Association of Pringle maneuver with postoperative recurrence and survival following hepatectomy for hepatocellular carcinoma: a multicenter propensity score and competing-risks regression analysis

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third most frequent cause of cancer-related mortality in the world (1). China alone accounts for more than one-half of the world’s HCC patients (2). Hepatectomy provides a potentially curative opportunity for surgically eligible HCC patients (3). Because of recent progress in operative techniques and perioperative management, short- and long-term outcomes following hepatectomy for patients with HCC have improved with perioperative mortality being less than 3% and 5-year survival being up to 50% (4,5). Long-term survival remains, however, unsatisfactory because of the high incidence of cancer recurrence (the main cause of poor prognosis), which can range from 50–70% at 5 years after surgery (6). Identifying and reducing risk factors associated with postoperative recurrence and death is critical to improve long-term oncological outcomes for patients undergoing hepatectomy for HCC.

Apart from patient- and tumor-related factors, some surgery-related factors have been identified as potential risk factors associated with postoperative recurrence and death for patients with HCC, including width of resection margin, resection type (anatomical or non-anatomical), intraoperative blood loss and subsequent perioperative blood transfusion (7-11). Hepatic pedicle clamping [Pringle maneuver (PM)] has been a commonly used technique to reduce intraoperative blood loss and the need for blood transfusion (12). From the perspective of reducing intraoperative blood loss and the possibility of blood transfusion, PM may be beneficial to the long-term oncological prognosis of patients with HCC. PM can, however, lead to some degree of ischemia-reperfusion injury to the liver (13-15), which has been demonstrated to upregulate inflammatory factors and cytokines that correlate with cancer recurrence and tumor invasiveness (16-18). The relative advantages versus disadvantages of PM related to decreased intraoperative blood loss/need for blood transfusions may be nullified or neutralized by the damage caused by hepatic ischemia-reperfusion. Therefore, the effect of PM on long-term oncologic prognosis for patients undergoing hepatectomy for HCC remains controversial. While some studies have reported that PM during hepatectomy for HCC was associated with a worse prognosis (19-21), others investigators did not note any adverse oncologic effect (22-24). Most previous studies were, however, from a single institution, had small sample sizes, and were subject to selection bias, which raises concerns about reliability and generalizability of the conclusions.

The objective of the current study was to characterize the effect of PM application on long-term recurrence and survival for patients with HCC using a prospectively-collected multicenter database. By using propensity score methods and competing-risks analysis to minimize selection bias and remove the effects of competitive events, the potential effects of PM application on long-term oncologic prognosis among patients undergoing hepatectomy for HCC were characterized. We present this article in accordance with the STROBE reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-23-7/rc).

Methods

Patients

Using a large multicenter database (Mengchao Hepatobiliary Hospital, Eastern Hepatobiliary Surgery Hospital, Affiliated Hospital of Nantong University, Zhejiang Provincial People’s Hospital, First Affiliated Hospital of Shandong First Medical University, First Affiliated Hospital of Anhui Medical University, Fourth Hospital of Harbin, Pu’er People’s Hospital, and First Affiliated Hospital of Harbin Medical University), consecutive patients who underwent open hepatectomy with curative intent from January 2010 to December 2018 for HCC were identified. The data were prospectively collected using a standardized form. Curative hepatectomy (R0 hepatectomy) was defined as removal of all microscopic and macroscopic tumors with a microscopically negative margin. Patients who meet one of the following criteria were excluded: (I) less than 18 years old; (II) had received other anti-HCC treatment before hepatectomy; (III) recurrent HCC; (IV) underwent palliative hepatectomy [R1 (microscopically positive) or R2 (macroscopically positive) resection]; (V) were performed by other vascular occlusion methods instead of PM, including total vascular exclusion, hemi-hepatic vascular occlusion, and hepatic vascular exclusion with veno-venous bypass; (VI) other concomitant surgical procedures, including splenectomy, portosystemic shunt, biliary reconstruction, or gastrointestinal surgery during hepatectomy; (VII) with portal/hepatic vein tumor thrombus; (VII) loss to follow-up within 6 months after surgery; (IX) missing important prognostic variables. The study was censored on December 31, 2021. Data were analyzed from January 2022 to July 2022. The retrospective study was performed in accordance with the Declaration of Helsinki (as revised in 2013) and the Ethical Guidelines for Clinical Studies of the Mengchao Hepatobiliary Hospital Ethics Committee (No. 2018-038-01), and was considered exempt from informed consent procedures.

Surgical procedures and application of PM

The indications for hepatectomy for HCC largely followed the Chinese Expert Consensus (25) and were generally consistent across participating hospitals. All operations were performed by surgeons with more than 5 years of extensive experience in hepatic surgery, and the resection criteria remained unchanged during the study to ensure consistency. The extent of hepatectomy (major or minor) was determined by tumor size and its deepest portion, combined with the minimum parenchymal sacrifice and the flattest cut surface. Major hepatectomy was defined as resection of three or more Couinaud liver segments, and minor hepatectomy was categorized as resection of fewer than three liver segments. Transection of the hepatic parenchyma was performed mainly using the clamp-crushing technique and/or ultrasound knife, and hemostasis was obtained with suture ligations and argon beam coagulator. The application of PM during hepatectomy depended on the habit and experience of the attending surgeon and the amount of intraoperative bleeding during the operation. The specific procedure of PM was performed by encircling the hepatoduodenal ligament with a catheter, and then the hepatic blood inflow was occluded by tightening the catheter. In most cases, the occlusion of PM was continuous if the transection time was less than 25–30 min; otherwise, intermittent PM occlusion was performed with cycles of 15–20 min clamping followed by 3–5 min of reperfusion, and the procedure was repeated until the end of liver parenchyma transection. Anatomical resection was defined by the Brisbane 2000 system (26), whereas non-anatomical resections included wedge resection or limited resection. Anatomical resection was generally the first choice, while non-anatomical resection with a sufficient resection margin was often adopted to assure an adequate volume of the remaining liver.

Clinicopathological variables

Baseline characteristics of patients included age, gender, American Society of Anesthesiologists (ASA) score, hepatitis B virus (HBV), hepatitis C virus (HCV), cirrhosis, Child-Pugh grade, preoperative hemoglobin, and preoperative platelet counts. Tumor-related variables included preoperative alpha-fetoprotein (AFP) level, maximum tumor size, tumor number, satellite nodules, tumor encapsulation, tumor differentiation, and microvascular invasion. Operative variables included the extent of hepatectomy (major vs. minor), type of hepatectomy (anatomical vs. non-anatomical), resection margin, intraoperative blood loss, and intraoperative blood transfusion.

Follow-up

After hospital discharge, patients were prospectively followed at each participating hospital. Postoperative surveillance strategy for recurrence consisted of serum AFP level, ultrasonography, contrast-enhanced computed tomography (CT), or magnetic resonance imaging (MRI) of the chest and abdomen every 2 to 3 months for the first 2 years after surgery, and at least every 6 months thereafter. CT, MRI, angiography, bone scan, or positron emission tomography were performed when recurrence or distant metastasis was suspected. Treatment of tumor recurrence was based on the pattern of recurrent tumor, residual hepatic functional reserve, and general condition of the patient, and included re-resection, liver transplantation, local ablation therapy, transcatheter arterial chemoembolization, radiotherapy, systemic therapy, or supportive therapy. The dates of tumor recurrence, death, and last follow-up were recorded.

Study endpoints

The primary endpoint was long-term oncologic outcome, including cumulative recurrence rate and cancer-specific mortality (CSM), while the secondary endpoint were short-term outcomes including postoperative 30-day morbidity and mortality, respectively. Time to recurrence was calculated as the time from the date of surgery to the date of confirmation of HCC initial recurrence, while time to CSM was calculated from the date of hepatectomy to either the date of cancer-specific death (end event) or the date of non-cancer-specific death (competing-risk event) or the date of last follow-up (censored event). The main causes of non-CSM included hepatic deterioration or upper gastrointestinal hemorrhage as a result of severe liver cirrhosis and cardiovascular or cerebrovascular accidents. According to the Clavien-Dindo system (27), postoperative morbidities were classified into 5 grades and major morbidity was defined as Clavien-Dindo grade ≥3.

Statistical analysis

Clinicopathological characteristics were summarized using frequencies and percentages for categorical covariates and mean ± standard deviation (SD) or median [interquartile range (IQR)] for continuous covariates. Continuous variables were tested by the Student’s t-test or Mann-Whitney U test, and categorical variables were analyzed using the chi-square test or Fisher exact test according to the situation. In addition to P values, standardized mean differences (SMD) were used to measure differences in baseline characteristics between the two comparative groups (the PM and non-PM groups), with SMD-values <0.1 to indicate negligible differences, and between 0.1 and 0.3 to indicate small differences.

After removing cases of postoperative early death (postoperative 90-day mortality), two propensity score methods [propensity score matching (PSM) and inverse probability of treatment weight (IPTW)] were used to balance baseline characteristics among patients in the PM and non-PM groups. Covariates entered into the propensity model included age, gender, ASA score, HBV, HCV, cirrhosis, Child-Pugh grade, preoperative hemoglobin, preoperative platelet counts, preoperative AFP level, maximum tumor size, tumor number, satellite nodules, tumor encapsulation, tumor differentiation, microvascular invasion, extent of hepatectomy, type of resection, intraoperative blood loss, intraoperative blood transfusion, and resection margin. The PSM method was performed as described by Rubin and Rosenbaum (28). To optimize the precision of the study, patients in the non-PM group were matched to individuals in the PM group in a 1:3 matching ratio by using a greedy, nearest neighbor matching algorithm. As for the IPTW procedure, a pseudo population was created by weighting the inverse of the probability of a patient receiving the application of PM based on propensity score (29). The model preserved the size of the study population and no study participants were dropped (and statistical power lost), which was advantageous compared with the PSM method. Taking into account the effects of competing events (non-CSM) before the outcome events and other prognostic variables, the Fine-Gray sub-distribution hazard regression model was used to clarify the real impact of the application of PM on recurrence and CSM. On univariate analysis, variables with P<0.1 were entered into multivariate competing-risks regression models. Statistical analysis was performed using IBM SPSS (version22.0) and R (version 4.1.2) software. All statistical analyses were two-tailed, and P<0.05 was considered statistically significant.

Results

Study population

There were 3,796 patients who underwent open curative-intent hepatectomy for HCC during the study period for inclusion in the present study. After strict screening by inclusion and exclusion criteria, 2,798 patients were enrolled into this multicenter retrospective study. The flowchart of this study is shown in Figure S1. Among all patients, 2,365 (84.5%) were male and 433 (15.5%) were female; 2,261 patients (80.8%) had chronic HBV infection, and 278 patients (9.9%) were positive for HCV-RNA. The mean (SD) age of the entire cohort was 51.7 (10.8) years. There were 2,404 patients (85.9%, the PM group) and 394 patients (14.1%, the non-PM group) who did or did not have PM during hepatectomy, respectively.

Clinical characteristics and short-term outcomes

Comparisons of clinical characteristics and short-term outcomes among patients in the PM and non-PM groups in the entire cohort are shown in Table 1. Compared with individuals in the PM group, patients in the non-PM groups had a higher preoperative hemoglobin level (141.2±16.4 vs. 138.9±15.9 g/dL, P=0.013), platelet counts (164.6±68.0 vs. 157.4±57.8 ×10⁹/L, P=0.026), and intraoperative blood loss (median: 400 vs. 380 mL, P=0.036), yet a smaller tumor size (4.8±3.4 vs. 6.7±4.1 cm, P<0.001), a lower proportion of cirrhosis (45.7% vs. 56.2%, P<0.001), and a lower proportion of multiple tumors (15.7% vs. 21.0%, P=0.016), and a lower proportion of incomplete tumor encapsulation (79.7% vs. 84.7%, P=0.014). Notably, intraoperative blood transfusion (12.1% vs. 15.5%, P=0.058), postoperative 30-day mortality (2.0% vs. 1.0%, P=0.181), and postoperative 30-day morbidity (35.4% vs. 37.1%, P=0.514) were comparable between patients in the PM and non-PM groups.

Cases of postoperative early death within 90 days after surgery [83 (3.6%) in the PM group and 12 (3.1%) in the non-PM group] were excluded from analyses of long-term outcomes. After applying propensity score analysis, comparisons of clinical characteristics of the matched (the PSM cohort) and weighted (the IPTW cohort) study participants are shown in Table 2. There were no significant differences between the patients in the PM and non-PM groups for any covariate (all P>0.050 and SMD <0.200) (Figure S2).

Long-term oncologic outcomes

At a median (interquartile range) follow-up of 47.0 (20.1, 60.2) months, 1,576 (58.3%), 464 (17.2%) and 935 (34.6%) of 2,703 patients had recurrence, non-cancer-specific death, and cancer-specific death, respectively. Comparison of long-term oncologic outcomes between patients who adopted and did not adopt PM in the entire, PSM, and IPTW cohorts are shown in Table 3, respectively. In the entire cohort, cumulative 5-year recurrence and CSM of patients in the PM group were 66.3% and 43.5%, which were higher than individuals in the non-PM group, respectively (55.3% and 31.6%, P=0.001 and P<0.001, respectively). In the PSM cohort, compared with the 382 patients in the non-PM group, the 1,146 patients in the PM group had higher cumulative 5-year recurrence and CSM, respectively (63.9% and 39.1% vs. 55.3% and 31.6%, P=0.023 and P=0.009, respectively). Similar results were also noted in the IPTW cohort (65.8% and 39.5% vs. 57.6% and 35.0%, P=0.035 and P=0.043, respectively). Using a competing risk regression model, Figure 1,2 depict the comparisons of cumulative recurrence and CSM between the patients in the PM and non-PM groups in the entire, PSM, and IPTW cohorts, respectively.

Figure 1 Cumulative recurrence rate curves between patients with and without the application of PM. (A) CRR in the entire cohort; (B) CRR in the PSM cohort; (C) CRR in the IPTW cohort. PM, Pringle maneuver; CRR, cumulative recurrence rate; PSM, propensity score matching; IPTW, inverse probability of treatment weight.

Figure 2 Cancer-specific mortality curves between patients with and without the application of PM. (A) CSM in the entire cohort; (B) CSM in the PSM cohort; (C) CSM in the IPTW cohort. PM, Pringle maneuver; CSM, cancer-specific mortality; PSM, propensity score matching; IPTW, inverse probability of treatment weight.

Univariate and multivariate analysis of recurrence and CSM

Univariate and multivariate competing-risks regression analyses were performed to identify risk factors associated with recurrence following hepatectomy for HCC in the entire cohort (Table S1), as well as in the PSM cohort (Table S2). As noted in Table 4, compared to the application of PM, the unadjusted and adjusted hazard ratios (HRs) of no application of PM on the risk of recurrence were 0.77 (95% CI: 0.66–0.91; P=0.001) and 0.82 (95% CI: 0.70–0.97; P=0.011) in the entire cohort, respectively, while its adjusted HR in the PSM cohort was 0.80 (95% CI: 0.67–0.95; P=0.012).

Univariate and multivariate competing-risks regression analyses were also performed to identify risk factors associated with CSM following hepatectomy for HCC in the entire cohort (Table S3), as well as in the PSM cohort (Table S4). Compared with the application of PM, the unadjusted and adjusted HRs of no application of PM on the risk of CSM were 0.68 (95% CI: 0.55–0.84; P<0.001) and 0.77 (95% CI: 0.61–0.96; P=0.031) in the entire cohort, respectively, while its adjusted HR in the PSM cohort was 0.73 (95% CI: 0.58–0.92; P=0.006) (Table 4).

Decreased risk of recurrence and CSM due to no application of PM during hepatectomy were also noted in the IPTW cohort on both univariate and multivariate regression analyses (Tables S5,S6). In the IPTW cohort, the adjusted HRs of no application of PM on the risk of recurrence and CSM were 0.80 (95% CI: 0.66–0.97; P=0.029) and 0.76 (95% CI: 0.59–0.98; P=0.044), respectively (Table 4).

Discussion

Use of PM may improve short-term outcomes of hepatectomy by reducing intraoperative blood loss and the possibility of blood transfusion (30-32). The long-term oncologic outcomes associated with PM among patients with HCC remains more controversial. With the improvement of surgical technique and perioperative management (33,34). PM has become more of an optional intraoperative technique, being not as necessary during hepatectomy in many experienced hepatobiliary centers (35,36). However, in some cases during hepatectomy, PM is still routinely adopted as an effective means to keep the surgical field clean and improve surgical safety (37). In the present study, analyzing a prospectively-collected multicenter database with propensity score methods and competing-risks analysis (i.e., entire, PSM, and IPTW) demonstrated that the avoidance of PM was independently associated with decreased recurrence and CSM following hepatectomy for HCC (HR, 0.82 and 0.77 in the adjusted entire cohort; HR 0.80 and 0.73 in the PSM cohort; and HR 0.80 and 0.76 in the IPTW cohort). The data suggested that no application of PM reduced the risk of postoperative recurrence and cancer-specific death by approximately 20~25%. Avoiding hepatic pedicle clamping (i.e., PM) during hepatectomy is therefore desirable to improve long-term oncologic prognosis for patients with HCC.

The association of PM application with increased recurrence has been confirmed by several experimental studies. PM causes ischemia/reperfusion injury, resulting in complex metabolic, immunological and microvascular changes that contribute to hepatocellular damage and dysfunction (38-40). Hepatic ischemia/reperfusion injury affects the behavior of tumor cells by activating cell invasion and migration signaling pathways, stimulating tumor cell adhesion, and accelerating tumor recurrence (41,42). The underlying detrimental mechanism of PM relates to ischemia-reperfusion injury causing cellular damage by inducing free-radical formation, upregulating inflammatory cytokines, dysregulating mitochondrial calcium handling, and upregulating matrix metalloproteinases. These events promote intrahepatic micro-metastases and even distant metastases (43,44). Recent animal studies have also suggested that hypoxia per se may increase tumor activity and migration ability (45-47). Acute-phase inflammatory responses, microcirculatory barrier dysfunction, and hypoxia create an environment that may promote tumor progression, migration, and invasion. These processes may promote liver tumor growth and metastases, leading to postoperative tumor recurrence.

Given the crucial role of cirrhosis in the pathogenesis of HCC, minor hepatectomies and non-anatomical resections are often performed among patients with cirrhosis to preserve more liver parenchyma. In the entire cohort of this study, the majority of patients with HCC underwent minor hepatectomy and received PM. Theoretically, PM is more likely to be used in major hepatectomy. However, some minor hepatectomies, such as posterosuperior segmentectomies (segment 7, segment 8, or segment 7-8) and complex core hepatectomies (segment 1 or segment 4-8), can be more complex and technically challenging, which makes the application of the PM more frequent in our real-world clinical practice.

In the present study, all surgeries were performed by surgeons with more than 5 years of extensive experience. However, we still observed variability in PM among different centers. This may be attributed to several factors. First, even experienced surgeons may have different levels of expertise and familiarity with PM due to differences in their training and practice settings. Second, the adoption and implementation of PM may vary across centers depending on factors such as local guidelines, institutional protocols, and resource availability. Additionally, the use of PM as a teaching tool for less experienced surgeons or trainees may contribute to the observed variability, as the performance of PM may be influenced by the learning curve and the need for close supervision. Lastly, certain centers may choose to adopt alternative techniques or approaches for managing HCC patients, leading to variations in the use of PM. It is important to consider these factors when interpreting the results of our study and evaluating the generalizability of our findings to different settings.

The strengths of the present study included the large sample size, the multicenter cohort, the prospectively collected database, the long-term follow-up, the convergence with real clinical situations, as well as study endpoints that more accurately reflect oncologic prognosis (recurrence and CSM, but not recurrence-free survival nor overall survival). In addition, analyses attempted to control for potential confounders by using the two propensity score methods (PSM and IPTW) and competing-risks regression analysis. Of note, non-cancer-specific death was more common among HCC patients, and the use of CSM as an outcome indicator was more consistent with oncological prognosis after adjusting for non-CSM as a competing factor. Propensity score analysis was carried out to balance the differences in baseline variables among patients with and without the application of PM during hepatectomy. After PSM or IPTW, the real impact of PM application on the oncologic prognosis of HCC after hepatectomy was more able to be determined. In addition, to further adjust for competing events and other confounding prognostic factors, a multivariate competing-risks regression analysis was applied to the entire and PSM cohorts (competing-risks analysis cannot be achieved in the IPTW cohort). A randomized controlled trial (RCT) to assess the impact of PM is not likely given the fundamental requirement of RCT not to allow arbitrary switching between intervention and control groups. As such, data from the current study were important because a rigorous statistical technique was adopted that accounted, as much as possible, for potent selection bias and confounding (37). While PM is effective to deal with intraoperative emergencies, such as increased blood oozing from the separated liver parenchyma particularly in cirrhotic patients, and sudden bleeding of intrahepatic large blood vessels, its use should be limited given the negative oncologic implications.

Several limitations of this study should be considered. This was a retrospective study. Although PSM, IPTW and competing-risks regression models were used, inherent limitations cannot be completely avoided. If an RCT study was to be conducted, how to ensure that switching between intervention and control groups would be challenging to address (i.e., that the adjusted rates are kept low, will be the key to obtaining rigorous and reliable conclusions). Patients from the current study also came exclusively from China. The main cause of HCC in East Asia (HBV infection) is different from those in European and the United States (predominantly as HCV infection and alcoholic liver diseases) (48), so these variations may affect surgical outcomes. Therefore, the findings need to be externally validated, especially among Western patients. Another limitation was the difficulty to distinguish whether PM was used in a continuous or intermittent fashion due to the variability of PM techniques and the different habits of attending surgeons at different centers. However, previous studies have demonstrated that there was no difference in liver damage and prognosis between continuous and intermittent PM (49,50). Last but not least, in the present study, we only enrolled patients with HCC who underwent open hepatectomy. Due to the limited number during the study period and the potential influence of the initial learning curve of the laparoscopic procedures, patients who underwent laparoscopic resection were excluded from the analytic cohort. Further studies are needed to determine the possibility of our findings among patients undergoing laparoscopic hepatectomy for HCC.

Conclusions

In conclusion, this large multicenter study demonstrated that the lack of PM use during hepatectomy was associated with nearly 20–25% decreased risk of long-term recurrence and cancer-specific death for patients with HCC. Avoiding hepatic pedicle clamping (the application of PM) during hepatectomy if possible, should be considered more desirable as the data suggested this may lead to improved long-term oncologic outcomes among patients with HCC.

Acknowledgments

The authors would like to thank all the surgeons and patients who participated in the study.

Funding: This study was supported by the Key Clinical Specialty Discipline Construction Program of Fuzhou, Fujian (No. 201912002), Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors (No. 2020Y2013), the Scientific Foundation of Fuzhou Municipal Health commission (No. 2021-S-wp1), the National Natural Science Foundation of China (No. 62275050), the Major Research Projects for Young and Middle-aged Talent of Fujian Provincial Health Commission (No. 2021ZQNZD013), Dawn Project Foundation of Shanghai (No. 21SG36), and Adjunct Talent Fund of Zhejiang Provincial People’s Hospital (No. 2021-YT). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-23-7/rc

Data Sharing Statement: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-23-7/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-23-7/coif). T.M.P. serves as an unpaid Deputy Editor-in-Chief of Hepatobiliary Surgery and Nutrition. T.Y. serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. 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 retrospective study was performed in accordance with the Declaration of Helsinki (as revised 2013) and the Ethical Guidelines for Clinical Studies of the Mengchao Hepatobiliary Hospital Ethics Committee (No. 2018-038-01), and was considered exempt from informed consent procedures.

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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