsp; in \u0026nbsp;vitro \u0026nbsp;and \u0026nbsp; in \u0026nbsp;vivo studies. Observational epidemiologic studies showed that aspirin, a nonselective cyclooxygenase (COX) inhibitor, commonly used in patients with cardiovascular disease prolongs survival in various cancers including NSCLC.[7]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe primary objective of this study is to investigate whether platelet inhibition can delay the onset of cerebral metastasis in NSCLC patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003ePatient selection\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patients who underwent surgical resection for brain metastasis at the neurosurgical department at the University Hospital Rostock and\u0026nbsp;Charit\u0026eacute;-Universit\u0026auml;tsmedizin Berlin\u0026nbsp; between 2016 and 2022 \u0026nbsp;were eligible to be included in the analysis. \u0026nbsp;Indication for craniotomy were neurological deficit, metastasis size unsuitable for radiotherapy and tumor size \u0026gt;3cm in diameter. The indication for surgical treatment was confirmed in advance at an interdisciplinary tumour conference for all cases. 417 patients were included in the study. Patient characteristics and medical data were collected via the institution\u0026rsquo;s electronic database. For this retrospective analysis, ethical approval was obtained from the Ethics Committee of the University Medicine Rostock, Germany (Identification number: A 2021-0112); as a non-interventional bicentric, retrospective study, patient consent was waived.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClinical and radiological data\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatient medical charts were analysed by two neurosurgeons (D.W. and A.R.). Metastasis and edema volume were analysed by semi-automatic segmentation with IPlannet 3 (Cranial planning software, Brainlab AG, Feldkirchen, Germany). All metastasis segmentation was done semi-automatically with the \u0026lsquo;Smartbrush\u0026rsquo; tool of the Brainlab Elements software. A two-dimensional segmentation was drawn in the axial image and a second two-dimensional segmentation was drawn in a coronal slide. These two segmentations automatically generated a three-dimensional graphic of the tumor. The three-dimensional graphic was then manually corrected by adding or erasing certain areas. Platelet inhibitors included Acetylsalicylic acid (Aspirin\u0026acirc;), Clopidogrel (Plavix\u0026acirc;), Prasugrel (Effient\u0026acirc;), Ticagrelor (Brilinta\u0026acirc;) und Cangrelor (Kengreal\u0026acirc;). Intracranial hemorrhage was defined as \u0026ge; 10 ml in volume, required surgical intervention, or was associated with clinical symptoms, such as nausea and vomiting, or focal neurologic deficit.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo estimate the survival rates and cerebral metastasis rates, the Kaplan-Meier analysis was used. The differences between curves were assessed using the log-rank test. Time to cerebral metastasis was defined as the time from NSCLC diagnosis to first neurosurgical intervention for metastasis resection. \u0026nbsp;Overall survival (OS) was defined as the time of first presentation to death.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatistics\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eKaplan\u0026ndash;Meier survival curve analysis and the log-rank test were conducted to obtain the median OS of the groups. Univariate and multivariate analyses were performed using a Cox proportional regression model. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Visualization was performed with Biorender. Multivariate analysis was performed on variates with \u003cem\u003ep\u0026nbsp;\u003c/em\u003evalues \u0026lt; 0.2, and \u003cem\u003ep\u0026nbsp;\u003c/em\u003evalues \u0026lt; 0.05 were considered to indicate statistical significance. All statistical analyses were conducted using the GraphPad Prism 10 (GraphPad Software, California, USA). For patient characteristics, descriptive statistics were used.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eCohort characteristics\u003c/p\u003e \u003cp\u003eThe study group consisted of 417 patients, the average age was 64.4 years old (IQR 53\u0026ndash;81) and 176 (42%) of the patients were female. Medical record of platelet inhibition showed a total of 74 patients (42%) cases. Singular cerebral metastasis was seen in 357 cases (85%) and multiple cerebral metastasis in 60 (15%) accordingly. The median volume of cerebral metastasis was 12 ml (IQR 8\u0026ndash;15)) and 67.1 (IQR 57\u0026ndash;73) for median volume of perilesional edema. Hydrocephalus was seen in 24 patients (6%). Hemorrhagic metastasis transformation was recorded for 87 patients (21%) and intracranial hemorrhage for 7 patients (2%). The median Karnofsky performance status (KPS) was 80 (IQR 70\u0026ndash;90) and median Graded Prognostic Assessment (GPA) 2 (IQR 1\u0026ndash;3). Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical features of NSCLC patients at the time of diagnosis of cerebral metastases. GPD: Graded Prognostic Assessment, KPS: Karnofsky performance status scale.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;417)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176 (42)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.9 (53\u0026ndash;81)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet inhibitor yes, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (18)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingular cerebral metastasis, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e357 (85)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple cerebral metastasis, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVolume of cerebral metastasis in ml, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (8\u0026ndash;15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVolume of perilesional edema in ml, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.1 (57\u0026ndash;73)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHydrocephalus, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemorrhagic transformation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87 (21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntracranial hemorrhage, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKPS, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (70\u0026ndash;90)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGPA, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to cerebral metastasis in months, median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival in months, median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate analysis of juxtaposed characteristics according to platelet inhibitor intake in NSCLC patients at the time of cerebral metastases diagnosis. Abbreviations: OR: odds ratio, IQR: interquartile range, GPD: Graded Prognostic Assessment, KPS: Karnofsky performance status scale.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePatient characteristics (n\u0026thinsp;=\u0026thinsp;417)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eplatelet inhibitor (n\u0026thinsp;=\u0026thinsp;74)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eno platelet inhibitor (n\u0026thinsp;=\u0026thinsp;343)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eUnivariable\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (6,2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e150 (36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.41\u0026ndash;1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.195\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.4 (10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.5 (10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.80\u0026ndash;3.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.513\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingular cerebral metastasis, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e294 (86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.47\u0026ndash;1.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple cerebral metastasis, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.51\u0026ndash;2.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVolume of cerebral metastasis in ml, median(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (21.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.1 (19.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.97\u0026ndash;5.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.969\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVolume of perilesional edema in ml, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.7 (60.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67.7 (61.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e14.74\u0026ndash;18.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.814\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHydrocephalus, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.99\u0026ndash;4.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemorrhagic transformation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e84 (24.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.64\u0026ndash;2.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.635\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntracranial hemorrhage, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.09\u0026ndash;6.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian KPS (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80 (14.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.75\u0026ndash;3.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian GPA (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.30\u0026ndash;0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to cerebral metastasis in months, median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.01\u0026ndash;1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival in months, median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.82\u0026ndash;1.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.020\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe univariate analysis showed no significant association between patients\u0026rsquo; sex or age and platelet inhibitor intake, p\u0026thinsp;=\u0026thinsp;0.195 and 0.513 respectively. The presence of a singular or multiple cerebral metastasis was also non-significant, p\u0026thinsp;=\u0026thinsp;1 and 1.000 respectively. The volumetric analysis of metastasis and its perilesional edema showed no significant association with platelet inhibitor intake (p\u0026thinsp;=\u0026thinsp;0.969 and 0.814). The presence of a hydrocephalus was borderline non-significant according to platelet inhibitor intake (p\u0026thinsp;=\u0026thinsp;0.061). Neither the hemorrhagic transformation nor the hemorrhage were statistically significant p\u0026thinsp;=\u0026thinsp;0.635 and 1.000 respectively. The median KPS was 80 in both the platelet inhibitor cohort and also 80 in patients without platelet inhibitor intake. Furthermore, time to cerebral metastasis showed a strong association with platelet inhibitor intake with 63 months for intake and 47 months for patients without platelet inhibition, p\u0026thinsp;=\u0026thinsp;0.001. In addition, patients with platelet inhibition had an overall survival of 12 months in comparison to 10 months (95% CI 0.82\u0026ndash;1.46) in patients without platelet inhibition which was also statistically significant, p\u0026thinsp;=\u0026thinsp;0.020. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. A multivariate analysis confirmed the non-significance of the above analysed parameters.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study investigated the retrospective effect of the use of platelet inhibitors on the occurrence of cerebral metastases and the risk of intracerebral hemorrhage complications in patients with NSCLC. The most important finding of our study was a significant association between platelet inhibition and the delayed onset of cerebral metastases as well as prolonged survival.\u003c/p\u003e \u003cp\u003eThe clinically significant effect of delayed onset of cerebral metastases in NSCLC is intriguing and the underlying mechanisms are complex. A prerequisite for cerebral metastasis formation is the disruption of the blood-brain-barrier (BBB). The tight junction complex of the BBB is composed of different junctional molecules, including occludin, claudins, and junctional adhesion molecules. [8] Recently, Wei et al., demonstrated their basic research analysis where aspirin was shown to upregulate the expression of tight junction proteins via the TNF-α/HSP70 signaling pathway in a time-dependent manner.[9] This mechanism could in part explain the phenomena observed in our study and aligns with our hypothesis.\u003c/p\u003e \u003cp\u003eIn addition, several studies confirmed that coculturing NSCLC cells with human platelets led to the induction of mesenchymal-like cancer cells characterized by downregulation of adhesion proteins, that enhanced cell mobility and a pro aggregatory action on platelets.[9] This effect leads to a coating process that protects circulating tumor cells from the deleterious effects of shear forces.[10, 11] Therefore, platelet inhibition hypothetically prevents this effect supporting the observed delayed cerebral metastasis formation in our cohort.\u003c/p\u003e \u003cp\u003eAnother mechanism that may explain the improved overall survival in our cohort, could be the direct anti-tumor effectiveness of platelet inhibitors. Several epidemiologic studies have reported an inverse association between aspirin use and the risk of cancer.[12] The anti-neoplastic effect of platelet inhibitors includes the inhibition of COX enzymes that promote carcinogenesis through the synthesis of prostaglandins.[13] Platelet inhibitors have also been shown to upregulate tumor-suppression genes and inhibit NF-kB activation, thus illustrating its anti-cancer activities in a COX independent pathway.[14] On the other hand, mounting preclinical evidence suggests, that platelet inhibitors may exhibit anti-neoplastic effects by inducing apoptosis suppressing angiogenesis, and inhibiting the proliferation of tumor cells.[15\u0026ndash;17]\u003c/p\u003e \u003cp\u003eAnother clinically relevant finding is the that the use of platelet inhibitors in patients with NSCLC did not cause increased intracranial hemorrhage or hemorrhagic metastasis transformation. This result suggests that the use of platelet inhibitors is safe in patients with NSCLC. This finding is consistent with a recent analysis of Miller et al., where the use of antiplatelet agents was not associated with an increase in the incidence, size, or severity of intracranial hemorrhage in the setting of cerebral metastases.[18, 19]\u003c/p\u003e \u003cp\u003eAlthough not the subject of this study, we must assume that the use of antiplatelets had an underlying cardiovascular indication and that survival was nevertheless better in NSCLC patients with platelet inhibitors. This means that the use of platelet inhibitors in patients with NSCLC can have a positive effect on the prognosis, even if the patients already have a poorer state of health. A prospective study with intake of platelet inhibitors in NSCLC patients without an underlying medical indication could clarify the effect.\u003c/p\u003e \u003cp\u003eWhile our analysis demonstrates the benefits of platelet inhibition in a sizable cohort of NSCLC patients, our study faces some limitations. The retrospective analysis prohibited the evaluation of prospective aspects of this effect. Furthermore, as this was a retrospective observational study, confounding, selection bias, and uncontrolled statistical error risk cannot be excluded. Hence, further prospective randomized trials with large cohorts must validate our findings.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur study shows that the use of platelet inhibitors in patients with NSCLC is associated with a delay in the formation of cerebral metastases and improved overall survival, without a relevant risk of bleeding.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003eCompeting Interests\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eDaniel Dubinski, David Wasilewski and Florian Gessler had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.\u003c/p\u003e\n\u003cp\u003eData Availability\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request\u003c/p\u003e\n\u003cp\u003eEthics approval\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the University Medicine Rostock, Germany (Identification number: A 2021-0112);\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKahraman S, Karakaya S, Kaplan MA, et al (2024) Treatment outcomes and prognostic factors in patients with driver mutant non-small cell lung cancer and de novo brain metastases. Sci Reports 2024 141 14:1\u0026ndash;13. https://doi.org/10.1038/s41598-024-56046-w\u003c/li\u003e\n\u003cli\u003eWang H, Ou Q, Li D, et al (2019) Genes associated with increased brain metastasis risk in non-small cell lung cancer: Comprehensive genomic profiling of 61 resected brain metastases versus primary non-small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036). Cancer 125:3535\u0026ndash;3544. https://doi.org/10.1002/cncr.32372\u003c/li\u003e\n\u003cli\u003eSingh R, Stoltzfus KC, Chen H, et al (2020) Epidemiology of synchronous brain metastases. Neuro-oncology Adv 2:vdaa041. https://doi.org/10.1093/NOAJNL/VDAA041\u003c/li\u003e\n\u003cli\u003eHinterleitner C, Str\u0026auml;hle J, Malenke E, et al (2021) Platelet PD-L1 reflects collective intratumoral PD-L1 expression and predicts immunotherapy response in non-small cell lung cancer. Nat Commun 2021 121 12:1\u0026ndash;16. https://doi.org/10.1038/s41467-021-27303-7\u003c/li\u003e\n\u003cli\u003eLi S, Lu Z, Wu S, et al (2023) The dynamic role of platelets in cancer progression and their therapeutic implications. Nat Rev Cancer 2023 241 24:72\u0026ndash;87. https://doi.org/10.1038/s41568-023-00639-6\u003c/li\u003e\n\u003cli\u003eHu X, Wu LW, Weng XU, et al (2018) Synergistic antitumor activity of aspirin and erlotinib: Inhibition of p38 enhanced aspirin plus erlotinib-induced suppression of metastasis and promoted cancer cell apoptosis. Oncol Lett 16:2715. https://doi.org/10.3892/OL.2018.8956\u003c/li\u003e\n\u003cli\u003eChuang MC, Yang YH, Hsieh MJ, et al (2021) The association of aspirin use with overall survival of patients with inoperable non-small cell lung cancer: a retrospective study. BMC Cancer 21:1257. https://doi.org/10.1186/S12885-021-08999-8\u003c/li\u003e\n\u003cli\u003eBlanchette M, Daneman R (2015) Formation and maintenance of the BBB. Mech Dev 138:8\u0026ndash;16. https://doi.org/10.1016/j.mod.2015.07.007\u003c/li\u003e\n\u003cli\u003eWei D, Tang M, Gong W, et al (2023) Aspirin Inhibits Brain Metastasis of Lung Cancer via Upregulation of Tight Junction Protein Expression in Microvascular Endothelial Cells. Front Biosci (Landmark Ed 28:. https://doi.org/10.31083/J.FBL2811320\u003c/li\u003e\n\u003cli\u003eDel Zoppo GJ, Gu YH (2021) Hemostasis and cerebral metastases in a model system. Blood 137:1139\u0026ndash;1140. https://doi.org/10.1182/blood.2020010130\u003c/li\u003e\n\u003cli\u003eFeinauer MJ, Schneider SW, Berghoff AS, et al (2021) Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model. Blood 137:1219\u0026ndash;1232. https://doi.org/10.1182/BLOOD.2020005710\u003c/li\u003e\n\u003cli\u003eChubak J, Whitlock EP, Williams SB, et al (2016) Aspirin for the prevention of cancer incidence and mortality: Systematic evidence reviews for the U.S. preventive services task force. Ann Intern Med 164:814\u0026ndash;825. https://doi.org/10.7326/M15-2117\u003c/li\u003e\n\u003cli\u003eChan AT, Ogino S, Fuchs CS (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356:2131\u0026ndash;2142. https://doi.org/10.1056/NEJMOA067208\u003c/li\u003e\n\u003cli\u003eKhuder SA, Herial NA, Mutgi AB, Federman DJ (2005) Nonsteroidal antiinflammatory drug use and lung cancer: a metaanalysis. Chest 127:748\u0026ndash;754. https://doi.org/10.1378/CHEST.127.3.748\u003c/li\u003e\n\u003cli\u003eKadu\u0026scaron;evičius E (2021) Novel applications of nsaids: Insight and future perspectives in cardiovascular, neurodegenerative, diabetes and cancer disease therapy. Int J Mol Sci 22:. https://doi.org/10.3390/ijms22126637\u003c/li\u003e\n\u003cli\u003eKashfi K, Rigas B (2005) Non-COX-2 targets and cancer: expanding the molecular target repertoire of chemoprevention. Biochem Pharmacol 70:969\u0026ndash;986. https://doi.org/10.1016/J.BCP.2005.05.004\u003c/li\u003e\n\u003cli\u003eKolawole OR, Kashfi K (2022) NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase. Int J Mol Sci 23:. https://doi.org/10.3390/ijms23031432\u003c/li\u003e\n\u003cli\u003eMiller EJ, Patell R, Uhlmann EJ, et al (2022) Antiplatelet medications and risk of intracranial hemorrhage in patients with metastatic brain tumors. Blood Adv 6:1559\u0026ndash;1565. https://doi.org/10.1182/BLOODADVANCES.2021006470\u003c/li\u003e\n\u003cli\u003eAntiplatelet medications and risk of intracranial hemorrhage in patients with metastatic brain tumors - PubMed. https://pubmed.ncbi.nlm.nih.gov/35086145/. Accessed 18 Nov 2024\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":"Aspirin, platelet function, cerebral metastases, survival analysis, cerebral metastasis prevention","lastPublishedDoi":"10.21203/rs.3.rs-6194346/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6194346/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePurpose: An inverse association between the use of platelet inhibitors and the risk of cancer has been reported by numerous epidemiological studies in the past. The effects of antiplatelet agents on the cerebral metastasis formation of non-small cell lung cancer (NSCLC) are largely unknown. We therefore, investigated the effect of platelet inhibition in NSCLC patients at the time of the first diagnosis of cerebral metastases.\u003c/p\u003e\n\u003cp\u003eMethods: We investigated the clinical course of 417 NSCLC patients with cerebral metastases who underwent craniotomy for metastasis resection during the course of their disease. The presence of platelet inhibition prior to cerebral metastases diagnosis was used to dichotomize the cohort. Relevant clinical parameters, including time to cerebral metastasis formation, overall survival, and the incidence of intracranial hemorrhage or hemorrhagic transformation of metastases, were compared between the two groups\u003c/p\u003e\n\u003cp\u003eResults: The presence of platelet inhibitor intake significantly prolonged time to cerebral metastasis in non-small cell lung cancer 63 vs. 47 months; \u0026nbsp;(p = 0.001). Furthermore, platelet inhibitor intake was also associated with an increased overall survival of 12 vs. 10 months (p=0.02). Statistically, no increased risk of hemorrhagic transformation of the metastasis or intracranial hemorrhage was found (p= 0.635 and p=1.000), respectively.\u003c/p\u003e\n\u003cp\u003eConclusion: While the use of platelet inhibitors did not show an increased risk of intracranial hemorrhage, the use of platelet inhibitors resulted in delayed cerebral metastasis and better survival in NSCLC patients.\u003c/p\u003e","manuscriptTitle":"Platelet inhibition delays cerebral metastasis in non-small cell lung cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-17 16:20:10","doi":"10.21203/rs.3.rs-6194346/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":"fb155645-fe6c-42b0-aacc-bbeb60f12148","owner":[],"postedDate":"March 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-25T08:23:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-17 16:20:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6194346","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6194346","identity":"rs-6194346","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}