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ORIGINAL ARTICLE
Year : 2022  |  Volume : 25  |  Issue : 9  |  Page : 1548-1556

Investigation of the effects of marsupialization on histomorphological and immunohistochemical markers of odontogenic keratocysts


1 Department of Oral Pathology, Gazi University Faculty of Dentistry, Ankara, Turkey
2 Department of Medical Microbiology, Gulhane Institute of Health Sciences, University of Health Sciences, Ankara, Turkey

Date of Submission07-Feb-2022
Date of Acceptance19-Apr-2022
Date of Web Publication22-Sep-2022

Correspondence Address:
Dr. E Baris
Department of Oral Pathology, Gazi University Faculty of Dentistry, Bişkek Cd. (8.Cd.) 1.Sk. No: 4 06490 Emek, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_103_22

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   Abstract 


Background: Despite its extensive bone resorption and high recurrence rate, marsupialization is the preferred option in the treatment of odontogenic keratocysts (OKCs). Aim: We aimed to assess the effect of marsupialization on histomorphological and biochemical markers of OKCs. Materials and Methods: The study is conducted on 48 paraffin blocks of 24 OKC cases between the years 2012 to 2018. The main clinical, radiographic, and histomorphometric measurements were recorded. Immunohistochemical staining with E-cadherin, Ki67, IL1α, TNFα, Slug, and Snail were performed and compared for pre-marsupialization and post-marsupialization values. Results: OKCs mostly located in the mandibular posterior region. The mean marsupialization period was 8.8 ± 6.5 (3-25) months. The mean radiographic size of OKC (57.1 ± 53.5 mm) was significantly reduced after marsupialization (22.6 ± 19.9 mm, P = 0.002). Histologically, significantly increased thickness of the OKC epithelium (p = 0.002) and collagen production (p = 0.034) was detected after marsupialization. The post-marsupialization group showed positive correlation of inflammation score to both TNFα (r: 0.69, P < 0.001) and IL-1α (r: 0.58, P = 0.008) expressions in connective tissue. Among immunohistochemical parameters, only Slug expression was significantly higher after marsupialization (p = 0.019). Conclusion: Our study suggests that increased Slug expression may enable the second surgery by increasing fibrosis in the cyst wall.

Keywords: EMT, keratocyst, marsupialization, slug, snail


How to cite this article:
Baris E, Secen A, Karabulut S, Gultekin S E. Investigation of the effects of marsupialization on histomorphological and immunohistochemical markers of odontogenic keratocysts. Niger J Clin Pract 2022;25:1548-56

How to cite this URL:
Baris E, Secen A, Karabulut S, Gultekin S E. Investigation of the effects of marsupialization on histomorphological and immunohistochemical markers of odontogenic keratocysts. Niger J Clin Pract [serial online] 2022 [cited 2022 Sep 28];25:1548-56. Available from: https://www.njcponline.com/text.asp?2022/25/9/1548/356648




   Introduction Top


Odontogenic keratocysts (OKCs), the third most common odontogenic cyst, reach large dimensions, create extensive bone destruction, and have high recurrence rate. Except for sporadic cases, OKCs can be seen together with the nevoid basal cell carcinoma syndrome, in which the Patched (PTCH) gene mutation is found.[1] Studies have shown that OKC epithelium has intrinsic growth potential, genomic DNA mutations, and loss of heterozygosity in tumor suppressor genes.[2],[3]

The treatment of OKC, which has a more aggressive biological behavior than other odontogenic cysts, may differ according to the clinical feature of the cyst. Treatment modalities may vary depending on the tendency of recurrence or the difficulty of surgical procedure. While conservative approaches include enucleation, marsupialization, and curettage, there are also aggressive treatment options such as local ostectomy, resection, and chemical curettage using Carnoy's solution.[4] According to WHO 2017 Blue Book, the recurrence rate following enucleation was 25%, with enucleation + Carnoy's solution 8%, and <2% in resected cases.[1] Marsupialization treatment is based on the principle of making the cystic cavity continuous with the oral cavity by removing a part of the intraosseous lesion via an incision. This leads to enlargement of the fibrous capsule and it becomes difficult to disperse after marsupialization, thus making total enucleation easier and reducing the recurrence rate of OKC.[5],[6] The case series and meta-analyses reported conflicting results concerning the effective surgical approach. Some clinicians recommend total enucleation or resection for OKCs due to the possibility of in-situ pathological remnants in the cavity.[4] On the other hand, there are also approaches suggesting that removing the entire lesion with a second surgical procedure after reducing the size of the cyst with marsupialization is the most appropriate treatment.[7] Until now, there is no consensus in the literature regarding the optimal treatment method for OKC treatment.

Cytokines are proteins secreted by leukocytes and other cell types that regulate the immune response. Among these cytokines, TNFα is responsible for local bone resorption that occurs during the inflammatory process.[8] TNFα stimulates osteoclastic differentiation by inducing RANKL expression together with IL 1. IL1α stimulates epithelial cell proliferation either directly or indirectly by interacting with fibroblasts.[9] Immunohistochemical studies have shown that IL1α and TNFα expressed in OKC epithelium may play an important role in the development of OKC.[9],[10] To the knowledge of the authors, there is no study in the English literature comparing the cytokine levels associated with marsupialization treatment of OKCs. Demonstration of proliferation markers in many tumors is the most commonly used method to explain the biological behavior and prognosis of the lesion. The proliferation ability of epithelial cells is directly responsible for the proliferation of OKC and the aggressive biological behavior of the cyst. Ki67 is a well-known proliferation marker that is widely used in the diagnosis of many pathological lesions.[11]

The epithelial-mesenchymal transition (EMT) is a complex process that begins with the loss of polarization in epithelial cells and followed by cytoskeletal re-organization, acquisition of mesenchymal phenotype, and finally increased migration.[12] Epithelial-mesenchymal interaction plays an important role in the growth regulation of odontogenic cysts and tumors.[13] Snail is one of the key regulators that contributes to EMT and increased Snail expression induces morphological changes by reducing E-cadherin expression.[14] Beside Snail, another transcription factor, Slug may play distinct roles in mediating local invasiveness in odontogenic tumors.[15] There is limited information in the literature regarding the effect of EMT on the biological behavior and prognosis of odontogenic cysts, especially in OKCs.

In this study, we aimed to assess the effect of marsupialization on histomorphological and immunohistochemical markers of OKCs.


   Material and Methods Top


Specimens, clinical, histological, and radiological data

The study was conducted on 48 paraffin blocks of 24 OKC cases between the years 2012 and 2018 retrieved from the archive of the Department of Oral Pathology. Cases with nevoid-basal cell carcinoma syndrome were excluded from the study. The materials included both incisional biopsy (pre-marsupialization) and total enucleation (post-marsupialization) specimens of each patient. The study was approved by the Ethics Committee for Clinical Research. Main clinical characteristics including the age, gender, localization, radiographic size, recurrence, and follow-up period were recorded for OKC samples. Radiologically, 17 of 24 cases could be assessed on orthopantomography. Orthopantomographs were taken with a digital panoramic X-ray unit (Sirona Dental Systems, Bensheim, Germany) in JPEG format. OKC lesions were measured before marsupialization and total enucleation on two dimensions with Image J 1.48v software (National Institutes of Health, USA) program. All two-dimensional measurements were calculated in square centimeters.

Histological and histomorphometric analysis

Two oral pathologists (EB and SEG) previously reviewed all OKC slides, stained with hematoxylin-eosin (HE). Histopathological evaluation and measurements were made on the pre-marsupialized epithelium and connective tissue of the OKC specimens. Epithelial thickness was measured in five different areas at x200 magnification with the Leica QWinV3 (Leica-Westlar-Germany) image analysis program and the mean values were calculated. Connective tissue was assessed regarding collagenization texture. The scoring was made as follows: 0, loose/myxoid; 1, cellular/thin collagen fibers; and 2, acellular, thick-collagen fibers. The presence of satellite cyst was also noted as 0: absent, 1: present. Inflammation intensity was scored as 0: no inflammation, 1: mild, 2: moderate, and 3: intense.

Immunohistochemical analysis

4 μm thick sections of formalin-fixed paraffin OKC sections were taken from the same block as the histomorphometry evaluation. The sections were incubated with primary antibodies E-cadherin, Ki67, IL1β, TNFα, Slug, and Snail [Table 1]. BOND Polymer Refine Detection Kit (catalog #DS9800, Leica Biosystems Buffalo Grove-USA,) and BOND Polymer Refine Red Detection Kit (catalog #DS9390, Leica Biosystems, Buffalo Grove-USA) were used as a protocol on Leica BOND-MAX fully automated IHC and ISH staining system (Leica microsystems, Buffalo Grove-USA). Both E-cadherin-Ki67 and IL1α–TNFα were double-stained while Slug and Snail were single-stained. For double staining, sections were baked and dewaxed after heat-induced EDTA antigen retrieval for 20 minutes and hydrogen peroxide for 10 minutes. The first primary antibody was incubated for 30 minutes, post-polymer for 8 minutes, polymer for 8 minutes, and DAB chromogen for 8 minutes. Subsequently, the second primary antibody was incubated for 30 minutes, post-polymer AP for 30 minutes, polymer AP for 20 minutes, red chromogen for 15 minutes, and hematoxylin for 10 minutes. Finally, sections were dehydrated and mounted to an aqueous medium.
Table 1: Summary of immunohistochemistry antibodies

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For evaluation of immunostaining score, five representative high power fields at x200 magnification with light microscope were counted by two blind oral pathologists (EB & SEG). The intensity of staining for E-cadherin (membranous staining), IL-1α (nuclear staining), TNFα (cytoplasmic staining), Slug (nuclear staining), and Snail (nuclear staining) was measured semi-quantitatively by using the full H-score system for the whole epithelial layer and connective tissue. The scores were all noted for the staining intensity (0: no staining, 1: weak staining, 2: moderate staining and 3: strong staining) and the percentage of positive cells (0: 0-10% of cells stained, 1: 11-25% of cells stained, 2: 26-50% of cells stained, 3: 51-100% of cells stained). The full H score was calculated by the equation: H score = staining intensity score x percentage of positive cells score.[16] On the other hand, the proliferation index (Pi) score was calculated for Ki67 staining (nuclear staining). Total epithelial cell number and total Ki67 positive cell number were counted five representative high power fields at x200 magnification under the image analyzing program. Pi was calculated using the following equation: Pi = Ki67 positive cell number/total epithelial cell number.[17]

Statistical analysis

Statistical analyze was carried out by IBM SPSS Statistics 21.0 (IBM Corp., IBM SPSS Statistics for Windows, Version 21.0, Armonk, NY: IBM Corp). The comparison between the “pre-marsupialization” and the “post-marsupialization” values for each variable was performed by Wilcoxon Signed Ranks Test. Non-parametric correlation test (Spearman's correlation test) was used to analyze immunohistochemistry antibody expression status correlation with clinical, radiological, and histological parameters. An overall 5% Type-I error level was used to infer statistical significance.


   Results Top


Clinical characteristics

Main clinical characteristics of the cases were summarized at [Table 2]. The mean age of the patients was 35.7 ± 16.7 years (range: 18-79 years). There were equal numbers of females and males. The majority (70.8%) of OKC cases were located in the mandibular posterior region. The mean marsupialization period was 8.8 ± 6.5 months (range: 3-25 months). The mean radiographic size of OKC (57.1 ± 53.5 mm) was significantly reduced after marsupialization (22.6 ± 19.9 mm, P = 0.002). The maximum follow-up period was 48 months, which was recorded for 14 cases (mean: 23.4 ± 13.1 months) and recurrence was observed in 3 of 24 cases.
Table 2: Clinical characteristics of the patients with treatment via marsupialization

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Histological and histomorphometric findings

Histologically, the pre-marsupialization materials consisted of parakeratinized squamous epithelium, usually 6-8 cell rows and without rete formation. Although post-marsupialization materials showed similar features, an increase in epithelial thickness was observed [Figure 1]a and [Figure 1]b. The thickness of the OKC epithelium significantly increased in the post-marsupialization group (p = 0.002). The connective tissue structure of OKCs generally consisted of cellular, thin collagen fibers (17 cases cellular/thin collagenized, 7 cases loose/myxoid) in the pre-marsupialization group. Seven of twenty-four cases, showed the transformation of the loose myxoid connective tissue into a cellular thin collagen structure after marsupialization. There was a significant collagen production in post-marsupialization specimens when compared to that in the pre-marsupialization group (p = 0.034). The numerical increase of the satellite cysts in the post-marsupialization specimens compared to that of the pre-marsupialization was not statistically significant (rho: -0.93; P = 0.67). While inflammation scores of 0 and 1 were dominant in the pre-marsupialization group, severe inflammation was observed in the post-marsupialization group, although with no difference [Table 3].
Figure 1: Histologic sections of groups before (Pre-MG) and after (Post-MG) marsupialization. While the OKC Pre-MG (Figure 1a, HE) had parakeratinized and corrugated epithelium; acanthosis was observed in the smooth-surfaced epithelium in the post-MG (Figure 1b, HE). E-cadherin immunoexpression was strong and membranous for both groups (Figures 1c and d, brown). While Ki67 (arrow) was localized in the suprabasal layer in the Pre-MG; it was limited to the basal layer in the Post-MG (Figures 1c and d, red). Expression of IL-1α and TNFα was observed in both epithelial and inflammatory cells in both groups. (Figs. 1e and f; IL-la: brown, TNFα: red). Nuclear Snail (Pictures 1g and h, brown) and Slug (Pictures 1i and j, brown) were positive in all layers of the epithelium except the basal layer. (Original magnification: a, c, e, g, i x 200, b, d, f, h, j x 400

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Table 3: The data of histopathological and immunohistochemical parameters

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Immunohistochemical findings

Strong and diffuse membranous E-cadherin positivity was seen in the OKC epithelium of both pre- and post-marsupialization groups [Figure 1]c and [Figure 1]d. There were no significant staining differences between the groups. Ki67 staining was observed especially in the suprabasal layer in the pre-marsupialization group whereas in the basal layer in the post-marsupialization group [Figure 1]c and [Figure 1]d.

IL-1α, TNFα, Slug, and Snail stainings were seen in both epithelium and connective tissue of pre- and post-marsupialization groups. Nuclear IL-1α and cytoplasmic TNFα expression were localized both in all layers of epithelium and in mononuclear inflammatory cells in connective tissue, irrespective of treatment modality. Nuclear Snail and Slug positivity were seen in all layers of epithelium except the basal layer [Figure 1]e, [Figure 1]f, [Figure 1]g, [Figure 1]h, [Figure 1]j.

Descriptive statistical data of histopathological parameters were presented in [Table 3]. The slight reductions observed in either Ki67 Pi or IL-1α H score in epithelial and connective tissue of the post-marsupialization group compared to that of the pre-marsupialization group were not statistically significant. Slug expression in the connective tissue was significantly higher in the post-marsupialization group (p = 0.019).

Correlations

The associations between immunoexpression status and clinical parameters were shown in [Figure 2]. Two immunohistochemistry markers showed statistically significant correlation with clinical parameters in the pre-marsupialization group as follows: We found higher expression of TNFα in the connective tissue with decreased radiographic size (rho: -0.625; P = 0.007) [Figure 2]a and increased Ki67 Pi with long follow-up period (rho: 0.576; P = 0.031). We further determined that the expression of Slug increased in both epithelium (rho: 0.600; P = 0.002) and connective tissue (rho: 0.413; P = 0.034) as the period of marsupialization was prolonged in the post-marsupialization group [Figure 2]b. There was no significant correlation between other immunohistochemistry markers and clinical variables in the post-marsupialization group.
Figure 2: Spearman's correlations in scatterplot matrix between immunoexpression status with clinical data. (a) Negative correlation betweenTNFα in connective tissue and radiographic size in the pre MG (b) Positive correlation between marsupialization period and Slug expression in the post MG. (pre_TNF_ct: TNFα expression in the connective tissue inpre marsupialization group, pre_radiographic_size: radiographic size in pre marsupialization group, post_Slug_ept: Slug expression in the epithelium in the post marsupialization group, post_Slug_ct: Slug expression in the connective tissue in the post marsupialization group, marsup_period: marsupialization period)

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Correlation between immunohistochemical staining with histological parameters was shown in [Figure 3]. There was no significant correlation between immunohistochemical staining and histological parameters except TNFα in the pre-marsupialization group. Increased TNFα expression in the epithelium was associated with increased fibrosis of the cyst wall (rho: 0.440; P = 0.046), [Figure 3]a. In the post-marsupialization group, only TNFα and IL-1α showed significant correlations with histological parameters. Positive correlations were noted between inflammation score with TNFα (rho: 0.688; P < 0.001) and IL-1α (rho: 0.582; p: 0.008) expressions in connective tissue [Figure 3]b. The number of satellite cysts showed negative correlation with TNFα immunoreactivity in connective tissue (rho: -0.406; P = 0.049), [Figure 3]c.
Figure 3: Spearman's correlations in scatterplot matrix between immunohistochemical staining and histological parameters. (a) Positive correlation between TNFα expression in the epithelium and cyst wall structure in the Pre-MG. (b) Inflammation score was showed positive correlations between both TNFα and IL-1α expressions in the connective tissue in the the Post-MG. (c) Negative correlation between TNFα expression in the connective tissue and the number of satellite cysts in the the Post-MG. (pre_TNF_ept: TNFα expression in the epithelium in the pre-marsupialization group, connective_tissue_stucture: connective tissue structure of the cyst wall in the pre-marsupialization group, post_TNF_ct: TNFα expression in the connective tissue in the post-marsupialization group, post_IL_ct: IL-1α expression in the connective tissue in the post-marsupialization group, post_inflammation: Inflammation score in the connective tissue in the post-marsupialization group. post_satellite_cyst: The number of satellite cysts in the the post-marsupialization group)

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Correlation between histological and clinical variables was shown in [Figure 4]. Inflammation was the only histological parameter that had significant correlation to clinical data in both groups. In the pre-marsupialization group, increased inflammation scores were observed with reduced radiographic size (rho: -0.483; P = 0.042), [Figure 4]a. A positive correlation was found between epithelial thickness and inflammation score in the pre-marsupialization group (rho: 0.454; P = 0.038), [Figure 4]b. On the other hand, inflammation was found to be positively associated with follow-up period in the post-marsupialization group (rho: 0.781; P = 0.001), [Figure 4]c.
Figure 4: Spearman's correlations in scatterplot matrix between histological parameters with clinical data (a) Negative correlation between inflammation scores and radiographic size in the pre-MG. (b) Positive correlation between inflammation scores and the epithelium size in the pre-MG. c: Positive correlation between inflammation scores and follow-up period in the post-MG. (pre_inflammation: Inflammation score in the connective tissue in the pre-marsupialization group., pre_radiographic_size: Radiographic size in pre-marsupialization group., pre_ept_size: The epithelial thickness of the pre-marsupialization group. Follow-up: follow-up period. post_inflammation: Inflammation score in the connective tissue in the post-marsupialization group.)

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   Discussion Top


Marsupialization is one of the most preferred surgical approaches in the treatment of OKCs. However, the success criteria for the treatment are still unclear due to the presence of recurrences or the aggressive biological behavior of the lesion. In addition, there are no histological criteria and/or biomarkers that predict the success of marsupialization. Therefore, the aim of our study was to assess the epithelial/connective tissue changes in OKCs through the use of histomorphological parameters and expression of proliferation, inflammatory and EMT markers before and after marsupialization treatment to determine whether the effect of treatment modality can reduce the aggressiveness of OKCs.

The most important clinical criteria that indicate the success of marsupialization is the reduction of the lesion on radiographic examination. The results of the present study indicated the statistically significant radiographic size reduction after marsupialization. Moreover, radiographic size showed negative correlation with histological inflammation score and TNFα expression in the connective tissue. Alterations in inflammation induced by marsupialization are well documented in the literature which is the main goal for success in the treatment.[18] Systematic reviews and meta-analyses revealed that decreased recurrences were detected in delayed enucleation treatment subsequent to marsupialization compared to enucleation alone.[19],[20] This was also supported by our results where the mean marsupialization period was 8.8 months with a recurrence rate of 12.5%. In addition, the post-marsupialization group had a slightly higher inflammation score than the pre-marsupialization. The outcomes in our study may be explained by the influence of the long marsupialization period on the continuation of the chronic inflammatory process which may have stimulated fibrosis and generated a thick cyst wall.

Another striking finding of our study was improved collagenization of connective tissue and increased thickness of cyst epithelium after marsupialization. Studies have reported that hyperplastic epithelial changes and fibrosis were seen due to inflammation after marsupialization.[5],[18],[21] When tissue is wounded, inflammatory responses occur, leading to EMT activation.[22] Prolonged and increased EMT stimulates fibroblast proliferation, resulting in hyperplasia.[23] Limited studies reported EMT marker expression profiles in OKCs,[13],[24] emphasizing higher Slug expression among the other markers. In our study, statistically significant Slug expression was found in the connective tissue of the post-marsupialization group. Zhong, Chen et al.[24] reported that MMP-9 was closely related with Slug expression in OKCs. MMP-9 was proposed as a crucial protein for fibrosis and remodeling via the cross-talk with pro-inflammatory cytokines.[25] Accordingly, we may hypothesize that Slug may have a crucial role for the epithelial and cyst wall alterations in marsupialization treatment through activating MMP-9 expression which is responsible for fibrosis.

Ki67 is a well-known proliferation marker that is widely used in OKCs in order to predict its biological behavior. Recent studies reported a decrease in Ki67 Pi in OKCs after marsupialization,[9],[18] which was confirmed by the results of our study.

IL-1α expression in keratinocytes is increased by mechanical forces and bacterial endotoxins. It has been shown that intracystic fluid pressure in odontogenic cysts is reduced by marsupialization treatment, thus reducing the mechanical stress on the cyst epithelium.[8] Ninomiya et al.[9] reported that OKC's IL-1α expression in epithelial cells could be partially regulated by changes in intracystic pressure. Considering our findings, we may suggest that IL-1α may have decreased in the post-marsupialization group in accordance with the interpretation of the literature.

Expressions of adhesion molecules, including E-cadherin, were investigated to understand their role in tumorigenesis,[14] cell differentiation, and invasion[26],[27] in odontogenic tumors. Although previous reports proposed that decreased E-cadherin expression might have a role in the invasive development of OKC[27]; there was no E-cadherin immunoexpression difference between pre- and post-marsupialization groups in our study specimens. Studies with similar results to our work reported that epithelial E-cadherin expression alone may not sufficient to explain the biological behavior of OKC.[13],[26]

IL-1α and TNFα were found in odontogenic jaw cysts[8],[28] and tumors[29]; therefore, these cytokines are thought to have important roles in the expansion of odontogenic lesions. While only epithelial TNFα was positively correlated with fibrosis of cyst wall (r: 0.44, P = 0.046) in the pre-marsupialization group, post-marsupialization group showed positive correlation of inflammation score to both TNFα (rho: 0.69, P < 0.001) and IL-1α (rho: 0.58, P = 0.008) expressions in connective tissue. In addition, the inflammation score was increased after marsupialization.


   Conclusion Top


In this study, an increase in collagenization and Slug expression in the cyst wall, together with the increase in epithelial thickness was observed after marsupialization. Those findings may indicate that marsupialization can effect cyst wall alteration through the EMT activity with special reference to higher slug expression. Therefore, we may speculate that increased Slug expression may enable the second surgery by increasing fibrosis in the cyst wall.

Ethical consideration

Ethical approval was granted according to the Gazi University Faculty of Dentistry, Clinical Research Committee (21071282-050.99-E.18602).

Financial support and sponsorship

This study was funded by the Gazi University Scientific Research Committee (03/2019-12).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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