Short-term oncological outcomes of hybrid minimally invasive esophagectomy: experience from a regional referral center

Introduction

Background

Esophageal cancer represents one of the most challenging malignancies, requiring complex surgical management and carrying substantial risks of morbidity and mortality. According to recent epidemiological data, it is the tenth most common malignancy worldwide and accounts for approximately one in every 18 cancer-related deaths (1). For patients with disease limited to the esophagus and regional lymph nodes who are medically fit for surgery, esophagectomy, with or without neoadjuvant therapy, remains the standard treatment approach (2). In the United Kingdom, the most frequently employed surgical technique is the two-stage Ivor Lewis esophagectomy, which involves both abdominal and thoracic incisions (3).

Minimally invasive approaches to esophagectomy have gained popularity due to their potential to reduce perioperative morbidity. The two primary minimally invasive techniques include the hybrid approach, which includes laparoscopic or robotic assistance for the abdominal phase combined with an open thoracic phase, and the totally minimally invasive esophagectomy (MIE), in which both phases are performed using minimally invasive methods. These procedures may employ either laparoscopic or robotic-assisted techniques. Compared to open esophagectomy, minimally invasive methods are associated with a lower incidence of major intraoperative and postoperative complications, particularly pulmonary complications, without compromising overall or disease-free survival at 3-year follow-up (4-6). Conversely, evidence from several meta-analyses suggests that open esophagectomy may be associated with a lower incidence of anastomotic and chyle leaks, emphasizing the need to tailor the surgical approach to each individual patient (7,8).

Rationale and knowledge gap

More recently, robotic-assisted surgery has emerged as a promising advancement, offering enhanced precision, improved visualization, and superior ergonomics for the surgeon (9). The robotic platform provides three-dimensional vision, tremor filtration, and articulated instruments that may facilitate complex dissection in confined anatomical spaces (10). While early studies suggest potential benefits of robotic-assisted minimally invasive esophagectomy (RAMIE), including reduced blood loss, shorter hospital stays, and comparable oncological outcomes, the evidence remains limited and comparative studies are scarce (11). Meta-analyses comparing RAMIE with conventional MIE further indicate a trend toward improved lymph node yield and fewer pulmonary complications with RAMIE (12). Despite these advantages, the steep learning curve and increased costs of robotic surgery, necessitate careful evaluation of its clinical benefits compared to established laparoscopic and thoracoscopic techniques (13). Evidence specifically evaluating hybrid robotic-assisted Ivor Lewis esophagectomy (H-RAILE) remains scarce, particularly in the context of short-term oncological outcomes, lymph node yield, and perioperative safety compared to hybrid laparoscopic approaches. Compared with recent studies such as Daiko et al., which focused on robotic versus conventional thoracoscopic esophagectomy in locally advanced tumors, our study provides real-world, consecutive cohort data on H-RAILE, including both perioperative outcomes and oncological adequacy, thus addressing an important evidence gap (14).

Objective

The primary aim of this study was to evaluate the oncological feasibility of H-RAILE in a regional referral center for esophageal and gastric cancers in the United Kingdom, with primary outcomes including lymph node yield and resection margins. Postoperative morbidity, length of stay, and early mortality were considered as secondary outcomes. A contemporaneous cohort of patients undergoing hybrid laparoscopic-assisted Ivor Lewis esophagectomy (H-LAILE) is also described to provide contextual information. We present this article in accordance with the STROBE reporting checklist (available at https://aoe.amegroups.com/article/view/10.21037/aoe-2026-1-0011/rc) (15).

Methods

Study design

This is a single-center retrospective cohort study designed to investigate the oncological feasibility of H-RAILE. The study was conducted at a regional referral center for esophago-gastric malignancies in the United Kingdom. Patients who underwent H-RAILE or H-LAILE between January 2022 and May 2025 were included. Approval from the Yorkshire & The Humber Research Ethics Committee was waived due to the observational nature of the study. Informed consent was obtained from all patients to participate in this study and all procedures conformed to the ethical principles of the Declaration of Helsinki and its subsequent amendments (16).

Patients aged over 18 years who underwent laparoscopic or robotic-assisted Ivor Lewis esophagectomy with curative intent, irrespective of tumor pathology or location (esophagus or gastroesophageal junction) were deemed as eligible and included in the study. Exclusion criteria included salvage esophagectomy, R2 or palliative resections, conversion to open surgery, and the need for McKeown esophagectomy. Patients with incomplete medical records, missing follow-up data, or a history of esophageal surgery or radiotherapy were also excluded.

The primary outcomes of the study were short-term oncological results, including lymph node yield and resection margins. Secondary outcomes included postoperative morbidity, length of stay, and early mortality. Where appropriate, comparisons between H-RAILE and H-LAILE are reported, however, the study was not designed or powered to support formal comparative or causal inferences between the two approaches.

Parameters evaluated

Three researchers extracted independently data from electronic medical records, surgical databases, pathology reports, imaging studies, intensive care unit (ICU) charts, outpatient clinic notes, and multidisciplinary team (MDT) records. Demographic variables included age, sex, body mass index (BMI), and Charlson comorbidity index (CCI). Clinical parameters comprised preoperative staging (cT and cN stages), tumor histology [adenocarcinoma (AC), squamous cell carcinoma (SCC), or gastrointestinal stromal tumor (GIST)], tumor location (middle third, lower third, or type I/II Siewert for gastroesophageal junction), and neoadjuvant treatment details, including type and response.

Perioperative data focused on short-term outcomes and postoperative complications, classified according to the Clavien-Dindo system. Variables included the occurrence of anastomotic or chyle leak, length of hospital stay, duration of ICU admission, and need for reoperation. Chyle leaks were categorized as grade I (managed with dietary modification), grade II (requiring total parenteral nutrition), and grade III (requiring surgical or interventional treatment) (17). Anastomotic leaks were classified as type I (no intervention required), type II (managed with interventional therapy), and type III (requiring surgical intervention) (17). Oncological outcomes included pathological staging (pT and pN), the number of harvested and positive lymph nodes, resection margin status (R0, R1, R2), tumor size, and histological grade of differentiation. Lymph node yield was recorded as the total number of nodes reported in the final pathological specimen. Adequate lymphadenectomy was defined as retrieval of ≥15 lymph nodes, consistent with recommendations for accurate nodal staging in esophageal cancer and prior studies demonstrating improved staging accuracy when at least 15 nodes are examined (18). Compartment-specific lymph node counts (thoracic vs. abdominal) were not consistently available due to non-standardized pathological labeling during the study period. R1 resection was defined as “tumors equal to or less than 1 mm from the margin” in accordance with the United Kingdom Royal College of Pathologists criteria (19). Operative time was not evaluated due to limitations in the retrospective dataset and because the robotic cases largely represented the surgeons’ initial learning curve, which could substantially prolong procedure duration and confound interpretation. Although both groups underwent an open thoracic phase, postoperative pulmonary complications, including pneumonia, pneumothorax, and acute respiratory distress syndrome (ARDS), were systematically recorded and analyzed. Exact intraoperative blood loss was not consistently available within the retrospective dataset and was therefore not included in the analysis. As an indirect measure of clinically relevant blood loss, the requirement for perioperative blood transfusion was assessed. Data on postoperative arrhythmias and other thoracic-specific complications were not consistently available in the retrospective database and were therefore not included. Longer-term outcomes included overall mortality, 30-day and 90-day mortality, and early recurrence within 6 months, categorized as local or systemic. The follow-up period differed significantly between the two groups, as the robotic cases were performed within the last year.

Surgical technique

Two experienced consultants specialized in esophagogastric resections performed all the operations. Each surgeon-upper gastrointestinal (GI) consultant provided their list with the patient details. Both surgeons performed H-RAILE, which had been introduced in the department within the past 2 years. The abdominal phase was performed robotically with intent to move to total robotic esophagectomy (both abdomen and chest). All robotic procedures were performed during the initial adoption phase of the robotic platform at Hull University Teaching Hospitals NHS Trust and therefore represent early learning-curve cases. No stratification or adjustment for learning-curve effects was performed, as the analysis was exploratory and not intended for comparative inference.

Two hybrid approaches were employed, the H-LAILE and the H-RAILE. In H-LAILE the abdominal phase was performed laparoscopically using a 4-port technique with a Nathanson liver retractor. In H-RAILE the DaVinci Xi platform was used with a bedside assistant handling an extra laparoscopic port. One 12 mm and three 8 mm robotic ports were inserted. Arm 1 used bipolar force grasper/stapler, arm 2 the 30-degree scope, arm 3 synchroseal/needle driver and arm 4 cadiere forceps. Gastric mobilization was performed by preserving the right gastroepiploic arcade. Then D1⁺ lymph node dissection was performed including stations 1–7, 8a, 9, and 11p. Following that, a gastric conduit 3–4 cm in width was fashioned, beginning at the incisura angularis and extending towards the gastric fundus. A 20 Fr Robinson drain was placed behind the stomach, across the hiatus towards the left chest.

For the thoracic phase, both groups underwent open right thoracotomy through the 5^th intercostal space after deflation of the right lung, with the patient in lateral decubitus position. The azygos vein was mobilized and divided and all nodal tissue from pericardium, pulmonary veins and thoracic aorta was taken en bloc. The thoracic duct was identified and ligated. The subcarinal lymph nodes were removed en bloc with the specimen. Reconstruction was achieved using a circular stapled anastomosis with a 25 mm Orvil device. Two 28 Fr chest drains were placed, one anterior apical and one posterior basal.

Perioperative management

Perioperatively all patients were assessed through MDT discussion. Preoperative staging included computed tomography (CT) of the chest, abdomen, and pelvis, endoscopic ultrasound, and esophagogastroduodenoscopy. Cardiopulmonary exercise testing was performed, and nutrition was optimized under dietitian guidance. Postoperatively, a standardized enhanced recovery protocol was followed, involving ICU monitoring, early mobilization and nutritional support via total parenteral nutrition or feeding jejunostomy. Routine imaging and contrast studies were performed on day 5 to assess for anastomotic leakage, in accordance with institutional protocol.

Statistical analysis

Given the retrospective design, small sample size, and surgeon-driven selection of surgical approach, no propensity score matching or multivariable adjustment was performed. The analysis was intentionally descriptive and exploratory, focusing on early oncological outcomes and feasibility rather than comparative effectiveness. Data were analyzed using SPSS version 20.0 (Armonk, NY, USA: IBM Corp). Qualitative data are reported as counts and percentages. Quantitative data were assessed for normality using the Kolmogorov-Smirnov test and reported as range, mean ± standard deviation (SD), median, and interquartile range (IQR) as appropriate. Exploratory comparisons between groups were performed using the Chi-squared test for categorical variables and the Student t-test for normally distributed continuous variables; however, no formal inferential conclusions should be drawn from these comparisons. Statistical significance was set at P<0.05. No formal sample size or power calculation was performed, as this study represents a retrospective feasibility analysis with a fixed sample determined by case availability. All findings should be interpreted as preliminary and hypothesis-generating, rather than definitive evidence of comparative effectiveness.

Results

Baseline characteristics

During the study period, 43 patients were deemed eligible and included in the analysis: 22 in the H-LAILE group and 21 in the H-RAILE group. A flowchart of the patient selection during the study period is depicted in Figure 1. Baseline demographic and clinicopathological characteristics were generally similar between the two groups. No differences were observed in age, BMI, sex distribution, CCI, tumor histology, tumor location, or type of received neoadjuvant therapy (P>0.05). Most patients presented with cT3 disease (86.4% in H-LAILE vs. 71.4% in H-RAILE). A significant difference was noted in nodal status, with the H-RAILE group demonstrating a higher proportion of cN1 disease, whereas the H-LAILE group more frequently presented with advanced nodal involvement (cN2–N3) (P=0.03). Tumors were most frequently located in the lower esophagus or at the esophagogastric junction. Regarding the neoadjuvant therapy, the majority of patients received chemotherapy, most commonly the fluorouracil, leucovorin, oxaliplatin, docetaxel (FLOT) regimen (Table 1).

Figure 1 Flow diagram of patient selection. H-LAILE, hybrid laparoscopic-assisted Ivor Lewis esophagectomy; H-RAILE, hybrid robotic-assisted Ivor Lewis esophagectomy.

Oncological outcomes

Pathological findings were comparable between H-LAILE and H-RAILE groups. Pathological T (pT) stage and pathological nodal (pN) stage distribution were not different between the groups (P=0.56 for both). Although, only one case of clinical T4 was reported, eventually five cases of pathologic T4 were documented. The total lymph node yield, which was the primary outcome of the study, was similar between H-LAILE and H-RAILE groups (mean 27.05±8.85 vs. 27.52±11.81, P=0.88). Harvesting more than 15 lymph nodes was achieved in more than 85% of patients in both groups (Table 2).

R0 resection rates were similar in both groups (81.8% in H-LAILE compared to 71.4% in H-RAILE, P=0.42) without any difference in the margin involvement pattern. Tumor width and length were also similar between the groups (P=0.31 and P=0.71, respectively). Histopathological differentiation also did not differ significantly, with most of the tumors being moderately or poorly differentiated (Table 2).

Postoperative outcomes and complications

Postoperative morbidity was largely similar between the two groups. According to the Clavien-Dindo classification, most patients experienced no complications (72.7% in H-LAILE vs. 57.1% in H-RAILE), and there was no significant difference in the distribution of complication grades (P=0.56). Length of ICU stay and overall hospital stay did not differ significantly, although the H-RAILE group showed a trend toward a longer mean ICU stay. Rates of pulmonary complications, anastomotic leak, chyle leak, and reoperation were low and not significantly different between groups (Table 3). Two patients in the H-RAILE group and one in the H-LAILE group required reoperation. One case of anastomotic leak occurred in the H-LAILE group (grade II), requiring endoscopic intervention. Two patients in the H-RAILE group developed chyle leaks. None of the patients in both of the groups required any peri-operative blood transfusion.

Mortality and early recurrence outcomes are reported descriptively (Table 3). One 30-day death occurred in the H-LAILE group due to an aortic injury during a drainage procedure. Four additional deaths within 90 days occurred after discharge and were recorded at external hospitals; exact causes could not be verified. No 30- or 90-day deaths were recorded in the H-RAILE group during the available follow-up period. Early disease recurrence was observed in 22.7% of H-LAILE patients and 0% of H-RAILE patients; however, the available follow-up in the H-RAILE group was shorter (Table 3).

Discussion

Key findings

Technological advances, particularly the introduction of robotic platforms, have substantially transformed esophagogastric surgery. The progression from open procedures to hybrid approaches and, more recently, to fully minimally invasive esophagectomies has led to improved surgical outcomes without compromising oncological safety. Randomized controlled trials such as MIRO and TIME, which compared hybrid and MIE to the open approach, demonstrated significant reductions in short-term complications, particularly pulmonary infections (4,6). In this single-center, retrospective study, H-RAILE demonstrated oncological feasibility, with satisfactory lymph node yield and R0 resection rates as primary outcomes. Postoperative morbidity was generally low, and rates of anastomotic and chyle leaks, as well as length of ICU and hospital stay, were acceptable, supporting a favorable short-term safety profile. Outcomes in a contemporaneous H-LAILE cohort were reported for context. Experimental comparisons suggest that H-RAILE outcomes are broadly in line with H-LAILE, although the study was not powered for formal comparative analysis, and observed differences should be interpreted with caution.

Strengths and limitations

Several limitations should be acknowledged when interpreting the findings of this study. Its retrospective, single-center design and the surgeon-led choice of approach entail significant risk of selection bias. For this reason, the results should not be viewed as a direct comparison between H-RAILE and H-LAILE. Furthermore, cases requiring conversion to open surgery or resulting in R2 resection were excluded by design, which may further introduce selection bias by omitting technically challenging cases or tumors with more advanced local invasion. In addition, the relatively small sample size restricted statistical power and did not allow for adjustment using propensity score matching or multivariable analyses. Consequently, the absence of statistically significant differences should not be taken as evidence of equivalence or non-inferiority, and the findings should be regarded as preliminary. Generalizability is further limited by the involvement of two consultants, each with different operative preferences. In addition, robotic procedures were introduced more recently at our institution and therefore had shorter follow-up compared with laparoscopic cases, which may introduce temporal bias and further limit direct comparisons between groups. Learning-curve effects are likely to have influenced the results, as most robotic procedures were performed during the early phase. This is particularly relevant for perioperative outcomes and further limits the interpretation of descriptive comparisons with the laparoscopic cohort.

Primary endpoint of the study was the short-term oncological outcomes. Although recurrence and 90-day mortality were reported, follow-up duration differed between groups, and the causes of death could not always be confirmed, when happened in other institutions. Mortality beyond 30 days may therefore be incompletely captured. Several data-related limitations should also be noted. Baseline differences in clinical nodal status were observed between groups; however, the small sample size precluded meaningful stratified or adjusted analyses. Compartment-specific lymph node counts were not available, preventing separate assessment of thoracic and abdominal lymphadenectomy. Operative duration and intraoperative blood loss were also unavailable, limiting evaluation of intraoperative performance during the learning curve. While indirect metrics such as transfusion requirement and postoperative morbidity were recorded, these do not accurately reflect the operative outcomes. Nevertheless, as the primary aim was to assess oncological safety, including cases performed during the learning curve, the absence of these variables is unlikely to substantially affect interpretation of the oncological findings. Finally, certain postoperative events, including arrhythmias and other thoracic complications, were not captured in the available dataset, which may have led to underestimation of overall morbidity. Despite these limitations, the study provides preliminary evidence that H-RAILE is oncologically feasible and associated with an acceptable short-term safety profile in a tertiary referral setting.

Explanation of findings and comparison with similar research

Both hybrid techniques were associated with satisfactory oncological outcomes with respect to lymph node yield and resection margins. The sole distinction between H-RAILE and H-LAILE lies in the abdominal phase (robotic versus laparoscopic assistance), while the chest phase was performed open in both approaches. Consequently, differences in lymph node harvest directly reflect the adequacy of abdominal dissection when comparing the two modalities. In this cohort, the total number of harvested lymph nodes was descriptively similar for H-RAILE and H-LAILE (27.52±11.81 vs. 27.05±8.85), with more than 85% of patients in both groups achieving the benchmark of ≥15 nodes. These findings are consistent with those reported by Giulini et al., who conducted the only published study to date directly comparing these two hybrid techniques. In their propensity-matched analysis of 84 patients, no significant differences were observed in lymph node yield (median 28 vs. 24) or R0 resection rates (P<0.05) (20). Regarding R1 resections, the overall rate in the present cohort was 23.2% (10/43 patients), with R1 defined as a distance <1 mm from the tumor. Although contemporary randomized trials in the era of modern perioperative chemotherapy, such as the ESOPEC trial, have reported relatively lower R1 rates, comparisons should be interpreted cautiously given differences in patient selection, sample size, and study design (21). Most patients had tumors staged below T4, with only one clinical T4 and five pathologic T4 cases. Together with the relatively high proportion of moderately and poorly differentiated tumors likely contributed to R1 rates. Moreover, strict pathological assessment criteria and learning-curve effects, particularly in the robotic cohort, may have influenced oncological precision. Observed R1 rates are broadly consistent with published hybrid series, including the ROMIO study (31% and 24% for open and hybrid surgery, respectively) (3).

When hybrid procedures are compared with totally minimally invasive approaches, the evidence remains mixed. Some studies comparing hybrid with totally robotic-assisted esophagectomy reported no significant differences in lymph node yield (22,23). However, another study by Tagkalos et al. identified a trend toward increased harvest with RAMIE (24). In contrast, a meta-analysis including 29 studies and 3,732 patients found that totally MIE was associated with a lower lymph node yield compared with hybrid laparoscopic esophagectomy (25). Taken together, these findings indicate that no single approach can be considered superior in terms of oncological adequacy. Ultimately, the surgeon’s expertise, particularly a thorough understanding of anatomy and the ability to follow the correct dissection planes, remains critical to ensure complete oncological resection with adequate lymph node harvest and negative margins.

Postoperative complications were generally low in the present cohort. One anastomotic leak occurred in the H-LAILE group (4.5%), and two H-RAILE patients developed chyle leaks. No major perioperative bleeding events were reported, and ICU and hospital stay were acceptable. Similarly, Giulini et al. reported no significant differences in anastomotic leak rates, which were 11.4% and 6.8% in the H-LAILE and H-RAILE groups, respectively (20). Previous studies have suggested that minimally invasive thoracic approaches may increase the risk of anastomotic leakage, highlighting the technical challenges of intrathoracic anastomosis (26). Although robotic platforms were introduced with the aim of mitigating this complication, a randomized trial by van der Sluis et al. comparing RAMIE with open esophagectomy demonstrated comparable leak rates (22% vs. 20%) (5). The main advantage of RAMIE appears to be the reduction in postoperative pulmonary complications, as demonstrated in a systematic review by Mederos et al. (27). In our study, chest-related complications were present in 13.6% in the H-LAILE group and 23.6% in the H-RAILE group. Likewise, Giulini et al. found no differences in pulmonary complications when comparing the same hybrid approaches (20).

In this study, all documented cases of mortality and recurrence occurred in the H-LAILE group. A total of five deaths were recorded, all within this cohort. However, most of these events occurred after hospital discharge, and the exact causes could not be determined, as they were recorded in external institutions. The only confirmed cause was an aortic injury following ultrasound-guided drainage of a pleural collection. With respect to recurrence, a higher number of cases were again observed in the H-LAILE group. This finding should be interpreted cautiously, as the follow-up period for the H-RAILE group was shorter, given that these procedures were performed more recently and represent preliminary outcomes. Long-term evidence from the MIRO trial has shown that hybrid esophagectomy is associated with improved oncological outcomes compared with open surgery, largely due to a reduction in postoperative complications (28). In contrast, studies comparing robotic- and laparoscopic-assisted approaches have generally demonstrated no significant differences in mortality or recurrence (27). Furthermore, recent analyses from the multicenter ENSURE trial reported that both hybrid and totally MIE were associated with improved overall survival compared with open surgery. Notably, however, totally minimally invasive procedures demonstrated superior disease-free survival and lower systemic recurrence rates compared with hybrid approaches (29).

Operative times were longer for H-RAILE cases, reflecting early experience during the learning curve. Blood loss was not formally quantified but no perioperative blood transfusions were required in both groups. Previous studies have suggested that RAMIE has a shorter learning curve compared with laparoscopic-assisted hybrid techniques, requiring approximately 9–85 cases to reach proficiency, versus 12–175 cases, respectively (30-32). The long-term objective of the department is to transition toward totally RAMIE for both the abdominal and thoracic phases. In future analyses, cumulative sum methodology will be applied to further evaluate the learning curve and establish benchmarking parameters for robotic cases.

Implications and actions needed

Overall, these preliminary findings indicate that H-RAILE is oncologically feasible and associated with a favorable short-term safety profile. Outcomes are descriptively similar to the H-LAILE cohort, but the study is not powered for formal comparison, and observed differences should be interpreted cautiously. At present, it remains uncertain which minimally invasive strategy (H-RAILE, H-LAILE, or totally minimally invasive techniques) should be preferred for the treatment of resectable esophageal cancer. Each method carries distinct advantages and limitations, yet current evidence suggests broadly similar oncological outcomes while offering reductions in postoperative morbidity. A tailored approach, taking into account patient-specific characteristics and predictors of complications such as high BMI, advanced age (>65 years), and smoking history, may optimize patient outcomes (33). Further prospective investigations with larger patient numbers are needed to better define long-term oncological outcomes, including recurrence and survival, and to refine patient selection for minimally invasive esophageal surgery.

Conclusions

This retrospective experience from a single referral center indicates that H-RAILE can be performed with acceptable short-term oncological results and a manageable postoperative morbidity profile, even during the early phase of surgeon adoption. Findings from the H-LAILE cohort are provided for context only, as the present study was not powered to support formal comparative inference.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://aoe.amegroups.com/article/view/10.21037/aoe-2026-1-0011/rc

Data Sharing Statement: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-2026-1-0011/dss

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-2026-1-0011/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-2026-1-0011/coif). D.K. serves as an unpaid editorial board member of Annals of Esophagus from August 2025 to December 2027. 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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The Yorkshire & The Humber Research Ethics Committee waived the approval due to the observational nature of the study. Informed consent was obtained to participate in this study.

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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