Abstract
Purpose
To investigate the computed tomography (CT) and magnetic resonance imaging (MRI) characteristics of intraductal tubulopapillary neoplasms (ITPNs) of the pancreas and to correlate these features with clinicopathologic findings for improved preoperative recognition.
Methods
Eight patients were retrospectively analyzed with surgically confirmed ITPNs treated between October 2015 and June 2024 (median age, 68 years; range, 47–76). All patients underwent preoperative CT, and six underwent MRI. Imaging features, including location, size, morphology, margins, imaging composition, and pancreatic duct dilatation, were assessed. Characteristic signs, such as the “two-tone duct sign” and “cork-of-wine-bottle sign,” were evaluated. Quantitative analysis included unenhanced and peak-enhanced CT attenuation, enhancement amplitude, and apparent diffusion coefficient (ADC) values, compared with adjacent normal pancreatic parenchyma.
Results
Lesions predominantly involved the pancreatic head (75%) and were irregular or lobulated in 75% of cases. Ill-defined margins were observed in 75%, and solid–cystic lesion in 25%. Main pancreatic duct dilatation was present in 75% of patients. The “two-tone duct sign” and “cork-of-wine-bottle sign” were detected in 25% and 12.5% of cases, respectively. Quantitative analysis revealed significantly lower enhancement amplitude in ITPNs compared with normal pancreas (35.00 ± 10.58 HU vs. 53.50 ± 11.64 HU, P = 0.03) and a trend toward lower ADC values (1.143 ± 0.312 × 10⁻³ mm²/s vs. 1.372 ± 0.287 × 10⁻³ mm²/s, P = 0.15).
Conclusion
ITPNs typically appear as intraductal, poorly enhancing lesions with irregular morphology and frequent pancreatic duct dilatation. Characteristic signs and quantitative imaging parameters can facilitate preoperative recognition, improve diagnostic accuracy, and guide surgical planning.
Keywords: Pancreas, Intraductal tubulopapillary neoplasm, Computed tomography, Magnetic resonance imaging
Introduction
Intraductal tubulopapillary neoplasms (ITPNs) are an uncommon subtype of pancreatic intraductal neoplasms, representing approximately 3% of all intraductal tumors, and are characterized by a mass-clogged duct with minimal mucin and high-grade tubulopapillary structures [1, 2]. Initially described as intraductal tubular carcinoma (ITC), ITPNs were subsequently reclassified under the current World Health Organization (WHO) classification [3]. Clinically, ITPNs exhibit high-grade dysplasia and a risk of progression to invasive carcinoma, and patients may present with recurrent pancreatitis or nonspecific abdominal symptoms, making preoperative identification challenging yet essential [4].
Endoscopic ultrasound can demonstrate characteristic features such as the “2-tone duct sign” and the “cork-of-wine-bottle sign,” which are valuable for preoperative differentiation from other intraductal lesion [5]. Despite increasing recognition, reports detailing CT and MRI features remain limited, emphasizing the need for comprehensive imaging-pathologic correlation to facilitate early diagnosis and guide surgical management [6]. Therefore, this study retrospectively analyzes the CT and MRI features of ITPNs and correlates these imaging findings with histopathology, aiming to improve preoperative identification and guide optimal surgical management.
Materials and methods
Patient enrollment
This retrospective study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University, with a waiver of informed consent. All procedures were performed in accordance with the ethical standards of the institutional research committee and the Declaration of Helsinki. Between October 2015 and June 2024, eight patients with pathologically confirmed ITPN following surgical resection were identified from the pathology database.
Clinical data evaluation
Clinical data were retrieved from the electronic medical record system. The collected variables included patient sex, age, clinical symptoms, medical history, and serum carbohydrate antigen 19 − 9 (CA19-9) levels.
CT imaging
CT examinations were performed using either a uCT 530 or uCT 760 scanner (United Imaging Healthcare). For the uCT 530, the parameters were as follows: tube voltage, 120 kV; tube current, 110 mAs; rotation time, 0.8 s; pitch, 1.0750. For the uCT 760, the parameters included: tube voltage, 120 kV; tube current, 105 mAs; rotation time, 0.5 s; pitch, 0.9875. A nonionic contrast agent (Optiray) was administered intravenously at a dose of 1.2 mL/kg at a flow rate of 2.5 mL/s. Arterial- and venous-phase images were obtained 30 s and 70–80 s after contrast injection, respectively.
MR imaging
MRI examinations were performed using 1.5-T systems (UIH 560 MR and Siemens Aera MR). The protocol included: axial breath-hold fat-suppressed T2-weighted fast spin-echo (T2W-FS); axial breath-hold in-phase and opposed-phase gradient-echo T1-weighted imaging (T1W IP-OP); and diffusion-weighted imaging (DWI) with b-values of 0 and 800 s/mm². Prior to contrast administration, a breath-hold fat-suppressed 3D T1-weighted spoiled gradient-echo sequence (T1W-FS) was acquired. For contrast-enhanced imaging, gadopentetate dimeglumine (Gd-DTPA; Magnevist, Bayer Schering Pharma, Berlin, Germany) was injected intravenously at 0.2 mL/kg, followed by a 20 mL saline flush at 2 mL/s. Dynamic post-contrast T1W-FS images were acquired in three phases: arterial (20–30 s after injection, triggered by bolus tracking of the ascending aorta), portal venous (60–70 s), and delayed (160–180 s).
Image analysis
All images were independently reviewed by two abdominal radiologists (C.G.Z., 15 years of experience; M.L.W., 20 years of experience). Discrepancies were resolved by consensus. Both reviewers were blinded to clinical and pathological data.
The following imaging features were assessed: location (head, body, tail or whole pancreas), maximum diameter, morphology, margins, imaging composition, pancreatic duct dilatation. Special emphasis was placed on two characteristic findings: the “2-tone duct sign” (low-attenuation pancreatic juice surrounding a mildly hyperattenuating tumor on CT, or high T2 signal pancreatic juice surrounding a slightly hyperintense tumor on MRI) and the “cork-of-wine-bottle sign” (hyperintense pancreatic juice surrounding a slightly hyperintense intraductal tumor on MRCP) [5].
For quantitative analysis, circular regions of interest (ROIs) were drawn to encompass as much of the lesion as possible, avoiding cystic or necrotic areas, with additional ROIs placed in adjacent normal for comparison. Each lesion was measured three times, and the mean value was recorded. Unenhanced and peak-enhanced CT attenuation values of lesions were measured, and enhancement amplitude (peak-enhanced CT value minus unenhanced value) was calculated. Apparent diffusion coefficient (ADC) values were obtained on the mid-lesion slice to reduce partial volume effects and motion artifacts. If lesion margins were unclear on ADC maps, DWI or T2-weighted images were used for guidance. ADC values were also measured and compared with adjacent normal pancreatic tissue.
Statistical analysis
Continuous variables were expressed as mean ± standard deviation or median with interquartile range (IQR). Comparisons were performed using the independent-samples t-test or Mann–Whitney U test, depending on distribution. Violin plots were used to compare unenhanced CT values, peak-enhanced CT values, enhancement amplitude, and ADC values between ITPN and normal pancreatic tissue. Statistical software (SPSS Statistics version 21.0, IBM; and R software version 3.4.1; and R Foundation for Statistical Computing) was used to perform all statistical analyses. A two-sided P-value < 0.05 was considered statistically significant.
Results
Patient characteristics
A total of eight patients with pathologically confirmed ITPN were included in this study, comprising five males and three females, with a median age of 68 years (range, 47–76 years) (Table 1). The most common presenting symptom was abdominal pain (5/8, 62.5%), followed by jaundice (1/8, 12.5%) and weight loss (1/8, 12.5%); one patient was asymptomatic and was diagnosed incidentally. Diabetes was the most frequent comorbidity (4/8, 50%). Serum CA19-9 elevation was observed in only one patient (12.5%). Histopathological analysis revealed that six patients (75.0%) were classified as T1 invasive ITPN, whereas the remaining two patients (25.0%) were staged as Tis.
Table 1.
Clinical characteristics of patients with ITPN
| Case | Clinical symptoms | Medical history | Tumor markers |
|---|---|---|---|
| 1 | Jaundice | Diabetes mellitus | Elevated CA19-9 |
| 2 | Abdominal pain | None | None |
| 3 | Abdominal pain | None | None |
| 4 | Abdominal pain | Diabetes mellitus | None |
| 5 | Abdominal pain | Diabetes mellitus | None |
| 6 | Abdominal pain | None | None |
| 7 | None | None | None |
| 8 | Weight loss | Diabetes mellitus | None |
Note. ITPN = intraductal tubulopapillary neoplasm; CA19-9 = carbohydrate antigen 19 − 9
Imaging features
All eight patients underwent CT examinations, and six of them additionally received MRI (Fig. 1). Most lesions were located in the pancreatic head (6/8, 75.0%), followed by the pancreatic tail (1/8, 12.5%), with one case involving the entire pancreas (1/8, 12.5%) (Fig. 1). The maximum tumor diameter ranged from 2.0 to 19.0 cm (Table 2). Morphologically, six lesions (75.0%) appeared irregular or lobulated, whereas two (25.0%) were ovoid in shape. Ill-defined margins were observed in six cases (75.0%), while two cases (25.0%) demonstrated well-defined margins. Solid–cystic lesion was present in two patients (25.0%). Main pancreatic duct dilatation was identified in six cases (75.0%), mainly among those with pancreatic head involvement. Regarding the characteristic signs, the “two-tone duct sign” was observed in two cases (25.0%), and the “bottle cork sign” was identified in one case (12.5%), both on MRI (Fig. 2).
Fig. 1.
CT findings of intraductal tubulopapillary neoplasms (ITPNs). (A) A patient with ITPN and invasive carcinoma. Non-contrast CT shows a lobulated hyperattenuating mass in the pancreatic tail with heterogeneous density and partially indistinct margins (arrow). (B) A patient with ITPN and high-grade dysplasia. Contrast-enhanced CT (portal venous phase) demonstrates a well-defined ovoid intraductal mass in the pancreatic head with hypoenhancement (arrow). (C) A patient with ITPN and high-grade dysplasia. Contrast-enhanced CT (arterial phase) reveals a hypoenhancing intraductal mass in the pancreatic body surrounded by low-attenuation pancreatic juice, producing the “two-tone duct sign” (arrow). (D) A patient with ITPN and invasive carcinoma. Contrast-enhanced CT (portal venous phase) shows a diffuse cystic-solid lesion with lobulated contour and irregular enhancing cyst walls, septa, and mural nodules, whereas the cystic component demonstrate no enhancement (arrow). (E) Histopathologic section demonstrates an intraductal tubulopapillary neoplasm (red star) with adjacent cystic change (blue star) and solid components (yellow star), corresponding to the mixed solid–cystic appearance observed on CT imaging. (F) Histopathologic section shows intraductal tubulopapillary neoplasm (red star) in close association with pancreatic intraepithelial neoplasia involving the adjacent ductal epithelium (green star)
Table 2.
Imaging features of patients with ITPN
| Case | Location | Maximum diameter (cm) | Morphology | Margin | Imaging composition | Main pancreatic duct dilatation | Two-tone duct sign | Bottle cork sign |
|---|---|---|---|---|---|---|---|---|
| 1 | Head | 2.9 | Irregular or lobulated | Ill-defined | Solid | Yes | No | No |
| 2 | Head | 2 | Irregular or lobulated | Ill-defined | Solid | Yes | No | N/A |
| 3 | Head | 3.9 | Ovoid | Well-defined | Solid | Yes | Yes | N/A |
| 4 | Head | 7.8 | Ovoid | Well defined | Solid–cystic | Yes | Yes | Yes |
| 5 | Head | 5.3 | Irregular or lobulated | Ill-defined | Solid | Yes | No | No |
| 6 | Head | 3.1 | Irregular or lobulated | Ill-defined | Solid | Yes | No | No |
| 7 | Tail | 3 | Irregular or lobulated | Ill-defined | Solid | No | No | No |
| 8 | Whole pancreas | 19 | Irregular or lobulated | Ill-defined | Solid–cystic | No | No | No |
Note. ITPN = intraductal tubulopapillary neoplasm, N/A = not applicable
Fig. 2.
MRI findings of pancreatic head ITPN. MRI shows a well-defined solid mass with a few cystic foci on T2 fat-suppressed imaging (A, arrow), high signal intensity on high b-value DWI (800 s/mm²) (B), and corresponding low signal intensity on ADC (C, arrow). Portal venous phase demonstrates heterogeneous low enhancement (D, arrow), while MRCP reveals main pancreatic duct dilation with an irregular filling defect surrounded by high-signal pancreatic fluid, producing the “bottle cork sign” (E, arrow). Histopathologic sections demonstrate a predominantly solid intraductal tumor with focal cystic changes (F). The lesion is composed of densely packed tubular and tubulopapillary epithelial structures (G, H), consistent with intraductal tubulopapillary neoplasm
Quantitative imaging analysis
Quantitative analysis demonstrated that unenhanced CT attenuation values of ITPN lesions (35.00 ± 8.39 HU) were slightly lower than those of adjacent normal pancreatic parenchyma (38.00 ± 4.05 HU), although the difference was not statistically significant (P = 0.27) (Fig. 3). Peak enhanced CT values were lower in ITPN (75.57 ± 17.73 HU) compared with normal pancreas (99.85 ± 25.41 HU), with marginal statistical significance (P = 0.05) (Table 3). The enhancement amplitude of ITPN lesions (35.00 ± 10.58 HU) was significantly lower than that of normal pancreatic tissue (53.50 ± 11.64 HU, P = 0.03). Regarding diffusion characteristics, the ADC of ITPN lesions (1.143 ± 0.312 × 10⁻³ mm²/s) tended to be lower than that of normal pancreas (1.372 ± 0.287 × 10⁻³ mm²/s), but this difference did not reach statistical significance (P = 0.15). These results suggest that ITPN exhibits lower enhancement and slightly restricted diffusion compared with normal pancreatic parenchyma.
Fig. 3.
Violin plots show the distribution of quantitative imaging parameters for pancreatic parenchyma and intraductal tubulopapillary neoplasm (ITPN). (A) On unenhanced CT, attenuation values did not differ significantly between pancreatic parenchyma and ITPN (P = 0.27). (B) On peak-enhanced CT, attenuation values of ITPN were lower than those of pancreatic parenchyma, with borderline significance (p = 0.05). (C) CT enhancement amplitude values were significantly lower in ITPN compared with pancreatic parenchyma (P < 0.05). (D) Apparent diffusion coefficient (ADC) values showed no significant difference between the two groups (P = 0.15). Boxplots indicate the median and interquartile range, whereas violin shapes depict the distribution density. Statistical comparisons were performed using the Mann–Whitney U test
Table 3.
Quantitative imaging parameters of ITPN and normal pancreas
| Quantitative parameter | ITPN | Normal pancreas | P value |
|---|---|---|---|
| Unenhanced CT attenuation (HU) | 35.00 ± 8.39 | 38.00 ± 4.05 | 0.27 |
| Peak enhanced CT attenuation (HU) | 75.57 ± 17.73 | 99.85 ± 25.41 | 0.05 |
| Enhancement amplitude (HU) | 35.00 ± 10.58 | 53.50 ± 11.64 | 0.03 |
| ADC (×10⁻³ mm²/s) | 1.143 ± 0.312 | 1.372 ± 0.287 | 0.15 |
Note. ITPN = intraductal tubulopapillary neoplasm; ADC = apparent diffusion coefficient; HU = Hounsfield unit
Histopathologic and surgical findings
Pathologic tumor size ranged from 2 to 15 cm and was generally comparable to the maximum tumor diameters measured on preoperative CT and MRI (Table 4). All eight patients underwent curative-intent surgical resection with negative margins. Radical pancreaticoduodenectomy was performed in five patients. Distal pancreatectomy with splenectomy was carried out in one patient, distal pancreatectomy combined with splenectomy and partial small bowel resection in one patient, and radical pancreatectomy with splenectomy in one patient. Histopathologic examination demonstrated a predominantly solid growth pattern in six cases, while two tumors showed solid–cystic pattern. Lymph node metastasis was identified in one patient, with a single metastatic lymph node detected on histopathologic examination, while synchronous distant metastasis to the liver was observed in one patient at the time of surgery.
Table 4.
Histopathologic and surgical characteristics of patients with ITPN
| Case | Maximum diameter (cm) | Surgical procedure | Resection margin | Histopathologic pattern | T stage | Lymph node metastasis | Distant metastasis |
|---|---|---|---|---|---|---|---|
| 1 | 2.5 | Radical pancreaticoduodenectomy | Negative | Solid | T1 | No | No |
| 2 | 2 | Radical pancreaticoduodenectomy | Negative | Solid | T1 | No | No |
| 3 | 2 | Distal pancreatectomy + splenectomy + partial small bowel resection | Negative | Solid | Tis | No | No |
| 4 | 6.5 | Radical pancreaticoduodenectomy | Negative | Solid–cystic | Tis | No | No |
| 5 | 5 | Distal pancreatectomy + splenectomy | Negative | Solid | T1 | Yes (1 node) | No |
| 6 | 4 | Radical pancreatectomy + splenectomy | Negative | Solid | T1 | No | No |
| 7 | 2 | Radical pancreaticoduodenectomy | Negative | Solid | T1 | No | No |
| 8 | 15 | Radical pancreaticoduodenectomy | Negative | Solid–cystic | T1 | No | Yes (Liver) |
Note. ITPN = intraductal tubulopapillary neoplasm
Discussion
Intraductal tubulopapillary neoplasm (ITPN) of the pancreas is an uncommon intraductal epithelial neoplasm, accounting for approximately 3% of all intraductal tumors and only recently recognized as a distinct entity in the WHO classification [7]. Accurate recognition of ITPN is clinically important because, despite its malignant potential, affected patients generally demonstrate a more favorable prognosis compared with conventional pancreatic ductal adenocarcinoma [8–10]. However, data remain limited, largely derived from small retrospective series or case reports, and systematic imaging-pathologic correlation is still scarce. Against this background, our study aimed to characterize the clinical, imaging, and histopathological features of ITPN, with a focus on identifying diagnostic hallmarks and prognostic implications.
From a prognostic standpoint, pancreatic ITPN generally confers a more favorable outcome compared with conventional pancreatic ductal adenocarcinoma, with reported 5-year survival rates exceeding 70–80% in several series [8–11]. Nevertheless, invasive components are frequent, occurring in approximately 60% of patients, underscoring its malignant potential [1, 12]. Survival strongly depends on invasion status: patients without invasion may achieve 100% 5-year survival, whereas those with invasive carcinoma show reduced but still superior outcomes compared with pancreatic ductal adenocarcinoma [1]. Although recurrence and metastasis are relatively uncommon, they have been documented, highlighting the need for vigilant surveillance [8, 13, 14]. Specific patterns of ductal involvement also appear prognostically relevant, with mixed-duct type significantly increasing the risk of relapse [4]. Certain morphologic clues, such as pancreatoliths or psammomatous calcification, may suggest a long disease course, though invasive transformation can still occur [12, 14]. Complete surgical resection remains the treatment of choice, with outcomes far superior to other hepatobiliary malignancies [15–17]. However, current evidence is limited by small, retrospective case series, and multicenter studies with longer follow-up are needed to clarify prognostic determinants.
ITPNs often present with nonspecific symptoms such as abdominal pain, pancreatitis, or jaundice [8, 13]. In our cohort, abdominal pain was the most common manifestation, similar to prior reports where ITPN was diagnosed in patients presenting with acute pancreatitis or abdominal discomfort [8, 13, 18]. For example, the case reported by Kanno et al. described a patient admitted for abdominal pain with a multicystic lesion discovered on endoscopic ultrasound-guided fine needle aspiration cytology confirmed ITPN [13]. Similarly, a patient with type 2 diabetes and recurrent abdominal pain was shown to have diffuse MPD dilatation filled with a “sausage-like” solid mass, again consistent with ITPN [18]. These reports highlight the variable but often subtle clinical manifestations of the disease, which may delay diagnosis until advanced stages.
In the spectrum of intraductal pancreatic neoplasms, ITPN represents a distinct entity from intraductal papillary mucinous neoplasm (IPMN), despite certain overlapping imaging appearances. Differentiating these two entities is clinically important because of their different biological behaviors, histopathological characteristics, and implications for surgical management and prognosis. From an imaging perspective, IPMNs are typically characterized by cystic dilatation of the pancreatic ductal system with mucin production, often accompanied by mural nodules and progressive ductal expansion [19]. In contrast, ITPNs usually present as intraductal solid or solid–cystic masses causing ductal obstruction rather than mucin overproduction. In our study, hypoenhancement relative to the surrounding pancreas was consistently observed, with significantly lower enhancement amplitude compared to normal tissue. This finding corroborates prior studies describing ITPN as a hypovascular lesion on dynamic contrast imaging [20]. Histopathologically, IPMNs are characterized by papillary growth with abundant extracellular mucin and varying degrees of dysplasia, whereas ITPNs demonstrate densely packed tubular or tubulopapillary structures with minimal mucin production and relatively high cellularity [1, 2]. Importantly, the imaging-pathologic correlation supports this observation, since ITPN cells grow in dense back-to-back tubular formations with little stroma or vascularity [18, 20]. Specific signs on EUS and MRCP have been proposed to aid diagnosis. Yamaguchi et al. described the “2-tone duct sign” and the “cork-of-wine-bottle sign,” which reflect intraductal tumor growth surrounded by pancreatic juice [20]. In our series, these signs were observed in three patients, demonstrating their value in noninvasive diagnosis. However, such signs are infrequently reported outside small series and may therefore lack sensitivity [18, 21]. Quantitative imaging analysis offers additional diagnostic insight. In our series, ITPN lesions demonstrated lower enhancement amplitude and slightly lower ADC values compared with adjacent normal pancreas. While the difference in ADC was not statistically significant, the trend toward restricted diffusion is consistent with dense cellularity observed histologically. With respect to lesion morphology, lesions demonstrating cystic components on CT or MRI consistently corresponded to mixed solid–cystic architecture on histopathology, whereas purely solid intraductal lesions on imaging were pathologically confirmed as solid tumors. These findings suggest that the cystic appearance in ITPN is more likely secondary to ductal dilatation or cystic degeneration induced by tumor growth, rather than true mucinous cyst formation, which is a hallmark of IPMN. In addition, pathologic tumor size showed good concordance with the maximum tumor diameter measured on preoperative imaging, supporting the reliability of CT and MRI for lesion size assessment and preoperative evaluation. Accurate preoperative differentiation between ITPN and IPMN has important implications for clinical management and prognosis [19, 22, 23]. IPMNs may be managed conservatively or surgically depending on established high-risk stigmata and worrisome features, whereas ITPNs are generally considered malignant or high-grade neoplasms and thus warrant surgical resection when feasible. In our series, all patients underwent curative-intent surgery with negative resection margins, underscoring the role of cross-sectional imaging in delineating tumor extent and guiding appropriate surgical planning.
Despite increasing recognition, current knowledge remains limited by small series and case reports. The largest imaging-focused study to date proposed the “2-tone duct” and “cork-of-wine-bottle” signs, but acknowledged limitations including retrospective design, heterogeneous imaging protocols, and lack of comparison with other tumor types. Our series contributes by providing a systematic correlation of CT/MRI findings with histopathology, as well as incorporating quantitative imaging measures. However, further prospective multicenter studies are warranted to validate imaging hallmarks and determine their diagnostic accuracy across diverse clinical settings.
In summary, ITPN is a rare but distinct intraductal neoplasm with unique pathologic and imaging characteristics. Hypovascular enhancement, restricted diffusion, and the potential presence of the “2-tone duct” and “cork-of-wine-bottle” signs should alert radiologists to this diagnosis. Future work should focus on refining radiologic criteria and validating imaging biomarkers to improve noninvasive preoperative diagnosis of this challenging entity.
Acknowledgements
None.
Author contributions
Chuge Zhang and Mingliang Wang conceived and designed the study. Chuge Zhang and Gengyun Miao were responsible for data acquisition, performed statistical analyses, and drafted the initial manuscript. Mengsu Zeng and Mingliang Wang critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.
Funding
This research received no funding.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethical approval
This retrospective study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University, with a waiver of informed consent. All procedures were conducted in accordance with the ethical standards of the institutional research committee and the Declaration of Helsinki.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Chuge Zhang and Gengyun Miao contributed equally to this work.
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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 datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.