International Journal of Molecular Imaging

International Journal of Molecular Imaging / 2012 / Article

Review Article | Open Access

Volume 2012 |Article ID 324686 | 9 pages | https://doi.org/10.1155/2012/324686

PET Imaging in Recurrent Medullary Thyroid Carcinoma

Academic Editor: Francesco S. Celi
Received23 Apr 2012
Accepted21 May 2012
Published18 Jul 2012

Abstract

Purpose. To perform an overview about the role of positron emission tomography (PET) or PET/computed tomography (PET/CT) using different radiopharmaceuticals in recurrent medullary thyroid carcinoma (MTC) based on biochemical findings (increased tumor marker levels after primary surgery). Methods. A comprehensive literature search of studies published in PubMed/MEDLINE, Scopus, and Embase databases through February 2012 regarding PET or PET/CT in patients with recurrent MTC was performed. Results. Twenty-nine studies comprising 714 patients with suspected recurrent MTC were retrieved. Twenty-seven articles evaluated the role of fluorine-18-fluorodeoxyglucose (FDG) PET or PET/CT in recurrent MTC with conflicting results. Diagnostic accuracy of FDG-PET and PET/CT increased in MTC patients with higher calcitonin and carcinoembryonic antigen values, suggesting that these imaging methods could be very useful in patients with more advanced and aggressive disease. Eight articles evaluated the role of fluorine-18-dihydroxyphenylalanine (FDOPA) PET or PET/CT in recurrent MTC reporting promising results. Overall, FDOPA seems to be superior but complementary compared to FDG in detecting recurrent MTC. Few studies evaluating other PET tracers are also discussed. Conclusions. PET radiopharmaceuticals reflect different metabolic pathways in MTC. FDOPA seems to be the most useful PET tracer in detecting recurrent MTC based on rising levels of tumor markers. FDG may complement FDOPA in patients with more aggressive MTC.

1. Introduction

Medullary thyroid carcinoma (MTC) is a slow-growing neuroendocrine tumor originating from parafollicular C cells. MTC accounts for approximately 5% of thyroid carcinomas, occurring in either sporadic (75% of cases) or familial forms (25% of cases). This tumor is frequently aggressive; most frequent sites of metastatic disease are cervical and mediastinal lymph nodes, lungs, liver, and bone. The main treatment for MTC is surgical resection that is the only strategy for potential cure; in patients with metastatic disease therapeutic options are limited as this tumor does not concentrate radioiodine and shows poor response to chemotherapy and radiation therapy [1]. Also targeted therapy with vandetanib seems to show promising results in the treatment of patients with metastatic/recurrent MTC [1].

Serum calcitonin represents the most sensitive and accurate tumor marker in the postoperative management and surveillance of MTC. In about one third of patients with MTC lesions also carcinoembryonic antigen (CEA) levels may be increased and this finding has prognostic significance, as increased CEA levels are characteristic of advanced forms when the tumor tends to dedifferentiation. Serum calcitonin and CEA doubling times are efficient tools for assessing tumor progression and are useful prognostic factors of survival in patients with MTC [1].

The early detection of recurrence represents an important step in the management of patients with MTC, because identifying recurrent tumor tissue impacts in patient outcome [14]. Conventional imaging modalities are often negative or inconclusive in presence of rising levels of tumor markers. Therefore, functional imaging with PET using different radiopharmaceuticals was explored as a way to detect MTC recurrence.

Fluorine-18-Fluorodeoxyglucose (FDG), a glucose analog, accumulates in neoplastic cells allowing scintigraphic visualization of tumors that use glucose as an energy source. FDG uptake in neoplastic cells correlates with poor differentiation and high proliferative activity. Neuroendocrine tumors usually show an indolent course, and consequently low FDG uptake [3, 4]. These tumors, however, when undergoing dedifferentiation become more aggressive and may show increased FDG uptake, and this is also the case in MTC as demonstrated by the immunoreactivity for KI-67 expression (KI-67 is a nuclear protein that is associated with cellular proliferation) in surgically removed lesions [3, 4].

Dihydroxyphenylalanine (DOPA) is an amino acid that is converted to dopamine by aromatic amino acid decarboxylase (AADC). Fluorine-18-DOPA (FDOPA) is taken up through ubiquitous transmembrane amino acid transporter systems that are significantly upregulated in neuroendocrine tumors, including MTC. This upregulation is presumably secondary to the increased activity of metabolic pathways involving the enzyme AADC which is a specific property of neuroendocrine tumors.

The aim of this paper is to perform an overview of the literature about the role of PET and PET/CT using different radiopharmaceuticals in patients with recurrent MTC based on biochemical findings (increased tumor marker levels after primary surgery).

2. Search Strategy and Data Abstraction

A comprehensive computer literature search of the PubMed/MEDLINE, Scopus and Embase databases was carried out to find relevant published articles on the role of PET or PET/CT using different radiopharmaceuticals in patients with recurrent MTC. We used a search algorithm based on a combination of the terms: (a) “PET” or “positron emission tomography” and (b) “medullary” or “thyroid”. No beginning date limit was used; the search was updated until February 29th 2012. To expand our search, references of the retrieved articles were also screened for additional studies. No language restriction was used.

Only those studies or subsets in studies that satisfied all of the following criteria were included: (a) PET or PET/CT performed in patients with suspected recurrent MTC after primary surgery; (b) sample size of at least 6 patients with MTC. The exclusion criteria were (a) articles not within the field of interest of this paper; (b) review articles, editorials or letters, comments, conference proceedings; (c) case reports or small case series (sample size of less than 6 patients with recurrent/residual MTC); (d) possible data overlap (in such cases the most complete article was included).

For each included study, information was collected concerning basic study (author names, journal, year of publication, and country of origin), patient characteristics (number of patients with suspected recurrent MTC performing PET or PET/CT, mean age, and sex), technical aspects (study design, device used, radiopharmaceutical used, injected dose, time interval between radiopharmaceutical injection and image acquisition, acquisition protocol, image analysis, and reference standard used), and diagnostic performance data (sensitivity and specificity). Patients evaluated with PET or PET/CT before primary surgery were excluded from the analysis. Only patients with a postoperative PET imaging were included.

3. Literature Data

Twenty-nine articles comprising 714 patients with suspected recurrent MTC were retrieved using the above cited criteria [533]. The characteristics of the included studies are presented in Table 1.


AuthorsYearCountryMTC patients performing PET for suspected recurrenceMean age (years)% MaleTracers used for PET or PET/CT

Treglia et al. [5]2012Italy185333%FDG, FDOPA, and Gallium-68-DOTANOC/DOTATOC
Kauhanen et al. [6]2011Finland195253%FDG and FDOPA
Ozkan et al. [7]2011Turkey335027%FDG
Gómez-Camarero et al. [8]2011Spain315645%FDG
Palyga et al. [9] 2010Poland85650%Gallium-68-DOTATATE
Jang et al. [10]2010Korea165156%FDG and Carbon-11-methionine
Luster et al. [11]2010Germany284846%FDOPA
Skoura et al. [12]2010Greece32 (38 scans)5231%FDG
Marzola et al. [13]2010Italy185144%FDG and FDOPA
Bogsrud et al. [14]2010USA and Norway295055%FDG
Conry et al. [15]2010UK and Singapore185472%FDG and Gallium-68-DOTATATE
Beheshti et al. [16]2009Austria19*5938%FDG and FDOPA
Faggiano et al. [17]2009Italy26NR49%FDG
Koopmans et al. [18]2008The Netherlands215648%FDG and FDOPA
Rubello et al. [19]2008Italy195342%FDG
Oudoux et al. [20]2007France335364%FDG
Giraudet et al. [21]2007France555662%FDG
Czepczyński et al. [22]2007Poland and Italy13*5057%FDG
Beuthien-Baumann et al. [23]2007Germany155653%FDG and FDOPA
Ong et al. [24]2007USA28 (38 scans)5964%FDG
Iagaru et al. [25]2007USA134846%FDG
Gotthardt et al. [26]2006Germany and the Netherlands264558%FDG
De Groot et al. [27]2004The Netherlands265158%FDG
Szakáll et al. [28]2002Hungary404845%FDG
Diehl et al. [29]2001Germany85 (100 scans)5347%FDG
Hoegerle et al. [30]2001Austria10*5755%FDG and FDOPA
Brandt-Mainz et al. [31]2000Germany17NR65%FDG
Adams et al. [32]1998Germany84950%FDG
Musholt et al. [33]1997USA and Germany103670%FDG

NR: not reported; FDG: fluorine-18-fluorodeoxyglucose; FDOPA: fluorine-18-dihydroxyphenylalanine; *patients evaluated before primary surgery were excluded from the analysis.

(A) PET and PET/CT Using Fluorine-18-Fluorodeoxyglucose
Twenty-seven articles evaluating the role of FDG-PET or PET/CT in patients with recurrent MTC were selected and retrieved from the literature (Tables 1 and 2) [58, 10, 1233]. Other six articles were not included for possible data overlap [3439]. Overall, the studies using FDG-PET or PET/CT have reported conflicting results about the diagnostic performance of these functional imaging methods in patients with suspected recurrent MTC. In particular, sensitivity of these methods ranged from 17% to 95% whereas specificity, when reported, ranged from 68% to 100% (Table 2). A possible explanation for these heterogeneous findings could be related to diversity between the studies in technical aspects (Table 2) and inclusion criteria (patients with known lesions versus patients with occult disease at conventional imaging methods; patients with slowly progressive disease versus patients with more aggressive disease) [40].


AuthorsStudy designDeviceInjected activityTime between tracer injection and image acquisition (min)PET acquisition protocolImage analysisReference standardSensitivity of FDG-PET or PET/CT*Specificity of FDG-PET or PET/CT*

Treglia et al. [5]Retrospective multicenterPET/CT259–407 MBq60Static acquisitionQualitativeHistology and/or clinical/imaging followup17%NC
Kauhanen et al. [6]Prospective multicenterPET/CT377 MBq60Static acquisition (3 min per bed position)Qualitative and semiquantitativeHistology and/or clinical/imaging followup53%NC
Ozkan et al. [7]Retrospective single centerPET/CT296–370 MBq60Static acquisition (4 min per bed position)Qualitative and semiquantitativeHistology and/or clinical/imaging followup93%68%
Gómez-Camarero et al. [8]Retrospective single centerPET and PET/CT333–434 MBq60Static acquisitionQualitative and semiquantitativeHistology and/or clinical/imaging followup88%85%
Jang et al. [10]Prospective single centerPET/CT370 MBq60Static acquisition (4 min per bed position)QualitativeHistology and/or clinical/imaging followup63%NC
Skoura et al. [12]Retrospective single centerPET/CT370 MBq60Static acquisition (4 min per bed position)Qualitative and semiquantitativeHistology and/or clinical/imaging followup47%NC
Marzola et al. [13]NR; multicenterPET/CT2.2 MBq/kg60Static acquisition (3 min per bed position)Qualitative and semiquantitativeHistology61%NC
Bogsrud et al. [14]Retrospective single centerPET and PET/CT740 MBq60–75Static acquisition (5 min per bed position)QualitativeHistology and/or clinical/imaging followup45%93%
Conry et al. [15]Retrospective multicenterPET/CT195–550 MBq50–75Static acquisition (1.5/5 min per bed position)Qualitative and semiquantitativeHistology and/or clinical/imaging followup78%NC
Beheshti et al. [16]Prospective single centerPET/CT370 MBq60Static acquisition (4 min per bed position)Qualitative and semiquantitativeHistology and/or clinical/imaging followup58%NC
Faggiano et al. [17]Retrospective multicenterPET222–370 MBq60–90Static acquisition (4 min per bed position)QualitativeHistology and/or clinical/imaging followup50%NC
Koopmans et al. [18]Prospective single centerPETNRNRStatic acquisition(5 min per bed position)QualitativeHistology and/or clinical/imaging followup24%NC
Rubello et al. [19]Prospective multicenterPET/CT5.5 MBq/kg60–90Static acquisition (4 min per bed position)Qualitative and semiquantitativeHistology79%100%
Oudoux et al. [20]Prospective multicenterPET/CT310–450 MBq60Static acquisitionQualitative and semiquantitativeHistology and/or clinical/imaging followup76%NC
Giraudet et al. [21]Prospective single centerPET/CT5 MBq/Kg60Static acquisitionQualitative and semiquantitativeHistology and/or clinical/imaging followup32%NC
Czepczyński et al. [22]NR; single centerPETNRNRStatic acquisitionQualitativeHistology and/or clinical/imaging followup58%NC
Beuthien-Baumann et al. [23]Retrospective single centerPET370 MBq60Static acquisitionQualitativeHistology and/or clinical/imaging followup47%NC
Ong et al. [24]Retrospective single centerPET and PET/CT555 MBqMinimum 45Static acquisition (4 min per bed position)Qualitative and semiquantitativeHistology and/or clinical/imaging followup62%NC
Iagaru et al. [25]Retrospective single centerPET and PET/CT550 MBq45/60Static acquisition (4/5 min per bed position)QualitativeHistology and/or clinical/imaging followup86%83%
Gotthardt et al. [26]NR; multicenterPET350 MBq60Static acquisitionQualitativeHistology and/or clinical/imaging followup70%NC
De Groot et al. [27]Prospective single centerPET400 MBq90Static acquisition (5 min per bed position)QualitativeHistology and/or clinical/imaging followup41%NC
Szakáll et al. [28]Retrospective single centerPET5.55 MBq/Kg40Static acquisition (10 min per bed position)QualitativeHistology and/or clinical/imaging followup95%NC
Diehl et al. [29]Retrospective multicenterPET300–500 MBqMinimum 30Static acquisitionQualitativeHistology and/or clinical/imaging followup78%79%
Hoegerle et al. [30]Prospective single centerPET330 MBq90Static acquisitionQualitativeHistology and/or clinical/imaging followup60%100%
Brandt-Mainz et al. [31]Prospective single centerPET350 MBq30Static acquisition (15–20 min per bed position)QualitativeHistology and/or clinical/imaging followup76%NC
Adams et al. [32]Prospective single centerPET374 MBq60Static acquisition (12–15 min per bed position)QualitativeHistology and/or clinical/imaging followup87%NC
Musholt et al. [33]NR; single centerPET370–555 MBq40Static acquisition (10 min per bed position)QualitativeHistology and/or clinical/imaging followup90%NC

NR: not reported; NC: not calculated; *sensitivity and specificity are reported on a per patient-based analysis.

False negative results of FDG-PET and PET/CT could be related to small lesions or to the slow growth of neuroendocrine tumors. Both factors impact the diagnostic accuracy of these imaging modalities. False positive results also occurred by using FDG-PET and PET/CT, and were typically due to inflammatory lesions [3, 4, 40].

It should be noted that a significant number of recurrent MTC, based on rising levels of tumor markers, remained unidentified using FDG-PET or PET/CT. On the other hand, it should be considered that FDG-PET and PET/CT were often performed in patients with suspected recurrent MTC after negative conventional imaging studies, affecting the surgical management of patients with recurrent MTC when hypermetabolic lesions were detected [24, 40].

Based on literature findings, the diagnostic performance of FDG-PET or PET/CT in patients with recurrent MTC improved in patients with higher serum calcitonin and CEA levels [40]. Also, sensitivity of FDG-PET and PET/CT improved in patients with shorter tumor markers (calcitonin and CEA) doubling times [6, 10, 14, 16, 18], confirming the usefulness of these imaging methods in patients with more aggressive disease (with high glucose consumption and high FDG uptake) compared to those with slowly progressive disease (with low glucose consumption and low FDG uptake) [40].

FDG-PET or PET/CT were usually performed in the included studies if no disease sites were identified on conventional imaging in patients with biochemical evidence of MTC recurrence or if calcitonin levels were elevated out of proportion to minor disease found on conventional imaging. The diagnostic performance of FDG-PET and PET/CT in recurrent MTC increased whether patients with known lesions at conventional imaging were included in the study population, because functional abnormalities are usually detectable by FDG-PET or PET/CT when anatomical changes are already evident.

(B) PET and PET/CT Using Fluorine-18-Dihydroxyphenylalanine
Eight articles evaluating the role of FDOPA-PET or PET/CT in patients with recurrent MTC were selected and retrieved from the literature (Tables 1 and 3) [5, 6, 11, 13, 16, 18, 23, 30]. Another article was not included for possible data overlap [41]. Overall, the studies using FDOPA-PET or PET/CT have reported promising results in recurrent MTC. In particular sensitivity of these methods ranged from 47% to 83% (Table 3); however, FDOPA-PET or PET/CT modified the surgical management of a significant number of patients with recurrent MTC when positive, because these functional imaging methods were often performed in patients with suspected recurrent MTC based on rising tumor markers after negative conventional imaging studies.


AuthorsStudy designDeviceInjected activityTime between tracer injection and image acquisition (min)PET acquisition protocolImage analysisReference standardSensitivity of FDOPA-PET or PET/CT*Specificity of FDOPA-PET or PET/CT*

Treglia et al. [5]Retrospective multicenterPET/CT4 MBq/kg60Static acquisition (3 min per bed position)no carbidopa premedicationQualitativeHistology and/or clinical/imaging followup72%NC
Kauhanen et al. [6]Prospective multicenterPET/CT243 MBq60Static acquisition (3 min per bed position)carbidopa premedicationQualitative and semiquantitativeHistology and/or clinical/imaging followup58%NC
Luster et al. [11]Retrospective single centerPET/CT298 MBq60Static acquisition (4 min per bed position)carbidopa premedicationQualitative and semiquantitativeHistology and/or clinical/imaging followup74%100%
Marzola et al. [13]MulticenterPET/CT2.2 MBq/kg60Static acquisition (3 min per bed position)no carbidopa premedicationQualitative and semiquantitativeHistology83%NC
Beheshti et al. [16]Prospective single centerPET/CT 4 MBq/Kg30Static acquisition (4 min per bed position)no carbidopa premedicationQualitative and semiquantitativeHistology and/or clinical/imaging followup81%NC
Koopmans et al. [18]Prospective single centerPET180 MBq60Static acquisition; (5 min per bed position)carbidopa premedicationQualitativeHistology and/or clinical/imaging followup62%NC
Beuthien-Baumann et al. [23]Retrospective single centerPET4.8 MBq/Kg45Static acquisition carbidopa premedicationQualitativeHistology and/or clinical/imaging followup47%NC
Hoegerle et al. [30]Prospective single centerPET220 MBq90Static acquisition no carbidopa premedicationQualitativeHistology and/or clinical/imaging followup60%NC

NC: not calculated; *sensitivity and specificity are reported on a per patient-based analysis.

Differences in technical aspects (Table 3) and inclusion criteria could explain the heterogeneity between studies about the sensitivity values reported. False positive results of FDOPA-PET or PET/CT in recurrent MTC are uncommon. On the other hand, possible causes of false negative results of FDOPA-PET or PET/CT should be kept in mind; they could be probably related to small MTC lesions or to dedifferentiation, both factors affecting the diagnostic accuracy of these imaging methods.

Based on literature findings, the diagnostic performance of FDOPA-PET or PET/CT in recurrent MTC improved in patients with higher serum calcitonin levels [5, 6, 11, 13, 16, 18, 23, 30].

Comparative analyses between FDOPA and FDG have shown better results with FDOPA in terms of sensitivity and specificity and a complementary role of the two radiopharmaceuticals in the assessment of recurrent MTC. The different behavior of FDOPA and FDG in recurrent MTC can be explained by their different uptake mechanisms that, in turn, reflect the different metabolic pathways of neuroendocrine cells, including MTC cells. FDOPA is a marker of amino acid decarboxylation that is a feature of the neuroendocrine origin of MTC; so, it can be assumed that a higher FDOPA uptake is related to a higher degree of cell differentiation, whereas a higher FDG uptake is related to a high proliferative activity and a poor differentiation.

In the study of Hoegerle et al. [30], 10 MTC patients underwent both FDOPA-PET and FDG-PET after thyroidectomy. The sensitivity of both methods on a per-patient-based analysis was the same (60%), with discordant results in two patients (discordance rate was 20%: one case was positive at FDOPA-PET and negative at FDG-PET, another case was positive at FDG-PET and negative at FDOPA-PET). Nevertheless, FDOPA-PET revealed more lymph nodal metastases on a per lesion-based analysis compared to FDG-PET [30].

In the study of Beuthien-Baumann et al. [23], 15 MTC patients underwent both FDOPA-PET and FDG-PET after thyroidectomy. The sensitivity of both methods on a per-patient-based analysis was the same (47%), with discordant results in most of the patients on a per lesion-based analysis [23].

Koopmans et al. [18] performed both PET methods in 17 patients with recurrent MTC, reporting a higher sensitivity of FDOPA-PET compared to FDG-PET on a per-patient-based analysis (62% versus 24%, resp.); furthermore, these authors found discordant results in 7/17 (41%) patients. In particular in 6 patients FDOPA-PET was positive and FDG-PET was negative for MTC recurrence [18].

In 2009 Beheshti et al. [16] found a superiority of FDOPA-PET/CT compared to FDG-PET/CT in 19 MTC patients evaluated after primary surgery (sensitivity on a per-patient-based analysis was 81% versus 58%, resp.). Discordant results between the two methods were found in most of the patients; in particular, FDOPA-PET/CT detected more lesions compared to FDG-PET/CT [16].

Marzola et al. [13] evaluated 18  patients who underwent both PET/CT methods for suspected MTC recurrence. These authors found a higher sensitivity of FDOPA-PET/CT compared to FDG PET/CT on a per-patient-based analysis (83% versus 61%, resp.). Discordant results were found in 6 cases (33%): in particular 5 patients were positive at FDOPA-PET/CT alone and one patient was positive at FDG-PET/CT alone [13].

Recently, Kauhanen et al. [6] evaluated 19  recurrent MTC patients with both methods, reporting a superiority of FDOPA-PET/CT compared to FDG-PET/CT (sensitivity on a per-patient-based analysis was 58% versus 53%, resp.). For most MTC patients with occult disease, FDOPA-PET/CT accurately detected metastases. In patients with an unstable calcitonin level, FDOPA-PET/CT and FDG-PET/CT were complementary. For patients with an unstable CEA doubling time, FDG-PET/CT was more feasible [6].

Lastly, in a recent multicentric study [5], 18 recurrent MTC performed both PET/CT methods. The sensitivity of FDOPA-PET/CT was superior compared to FDG-PET/CT on a per-patient-based analysis (72% versus 17%, resp.). Discordant results between FDOPA-PET/CT and FDG-PET/CT were found in 10/18 patients (56%), in whom FDOPA-PET/CT was positive and FDG-PET/CT was negative for MTC recurrence [5].

(C) PET and PET/CT Using Other Radiopharmaceuticals
Neuroendocrine tumors usually overexpress somatostatin receptors on their cell surface and this represents the rationale for using somatostatin analogues for diagnosis and therapy of these tumors. In fact, PET or PET/CT using somatostatin analogues labelled with Gallium-68 are valuable diagnostic tools for patients with neuroendocrine tumors [42]. Nevertheless, the experience with somatostatin analogues PET tracers in recurrent MTC is very limited [5, 9, 15]. A recent study comparing FDOPA, FDG, and somatostatin analogues labelled with Gallium-68 in recurrent MTC showed a significantly lower sensitivity of somatostatin receptor PET/CT (33%) compared to FDOPA-PET/CT (72%) [5]. Another study reported a complementary role of somatostatin receptor PET/CT compared to FDG-PET/CT in recurrent MTC [15].

However, somatostatin receptor PET could be a useful method in selecting patients for radioreceptor therapy to treat metastatic lesions showing a high expression of somatostatin receptors.

Lastly, Carbon-11-Methionine, a PET radiopharmaceutical used to evaluate the amino acid metabolism, was also used in detecting recurrent MTC, without significant advantages compared to FDG [10].

4. Conclusion and Future Perspectives

PET radiopharmaceuticals reflect different metabolic pathways and seem to show complementary role in detecting recurrent MTC.

There is an increasing evidence in the literature about the role of FDG-PET and PET/CT in recurrent MTC. FDG-PET and PET/CT should not be considered as first-line diagnostic imaging methods in patients with suspected recurrent MTC, but could be very helpful in detecting recurrence in those patients in whom a more aggressive disease is suspected.

To date, FDOPA seems to be the most useful PET radiopharmaceutical in detecting recurrent MTC based on rising levels of tumor markers. Nevertheless, the literature focusing on the use of FDOPA-PET or PET/CT in the detection of recurrent MTC remains still limited.

Other PET radiopharmaceuticals, such as somatostatin analogues labelled with Gallium-68, were also evaluated for this indication in a limited number of studies.

Multicenter and prospective studies investigating a larger patient population and comparing different PET radiopharmaceuticals in recurrent MTC are needed.

Conflict of Interests

The authors declare that they have no conflict of intrests.

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Copyright © 2012 Giorgio Treglia et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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