The role of postoperative radiotherapy for invasive thymic epithelial tumors: a single-center experience

Introduction

Thymomas are the most common anterior mediastinal thymic epithelial tumors (TETs), though they remain relatively rare overall (1). The global incidence of TETs is approximately 1.3–3.2 cases per million, with the majority of diagnoses occurring in individuals aged 40–60 years (2). The Masaoka-Koga classification, originally proposed in 1981 (3) and revised in 1994 (4), is the most widely adopted staging system due to its prognostic relevance (5-7). This classification is a pathology-based system, assessable only after surgical resection of the tumor. Additionally, the International Association for the Study of Lung Cancer and the International Thymic Malignancy Interest Group developed a more recent staging system, which has been endorsed by the Union for the International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) in the eighth edition of the TNM classification (UICC TNM Classification, 8th Edition) (8,9). The treatment strategy for thymoma and thymic carcinoma depends on whether the tumor is resected upfront. Complete tumor resection has been established as the most significant favorable prognostic factor, both on relapse-free survival (RFS) and overall survival (OS) (10-12). Moreover, radiation therapy (RT) serves as an important component of adjuvant and palliative treatment, as these tumors are radiosensitive. However, the effectiveness of postoperative radiotherapy (PORT) in TETs remains controversial. According to the guidelines of the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), PORT is recommended for incompletely resected thymomas and thymic carcinomas, as well as for completely resected thymomas and thymic carcinomas at Masaoka-Koga stage III–IV (13,14). To evaluate the efficacy of PORT, we reviewed data from 211 patients with thymoma treated at the Cardiovascular Thoracic Surgery Department, Tianjin Medical University General Hospital, between October 2001 and July 2021. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1805/rc).

Methods

Patient selection

This study included thymoma patients diagnosed by postoperative pathology at Tianjin Medical University General Hospital between October 2001 and July 2021. Patients classified as Masaoka-Koga stage II to IVA were retrospectively enrolled. Patients with other malignancies, those who received neoadjuvant treatment, and those with incomplete data were excluded from the study. Based on pathological type, pathological stage, and PORT status, patients were stratified into different groups to analyze the prognostic impact of PORT. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study does not require ethical approval because it is based on secondary analysis of existing data and does not pose any additional risk or burden to the participants, and does not involve direct patient interaction, identifiable personal information, or any intervention that affects human subjects. The data used in this study were obtained from existing medical records and were de-identified to ensure patient confidentiality. No identifiable patient information was included. Additionally, all patients signed institutional informed consent forms upon hospital admission, acknowledging their awareness that their clinical data might be used for research purposes.

Definitions

In this study, OS was defined as the time interval from the date of surgery to the date of death from any cause. Patients who were alive at the last follow-up were censored, while RFS was defined as the time interval from the date of surgery to the date of the first documented recurrence (local, regional, or distant) or death from any cause, whichever occurred first.

RT and chemotherapy regimens were administered in accordance with the clinical practice guidelines for thymoma by the NCCN and the Chinese Clinical Oncology guidelines for the diagnosis and treatment of TETs. Additionally, the radiation dose for thymoma patients in this study adhered to the NCCN guidelines, which recommend a PORT dose range of 45–50 gray (Gy) for completely resected disease (R0).

Postoperative tumor recurrence was primarily evaluated using chest computed tomography (CT). Follow-up data were obtained through telephone interviews and email correspondence to document thymoma recurrence and patient survival status. Chest CT scans were conducted every six months during the first two years postoperatively and annually thereafter, or as clinically indicated. Recurrence was categorized according to International Thymic Malignancy Interest Group (ITMIG) standards as local (anterior mediastinum), regional (intra-thoracic recurrence not contiguous with the thymus or previous thymoma site), or distant (pulmonary nodules or extrathoracic metastases).

Surgical resection remained the cornerstone of thymoma treatment, with thoracoscopic thymectomy (TT) being performed in all patients included in this study. Total thymectomy was performed based on tumor size, location, and surgeon preference, utilizing approaches such as median sternotomy, video-assisted thoracoscopic surgery (VATS), or transcervical thymectomy. In accordance with the guidelines of the ITMIG, the procedure was aimed at achieving complete resection of the thymus gland, including all mediastinal adipose tissue from the lower neck to the diaphragm and between both phrenic nerves. For tumors invading adjacent structures, en bloc resection of the involved organs (e.g., pericardium, great vessels, or lung) was conducted to ensure R0 resection. Careful attention was paid to preserving the phrenic nerves and other critical structures. In cases where transcervical thymectomy was performed, a three-port technique was employed to facilitate adequate visualization and access to the anterior mediastinum. Hemostasis was meticulously achieved, and intraoperative assessments of resection margins were routinely performed. Postoperative care focused on monitoring respiratory function and managing complications such as myasthenic crisis or bleeding.

Statistical analysis

Values were presented as mean ± standard deviation (SD) or median with range. For continuous variables, the Wilcoxon rank-sum test was used, while categorical variables were compared using the Chi-squared test or Fisher’s exact test, as appropriate. Relapse-free survival (RFS) and OS were calculated from the date of surgery. Time-to-event curves for RFS and OS were estimated using the Kaplan-Meier method, and differences between groups (with and without PORT) were evaluated using the log-rank test. Clinicopathological factors were assessed using univariable analysis, and variables with P values <0.2 were included in multivariable Cox regression analysis. Results were expressed as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). All P values were two-sided, with P values <0.05 considered statistically significant. Statistical analyses were performed using SPSS 26.0.

Results

Baseline characteristics

A total of 318 patients with Masaoka-Koga stage II to IVA thymoma were initially included in the study. Among these, 107 patients were excluded due to missing data, leaving 211 thymoma patients for final analysis. The median follow-up duration was 47 months (range, 26–84 months). Of the included patients, 94 (44.5%) were men and 117 (55.5%) were women. A total of 138 (65.4%) patients were classified as Masaoka-Koga stage II, while 73 (34.6%) were classified as Masaoka-Koga stage III or IVA. PORT was administered to 141 (66.8%) patients, with no treatment interruptions or deaths related to RT-associated adverse events. A total of 207 (98.1%) patients achieved complete resection (R0), while 4 (1.9%) patients had incomplete resection (R2). Detailed baseline characteristics of the thymoma patients are summarized in Table 1.

OS and RFS for thymoma

The median follow-up period was 48 months (range, 27–84 months). The 5-year OS and RFS rates for thymoma patients were 94.7% and 95.0%, respectively. Among thymoma patients, the 5-year OS rates for the PORT group (n=141) and the no-PORT group (n=70) were 93.0% and 97.1%, respectively (HR: 0.987; 95% CI: 0.235–4.142; P=0.63) (Figure 1A). Similarly, the 5-year RFS rates for the PORT group and the no-PORT group were 94.8% and 95.6%, respectively (HR: 1.185; 95% CI: 0.295–4.750; P=0.67) (Figure 1B).

Figure 1 Kaplan-Meier plots and log-rank P values for PORT versus non-PORT: (A) overall survival for all thymoma patients, (B) relapse-free survival for all thymoma patients. PORT, postoperative radiotherapy.

The 5-year OS rates for Masaoka-Koga stage II and Masaoka-Koga stage III/IVA thymoma patients were 96.0% and 91.9%, respectively (HR: 3.324; 95% CI: 0.792–13.949; P=0.06) (Figure 2A). Similarly, the 5-year RFS rates for Masaoka-Koga stage II and stage III/IVA thymoma patients were 97.1% and 91.1%, respectively (HR: 1.543; 95% CI: 0.412–5.782; P=0.32) (Figure 2B). PORT for Masaoka-Koga stage II thymoma was not statistically associated with OS (92.5% vs. 100%; HR: 57.142; 95% CI: 0.005–650,959.944; P=0.11) or RFS (94.9% vs. 100%; HR: 3.490; 95% CI: 0.388–31.385; P=0.24) (Figure 2C,2D). Among Masaoka-Koga stage III/IVA patients, the PORT group had better OS compared to the non-PORT group (93.0% vs. 85.7%; HR: 0.185; 95% CI: 0.031–1.111; P=0.01) (Figure 3A). For Masaoka-Koga stage III/IVA patients, there were no significant differences in RFS between the PORT and non-PORT groups; the 5-year RFS rates were 93.6% and 91.7%, respectively (HR: 0.256; 95% CI: 0.036–1.828; P=0.12) (Figure 3B).

Figure 2 Kaplan-Meier plots and log-rank P values for Masaoka-Koga stage II versus Masaoka-Koga stages III and IVA. (A) Overall survival for thymoma patients; (B) relapse-free survival for thymoma patients. Kaplan-Meier plots and log-rank P values for PORT versus non-PORT: (C) overall survival for Masaoka-Koga stage II thymoma patients; (D) relapse-free survival for Masaoka-Koga stage II thymoma patients. PORT, postoperative radiotherapy.

Figure 3 Kaplan-Meier plots and log-rank P values for PORT versus non-PORT. (A) Overall survival for Masaoka-Koga stage III and IVA thymoma patients; (B) relapse-free survival for Masaoka-Koga stage III and IVA thymoma patients; (C) overall survival for Masaoka-Koga stage III thymoma patients; (D) relapse-free survival for Masaoka-Koga stage III thymoma patients. PORT, postoperative radiotherapy.

Furthermore, subgroup analyses revealed that the 5-year OS rate was significantly higher in patients with Masaoka-Koga stage III thymoma who received PORT compared to those who did not (96.8% vs. 90.9%; HR: 0.139; 95% CI: 0.012–1.562; P=0.04) (Figure 3C). However, in the same subgroup, RFS rates were not significantly different between the PORT and non-PORT groups (HR: 0.263; 95% CI: 0.037–1.883; P=0.13) (Figure 3D).

For thymoma patients stratified by the TNM staging system, the 5-year OS rates for TNM stage I/II and TNM stage III were 96.5% and 87.9%, respectively (HR: 5.669; 95% CI: 1.347–23.852; P=0.004) (Figure 4A). Similarly, the 5-year RFS rates for TNM stage I/II and TNM stage III were 96.7% and 89.5%, respectively (HR: 1.671; 95% CI: 0.413–6.761; P=0.33) (Figure 4B). PORT for TNM stage I/II thymoma was not significantly associated with OS (93.5% vs. 100%; HR: 54.168; 95% CI: 0.004–652392.040; P=0.12) or RFS (94.5% vs. 94.4%; HR: 3.947; 95% CI: 0.457–34.064; P=0.11) (Figure 4C,4D). However, among patients with TNM stage III thymoma, the PORT group demonstrated significantly better 5-year OS (90.4% vs. 80.0%; HR: 0.168; 95% CI: 0.028–1.011; P=0.01) and RFS (95.2% vs. 65.6%; HR: 0.118; 95% CI: 0.011–1.304; P=0.03) compared to the non-PORT group (Figure 5A,5B).

Figure 4 Kaplan-Meier plots and log-rank P values for TNM stages I and II versus TNM stage III. (A) overall survival for thymoma patients; (B) relapse-free survival for thymoma patients. Kaplan-Meier plots and log-rank P values for PORT versus non-PORT: (C) overall survival for TNM stages I and II thymoma patients; (D) relapse-free survival for TNM stages I and II thymoma patients. PORT, postoperative radiotherapy; TNM, tumor-node-metastasis.

Figure 5 Kaplan-Meier plots and log-rank P values for PORT versus non-PORT. (A) Overall survival for TNM stage III thymoma patients; (B) relapse-free survival for TNM stage III thymoma patients. PORT, postoperative radiotherapy; TNM, tumor-node-metastasis.

Cox regression analysis

In the univariate analysis of all aggressive thymoma patients, the TNM classification emerged as an independent prognostic factor for OS rates (TNM stage I/II vs. TNM stage III; HR: 5.669; 95% CI: 1.347–23.852; P=0.02) (Table 2). However, no factors were found to be significantly associated with OS or RFS in the multivariate Cox regression models (Table 2).

Subgroup Cox regression analysis stratified by TNM stage revealed that, for TNM stage I/II thymoma, no factors were identified as independent prognostic factors for either OS or RFS (Table 3). In contrast, in the univariate analysis of TNM stage III thymoma patients, PORT was found to be an independent prognostic factor for OS rates (PORT vs. non-PORT; HR: 13.646; 95% CI: 1.522–122.356; P=0.02) (Table 4). However, similar to the overall cohort, no factors were significantly associated with OS or RFS in the multivariate Cox regression models for TNM stage III thymoma patients (Table 4).

Discussion

Radical surgery has long been recognized as the cornerstone of treatment for resectable TETs; however, the role of PORT remains controversial (15,16). In the management of thymic tumor patients, the Masaoka-Koga staging system continues to play a crucial role, providing essential guidance for treatment decisions in TETs. Nevertheless, the status and utility of the TNM staging system are continuously evolving. The observed differences in patient outcomes when comparing the Masaoka-Koga staging system and the TNM staging system may be attributed to the fundamental differences in their design and focus. Conceptual differences: the Masaoka-Koga staging system emphasizes the extent of local invasion and biological behavior of the tumor, making it particularly useful in guiding surgical decisions and evaluating the risk of local recurrence. In contrast, the TNM staging system, widely used for other solid tumors, incorporates a more detailed assessment of tumor size (T), nodal involvement (N), and distant metastasis (M), providing a standardized framework for prognostic evaluation and clinical trial stratification (17). Clinical Implications of differences: the differences in staging outcomes observed in this study highlight the potential for each system to inform different aspects of patient management. The Masaoka-Koga system may better stratify patients for surgical resection and immediate postoperative care, whereas the TNM system may offer additional prognostic insights, particularly for cases involving lymph node metastasis or distant dissemination. These differences underscore the importance of selecting the appropriate staging system based on the clinical context and study objectives. Future research directions: future studies should aim to integrate the strengths of both staging systems to enhance their predictive accuracy and clinical utility. For instance, combining the Masaoka-Koga system’s focus on local invasion with the TNM system’s detailed assessment of nodal and distant spread may provide a more comprehensive framework for prognosis and treatment planning. Additionally, large-scale, multicenter analyses are needed to validate these findings and explore how the two systems might be harmonized in clinical practice. In 2022, a comprehensive meta-analysis conducted by the Ontario Department of Health’s evidence-based nursing project and the lung cancer disease field team offered an in-depth review of the surgical, radiotherapeutic, and systemic treatment modalities for TETs, utilizing the TNM staging system (14). There is a certain degree of correlation between the Masaoka-Koga and TNM staging systems, suggesting that they can be integrated and used together in the clinical diagnosis and treatment of TETs. In our cohort, discrepancies arose where locally invasive tumors were staged higher in the Masaoka-Koga system but classified as early-stage in the TNM system due to the absence of nodal or distant spread. Conversely, nodal involvement led to higher TNM stages despite minimal local invasion. These differences underscore the need for careful consideration of staging systems in research and clinical practice. Future efforts to integrate these approaches may improve prognostic accuracy and standardization. This study included patients with Masaoka-Koga stage II to stage IVA thymoma. Minimizing bias in the study population: patients undergoing neoadjuvant therapy often represent a distinct subgroup with more advanced disease or specific clinical characteristics. Including these patients might introduce heterogeneity in the study population and confound the comparison of treatment outcomes. By excluding these cases, we aimed to create a more homogeneous cohort to allow for clearer interpretation of the effects of surgery and PORT. Neoadjuvant therapy can significantly alter the pathological staging of tumors, making it challenging to directly compare outcomes with patients who did not receive such treatment. The role of PORT in stage II thymoma and thymic carcinoma remains the most controversial. According to the 2022 NCCN Guidelines for Thymoma and Thymic Carcinoma, PORT may be considered for patients with Masaoka-Koga stage II thymoma exhibiting envelope invasion (18). In contrast, the 2015 ESMO guidelines do not recommend routine PORT after complete resection of Masaoka-Koga stage II thymoma, though it may be considered for invasive histology (e.g., B2, B3) or extensive envelope infiltration (IIB stage) (8). A 2024 study published in the Journal of Surgery demonstrated that among their 113 patients with Masaoka-Koga stage II thymoma, PORT did not provide any additional benefit in terms of disease-free survival (DFS). Based on their findings, the authors concluded that patients with stage II thymoma who undergo radical resection should not receive any form of locoregional adjuvant therapy (19). A meta-analysis in 2022 concluded that patients receiving PORT after surgery did not demonstrate significant survival advantages compared to those who did not undergo PORT. Furthermore, patients with Masaoka-Koga stage I/II thymoma may benefit less from PORT compared to those with stage III/IV thymoma, leading to the recommendation that PORT is not routinely recommended in this population (14). Our study also found that for patients with Masaoka-Koga stage II thymoma, PORT did not show significant improvement in the 5-year OS rate (P=0.11) or the 5-year RFS rate (P=0.24). Research by Mitsugu indicated that the 5-year RFS rates for the PORT and non-PORT groups of Masaoka-Koga stage III thymoma were 62.0% and 69.3%, respectively, showing no survival benefit from PORT for stage III thymoma patients (20). However, it is widely accepted that, regardless of complete resection, PORT is valuable in improving the prognosis of patients with Masaoka-Koga stage III–IV thymoma (11,21-23). PORT is an important therapeutic approach for thymoma; however, it can lead to various adverse effects that warrant careful attention in clinical practice. Common complications include radiation-induced pneumonitis, esophagitis, and cardiotoxicity (24). Esophagitis often presents with dysphagia and retrosternal discomfort, typically emerging during the middle phase of treatment. Radiation pneumonitis is another frequent complication, especially when large areas of adjacent lung tissue are exposed to radiation. Additionally, the risk of cardiotoxicity should not be overlooked, manifesting as pericarditis, pericardial effusion, or coronary artery disease, which may occur years after treatment. To enhance the safety of PORT, it is crucial to optimize RT techniques to minimize the radiation dose to surrounding normal tissues and to closely monitor patients for adverse reactions during and after treatment (25). Our study also demonstrated that, although no statistical benefit was observed in the 5-year RFS rates, PORT had a positive impact on the 5-year OS rates of patients with Masaoka-Koga stage III–IV thymoma, reducing the risk of death by nearly 80% (HR: 0.185; P=0.01). Additionally, in subgroup analysis, PORT significantly improved survival in patients with stage III Masaoka-Koga thymoma, reducing the risk of death by nearly 86% (HR: 0.139; P=0.04). Patients with more locally invasive tumors, positive resection margins, or advanced stages may derive greater benefits from PORT due to its ability to control residual microscopic disease and reduce local recurrence risk. Conversely, patients with early-stage tumors or complete resections may not benefit as significantly, as their baseline risk of recurrence is inherently low. Similar findings have been reported in other study (26), highlighting the role of PORT in high-risk patients while questioning its necessity in low-risk cases. The results of this study suggest that the efficacy of PORT may vary among different patient subgroups, warranting further investigation. Future research should focus on more detailed subgroup analyses based on TNM staging, such as evaluating the necessity of PORT in early-stage (I–II) low-risk patients and its potential benefits in locally advanced (stage III) patients with high-risk features. Additionally, the role of PORT in patients with positive surgical margins (R1/R2 resection) needs to be further validated to determine its impact on reducing recurrence risk. Analyses based on pathological subtypes are equally important, for instance, assessing whether PORT can be omitted in low-risk types such as type A and AB thymomas, while exploring its benefits in more aggressive types such as B2 and B3 thymomas. Moreover, individual patient characteristics, including age, comorbidities, and molecular biomarkers associated with RT sensitivity, warrant further exploration. Large-scale, multicenter studies with stratified analyses are necessary to provide robust evidence for optimizing PORT strategies and advancing personalized treatment approaches. Currently, there are relatively few reports addressing treatment recommendations for thymic tumors in conjunction with the TNM staging system. A meta-analysis published in 2022 emphasized that surgical treatment is the first-line option for TNM stage I and stage II thymoma. Regarding RT, the existing evidence suggests that patients with these stages benefit less from receiving PORT, and therefore, PORT is not routinely recommended. However, PORT should be considered for TNM stage II patients with incomplete excision or positive margins. For TNM stage III patients, the analysis found that the benefits of PORT outweigh the risks, and it is recommended as an important treatment modality (14). TNM stage III patients correspond to Masaoka-Koga stage III patients, who exhibit significant tumor invasion, leading most scholars to support the use of PORT in these cases (11,21-23). In this study, no significant benefits were observed in terms of the 5-year OS and RFS rates for TNM stages I and II patients receiving PORT. However, for TNM stage III patients, both the OS and RFS rates showed significant improvements in the PORT group. Patients receiving PORT experienced a nearly 83% reduction in the risk of death (HR: 0.168; P=0.01) and an 88% reduction in the risk of recurrence (HR: 0.118; P=0.03). TNM classification was identified as an independent prognostic factor for OS rates in the univariate analysis of all thymoma patients (TNM stages I and II vs. TNM stage III; HR: 5.669; 95% CI: 1.347–23.852; P=0.02). This suggests that TNM classification is a potentially important factor influencing OS, which has been confirmed by multiple studies (7,27). In the univariate analysis of TNM stage III thymoma patients, PORT was found to be an independent prognostic factor for OS rates (PORT vs. non-PORT; HR: 13.646; 95% CI: 1.522–122.356; P=0.02). This indicates that PORT may be a potentially important prognostic factor for OS in TNM stage III thymoma patients.

Limitations

There are several limitations in this study. First, it is a single-center retrospective analysis, which introduces a potential selection bias due to the relatively homogenous patient population. Second, there were a significant number of lost follow-ups, and the median follow-up time was 47 (range, 26–84) months. Long-term follow-up is necessary to better assess the long-term effects. Most patients were contacted by phone, which introduces potential recall bias due to the varying lengths of the case cycle. Third, thymic tumors are often asymptomatic, and some patients did not undergo timely follow-ups or were only examined once symptoms appeared, leading to inaccurate survival and recurrence statistics. Fourth, the sample size in this study is relatively small, and matching of data symmetry was not achieved. Stage III thymomas are highly heterogeneous, with variability in tumor infiltration patterns that may affect biological behavior and clinical outcomes. For example, phrenic nerve or lung invasion differs prognostically from major vascular involvement, such as the superior vena cava or pulmonary artery. However, due to limitations in data collection, detailed information on specific infiltration patterns was unavailable in this study. We acknowledge this heterogeneity as a limitation and highlight the need for future multicenter studies to collect detailed clinical and pathological data. Such efforts could enable better stratification of stage III thymomas and clarify the impact of different infiltration patterns on treatment outcomes and prognosis, ultimately improving precision in treatment planning and patient outcomes.

Conclusions

PORT plays a crucial role in the treatment of thymic tumors. However, for Masaoka-Koga stage II thymoma patients, the benefits of PORT need further investigation. For Masaoka-Koga stage III to IVA thymoma, PORT can significantly improve 5-year OS rates, reducing the risk of death by nearly 80%. However, it does not have a positive impact on RFS rates. PORT can benefit both 5-year OS and RFS rates in TNM stage III thymoma, reducing the risk of death by nearly 83% and the risk of recurrence by 88%. Furthermore, Cox regression analysis suggests that TNM staging is a potential independent prognostic factor for survival in invasive thymoma patients, while PORT is a potentially important prognostic factor for survival in TNM stage III thymoma patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1805/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1805/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1805/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1805/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. This study does not require ethical approval because it is based on secondary analysis of existing data, poses no additional risk or burden to the participants, and does not involve direct patient interaction, identifiable personal information, or any intervention that affects human subjects. The data used in this study were obtained from existing medical records and were de-identified to ensure patient confidentiality. No identifiable patient information was included. Additionally, all patients signed institutional informed consent forms upon hospital admission, acknowledging their awareness that their clinical data might be used for research purposes.

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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