Abstract
Histopathologic surgical margin assessment in veterinary patients is an imprecise science with assessment limited to a small proportion of the surgical margin due to time and finances. Incomplete excision of canine mast cell tumours (MCTs) alters treatment recommendations and prognosis. Optical coherence tomography (OCT) is a novel imaging modality that has been reported in a single veterinary study for surgical margin assessment. Twenty-five dogs with 34 MCTs were enrolled in a prospective pilot-study to assess the imaging characteristics of canine MCTs with OCT and to evaluate the feasibility and utility of OCT-guided histopathology. All dogs underwent routine surgical excision of MCTs. OCT imaging was used to assess the entire surgical margin prior to placement in formalin. Either normal areas or areas suspected of incomplete MCT excision were inked. Standard histopathologic sectioning and tangential sectioning of inked areas were performed and compared to OCT results. OCT identified MCT near the surgical margin in 10 of 26 specimens (38.4%). Four specimens suspicious for incomplete margins on OCT had incomplete MCT excision that was missed on standard histopathologic sectioning. Six specimens had OCT-guided sections taken as suspicious, which did not show MCT on histopathology. OCT-guided pathology sections were able to detect incompletely excised MCT near the surgical margin with a sensitivity of 90% and specificity of 56.2% in this preliminary study. OCT imaging shows promise for guiding pathologists to areas of interest to improve the diagnostic accuracy of surgical margin assessment in excised canine MCTs.
Keywords: dogs, histopathology, mast cell tumours, optical coherence tomography, surgical margins
1 ∣. INTRODUCTION
Surgical excision of canine mast cell tumours (MCTs) with either 2 cm lateral margins or proportional margins to the diameter of the tumour is the recommended as the first line therapy for disease control.1,2 Accurate surgical margin assessment following MCT excision is necessary to provide treatment recommendations and prognostic information.3-7 Surgical margin evaluation currently relies on a non-standardized histopathology-based approach that involves sampling only a small proportion of the surgical margin due to constraints in time and resources, and furthermore takes several days to become available.3,4,8,9 Standard histopathology of excised small- and medium-sized tumours typically involves radial sectioning to evaluate representative areas of the surgical margin (< 1% total surgical margin area).3,4 In some instances, tangential sectioning may also be performed for regions that are grossly suspicious for incomplete resection at the pathologist's discretion.3,4 Unfortunately, this limited sampling assumes that selected sections are representative of the entire specimen and may not appreciate asymmetric tumour growth.3,4 This assumption can lead to false diagnosis of a complete excision, resulting in a missed opportunity for adjuvant therapy.3,4
Previous studies have reported initial evaluations of a novel technology known as optical coherence tomography (OCT) and its potential applications in veterinary surgical oncology patients.10,11 OCT produces high-resolution images using near-infrared light waves that penetrate non-transparent tissues up to approximately 2 mm in depth, depending on the optical properties of the tissue. These images show tissue microstructure comparable to that seen on a low-magnification histology slide.12-16 The images can be interpreted with a high diagnostic accuracy by observers in various specialties after a short standardized training module, and can accurately differentiate normal tissues from canine soft tissue sarcoma and human breast cancer.10-15,17,18 In light of these findings, the authors suspect that OCT could have applications in guiding pathology sampling in excised tumour specimens to aid in surgical margin assessment. Other surgical margin imaging modalities, such as near-infrared fluorescent imaging, imprint cytology and shaved margins have demonstrated variable diagnostic accuracies and clinical feasibility.10,16,19-21
Given the limitations in current pathology assessment, there is a need to improve surgical margin assessment in veterinary surgical oncology patients to improve patient care and recommendations. The first objective of this study was to develop a small image library with comparisons of normal and abnormal features of OCT images with histopathology from the tissues at surgical margins of excised MCTs. The second objective was to determine the feasibility and utility of OCT-guided histopathology of excised MCTs. The authors hypothesized that OCT could be used to distinguish MCT from normal tissues, and that OCT-guided histopathology would be feasible and identify cases with incomplete surgical margins that were not detected with standard histopathological sections.
2 ∣. MATERIALS AND METHODS
Dogs were enrolled in this study between May 17th 2017 and February 19th 2019 at the University of Illinois Veterinary Teaching Hospital and the Ohio State University Veterinary Medical Center. The study protocol was approved by the Institutional Animal Care and Use Committee at each institution. Informed and written owner consent was obtained for each case prior to enrollment in this study.
2.1 ∣. Study population
Inclusion criteria were any dog with a cytologically diagnosed cutaneous or subcutaneous MCT that was undergoing planned surgical excision at either institution. An American College of Veterinary Surgeons board-certified surgeon, or a trainee under direct supervision, performed surgical excision of the MCT(s). The planned surgical margins were determined by the primary surgeon for each dog and not altered based on enrolment into this study. After excision, the specimen was wrapped in a saline-soaked laparotomy sponge and OCT imaging was performed within 2 hour of excision.
Prior to imaging the specimen, two photographs were taken of the excised tissue (skin surface and deep surface) that included a ruler for scale. These images were sent real-time to the institutional American College of Veterinary Pathology board-certified pathologist (JS: University of Illinois; RJ: Ohio State University) to determine where tissue trimming would be performed and the orientation of sections based on the gross appearance and size of the surgical specimen. An example of this predetermined radial sectioning of the short- and long-axes of the tissues is shown here (Figure 1). In the majority of cases, an additional cross-section was taken from the centre of the tumour to confirm the diagnosis of MCT and to assess grade.
FIGURE 1.
An excised MCT is shown. The dashed lines mark the pre-determined radial sectioning that will be performed after OCT imaging. A complete cross-section will also be performed to assess MCT grade as shown by continuation of the dorsoventral line passing vertically through the center of the specimen. MCT, mast cell tumour; OCT, optical coherence tomography
2.2 ∣. OCT Imaging
Imaging performed at the University of Illinois Veterinary Teaching Hospital was performed using a custom-built spectral-domain OCT system (Custom OCT system, Biophotonic Laboratory, University of Illinois) with a custom-built handheld OCT probe (Diagnostic Photonics, Chicago, IL). Image acquisition was performed using custom-written software (Biophotonics Laboratory, University of Illinois) prior to OCT images being exported to an image processing software (MatLab;Mathworks, Natick, MA) to generate sequential multi-frame series representative of each marked area of interest. Cases enrolled at the Ohio State University Veterinary Medical Center were imaged with a commercial spectral-domain high axial resolution OCT imaging system with a compact handheld scanner, and image acquisition and processing software (Telesto series SD-OCT systems, ThorImage OCT Software, Newton, NJ). For both systems, final image rendering to remove background noise and saturation within the OCT image frames was performed as reported by Mesa et al.11
Imaging and image interpretation for each specimen was performed by one or two authors with experience in surgical margin imaging using OCT (CC and/or LES). The handheld OCT probe was used to image the entire surgical margin of each specimen. OCT imaging was interpreted in real-time by the author(s). Any areas that were suspicious for MCT were inked for later sectioning by the institutional pathologist. If no areas of suspicion were identified, either no areas were marked or an area of normal tissue was selected and inked in an identical fashion. Examples of areas on the ex vivo specimen where tangential sectioning may be performed are shown (Figure 2): After one to four areas of interest were inked on each specimen, the surgical ink was allowed to dry and the specimen was placed in a 1:10 ratio solution of 10% neutral buffered formalin for tissue fixation.
FIGURE 2.
An excised MCT is shown. Dashed lines mark areas along the tumour surface (skin edge, A, or deep surface, B, that are examples of where tangential sectioning of areas of interest are sectioned after OCT imaging for histologic evaluation of the surgical margin. MCT, mast cell tumour; OCT, optical coherence tomography
2.3 ∣. Pathology
After 24 to 48 hours, the specimens were removed from formalin and the institutional pathologist performed the radial sectioning that had been determined prior to OCT imaging. For specimens for the first objective, inked areas had two perpendicular sections taken. For specimens for the second objective, a tangential section (2-3 mm thick) was acquired for each inked area of interest. All sections were paraffin embedded and slides were stained with haematoxylin and eosin. For the first objective, the slides from inked areas were digitized with a slide scanner at ×4 magnification (NanoZoomer 2.0 RS, Hamamatzu C10730, Bridgewater, NJ).
The institutional pathologist was blinded to the results of the OCT imaging and assessed the slides for each specimen. Diagnostic pathology reports were generated, including tumour type, tumour grade and surgical margin status.22,23 For specimens for objective 1, the pathologist determined the tissue types present. For objective 2, the pathologist determined the surgical margins as complete or incomplete for the inked sections, and the standard radial sections. Tumour-free histologic margins were termed “complete” margins for the purpose of this study. Results of the OCT-guided (inked) sections were considered complete if tumour cells were not present in tangential inked sections, as sections were 2 to 3 mm thick. Margins were also considered complete regardless of margin distance if an intact fascial plane separated the tumour cells from the surgical margin, as this is how cases would be classified in the clinical setting. The entire surgical excision was considered incomplete if any of the sectioned areas (inked or standard sectioning) were classified as incomplete.
2.4 ∣. Analysis
This study was designed as a pilot study with five dogs to be enrolled in objective 1 to describe image characteristics for tissues at surgical margins, and 25 MCT specimens to be assessed in objective 2 for determining feasibility and utility of this technique for surgical margin assessment for canine MCT.
Descriptive statistics were calculated to summarize dog signalment information for both objectives. To create a training set of images, OCT images from specimens from objective 1 were compared to digitized pathology slides of the inked areas with known tissue type. Imagers (CC and/or LES) identified image characteristics to identify normal and abnormal tissues at surgical margins on OCT imaging of MCT specimens. Following completion of the first objective case accrual, two authors (CC and/or LES) performed OCT imaging immediately after surgical resection for second objective cases using the image characteristics identified to determine whether tissue was normal or abnormal real-time and should be sampled for pathology. The results of this OCT-guided pathology were compared to standard pathology results for agreement.
2.5 ∣. Cell line validation statement
No cell lines were used in this project.
3 ∣. RESULTS
3.1 ∣. Objective 1
Five dogs with eight MCTs were enrolled into objective 1. Median age for these dogs was 10.2 years old (range: 9.0-12.1), and the breeds represented included two mixed breed dogs, and one each Labrador retriever, Bernese mountain dog and Boxer.
For objective 1, inked areas from surgical margins of resected MCT were comprised of four major histological tissue types including skeletal muscle, adipose tissue, fascia and MCT. The depth of the OCT image varied depending on the type of tissue examined and its inherent optical properties, and how these attenuated the near-infrared light. Adipose tissue could be imaged up to 2 mm due to its lower optical scattering and lower cellular density, whereas highly scattering cellular tissue like MCT had a reduced imaging depth.
Various tissue characteristics based on OCT imaging were determined for different tissue types represented in the area of interest. Skeletal muscle appeared dense and high scattering with organized and repeating subcellular units corresponding to its normal myofibril arrangement. A striated appearance can also be seen with longitudinal scanning of this tissue type. Adipose tissue exhibited a diffuse low-scattering appearance with a characteristic honeycombed pattern to the tissue. Individual adipocytes were visible with low scattering cytoplasm and higher scattering peripheral nucleus and cell membrane. Fascial tissue produced a linear and discrete high-scattering band normally covering an underlying layer of skeletal muscle or adipose. MCT was characterized by a dense, high-scattering, granular pattern and could be distinguished from other tissue types by a lack of microstructural architecture and loss of repeating subcellular structures (Figure 3). Tumour tissue appeared heterogeneous with a haphazard arrangement of architecture and loss of structure. Variation in optical scattering between tumours was minimal and dependent on tumour cell density.
FIGURE 3.
Corresponding OCT A, and histopathology B, images of a canine MCT. The broad arrows point out regions of low-scattering adipose tissue with a classic OCT “honey-comb” pattern, A, and their corresponding histopathologic sectioning appearance, B,. The narrow arrows point to areas of dense, irregular, highly-scattering tissue consistent with MCT, A, and its corresponding histopathology, B. MCT, mast cell tumour; OCT, optical coherence tomography
3.2 ∣. Objective 2
Imaging of ex vivo specimens from both objectives took approximately 5 to 10 minutes per sample. Twenty dogs with 26 MCTs were enrolled in objective 2, and signalment information for this group is summarized in Table 1. Ten dogs (38.4%) underwent planned ≥2 cm excision, while 10 and 6 dogs (38.4% and 23.1%) underwent 1 to 2 cm and < 1 cm excision, respectively.
TABLE 1.
The signalment, number, and location of excised MCTs included in this study
| Dog number | Age (years) | Breed | Number MCT tumours | Anatomic location of tumour(s) |
|---|---|---|---|---|
| 1 | 12.05 | Pug | 1 | Dorsolateral cervical |
| 2 | 8.85 | Golden retriever | 2 | Right flank and left tarsus |
| 3 | 8.03 | Labrador retriever | 1 | Right lateral thorax |
| 4 | 10.67 | Mixed breed dog | 2 | Ventral abdomen and left hip |
| 5 | 7.59 | Golden retriever | 1 | Ventral abdomen |
| 6 | 7.51 | Mixed breed dog | 1 | Left caudal thigh |
| 7 | 9.19 | American bulldog | 2 | Left lateral thorax and left cranial thigh |
| 8 | 11.83 | Mixed breed dog | 1 | Left lateral elbow |
| 9 | 8.06 | Mixed breed dog | 1 | Left muzzle |
| 10 | 5.64 | Mixed breed dog | 1 | Base of right ear |
| 11 | 6.97 | Mixed breed dog | 1 | Medial left thigh |
| 12 | 7.05 | Mixed breed dog | 2 | Left lateral thigh and perivulvar |
| 13 | 5.61 | Labrador retriever | 1 | Left inguinal |
| 14 | 5.77 | Golden retriever | 1 | Left tarsus |
| 15 | 11.55 | Golden retriever | 1 | Left flank |
| 16 | 9.74 | Belgian malinois | 1 | Right tarsus |
| 17 | 4.49 | Beagle | 1 | Right ear |
| 18 | 8.97 | Mixed breed dog | 1 | Right antebrachium |
| 19 | 8.08 | American bulldog | 1 | Right lateral thigh |
| 20 | 9.69 | American bulldog | 3 | Right cheek, left interdigital, left perianal |
Abbreviation: MCT, mast cell tumour.
Sixteen tumours (61.5%) had areas that were suspected for incomplete MCT excision after OCT imaging, and 10 tumours (38.4%) were identified as not having any areas of suspicion.
In 14 of 26 cases (53.8%), the OCT imaging and standard histopa-hology were in agreement, while there were 12 cases (46.2%) in disagreement. OCT areas of interest identified 10 cases (38.4%) where MCT was visible within 2 mm of the surgical margin and was suspicious for MCT near the surgical margin in 6 cases (23.1%). In 4 of 26 cases (15.3%), OCT imaging was able to detect MCT near the surgical margin that was missed by standard histopathology sectioning, resulting in a change of diagnosis to incomplete excision. Only one case (3.8%) was identified to have incomplete excision on standard sectioning that was missed by OCT imaging (Table 2).
TABLE 2.
The data below show each case and tumour enrolled in the second aim of this study
| Dog number |
Tumour number |
Plannedsurgical margins (cm) |
OCT Imaging assessment |
Narrowest histopathologicmargin (cm) |
Standardhistopathology assessment |
OCT Area histopathology |
OCT and pathology agreement |
Final histopathology result |
|---|---|---|---|---|---|---|---|---|
| 1 | 1 | 3 | Incomplete | 0.1 | Incomplete | Incomplete | Agree | Incomplete |
| 2 | 2 | 2 | Incomplete | 1.5 | Complete | Complete | Disagree | Complete |
| 2 | 3 | 1 | Incomplete | 0.1 | Incomplete | Incomplete | Agree | Incomplete |
| 3 | 4 | 2 | Incomplete | 0.1 | Incomplete | Incomplete | Agree | Incomplete |
| 4 | 5 | 3 | Complete | 2 | Complete | Complete | Agree | Complete |
| 4 | 6 | Incomplete | 0 | Complete | Incomplete | Disagree | Incomplete | |
| 5 | 7 | 2 | Complete | 1.5 | Complete | Complete | Agree | Complete |
| 6 | 8 | 2 | Incomplete | 0.5 | Complete | Complete | Disagree | Complete |
| 7 | 9 | 2 | Complete | 0.7 | Complete | Complete | Agree | Complete |
| 7 | 10 | 2 | Incomplete | 0.9 | Complete | Complete | Disagree | Complete |
| 8 | 11 | Incomplete | 0 | Complete | Incomplete | Disagree | Incomplete | |
| 9 | 12 | 1 | Incomplete | 0.1* | Complete* | Complete* | Disagree | Complete |
| 10 | 13 | 2 | Incomplete | 1 | Complete | Complete | Disagree | Complete |
| 11 | 14 | 1.5 | Complete | 0.9 | Complete | Complete | Agree | Complete |
| 12 | 15 | 1.5 | Complete | 0.5 | Complete | Complete | Agree | Complete |
| 12 | 16 | 1 | Complete | 2 | Complete | Complete | Agree | Complete |
| 13 | 17 | 1.5 | Incomplete | 1 | Complete | Complete | Disagree | Complete |
| 14 | 18 | Incomplete | 0 | Incomplete | Incomplete | Agree | Incomplete | |
| 15 | 19 | 2 | Complete | 1 | Complete | Complete | Agree | Complete |
| 16 | 20 | 1 | Complete | 0.3 | Complete | Complete | Agree | Complete |
| 17 | 21 | 1.5 | Incomplete | 1.5 | Complete | Complete | Disagree | Complete |
| 18 | 22 | 1.5 | Incomplete | 0 | Incomplete | Incomplete | Agree | Incomplete |
| 19 | 23 | 1.5 | Complete | 0.1 | Incomplete | Complete | Disagree | Incomplete |
| 20 | 24 | 0.4 | Complete | 0.3 | Complete | Complete | Agree | Complete |
| 20 | 25 | 0.3 | Incomplete | 0 | Complete | Incomplete | Disagree | Incomplete |
| 20 | 26 | Incomplete | 0 | Complete | Incomplete | Disagree | Incomplete |
Note:Information includes what pre-planned surgical margins were obtained intraoperatively, whether OCT imaging suspected the excision to be complete or incomplete, the narrowest margin noted histopathologic analysis, the results of standard histopathologic sectioning, tangential sectioning results of the OCT indicated area of interest, whether standard histopathology and OCT imaging were in agreement, and the final histopathologic result of the excised specimen after evaluating both the standard sectioning and the OCT area of interest. Complete excision indicates neoplastic cells are not seen within 2 mm of the surgical margin. Decimal points indicate missing data for cases with marginal excision. The * marks the specimen that was determined to be completely excised despite narrow margins due to the presence of an intact plane of collagen between the neoplastic cells and the surgical margin.
Abbreviations: MCT, mast cell tumour; OCT, optical coherence tomography.
One specimen suspected of an incomplete resection on OCT imaging was identified to have an intact barrier of collagen separating the MCT from the surgical margin 2 mm away. Because of this collagen barrier, the final diagnosis of a complete excision was made despite the proximity of the MCT to the margin, as would be the case in a clinical setting (Table 2). After comparing the OCT areas of interest with standard histopathology sectioning, the final determination for this population was 16 and 10 completely and incompletely excised tumours, respectively. The overall sensitivity and specificity for OCT to accurately identify incomplete vs complete excision was 90% and 56.2%, respectively.
4 ∣. DISCUSSION
In this report, OCT was able to accurately identify MCT near the surgical margin in all but one of the excised specimens with incomplete excision, including identifying four incompletely excised tumours that would have been missed by standard histopathology sectioning. This imaging modality can identify canine MCT near the surgical margin of excised specimens with good preliminary accuracy. The results of this report show promise for the use of OCT imaging to guide pathologist sectioning of excised canine MCTs to increase the diagnostic accuracy of surgical margin assessment.
Previous efforts to develop techniques for real-time assessment of surgical margins in veterinary patients have included studies assessing near-infrared fluorescence imaging, shaved margin assessment and imprint cytology.19-21,24,25 Thus far, these modalities have been shown to have varied diagnostic accuracies and limited feasible application in a large-scale clinical setting. OCT evaluation of the surgical margin in this report had a high sensitivity and moderate specificity, allowing it to identify incomplete excision in four specimens when standard sectioning did not identify residual MCT cells. OCT is an imaging technology that is easy to learn and interpret with a high degree of accuracy.14,18 A study currently under peer review has identified that a short training module was sufficient to teach clinicians of multiple specialties and experience levels how to interpret OCT imaging to discern canine soft tissue sarcoma from normal tissues with good accuracy.18
The most accurate technique for surgical margin assessment of excised tumours is tangential sectioning of the entire surgical margin.3,4 Unfortunately, the resources to perform this diagnostic (time, personnel, expense) are not readily available in veterinary pathology.3,4 Should OCT-guided histopathology continue to prove efficacious in future studies, this technology could be readily introduced into the veterinary clinical setting. With OCT, clinicians could identify areas suspicious for incomplete excision. The imaging equipment does not take up a large amount of laboratory space, and imaging excised specimens takes approximately 5 to 10 minutes. Tangential sectioning of a few additional areas can be readily performed, in addition to standard trimming, without creating a strain on resources, making OCT feasible in a busy referral practice or diagnostic pathology laboratory.
In this report, “complete” margins were defined as tumour cells >2 to 3 mm away from the surgical margin on all sectioning, as the OCT imaging modality only penetrates tissues up to a depth of 2 mm and tangential sectioning of tissues results in slices that are approximately 2 to 3 mm thick. In the clinical setting, there is clinician variation for the use of the term “complete” excision of MCTs. As such, some of the “incomplete” tumours in this report may have been classified as “complete” by some based on their histologically tumour-free margins.
Some reports in the human literature have identified that OCT can accurately discern human breast cancer from normal surrounding tissues and have found this modality to have a high degree of accuracy in both ex vivo excised specimens and in vivo surgical wound beds.12,13 A previous study used OCT to accurately discern canine STS tumours from normal tissues, however prior to this report, OCT imaging had not yet been used to describe canine round cell neoplasms.10 Objective 1 in this report was performed to demonstrate that accurate differentiation between a round cell neoplasm and normal surrounding tissues was possible prior to assessing the diagnostic accuracy of OCT guided histopathologic sectioning performed in objective 2. Similar to canine soft tissue sarcoma, MCT appears on OCT images as a heterogeneous, highly-scattering structure without any organized pattern (consistent with the rapid, disorganized growth that is classic for tumours).10 Though very similar in appearance, the authors subjectively think canine soft tissue sarcoma appears mildly coarser or more granular in appearance compared to canine MCT. The highly-scattering appearance of tumour cells on OCT is attributed to an increase in nuclear-to-cytoplasmic ratio and cell population density.13 Surrounding normal tissues, such as muscle or connective tissues like fascia, also have a highly-scattering appearance.10,12,13 The difference between these tissues is the organization of the cells: muscle and connective tissues have a discernable linear, organized pattern compared to the disorganized cells and features found in MCT and soft tissue sarcoma.10,12,13 Adipocytes are the easiest tissue type to discern, with their honeycomb structure and low-scattering appearance (Figure 3).10,12 Information regarding the appearance of canine MCT collected in this pilot study was used to guide study designs for a report assessing canine cutaneous and subcutaneous neoplasms that is currently in the process of data collection.
4.1 ∣. Limitations
While OCT was able to identify additional cases with incomplete margins, this was a small sample population of 26 tumours, and a larger sample population may reveal different calculations for the accuracy of this imaging modality. Ideally, the results from the OCT imaged areas of interest and standard histopathological sectioning would have been compared to complete tangential sectioning of the entire surgical margin. Unfortunately, tangential sectioning of the entire surgical margin for each specimen would have been very costly and was unable to be performed in this preliminary study. Further studies are needed to assess OCT-guided histopathology sectioning with other tumour types to assess its full range of applications in veterinary surgical margin assessment.
4.2 ∣. Conclusions
OCT-guided histopathology sectioning is feasible in a clinical setting and increases the diagnostic accuracy of surgical margin assessment in excised canine MCTs. Future studies will use this imaging with a variety of excised benign and malignant cutaneous and subcutaneous neoplasms to further assess its ability to evaluate surgical margins in the canine species. Further research is needed to assess more application of OCT imaging before recommending widespread implementation of this technology in the veterinary field.
ACKNOWLEDGEMENTS
The authors would like to acknowledge all clinicians that contributed to case identification and accrual for this study.
Funding information
Funding for Dr. Boppart from the National Institutes of Health, Grant/Award Number: 1R01CA213149
Footnotes
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.