Stroke as Initial Manifestation of Non-Small Cell Lung Cancer with Trousseau Syndrome

Stroke as Initial Manifestation of Non-Small Cell Lung Cancer with Trousseau Syndrome | 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 Stroke as Initial Manifestation of Non-Small Cell Lung Cancer with Trousseau Syndrome Weiping Hong, Tongtong Zhang, Changguo Shan, Hainan Li, Tao Lin, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2528570/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Nov, 2023 Read the published version in BMC Cancer → Version 1 posted 10 You are reading this latest preprint version Abstract Objective Stroke is a rare but fatal complication of advanced cancer with Trousseau syndrome, especially as initial symptoms. Here, we report the clinical characteristics, treatment, and prognosis of patients with non-small cell lung cancer (NSCLC) who initially presenting with acute multiple cerebral infarction. Methods The clinical characteristics, imaging, treatment, and oncological outcomes of 10 patients diagnosed with Trousseau syndrome and NSCLC between 2015 and 2021 at Guangdong Sanjiu Brain Hospital were retrospectively collected and analyzed. The clinical course of two typical cases were presented. Results All 10 patients with pathologically confirmed lung adenocarcinoma initially presented with neurological symptoms, including hemiplegic paralysis (7 patients, 70%), dizziness (5 patients, 50%), and unclear speech (3 patients, 30%). The median age was 63.5 years. Eight and two cases were stage III and IV, respectively, at the initial diagnosis. Five patients underwent driver gene testing, revealing three patients with EGFR-sensitive mutations, one patient with ALK fusion, and one patient with wild-type EGFR. All 10 patients received antiplatelet therapy, and six patients subsequently received anti-cancer treatment. The median overall survival of the patients was 8.5 months (95% confidence interval) and 1-year survival rate was 57.1%. Patients who received antitumor treatment, especially those harboring driver gene mutations and received tyrosine kinase inhibitors, had better neurological symptom recovery and superior oncological prognosis (median overall survival, not reached versus 7.4 months, p = 0.038). Conclusion Trousseau syndrome, presenting as multiple cerebral infarctions, is a rare complication of lung adenocarcinoma. Both antiplatelet and antitumor treatment are recommended to achieve better neurological recovery and oncological prognosis in these patients. Stroke Lung Adenocarcinoma Trousseau Syndrome Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Lung cancer ranks first incidence among cancers and accounting for one-fifth of all cancer-related mortality worldwide [ 1 ]. Although advanced diagnostic and therapeutic strategies have been used in recent years, the prognosis of lung cancer remains unsatisfactory, partly associated with delayed diagnosis. The most common symptoms are respiratory-related symptoms, such as cough, sputum, hemoptysis, and chest tightness. However, arterial thromboembolism as the first presentationof lung cancer is not so common, especially stroke which is relatively rare as the initial symptom. Cancer patients are in a hypercoagulable state and are at higher risk for the development of cancer-associated thromboembolism than those without cancer. Almantroso et al. first identified the relationship between thrombosis and cancer in 1865, and several studies have confirmed that thrombosis is a common pathogenic condition in patients with cancer [ 2 ]. Trousseau’s syndrome (cancer-associated thrombosis) is a common complication and the second leading cause of death in cancer patients [ 3 ]. The reasons of the abnormal coagulation function are associated with general patient-related risk factors, and other factors that are specific to the particular cancer type or treatment. The incidence of arterial thrombosis is estimated to be 2–5%, accounting for 10–30% of all thrombotic complications [ 4 , 5 ]. Brain is injured by this pathophysiology because of the rich distribution of the procoagulation factor, thromboplastin, combined with the low levels of the anticoagulation factor, thrombomodulin, in the brain epithelium [ 6 ]. Among all cancers, lung cancer shows a higher incidence of thrombosis, followed by rectal and prostate cancer; however, lung cancer with stroke as the first symptom has rarely been reported. In this study, we retrospectively reviewed the clinical data, treatment and prognosis of 10 patients with lung adenocarcinoma who presented with stroke as the first symptom. Methods Patients Patients diagnosed with non-small cell lung cancer (NSCLC) and Trousseau syndrome from January 1, 2015, to December 31, 2021, at Guangdong Sanjiu Brain Hospital were screened. Patients were included if they met the following criteria: 1) initially presenting with acute neurological-related symptoms and signs, such as hemiplegia, dizziness, slurred speech; 2) imaging manifestation of acute ischemic infarction in multiple areas of the brain using magnetic resonance imaging (MRI), and the diagnosis of acute cerebral infarction were confirmed by an experienced neurologist and radiologist; 3) pathological diagnosis of lung cancer; 4) acute cerebral infarction and NSCLC were diagnosed simultaneously (within 1 month); 5) those with brain metastases, primary brain tumors, hematological system tumors, and other diseases that could induce acute cerebral infarction, such as atrial fibrillation, rheumatic heart disease, and heart failure, were excluded. This study was approved by the Ethics Committee of Guangdong Sanjiu Brain Hospital. Data Collection The demographic and clinicopathological data of all patients were collected, including age, gender, comorbidities (hypertension, diabetes), laboratory findings (D-dimer, serum carcinoembryonic antigen [CEA]), as well as histological classification of lung cancer. Lung cancer was staged according to American Joint Committee on Cancer (8th edition). The National Institutes of Health Stroke Scale (NIHSS) score index was used to measure the neurological impairments caused by cerebral infarction. Treatment strategies, including antiplatelet and antitumor therapy (targeted therapy, chemotherapy, radiatherapy and surgery) were collected. The Response Evaluation Criteria In Solid Tumors (v1.1) was used to assess the efficiency of antitumor treatment. Statistical Analysis Continuous variables, such as age, serum CEA levels, and D-dimer levels were described as median (range). Categorical variables are described using absolute numbers and percentages. Overall survival was defined as the time from the diagnosis of NSCLC to death or the time to the last follow-up. Kaplan-Meier survival curves were generated and compared using log-rank tests. All statistical analyses were performed using the R software ( https://cran.r-project.org/ ). Results Patient Characteristics Ten patients diagnosed with NSCLC and acute stroke met the inclusion criteria and were included in the present study. The median age was 63.5 years (range, 56–77 years); 6 patients were men and 4 were women. All patients initially presented with neurological symptoms, including hemiplegic paralysis (7 patients, 70%), dizziness (5 patients, 50%), and unclear speech (3 patients, 30%), etc. The median NIHSS score was 5 (range, 0–14) when admitted to hospital. All patients were pathologically diagnosed with primary lung adenocarcinoma within one month of the first presentation of ischemic stroke. Eight patients had stage III and two patients had stage IV disease at initial diagnosis. Among the 10 patients, six had a history of hypertension, three had a history of smoking, and two had diabetes mellitus and hyperlipidemia (Table 1 ). Table 1 Clinical characteristics of 10 NSCLC patients initially presented with Trousseau Syndrome. Abrreviations: AD, adenocarcinoma; BM, brain metastases; CEA, carcinoembryonic antigen; NIHSS, national institute of health stroke scale; KPS, karnofsky performance status. Case Age Sex NIHSS KPS Pathology D-Dimer (mg/L) CEA (ng/L) BM Medical history Symptoms 1 56 M 5 30 AD 8.23 126 No Hypertension, Smoking Dizzy, unclear speech, facial paralysis, hemiplegic paralysis, mental disorder 2 63 F 8 50 AD 0.84 17.14 No Hypertension, Hyperlipidemia, Diabetes Hemiplegic paralysis, motor aphasia 3 56 M 11 50 AD 34.18 4.56 No Smoking Unclear speech, hemiplegic paralysis 4 58 F 14 60 AD 28.9 1.1 No Hypertension, Hyperlipidemia, Diabetes Hemiplegic paralysis, lethargy 5 63 F 1 80 AD 18.86 26.03 No - Hemiplegic paralysis, blurred vision 6 69 M 4 60 AD 7.24 11.3 No Hypertension Dizzy, unclear speech, facial paralysis 7 77 M 0 60 AD 3.04 4.31 No - Dizzy, blurred vision, nausea 8 66 M 14 20 AD 4.5 4.25 No Smoking Lethargy, hemiplegic paralysis 9 64 M 5 40 AD 0.31 125 No - Dizzy, hemiplegic paralysis, facial paralysis 10 71 F 0 50 AD 3.04 1.82 No Hypertension Dizzy, Vmoitting Laboratory, Imaging And Pathological Findings D-dimer (median, 5.87 mg/L; range, 0.31–34.18 mg/L) were elevated in all 10 patients at initial diagnosis. Tumor marker CEA was elevated in five patients while it was detected in normal levels in the rest five patients (7.93 ng/L; range, 1.1–126 ng/L) (Table 1 ). Cranial MRI DWI revealed multifocal diffuse signal restriction, suggesting multiple acute cerebral infarction in all 10 patients. Enhanced MRI did not reveal obvious parenchymal or meningeal metastases. Pathological diagnosis (HE and immunohistochemistry) of all 10 patients supported lung adenocarcinoma. Five patients underwent gene analysis, identifying EGFR-sensitive mutations in three cases, ALK fusion in one case, and wild-type in one case (Fig. 2 ). Treatment And Prognosis All 10 patients received antiplatelet therapy (aspirin and/or clopidogrel) when an ischemic stroke was diagnosed. Six patients received further anticancer treatment after primary lung adenocarcinoma was confirmed. After a median follow-up of 17.9 months, five patients were dead and five were still alive. (Fig. 3 ) The median overall survival were 12.1 months (95%CI: 1.1 to 23.1 months) and one year overall survival rate was 57.1%. First-generation EGFR tyrosine kinase inhibitors (TKI) were administered to three patients with EGFR mutations (icotinib in two patients and gefitinib in one patient) and partial response and stable disease were reached in 2 and 1 patients, respectively. One patient with ALK fusion was treated with ensartinib and persistent partial response was acheived. Two patients with stage IIIA disease underwent surgical resection, and one patient was dead and one was alive. Four patients did not receive any anticancer treatment for personal reasons and all of them were dead. (Table 2 ). The median overall survival was significantly longer in patients who received both anticancer and antiplatelet treatment than in those who received antiplatelet treatment only (not reached versus 7.4 months, p = 0.038). (Fig. 4 ) Table 2 treatment, response and survival status of 10 paitents. Case Stage* Gene Mutation Antitumor Antithrombosis Tumor response Neurological response Status OS (mo.) 1 T3N2M0, IIIB EGFR 19DEl Icotinib; Lung radiotherapy Aspirin, Clopidogrel PR Makerd Improved Alive 10 2 T1N2M0, IIIA NA No treatment Clopidogrel NA Stable Dead 7 3 T2N1M1, IVA EGFR L858R Gefitinib; Lung radiotherapy Aspirin SD Stable Alive 27 4 T1N1M0, IIIB ALK Ensartinib; Lung radiotherapy Aspirin, Clopidogrel PR Makerd Improved Alive 6 5 T1N3M1, IVB EGFR L858R Icotinib; Chemotherapy Clopidogrel PR Makerd Improved Alive 17 6 T2N3M0, IIIB NA No treatment Clopidogrel NA Stable Dead 6 7 T1N2Mo, IIIA NA Surgical Aspirin NED Improved Alive 48 8 T2N2M0, IIIA Wild Type Chemotherapy; Surgery Aspirin, Clopidogrel PD Improved Dead 6 9 T2N1M0, IIIB NA No treatment Aspirin, Clopidogrel NA Stable Dead 12 10 T2N2M0, IIIA NA No treatment Clopidogrel NA Stable Dead 7 *Accoding to the American Joint Committee on Cancer(8th edition). Abbreviations: OS, overall survival; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; PR, partial response; SD, stable; PD, progressive disease; NED, no evidence of disease; NA, not available. Typical Cases Case 1 was a 53-year-old man presented with dizzy, unclear speech, facial paralysis, hemiplegic paralysis and mental disorder. The NIHSS score was 5 and KPS was 30 when admitted to hospital. Cranial MRI DWI revealed multiple acute infarctions on both cerebral hemispheres. (Fig. 1 ) The d-dimer was elevated to 8.23 mg/L. Antiplatelet treatment with aspirin and clopodorel was given but his neurological symptoms was not improved. Then elevated serum CEA (126 ng/L) and a tumor as well as cancerous lymphangitis in right lung on chest computed tomography was found. Tumor biopsy confimed the diagnosis of primary lung adenocarcinoma. (Fig. 1 ) Targeted therapy with icotinib (125mg, tid) was administrated after EGFR 19 deletion was detected by tissue gene testing. One month later, he had significant improvement in mental status and aphasia. D-dimer and CEA decreased to normal level gradually. The primary lung tumor and cancerous lymphangitis was significantly shrank and a radiologically partial response was achieved. (Fig. 5 ) His tumor was still under control and he has survived for 10 months. Case 4 was a 58-year-old woman admitted with left-sided limb weakness that had persisted for 2 days. After admission, cranial imaging DWI suggested multiple infarct foci in the bilateral cerebral hemispheres. (Fig. 1 ) D-dimer was elevated to 28.9 mg/L and tumor marker CA125 was 116 U/ml. Chest CT revealed suspicious primary lung cancer with enlarged lymphnodes in mediastinum. Antiplatelet treatment were given but her condition worsened rapidly, with deterioration of mental drowsiness and NIHSS score of 14 points. She was diagnosed with primary lung adenocarcinoma after lung tumor biopsy, (Fig. 1 ) and genetic testing suggested EML4-ALK fusion mutaion. She received second-generation ALK-TKI enzatinib (200mg qd). Her consciousness gradually improved after approximately one week of treatment. After one month, the patient's mental and physical condition improved significantly. D-dimer and CA125 decreased to normal level 3 months later. Chest CT showed decrease diameter in primary tumor, and a radiological PR was achieved and maintained till last follow up. (Fig. 5 ) Discussion Various causes of ischemic stroke, but malignant tumors as the origin is usually overlooked. In the present study, there were 10 patients diagnosed with lung adenocarcinoma with Trousseau syndrome. It is noteworthy that all 10 patients had stroke as the first symptom, and the lung malignancy lesion was found after examination; therefore, stroke can be included as one of the first manifestations in patients with undiagnosed lung tumor [ 7 ]. Trousseau syndrome is a clinically relevant coagulation abnormality in patients with cancer. In this study, we found that most patients with Trousseau syndrome had elevated serum D-dimer levels, which decreased after effective antitumor therapy. Therefore, if the patient is not diagnosed and treated at an early stage, it will lead to a persistent elevation of D-dimer levels, which will cause ischemic stroke. The data also illustrated that D-dimer levels can be used as a reference for the diagnosis and prognostic index of Trousseau syndrome. It has been pointed out[ 8 , 9 ] that the expression of tumor markers CEA and CA125 is associated with the occurrence of embolism in patients with cancer, and elevation of this index is associated with the recurrence of ischemic stroke of these patients. Most patients in this study had various degrees of elevated CEA and CA125; therefore, elevated tumor markers in patients with Trousseau syndrome were also considered to be associated with thrombosis. All patients in this study started with neurological symptoms, including weakness of the extremities, dizziness, and slurred speech. The mean NIHSS score was 5.4 (range, 14–0), and the neurological symptoms caused by Trousseau syndrome were considered similar to those of general ischemic stroke. Imaging findings showed multiple infarct lesions on DWI in all patients. Therefore, additional attention is needed to screen for neoplastic lesions in patients with such features when performing imaging examinations. The most effective treatment for Trousseau syndrome is antitumor therapy for the primary tumor[ 10 ], including targeted therapy, combined radiotherapy and surgery, and anticoagulation therapy. In this study, six out of ten patients received antitumor therapy; three of them showed significant improvement in symptoms and a decrease in serum D-dimer levels and tumor markers after receiving antitumor therapy. One patient died due to disease progression, four patients did not receive antitumor therapy but only anticoagulation, and two died due to disease progression. In conclusion, we presented here the characteristic results of 10 NSCLC patients in this study with stroke as the first symptom. Patients with potential Trusso syndrome together with the above characteristics should also be considered for the possibility of lung malignancy, and tumor-related tests should be clarified in a timely manner to achieve effective treatments. After diagnosing Trusso syndrome, the key to treatment is to combine antitumor therapy with anticoagulation therapy for the primary tumor, which is significantly more effective than anticoagulation therapy alone. Declarations Declarations: Declarations Ethics approval and consent to participate: All methods were carried out in accordance with relevant guidelines and regulations. All experimental protocols were approved by he Ethics Committee of Guangdong Sanjiu Brain Hospital. Informed consent was obtained from all patients. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Guangdong Sanjiu Brain Hospital. Consent for publication: Not applicable. Availability of data and materials: All data generated or analysed during this study are included in this published article. Competing interests: The authors declare that they have no competing interests. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors’ contributions: Weiping Hong, Tongtong Zhang, Changguo Shan, Junjie Zhen, Juan Li analyzed and interpreted the patient data. Hainan Li, Tao Lin, Da Liu, Mingyao Lai performed the histological examination of the Lung and Cheng Zhou, Zhaoming Zhou, Meijuan Zhou, Minghua Wang, Linbo Cai, Lei Wen were major contributor in writing the manuscript. All authors read and approved the final manuscript. Acknowledgements: The authors thank for his participation in this study and for the patients’ agreement to the publication of the report. References Bray F, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol. 2005;6(6):401–10. Abdol Razak NB, et al. Cancer-Associated Thrombosis: An Overview of Mechanisms, Risk Factors, and Treatment. Volume 10. Cancers (Basel); 2018. 10. Sanon S, Lenihan DJ, Mouhayar E. Peripheral arterial ischemic events in cancer patients. Vasc Med. 2011;16(2):119–30. Di Nisio M, et al. Arterial thrombosis in ambulatory cancer patients treated with chemotherapy. Thromb Res. 2011;127(4):382–3. Ikushima S, et al. Trousseau's syndrome: cancer-associated thrombosis. Jpn J Clin Oncol. 2016;46(3):204–8. Chen W, He Y, Su Y. Multifocal cerebral infarction as the first manifestation of occult malignancy: Case series of trousseau's syndrome and literature review. Brain Circ. 2018;4(2):65–72. Tesselaar ME, et al. Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost. 2007;5(3):520–7. Jovin TG, et al. High titers of CA-125 may be associated with recurrent ischemic strokes in patients with cancer. Neurology. 2005;64(11):1944–5. Ishikawa M, et al. Case series of cerebral infarction with Trousseau's syndrome associated with malignant gynecological tumors. Mol Clin Oncol. 2016;5(1):138–42. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 10 Nov, 2023 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Major revision 13 Sep, 2023 Reviews received at journal 03 Sep, 2023 Reviews received at journal 28 Jul, 2023 Reviewers agreed at journal 17 Jul, 2023 Reviewers agreed at journal 15 Jul, 2023 Reviewers invited by journal 14 Jul, 2023 Editor assigned by journal 13 Jul, 2023 Editor invited by journal 15 Feb, 2023 Submission checks completed at journal 15 Feb, 2023 First submitted to journal 30 Jan, 2023 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2528570","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":176428327,"identity":"f6e24250-de6b-473e-bacf-4d2ef78f3fc7","order_by":0,"name":"Weiping Hong","email":"","orcid":"","institution":"Guangdong Sanjiu Brain Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Weiping","middleName":"","lastName":"Hong","suffix":""},{"id":176428328,"identity":"e2e16ebb-340b-46e6-8259-a7060c6f136f","order_by":1,"name":"Tongtong Zhang","email":"","orcid":"","institution":"The Affiliated Hospital of Guizhou 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Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Linbo","middleName":"","lastName":"Cai","suffix":""},{"id":176428346,"identity":"6fcfeb83-c85d-4bba-9c73-489d4b0e3956","order_by":14,"name":"Lei Wen","email":"","orcid":"","institution":"Guangdong Sanjiu Brain Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Wen","suffix":""}],"badges":[],"createdAt":"2023-01-30 08:29:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2528570/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2528570/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-023-11627-2","type":"published","date":"2023-11-10T15:01:23+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":33094132,"identity":"565f902e-5602-4db1-9bd2-ebdd50fd0546","added_by":"auto","created_at":"2023-02-17 15:54:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1616250,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImaging and pathological results of two representative patients diagnosed with primary lung adenocarcinoma and multiple cerebral infarctions. \u003c/strong\u003eBoth patients presented with stoke-related symptoms and brain MRI DWI revealed acute infarctions in multiple cerebrum (a, b, i, j). Lung mass was found by chest CT (c, d, k, l) and primary lung adenocarcinoma were confirmed pathologically (HE and immunohistochemistry) (e-h, m-p).\u003c/p\u003e","description":"","filename":"F1.png","url":"https://assets-eu.researchsquare.com/files/rs-2528570/v1/0790593b68210314cbdc4b7f.png"},{"id":33094979,"identity":"e97214e6-057b-432b-a33c-78b6f6ec227c","added_by":"auto","created_at":"2023-02-17 16:02:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":51577,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHeatmap for altered genes in five patients with lung cancer and cerebral infarction.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"F2.png","url":"https://assets-eu.researchsquare.com/files/rs-2528570/v1/a480d947571ac5faa3d75f08.png"},{"id":33094131,"identity":"d0c7b720-a97f-4dff-aad7-081071ffa706","added_by":"auto","created_at":"2023-02-17 15:54:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":57560,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTreatment, response, and survival status of 10 patients by swimming plot.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"F3.png","url":"https://assets-eu.researchsquare.com/files/rs-2528570/v1/84c9466293c73df01d547ba6.png"},{"id":33094978,"identity":"5c97c1d7-9efe-49e6-be8a-72e4d052df26","added_by":"auto","created_at":"2023-02-17 16:02:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":44312,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier estimates of overall survival according to treatment group. \u003c/strong\u003eMedian overall survival was not reached in antitumor plus antiplatelet group and 7.4 months in antiplatelet group (p=0.038).\u003c/p\u003e","description":"","filename":"F4.png","url":"https://assets-eu.researchsquare.com/files/rs-2528570/v1/92dc832e4efe1d8be249116c.png"},{"id":33094135,"identity":"258e302d-1b71-42b6-a764-cd7b6b16b352","added_by":"auto","created_at":"2023-02-17 15:54:49","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":192688,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDynamic serum CEA, D-dimer and radiological response changes in 2 representative patients.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"F5.png","url":"https://assets-eu.researchsquare.com/files/rs-2528570/v1/20e453c810c7e60e11abf323.png"},{"id":46349116,"identity":"c949aa8e-f0d3-457b-b7a1-a29a45cd007a","added_by":"auto","created_at":"2023-11-13 15:08:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2273691,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2528570/v1/ac5dc3d0-97ef-449f-b0a2-4a0702d705cb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Stroke as Initial Manifestation of Non-Small Cell Lung Cancer with Trousseau Syndrome","fulltext":[{"header":"Background","content":"\u003cp\u003eLung cancer ranks first incidence among cancers and accounting for one-fifth of all cancer-related mortality worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although advanced diagnostic and therapeutic strategies have been used in recent years, the prognosis of lung cancer remains unsatisfactory, partly associated with delayed diagnosis. The most common symptoms are respiratory-related symptoms, such as cough, sputum, hemoptysis, and chest tightness. However, arterial thromboembolism as the first presentationof lung cancer is not so common, especially stroke which is relatively rare as the initial symptom.\u003c/p\u003e \u003cp\u003eCancer patients are in a hypercoagulable state and are at higher risk for the development of cancer-associated thromboembolism than those without cancer. Almantroso \u003cem\u003eet al.\u003c/em\u003e first identified the relationship between thrombosis and cancer in 1865, and several studies have confirmed that thrombosis is a common pathogenic condition in patients with cancer [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Trousseau\u0026rsquo;s syndrome (cancer-associated thrombosis) is a common complication and the second leading cause of death in cancer patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The reasons of the abnormal coagulation function are associated with general patient-related risk factors, and other factors that are specific to the particular cancer type or treatment. The incidence of arterial thrombosis is estimated to be 2\u0026ndash;5%, accounting for 10\u0026ndash;30% of all thrombotic complications [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Brain is injured by this pathophysiology because of the rich distribution of the procoagulation factor, thromboplastin, combined with the low levels of the anticoagulation factor, thrombomodulin, in the brain epithelium [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Among all cancers, lung cancer shows a higher incidence of thrombosis, followed by rectal and prostate cancer; however, lung cancer with stroke as the first symptom has rarely been reported.\u003c/p\u003e \u003cp\u003eIn this study, we retrospectively reviewed the clinical data, treatment and prognosis of 10 patients with lung adenocarcinoma who presented with stroke as the first symptom.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003ePatients diagnosed with non-small cell lung cancer (NSCLC) and Trousseau syndrome from January 1, 2015, to December 31, 2021, at Guangdong Sanjiu Brain Hospital were screened. Patients were included if they met the following criteria: 1) initially presenting with acute neurological-related symptoms and signs, such as hemiplegia, dizziness, slurred speech; 2) imaging manifestation of acute ischemic infarction in multiple areas of the brain using magnetic resonance imaging (MRI), and the diagnosis of acute cerebral infarction were confirmed by an experienced neurologist and radiologist; 3) pathological diagnosis of lung cancer; 4) acute cerebral infarction and NSCLC were diagnosed simultaneously (within 1 month); 5) those with brain metastases, primary brain tumors, hematological system tumors, and other diseases that could induce acute cerebral infarction, such as atrial fibrillation, rheumatic heart disease, and heart failure, were excluded. This study was approved by the Ethics Committee of Guangdong Sanjiu Brain Hospital.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eThe demographic and clinicopathological data of all patients were collected, including age, gender, comorbidities (hypertension, diabetes), laboratory findings (D-dimer, serum carcinoembryonic antigen [CEA]), as well as histological classification of lung cancer. Lung cancer was staged according to American Joint Committee on Cancer (8th edition). The National Institutes of Health Stroke Scale (NIHSS) score index was used to measure the neurological impairments caused by cerebral infarction. Treatment strategies, including antiplatelet and antitumor therapy (targeted therapy, chemotherapy, radiatherapy and surgery) were collected. The Response Evaluation Criteria In Solid Tumors (v1.1) was used to assess the efficiency of antitumor treatment.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eContinuous variables, such as age, serum CEA levels, and D-dimer levels were described as median (range). Categorical variables are described using absolute numbers and percentages. Overall survival was defined as the time from the diagnosis of NSCLC to death or the time to the last follow-up. Kaplan-Meier survival curves were generated and compared using log-rank tests. All statistical analyses were performed using the R software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cran.r-project.org/\u003c/span\u003e\u003cspan address=\"https://cran.r-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePatient Characteristics\u003c/h2\u003e \u003cp\u003eTen patients diagnosed with NSCLC and acute stroke met the inclusion criteria and were included in the present study. The median age was 63.5 years (range, 56\u0026ndash;77 years); 6 patients were men and 4 were women. All patients initially presented with neurological symptoms, including hemiplegic paralysis (7 patients, 70%), dizziness (5 patients, 50%), and unclear speech (3 patients, 30%), etc. The median NIHSS score was 5 (range, 0\u0026ndash;14) when admitted to hospital. All patients were pathologically diagnosed with primary lung adenocarcinoma within one month of the first presentation of ischemic stroke. Eight patients had stage III and two patients had stage IV disease at initial diagnosis. Among the 10 patients, six had a history of hypertension, three had a history of smoking, and two had diabetes mellitus and hyperlipidemia (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\u003e\u003cb\u003eClinical characteristics of 10 NSCLC patients initially presented with Trousseau Syndrome.\u003c/b\u003e Abrreviations: AD, adenocarcinoma; BM, brain metastases; CEA, carcinoembryonic antigen; NIHSS, national institute of health stroke scale; KPS, karnofsky performance status.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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 \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNIHSS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKPS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePathology\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eD-Dimer\u003c/p\u003e \u003cp\u003e(mg/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCEA\u003c/p\u003e \u003cp\u003e(ng/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMedical history\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSymptoms\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e8.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHypertension, Smoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eDizzy, unclear speech, facial paralysis, hemiplegic paralysis, mental disorder\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e17.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHypertension, Hyperlipidemia, Diabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eHemiplegic paralysis, motor aphasia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e34.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eUnclear speech, hemiplegic paralysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e28.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHypertension, Hyperlipidemia, Diabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eHemiplegic paralysis, lethargy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e18.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e26.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eHemiplegic paralysis, blurred vision\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e7.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eDizzy, unclear speech, facial paralysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eDizzy, blurred vision, nausea\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eLethargy, hemiplegic paralysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eDizzy, hemiplegic paralysis, facial paralysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eDizzy, Vmoitting\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLaboratory, Imaging And Pathological Findings\u003c/h3\u003e\n\u003cp\u003eD-dimer (median, 5.87 mg/L; range, 0.31\u0026ndash;34.18 mg/L) were elevated in all 10 patients at initial diagnosis. Tumor marker CEA was elevated in five patients while it was detected in normal levels in the rest five patients (7.93 ng/L; range, 1.1\u0026ndash;126 ng/L) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Cranial MRI DWI revealed multifocal diffuse signal restriction, suggesting multiple acute cerebral infarction in all 10 patients. Enhanced MRI did not reveal obvious parenchymal or meningeal metastases. Pathological diagnosis (HE and immunohistochemistry) of all 10 patients supported lung adenocarcinoma. Five patients underwent gene analysis, identifying EGFR-sensitive mutations in three cases, ALK fusion in one case, and wild-type in one case (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eTreatment And Prognosis\u003c/h3\u003e\n\u003cp\u003eAll 10 patients received antiplatelet therapy (aspirin and/or clopidogrel) when an ischemic stroke was diagnosed. Six patients received further anticancer treatment after primary lung adenocarcinoma was confirmed. After a median follow-up of 17.9 months, five patients were dead and five were still alive. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e) The median overall survival were 12.1 months (95%CI: 1.1 to 23.1 months) and one year overall survival rate was 57.1%. First-generation EGFR tyrosine kinase inhibitors (TKI) were administered to three patients with EGFR mutations (icotinib in two patients and gefitinib in one patient) and partial response and stable disease were reached in 2 and 1 patients, respectively. One patient with ALK fusion was treated with ensartinib and persistent partial response was acheived. Two patients with stage IIIA disease underwent surgical resection, and one patient was dead and one was alive. Four patients did not receive any anticancer treatment for personal reasons and all of them were dead. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median overall survival was significantly longer in patients who received both anticancer and antiplatelet treatment than in those who received antiplatelet treatment only (not reached versus 7.4 months, p\u0026thinsp;=\u0026thinsp;0.038). (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\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\u003etreatment, response and survival status of 10 paitents.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStage*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGene Mutation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAntitumor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAntithrombosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTumor response\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNeurological response\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eStatus\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eOS (mo.)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT3N2M0, IIIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEGFR 19DEl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIcotinib; Lung radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAspirin, Clopidogrel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMakerd Improved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1N2M0, IIIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClopidogrel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT2N1M1, IVA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEGFR\u003c/p\u003e \u003cp\u003eL858R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGefitinib; Lung radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAspirin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1N1M0, IIIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eALK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEnsartinib; Lung radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAspirin, Clopidogrel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMakerd Improved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1N3M1, IVB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEGFR\u003c/p\u003e \u003cp\u003eL858R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIcotinib; Chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClopidogrel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMakerd Improved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT2N3M0, IIIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClopidogrel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1N2Mo, IIIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSurgical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAspirin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNED\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eImproved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT2N2M0, IIIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWild Type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eChemotherapy; Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAspirin, Clopidogrel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eImproved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT2N1M0, IIIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAspirin, Clopidogrel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT2N2M0, IIIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClopidogrel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e*Accoding to the American Joint Committee on Cancer(8th edition).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eAbbreviations: OS, overall survival; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; PR, partial response; SD, stable; PD, progressive disease; NED, no evidence of disease; NA, not available.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eTypical Cases\u003c/h3\u003e\n\u003cp\u003e \u003cstrong\u003eCase 1\u003c/strong\u003e \u003cp\u003ewas a 53-year-old man presented with dizzy, unclear speech, facial paralysis, hemiplegic paralysis and mental disorder. The NIHSS score was 5 and KPS was 30 when admitted to hospital. Cranial MRI DWI revealed multiple acute infarctions on both cerebral hemispheres. (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003e) The d-dimer was elevated to 8.23 mg/L. Antiplatelet treatment with aspirin and clopodorel was given but his neurological symptoms was not improved. Then elevated serum CEA (126 ng/L) and a tumor as well as cancerous lymphangitis in right lung on chest computed tomography was found. Tumor biopsy confimed the diagnosis of primary lung adenocarcinoma. (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003e) Targeted therapy with icotinib (125mg, tid) was administrated after EGFR 19 deletion was detected by tissue gene testing. One month later, he had significant improvement in mental status and aphasia. D-dimer and CEA decreased to normal level gradually. The primary lung tumor and cancerous lymphangitis was significantly shrank and a radiologically partial response was achieved. (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e) His tumor was still under control and he has survived for 10 months.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 4\u003c/strong\u003e \u003cp\u003ewas a 58-year-old woman admitted with left-sided limb weakness that had persisted for 2 days. After admission, cranial imaging DWI suggested multiple infarct foci in the bilateral cerebral hemispheres. (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003e) D-dimer was elevated to 28.9 mg/L and tumor marker CA125 was 116 U/ml. Chest CT revealed suspicious primary lung cancer with enlarged lymphnodes in mediastinum. Antiplatelet treatment were given but her condition worsened rapidly, with deterioration of mental drowsiness and NIHSS score of 14 points. She was diagnosed with primary lung adenocarcinoma after lung tumor biopsy, (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and genetic testing suggested EML4-ALK fusion mutaion. She received second-generation ALK-TKI enzatinib (200mg qd). Her consciousness gradually improved after approximately one week of treatment. After one month, the patient's mental and physical condition improved significantly. D-dimer and CA125 decreased to normal level 3 months later. Chest CT showed decrease diameter in primary tumor, and a radiological PR was achieved and maintained till last follow up. (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eVarious causes of ischemic stroke, but malignant tumors as the origin is usually overlooked. In the present study, there were 10 patients diagnosed with lung adenocarcinoma with Trousseau syndrome. It is noteworthy that all 10 patients had stroke as the first symptom, and the lung malignancy lesion was found after examination; therefore, stroke can be included as one of the first manifestations in patients with undiagnosed lung tumor [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTrousseau syndrome is a clinically relevant coagulation abnormality in patients with cancer. In this study, we found that most patients with Trousseau syndrome had elevated serum D-dimer levels, which decreased after effective antitumor therapy. Therefore, if the patient is not diagnosed and treated at an early stage, it will lead to a persistent elevation of D-dimer levels, which will cause ischemic stroke. The data also illustrated that D-dimer levels can be used as a reference for the diagnosis and prognostic index of Trousseau syndrome. It has been pointed out[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] that the expression of tumor markers CEA and CA125 is associated with the occurrence of embolism in patients with cancer, and elevation of this index is associated with the recurrence of ischemic stroke of these patients. Most patients in this study had various degrees of elevated CEA and CA125; therefore, elevated tumor markers in patients with Trousseau syndrome were also considered to be associated with thrombosis.\u003c/p\u003e \u003cp\u003eAll patients in this study started with neurological symptoms, including weakness of the extremities, dizziness, and slurred speech. The mean NIHSS score was 5.4 (range, 14\u0026ndash;0), and the neurological symptoms caused by Trousseau syndrome were considered similar to those of general ischemic stroke. Imaging findings showed multiple infarct lesions on DWI in all patients. Therefore, additional attention is needed to screen for neoplastic lesions in patients with such features when performing imaging examinations.\u003c/p\u003e \u003cp\u003eThe most effective treatment for Trousseau syndrome is antitumor therapy for the primary tumor[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], including targeted therapy, combined radiotherapy and surgery, and anticoagulation therapy. In this study, six out of ten patients received antitumor therapy; three of them showed significant improvement in symptoms and a decrease in serum D-dimer levels and tumor markers after receiving antitumor therapy. One patient died due to disease progression, four patients did not receive antitumor therapy but only anticoagulation, and two died due to disease progression.\u003c/p\u003e \u003cp\u003eIn conclusion, we presented here the characteristic results of 10 NSCLC patients in this study with stroke as the first symptom. Patients with potential Trusso syndrome together with the above characteristics should also be considered for the possibility of lung malignancy, and tumor-related tests should be clarified in a timely manner to achieve effective treatments. After diagnosing Trusso syndrome, the key to treatment is to combine antitumor therapy with anticoagulation therapy for the primary tumor, which is significantly more effective than anticoagulation therapy alone.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cdiv class=\"Heading\"\u003eDeclarations:\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eAll methods were carried out in accordance with relevant guidelines and regulations. All experimental protocols were approved by he Ethics Committee of Guangdong Sanjiu Brain Hospital. Informed consent was obtained from all patients. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Guangdong Sanjiu Brain Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u0026nbsp;\u003c/strong\u003eWeiping Hong, Tongtong Zhang, Changguo Shan, Junjie Zhen, Juan Li analyzed and interpreted the patient data. Hainan Li, Tao Lin, Da Liu, Mingyao Lai performed the histological examination of the Lung and Cheng Zhou, Zhaoming Zhou, Meijuan Zhou, Minghua Wang, Linbo Cai, Lei Wen were major contributor in writing the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp; Acknowledgements:\u0026nbsp;\u003c/strong\u003eThe authors thank for his participation in this study and for the patients\u0026rsquo; agreement to the publication of the report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394\u0026ndash;424.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol. 2005;6(6):401\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbdol Razak NB, et al. Cancer-Associated Thrombosis: An Overview of Mechanisms, Risk Factors, and Treatment. Volume 10. Cancers (Basel); 2018. 10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanon S, Lenihan DJ, Mouhayar E. Peripheral arterial ischemic events in cancer patients. Vasc Med. 2011;16(2):119\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDi Nisio M, et al. Arterial thrombosis in ambulatory cancer patients treated with chemotherapy. Thromb Res. 2011;127(4):382\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIkushima S, et al. Trousseau's syndrome: cancer-associated thrombosis. Jpn J Clin Oncol. 2016;46(3):204\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen W, He Y, Su Y. Multifocal cerebral infarction as the first manifestation of occult malignancy: Case series of trousseau's syndrome and literature review. Brain Circ. 2018;4(2):65\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTesselaar ME, et al. Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost. 2007;5(3):520\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJovin TG, et al. High titers of CA-125 may be associated with recurrent ischemic strokes in patients with cancer. Neurology. 2005;64(11):1944\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIshikawa M, et al. Case series of cerebral infarction with Trousseau's syndrome associated with malignant gynecological tumors. Mol Clin Oncol. 2016;5(1):138\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Stroke, Lung Adenocarcinoma, Trousseau Syndrome","lastPublishedDoi":"10.21203/rs.3.rs-2528570/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2528570/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eStroke is a rare but fatal complication of advanced cancer with Trousseau syndrome, especially as initial symptoms. Here, we report the clinical characteristics, treatment, and prognosis of patients with non-small cell lung cancer (NSCLC) who initially presenting with acute multiple cerebral infarction.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe clinical characteristics, imaging, treatment, and oncological outcomes of 10 patients diagnosed with Trousseau syndrome and NSCLC between 2015 and 2021 at Guangdong Sanjiu Brain Hospital were retrospectively collected and analyzed. The clinical course of two typical cases were presented.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAll 10 patients with pathologically confirmed lung adenocarcinoma initially presented with neurological symptoms, including hemiplegic paralysis (7 patients, 70%), dizziness (5 patients, 50%), and unclear speech (3 patients, 30%). The median age was 63.5 years. Eight and two cases were stage III and IV, respectively, at the initial diagnosis. Five patients underwent driver gene testing, revealing three patients with EGFR-sensitive mutations, one patient with ALK fusion, and one patient with wild-type EGFR. All 10 patients received antiplatelet therapy, and six patients subsequently received anti-cancer treatment. The median overall survival of the patients was 8.5 months (95% confidence interval) and 1-year survival rate was 57.1%. Patients who received antitumor treatment, especially those harboring driver gene mutations and received tyrosine kinase inhibitors, had better neurological symptom recovery and superior oncological prognosis (median overall survival, not reached versus 7.4 months, p\u0026thinsp;=\u0026thinsp;0.038).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eTrousseau syndrome, presenting as multiple cerebral infarctions, is a rare complication of lung adenocarcinoma. Both antiplatelet and antitumor treatment are recommended to achieve better neurological recovery and oncological prognosis in these patients.\u003c/p\u003e","manuscriptTitle":"Stroke as Initial Manifestation of Non-Small Cell Lung Cancer with Trousseau Syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-02-17 15:54:44","doi":"10.21203/rs.3.rs-2528570/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-09-13T10:08:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-09-03T07:39:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-07-28T15:25:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"bf48b2d3-c02e-4b92-9688-804008904490","date":"2023-07-18T02:04:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8577bc76-7402-4f08-a891-9d2dbdb0ff15","date":"2023-07-15T14:23:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-07-14T09:02:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-07-13T16:10:55+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-02-15T19:45:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-02-15T19:40:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2023-01-30T08:15:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"810b90f8-6086-4755-8ef8-5c364108b753","owner":[],"postedDate":"February 17th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-11-13T15:04:51+00:00","versionOfRecord":{"articleIdentity":"rs-2528570","link":"https://doi.org/10.1186/s12885-023-11627-2","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2023-11-10 15:01:23","publishedOnDateReadable":"November 10th, 2023"},"versionCreatedAt":"2023-02-17 15:54:44","video":"","vorDoi":"10.1186/s12885-023-11627-2","vorDoiUrl":"https://doi.org/10.1186/s12885-023-11627-2","workflowStages":[]},"version":"v1","identity":"rs-2528570","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2528570","identity":"rs-2528570","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}