Adjuvant chemotherapy for completely resected stage IB–IIA non-small cell lung cancer according to the AJCC 8th edition staging system: a real-world retrospective cohort study based on the SEER database

Introduction

Lung cancer is the leading cause of cancer mortality worldwide (1). Surgical resection is the most effective therapeutic approach for early-stage non-small cell lung cancer (NSCLC). However, tumor recurrence remains the major cause of treatment failure after complete resection (2,3). Personalized perioperative systemic treatment has proven to diminish recurrence rates and provide survival benefits to resectable NSCLC patients, especially for those with locally-advanced disease (4-6). Nevertheless, for completely resected stage IB–IIA NSCLC [American Joint Committee on Cancer (AJCC) 8th edition], whether to administer adjuvant systemic therapy remains debatable (7).

Since the International Adjuvant Lung Cancer Trial (IALT) in 2004 (8), accumulating positive randomized controlled trials (RCTs) have established adjuvant chemotherapy as standard-of-care for completely resected NSCLC (9,10). However, in stage IB–IIA disease, postoperative recurrence risk is relatively low; whether survival benefit outweighs chemotherapy-associated adverse effects remains unknown. The Cancer and Leukemia Group B (CALGB) 9633 trial was the only RCT designed specifically for stage IB NSCLC and demonstrated no survival advantage from adjuvant chemotherapy (11). The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis also showed no benefit for stage I NSCLC [hazard ratio (HR) for stage IA 1.40, 95% confidence interval (CI): 0.95–2.06; HR for stage IB 0.93, 95% CI: 0.78–1.10] (12). However, these studies used AJCC 6th edition staging system; tumors diagnosed as stage IB NSCLC would be reclassified as stage IB, IIA, or IIB in the 8th edition system. We adopted the 8th edition tumor-node-metastasis (TNM) staging system because it provides a clear and consistent definition of stage IB–IIA disease, reducing ambiguity from prior staging editions, and aligns with current clinical decision-making and National Comprehensive Cancer Network (NCCN) guideline frameworks. Currently, NCCN guidelines recommend adjuvant chemotherapy for stage IIB patients, while for stage IB–IIA NSCLC (AJCC 8th edition), it might be recommended only for patients with high-risk features, although these factors independently may not be an indication for adjuvant chemotherapy (7).

Recent advances have modified adjuvant treatment strategies. Multiple phase III trials showed adjuvant immune checkpoint inhibitors (ICIs) conferred disease-free survival (DFS) benefit in stage II–IIIA NSCLC with programmed death-ligand 1 (PD-L1) ≥1% (IMpower010) (13) or stage IB–IIIA regardless of PD-L1 expression (PEARLS/KEYNOTE-091) (14). The ADAURA (15) and ALINA (16) trials demonstrated DFS improvement with targeted therapy in EGFR-mutated or anaplastic lymphoma kinase (ALK)-rearranged NSCLC. These promising research findings are ushering in a new era of precision medicine in adjuvant treatment of resectable NSCLC; however, in-depth subgroup analyses are further required to validate the effect of adjuvant ICIs/targeted therapy in an earlier-stage population (17).

Here, we conducted a real-world study to characterize clinical practice patterns of adjuvant systemic therapy, primarily chemotherapy, in surgically resected stage IB–IIA NSCLC (AJCC 8th edition), and to assess its impact on survival outcomes in this population. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1403/rc).

Methods

Study cohort

We used the National Cancer Institute Surveillance, Epidemiology, and End Results [SEER]*Stat version 8.4.4 (www.seer.cancer.gov/seerstat) to select patients from the Incidence-SEER Research Data, 17 Registries [2000–2021] based on the November 2023 submission, which covers approximately 26.5% of the U.S. population. Histological subtypes were coded using the third version of the International Classification of Disease for Oncology (ICD-O-3). Cases diagnosed as primary malignant (Behavior code ICD-O-3: “Malignant”) NSCLC (AYA site recode 2020 Revision: “9.4.2 Non-small cell carcinoma”) of lung and bronchus (Site recode ICD-O-3/WHO 2008 = “Lung and Bronchus”) were included in initial eligibility screening process.

Among these cases, a total of 26245 surgically resected stage IB–IIA NSCLC patients were included in the study after modifying AJCC 6th or 7th edition staging system into the 8th edition one. Cases were excluded if (I) there was absence of pathological diagnostic confirmation; (II) instead of resection of lung, local tumor destruction or excision was performed (SEER Surgery Codes of Lung: B120-B190); (III) sequencing of systemic therapy and surgical procedure was unknown; (IV) underlying cause of death was unknown; and (V) shared the same patient ID and thus diagnosed as multiple primary lung cancer. Finally, we used the item “SYSTEMIC/SUR SEQ” to identify patients who underwent different postoperative treatment modalities: (I) “Systemic therapy after surgery” for the adjuvant therapy group; and (II) “No systemic therapy” for the observation group. However, SEER database does not report regimen details or distinguish chemotherapy from targeted therapy or immunotherapy. Given that adjuvant targeted therapy (osimertinib) and immunotherapy (atezolizumab) were FDA-approved only in late 2020 and 2021, respectively, and most patients in our cohort [2007–2021] were diagnosed before widespread adoption of these agents, it is reasonable to infer that most adjuvant systemic therapy recorded in this study represents conventional platinum-based chemotherapy. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Covariables and endpoint

Baseline clinicopathological characteristics were extracted from the SEER database. The covariables included age, sex, race, year of diagnosis, histologic type, tumor size, pathological stage, tumor grade, surgical procedure, lymph node dissection status, and visceral pleural involvement. The year of diagnosis was categorized into 2007–2010, 2011–2015, and 2016–2021. To comply with the NCCN guidelines’ definition of “poorly differentiated tumors” [including lung neuroendocrine tumors (NETs) (excluding well-differentiated NETs)], tumor grade was dichotomized into well- and poorly-differentiated groups according to both SEER Histologic Type and Grade Codes. Well-differentiated tumors were defined as G1 (well differentiated) and G2 (moderately differentiated) tumors, excluding G2 NETs; poorly-differentiated tumors referred to G3 (poorly differentiated), G4 (undifferentiated), and NETs with moderate differentiation. Surgical procedure of primary tumor was classified into four categories according to SEER Surgery Codes of Lung: (I) wedge resection: B210; (II) segmental resection, including lingulectomy: B220; (III) lobe or bilobectomy: B300–B480; and (IV) pneumonectomy: B550–B660. Both wedge and segmental resection fell under the category of sublobar resections. Finally, according to the NCCN guidelines, we defined cases with high-risk features as the presence of at least one of the following situations (7): (I) poorly differentiated tumors; (II) wedge resection; (III) visceral pleural involvement (VPI); and (IV) unknown lymph node status (Nx). Notably, high-risk features in this study did not include data describing the vascular invasion, which was not captured in SEER database.

The survival endpoints of this study were overall survival (OS) and lung cancer-specific survival (LCSS). OS was calculated from the date of initial diagnosis to death from any cause, while LCSS was measured from the date of diagnosis to death only attributed to lung cancer. Although OS is one of the most important survival outcomes, nearly half of patients with early-stage NSCLC die from non-cancer-specific causes, making LCSS a more accurate reflection of oncologic treatment efficacy. The final follow-up date for survival status was December 2021.

Statistical analysis

Baseline characteristics were compared using Wilcoxon rank-sum test for non-normally distributed continuous variables and Pearson’s Chi-squared test for categorical variables. The Kaplan-Meier method with log-rank test was performed to compare survival curves for OS. Competing risk analysis was applied to analyze cumulative incidence of lung cancer-specific mortality, considering non-cancer-specific death as competing events. Cox proportional hazards regression models were constructed to determine predictors for OS, while Fine and Gray’s competing risk regression models were built to identify prognostic factors for LCSS (18). To address multicollinearity during the variable selection process, a least absolute shrinkage and selection operator (LASSO)-based Cox regression model with cross-validation was applied to identify prognostic factors for OS in multivariate analyses (19). For LCSS, multivariate regression models were constructed incorporating both covariables with P values <0.10 identified in univariate analyses and the target exposure variable of the study. Besides, multivariate analyses were applied to adjust for covariates in all subgroup analyses. P values for interaction were calculated to assess treatment effect heterogeneity across subgroups.

To further eliminate confounding bias, propensity score matching (PSM) was performed with a caliper of 0.20. A logistic regression model was established to calculate propensity score based on the significantly unbalanced covariates between cohorts. Patients who received adjuvant systemic therapy were matched with those treated with surgery alone by a 1:2 greedy algorithm without replacement.

All statistical analyses were conducted using R software version 4.4.2 (www.r-project.org). All hypothesis tests were two-sided, with a predetermined significance threshold of P values <0.05 without multiple comparison adjustments.

Results

A total of 25,919 surgically resected stage IB–IIA NSCLC patients were enrolled in this study. Of these patients, only 3,497 (13.5%) received adjuvant systemic therapy after surgery in the real world. The adjuvant therapy rates for stage IB, IIA, and stage IB–IIA patients with high-risk features were 10.9%, 25.0%, and 14.6%, respectively. Baseline clinicopathological characteristics are summarized in Table 1. Compared with the observation group, patients underwent adjuvant therapy had more advanced tumor stage (stage IIA: 34.3% vs. 16.0%, P<0.001), and poorly differentiated grade (43.5% vs. 32.0%, P<0.001); however, they had slightly lower wedge resection (9.6% vs. 12.2%, P<0.001), and unknown lymph node status (5.1% vs. 6.0%, P=0.03) rates.

Kaplan-Meier analysis was conducted to compare OS in the entire cohort (Figure 1). Patients received adjuvant systemic therapy had significantly longer OS than those who underwent surgical resection alone [median survival time (MST): 112 vs. 86 months, log-rank P<0.001]. Yet, the OS advantage was mainly attributed to a significantly decreased non-cancer-specific mortality (P<0.001), rather than to the LCSS improvement (P=0.46). On the other hand, patients with earlier tumor stages and those without high-risk features also had prolonged OS (both log-rank P<0.001). However, these OS benefits were mostly derived from significantly improved LCSS, instead of non-cancer specific survival improvement (both P<0.001). In addition, patients underwent sublobar resection, those with poorly differentiated tumors, VPI, and Nx had both significantly worse OS and LCSS (Figure S1).

Figure 1 Kaplan-Meier survival curves of OS and cumulative incidence of mortality (LCSD and NCSD) stratified by adjuvant systemic therapy (A,B), pathological stage (C,D), and high-risk features (E,F) in surgically resected stage IB–IIA NSCLC. CIF, cumulative incidence function; LCSD, lung cancer-specific death; NCSD, non-lung cancer-specific death; NSCLC, non-small cell lung cancer; OS, overall survival.

Results of univariate and multivariate Cox proportional hazards regression and competing risks regression for the entire surgically resected stage IB–IIA NSCLC are summarized in Table 2. A LASSO-based Cox regression model was built to select the most OS-relevant prognostic factors for multivariate analysis (Figure S2). Patients who were older, underwent sublobar resection, exhibited larger tumor size, poorly differentiated grade, VPI and Nx had significant worse OS and LCSS in multivariate analysis. Adjuvant systemic therapy was independent favorable prognostic factor for OS (HR 0.89, 95% CI: 0.84–0.95, P<0.001) after adjusting for confounding variables; however, it was not associated with improved LCSS [subhazard ratio (SHR) 1.04, 95% CI: 0.97–1.12, P=0.29] in multivariate analysis.

Stratified analyses by tumor stages (IB vs. IIA) and high-risk features (absence vs. presence) were further conducted to assess the prognostic effect of adjuvant systemic therapy. Patients received adjuvant therapy had significantly improved OS in both stage IB and IIA populations (both log-rank P<0.001, Figure 2). For stage IB patients, adjuvant therapy was associated with slightly worse LCSS (P=0.10), thus, the OS advantage was totally derived from significantly decreased non-cancer-specific mortality; however, the OS advantage for stage IIA patients was attributed to both significantly improved LCSS (P=0.006) and decreased non-cancer-specific mortality. Similarly, patients treated with adjuvant therapy had significantly longer OS no matter without or with high-risk features (both log-rank P<0.001, Figure 3). Yet, adjuvant therapy was either associated with significantly worse LCSS (P=0.04) or not associated with improved LCSS (P=0.40) in patients without or with high-risk features, respectively.

Figure 2 Kaplan-Meier survival curves of OS and cumulative incidence of mortality (LCSD and NCSD) stratified by adjuvant systemic therapy in surgically resected stage IB (A,B), and stage IIA (C,D) NSCLC cohorts. CIF, cumulative incidence function; LCSD, lung cancer-specific death; NCSD, non-lung cancer-specific death; NSCLC, non-small cell lung cancer; OS, overall survival.

Figure 3 Kaplan-Meier survival curves of OS and cumulative incidence of mortality (LCSD and NCSD) stratified by adjuvant systemic therapy in surgically resected stage IB–IIA NSCLC without (A,B), or with (C,D) high-risk features. CIF, cumulative incidence function; LCSD, lung cancer-specific death; NCSD, non-lung cancer-specific death; NSCLC, non-small cell lung cancer; OS, overall survival.

Subgroup analyses stratified by tumor size, histology, stage, high-risk features, and the combination of stage and high-risk features were performed with multivariate regression models adjusting for covariates (Figure 4). Not surprisingly, patients with larger tumor size tended to gain remarkable survival benefits from postoperative adjuvant therapy (P for interaction <0.05). In terms of histologic subtypes, patients with squamous cell carcinoma could achieve improved survival outcomes through adjuvant therapy (OS: HR 0.76, 95% CI: 0.67–0.85, P<0.001; LCSS: SHR 0.86, 95% CI: 0.74–1.01, P=0.07). Moreover, it was noteworthy that adjuvant systemic therapy was independent favorable prognostic factor for stage IIA patients (OS: HR 0.75, 95% CI: 0.67–0.83, P<0.001; LCSS: SHR 0.87, 95% CI: 0.76–0.99, P=0.044), especially for those with high-risk features (OS: HR 0.69, 95% CI: 0.60–0.79, P<0.001; LCSS: SHR 0.76, 95% CI: 0.64–0.90, P=0.001).

Figure 4 Adjusted multivariate regressions comparing adjuvant systemic therapy vs. none (surgery alone) for OS and LCSS in surgically resected NSCLC subgroups stratified by tumor size, histology, pathological stage, high-risk features, and the combination of pathological stage and high-risk features. ADC, adenocarcinoma; ASC, adenosquamous carcinoma; CI, confidence interval; HR, hazard ratio; LCSS, lung cancer-specific survival; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; NSCLC, non-small cell lung cancer; OS, overall survival; SCC, squamous cell carcinoma.

Finally, PSM was performed to further balance confounding biases between adjuvant therapy and observation groups. No significant difference regarding clinicopathological features was found across the two above-mentioned groups after matching (Table S1). Although patients received adjuvant therapy had improved OS in the entire matched cohort, no significant LCSS difference was observed between the two groups (P=0.21, Figure 5). Notably, adjuvant systemic therapy was associated with significant worse LCSS for stage IB patients (P=0.002); however, it contributed to significant OS (log-rank P<0.001) and LCSS (P=0.04) benefits for patients with stage IIA disease after PSM.

Figure 5 Kaplan-Meier survival curves of OS and cumulative incidence of mortality (LCSD and NCSD) stratified by adjuvant systemic therapy in matched entire surgically resected stage IB–IIA (A,B), stage IB (C,D), and stage IIA (E,F) NSCLC cohorts. CIF, cumulative incidence function; LCSD, lung cancer-specific death; NCSD, non-lung cancer-specific death; NSCLC, non-small cell lung cancer; OS, overall survival.

Discussion

Despite guideline recommendations, this large-scale real-world analysis of 25,919 surgically resected stage IB–IIA NSCLC patients found that only 14.6% with high-risk features received adjuvant systemic therapy. This remarkably low utilization rate is consistent with previous studies (20). Multiple factors contribute to this gap, including physician-related variability in risk assessment, patient factors such as advanced age and comorbidities limiting eligibility (21), and system-level barriers such as healthcare access. Notably, current guidelines do not routinely recommend adjuvant therapy for stage IB patients without high-risk features, making this low utilization appropriate.

A notable finding was the discordance between OS and LCSS. While adjuvant therapy was associated with improved OS (MST: 112 vs. 86 months, P<0.001), this advantage was primarily driven by reduced non-cancer-specific mortality (P<0.001), rather than improved LCSS (P=0.46). This discrepancy likely reflects patient selection bias, recipients of adjuvant therapy are typically younger with better performance status and fewer comorbidities. Intensified medical surveillance during treatment—including frequent follow-up, complication management, and psychological support—may further reduce non-cancer mortality (20). Given that non-cancer deaths comprise 30–40% of mortality in early-stage lung cancer (22), even modest reductions can translate into detectable OS improvements without a true anticancer effect. Thus, LCSS, as a cancer-specific endpoint, warrants greater emphasis when evaluating treatment benefit.

Several studies have evaluated adjuvant systemic therapy in node-negative early-stage NSCLC (23-28). Pathak et al. found adjuvant chemotherapy conferred survival benefit for 3–4 cm tumors only after sublobar resection (HR 0.72, P=0.004) (23), while Li et al. reported no benefit in stage IB (T2aN0M0, AJCC 7th edition) Chinese patients regardless of tumor size (24). In our cohort, while stage IIA patients, particularly those with high-risk features, experienced significant benefits (OS: HR 0.69, P<0.001; LCSS: SHR 0.76, P=0.001), stage IB patients derived no benefit (OS: HR 0.95, P=0.14) and had potentially harmful effects (LCSS: SHR 1.16, P=0.001) regardless of high-risk status. These findings suggest that adjuvant chemotherapy may be associated with survival benefit primarily in stage IIA patients, while its routine use in stage IB disease warrants caution given the lack of cancer-specific benefit observed in this cohort. Moreover, our findings validate the AJCC 8th edition’s T2 subdivision at 4 cm, which reclassified T2bN0M0 from stage IB to IIA. This staging refinement accurately reflects prognosis and informs optimal treatment strategies simultaneously. Given that SEER lacks molecular alterations and contemporary perioperative strategies (ICIs, targeted agents), our findings should be interpreted as a historical real-world benchmark for conventional adjuvant chemotherapy rather than a guide to current precision oncology practice.

The paradoxical observation that stage IB patients exhibited worse LCSS with adjuvant therapy, even after PSM (P=0.002), may be biologically plausible. Early-stage tumors generally exhibit preserved immune surveillance with greater CD8⁺ T-cell infiltration. Chemotherapy-induced lymphocyte depletion disrupts this balance, with persistently suppressed CD4⁺/CD8⁺ ratios for over 6 months (29). The IALT trial showed increased mortality in the chemotherapy arm after 5 years (30). Preclinically, one possible explanation is that chemotherapy-induced tissue damage and consequent damage-associated molecular patterns (DAMPs) release may interrupt micrometastatic dormancy, elevating late relapse risk (31), though direct causal evidence is lacking.

Subgroup analysis revealed differential effects by histologic subtype. Squamous cell carcinoma patients showed greater benefit (OS: HR 0.76, P<0.001; LCSS: SHR 0.86, P=0.07) than adenocarcinoma (OS: HR 0.90, P=0.008; LCSS: SHR 1.08, P=0.12). This histology-dependent response likely reflects underlying biology: squamous cell carcinomas have higher proliferation rates and more complex genomic alterations [e.g., tumor protein p53 (TP53), cyclin dependent kinase inhibitor 2A (CDKN2A), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)] (32), making them more susceptible to cell cycle-specific chemotherapeutic agents. Our findings align with Asian studies showing significant benefits in squamous carcinoma but limited benefit in adenocarcinoma (33-35). This consistency across ethnic populations further supports histology-based treatment strategies.

This study should be interpreted with caution due to several limitations. First, the confounding bias was inevitable. Although multivariate regression and PSM were conducted to mitigate this bias, unmeasured confounders not captured in the SEER database, such as Eastern Cooperative Oncology Group (ECOG) performance status and comorbidities index, may still have influenced the results. The significantly lower non-cancer-specific mortality in the adjuvant group persisted post-matching (P<0.001), suggesting residual confounding. This underscores why OS alone should not be used to guide adjuvant chemotherapy decisions in early-stage NSCLC; LCSS provides a more treatment-relevant endpoint. Rigorous studies with randomized-controlled design are essential to eradicate confounding biases. Second, detailed information about systemic therapy and molecular testing results, such as the chemotherapy regimens, dose intensity, number of cycles, treatment completion, PD-L1 status, epidermal growth factor receptor (EGFR) mutations, and ALK rearrangements, were unavailable. However, only 6.2% (1,614/25,919) of our patients were diagnosed after 2020, and adjuvant osimertinib (15) and atezolizumab (13) were only Food and Drug Administration (FDA)-approved in late 2020 and 2021, most patients recruited in this study [2007–2021] likely received platinum-based chemotherapy as adjuvant treatment. The extended study period [2007–2021] may introduce temporal confounding; however, given that platinum-doublet adjuvant chemotherapy has remained the standard backbone regimen throughout this period, we consider the timeframe acceptable for our research question. Third, only four of the five NCCN-defined high-risk features were included; “vascular invasion” was omitted due to database limitations (7). As a result, some patients with lymphovascular invasion were misclassified into the no high-risk feature population, potentially underestimating the survival benefit of adjuvant therapy in those at high recurrence risk. This omission may also dilute observed treatment effects by misclassifying truly high-risk (LVI-positive) patients into the non-high-risk group. Future datasets incorporating both complete pathological variables and molecular residual disease (MRD) markers [e.g., circulating tumor DNA (ctDNA)] may better identify truly high-risk populations and inform optimal selection for adjuvant systemic therapy (36). Finally, limitations in SEER treatment data should be acknowledged (37). The sensitivity and positive predictive value of SEER data for identifying chemotherapy in lung cancer patients are 80.1% and 89.4%, respectively (38). We used both “Chemotherapy recode” and “RX SUMM--SYSTEMIC/SUR SEQ” variables to optimize data accuracy, but misclassification remains possible.

This study demonstrates that benefit-risk profiles differ substantially between stage IB and IIA NSCLC. The potential harm signal in stage IB suggests that routine chemotherapy may not be beneficial in this population, supporting molecular marker-guided approaches such as ctDNA-based MRD detection for patient selection. Circulating tumor DNA may identify stage IB patients with MRD who might benefit from adjuvant therapy (39). In contrast, the clear benefit in stage IIA reinforces guidelines but underscores low utilization rates. As precision oncology with ICIs and targeted therapy transforms perioperative treatment landscape, these findings provide important context for optimizing strategies to maximize benefit and minimize harm in patients with resected early-stage NSCLC.

Conclusions

Adjuvant chemotherapy was associated with improved survival in stage IIA NSCLC, especially for those with high-risk features; however, it did not confer a prognostic benefit in stage IB NSCLC, regardless of the risk status. These real-world findings enhance current understanding of adjuvant chemotherapy for driver-mutation negative early-stage NSCLC, underscoring the importance of tailored therapeutic approaches based on tumor stages and high-risk features. Treatment decisions should remain individualized and ideally informed by prospective validation and/or molecular risk stratification (e.g., ctDNA-based MRD detection).

Acknowledgments

We would like to thank all the staff members who work with the SEER program.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1403/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1403/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1403/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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