The role of B-Raf V600E Gene Mutation and chronic lymphocytic thyroiditis in papillary thyroid carcinoma

The role of B-Raf V600E Gene Mutation and chronic lymphocytic thyroiditis in papillary thyroid carcinoma | 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 The role of B-Raf V 600E Gene Mutation and chronic lymphocytic thyroiditis in papillary thyroid carcinoma Haidi Chu, Wanzhong Zhao, Dong Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6240454/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 Background Our aim of this article was to investigate in the papillary thyroid carcinoma(PTC) patients, whether B-Raf V600E gene mutation and chronic lymphocytic thyroiditis(CLT) were in association with their clinicopathological characteristics and the interplay between them. Methods We had chosen 185 PTC patients who had treated in Affiliated Hospital of Qingdao University –Yantai YuHuangDing Hospital and Yantaishan Hospital during April 2023 to March 2024.We recorded gender, age, the status of B-Raf V600E gene mutation, CLT or not, the size of tumor, single/multifocality, family history, muscle invasion, capsular infiltration, central lymph node metastasis and clinical stage, analyzed them using logistic regression analysis by SPSS20.0. Results There were 185 patients, 138 patients were with B-Raf V600E gene mutation and 47 with wild type, the percentage of B-Raf V600E mutation was 74.59%, and the B-Raf V600E mutation had correlation with CLT(OR = 0.335,P = 0.009) and the size of tumor (OR = 3.751,P = 0.004). 42 patients were with CLT and 143 not, the percentage of CLT was 74.59%, and CLT had correlation with gender(OR = 3.271,P = 0.043) and B-Raf V600E gene mutation status (OR = 0.341,P = 0.01). Conclusions In PTC patients, B-Raf V600E gene mutation and CLT were in association with clinicopathological characteristics. Further investigation for the interplay between CLT and B-Raf V600E gene mutation in PTC needs to be done. Papillary thyroid carcinoma B-RafV600E gene mutation Chronic lymphocytic thyroiditis Figures Figure 1 Figure 2 Background Thyroid carcinoma(TC) is the most widespread endocrine malignancy in the whole world, and the incidence has been up to tenfold in the last 30 years [ 1 , 2 ]. Among the different pathological types of TC, PTC is well-differentiated, accounting for about 80% of all TC[ 3 ], with the most favorable prognosis: 10-year survival rate has been up to 93%[ 4 ]. The excellent prognosis is related to several factors, such as age, tumor size, lymph node metastasis, clinical stage, and so on[ 5 ]. B‑Raf belongs to the Raf kinase family, encodes a serine-threonine kinase, is an activator of the MAPK/ERK pathway. The pathway is responsible for transferring signals from the extracellular matrix to the nucleus, to control cell cycle, proliferation, growth, and survival. With a specific B‑Raf mutation, V600E, kinase activity is enhanced almost 500-fold, typically resulted in constitutive activation of the MAPK/ERK pathway and subsequent development of PTC[ 6 , 7 ]. CLT, also known as Hashimoto’s thyroiditis, is an autoimmune tissue-specific thyroid inflammatory disease, with histologically characterized by extensive infiltration of auto-reactive T and B cells, parenchymal atrophy, and fibrosis. CLT is the most frequently inflammatory disease of thyroid gland, also the most common reason for hypothyroidism in iodine-sufficient countries [ 8 – 10 ]. Likewise, CLT incidence has been rapidly rising worldwide, about 0.3–1.5 per 1000 individuals [ 11 ], currently younger patients are diagnosed than before[ 12 ].Coexistence of TC and CLT was suggested firstly in 1955 by Dailey [ 13 ]. Lately, various studies had mentioned the rate for coexistence of TC and CLT was ranged up to 45% [ 12 , 14 – 18 ]. It is still a matter of debate whether CLT plays a promoting or inhibiting role in PTC progression. In this study, we intended to investigate whether B-Raf V600E gene mutation and CLT were in association with PTC patients’ clinicopathological characteristics, and the possible interplay between them. Patients and Statistical analysis : 1. Patients: 185 participants who had undergone different thyroidectomy for PTC at the Affiliated Hospital of Qingdao University – Yantai YuHuangDing Hospital from April 2022 to March 2024 were enrolled. All of them were untreated before (such as drugs, surgeries or ablation), finished the clinical examinations including ultrasonography and computed tomography of the neck to establish pre-operative assessment. All patients were diagnosed PTC based on postoperative histopathological analysis by two experienced pathologists. The patients’ gender, age, the status of B-Raf V600E gene mutation, CLT, the size of tumor, single/multifocality, family history, muscle invasion, capsular infiltration, central lymph node metastasis and clinical stage were recorded. We chose the diameter of the largest one when there was multifocality. Patient considered benign tumor, re-operation, distant metastasis or refused surgery was excluded. In our article, B-Raf V600E gene mutation and CLT were demonstrated by histopathology, as the pathologic definition was the gold standard. 2. Statistical analysis Statistical analysis was mainly performed using software package SPSS20.0. Patients’ information and clinicopathological characteristics were analyzed retrospectively using logistic regression analysis, and P < 0.05 had been chosen as significant. Result There were totally 185 patients rolled in our study, consisting of 40 male and 145 female; 132 patients were younger than 55 years, 53 patients were elder; the B-Raf V600E gene mutation was observed in138 tumor tissues, wild type was observed in 47; patients with CLT were 42,non-CLT were 143; measuring tumor diameter < 1cm was 67, ≥ 1 cm was 118; 124 patients had single tumor, whereas 61 had multifocality;13 patients with family history and 172 without; 23 patients had muscle invasion and 162 without; 61 patients were found capsular infiltration and 124 without; 100 patients had positive central lymph node and 85 without; 161 patients had TNM stageⅠ, 24 had TNM stageⅡ(Table 1 ). Table 1 185 PTCs' clinicopathological characteristics Total Gender Male 40 Female 145 Age < 55years 132 ≥ 55years 53 B-Raf V600E Mutation 138 Wild 47 CLT Yes 42 No 143 Size of tumor < 1cm 67 ≥ 1cm 118 Single/Multifocality Single 124 Multifocality 61 Family history Yes 13 No 172 Muscle invasion Yes 23 No 162 Capsular infiltration Yes 61 No 124 Central lymph node metastasis Yes 100 No 85 Clinical stage Ⅰ 161 Ⅱ 24 Total 185 From our analysis we could find, the B-Raf V600E gene mutation was associated with CLT(OR = 0.335,P = 0.009) and the size of tumor (OR = 3.751,P = 0.004). However, presence of the B-Raf V600E mutation was not associated with other clinicopathological features, including gender(OR = 0.723,P = 0.535), age(OR = 2.229, 0.097), single/multifocality(OR = 0.675,P = 0.328), family history(OR = 0.618,P = 0.449), muscle invasion(OR = 0.591,P = 0.407), capsular infiltration(OR = 1.442,P = 0.444), central lymph node metastasis(OR = 1.289,P = 0.519) and clinical stage(OR = 1.097,P = 0.89) (Table 2 , Fig. 1 ). Table 2 the analysis of B-RafV600E with PTC clinicopathological characteristics OR 95%CI P Gender 0.723 0.259–2.018 0.535 Age 2.229 0.865–5.746 0.097 CLT 0.335 0.147–0.759 0.009 Size of tumor 3.751 1.542–9.122 0.004 Single/Multifocality 0.675 0.307–1.483 0.328 Family history 0.618 0.178–2.144 0.449 Muscle invasion 0.591 0.171–2.049 0.407 Capsular infiltration 1.442 0.566–3.675 0.444 Central lymph node metastasis 1.289 0.307–1.483 0.519 Clinical stage 1.097 0.293–4.103 0.89 CLT was associated with gender(OR = 3.271,P = 0.043) and B-Raf V600E gene mutation(OR = 0.341,P = 0.01). Analysis regarding the correlation between age(OR = 1.787,P = 0.267), single/multifocality(OR = 0.905,P = 0.803), family history(OR = 0.764,P = 0.712), muscle invasion(OR = 0.609,P = 0.521), capsular infiltration(OR = 0.511,P = 0.182), central lymph node metastasis(OR = 0.835,P = 0.651) and clinical stage(OR = 2.722,P = 0.167) did not yield any perceivable significant (Table 3 , Fig. 2 ). Table 3 the analysis of CLT with PTC clinicopathological characteristics OR 95%CI P Gender 3.271 1.037–10.322 0.043 Age 1.787 0.641–4.983 0.267 B-Raf V600E 0.341 0.150–0.774 0.01 Size of tumor 1.846 0.840–4.060 0.127 Single/Multifocality 0.905 0.412–1.989 0.803 Family history 0.764 0.184–3.180 0.712 Muscle invasion 0.609 0.133–2.775 0.521 Capsular infiltration 0.511 0.190–1.371 0.182 Central lymph node metastasis 0.835 0.383–1.822 0.651 Clinical stage 2.722 0.658–11.265 0.167 According to our analysis, the B-Raf V600E gene mutation was observed in 74.59% (138/185)of tumor tissues, CLT was observed in 22.7%(42/185) of them. In CLT patients, the B-Raf V600E gene mutation was 59.52%(25/42), in non-CLT ones, it was 79.02%(113/143), the incidence of B-Raf V600E gene mutation was lower in CLT group. Discussion It is currently unknown whether the rise in PTC occurrence worldwide is due to improved diagnostic techniques, or the increased morbidity, but the former seems to be more important. As we all known, B-Raf V600E gene mutation has been proven to be an oncogene in PTC(6), typically resulting in the constitutive activation of the MAPK/ERK pathway, inducing excessive proliferation and differentiation of tumor cells, strongly related to advanced clinicopathological characteristics and poor prognosis[ 6 , 19 ], through upregulated of immune checkpoints and cancer-associated fibroblasts and downregulated of CD8 + T cells and endothelial cells[ 20 ]. Smallridge RC had found that compared with B-Raf wild type, in PTC patients, B-Raf V600E gene mutation could reduce expression of inflammatory response through lymphocyte infiltration(21). CLT was unknown up to the late 1950s, and now its incidence has been steadily increase, the exact etiology of CLT remains unclear. The relationship between CLT and PTC has been a topic of intense debate over the past two decades: ①through autoimmune response, CLT increases TSH level, chronically stimulates thyroid, causes cellular damage, promotes the appearance of PTC [ 10 , 22 ].The proposed mechanisms may include RET/PTC, B-Raf gene, reactive oxygen species, oxidative stress, cell cycle and apoptosis, DNA damage and repair, immune tolerance and so on ( 9,23–25). ②Through inducing immunologic response to pre-existing PTC, destructing of tumor cells, inhibiting neoplastic transformation or tumor progression, lessening the invasive potential of tumor(12), CLT plays a protective role, the proposed mechanisms may include Fas-mediated apoptotic pathway, production of IL-1 from lymphocytes, activated cytotoxic T cells, MHC class I expression, and other genetic mechanisms(26–28). Our study showed a coexistence between PTC and B-Raf V600E gene mutation was 74.59%; a coexistence between PTC and CLT was 22.7%, which was similar with Kim WW and Ma B (6, 29). The incidence of B-Raf V600E gene mutation was lower in CLT group, previous articles supported our result (30, 31, 6). We observed that the presence of CLT played a protective role in PTC with B-Raf V600E gene mutation, the same with Borowczyk M and Zeng RC (12, 32), a negative association between CLT and B-Raf V600E gene mutation induced poor clinicopathological characteristics was also proposed (33,7). And the size of tumor was a risk factor. It was also showed that coexistent CLT was more prevalent in female PTC patients, and female was a risk factor,‌ Ma B found the same result[ 29 ]. Molnár et al. proposed that in CLT-PTC patients, B-Raf may not an oncogene in tumor progression(34), and we found B-Raf V600E gene mutation played a protective role . In CLT-PTC patients, total thyroidectomy should be taken because of the higher incidence of multifocality(23); with B-Raf V600E gene mutation, total thyroidectomy should be considered, too(35); as B-Raf wild type patients, in the absence of other risk factors, more conservative thyroidectomy should be performed to reduce postoperative complications(7). Because of the autoimmune process, CLT-PTC patients are more likely to have suspicious lymph nodes metastases as false positive imaging results, surgeons should keep this in mind to avoid unnecessary interventions(23). However, Chen et al. indicate that in CLT-PTC patients, B-Raf V600E gene mutation might not have a valuable predictive role for central lymph node metastasis, and they provided a nomogram to predict central lymph node metastasis [ 36 ]. As for with larger tumor size patients, the appropriate treatment plan with close monitoring should be taken(29). Whether through inherently protective effect or lower prevalence of B-Raf V600E gene mutation, there is no consensus on the interplay between CLT and B-Raf V600E gene mutation in PTC. The interplay maybe a potential treatment option in advanced TC, and it needs to be explored in the future. There were some limitations in our article:1) we did not include any stage III or IV PTC patients;2) because of the short time, we couldn’t get enough data such as recurrence, disease-free survival or rate of distant metastases in these patients. Longer time follow-up, larger sample of patients and multiple institutions’ participation are needed to further investigate the interplay between CLT and B-Raf V600E gene mutation in PTC. Conclusion In PTC patients, B-Raf V600E gene mutation and CLT were in association with clinicopathological characteristics. Further investigation for the interplay between CLT and B-Raf V600E gene mutation in PTC needs to be done. Declarations Ethics approval and consent to participate: The present study was approved by the Clinical Trial Ethics Committee of Yantai Yuhuangding Hospital. Consent for publication: Not applicable. Availability of data and materials: The datasets used during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. Funding: Not applicable. Authors' contributions: HD C analyzed and interpreted the patient data and was a major contributor in writing the manuscript. WZ W performed the collection of the patient data. DW was responsible for the conception and design of the study. All authors read and approved the final manuscript. Acknowledgements: Not applicable. References Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh J W W, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012.Eur J Cancer. 2013;49:1374-403. 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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-6240454","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":439527986,"identity":"1719b11b-8fe1-43e6-9624-761eedd810fd","order_by":0,"name":"Haidi Chu","email":"","orcid":"","institution":"Yantaishan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Haidi","middleName":"","lastName":"Chu","suffix":""},{"id":439527987,"identity":"fd6c4e89-35a5-46f9-9eea-17d5dddae23c","order_by":1,"name":"Wanzhong Zhao","email":"","orcid":"","institution":"Yantaishan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wanzhong","middleName":"","lastName":"Zhao","suffix":""},{"id":439527988,"identity":"da99b177-50a4-4f78-87ab-522bcf685900","order_by":2,"name":"Dong Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBklEQVRIie2QsUrEQBCGZxnYar20CSL4CAOBRSGcD2KT5SBVFB/gioBwV6ZNpa8Q8QVyDGijpE1hERDE4ortDWhiJ0filYL7FbPw73z87AI4HH+XCgCHk6K5h8jtnsrgXCWLYC0T2k/5rrEsylod+1O79PjM79C9mHztbawlxJAVECyj81Hl6TI5Eas3UzBiUJCcaT6oWnhILrIRRVepJpGxyRjhUJFCzbN4SMaVeqsJOja3fcuHIl/cXw9zSmnSsAXJpmSUfQuJEn9RzpqtBrPi8I5RnxYUL3zuPzmeeEuQp6G1HR/d1JvXxnafcy9nbu0yGlV6pB/vZLvJD9BO3zscDse/5wvqVl0jfzFeeQAAAABJRU5ErkJggg==","orcid":"","institution":"Affiliated Hospital of Qingdao University, Yantai Yuhuangding Hospital","correspondingAuthor":true,"prefix":"","firstName":"Dong","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-03-17 03:08:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6240454/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6240454/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80813568,"identity":"3b4a7a2c-6b48-4529-b85a-063bc598f1e6","added_by":"auto","created_at":"2025-04-17 10:41:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":37185,"visible":true,"origin":"","legend":"\u003cp\u003ethe analysis of B-Raf\u003csup\u003eV600E\u0026nbsp; \u003c/sup\u003ewith PTC clinicopathological characteristics\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6240454/v1/cd0939f15198ee3d24f62ff0.png"},{"id":80813569,"identity":"123b00e4-5f29-4e96-906c-c4abaa5f1208","added_by":"auto","created_at":"2025-04-17 10:41:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":35637,"visible":true,"origin":"","legend":"\u003cp\u003ethe analysis of CLT with PTC clinicopathological characteristics\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6240454/v1/32b96624922d236baabf5d84.png"},{"id":84638130,"identity":"558112ed-bae1-468e-812b-9ae623899b66","added_by":"auto","created_at":"2025-06-15 13:31:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":518374,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6240454/v1/7d054c78-92db-4b9e-bb6e-6176c96f7c57.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eThe role of B-Raf V\u003csup\u003e600E\u003c/sup\u003e Gene Mutation and chronic lymphocytic thyroiditis in papillary thyroid carcinoma\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eThyroid carcinoma(TC) is the most widespread endocrine malignancy in the whole world, and the incidence has been up to tenfold in the last 30 years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Among the different pathological types of TC, PTC is well-differentiated, accounting for about 80% of all TC[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], with the most favorable prognosis: 10-year survival rate has been up to 93%[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The excellent prognosis is related to several factors, such as age, tumor size, lymph node metastasis, clinical stage, and so on[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eB‑Raf belongs to the Raf kinase family, encodes a serine-threonine kinase, is an activator of the MAPK/ERK pathway. The pathway is responsible for transferring signals from the extracellular matrix to the nucleus, to control cell cycle, proliferation, growth, and survival. With a specific B‑Raf mutation, V600E, kinase activity is enhanced almost 500-fold, typically resulted in constitutive activation of the MAPK/ERK pathway and subsequent development of PTC[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCLT, also known as Hashimoto\u0026rsquo;s thyroiditis, is an autoimmune tissue-specific thyroid inflammatory disease, with histologically characterized by extensive infiltration of auto-reactive T and B cells, parenchymal atrophy, and fibrosis. CLT is the most frequently inflammatory disease of thyroid gland, also the most common reason for hypothyroidism in iodine-sufficient countries [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Likewise, CLT incidence has been rapidly rising worldwide, about 0.3\u0026ndash;1.5 per 1000 individuals [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], currently younger patients are diagnosed than before[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].Coexistence of TC and CLT was suggested firstly in 1955 by Dailey [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Lately, various studies had mentioned the rate for coexistence of TC and CLT was ranged up to 45% [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15 CR16 CR17\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. It is still a matter of debate whether CLT plays a promoting or inhibiting role in PTC progression.\u003c/p\u003e \u003cp\u003eIn this study, we intended to investigate whether B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation and CLT were in association with PTC patients\u0026rsquo; clinicopathological characteristics, and the possible interplay between them.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePatients and Statistical analysis\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e1. Patients:\u003c/p\u003e \u003cp\u003e 185 participants who had undergone different thyroidectomy for PTC at the Affiliated Hospital of Qingdao University \u0026ndash; Yantai YuHuangDing Hospital from April 2022 to March 2024 were enrolled. All of them were untreated before (such as drugs, surgeries or ablation), finished the clinical examinations including ultrasonography and computed tomography of the neck to establish pre-operative assessment. All patients were diagnosed PTC based on postoperative histopathological analysis by two experienced pathologists. The patients\u0026rsquo; gender, age, the status of B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation, CLT, the size of tumor, single/multifocality, family history, muscle invasion, capsular infiltration, central lymph node metastasis and clinical stage were recorded. We chose the diameter of the largest one when there was multifocality. Patient considered benign tumor, re-operation, distant metastasis or refused surgery was excluded.\u003c/p\u003e \u003cp\u003eIn our article, B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation and CLT were demonstrated by histopathology, as the pathologic definition was the gold standard.\u003c/p\u003e \u003cp\u003e2. Statistical analysis\u003c/p\u003e \u003cp\u003eStatistical analysis was mainly performed using software package SPSS20.0. Patients\u0026rsquo; information and clinicopathological characteristics were analyzed retrospectively using logistic regression analysis, and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 had been chosen as significant.\u003c/p\u003e"},{"header":"Result","content":"\u003cp\u003eThere were totally 185 patients rolled in our study, consisting of 40 male and 145 female; 132 patients were younger than 55 years, 53 patients were elder; the B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation was observed in138 tumor tissues, wild type was observed in 47; patients with CLT were 42,non-CLT were 143; measuring tumor diameter\u0026thinsp;\u0026lt;\u0026thinsp;1cm was 67, \u0026ge;\u0026thinsp;1 cm was 118; 124 patients had single tumor, whereas 61 had multifocality;13 patients with family history and 172 without; 23 patients had muscle invasion and 162 without; 61 patients were found capsular infiltration and 124 without; 100 patients had positive central lymph node and 85 without; 161 patients had TNM stageⅠ, 24 had TNM stageⅡ(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\u003e185 PTCs' clinicopathological characteristics\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\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;55years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e132\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;55years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB-Raf\u003csup\u003eV600E\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCLT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e143\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize of tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle/Multifocality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultifocality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e172\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e162\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCapsular infiltration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCentral lymph node metastasis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅠ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e161\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e185\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\u003eFrom our analysis we could find, the B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation was associated with CLT(OR\u0026thinsp;=\u0026thinsp;0.335,P\u0026thinsp;=\u0026thinsp;0.009) and the size of tumor (OR\u0026thinsp;=\u0026thinsp;3.751,P\u0026thinsp;=\u0026thinsp;0.004). However, presence of the B-Raf\u003csup\u003eV600E\u003c/sup\u003e mutation was not associated with other clinicopathological features, including gender(OR\u0026thinsp;=\u0026thinsp;0.723,P\u0026thinsp;=\u0026thinsp;0.535), age(OR\u0026thinsp;=\u0026thinsp;2.229, 0.097), single/multifocality(OR\u0026thinsp;=\u0026thinsp;0.675,P\u0026thinsp;=\u0026thinsp;0.328), family history(OR\u0026thinsp;=\u0026thinsp;0.618,P\u0026thinsp;=\u0026thinsp;0.449), muscle invasion(OR\u0026thinsp;=\u0026thinsp;0.591,P\u0026thinsp;=\u0026thinsp;0.407), capsular infiltration(OR\u0026thinsp;=\u0026thinsp;1.442,P\u0026thinsp;=\u0026thinsp;0.444), central lymph node metastasis(OR\u0026thinsp;=\u0026thinsp;1.289,P\u0026thinsp;=\u0026thinsp;0.519) and clinical stage(OR\u0026thinsp;=\u0026thinsp;1.097,P\u0026thinsp;=\u0026thinsp;0.89) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\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\u003ethe analysis of B-RafV600E with PTC clinicopathological characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.723\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.259\u0026ndash;2.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.535\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.229\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.865\u0026ndash;5.746\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.097\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCLT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.335\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.147\u0026ndash;0.759\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize of tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.751\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.542\u0026ndash;9.122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle/Multifocality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.675\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.307\u0026ndash;1.483\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.328\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.618\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.178\u0026ndash;2.144\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.449\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.591\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.171\u0026ndash;2.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.407\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCapsular infiltration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.442\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.566\u0026ndash;3.675\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.444\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCentral lymph node metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.307\u0026ndash;1.483\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.519\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.097\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.293\u0026ndash;4.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.89\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 \u003c/p\u003e \u003cp\u003eCLT was associated with gender(OR\u0026thinsp;=\u0026thinsp;3.271,P\u0026thinsp;=\u0026thinsp;0.043) and B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation(OR\u0026thinsp;=\u0026thinsp;0.341,P\u0026thinsp;=\u0026thinsp;0.01). Analysis regarding the correlation between age(OR\u0026thinsp;=\u0026thinsp;1.787,P\u0026thinsp;=\u0026thinsp;0.267), single/multifocality(OR\u0026thinsp;=\u0026thinsp;0.905,P\u0026thinsp;=\u0026thinsp;0.803), family history(OR\u0026thinsp;=\u0026thinsp;0.764,P\u0026thinsp;=\u0026thinsp;0.712), muscle invasion(OR\u0026thinsp;=\u0026thinsp;0.609,P\u0026thinsp;=\u0026thinsp;0.521), capsular infiltration(OR\u0026thinsp;=\u0026thinsp;0.511,P\u0026thinsp;=\u0026thinsp;0.182), central lymph node metastasis(OR\u0026thinsp;=\u0026thinsp;0.835,P\u0026thinsp;=\u0026thinsp;0.651) and clinical stage(OR\u0026thinsp;=\u0026thinsp;2.722,P\u0026thinsp;=\u0026thinsp;0.167) did not yield any perceivable significant (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ethe analysis of CLT with PTC clinicopathological characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.271\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.037\u0026ndash;10.322\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.787\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.641\u0026ndash;4.983\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.267\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB-Raf\u003csup\u003eV600E\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.341\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.150\u0026ndash;0.774\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize of tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.846\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.840\u0026ndash;4.060\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle/Multifocality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.905\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.412\u0026ndash;1.989\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.803\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.764\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.184\u0026ndash;3.180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.712\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.609\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.133\u0026ndash;2.775\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.521\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCapsular infiltration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.511\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.190\u0026ndash;1.371\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.182\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCentral lymph node metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.835\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.383\u0026ndash;1.822\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.651\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.722\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.658\u0026ndash;11.265\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.167\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 \u003c/p\u003e \u003cp\u003eAccording to our analysis, the B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation was observed in 74.59% (138/185)of tumor tissues, CLT was observed in 22.7%(42/185) of them. In CLT patients, the B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation was 59.52%(25/42), in non-CLT ones, it was 79.02%(113/143), the incidence of B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation was lower in CLT group.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIt is currently unknown whether the rise in PTC occurrence worldwide is due to improved diagnostic techniques, or the increased morbidity, but the former seems to be more important.\u003c/p\u003e \u003cp\u003eAs we all known, B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation has been proven to be an oncogene in PTC(6), typically resulting in the constitutive activation of the MAPK/ERK pathway, inducing excessive proliferation and differentiation of tumor cells, strongly related to advanced clinicopathological characteristics and poor prognosis[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], through upregulated of immune checkpoints and cancer-associated fibroblasts and downregulated of CD8\u0026thinsp;+\u0026thinsp;T cells and endothelial cells[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Smallridge RC had found that compared with B-Raf wild type, in PTC patients, B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation could reduce expression of inflammatory response through lymphocyte infiltration(21).\u003c/p\u003e \u003cp\u003eCLT was unknown up to the late 1950s, and now its incidence has been steadily increase, the exact etiology of CLT remains unclear. The relationship between CLT and PTC has been a topic of intense debate over the past two decades: ①through autoimmune response, CLT increases TSH level, chronically stimulates thyroid, causes cellular damage, promotes the appearance of PTC [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].The proposed mechanisms may include RET/PTC, B-Raf gene, reactive oxygen species, oxidative stress, cell cycle and apoptosis, DNA damage and repair, immune tolerance and so on ( 9,23\u0026ndash;25). ②Through inducing immunologic response to pre-existing PTC, destructing of tumor cells, inhibiting neoplastic transformation or tumor progression, lessening the invasive potential of tumor(12), CLT plays a protective role, the proposed mechanisms may include Fas-mediated apoptotic pathway, production of IL-1 from lymphocytes, activated cytotoxic T cells, MHC class I expression, and other genetic mechanisms(26\u0026ndash;28).\u003c/p\u003e \u003cp\u003eOur study showed a coexistence between PTC and B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation was 74.59%; a coexistence between PTC and CLT was 22.7%, which was similar with Kim WW and Ma B (6, 29). The incidence of B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation was lower in CLT group, previous articles supported our result (30, 31, 6). We observed that the presence of CLT played a protective role in PTC with B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation, the same with Borowczyk M and Zeng RC (12, 32), a negative association between CLT and B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation induced poor clinicopathological characteristics was also proposed (33,7). And the size of tumor was a risk factor. It was also showed that coexistent CLT was more prevalent in female PTC patients, and female was a risk factor,\u0026zwnj; Ma B found the same result[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Moln\u0026aacute;r et al. proposed that in CLT-PTC patients, B-Raf may not an oncogene in tumor progression(34), and we found B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation played a protective role .\u003c/p\u003e \u003cp\u003eIn CLT-PTC patients, total thyroidectomy should be taken because of the higher incidence of multifocality(23); with B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation, total thyroidectomy should be considered, too(35); as B-Raf wild type patients, in the absence of other risk factors, more conservative thyroidectomy should be performed to reduce postoperative complications(7). Because of the autoimmune process, CLT-PTC patients are more likely to have suspicious lymph nodes metastases as false positive imaging results, surgeons should keep this in mind to avoid unnecessary interventions(23). However, Chen et al. indicate that in CLT-PTC patients, B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation might not have a valuable predictive role for central lymph node metastasis, and they provided a nomogram to predict central lymph node metastasis [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. As for with larger tumor size patients, the appropriate treatment plan with close monitoring should be taken(29).\u003c/p\u003e \u003cp\u003eWhether through inherently protective effect or lower prevalence of B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation, there is no consensus on the interplay between CLT and B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation in PTC. The interplay maybe a potential treatment option in advanced TC, and it needs to be explored in the future.\u003c/p\u003e \u003cp\u003eThere were some limitations in our article:1) we did not include any stage III or IV PTC patients;2) because of the short time, we couldn\u0026rsquo;t get enough data such as recurrence, disease-free survival or rate of distant metastases in these patients. Longer time follow-up, larger sample of patients and multiple institutions\u0026rsquo; participation are needed to further investigate the interplay between CLT and B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation in PTC.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn PTC patients, B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation and CLT were in association with clinicopathological characteristics. Further investigation for the interplay between CLT and B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation in PTC needs to be done.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: The present study was approved by the Clinical Trial Ethics Committee of Yantai Yuhuangding Hospital.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication: Not applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: The datasets used during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding: Not applicable.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions: HD C analyzed and interpreted the patient data and was a major contributor in writing the manuscript. WZ W performed the collection of the patient data. DW was responsible for the conception and design of the study. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFerlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh J W W, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012.Eur J Cancer. 2013;49:1374-403. \u003c/li\u003e\n\u003cli\u003eMorris LG, Sikora AG, Tosteson TD, Davies Louise. The increasing incidence of thyroid cancer: the influence of access to care. Thyroid. 2013;23:885-91.\u003c/li\u003e\n\u003cli\u003eAbdullah MI, Junit SM, Ng KL, Jayapalan JJ, Karikalan B, Hashim OH. Papillary thyroid cancer: genetic alterations and molecular biomarker investigations. Int J Med Sci. 2019;16:450-60.\u003c/li\u003e\n\u003cli\u003eCampos LA, Picado SM, Guimar\u0026atilde;es AV, Ribeiro DA, Dedivitis RA. 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Pathol Oncol Res.2019;25:1191-7. \u003c/li\u003e\n\u003cli\u003eKrajewska J, Chmielik E, Dedecjus M, Jarzą b B, Hubalewska-Dydejczyk A, Karbownik-Lewińska M, et al. Diagnosis and treatment of thyroid cancer in adult patients - Recommendations of Polish Scientific Societies and the National Oncological Strategy. Update of the 2022 Update [Diagnostyka i leczenie raka tarczycy u chorych dorosłych - Rekomendacje Polskich. Endokrynologia Polska.2022;73:799-802.\u003c/li\u003e\n\u003cli\u003eChen Y, Zhao S, Zhang Z, Chen Z, Jiang B, An M, et al. A comprehensive prediction model for central lymph node metastasis in papillary thyroid carcinoma with Hashimoto\u0026rsquo;s thyroiditis: BRAF may not be a valuable predictor. Front Endocrinol (Lausanne).2024;15:1429382.\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":"Papillary thyroid carcinoma, B-RafV600E gene mutation, Chronic lymphocytic thyroiditis","lastPublishedDoi":"10.21203/rs.3.rs-6240454/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6240454/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOur aim of this article was to investigate in the papillary thyroid carcinoma(PTC) patients, whether B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation and chronic lymphocytic thyroiditis(CLT) were in association with their clinicopathological characteristics and the interplay between them.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe had chosen 185 PTC patients who had treated in Affiliated Hospital of Qingdao University \u0026ndash;Yantai YuHuangDing Hospital and Yantaishan Hospital during April 2023 to March 2024.We recorded gender, age, the status of B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation, CLT or not, the size of tumor, single/multifocality, family history, muscle invasion, capsular infiltration, central lymph node metastasis and clinical stage, analyzed them using logistic regression analysis by SPSS20.0.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThere were 185 patients, 138 patients were with B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation and 47 with wild type, the percentage of B-Raf\u003csup\u003eV600E\u003c/sup\u003e mutation was 74.59%, and the B-Raf\u003csup\u003eV600E\u003c/sup\u003e mutation had correlation with CLT(OR\u0026thinsp;=\u0026thinsp;0.335,P\u0026thinsp;=\u0026thinsp;0.009) and the size of tumor (OR\u0026thinsp;=\u0026thinsp;3.751,P\u0026thinsp;=\u0026thinsp;0.004). 42 patients were with CLT and 143 not, the percentage of CLT was 74.59%, and CLT had correlation with gender(OR\u0026thinsp;=\u0026thinsp;3.271,P\u0026thinsp;=\u0026thinsp;0.043) and B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation status (OR\u0026thinsp;=\u0026thinsp;0.341,P\u0026thinsp;=\u0026thinsp;0.01).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIn PTC patients, B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation and CLT were in association with clinicopathological characteristics. Further investigation for the interplay between CLT and B-Raf\u003csup\u003eV600E\u003c/sup\u003e gene mutation in PTC needs to be done.\u003c/p\u003e","manuscriptTitle":"The role of B-Raf V600E Gene Mutation and chronic lymphocytic thyroiditis in papillary thyroid carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-17 10:41:39","doi":"10.21203/rs.3.rs-6240454/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":"63d04cce-6b74-4c49-b33a-c3d6d380f8a6","owner":[],"postedDate":"April 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-15T13:23:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-17 10:41:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6240454","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6240454","identity":"rs-6240454","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}