Inconsistent definitions of radical resection in perioperative trials of non-small cell lung cancer: a scoping review

Introduction

Over recent years, the therapeutic landscape for early non-small cell lung cancer (NSCLC) has evolved significantly. The integration of perioperative strategies, including neoadjuvant, adjuvant, and combined perioperative immunotherapy or targeted therapy, has reshaped the concept of curative-intent treatment in resectable disease. Trials combining immunotherapy with platinum-based regimens have demonstrated significantly improved event-free survival and pathological response rates compared with chemotherapy alone (1-5). Similarly, landmark studies such as ADAURA and ALINA have shown that the use of tyrosine kinase inhibitors (TKIs) as adjuvant therapy can favorably shift survival curves, redefining expectations for postoperative disease control in molecularly driven NSCLC (6,7). These advances indicate that surgery alone is no longer sufficient for many patients and that curative intent increasingly requires a multimodal approach.

Across this evolving therapeutic landscape, the completeness of surgical resection remains a pivotal determinant of outcome. Numerous studies have consistently demonstrated that radical (R0) resection is strongly associated with improved local control and a reduced risk of distant relapse (8), whereas non-radical resections are linked to inferior oncologic outcomes regardless of perioperative systemic therapy (9). In this context, incomplete resection may offset the benefits of adjuvant or neoadjuvant treatment.

Despite its central role, the definition of “radical resection” has not been applied uniformly across clinical trials. Definitions of R0 resection have varied with respect to margin assessment, handling of close or indeterminate margins, lymph node evaluation, and the inclusion of cytological criteria (9). This heterogeneity has largely gone unaddressed in comparative analyses and meta-analyses of perioperative NSCLC trials, implicitly assuming equivalence between studies that may, in fact, apply different criteria.

This issue has gained further significance with the introduction of the 9th edition of the tumor-node-metastasis (TNM) classification for Lung Cancer in 2025 (10). While T descriptors remain unchanged, the refined subdivision of N2 disease (N2a vs. N2b) and adjustments in stage grouping introduce a contemporary framework that may influence the interpretation of surgical radicality, nodal clearance, and residual disease status (8,11). As a result, historical trial outcomes, particularly those relying on R0 rates as key endpoint, may not be directly comparable when viewed through the lens of current staging standards.

Given these considerations, it becomes essential to reassess how radical resection has been defined and operationalized across perioperative NSCLC trials. It is equally important to determine whether these definitions were consistent or varied across studies. Addressing this gap is necessary to properly interpret existing evidence and to guide the design and interpretation of future NSCLC trials in the era of the 9th edition of the TNM classification. We present this article in accordance with the PRISMA-ScR reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0337/rc) (12).

Methods

This review was not registered in PROSPERO, and no review protocol was prepared, as it is a scoping review focusing on methodological aspects of clinical trial protocols rather than on patient-level clinical outcomes.

Search strategy

The PubMed database and the ClinicalTrials.gov registry were searched in September 2025 using the search terms ‘adjuvant therapy AND NSCLC’ and ‘neoadjuvant therapy AND NSCLC’. The search was limited to publications from 2020 to 2025, and to the article types clinical trial and randomized controlled trial. The literature search strategy was conceptually based on the PICO (Population, Intervention, Comparison, Outcome) framework, defining the population as patients with resectable NSCLC, the intervention as neoadjuvant or adjuvant systemic therapy, and the outcome as the reporting of surgical standards, including the radicality of resection and the extent of lymphadenectomy, in clinical trial protocols. Retrieved records were subsequently summarized in tabular form.

Study selection process and criteria

After retrieval, the literature underwent a three-step screening process. Firstly, duplicate records were removed prior to further assessment. Secondly, articles deemed unrelated to the study topic based on title and abstract screening were excluded. Only articles in English were taken into consideration; consequently, one article in Japanese was excluded. Thirdly, full-text analysis of the remaining studies was performed. At this stage, the inclusion criteria were as follows: (I) availability of the full study protocol; (II) primary analysis (excluding secondary analyzes of the same clinical trials); and (III) inclusion of surgery as a part of the therapeutic approach. Study selection was performed independently by three researchers (J.N., N.S., T.M.), and any disagreements were resolved through discussion until consensus was reached.

Data collection and synthesis

Relevant data were extracted for the following variables: (I) year of publication; (II) stage at diagnosis; (III) AJCC staging edition; (IV) surgical approach; (V) type of surgical procedure; (VI) radicality of resection; and (VII) extent of lymphadenectomy.

Given the nature and heterogeneity of the outcomes of interest, data were summarized descriptively in tabular form. As availability of the full study protocol, published in the main text or supplementary materials, was one of the inclusion criteria, only information explicitly reported in the protocol was extracted. Studies in which relevant variables were reported solely in the main publication but not in the protocol were excluded. This approach was adopted to minimize potential bias. In several instances, corresponding main publications contained partial information relevant to the analysis; however, reliance on these sources could introduce uncertainty as to whether missing data reflected absence from the original protocol, incomplete reporting, or lack of the protocol availability. To ensure consistency and transparency, only studies with accessible and comprehensive protocols were included.

The descriptive data were further encoded according to guideline-defined criteria for surgical radicality and the extent of lymphadenectomy, as specified by the National Comprehensive Cancer Network (NCCN) and the International Association for the Study of Lung Cancer (IASLC). For each study, individual guidelines components were assessed separately.

The evaluated components were as follows:

• According to NCCN guidelines, version 8.2025 for NSCLC:
  • Complete resection: (I) free resection margins; (II) systematic node dissection or sampling; and (III) a negative highest mediastinal node.
  • Lymphadenectomy: (I) systematic node dissection or (II) systematic node sampling.
• According to IASLC Staging Manual, Third Edition:
  • Complete resection: (I) negative surgical margins; (II) adequate node assessment; and (III) a negative highest assessed node station.
  • Lymphadenectomy: (I) adequate.

According to the NCCN guidelines, systematic node dissection is defined as removal of stations 2R, 4R, 7, 8, and 9 for right-sided tumors, or stations 4L, 5, 6, 7, 8, and 9 for left-sided tumors. Systematic node sampling is defined as removal of at least one N1 and three N2 stations, where N1 includes ipsilateral intrapulmonary and hilar nodes, and N2 includes ipsilateral mediastinal or subcarinal nodes.

In accordance with the IASLC staging manual, lymphadenectomy is considered adequate when at least six node stations are removed, including subcarinal station (station 7) and at least two additional mediastinal stations. With respect to lymphadenectomy, an additional category—study-specific—was introduced, as a significant proportion of studies reported the extent of lymph node dissection in a manner that did not fully align with any established guidelines or lacked sufficient details for classification.

Each component was assigned a value of ‘1’ if the criterion was met and ‘0’ if it was not. These binary scores were subsequently combined to assess the overall compliance with guideline-based definitions of radical resection and lymphadenectomy for each study. This approach enabled a standardized and transparent evaluation of the adherence to NCCN and IASLC criteria. As compliance was assessed using binary scoring system, results were summarized as counts and percentages, and no conventional effect measures (e.g., risk ratios or mean differences) were applicable. Details of all retrieved records, along with organized and coded data, are available in the supplementary materials (available at https://cdn.amegroups.cn/static/public/tlcr-2026-0337-1.xlsx).

Data were entered and processed in Microsoft Excel (version 16.83; Microsoft Corporation, Redmond, WA, USA) with conditional formulas. Figures were generated using GraphPad Prism (version 10.6.1; GraphPad Software, San Diego, CA, USA).

Results

Literature search results

The search yielded 563 results: 198 from the PubMed database and 365 from the ClinicalTrials.gov registry. After removal of 55 duplicate records, 508 articles remained for more detailed screening. Of these, 127 records were excluded—one was not published in English and 126 were not relevant to the topic of this review. A total of 381 studies proceeded to full-text assessment, resulting in the exclusion of 334 articles: 209 did not provide a full study protocol, 68 represented secondary analysis of trials already included, and 57 did not include surgery as part of the therapeutic approach. Finally, 47 studies met all predefined eligibility criteria and were included in the scoping review (available at https://cdn.amegroups.cn/static/public/tlcr-2026-0337-1.pdf). The study selection process is summarized in Figure 1.

Figure 1 Study selection process. In accordance with the PRISMA 2020 flow diagram (13).

Study characteristics

Of the 47 included studies, 36 were identified through the PubMed database and 11 through the ClinicalTrials.gov registry. Among the PubMed-derived studies, 35 were categorized as clinical trials, while one was classified as a randomized controlled trial (5). For studies retrieved from ClinicalTrials.gov, trial status was as follows: one trial had an unknown status (14), one was completed (15), one was active but not recruiting (16), two were not yet recruiting (17,18), two were terminated due to recruitment challenges, and four were terminated due to poor accrual (19-24).

Individual studies were subsequently characterized according to their compliance with NCCN and IASLC criteria for radical resection and lymphadenectomy, as described in the Methods section. The distribution of publication years for the included studies is presented in Figure 2, with registered trials analyzed as a separate group due to the heterogeneity of their recruitment status. In the following figures percentages were rounded to whole numbers. In addition, the AJCC staging editions specified in the study protocols were examined. The 7^th and 8^th edition dominated, being used in 21 of 47 studies (45%) and 22 of 47 studies (47%), respectively. Both editions were referenced in one protocol (2%), while the AJCC edition was not specified in three protocols (6%). These data are summarized in Figure 3.

Figure 2 The year of publication of the included studies. Registered trials are portrayed as a single group due to different registration statuses.

Figure 3 AJCC staging editions used in the included studies. AJCC, American Joint Committee on Cancer.

Radical resection

Compliance of the reviewed literature with NCCN criteria for radical resection is presented in Figure 4. Based on the study protocols, radical resection was defined as free resection margin alone in 12 of 47 studies (26%); a free margin combined with systematic lymph node dissection or sampling in one study (2%); or a free margin together with systematic node dissection or sampling and a negative highest mediastinal lymph node in seven studies (15%). Notably, 27 of 47 studies (57%) did not formally include any of the three criteria specified in the NCCN guidelines.

Figure 4 Radical resection criteria according to the included studies’ protocols. The upper panel shows compliance with NCCN criteria, and the lower panel with IASLC criteria. IASLC, International Association for the Study of Lung Cancer; NCCN, National Comprehensive Cancer Network.

Figure 4 also summarizes compliance with IASLC criteria for radical resection. According to the trial protocols, radical resection was defined as negative surgical margins in 13 of 47 studies (28%); negative margins combined with adequate nodal assessment in one study (2%); and negative margins together with adequate nodal assessment and a negative highest assessed nodal station in seven studies (15%). A total of 26 studies (55%) did not specify any of the three criteria defined by IASLC.

In studies where no explicit criteria for radical resection were provided, resection was typically described as ‘R0’, ‘complete’ or ‘curative’ without further specification or was not defined at all. Notably, one protocol required not only free resection margins, systematic lymph node dissection or sampling, and a negative highest mediastinal lymph node, but also negative pleural or pericardial effusions, if present, for the resection to be classified as complete (4). In contrast, another study allowed resection classified as R0, R1(is), or R1(cy+) to be classified as complete (25). According to the IASLC Staging Manual, Third Edition, R1(is) is defined as carcinoma in situ at the bronchial margin, whereas R1(cy+) refers to malignant cells detected on pleural lavage cytology. Both R1(is) and R1(cy+) are categorized to the R1(un) resections by IASLC criteria.

Adherence of the reviewed studies to NCCN lymphadenectomy guidelines is presented in Figure 5. According to the study protocols, lymphadenectomy requirements were defined as study-specific in 18 of 47 studies (38%) and as systematic node sampling in 14 of 47 studies (30%). In 15 of 47 protocols (32%), the extent of lymphadenectomy was not specified. Notably, no studies (0 of 47; 0%) reported the use of systematic node dissection fully consistent with the NCCN definition.

Figure 5 Lymphadenectomy criteria according to the included studies’ protocols. The upper panel shows adherence to NCCN criteria, and the lower panel to IASLC criteria. IASLC, International Association for the Study of Lung Cancer; NCCN, National Comprehensive Cancer Network.

Figure 5 also illustrates compliance with the IASLC lymphadenectomy guidelines. Based on protocol descriptions, lymphadenectomy was classified as study-specific in 25 of 47 studies (53%) and as adequate in seven of 47 studies (15%). The remaining 15 studies (32%) did not report any explicit requirements regarding nodal procedures.

Discussion

The key message derived from this work is that there is no universally accepted standard for defining essential surgical and pathological descriptors in NSCLC. The definitions of radical resection and staging according to the latest, 9th edition of the TNM classification, vary substantially among studies, affecting not only the interpretation of outcomes but also the validity of cross-trial comparisons. Importantly, this heterogeneity is not limited to historical data but also extends to contemporary and ongoing clinical trials, where the evolving 9th edition of the TNM classification may substantially affect endpoint interpretation and patient stratification. The absence of a uniform approach to defining radical resection in studies currently underway or in early initiation phases is therefore likely to prolong ambiguity for many years. Given the timelines required for trial completion, data maturation, and publication, this uncertainty may reasonably persist for a decade or longer, warranting close examination of its methodological implications for future research and clinical practice.

The concept of residual tumor (R) classification was first introduced in 1977 and subsequently incorporated into the fourth edition of the Union for International Cancer Control (UICC) TNM classification in 1987, where it has remained an essential component through successive editions. Initially, four categories were distinguished—R0, R1, R2, and RX (unknown) (26). Over time, additional subcategories were proposed to refine the concept of surgical completeness, including R0 with margins smaller or greater than 1 mm, the “uncertain resection” category R(un), and several R1 and R2 subtypes (27). Early definitions of complete resection evolved through successive milestones. Naruke et al. [1978] defined complete resection as the absence of visceral pleural invasion or suture line involvement, negative mediastinal lymph nodes, and complete lymph node dissection (28). Mountain et al. [1983] emphasized that, in the surgeon’s judgment, all detectable disease must be removed, with microscopically negative bronchial margins, intact lymph node capsules, and the most distant node free of tumor (29). Martini and Ginsberg [1995] further refined this concept by requiring lobectomy or pneumonectomy with en bloc resection of invaded structures, intraoperative assessment of all margins, and complete mediastinal lymphadenectomy (30).

Among subsequent developments, the IASLC-proposed “uncertain resection” category R(un) category, introduced in 2005, acknowledged that some resections may fail to meet the criteria for complete resection despite the absence of evident residual tumor (27). This category applied to cases involving inadequate nodal dissection, carcinoma in situ at the bronchial margin, involvement of the highest mediastinal lymph node, or positive pleural lavage cytology. Despite detailed recommendations, global implementation of R(un) criteria remains inconsistent. Surveys among experts in certified lung cancer centers have revealed persistent heterogeneity in both the interpretation and practical application of R classification (31).

At that time, the role of lymph node metastases in determining resection radicality was neither widely discussed nor considered controversial (32). Nodal involvement—whether the hilar or mediastinal—was not systematically incorporated into formal assessment of resection completeness across the literature. Among all identified studies, only three explicitly mentioned extracapsular extension (ECE) (33-35). Moreover, in the PEARLS/KEYNOTE-091 trial, ECE in hilar lymph nodes was not considered an R1 feature, further complicating interpretation, and cross-study comparability (36). Collectively, these inconsistencies indicate that the integration of nodal factors into definitions of radicality has remained largely unstandardized, hindering meaningful comparisons of surgical quality and oncological outcomes between historical and contemporary cohorts (33,36). Variability in definitions of radical resection is further influenced by national standards and regional practice patterns. Studies conducted under the auspices of different scientific committees often reflect varying interpretations radicality shaped by regional guidelines and professional consensus. For instance, in Japan, approximately 60% of pathologists involved in R-status assessment categorize inadequate lymph node dissection as R(un), and surgical teams more frequently include the most proximal mediastinal lymph node identified by the surgeon in resections performed with curative intent. In contrast, nodal factors are less commonly incorporated into definitions of radicality in the United Kingdom and most European countries. These regional differences highlight how local practices continue to shape the application of residual tumor classification and contribute to persistent inconsistencies in defining and comparing complete resection across international studies (31).

From the pathologist’s perspective, assessing the completeness of excision of a tumor that has metastasized to lymph nodes is uncertain and inherently challenging. This is primarily due to the fact that lymph nodes removed during lobectomy are submitted in fragments, which significantly hampers the evaluation of possible ECE by the metastatic tumor and, in practice, makes it nearly impossible to assess the completeness of metastatic deposit removal. ECE assessment is further complicated because it not only involves direct invasion into surrounding tissues, but also the presence of tumor cells within lymphatic vessels or perinodal fat tissue that are nearly impossible to evaluate reliably when the nodal capsule is disrupted. These issues have already been a source of concern in earlier publications (37-39). A related challenge arises when assessing whether the recommended minimum number of lymph node stations has been adequately resected. This includes not only nodes obtained intraoperatively but also preoperative material such as endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) samples, as well as N1 nodes sampled by the pathologist from the surgical specimen. Integrating these heterogeneous sources of material significantly increases the workload for the pathologist in counting and verifying lymph node stations. Moreover, accurate assessment can be compromised if the clinical documentation does not clearly indicate the anatomical origin of each lymph node, further limiting reproducibility and potentially leading to misclassification. In practice, these technical limitations such as fragmentation of nodes, absence of an intact capsule, and the labor-intensive process of counting and evaluating multiple nodal stations, make definitive verification of R0 resection criteria with respect to lymph nodes challenging. Consequently, a fully reliable assessment of resection radicality requires a multidisciplinary approach that integrates surgical, pathological, and clinical documentation to ensure accuracy.

Both the ADAURA and ALINA trials demonstrated a clear survival benefit of adjuvant TKI therapy in patients with completely resected, driver-mutated NSCLC. In ADAURA, adjuvant osimertinib significantly reduced the risk of recurrence or death compared with placebo in patients with EGFR-mutated stage IB–IIIA disease (6). Similarly, the ALINA trial confirmed the efficacy of adjuvant alectinib in radically resected ALK-positive NSCLC, establishing TKI therapy as a standard of care in these populations (7). Importantly, eligibility in both trials required radical resection, and these trial-specific definitions are now being extrapolated to contemporary clinical practice shaped by the 9th edition of the TNM classification, whose more restrictive criteria for radical resection may further narrow eligibility for adjuvant targeted therapy.

Despite these advances, biologically plausible patient subgroups who may derive benefit from TKI therapy remain excluded under current trial designs, particularly those who have underwent non-radical (incomplete) surgical resection. These small and heterogeneous populations are rarely represented in prospective trials, making adequately powered studies of TKI efficacy difficult. Nevertheless, such patients are likely to harbor microscopic residual disease that may be sensitive to targeted therapy. Excluding them from adjuvant or consolidative TKI treatment lacks clear biological justification. Patients with incomplete resections occupy an intermediate prognostic space. Expectant management leaves these high-risk individuals without systemic disease control, despite a rationale for earlier intervention. Notably, patients excluded from pivotal trials, including those with incomplete resections, often exhibit aggressive tumor biology and an elevated risk of central nervous system failure (40). Their prognosis may be inferior to that of stage III disease, further emphasizing the rationale for earlier systemic intervention rather than deferring treatment until overt dissemination occurs. Although the quality of local treatment remains a key determinant of outcomes, the prevailing evidence base largely addresses scenarios in which the intended treatment strategy could not be fully delivered.

Studies conducted in 2025 that fully adopt the framework of the 9th edition of the TNM classification indicate that resectability-related nuances are not uniformly interpreted under the proposed new criteria (41). Rather than promoting simplification or unification, the current trajectory appears to introduce additional layers of complexity. The increasing number of factors influencing resectability, including nodal involvement pattern, extent of invasion, and residual disease assessment, contributes to greater variability in therapeutic decision-making. Consequently, interpretations of radicality and resectability have become progressively multifactorial, with direct implications for patient selection, surgical strategy, and the comparability of outcomes across clinical studies. In the light of this growing complexity, the binary scoring system used in our analysis does not fully capture all the nuances of surgical practice. Nevertheless, we believe that such an approach represents a step towards improving the clarity and reproducibility of our study.

The recent alignment of IASLC and UICC approaches to the definition of resection radicality appears to carry important implication for ongoing and planned clinical trials, as well as for regulatory process governing medicinal product approval (11). Until 2025, however, differing approaches to the R0 category were presented by the IASLC and the UICC, particularly within the frameworks of the 7th and 8th editions of the TNM classification (27,42). In its 2010 document, the UICC defined radicality status as R0, R1, or R2, with an additional, loosely specified RX category. Given this history of inconsistent and often chaotic handling of radicality definitions, there is little assurance that the current harmonization effort will yield tangible improvements in study design, patient satisfaction, or outcome comparability.

Paradoxically, the situation resembles the well-known idiom that “the emperor has no clothes”. The criteria for resection radicality endorsed by the UICC in 2025 are not conceptually novel, yet they remain absent even from the most advanced perioperative and adjuvant treatment protocols. Given the strikingly heterogeneous and often incompatible definitions of radicality used across the literature, frequently diverging from the IASLC standards, the concept of “radical resection” should not be directly compared in most published studies. This raise a fundamental question as to whether scientific societies retain the authority to define surgical and oncological standards when their recommendations are not adopted in either academic or industry-sponsored trials. Although an independent, large-scale analysis of high-quality source data could theoretically address this discrepancy, such an undertaking appears unlikely in the context of fragmented datasets, heterogenous methodologies, and competing stakeholder interests.

This conceptual inconsistency is reflected in several methodological limitations of the present study. Most of the screened and analyzed publications do not report, either in the main text or in supplementary materials, the detailed criteria used to define resection radicality. This lack of transparency limits the precision of comparison and interpretation. At the same time, it constitutes a finding in itself, underscoring the central observation of this analysis: the absence of clearly defined and consistently reported criteria for radical resection remains a pervasive and unresolved. We acknowledge that, in some cases, certain surgical details were included in the supplementary materials. However, it was not possible to determine whether some information was lacking because it was not addressed in the trial at all or simply not reported in the appendix while being present in the full trial protocol. Hence, we decided to include only trials with a full protocol to improve the consistency of our study. However, given the substantial number of studies (n=209) that had to be excluded for this reason, this decision may have influenced the results. Additional analyses may be valuable to assess the surgical guidelines applied in trials using sources other than the trial protocol, which might reveal a higher level of adherence to the guidelines.

Another aspect worth mentioning is that the followed guidelines may vary across different geographical regions. For instance, the European Society for Thoracic Surgeons (ESTS) guidelines for intraoperative lymph node staging in NSCLC may be preferred over NCCN or UICC criteria in European centers. According to ESTS guidelines, systematic nodal dissection is recommended in all cases to ensure complete resection (43). For peripheral T1 squamous tumors, lobe-specific systematic nodal dissection is acceptable and involves resection of at least three hilar and interlobar lymph nodes, as well as three mediastinal lymph nodes from three stations, including the subcarinal station (43). However, these ESTS guidelines are relatively outdated, whereas NCCN and UICC guidelines are more recent. Although the ESTS guidelines were revised in 2014, the update focused on pre-operative nodal assessment rather than intraoperative lymph node staging (44). Nonetheless, the existence of recommendations other than NCCN or UICC implies further heterogeneity in surgical practice and lymph node assessment across different regions. As it may influence the comparability of included studies and the interpretation of results, future research in this direction is warranted.

Conclusions

In summary, the collected findings indicate that the lack of a clear and uniform definition of resection radicality not only persists but is unlikely to be resolved in the coming years, as no consistent trend toward standardization can be observed. This ongoing heterogeneity continues to undermine the interpretability of regulatory documents and limits the external validity of both clinical trials results and real-world evidence in surgically treated NSCLC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA-ScR reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0337/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0337/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-2026-0337/coif). A.C. reports personal payment from Roche Genentech, AstraZeneca, and MSD related to support for attending meetings and/or travel. J.B. reports personal payment from AstraZeneca for lectures, presentations, speakers bureaus, manuscript writing or educational events. T.M. reports personal payment from Roche Genentech, AstraZeneca, and MSD related to support for the present manuscript, consulting fees, lectures, presentations, speakers bureaus, manuscript writing or educational events, support for attending meetings and/or travel, and participation on a Data Safety Monitoring Board or Advisory Board. The other 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.

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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