|Year : 2019 | Volume
| Issue : 5 | Page : 298-309
EUS versus percutaneous management of postoperative pancreatic fluid collection: A systematic review and meta-analysis
Babu P Mohan1, Mohammed Shakhatreh2, Sushma Dugyala1, Vaishali Geedigunta1, Ashwini Gadalay1, Parul Pahal1, Suresh Ponnada3, Kapil Nagaraj4, Ravishankar Asokkumar5, Douglas G Adler6
1 University of Arizona/Banner University Medical Center, Tucson, USA
2 Rapides Regional Medical Center, Alexandria, Louisiana, USA
3 Department of Hospital Medicine, Carilion Roanoke Memorial Hospital, Roanoke, Virginia, USA
4 Department of Surgical Gastroenterology, Meenakshi Medical College and Research Institute, Kanchipuram, Tamil Nadu, India
5 Division of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
6 Division of Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, Utah, USA
|Date of Submission||29-Nov-2018|
|Date of Acceptance||04-Mar-2019|
|Date of Web Publication||20-Jun-2019|
Dr. Douglas G Adler
Division of Gastroenterology and Hepatology, Huntsman Cancer Center, University of Utah School of Medicine, 30N 1900E 4R118, Salt Lake City, Utah 84132
Source of Support: None, Conflict of Interest: None
Postoperative pancreatic fluid collection (POPFC) is an important complication following abdominal surgery. POPFC causes significant morbidity and mortality. Management options are time-consuming and severely affect patient's quality of life. Surgical and/or percutaneous drainage (PCD) is the traditional mainstay of treatment. Studies have shown that EUS could have a role to play in the management of POPFC. Data are limited in the comparison of clinical outcomes with EUS as compared to PCD to this end. We conducted a comprehensive search of multiple electronic databases and conference proceedings including PubMed, EMBASE, Google Scholar, LILACS, and Web of Science databases (earliest inception through September 2018) to identify studies that reported on the clinical outcomes of EUS and PCD in the management of POPFC. The goals were to estimate and compare the pooled rates of technical success, clinical success, adverse events, and POPFC recurrence with EUS and PCD. A total of 13 studies were included in the analysis. Ten studies (239 patients) used EUS and 6 studies (267 patients) used PCD in the management of POPFC. The pooled rate of clinical success with EUS was 93.2% (95% confidence interval [CI] 88.2–96.2, I2 = 0) and with PCD was 79.8% (95% CI 70–87, I2 = 74). The difference was statistically significant, P = 0.002. Recurrence rate was significantly lower with EUS as compared to PCD (9.4%: 95% CI 5.2–16.5 vs. 25.7%: 95% CI 24.3–41.7; P = 0.02). Pooled rates of technical success and adverse events were similar with EUS and PCD. Our meta-analysis shows that EUS has significantly better clinical outcomes, in terms of clinical success and disease recurrence, in the management of POPFC as compared to PCD.
Keywords: Abdominal surgery, EUS, percutaneous drainage, postoperative pancreatic fluid collection
|How to cite this article:|
Mohan BP, Shakhatreh M, Dugyala S, Geedigunta V, Gadalay A, Pahal P, Ponnada S, Nagaraj K, Asokkumar R, Adler DG. EUS versus percutaneous management of postoperative pancreatic fluid collection: A systematic review and meta-analysis. Endosc Ultrasound 2019;8:298-309
|How to cite this URL:|
Mohan BP, Shakhatreh M, Dugyala S, Geedigunta V, Gadalay A, Pahal P, Ponnada S, Nagaraj K, Asokkumar R, Adler DG. EUS versus percutaneous management of postoperative pancreatic fluid collection: A systematic review and meta-analysis. Endosc Ultrasound [serial online] 2019 [cited 2019 Oct 18];8:298-309. Available from: http://www.eusjournal.com/text.asp?2019/8/5/298/260851
| Introduction|| |
Postoperative fluid leaks are a well-recognized adverse event-causing significant morbidity and mortality after pancreatic resection. The reported incidence of pancreatic leak ranges from 5% to 20%., The reported rates of morbidity and mortality range from 40% to 60%. The leaking pancreatic fluid has potential enzymatic action and can result in various complications. It can cause bleeding from adjacent vessels, tissue necrosis, and abscess formation. Patients can present with pancreatic ascites, pancreaticopleural or pancreaticocutaneous fistulae, or just pancreatic fluid collection. Such fluid collections following pancreatic surgery are termed as postoperative pancreatic fluid collection (POPFC).
Traditionally, POPFCs have been managed by noninterventional conservative approach that includes long-term jejunal feeding, total parenteral nutrition, octreotide, and/or antibiotics. Interventional approaches such as percutaneous drainage (PCD), endoscopic retrograde cholangiography transpapillary stent placement, EUS-guided drainage, and surgical cystgastrostomy with or without debridement may be needed if the POPFC is persistent, large, or symptomatic. Treatment most often entails a time-consuming process with multiple imaging tests, multiple drainage procedures, increased intensive care unit and/or hospital length of stay, and readmission to hospital., Surgical intervention on a POPFC increases the risk of overall morbidity and mortality.
PCD has been the conventional approach to managing symptomatic POPFC. External catheters require daily care, maintenance, can cause local skin irritation, infections, fistula formation, and compromise patient's quality of life. EUS-guided management of POPFC has important advantages including obviating the need for an external drain, minimizing the risk of external pancreatic fistulae, and preventing fluid and electrolyte losses. Reported literature evaluating and comparing EUS to PCD shows similar clinical outcomes.,, The data are limited by small-sized retrospective studies, with no randomized controlled trials to this date. We therefore conducted this meta-analysis to compare EUS-guided management to percutaneous (PCD) management of POPFC.
| Methods|| |
We conducted a comprehensive search of several databases and conference proceedings including PubMed, EMBASE, Google Scholar, LILACS, and Web of Science databases (earliest inception to September 2018). We followed the Preferred Reporting items for Systematic Reviews and Meta-Analyses guidelines, using predefined protocol, to identify studies reporting the use of EUS and PCD in the management of POPFC. An experienced medical librarian using inputs from the study authors helped with the literature search.
Key words used in search included a combination of “postoperative,” “post-surgical,” “post-pancreatectomy,” “pancreatic fluid collection,” “abdominal fluid collection,” “endoscopic management,” “EUS guided drainage,” and “percutaneous drainage.” The search was restricted to studies in human subjects and published in English language in peer-reviewed journals. Three authors (M.B., S.M., D.S.) independently reviewed the title and abstract of studies identified in primary search and excluded studies that did not address the research question, based on prespecified exclusion and inclusion criteria. The full text of remaining articles was reviewed to determine whether it contained relevant information. Any discrepancy in article selection was resolved by consensus and in discussion with a coauthor.
The bibliographic section of the selected articles as well as the systematic and narrative articles on the topic was manually searched for additional relevant articles.
In this meta-analysis, we included studies that evaluated the following: (1) technical success, clinical success in EUS management of POPFC (EUS-POPFC), and (2) technical success, clinical success in PCD management of POPFC (PCD-POPFC). Studies on nonpancreatic surgery were included as long as they provided information on POPFC. Studies irrespective of the simultaneous use of transpapillary drainage, study design, inpatient/outpatient setting, geography, and abstract/manuscript status were included as long as they provided data needed for the analysis.
Following were our exclusion criteria: (1) studies with no data on pancreatic surgery, (2) studies reporting on abdominal fluid collections not classified as pancreatic, (3) studies reporting on abdominal fluid collections without data on pancreatic collections, (4) studies on POPFC where the standard endoscope was used, (5) studies that did not report on the technical success of EUS-POPFC, (6) studies that did not report on the clinical success of EUS-POPFC, and (7) studies done in pediatric population (age <18 years).
In case of multiple publications from the same cohort, data from the most recent and/or most appropriate comprehensive report were included. In our search process, we did not encounter any such study.
Data abstraction and quality assessment
Data on study-related outcomes in the individual studies were abstracted onto a standardized form by at least three authors (S.M., D.S., G.V.) independently, and three authors (S.M., D.A., M.B.) did the quality scoring independently.
In the situation of randomized trials, and case–control studies, the data collection was done as number of reported events (n) out of total number of patients (N) from each study. The collected data were treated akin to cohort studies, and therefore, we used the Newcastle–Ottawa scale for cohort studies to assess the quality of studies. This quality score consisted of 7 questions: representative of the average adult in the community (1 point for population-based studies, 0.5 point for multicenter studies, 0 point for a single-center hospital-based study); cohort size (1 point for >40 patients, 0.5 point for 39–20, and 0 point for <20 patients); information on technical and clinical success (1 point if reported, 0.5 point if not reported and had to be derived from percentage value, 0 point if not reported); outcome not present at start of study (1 point if not present, 0 point if present); factors comparable with PCD group (1 point if yes, 0 point if no); adequate clinical assessment (1 point if yes, and 0 point if no), long enough follow-up time for outcomes to occur (1 point if yes, 0 point if not mentioned); adequate follow-up time for outcome to occur (1 point if yes, 0 point if no); and adequacy of follow-up (1 point if all patients were accounted for, 0.5 point if <50% patients lost to follow-up, 0 point if >50% patients lost to follow-up). A score of >6, 4–6, and ≤3 were considered suggestive of high-quality, medium-quality, and low-quality study, respectively.
- Pooled rates of technical success and clinical success in the management of POPFC: EUS-POPFC versus PCD-POPFC
- Pooled rates of adverse events and rates of recurrence in POPFC.
Assessment methodology and definitions
The collected data were matched between the EUS and PCD management groups. The baseline patient characteristics, symptomatology, indication for surgery, time to drain placement, and the number of drains used were comparable between the groups. Although this model of comparison is indirect and should be considered weak when compared to a randomized controlled trial, the approach is comparable to a retrospective case–control study with matched groups.
In the included studies, technical success with EUS and PCD management was defined as follows:
- Successful deployment of at least one endoscopically placed stent into the fluid collection, and/or
- The ability to access and drain a collection by placement of one or more transmural drains
- The ability to access and drain a collection by placement of one or more percutaneous catheters under computed tomography (CT) or ultrasound guidance.
Clinical success was evaluated at the end of follow-up period and was defined as follows:
- Stable, ambulatory patient with no external drainage, with resolution of sepsis, no antibiotics treatment, and on normal oral food intake, and/or
- Resolution of the fluid collection on follow-up CT scan, and/or
- Resolution of symptoms present before the procedure(s), and/or
- Resolution of symptoms at 6–8 weeks of follow-up, and/or.
Procedure-related complications or adverse events were defined as follows:
- Any newly developed complications after procedure, such as bleeding, peritonitis, or symptomatic pneumoperitoneum
- Sepsis or infection was considered if it occurred after the initial endoscopy or IR procedure and caused by contamination of the POPFC and proven by new-onset fever, positive blood cultures, or by positive fluid cultures obtained at re-endoscopy
- Stent migration within and/or outside the collection was considered as a complication only if a repeat endoscopy was needed to retrieve the stent and/or to drain the collection
- Bleeding was included as an adverse event if the patient required endoscopic therapy, transfusion of packed red blood cells, or inpatient observation
- Perforation was included when pneumoperitoneum was evident on imaging with peritoneal signs; and
- Recurrence was defined by the occurrence of the collection after removal of the stents or drains after initial resolution.
We used meta-analysis techniques to calculate the pooled estimates in each case following the methods suggested by DerSimonian and Laird using the random effects model and our application can be seen to fit within their general approach (where effect is measured by probability of risk). When the incidence of an outcome was zero in a study, a correction of 0.5 was added to the number of incident cases before statistical analysis. We assessed heterogeneity between study-specific estimates using Cochran Q statistical test for heterogeneity, 95% prediction interval (PI), which deals with the dispersion of the effects,, and the I2 statistics., In this, values of <30%, 30%–60%, 61%–75%, and >75% were suggestive of low, moderate, substantial, and considerable heterogeneity, respectively. Publication bias was ascertained, qualitatively, by visual inspection of funnel plot and quantitatively, by the Egger test. When publication bias was present, further statistics using the fail-Safe N test and Duval and Tweedie's 'Trim and Fill' test was used to ascertain the impact of the bias. Three levels of impact were reported based on the concordance between the reported results and the actual estimate if there were no bias. The impact was reported as minimal if both versions were estimated to be the same, modest if effect size changed substantially but the final finding would still remain the same, and severe if basic final conclusion of the analysis is threatened by the bias.
All analyses were performed using Comprehensive Meta-Analysis software, version 3 (BioStat, Englewood, NJ, USA).
| Results|| |
Search results and population characteristics
From an initial total of 4084 studies, 128 records were screened and 39 full-length articles were assessed. Thirteen studies were included in the final analysis.,,,,,,,,,,,, Out of the 13 studies, 10 studies provided data on the use of EUS in POPFC management (EUS-POPFC),,,,,,,,, and 6 provided data on the use of PCD in POPFC (PCD-POPFC).,,,,,
The schematic diagram of study selection is illustrated in [Figure 1].
|Figure 1: Preferred Reporting items for Systematic Reviews and Meta-Analyses study flow selection. POPFC: postoperative pancreatic fluid collection|
Click here to view
Baseline population characteristics were comparable in EUS and PCD groups. The mean and/or median age was from 53 to 67 years, with predominantly male population (range 40%–80%). Commonly reported symptoms were abdomen pain, nausea and/or vomiting, fever and/or leukocytosis with or without signs of sepsis. The most common surgical procedure was distal pancreatectomy (57%) and the most frequently encountered pathologic indications were pancreatic adenocarcinoma, neuroendocrine tumor of the pancreas, intraductal papillary mucinous neoplasms (IPMNs), and mucinous cyst neoplasms. The maximum fluid dimension ranged from 7 to 10 cm. Time to drain placement after index surgery ranged from 2 to 547 days. Transgastric was the most commonly used route (86%). Median number of stents placed was 2 and median number of procedure session was 1. Median follow-up time ranged from 15 to 44 months.
The details are given in [Table 1], and the outcome data are summarized in [Table 2].
Characteristics and quality of included studies
All 13 studies were of retrospective nature.,,,,,,,,,,,, Out of the included 13 studies, none were population based. Two studies, were from multicenter data and rest were from single center. Four studies had more than 40 patients,,,, seven studies had 20–39 patients,,,,,,, and the rest had <20 patients in their study group. All studies reported adequately on the technical success and clinical success outcomes. All baseline patient characteristics between the studies were comparable, except for the interventions. Seven studies had no mention on the duration of follow-up.,,,,, Overall, five studies,,,, were considered of high quality and rest were considered medium quality. There were no low-quality studies. The detailed assessment of study quality is given in [Supplementary Table 1 [Additional file 1]].
Procedures were done under general anesthesia or sedation. The therapeutic linear echoendoscope was used for the initial puncture in all studies. The puncture site was selected based on minimal distance between the EUS transducer and the collection without interposed vessels on Doppler assessment. After puncturing the gastric or duodenal wall to gain access to the collection, the fluid was aspirated. With the help of a guide wire inserted into the cavity, the tract was dilated and double pigtail stents were placed. In cases where a lumen-apposing metal stent (LAMS) was used, the LAMS delivery system was advanced and the flanges were deployed, distal followed by proximal, under EUS guidance.
Majority of studies reported the use of CT guidance, with few using ultrasound guidance, to select a safe drainage route. After procedural sedation and local anesthesia to the skin, a 21-gauge needle was inserted into the fluid collection. Fluid aspiration was done to characterize the fluid and send it for laboratory tests. Using the Seldinger or the trocar method, a 7–14 Fr self-retaining pigtail drainage catheters were placed into the fluid collection.
Post operative pancreatic fluid collection
Ten studies (239 patients) reported the outcomes of EUS in POPFC management (EUS-POPFC),,,,,,,,, and 6 studies (267 patients) reported the outcomes of PCD in POPFC management (PCD-POPFC).,,,,,
The pooled rate of technical success in EUS-POPFC was 97.3% (95% confidence interval [CI] 94.0–98.8) (95% PI 93.2–99.0, I2 = 0) and in PCD-POPFC was 97.2% (95% CI 93.9–98.7) (95% PI 92.0–99.1, I2 = 0). There was no statistical significance to the difference, P = 0.93 [Figure 2].
|Figure 2: Forest plot. Technical success in postoperative pancreatic fluid collection: EUS versus percutaneous drainage|
Click here to view
The pooled rate of clinical success in EUS-POPFC was 93.2% (95% CI 88.2–96.2) (95% PI 86.9–96.6, I2 = 0) and in PCD-POPFC was 79.8% (95% CI 70.0–87.0) (95% PI 32.9–97.0, I2 = 74). The difference was statistically significant, P = 0.002 [Figure 3].
|Figure 3: Forest plot. Clinical success in postoperative pancreatic fluid collection: EUS versus percutaneous drainage|
Click here to view
Adverse events and recurrence
Nine studies (200 patients) reported an overall of 18 adverse events and 14 recurrences in EUS-POPFC.,,,,,,,, Six studies (267 patients) reported an overall of 17 adverse events and 26 recurrences in PCD-POPFC.,,,,,
The pooled rate of all adverse events in EUS-POPFC was 9.3% (95% CI 4.4–18.6) (95% PI 1.9–34.8, I2 = 33.0%) and in PCD-POPFC was 7.9% (95% CI 3.6–16.6) (95% PI 0.5–60.4, I2 = 67.7%). The difference was not statistically significant, P = 0.77.
The pooled rate of early adverse events in EUS-POPFC was 7.9% (95% CI 4.5–13.2) (95% PI 4.1–14.6, I2 = 0%) and the pooled rate of delayed adverse events in EUS-POPFC was 6.3% (95% CI 3.3–12.0) (95% PI 2.6–14.5, I2 = 0%).
The pooled rate of POPFC recurrence after EUS was 9.4% (95% CI 5.2–16.5) (95% PI 1.6–39.4, I2 = 39.7%) and after PCD was 25.7% (95% CI 24.3–41.7) (95% PI 0.3–97.5, I2 = 0%). The difference was statistically significant, P = 0.02.
All the results along with the calculated pooled rates for bleeding, perforation, and stent-migration are summarized in [Table 3] [Supplementary Figure 1 [Additional file 2]], [Supplementary Figure 2 [Additional file 3]], [Supplementary Figure 3 [Additional file 4]], [Supplementary Figure 4 [Additional file 5]].
| Validation of Meta-Analysis Results|| |
To assess whether any one study had a dominant effect on the meta-analysis, we excluded one study at a time and analyzed its effect on the main summary estimate. On this analysis, no single study significantly affected the outcome or the heterogeneity.
We assessed dispersion of the calculated rates using the PI and I2 percentage values, which are mentioned above with each resulted outcome. The PI gives an idea of the range of the dispersion and I2 tells us what proportion of the dispersion is true versus chance. Our significant finding was a narrow PI with no heterogeneity in the rates of technical success and clinical success with EUS-POPFC. Clinical success with PCD-POPFC and the rates of all adverse events had a wide dispersion with substantial heterogeneity.
Based on visual inspection of the funnel plot as well as quantitative measurement that used the Egger regression test, there was evidence of publication bias. Further statistics using the fail-safe N test and Duval and Tweedie's “Trim and Fill” test revealed that the impact of the possible publication bias appeared to be minimal and would not change the calculated estimate or the conclusion of this meta-analysis [Supplementary Figure 5 [Additional file 6]].
| Discussion|| |
POPFCs are established adverse events after pancreatic resection and can occur despite efforts to prevent it. Surgery and/or PCD has been the traditional mainstay of treatment. These approaches are associated with reduced quality of life, risk of infection, and nonhealing fistula with fluid and electrolyte losses.,,, Retrospective studies have reported that EUS-guided drainage may provide long-lasting results with minimal complications in the treatment of abdominal fluid collections.,,, The fluid collection can be potentially drained internally resulting in less chances of infection, avoiding fluid and/or electrolyte loss, and additional treatment modalities such as necrosectomy and debridement can be performed.
Based on our analysis, EUS had better clinical outcomes in the management of POPFC when compared to PCD. We report a statistically significant clinical success rate in EUS-POPFC (93.2% vs. 79.8%, P = 0.002) and significantly lower rates of POPFC recurrence with EUS when compared to PCD (9.4% vs. 25.7%, P = 0.02). Our calculated rates of technical success were similar in EUS and PCD groups (97.3% vs. 97.2). In prior studies that evaluated the role of EUS in the management of POPFC, the technical success ranged from 96% to 100%, clinical success from 80% to 100%, but the outcomes were similar when compared to PCD.,, Our calculated rates fall within the range reported in literature; however, using meta-analysis, we demonstrate a statistical significance to the calculated rates of clinical success and rates of POPFC recurrence with EUS as compared to PCD.
Appropriate patient selection and technique is important for a successful outcome. Expertise and access to resources determine the choice of treatment. After the index surgery, the time to place a drain depends on clinical indication and patient symptoms. Drains were placed as soon as 5 days in studies by Tilara et al. and Jürgensen et al. In EUS-POPFC, the transgastric route was used in 86% of the patients. Therefore, appropriate imaging modalities are important to ascertain ease of access from the gastric cavity. In majority of patients, adequate drainage was achieved with a median of one procedure session and using a median of two plastic stents. The endoscopist has to take into consideration the fluidity of the aspirate and the amount of necrotic debris to help decide the appropriate number of stents needed. Owing to their larger diameter, LAMS may have an advantage over plastic stents in this regard. Repeat procedures and catheter exchanges may be needed based on clinical course. Serial measurement of amylase in the draining fluid is an important parameter in PCD to ascertain cessation of pancreatic leak. This does not apply to EUS-POPFC, as the fluid is internally drained. The adequate follow time is unknown and ranged from 15 to 44 months in the studies included in our analysis.
In our analysis of the adverse events, similar rates were noted for early and delayed adverse events after EUS-POPFC. Nine studies reported 10 early adverse events with a calculated pooled rate of 7.9% and 7 studies reported 6 delayed adverse events with a calculated pooled rate of 6.3%. The most commonly reported adverse events with EUS-POPFC were bleeding (5 events reported from 5 studies) and stent migration (5 events reported from 3 studies). The most common reported adverse event in PCD-POPFC group was perforation (5 events reported from 4 studies). Infection was another important adverse event. 5 events were reported in EUS-POPFC group and 1 event was reported in PCD-POPFC group. Risk of infection due to enteric contamination is a theoretical possibility that should not be overlooked with EUS. In the PCD-POPFC group, there were 1 reported event each of acute pancreatitis, pneumothorax, and intractable pain. The data were limited to calculate the pooled rates. There was no death reported in EUS-POPFC group. Four deaths were reported in the PCD group and they were not procedure related. Overall, the pooled rates for all adverse events were similar in EUS-POPFC and PCD-POPFC groups (9.3% vs. 7.9%, P = 0.77).
The strengths of this review are as follows: systematic literature search with well-defined inclusion criteria, careful exclusion of redundant studies, inclusion of good-quality studies with detailed extraction of data, rigorous evaluation of study quality, matching basic patient and study characteristics between the study groups, and statistics to establish and/or refute the validity of the results of our meta-analysis. To the best of our knowledge, our study is the first meta-analysis to evaluate the role of EUS in the management of POPFC and compare it to PCD. The statistically significant clinical success rate and recurrence rate are the key findings of our study. A randomized trial between EUS and PCD in POPFC is unlikely to be performed due to the complexity of the condition and the treatment process.
There were limitations to this study, most of which are inherent to any meta-analysis. The included studies were not entirely representative of the general population and community practice, with most studies being performed in tertiary-care referral centers. All studies included in the analysis were of retrospective nature, thereby contributing to selection bias. Heterogeneity with wide prediction intervals was noted in the analysis of clinical success and recurrence in PCD-POPFC. The stent type, size, repeat procedures, exchanges, and the need for pancreatic duct stenting varied within and across studies. Since we had only one study that exclusively evaluated LAMS, we were not able to assess the outcomes comparing plastic stents to LAMS. Although we were able to adjust for most of these parameters between the EUS and PCD groups, variability within the group still existed and our analysis has the element of indirect comparison. Nevertheless, in the real world, POPFCs constitute a very small population, and our study is still the best evidence available to counsel patients. Novel lumen-apposing, fully covered, and self-expanding metal stents have gathered lot of interest in the drainage of pancreatic fluid collections, and studies are needed to evaluate their role in the treatment of EUS-POPFC.
| Conclusion|| |
Our meta-analysis demonstrates significantly better clinical success with EUS in the management of POPFC with significantly less chances of recurrence, when compared to the percutaneous route of management. Bleeding and stent migration were the main adverse events reported with EUS, whereas perforation was the most common with PCD.
Supplementary information is linked to the online version of the paper on the Endoscopic Ultrasound website.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]