Survival Analysis of Adjuvant Therapy in Stage I STAS-Positive Lung Adenocarcinoma Patients Undergoing Different Surgical Approaches

Survival Analysis of Adjuvant Therapy in Stage I STAS-Positive Lung Adenocarcinoma Patients Undergoing Different Surgical Approaches | 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 Survival Analysis of Adjuvant Therapy in Stage I STAS-Positive Lung Adenocarcinoma Patients Undergoing Different Surgical Approaches yanfeng dong, Shihu Liu, Yongjie Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8434927/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background Recent research on spread through air spaces (STAS) has gained prominence. The presence of STAS is not only an independent factor associated with lung cancer recurrence and prognosis, but it remains unclear whether adjuvant therapy (AT) affects survival in STAS-positive stage I lung adenocarcinoma (ADC) patients undergoing different surgical approaches. Methods A retrospective analysis was conducted on patients with pT1-2aN0M0 ADC who underwent complete resection at the Department of Thoracic Surgery, Qingdao University Affiliated Hospital, between 2019 and 2021. Among these, 528 cases with pathologically confirmed STAS were ultimately included. Propensity score matching (PSM) was employed to match patients across different groups. Kaplan-Meier analysis and Cox proportional hazards regression models were employed to evaluate surgical approaches and validate whether AT confers a survival benefit in patients with STAS undergoing different surgical procedures. Results Among stage I ADC patients with STAS, matched patients undergoing sublobar resection versus lobectomy demonstrated a significant difference in recurrence-free survival (RFS) (P = 0.0019) but no significant difference in overall survival (OS) (P = 0.61). Multivariate analysis confirmed these findings. (Lobectomy vs. Sublobar resection, OS: HR = 0.24, 95% CI, 0.10–0.56, P = 0.001; RFS: HR = 0.19, 95% CI, 0.11–0.34, P < 0.001). Patients undergoing sublobar resection achieved superior 5-year RFS following adjuvant therapy (P = 0.0046), with recurrence rates nearly comparable to lobectomy (5.9% vs 8.9%). However, adjuvant therapy did not improve 5-year RFS in patients undergoing lobectomy (P = 0.76). Multivariate analysis results are as follows (adjuvant therapy vs. no adjuvant therapy): OS: HR = 0.18, 95% CI, 0.07–0.49, P = < 0.001; RFS: HR = 0.15, 95% CI 0.07–0.32, P = < 0.001). Conclusion In stage I adenocarcinoma patients with STAS, lobectomy yields superior outcomes compared to sublobar resection. Patients undergoing sublobar resection with pathologically confirmed STAS may benefit from adjuvant therapy. Spread through air spaces Lung adenocarcinoma Surgical approach Adjuvant therapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Lung cancer remains the leading cause of cancer mortality worldwide 1 , 2 , with adenocarcinoma being the most prevalent subtype of non-small cell lung cancer (NSCLC). This category encompasses histological subtypes, including well-differentiated, acinar, papillary, micropapillary, and solid adenocarcinoma 3 . The 2015 World Health Organisation (WHO) classification of lung cancer pathologies introduced STAS for the first time, defined as the presence of micropapillary cell clusters, solid cell nests, or solitary tumour cells within air spaces beyond the primary tumour margin 4 . Beyond the conventional ADC infiltration patterns (involvement of stroma, vasculature, and pleura), STAS has been identified as a novel mode of pulmonary invasive adenocarcinoma, often associated with higher recurrence rates and poorer survival outcomes 5 – 8 . Lobectomy has long been the standard surgical approach for stage I NSCLC. In recent years, with advances in imaging and surgical techniques, sublobar resection has gained widespread application for small nodules or patients with poorer general health. Multiple clinical trials and observational studies comparing sublobar resection versus lobectomy in stage I NSCLC patients have reported comparable recurrence rates and long-term survival rates 9 , 10 . However, for patients with STAS, a growing body of research suggests that lobectomy and sublobar resection may correspond to different overall survival (OS) and recurrence-free survival (RFS) outcomes 11 – 13 . For stage II and some stage III patients, AT may improve survival rates 14 ; however, for stage I patients, whether AT enhances survival remains inconclusive 15 – 17 , particularly for those with SATS, where AT may potentially be associated with better prognosis 18 – 20 . And for patients who have already undergone different surgical procedures, will AT produce different effects for them? This retrospective analysis, therefore, examines whether different surgical approaches and adjuvant therapy (AT) influence survival outcomes in stage I adenocarcinoma (ADC) patients with SATS. Method Patient Selection : This study was approved by the Ethics Committee of Qingdao University Affiliated Hospital. As a retrospective study design, patient-informed consent was waived. The retrospective review examined patients with pT1-2aN0M0 adenocarcinoma of the lung who underwent surgical resection with complete excision at the Thoracic Surgery Department of Qingdao University Affiliated Hospital between 2019 and 2021, all possessing complete follow-up data. Patients meeting any of the following criteria were excluded: 1. History of malignant tumour disease, 2. Preoperative tumour-related adjuvant therapy 3. Multiple primary lung cancers 4. Loss to follow-up. This study strictly adhered to the Declaration of Helsinki. Due to the retrospective nature of the design, informed consent was waived. Data analysed and reported in our study were derived from existing medical records, ensuring patient anonymity and privacy. The patient selection process is illustrated in Fig. 1 . Age at surgery, gender, histological type, pathological tumour-lymph node-metastasis staging, surgical approach, nodular pattern, pleural involvement, and other clinical-pathological characteristics were standardised, recorded, and analysed 21 . Wedge resection and segmentectomy of the lung were categorised as sublobar resection, lobectomy was defined as anatomic lobectomy plus radical mediastinal lymph node dissection. The choice of surgical approach was determined based on the patient's preoperative investigations, imaging studies, and individual tolerance. Postoperatively, adjuvant therapy (AT), including but not limited to chemotherapy, radiotherapy, and targeted therapy, was recommended for patients with high-risk recurrence factors (e.g., high-risk histological type, poorly differentiated tumour, high stage, and vascular/lymphatic invasion). The final decision regarding AT administration depended on postoperative pathological findings and patient preference. Histological assessment All resected specimens were immediately fixed in formalin and stained with haematoxylin and eosin. Sections are independently reviewed and summarised by two pathologists, with specimens classified according to the IASLC/ATS/ERS histological classification of pulmonary invasive adenocarcinoma 3 . Pulmonary invasive adenocarcinoma is categorised as well-differentiated, acinar, micropapillary, papillary, or solid based on the predominant tumour growth pattern (even if < 50%) 3 . Additional relevant pathological findings, such as differentiation grade and vascular/lymphatic invasion, were also recorded and collated. STAS lesions were defined as the spread of micropapillary clusters, solid nests, and/or solitary cancer cells into the air spaces of the lung parenchyma beyond the margins of the primary tumour 5 . Postoperative follow-up Patients were examined every three months during the first year post-resection, followed by six-monthly intervals thereafter. We then collated hospital and outpatient records or conducted telephone follow-ups to document patients' postoperative management. Recurrence-free survival (RFS) was defined as the time from the surgical date to the first recurrence or last follow-up. Local recurrence was defined as recurrence in ipsilateral hilar or mediastinal lymph nodes, ipsilateral pleura, or ipsilateral lung lobe. Distant recurrence was defined as recurrence in contralateral hilar or mediastinal lymph nodes, contralateral lung lobe, contralateral pleura, or other organs. All recurrences were confirmed by clinical, imaging, and pathological assessment. Overall survival (OS) is defined as the time interval between the date of surgery and the date of all-cause death or last follow-up. Statistical analysis : Continuous variables were analysed using t-tests and categorical variables using chi-square tests. RFS and OS were assessed using the Kaplan–Meier method, with log-rank tests comparing survival rate differences. Cox proportional hazards regression models assessed independent risk factors for RFS and OS. Patients were baseline-matched using propensity score matching (PSM) with a 1:1 ratio based on the nearest matching principle (matching tolerance: 0.02). All p-values were based on two-tailed statistical analysis, with p < 0.05 considered statistically significant. All statistical analyses were performed using R-studio (version 4.5.0). Results Patient characteristics and factor analysis Between 2019 and 2021, patients with pT1-2aN0M0 lung adenocarcinoma undergoing surgical resection with complete excision were enrolled. Among these, 528 patients were pathologically confirmed to have STAS postoperatively and included in our study. Clinical and pathological characteristics are summarised in Tables 1 and 2. Variables Adjuvant therapy No Adjuvant therapy p 128(24.2) 400 (75.8) Age (%) <60 52(40.6) 209(52.3) 0.023 ≥ 60 76(59.4) 191(47.4) Sex (%) Male 69 (53.9) 180 (45.0) 0.098 Female 59 (46.1) 220 (55.0) Smoking (%) No 103 (80.5) 296 (74.0) 0.172 Yes 25 (19.5) 104 (26.0) T (%) T1a 9 (7.0) 48 (12.0) < 0.001 T1b 37 (28.9) 203 (50.7) T1c 52 (40.6) 119 (29.8) T2a 30 (23.4) 30 (7.5) Surgical method (%) Sublobar resection 53 (41.4) 175 (43.8) 0.716 Lobectomy 75 (58.6) 225 (56.2) Survival status (%) Alive 121 (94.5) 366 (91.5) 0.355 Dead 7 (5.5) 34 (8.5) Recurrence status (%) No 118 (92.2) 330 (82.5) 0.014 Yes 10 (7.8) 70 (17.5) Histological type (%) Acinar 35 (27.3) 120 (30.0) 0.007 Micropapillary 55 (43.0) 110 (27.5) Papillary 17 (13.3) 58 (14.5) Solid 2 (1.6) 4 (1.0) Lepidic 19 (14.8) 108 (27.0) Degree of differentiation (%) Moderately to highly differentiated 123 (96.1) 384 (96.0) 1.000 Poorly differentiated 5 (3.9) 16 (4.0) Vascular invasion (%) Absence 117 (91.4) 390 (97.5) 0.005 Existence 11 (8.6) 10 (2.5) Invasion of the dirty pleura (%) Absence 111 (86.7) 372 (93.0) 0.042 Existence 17 (13.3) 28 (7.0) Tables 1: Clinicopathological characteristics of the 1,004 included patients Variables Sublobar resection Lobectomy p 228(43.2) 300(56.8) Age (%) <60 107(46.9) 154(51.3) 0.552 ≥ 60 121 (53.1) 146(48.7) Sex (%) Male 102 (44.7) 147 (49.0) 0.377 Female 126 (55.3) 153 (51.0) Smoking (%) No 165 (72.4) 234 (78.0) 0.165 Yes 63 (27.6) 66 (22.0) T (%) T1a 48 (21.1) 9 (3.0) < 0.001 T1b 123 (53.9) 117 (39.0) T1c 42 (18.4) 129 (43.0) T2a 15 (6.6) 45 (15.0) Adjuvant therapy (%) No Adjuvant 175 (76.8) 225 (75.0) 0.716 Adjuvant therapy 53 (23.2) 75 (25.0) Survival status (%) Alive 209 (91.7) 278 (92.7) 0.794 Dead 19 (8.3) 22 (7.3) Recurrence status (%) No 178 (78.1) 270 (90.0) < 0.001 Yes 50 (21.9) 30 (10.0) Histological type (%) Acinar 55 (24.1) 100 (33.3) < 0.001 Micropapillary 60 (26.3) 105 (35.0) Papillary 48 (21.1) 27 (9.0) Solid 6 (2.6) 0 (0.0) Lepidic 59 (25.9) 68 (22.7) Degree of differentiation (%) Moderately to highly differentiated 222 (97.4) 285 (95.0) 0.248 Poorly differentiated 6 (2.6) 15 (5.0) Vascular invasion (%) Absence 222 (97.4) 285 (95.0) 0.248 Existence 6 (2.6) 15 (5.0) Invasion of the dirty pleura (%) Absence 210 (92.1) 273 (91.0) 0.769 Existence 18 (7.9) 27 (9.0) Tables 2: Clinicopathological characteristics of the 1,004 included patients Among these, 300 patients underwent lobectomy, while 228 patients underwent sublobar resection; significant differences were observed in T stage (p < 0.001) and histological type (p < 0.001). Among the 128 patients who received adjuvant therapy postoperatively, differences were noted in T stage (p < 0.001), histological type (p = 0.007), and vascular invasion (p = 0.005), with a median follow-up period of 70 months. The results of univariate and multivariate analyses are presented in Table 3 . Table 3 Univariate and multivariate Cox regression analysis OS RFS Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis Variables p p HR (95% CI) p p HR (95% CI) Age(≤65 vs > 65) 0.672 0.569 0.99 (0.96–1.02) 0.192 0.219 1.02 (0.99–1.04) Sex(male vs female) 0.229 0.237 2.48 (0.55–11.14) 0.771 0.487 1.34 (0.58–3.08) Smoking(yes vs no) < 0.001 0.013 6.63 (1.50-29.34) 0.001 0.147 1.89 (0.80–4.48) Pathological staging(vs T1a) T1b 0.206 0.808 0.83 (0.19–3.66) 0.438 0.669 0.82 (0.33–2.03) T1c 0.231 0.025 4.33 (1.20–15.60) 0.466 0.032 2.64 (1.09–6.41) T2a 0.008 0.002 9.08 (2.24–36.69) 0.005 < 0.001 6.53 (2.53–16.86) Histological type(vs Acinar) Papillary 0.869 0.712 0.84 (0.33–2.15) 0.350 0.504 1.24 (0.66–2.32) Micropapillary 0.289 0.240 0.42 (0.10–1.77) 0.063 0.411 1.37 (0.65–2.92) Solid 0.024 0.970 0.96 (0.13–7.17) 0.111 0.899 0.90 (0.17–4.85) Lepidic 0.600 0.863 1.08 (0.44–2.67) 0.352 0.261 0.65 (0.30–1.38) Degree of differentiation < 0.001 < 0.001 13.12 (4.93–34.93) < 0.001 < 0.001 13.03 (6.29–26.99 Vascular invasion < 0.001 0.002 6.16 (1.92–19.74) 0.001 0.003 4.53 (1.65–12.41) Invasion of the dirty pleura < 0.001 < 0.001 5.38 (2.03–14.28) < 0.001 < 0.001 3.61 (1.86–7.02) Surgical method(Lob vs Sublobar) 0.680 0.001 0.24 (0.10–0.56) < 0.001 < 0.001 0.19 (0.11–0.34) Adjuvant therapy(with vs without) 0.262 < 0.001 0.18 (0.07–0.49) 0.012 < 0.001 0.15 0.07–0.32) In both univariate and multivariate analyses, surgical approach and adjuvant therapy demonstrated significant protective effects. Multivariate analysis comparing lobectomy versus sublobar resection yielded the following results: RFS: HR = 0.19, 95% CI 0.11–0.34, P < 0.001. Multivariate analysis comparing adjuvant therapy versus no adjuvant therapy yielded: OS: HR = 0.18, 95% CI 0.07–0.49, P < 0.001; RFS: HR = 0.15, 95% CI 0.07–0.32, P < 0.001. This suggests that STAS-positive patients undergoing lobectomy may derive superior survival benefit, while STAS-positive patients undergoing sublobar resection also exhibit improved prognosis with adjuvant therapy. Other factors, such as low differentiation (OS: HR = 13.12, 95% CI, 4.93–34.93, P = < 0.001; RFS: HR = 13.03, 95% CI 6.29–26.99, P = < 0.001) and higher stage (OS: HR = 9.08, 95% CI 2.24–36.69, P = 0.002; RFS: HR = 6.53, 95% CI, 2.53–16.86, P = < 0.001) and vascular invasion (OS: HR = 6.16, 95% CI, 1.92–19.74, P = 0.002; RFS: HR = 4.53, 95% CI, 1.65–12.41, P = 0.003) and pleural invasion (OS: HR = 5.38, 95% CI, 2.03–14.28, P = < 0.001; RFS: HR = 3.61, 95% CI, 1.86–7.02, P = < 0.001) were both strongly associated with poorer prognosis in factor analysis, whilst other factors such as smoking and high-risk histological types also demonstrated some predictive value for poorer outcomes. Impact of surgical approach on patient survival : Due to baseline imbalances in the selected patient cohorts, such as a significantly higher proportion of higher TNM stages in the lobectomy group versus the limited resection group prior to PSM (T2a: 15 [6.6%] vs 45 [15.0%]), along with notable differences in histological type (p < 0.001). Ultimately, incorporating multifactorial analysis and high-risk factors documented in the literature, we selected histological type, degree of differentiation, and pleural/vascular invasion for PSM matching across patient subgroups. Following the matching of 528 patients, 456 entered our survival analysis. Employing a 1:1 matching ratio yielded 228 patients in each subgroup. Survival analysis was then conducted on the matched cohort, with results presented in Fig. 2 . According to Kaplan–Meier survival analysis, matched patients in the lobectomy group and sublobar resection group demonstrated a significant difference in 5-year RFS (10.0% vs 21.9%, P = 0.0019), whereas no significant difference was observed in 5-year overall survival (OS) (7.3% vs 8.3%, P = 0.919). Furthermore, the aforementioned multivariate analysis confirmed that lobectomy constitutes a protective factor. Survival analysis of adjuvant therapy in patients undergoing different surgical procedures : Regarding adjuvant therapy (AT), 75 (25.0%) patients who underwent lobectomy received postoperative adjuvant therapy, while 53 (23.2%) patients who underwent sublobar resection received postoperative adjuvant therapy. The decision to administer postoperative adjuvant therapy was determined by the patient's condition and preference. We similarly employed the aforementioned factors to conduct a 1:1 propensity score matching analysis on two patient subgroups, resulting in 67 patients in the lobectomy group and 51 in the sublobar resection group. Kaplan-Meier survival analysis indicated a significant difference in recurrence-free survival (RFS) between patients who did and did not receive adjuvant therapy in the sublobar resection group, whereas no significant difference was observed in overall survival (OS: P = 0.7; RFS: P = 0.0046) (Fig. 3 ). However, no significant differences in RFS or OS were observed within the lobectomy group (OS: P = 0.71; RFS: P = 0.74) (Fig. 4 ). Discussion In the 2015 WHO classification of lung cancer, STAS was identified as a newly recognised pattern of invasion. Numerous studies have now established that the presence of STAS is a significant factor influencing increased postoperative recurrence risk and reduced survival duration in patients with adenocarcinoma of the lung (ADC) 11 – 13 , 22 , 23 . However, the impact of surgical approach and postoperative adjuvant therapy on the prognosis of stage I STAS-positive lung adenocarcinoma patients remains unclear. Particularly scarce are reports on whether stage I ADC patients with STAS benefit from adjuvant therapy following different surgical approaches. Our findings may offer some reference in this regard. After performing multivariate analysis on patients, we found that adjuvant therapy (overall survival: HR = 0.18, 95% CI, 0.07–0.49, P = < 0.001; RFS: HR = 0.15, 95% CI 0.07–0.32, P = < 0.001) and lobectomy (OS: HR = 0.24, 95% CI 0.10–0.56, P = 0.001; RFS: HR = 0.19, 95% CI, 0.11–0.34, P = < 0.001) demonstrated significant protective effects for patients. Conversely, low differentiation, higher stage, vascular invasion, and pleural invasion exhibited adverse effects in multivariate analysis, consistent with numerous prior studies 24 , 25 . To further validate the prognostic impact of AT across different surgical approaches, patients were stratified into lobectomy and sublobar resection cohorts. Given baseline imbalances due to confounding factors in multivariate analysis and multiple adverse prognostic factors (e.g., high-risk histology, pleural vascular invasion, poorly differentiated tumours) 26 – 28 , 1:1 propensity score matching was employed to optimise comparability and clarify STAS's prognostic significance. We performed 1:1 propensity score matching between patients in different subgroups. Following survival analysis of the matched cohort, our study confirmed that patients with stage I adenocarcinoma with STAS undergoing lobectomy demonstrated superior survival outcomes, particularly in 5-year recurrence-free survival (RFS) (10.0% vs 21.9%, P = 0.0019), compared to those undergoing sublobar resection. This establishes the prognostic significance of lobectomy in STAS patients. Regarding postoperative adjuvant therapy, no survival benefit was observed for stage I STAS patients undergoing lobectomy in terms of 5-year overall survival (OS: 6.0% vs 7.5%, P = 0.71) or 5-year RFS (9.0% vs 10.4%, p = 0.74). In contrast, among patients undergoing sublobar resection, postoperative adjuvant therapy demonstrated divergent prognostic outcomes between the treated and untreated groups (OS: 5.9% vs 7.8%, P = 0.7; RFS: 5.9% vs 27.5%, P = 0.0046), with adjuvant therapy improving RFS in sublobar resection recipients. From the above data, we can confidently conclude that STAS-positive patients may benefit from lobectomy, unlike previously established findings where lobectomy or sublobar resection yielded equivalent outcomes in STAS-negative patients. Moreover, for patients undergoing subtotal lobectomy, adjuvant therapy (AT) can protect against the adverse prognostic outcomes associated with STAS, which is highly significant. It also reminds us that for patients with stage I STAS, AT does not provide additional benefit; lobectomy alone is sufficient, thereby avoiding imposing further treatment burden on patients. It likewise offers guidance for managing STAS-positive patients postoperatively, aiding clinicians in determining the necessity of adjuvant therapy. The limitations of this study are as follows: firstly, being retrospective in nature, it may introduce Type II errors. Secondly, the number of patients receiving adjuvant therapy postoperatively within different groups was limited. Despite performing propensity score matching (PSM) on study subjects, some selection bias may still exist. Our study confirms that the presence of STAS impacts patient prognosis. However, there remains no accurate preoperative method to determine STAS presence, with diagnosis still heavily reliant on postoperative pathological examination. Conclusion The presence of STAS correlates with poor prognosis in stage I lung adenocarcinoma patients. Our study demonstrates that stage I patients with STAS undergoing lobectomy achieve superior outcomes compared to those undergoing sublobar resection. Adjuvant therapy did not confer additional survival benefit to stage I STAS patients undergoing lobectomy. However, it did improve outcomes for stage I patients undergoing sublobar resection, nearly achieving the same prognosis as lobectomy. Nevertheless, longer follow-up periods and more comprehensive data analysis are required to validate these findings. Declarations Ethics approval and consent to participate This article has been approved by the Ethics Committee of Qingdao University Affiliated Hospital. Authors' contributions Yanfeng Dong has made contributions to drafting the article, revision of article, and data interpretation. Shihu Liu and Yongjie Wang have made contributions to data interpretation. All authors read and approved the final manuscript. Availability of data and materials All data generated or analysed during this study are included in this published article. Competing interests The authors declare no competing interests. Funding This case report did not receive any financial support. Acknowledgements Not applicable 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;68:394–424. 10.3322/caac.21492 . Bade BC, Dela Cruz CS, Lung Cancer. 2020: Epidemiology, Etiology, and Prevention. 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Prognostic Impact of Margin Distance and Tumor Spread Through Air Spaces in Limited Resection for Primary Lung Cancer. J Thorac Oncol. 2017;12:1788–97. 10.1016/j.jtho.2017.08.015 . Kumbasar U. Spread through air spaces positivity and extent of resection in patients with Stage I non-small cell lung cancer: A contemporary review. Turk Gogus Kalp Damar Cerrahisi Derg. 2022;30:141–4. 10.5606/tgkdc.dergisi.2022.21284 . Chae M, et al. Prognostic significance of tumor spread through air spaces in patients with stage IA part-solid lung adenocarcinoma after sublobar resection. Lung Cancer. 2021;152:21–6. 10.1016/j.lungcan.2020.12.001 . Han YB, et al. Tumor spread through air spaces (STAS): prognostic significance of grading in non-small cell lung cancer. Mod Pathol. 2021;34:549–61. 10.1038/s41379-020-00709-2 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 20 Mar, 2026 Reviews received at journal 10 Feb, 2026 Reviewers agreed at journal 05 Feb, 2026 Reviewers agreed at journal 04 Feb, 2026 Reviewers invited by journal 04 Feb, 2026 Editor assigned by journal 05 Jan, 2026 Submission checks completed at journal 05 Jan, 2026 First submitted to journal 23 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8434927","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":586091760,"identity":"f45fc22c-f31c-4713-9f3a-571efccde4bd","order_by":0,"name":"yanfeng dong","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"yanfeng","middleName":"","lastName":"dong","suffix":""},{"id":586091762,"identity":"b86cee4a-065b-4825-9665-a6dd547a8707","order_by":1,"name":"Shihu Liu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Shihu","middleName":"","lastName":"Liu","suffix":""},{"id":586091765,"identity":"c1eaf68e-d1b3-4595-9f50-810f2edc28c4","order_by":2,"name":"Yongjie Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYDADxmYGxgcMbCBmAvFamA1I0wIEbBJEaTE4fvbwa56KO3bN7czHKt6UHWbgZ88xYPi5A4+WM3lp1jxnniU3NrOl3Zxz7jCDZM8bA8beM7i1mB3IMTPmbTuczNjMY3YbyGAwuJFjwMzYhkfL+TcwLfzfikFa7AlquZFj/Bio0g5oCxsz2BYJAlrsb7wxY5xz5nACYzObseScc+k8EmeeFRzsxaNFsj/H+MObisP2hv2HH354U2Ytx9+evPHBTzxagIBNioeBIXFjA5DJA0YMDAfwamBgYP74A+hAeQYGqPpRMApGwSgYBWgAANJEUwCY1rFVAAAAAElFTkSuQmCC","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Yongjie","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-12-23 14:38:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8434927/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8434927/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102296986,"identity":"3a06d1a9-2f92-4169-aca0-54107138ffc7","added_by":"auto","created_at":"2026-02-10 10:24:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1444486,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8434927/v1/38e1323bb7ba1e23ab2d771a.png"},{"id":102212442,"identity":"2085ebe9-eb46-42df-b911-bce190419d80","added_by":"auto","created_at":"2026-02-09 12:32:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":353280,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8434927/v1/c1df9420f5b973b3f922d8e1.png"},{"id":102212444,"identity":"9977b61c-930d-4118-ace1-c90fbaefcbe9","added_by":"auto","created_at":"2026-02-09 12:32:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":337675,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8434927/v1/c92c764008d7b5d23bbdd9c7.png"},{"id":102297018,"identity":"5ec6239a-e071-45ce-842e-732844906b0c","added_by":"auto","created_at":"2026-02-10 10:24:55","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":336329,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8434927/v1/262321155673f441eac90832.png"},{"id":102300358,"identity":"f192760c-70d0-4c80-9b8d-e2b0e9cdd632","added_by":"auto","created_at":"2026-02-10 11:13:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3204799,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8434927/v1/da4aa9be-cf84-4936-bea8-2370caaf74b4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Survival Analysis of Adjuvant Therapy in Stage I STAS-Positive Lung Adenocarcinoma Patients Undergoing Different Surgical Approaches","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLung cancer remains the leading cause of cancer mortality worldwide\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, with adenocarcinoma being the most prevalent subtype of non-small cell lung cancer (NSCLC). This category encompasses histological subtypes, including well-differentiated, acinar, papillary, micropapillary, and solid adenocarcinoma\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. The 2015 World Health Organisation (WHO) classification of lung cancer pathologies introduced STAS for the first time, defined as the presence of micropapillary cell clusters, solid cell nests, or solitary tumour cells within air spaces beyond the primary tumour margin\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Beyond the conventional ADC infiltration patterns (involvement of stroma, vasculature, and pleura), STAS has been identified as a novel mode of pulmonary invasive adenocarcinoma, often associated with higher recurrence rates and poorer survival outcomes\u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Lobectomy has long been the standard surgical approach for stage I NSCLC. In recent years, with advances in imaging and surgical techniques, sublobar resection has gained widespread application for small nodules or patients with poorer general health. Multiple clinical trials and observational studies comparing sublobar resection versus lobectomy in stage I NSCLC patients have reported comparable recurrence rates and long-term survival rates\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. However, for patients with STAS, a growing body of research suggests that lobectomy and sublobar resection may correspond to different overall survival (OS) and recurrence-free survival (RFS) outcomes\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. For stage II and some stage III patients, AT may improve survival rates\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e; however, for stage I patients, whether AT enhances survival remains inconclusive\u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, particularly for those with SATS, where AT may potentially be associated with better prognosis\u003csup\u003e\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. And for patients who have already undergone different surgical procedures, will AT produce different effects for them? This retrospective analysis, therefore, examines whether different surgical approaches and adjuvant therapy (AT) influence survival outcomes in stage I adenocarcinoma (ADC) patients with SATS.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003e \u003cb\u003ePatient Selection\u003c/b\u003e: This study was approved by the Ethics Committee of Qingdao University Affiliated Hospital. As a retrospective study design, patient-informed consent was waived. The retrospective review examined patients with pT1-2aN0M0 adenocarcinoma of the lung who underwent surgical resection with complete excision at the Thoracic Surgery Department of Qingdao University Affiliated Hospital between 2019 and 2021, all possessing complete follow-up data. Patients meeting any of the following criteria were excluded: 1. History of malignant tumour disease, 2. Preoperative tumour-related adjuvant therapy 3. Multiple primary lung cancers 4. Loss to follow-up. This study strictly adhered to the Declaration of Helsinki. Due to the retrospective nature of the design, informed consent was waived. Data analysed and reported in our study were derived from existing medical records, ensuring patient anonymity and privacy. The patient selection process is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAge at surgery, gender, histological type, pathological tumour-lymph node-metastasis staging, surgical approach, nodular pattern, pleural involvement, and other clinical-pathological characteristics were standardised, recorded, and analysed\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Wedge resection and segmentectomy of the lung were categorised as sublobar resection, lobectomy was defined as anatomic lobectomy plus radical mediastinal lymph node dissection. The choice of surgical approach was determined based on the patient's preoperative investigations, imaging studies, and individual tolerance. Postoperatively, adjuvant therapy (AT), including but not limited to chemotherapy, radiotherapy, and targeted therapy, was recommended for patients with high-risk recurrence factors (e.g., high-risk histological type, poorly differentiated tumour, high stage, and vascular/lymphatic invasion). The final decision regarding AT administration depended on postoperative pathological findings and patient preference.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eHistological assessment\u003c/strong\u003e \u003cp\u003eAll resected specimens were immediately fixed in formalin and stained with haematoxylin and eosin. Sections are independently reviewed and summarised by two pathologists, with specimens classified according to the IASLC/ATS/ERS histological classification of pulmonary invasive adenocarcinoma\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Pulmonary invasive adenocarcinoma is categorised as well-differentiated, acinar, micropapillary, papillary, or solid based on the predominant tumour growth pattern (even if\u0026thinsp;\u0026lt;\u0026thinsp;50%)\u003csup\u003e3\u003c/sup\u003e. Additional relevant pathological findings, such as differentiation grade and vascular/lymphatic invasion, were also recorded and collated. STAS lesions were defined as the spread of micropapillary clusters, solid nests, and/or solitary cancer cells into the air spaces of the lung parenchyma beyond the margins of the primary tumour\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003ePostoperative follow-up\u003c/strong\u003e \u003cp\u003ePatients were examined every three months during the first year post-resection, followed by six-monthly intervals thereafter. We then collated hospital and outpatient records or conducted telephone follow-ups to document patients' postoperative management. Recurrence-free survival (RFS) was defined as the time from the surgical date to the first recurrence or last follow-up. Local recurrence was defined as recurrence in ipsilateral hilar or mediastinal lymph nodes, ipsilateral pleura, or ipsilateral lung lobe. Distant recurrence was defined as recurrence in contralateral hilar or mediastinal lymph nodes, contralateral lung lobe, contralateral pleura, or other organs. All recurrences were confirmed by clinical, imaging, and pathological assessment. Overall survival (OS) is defined as the time interval between the date of surgery and the date of all-cause death or last follow-up.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical analysis\u003c/b\u003e: Continuous variables were analysed using t-tests and categorical variables using chi-square tests. RFS and OS were assessed using the Kaplan\u0026ndash;Meier method, with log-rank tests comparing survival rate differences. Cox proportional hazards regression models assessed independent risk factors for RFS and OS. Patients were baseline-matched using propensity score matching (PSM) with a 1:1 ratio based on the nearest matching principle (matching tolerance: 0.02). All p-values were based on two-tailed statistical analysis, with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered statistically significant. All statistical analyses were performed using R-studio (version 4.5.0).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cstrong\u003ePatient characteristics and factor analysis\u003c/strong\u003e \u003cp\u003eBetween 2019 and 2021, patients with pT1-2aN0M0 lung adenocarcinoma undergoing surgical resection with complete excision were enrolled. Among these, 528 patients were pathologically confirmed to have STAS postoperatively and included in our study. Clinical and pathological characteristics are summarised in Tables\u0026nbsp;1 and 2.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"5\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdjuvant therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo Adjuvant therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e128(24.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e400 (75.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAge (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52(40.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e209(52.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76(59.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e191(47.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSex (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 (53.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e180 (45.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.098\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (46.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e220 (55.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSmoking (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e103 (80.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e296 (74.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.172\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e104 (26.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eT (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e48 (12.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (28.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e203 (50.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52 (40.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e119 (29.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT2a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (23.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (7.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSurgical method (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSublobar resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 (41.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e175 (43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.716\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLobectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75 (58.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e225 (56.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSurvival status (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e121 (94.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e366 (91.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.355\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (8.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRecurrence status (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e118 (92.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e330 (82.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70 (17.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eHistological type (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAcinar\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e120 (30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMicropapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (43.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e110 (27.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (13.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58 (14.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (1.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLepidic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (14.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e108 (27.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDegree of differentiation (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModerately to highly differentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e123 (96.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e384 (96.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePoorly differentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVascular invasion (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e117 (91.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e390 (97.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExistence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (2.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eInvasion of the dirty pleura (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e111 (86.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e372 (93.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExistence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (13.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (7.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eTables\u0026nbsp;1: Clinicopathological characteristics of the 1,004 included patients\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"5\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSublobar resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLobectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e228(43.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e300(56.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAge (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e107(46.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e154(51.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.552\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e121 (53.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e146(48.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSex (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e102 (44.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e147 (49.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.377\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e126 (55.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e153 (51.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSmoking (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e165 (72.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e234 (78.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.165\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66 (22.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eT (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e123 (53.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e117 (39.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (18.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e129 (43.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT2a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (6.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45 (15.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAdjuvant therapy (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo Adjuvant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e175 (76.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e225 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.716\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjuvant therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 (23.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSurvival status (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e209 (91.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e278 (92.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.794\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDead\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (7.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRecurrence status (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e178 (78.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e270 (90.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (21.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (10.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eHistological type (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAcinar\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (24.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMicropapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60 (26.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e105 (35.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (9.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLepidic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (25.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68 (22.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDegree of differentiation (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModerately to highly differentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e222 (97.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e285 (95.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.248\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePoorly differentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVascular invasion (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e222 (97.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e285 (95.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.248\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExistence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (5.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eInvasion of the dirty pleura (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e210 (92.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e273 (91.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.769\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExistence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (7.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (9.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eTables\u0026nbsp;2: Clinicopathological characteristics of the 1,004 included patients\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong these, 300 patients underwent lobectomy, while 228 patients underwent sublobar resection; significant differences were observed in T stage (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and histological type (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Among the 128 patients who received adjuvant therapy postoperatively, differences were noted in T stage (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), histological type (p\u0026thinsp;=\u0026thinsp;0.007), and vascular invasion (p\u0026thinsp;=\u0026thinsp;0.005), with a median follow-up period of 70 months. The results of univariate and multivariate analyses are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e3\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 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate Cox regression analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eRFS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(\u0026le;65 vs\u0026thinsp;\u0026gt;\u0026thinsp;65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.672\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.569\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.99 (0.96\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.219\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.02 (0.99\u0026ndash;1.04)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex(male vs female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.229\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.237\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.48 (0.55\u0026ndash;11.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.771\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.487\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.34 (0.58\u0026ndash;3.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking(yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.63 (1.50-29.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.147\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.89 (0.80\u0026ndash;4.48)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological staging(vs T1a)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.206\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.808\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.83 (0.19\u0026ndash;3.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.438\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.669\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.82 (0.33\u0026ndash;2.03)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.33 (1.20\u0026ndash;15.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.466\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.64 (1.09\u0026ndash;6.41)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.08 (2.24\u0026ndash;36.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.53 (2.53\u0026ndash;16.86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistological type(vs Acinar)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.869\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.712\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.84 (0.33\u0026ndash;2.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.350\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.504\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.24 (0.66\u0026ndash;2.32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicropapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.240\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.42 (0.10\u0026ndash;1.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.063\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.411\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.37 (0.65\u0026ndash;2.92)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSolid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.970\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.96 (0.13\u0026ndash;7.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.899\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.90 (0.17\u0026ndash;4.85)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLepidic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.600\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.863\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.08 (0.44\u0026ndash;2.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.352\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.261\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65 (0.30\u0026ndash;1.38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDegree of differentiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.12 (4.93\u0026ndash;34.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e13.03 (6.29\u0026ndash;26.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVascular invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.16 (1.92\u0026ndash;19.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.53 (1.65\u0026ndash;12.41)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvasion of the dirty pleura\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.38 (2.03\u0026ndash;14.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.61 (1.86\u0026ndash;7.02)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical method(Lob\u0026nbsp;vs\u0026nbsp;Sublobar)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.680\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.24 (0.10\u0026ndash;0.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.19 (0.11\u0026ndash;0.34)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdjuvant therapy(with\u0026nbsp;vs\u0026nbsp;without)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.262\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.18 (0.07\u0026ndash;0.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.15 0.07\u0026ndash;0.32)\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\u003eIn both univariate and multivariate analyses, surgical approach and adjuvant therapy demonstrated significant protective effects. Multivariate analysis comparing lobectomy versus sublobar resection yielded the following results: RFS: HR\u0026thinsp;=\u0026thinsp;0.19, 95% CI 0.11\u0026ndash;0.34, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001. Multivariate analysis comparing adjuvant therapy versus no adjuvant therapy yielded: OS: HR\u0026thinsp;=\u0026thinsp;0.18, 95% CI 0.07\u0026ndash;0.49, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; RFS: HR\u0026thinsp;=\u0026thinsp;0.15, 95% CI 0.07\u0026ndash;0.32, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001. This suggests that STAS-positive patients undergoing lobectomy may derive superior survival benefit, while STAS-positive patients undergoing sublobar resection also exhibit improved prognosis with adjuvant therapy. Other factors, such as low differentiation (OS: HR\u0026thinsp;=\u0026thinsp;13.12, 95% CI, 4.93\u0026ndash;34.93, P\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001; RFS: HR\u0026thinsp;=\u0026thinsp;13.03, 95% CI 6.29\u0026ndash;26.99, P\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and higher stage (OS: HR\u0026thinsp;=\u0026thinsp;9.08, 95% CI 2.24\u0026ndash;36.69, P\u0026thinsp;=\u0026thinsp;0.002; RFS: HR\u0026thinsp;=\u0026thinsp;6.53, 95% CI, 2.53\u0026ndash;16.86, P\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and vascular invasion (OS: HR\u0026thinsp;=\u0026thinsp;6.16, 95% CI, 1.92\u0026ndash;19.74, P\u0026thinsp;=\u0026thinsp;0.002; RFS: HR\u0026thinsp;=\u0026thinsp;4.53, 95% CI, 1.65\u0026ndash;12.41, P\u0026thinsp;=\u0026thinsp;0.003) and pleural invasion (OS: HR\u0026thinsp;=\u0026thinsp;5.38, 95% CI, 2.03\u0026ndash;14.28, P\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001; RFS: HR\u0026thinsp;=\u0026thinsp;3.61, 95% CI, 1.86\u0026ndash;7.02, P\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were both strongly associated with poorer prognosis in factor analysis, whilst other factors such as smoking and high-risk histological types also demonstrated some predictive value for poorer outcomes.\u003c/p\u003e \u003cp\u003e \u003cb\u003eImpact of surgical approach on patient survival\u003c/b\u003e: Due to baseline imbalances in the selected patient cohorts, such as a significantly higher proportion of higher TNM stages in the lobectomy group versus the limited resection group prior to PSM (T2a: 15 [6.6%] vs 45 [15.0%]), along with notable differences in histological type (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Ultimately, incorporating multifactorial analysis and high-risk factors documented in the literature, we selected histological type, degree of differentiation, and pleural/vascular invasion for PSM matching across patient subgroups. Following the matching of 528 patients, 456 entered our survival analysis. Employing a 1:1 matching ratio yielded 228 patients in each subgroup. Survival analysis was then conducted on the matched cohort, with results presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAccording to Kaplan\u0026ndash;Meier survival analysis, matched patients in the lobectomy group and sublobar resection group demonstrated a significant difference in 5-year RFS (10.0% vs 21.9%, P\u0026thinsp;=\u0026thinsp;0.0019), whereas no significant difference was observed in 5-year overall survival (OS) (7.3% vs 8.3%, P\u0026thinsp;=\u0026thinsp;0.919). Furthermore, the aforementioned multivariate analysis confirmed that lobectomy constitutes a protective factor.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSurvival analysis of adjuvant therapy in patients undergoing different surgical procedures\u003c/b\u003e: Regarding adjuvant therapy (AT), 75 (25.0%) patients who underwent lobectomy received postoperative adjuvant therapy, while 53 (23.2%) patients who underwent sublobar resection received postoperative adjuvant therapy. The decision to administer postoperative adjuvant therapy was determined by the patient's condition and preference. We similarly employed the aforementioned factors to conduct a 1:1 propensity score matching analysis on two patient subgroups, resulting in 67 patients in the lobectomy group and 51 in the sublobar resection group. Kaplan-Meier survival analysis indicated a significant difference in recurrence-free survival (RFS) between patients who did and did not receive adjuvant therapy in the sublobar resection group, whereas no significant difference was observed in overall survival (OS: P\u0026thinsp;=\u0026thinsp;0.7; RFS: P\u0026thinsp;=\u0026thinsp;0.0046) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). However, no significant differences in RFS or OS were observed within the lobectomy group (OS: P\u0026thinsp;=\u0026thinsp;0.71; RFS: P\u0026thinsp;=\u0026thinsp;0.74) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the 2015 WHO classification of lung cancer, STAS was identified as a newly recognised pattern of invasion. Numerous studies have now established that the presence of STAS is a significant factor influencing increased postoperative recurrence risk and reduced survival duration in patients with adenocarcinoma of the lung (ADC)\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. However, the impact of surgical approach and postoperative adjuvant therapy on the prognosis of stage I STAS-positive lung adenocarcinoma patients remains unclear. Particularly scarce are reports on whether stage I ADC patients with STAS benefit from adjuvant therapy following different surgical approaches. Our findings may offer some reference in this regard. After performing multivariate analysis on patients, we found that adjuvant therapy (overall survival: HR\u0026thinsp;=\u0026thinsp;0.18, 95% CI, 0.07\u0026ndash;0.49, P\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001; RFS: HR\u0026thinsp;=\u0026thinsp;0.15, 95% CI 0.07\u0026ndash;0.32, P\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and lobectomy (OS: HR\u0026thinsp;=\u0026thinsp;0.24, 95% CI 0.10\u0026ndash;0.56, P\u0026thinsp;=\u0026thinsp;0.001; RFS: HR\u0026thinsp;=\u0026thinsp;0.19, 95% CI, 0.11\u0026ndash;0.34, P\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001) demonstrated significant protective effects for patients. Conversely, low differentiation, higher stage, vascular invasion, and pleural invasion exhibited adverse effects in multivariate analysis, consistent with numerous prior studies\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. To further validate the prognostic impact of AT across different surgical approaches, patients were stratified into lobectomy and sublobar resection cohorts. Given baseline imbalances due to confounding factors in multivariate analysis and multiple adverse prognostic factors (e.g., high-risk histology, pleural vascular invasion, poorly differentiated tumours)\u003csup\u003e\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, 1:1 propensity score matching was employed to optimise comparability and clarify STAS's prognostic significance. We performed 1:1 propensity score matching between patients in different subgroups. Following survival analysis of the matched cohort, our study confirmed that patients with stage I adenocarcinoma with STAS undergoing lobectomy demonstrated superior survival outcomes, particularly in 5-year recurrence-free survival (RFS) (10.0% vs 21.9%, P\u0026thinsp;=\u0026thinsp;0.0019), compared to those undergoing sublobar resection. This establishes the prognostic significance of lobectomy in STAS patients. Regarding postoperative adjuvant therapy, no survival benefit was observed for stage I STAS patients undergoing lobectomy in terms of 5-year overall survival (OS: 6.0% vs 7.5%, P\u0026thinsp;=\u0026thinsp;0.71) or 5-year RFS (9.0% vs 10.4%, p\u0026thinsp;=\u0026thinsp;0.74). In contrast, among patients undergoing sublobar resection, postoperative adjuvant therapy demonstrated divergent prognostic outcomes between the treated and untreated groups (OS: 5.9% vs 7.8%, P\u0026thinsp;=\u0026thinsp;0.7; RFS: 5.9% vs 27.5%, P\u0026thinsp;=\u0026thinsp;0.0046), with adjuvant therapy improving RFS in sublobar resection recipients.\u003c/p\u003e \u003cp\u003eFrom the above data, we can confidently conclude that STAS-positive patients may benefit from lobectomy, unlike previously established findings where lobectomy or sublobar resection yielded equivalent outcomes in STAS-negative patients. Moreover, for patients undergoing subtotal lobectomy, adjuvant therapy (AT) can protect against the adverse prognostic outcomes associated with STAS, which is highly significant. It also reminds us that for patients with stage I STAS, AT does not provide additional benefit; lobectomy alone is sufficient, thereby avoiding imposing further treatment burden on patients. It likewise offers guidance for managing STAS-positive patients postoperatively, aiding clinicians in determining the necessity of adjuvant therapy.\u003c/p\u003e \u003cp\u003eThe limitations of this study are as follows: firstly, being retrospective in nature, it may introduce Type II errors. Secondly, the number of patients receiving adjuvant therapy postoperatively within different groups was limited. Despite performing propensity score matching (PSM) on study subjects, some selection bias may still exist. Our study confirms that the presence of STAS impacts patient prognosis. However, there remains no accurate preoperative method to determine STAS presence, with diagnosis still heavily reliant on postoperative pathological examination.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe presence of STAS correlates with poor prognosis in stage I lung adenocarcinoma patients. Our study demonstrates that stage I patients with STAS undergoing lobectomy achieve superior outcomes compared to those undergoing sublobar resection. Adjuvant therapy did not confer additional survival benefit to stage I STAS patients undergoing lobectomy. However, it did improve outcomes for stage I patients undergoing sublobar resection, nearly achieving the same prognosis as lobectomy. Nevertheless, longer follow-up periods and more comprehensive data analysis are required to validate these findings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis article has been approved by the Ethics Committee of Qingdao University Affiliated Hospital.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eYanfeng Dong has made contributions to drafting the article, revision of article, and data interpretation. \u0026nbsp;Shihu Liu and Yongjie Wang have made contributions to data interpretation. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis case report did not receive any financial support.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eNot applicable\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. 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Mod Pathol. 2021;34:549\u0026ndash;61. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41379-020-00709-2\u003c/span\u003e\u003cspan address=\"10.1038/s41379-020-00709-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Spread through air spaces, Lung adenocarcinoma, Surgical approach, Adjuvant therapy","lastPublishedDoi":"10.21203/rs.3.rs-8434927/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8434927/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRecent research on spread through air spaces (STAS) has gained prominence. The presence of STAS is not only an independent factor associated with lung cancer recurrence and prognosis, but it remains unclear whether adjuvant therapy (AT) affects survival in STAS-positive stage I lung adenocarcinoma (ADC) patients undergoing different surgical approaches.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective analysis was conducted on patients with pT1-2aN0M0 ADC who underwent complete resection at the Department of Thoracic Surgery, Qingdao University Affiliated Hospital, between 2019 and 2021. Among these, 528 cases with pathologically confirmed STAS were ultimately included. Propensity score matching (PSM) was employed to match patients across different groups. Kaplan-Meier analysis and Cox proportional hazards regression models were employed to evaluate surgical approaches and validate whether AT confers a survival benefit in patients with STAS undergoing different surgical procedures.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong stage I ADC patients with STAS, matched patients undergoing sublobar resection versus lobectomy demonstrated a significant difference in recurrence-free survival (RFS) (P\u0026thinsp;=\u0026thinsp;0.0019) but no significant difference in overall survival (OS) (P\u0026thinsp;=\u0026thinsp;0.61). Multivariate analysis confirmed these findings. (Lobectomy vs. Sublobar resection, OS: HR\u0026thinsp;=\u0026thinsp;0.24, 95% CI, 0.10\u0026ndash;0.56, P\u0026thinsp;=\u0026thinsp;0.001; RFS: HR\u0026thinsp;=\u0026thinsp;0.19, 95% CI, 0.11\u0026ndash;0.34, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients undergoing sublobar resection achieved superior 5-year RFS following adjuvant therapy (P\u0026thinsp;=\u0026thinsp;0.0046), with recurrence rates nearly comparable to lobectomy (5.9% vs 8.9%). However, adjuvant therapy did not improve 5-year RFS in patients undergoing lobectomy (P\u0026thinsp;=\u0026thinsp;0.76). Multivariate analysis results are as follows (adjuvant therapy vs. no adjuvant therapy): OS: HR\u0026thinsp;=\u0026thinsp;0.18, 95% CI, 0.07\u0026ndash;0.49, P\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001; RFS: HR\u0026thinsp;=\u0026thinsp;0.15, 95% CI 0.07\u0026ndash;0.32, P\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn stage I adenocarcinoma patients with STAS, lobectomy yields superior outcomes compared to sublobar resection. Patients undergoing sublobar resection with pathologically confirmed STAS may benefit from adjuvant therapy.\u003c/p\u003e","manuscriptTitle":"Survival Analysis of Adjuvant Therapy in Stage I STAS-Positive Lung Adenocarcinoma Patients Undergoing Different Surgical Approaches","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-09 12:32:40","doi":"10.21203/rs.3.rs-8434927/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-20T15:31:33+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-10T16:22:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"262413253341945977401608430463618182196","date":"2026-02-05T05:13:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"333053926767249036798997670021673578509","date":"2026-02-04T13:02:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-04T12:42:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-05T05:20:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-05T05:20:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cardiothoracic Surgery","date":"2025-12-23T14:29:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f8a2a69c-8c6d-4f68-b860-9e0466e31478","owner":[],"postedDate":"February 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-18T08:38:19+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-09 12:32:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8434927","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8434927","identity":"rs-8434927","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}