Postoperative innate immune function after minimally invasive transcervical esophagectomy (MICE) versus minimally invasive transthoracic esophagectomy (MIE)

Introduction

Esophageal cancer ranks as the sixth most common cause of cancer-related mortality. Treatment often includes chemotherapy, radiotherapy, and/or surgical resection of the tumor (1). Although esophagectomy is often crucial in curative treatment, it is associated with considerable morbidity and risk of complications (2-4). Recently, a new esophagectomy technique was implemented at Radboudumc (Nijmegen, the Netherlands), called minimally invasive transcervical esophagectomy (MICE) (5). This technique combines laparoscopic transhiatal and single-port transcervical mediastinoscopic dissections and was developed in Japan in 2015 (6-8).

Previous research has shown that the transcervical approach may provide the same feasibility and oncological outcomes as the most commonly used technique at present, minimally invasive transthoracic esophagectomy (MIE), even for patients with significantly lower pulmonary function (9). Moreover, the transcervical approach is superior in terms of removing the upper mediastinal lymph nodes and reducing pulmonary complications (10,11). Other reported advantages reported in a recent meta-analysis and systematic review include reduced operative time and postoperative hospital stay. However, a higher incidence of recurrent laryngeal nerve (RLN) paralysis was observed after transcervical procedures (11).

By avoiding transthoracic access and preservation of pleural integrity, the MICE technique is expected to reduce the extent of surgical trauma and lower the risk of postoperative infectious complications. Surgical trauma impacts immune function by triggering a cascade that induces a suppressive state called immunosuppression (12). Shortly after surgery, the innate immune system is predominantly active, responding rapidly to tissue damage and potential pathogens. Tissue damage sparks the release of damage-associated molecular patterns (DAMPs) into the bloodstream, which affect immune homeostasis. Among others, the DAMPs S100A8/A9 and S100A12 play a key role in progression of inflammation (13,14). Consequently, both pro- and anti-inflammatory cytokines are released (15-18). Most importantly, concentrations of the anti-inflammatory cytokine interleukin (IL)-10 in plasma are already increased shortly after damage occurs, followed by a rise in pro-inflammatory IL-6. An imbalance in the immune response caused by surgery can lead to postoperative immunosuppression, which is closely linked to the development of postoperative infections (19).

We hypothesized that by avoiding transthoracic access combined with preservation of pleural integrity, the novel MICE procedure might positively influence postoperative immune homeostasis. Therefore, the aim of this explorative study was to compare the effects of MICE versus MIE on postoperative innate immune function. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1569/rc).

Methods

Study population

For this explorative cohort study, data regarding patients who participated in the F4S PREHAB trial (NL8699 in the International Clinical Trials Registry Platform) were used (20). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of the Radboud University Medical Center (Radboudumc) and local Medical Ethics Committee—METC Oost-Nederland (NL73777.091.20) and informed consent was obtained from all individual participants. For additional patients included for CRP measurements, the institute’s opt-out registry was consulted to determine whether or not patients objected to participating in scientific research. Participants of the F4S PREHAB trial adhered to a multimodal prehabilitation program, consisting of an exercise program, nutritional intervention, psychological support and smoking cessation support. Patients were included in the current analysis if they underwent an MIE or MICE procedure between August 2022 and October 2023 at the Radboudumc (Nijmegen, the Netherlands). The choice between MIE and MICE was not randomized but made in a shared decision-making process between the patient and the multidisciplinary treatment team. The team assessed whether the patient and tumor characteristics were suitable for both procedures and then offered the patient the choice between MIE and MICE. Patients were excluded in case of deviation from the intended procedure. Neoadjuvant therapy consisted of chemotherapy with the FLOT regimen (fluorouracil, leucovorin, oxaliplatin, and docetaxel) (21) or chemoradiotherapy according to the CROSS protocol (carboplatin/paclitaxel with concurrent radiotherapy) (2).

Specifically for the analysis of postoperative circulating C-reactive protein (CRP) concentrations, the cohort was expanded with all additional patients who underwent MIE or MICE at the Radboudumc between January 2022 and August 2024, provided they did not opt out of the use of their data for research purposes.

Surgical approach

All surgeries were performed at a single (high-volume) center, with standardized technique for both approaches. MIE (Ivor-Lewis) was performed minimally invasive, with first the abdominal phase in supine (French) position, followed by the thoracic phase in prone position with CO₂ insufflation to induce collapse of the right lung without the use of one-lung ventilation. Prone position improves postoperative oxygenation and is associated with less impairment of pulmonary function, reduced pulmonary complications, and earlier recovery compared to the left lateral decubitus position in open and thoracoscopic procedures (22,23). MICE was performed in supine (French) position with mediastinoscopic dissection via left transcervical approach (24) and laparoscopic abdominal/transhiatal dissection, without entering pleural cavity, maintaining two-lung ventilation.

For distal esophageal tumors without radiological signs of high mediastinal/paratracheal lymph node involvement, a high mediastinal/paratracheal lymphadenectomy is not routine at our center when patients are treated with MIE. Therefore, patients treated with MICE include a more extensive upper mediastinal (including paratracheal and RLN stations) lymphadenectomy, compared to MIE in this cohort.

Outcomes

Blood samples were obtained before surgery (upon hospital admission) and on postoperative day 1 (POD1). Analyses included concentrations of DAMPs (S100A8/A9 and S100A12) and cytokines [IL-6, tumor necrosis factor (TNF), and IL-10] in plasma, ex vivo cytokine production following whole blood stimulation with endotoxin, and quantification of inflammation-related proteins in plasma.

Baseline characteristics, perioperative parameters, postoperative outcomes, and circulating CRP concentrations (from end of surgery until POD7) were obtained from digital patient files and the Dutch Upper Gastrointestinal Cancer Audit (DUCA). The severity of postoperative complications (within 30 days after surgery) was systematically evaluated in accordance with the Clavien-Dindo classification (25). Estimated peak VO₂ was measured preoperatively using the Steep Ramp Test protocol on a cycle ergometer and a leg press machine was used to evaluate the one-repetition maximum (1RM).

Sample collection

Blood samples were collected in tubes containing lithium heparin (LH) or ethylenediaminetetraacetic acid (EDTA) as anticoagulants. All blood tubes were centrifuged at 2,970 RCF for 10 minutes at room temperature. EDTA anti-coagulated plasma samples were centrifuged again at 16,000 RCF for 10 minutes at room temperature. Plasma aliquots were stored at −80 °C until further analysis.

Plasma DAMP and cytokine concentrations

Plasma concentrations of S100A8/A9 and S100A12 were determined using Human S100A8/S100A9 Heterodimer and Human EN-RAGE DuoSet enzyme-linked immunosorbent assays (ELISAs) (R&D Systems, Minneapolis, MN, USA, catalogue Nos. DY8226-05 and DY1052-05, respectively). Both S100A8/A9 and S100A12 are important DAMPs that provoke inflammation (17,26). Measurement of these DAMPs may reveal differences in surgical tissue injury, as higher concentrations have previously been observed in patients undergoing mastectomy compared to breast-conserving surgery (27). Plasma concentrations of the pro-inflammatory cytokines IL-6 and tumour necrosis factor (TNF), along with the anti-inflammatory cytokine IL-10, were measured as they are generally released following tissue injury (19,28). Plasma cytokine concentrations were quantified using a Luminex assay on plasma from EDTA-anticoagulated blood, following the manufacturer’s instructions (Milliplex; Millipore, Billerica, MA, USA).

Ex vivo cytokine production capacity upon whole blood stimulation

Ex vivo leukocyte cytokine production capacity was assessed by stimulating whole blood with Escherichia coli (E. coli) lipopolysaccharides (LPS, serotype O55, Sigma Aldrich, St. Louis, MO, USA) to effectively evaluate immune system functionality. LH-anticoagulated blood was added to prefilled tubes containing Dutch-modified Roswell Park Memorial Institute (RPMI) culture medium (negative control) or culture medium supplemented with E. coli LPS (final concentration 10 ng/mL), as previously described (19). After 24 hours of incubation at 37 °C, the tubes were centrifuged at 2,970 RCF for 10 minutes at room temperature, and the supernatant was stored at −80 °C until analysis. Concentrations of pro-inflammatory cytokines IL-6, IL-1β, TNF, and the anti-inflammatory cytokine IL-10 were measured batch-wise using Human Bio-Techne R&D ELISAs according to the manufacturer’s instructions (R&D Systems, Minneapolis, MN, USA; catalogue Nos. DY206, DY201, DY210, and DY217B).

Plasma protein concentrations

Circulating inflammatory plasma protein expression was assessed in EDTA-anticoagulated plasma using the commercially available multiplex proximity extension assay from Olink^® Proteomics AB (Uppsala, Sweden). The Target 96 Inflammation Panel was run, which is used to measure 92 inflammatory proteins. Proteins with >25% of the values below the limit of detection (LOD) at both timepoints (preoperatively and on POD1) were excluded, resulting in 80 proteins for the data analysis. Quality control and outlier detection did not result in exclusion of samples.

Statistical analysis

Continuous data in tables and figures are expressed as mean ± standard deviation (SD) and median ± interquartile range (IQR), respectively. Categorical data are presented as numbers with percentages. Independent samples t-tests or Chi-squared tests (as applicable) were used to determine differences in baseline characteristics and postoperative outcomes between the groups. Differences in postoperative CRP patterns between MIE and MICE were evaluated using a linear mixed model to correct for baseline characteristics and intraoperative outcomes that differed significantly between the groups. In this model, surgery type, Eastern Cooperative Oncology Group (ECOG) performance status, comorbidities (malignant conditions), and neoadjuvant therapy were included as fixed factors, with surgery duration as a covariate. As CRP data were not normally distributed, the natural logarithm (Ln) of CRP values was calculated and used as the dependent variable in the analysis. Differences in cytokine and DAMP concentrations in plasma and ex vivo cytokine production between the groups on POD1 were determined using linear regression analyses to allow for correction of baseline characteristics and intraoperative outcomes that differed significantly between the groups. In all analyses, surgery type, preoperative concentrations of the assessed biomarker, neoadjuvant therapy, surgery duration, and estimated peak VO_2max were included as independent variables. These analyses were also performed after calculating the Ln of the measured concentrations. Correlations between CRP, plasma cytokines, DAMPs, and ex vivo cytokine production were determined using Spearman’s rank correlation (Spearman’s r).

For analysis of data from the Olink inflammation panel, statistical testing was performed by using the Wilcoxon matched-pairs signed rank test to compare timepoints and Mann-Whitney U test to compare the groups on POD1. The Benjamini-Hochberg procedure was employed to correct for multiple testing errors and provided false discovery rate (FDR)-adjusted P values.

Statistical analyses were performed using SPSS Statistics version 29 (IBM Corporation, Armonk, NY, USA) and RStudio version 2023.12.1 (Posit, PBC, Boston, MA, USA). Figures were created using Graphpad Prism version 9 (Graphpad Software, NY, USA) and RStudio. P values <0.05 were considered statistically significant.

Results

Patient characteristics

From July 2022 until December 2023, 44 patients undergoing esophagectomy participated in the immunology sub-study of the F4S PREHAB trial. Two patients were excluded from the current analysis due to undergoing conversion or surgery other than MIE or MICE. As a result, 42 patients, including 21 patients undergoing MIE and 21 patients undergoing MICE, were included in the analysis. The groups were similar in age, gender, body mass index (BMI), American Society of Anesthesiologists (ASA) classification, and ECOG performance status (Table 1). Additionally, tumor histology and tumor-node-metastasis (TNM) classification were similar, but the groups differed in administered neoadjuvant therapy (P=0.03), with all patients in the MICE group receiving chemoradiotherapy while in the MIE group some patients only received chemotherapy (n=4) or received no neoadjuvant therapy (n=2). Regarding prehabilitation parameters prior to surgery, patients in the MICE group had a higher preoperative estimated peak VO_2max compared to the MIE group (25.7±4.4 and 23.0±3.5 mL/kg/min, respectively, P=0.045), while both groups had similar 1RM measurements.

The expanded CRP cohort, including 66 patients in the MIE group and 61 patients in the MICE group, used to analyze postoperative circulating CRP concentrations, also had a difference in the administered neoadjuvant therapy (Table 1). Furthermore, the MIE and MICE groups within this larger cohort differed in preoperative ECOG performance status and specific comorbidities (malignant conditions).

Intra- and postoperative outcomes

In both cohorts, duration of surgery was significantly longer in the MICE group compared to the MIE group (P<0.001 in both cohorts), while blood loss was similar (Table 2). Postoperative outcomes including length of stay at the intensive care unit (ICU), hospital stay, and readmissions were also equal in the groups. Additionally, there was no significant difference in the total number of patients with postoperative complications and severity of complications, as assessed using Clavien-Dindo classification, between the groups. A more detailed overview of postoperative complications is provided in Table S1. Also, no differences in the incidence of postoperative infectious complications were observed.

Postoperative immune function

Postoperative concentrations of circulating CRP increased after surgery, peaking at POD3 (Figure 1). Linear mixed model analysis showed no differences in postoperative CRP trajectory after MIE versus MICE.

Figure 1 Plasma CRP concentrations in patients undergoing MICE (n=61) versus MIE (n=66) at the end of surgery and on POD1–7. CRP, C-reactive protein; MICE, minimally invasive transcervical esophagectomy; MIE, minimally invasive esophagectomy; POD, postoperative day.

Plasma concentrations of pro-inflammatory cytokines IL-6 and TNF, anti-inflammatory IL-10, and DAMPs S100A8/9 and S100A12 did not differ between the groups on POD1 (Figure 2A-2E). Concentrations of IL-6, IL-10, S100A8/A8, and S100A12 in plasma were increased on POD1 compared to preoperatively, and TNF was lowered.

Figure 2 Immune function pre-op and on POD1 in patients undergoing MICE (n=21) versus MIE (n=21). (A-E) Plasma concentrations of cytokines IL-6, TNF, IL-10 and DAMPs S100A8/A9 and S100A12. (F-I) Ex vivo production of IL-1β, IL-6, TNF, and IL-10 by leukocytes upon 24 h whole blood stimulation with Escherichia coli lipopolysaccharides. DAMPs, damage-associated molecular patterns; IL, interleukin; MICE, minimally invasive transcervical esophagectomy; MIE, minimally invasive esophagectomy; POD, postoperative day; pre-op, preoperatively; TNF, tumor necrosis factor.

Ex vivo cytokine production of pro-inflammatory cytokines IL-1β, IL-6, and TNF, and anti-inflammatory cytokine IL-10 also did not differ between the groups on POD1. Ex vivo cytokine production of proinflammatory cytokines was reduced on POD1 compared to preoperatively (Figure 2F-2I).

Correlations between the different measures of immune function are shown in Figure 3. Plasma concentrations of IL-6 on POD1 correlated with CRP concentrations on POD1–5. Furthermore, preoperative plasma concentrations of IL-10 were inversely correlated with CRP concentrations at the end of surgery, POD2, and POD3. CRP levels on POD1 and POD2 also correlated with concentrations of S100A8/A9 in plasma on POD1.

Figure 3 Correlation heatmap displaying Spearman’s r of statistically significant correlations (P<0.05) between concentrations of CRP, ex vivo cytokine production upon 24 h whole blood stimulation with Escherichia coli lipopolysaccharides, and plasma concentrations of cytokines and damage-associated molecular patterns (n=42). CRP, C-reactive protein; IL, interleukin; POD, postoperative day; TNF, tumor necrosis factor.

Dysregulation of circulating protein concentrations

Using targeted proteomics, we observed that many proteins were differentially expressed between POD1 and preoperative samples (Figure 4A,4B). We identified 41 (51%) proteins that were differentially expressed between the two timepoints in patients undergoing MICE and 41 (51%) in patients undergoing MIE, with 36 proteins showing a similar change between POD1 and the preoperative period in both groups. No differences in protein expression were observed between the MIE and MICE groups on POD1 (Figure 5A). IL-6 was most upregulated on POD1 in both groups, while interferon-gamma (IFNγ) was most downregulated in both groups (Figure 5B). Five proteins were only up- or downregulated in the MICE group (ADA, CD244, IL-18R1, TNFRSF9, and VEGFA) and five proteins were only up- or downregulated in the MIE group (CD8A, FGF-2, IL-17A, TGFα, and TSLP).

Figure 4 Volcano plots showing the fold change (log₂ FC) of differentially expressed proteins on POD1 compared to pre-op in (A) patients undergoing MIE (n=21) and (B) patients undergoing MICE (n=21). Dark red indicates significantly (FDR-adjusted P value <0.05) elevated or lowered inflammatory proteins. FC, foldchange; FDR, false discovery rate; MICE, minimally invasive transcervical esophagectomy; MIE, minimally invasive esophagectomy; POD, postoperative day; pre-op, preoperatively.

Figure 5 Volcano and comparison plots evaluating differences in postoperative protein expression between esophagectomy techniques. (A) Volcano plot showing the fold change (log₂ FC) of differentially expressed proteins between the MICE and MIE group on POD1. No differences in inflammatory protein levels between MICE and MIE were observed on POD1, as assessed by FDR-adjusted P value <0.5. (B) Comparison plot showing the fold change (log₂ FC) of POD1 compared to preoperatively for both types of surgery. Dots on the diagonal line represent no difference in fold change (POD1 vs. pre-op) between the MIE and MICE groups. FC, foldchange; FDR, false discovery rate; MICE, minimally invasive transcervical esophagectomy; MIE, minimally invasive esophagectomy; POD, postoperative day; pre-op, preoperatively.

Discussion

This explorative study evaluated the impact of MICE versus MIE on the postoperative innate immune function. We found no significant differences in CRP trajectory during the first postoperative week and other inflammatory outcomes measured on POD1 between the groups.

In this study, circulating CRP dynamics from the end of surgery until POD7 did not differ between MICE and MIE groups. While no other studies have specifically compared CRP concentrations after MICE versus MIE, previous research has reported significantly lower CRP concentrations after minimally invasive procedures compared to open esophagectomy on POD1 and POD2 (29). Similarly, in patients undergoing colorectal surgery, CRP concentrations were significantly lower in those undergoing a minimally invasive procedure compared to the open surgery group (30). In addition to the general benefits of minimally invasive surgery, evidence suggests that newer techniques, such as robot-assisted surgery, may further improve outcomes. For example, lower CRP concentrations have been observed after robot-assisted versus laparoscopic left (hemi)colectomy or hysterectomy (31-33). These findings do highlight the potential for advancements in surgical techniques to enhance postoperative outcomes.

In our esophagectomy cohort, concentrations of circulating CRP on POD1–5 correlated with IL-6 concentrations on POD1. Circulating CRP concentrations at the end of surgery and on POD2 and POD3 were inversely correlated with preoperative concentrations of IL-10 in plasma. IL-6 is the primary cytokine responsible for inducing CRP expression in hepatocytes (34), which explains the correlation between postoperative circulating IL-6 and CRP concentrations. In contrast, to the best of our knowledge, no previous studies have investigated correlations between preoperative plasma IL-10 concentrations and postoperative circulating CRP concentrations. These exploratory, post-hoc findings suggest that a more anti-inflammatory preoperative immune status may be associated with lower postoperative CRP production. Preoperative IL-10 concentrations were also inversely correlated with IL-6 concentrations on POD1. Preoperative inflammatory status can, for example, be influenced by chronic exercise, which reduces inflammation and increases concentrations of anti-inflammatory cytokines (35). Studies investigating the effect of preoperative circulating IL-10 on postoperative complications are lacking. As this was a hypothesis-generating observation, specifically designed studies are warranted to investigate possible associations between preoperative plasma IL-10 concentrations, postoperative inflammatory status, and postoperative complications.

No differences in postoperative immune function were found between the MIE and MICE group despite significantly longer surgery duration of the MICE procedure and extensive mediastinal dissection. Potential benefits of transcervical esophagectomy may have been masked by the long surgery duration in the MICE group. Surgery for patients undergoing MICE took more than 1.5 hours longer than for those undergoing MIE, possibly due in part to the learning curve associated with the new technique (24). Moreover, in our hospital, the transcervical mediastinoscopic and laparoscopic transhiatal procedures are not performed synchronously. Surgery inevitably triggers the release of cytokines into the circulation, with the extent of this release, particularly for IL-6, correlating with the duration of the procedure and the extent of surgery (36). For example, differences in immune function after mastectomy compared to breast-conserving surgery have been reported (27). Also, correlations between surgery duration and postoperative CRP concentrations have been reported (37-39). However, in our study, no significant differences in IL-6 and CRP were observed between the groups, despite circulating IL-6 and CRP concentrations showing a tendency to be lower in the MICE group. Reducing the operation time by performing the transcervical mediastinoscopic and laparoscopic transhiatal procedures simultaneously might be beneficial in terms of postoperative inflammatory response. Therefore, the clinical relevance of the lack of observed differences in our study remains uncertain.

Postoperative inflammatory status was very different on POD1 compared to preoperatively, as shown by many differentially expressed proteins in both groups. However, no differences in inflammatory protein levels on POD1 were observed between the MIE and MICE groups. Also, no differences were observed in fold change on POD1 compared to preoperatively between the groups. Although some proteins were differentially expressed on POD1 compared to preoperative levels in only one of the groups, the fold changes were highly comparable between the MIE and MICE groups, suggesting that this difference is likely of limited clinical significance. Postoperative inflammatory status has been previously studied by Albers et al., who described pre- to post-operative proteomic changes in patients undergoing colorectal surgery (40). Most of the up- or downregulated proteins on POD1 in colorectal surgery patients overlap with those on POD1 in our esophagectomy cohort. Similarly, during a gout flare—another example of acute inflammation—the most significantly up- and downregulated proteins show notable similarity to the differentially expressed proteins in our cohort, although the gout cohort contained notably fewer differentially expressed proteins overall (41). In contrast, changes in inflammatory protein expression during the acute phase of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection only partly overlap and are partly opposite to changes observed after esophagectomy (42). This shows that inflammatory responses vary across different conditions, with both shared and distinct proteomic changes depending on the type and context of inflammation.

This study has several limitations. First, this study is limited by its small sample size. This constraint may have resulted in missed effects due to the increased risk of type II errors, limiting the ability to detect statistically significant differences and reducing the overall statistical power of the study. The lack of differences in immune outcomes may therefore be due to a lack of power rather than a true absence of difference. Additionally, the learning curve for the MICE technique is a potential confounder, as initial procedures may have been affected by factors such as longer surgery duration, which are a possible driver of inflammation. This could have attenuated the observation of differences in outcomes. Furthermore, only measurements from two timepoints could be included in the current analysis, which may not capture the full dynamics of the immune response difference between the two techniques. Important differences during the days after POD1 may have been missed. Lastly, the MIE and MICE groups differed in terms of neoadjuvant therapy, ECOG performance status, comorbidities, estimated peak VO_2max, and duration of surgery, which may have affected the postoperative immune response. However, we used appropriate statistical methods to correct for these differences. Studies with larger sample sizes and additional timepoints may provide further insight into potential differences in postoperative inflammatory status beyond POD1.

Conclusions

This study provides initial insights into the inflammatory response associated with MICE. We found no differences in postoperative inflammatory status after MICE compared to MIE, despite a considerably longer surgery duration and extensive mediastinal dissection. Limited statistical power and sample size warrant larger trials to further investigate potential differences in postoperative immune response beyond POD1 and clinically relevant outcomes.

Acknowledgments

The authors kindly thank Liesbeth van Emst (Department of Internal Medicine), Maarten Arends, and Arjen de Boer (both Department of Surgery), Radboud University Medical Center, Nijmegen, the Netherlands, for their assistance during data collection.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1569/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1569/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1569/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-2025-1569/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 approved by the Institutional Review Board of the Radboud University Medical Center (Radboudumc) and local Medical Ethics Committee—METC Oost-Nederland (NL73777.091.20) and informed consent was obtained from all individual participants. For additional patients included for CRP measurements, the institute’s opt-out registry was consulted to determine whether or not patients objected to participating in scientific research.

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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