original articles
Annals of Oncology
Annals of Oncology 23: 1030–1036, 2012 doi:10.1093/annonc/mdr300 Published online 21 June 2011
Vascular and pharmacokinetic effects of EndoTAG-1 in patients with advanced cancer and liver metastasis U. Fasol1*, A. Frost2, M. Bu¨chert1, J. Arends2, U. Fiedler3, D. Scharr2, J. Scheuenpflug4 & K. Mross2 1 Magnetic Resonance Development and Application Center, Department of Radiology, University Medical Center Freiburg, Freiburg; 2Tumor Biology Center, AlbertLudwigs-University, Freiburg; 3ProQinase GmbH, Freiburg; 4AiCuris GmbH Co. KG, Wuppertal, Germany
Received 8 February 2011; revised 28 April 2011; accepted 29 April 2011
Background: EndoTAG-1 (ET), a novel formulation of cationic liposomes carrying embedded paclitaxel (Taxol), shows antitumoral activity, targeting tumor endothelial cells in solid tumors. Patients with advanced metastatic cancer were evaluated investigating effects on pharmacokinetics and tumor vasculature using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and contrast-enhanced ultrasound (CEUS). Patients and methods: The pharmacokinetic (PK) profile of ET (22 mg/m2 i.v.) was evaluated after single and repeated doses. DCE-MRI and CEUS explored hepatic metastases before, during and after the 4-week treatment cycle. Angiogenic biomarkers were assessed. Tumor response was evaluated by modified RECIST. Results: The PK profile demonstrated slight accumulation of paclitaxel after repeated doses. DCE-MRI parameters Ktrans and/or iAUC60 showed a trend to decrease. Changes of blood flow-dependent parameters of DCE-MRI and CEUS were well correlated. Angiogenic biomarkers revealed no clear trend. ET was generally well tolerated; common toxic effects were fatigue and hypersensitivity reactions. Nine (9 of 18) patients had stable disease after the first treatment cycle. Four patients without disease progression continued treatment. Conclusions: This study including multiple pretreated patients with different metastatic cancer revealed individually distinctive hemodynamic alterations by DCE-MRI. The PK profiles of ET were similar as observed previously. Key words: angiogenesis, contrast-enhanced ultrasound (CEUS), DCE-MRI, EndoTAG-1, liver metastasis, pharmacokinetic profile
introduction Tumor vitality depends critically on blood supply. Thus, tumor vasculature presents an ideal target for therapy and numerous antivascular strategies are currently under investigation. Endothelial cells display higher proliferation rates in tumors than in nonmalignant tissue, which makes them more vulnerable to cytotoxic agents [1, 2]. Therefore, selective delivery of cytotoxic drugs to tumor endothelium and thus vascular-targeting chemotherapy is of considerable interest. EndoTAG-1 (ET) is a novel cationic liposomal formulation of paclitaxel being developed for the treatment of solid tumors. ET targets activated tumor endothelial cells that express negatively charged cell-surface molecules. Targeted delivery of cationic liposomes has been demonstrated in various tumor models and therapeutic effects have been shown [3]. Therapy with cationic liposomal paclitaxel resulted in reduced tumor perfusion and growth [4, 5]. Furthermore, ET has shown effects of reduced tumor vessel density and a reduction of endothelial *Correspondence to: Dr U. Fasol, Department of Radiology, Medical Physics, University Medical Center Freiburg, Breisacherstrasse 61a, 79106 Freiburg im Breisgau, Germany. Tel: +49-761-270-74130; Fax: +49-761-270-74130; E-mail:
[email protected]
cell mitosis resulting in antitumor activity [6, 7]. Thus, ET presents a selective vascular-targeting drug delivery system with antivascular and potentially antiangiogenic properties. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a technique that is capable to measure tumor hemodynamics [8, 9]. It is therefore suitable for monitoring vascular-targeted therapies of tumors. DCE-MRI utilizes a lowmolecular-weight paramagnetic contrast medium (CM), which readily diffuses from the blood to the extravascular extracellular space. The time course of changing CM concentration in tissue can be characterized by semiquantitative or pharmacokinetic (PK) parameters. Although DCE-MRI parameters are incompletely validated end points that are sensitive to changes in a number of hemodynamic parameters, including blood flow, blood volume, vessel permeability and vessel surface area [10], emerging data from clinical trials with a number of vascular endothelial growth factor (VEGF) signaling inhibitors have demonstrated reductions that are consistent with reductions in VEGF-dependent tumor perfusion and vascular permeability [11–14]. However, also negative results in case of vandetanib have to be mentioned [15]. The primary end point of this open-label phase I study (study code NCT00542048) was to establish the PK profile after single and repeated doses of ET. Furthermore, the effect on
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
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original articles
Annals of Oncology
tumor vasculature measured by DCE-MRI and contrastenhanced ultrasound (CEUS) scans, soluble markers of angiogenesis as well as tumor response were evaluated.
patients and methods patients Patients aged 31–72 with unresectable hepatic metastases of carcinomatous origin with exception of hepatocellular, biliary or bile duct carcinoma with at least one measurable metastatic lesion ‡20 mm in the liver, Eastern Cooperative Oncology Group performance status of zero to two, life expectancy ‡12 weeks and no significant cardiac, hematopoietic, hepatic and renal dysfunction were included. Key exclusion criteria were palliative chemotherapy within the last 7 days and history of taxane administration within 4 weeks before study.
study design In this open-label study, 20 patients were to receive an i.v. dose of ET with 22 mg/m2 twice weekly as a 4-h infusion for 4 weeks (altogether 176 mg/ m2/patient). Patients could continue treatment beyond the first cycle until progressive disease. The trial was designed to establish the PK profile of ET and to assess the effect on target liver metastases perfusion by DCE-MRI and CEUS. Further objectives included assessment of tumor response of hepatic lesions, evaluation of safety and tolerability and measurement of soluble markers of angiogenesis. The trial was approved by the Bundesinstitut fu¨r Arzneimittel und Medizinprodukte and institutional review board/research ethics committee of the Albert-Ludwigs-Universita¨t Freiburg and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. All patients provided written informed consent.
assessments pharmacokinetics. PK properties of paclitaxel (Taxol) (USP grade was obtained by Cedarburg Pharmaceuticals), 6a-OH-paclitaxel and DOTAP (N-[1-(2,3-dioleoyloxy)]-N,N,N-trimethylammonium propane methylsulfate) were evaluated from plasma samples using reverse-phase liquid chromatography and detection by tandem mass spectrometry. Blood samples were collected pre-dose, during infusion (at 0.25, 0.5, 0.75 and 1 h), at the end of and after infusion after single dose (day 1) and in steady state (day 25; at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24 and 48 h). Trough levels were determined on day 4, 8 and 15. PK parameters were evaluated by noncompartimental analysis using WinNonlin5.2. (Pharsight Corp., St Louis, MI). soluble markers of angiogenesis. Blood samples for assessment of soluble markers of angiogenesis were collected pre-dose, on day 1, 4, 15 and 29. Levels of soluble VEGF, soluble vascular endothelial growth factor receptor2 (sVEGF-R2), angiopoietin-2 (Ang-2), endothelin-1 (ET-1) and interleukin (IL)-6/IL-8 were measured using commercially available immunoassay kits (R&D Systems Inc., Minneapolis, MN). safety and tolerability. Adverse events were reviewed at each scheduled visit and graded according to the National Cancer Institute—Common Terminology Criteria for Adverse Events (CTCAE) version 3. The possible relationship of an adverse event to study treatment was assessed by the investigator. tumor response. Tumor response was evaluated for hepatic lesions based on a modified version of RECIST [16] at baseline, day 4, 15 and 29. dynamic contrast-enhanced magnetic resonance imaging. DCE-MRI was carried out at baseline, day 4, 15 and 29. MRI data were acquired using a 1.5 T system (Magnetom Sonata; Siemens, Germany) following a protocol that included standard T1- and T2-weighted images and DCE-MRI.
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As reference target lesion, one liver metastasis (longest diameter in plane >20 mm) was chosen. DCE-MRI was carried out on one coronal slice of 10 mm passing through the center of the reference target lesion. An inversion recovery TrueFISP sequence [17] was used in a time series for 5 : 30 min, covering the period before, during and after CM injection. The temporal resolution was 3 s. T1 relaxation rates were calculated from a region of interest (ROI) enclosing the reference target lesion and converted into CM concentrations [18]. The CM (Magnevist; Bayer-Schering, Germany) was injected at a flow rate of 3 ml/s (power injector; MEDRAD, Inc., Pittsburgh, PA) applying a dosage of 0.1 mmol/kg body weight. Software, developed under MATLAB (http://www.mathworks.com), was used for data analysis. The initial area under concentration curve for the first 60 s after the bolus reached the tissue (iAUC60) is a modelindependent parameter. It measures the uptake of CM in the ROI and depends on blood supply, permeability and surface area of the vessel wall and leakage space [19, 20]. Applying the tracer kinetic model of Tofts [21], the volume transfer constant between blood plasma and extravascular extracellular space (Ktrans) was evaluated. The physiological interpretation of Ktrans depends on the properties of the tissue microvessels, in particular the magnitude of blood flow compared with capillary permeability [19]. contrast-enhanced ultrasound. CEUS was scheduled as DCE-MRI. Scans (duration 60 s) were carried out after manual injection of 2.3 ml over 5 s of an ultrasound contrast agent containing microbubbles (SonoVue; Bracco Inc., Italy). Video clips of contrast enhancement were recorded using a Logiq 9 ultrasound machine, a 4C transducer (4 MHz) and ‘True Agent’ acquisition software (General Electric Co., UK). Acoustical output was adjusted to avoid destroying the microbubbles. Each scan visualized a tumor reference lesion and tumor-free liver parenchyma simultaneously during periods of minimal breathing excursions. Time-intensity curves (TICs) of ROIs, a circle of 20 mm diameter placed at a well-enhancing region within the reference tumor lesion and in tumor-free liver parenchyma, were plotted and modeled by nonlinear regression using a saturation kinetic model: C t =DCmax 12e2kðt2dÞ +B:
B is the baseline signal and d is the time delay between injection of the contrast agent and first appearance in the ROI. The maximal contrast enhancement DCmax, normalized to the maximal enhancement in tumorfree liver parenchyma, and the rate constant k were documented. With suitable assumptions, it can be shown that the rate constant is proportional to the mean velocity of microbubbles, while DCmax is proportional to the sum of cross-sectional area of microvessels within the beam thickness. Thus, the product DCmaxk is proportional to the local blood flow [22].
statistical analyses All effects were analyzed descriptively.
results patients Twenty patients were enrolled in the ‘Tumor Biology Centre (Albert-Ludwigs-University, Freiburg, Germany)’ and received treatment. Eighteen subjects completed the first treatment phase (4 weeks) and received at least eight doses of ET. Two patients prematurely discontinued. Four patients had stable disease after 4 weeks and continued study treatment. Demographic characteristics (see Table 1) and numerous
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previous anticancer treatments indicate a heterogeneous patient population with last-line therapy.
safety and tolerability ET 22 mg/m2 twice weekly was generally well tolerated. The majority of adverse events were CTCAE grade 1 or 2. Most frequently reported were fatigue, nausea, vomiting and abdominal pain (Table 2). The most common adverse events considered by the investigator to be related to ET were hypersensitivity and fatigue. No death occurred during the study or during the 28-day observation period following the
Table 1. Patient characteristics (Intent to Treat population) Baseline characteristics
EndoTAG-1 (n = 20)
Median age (range), years Male, n (%) Female, n (%) ECOG performance status, n (%) 0 1 2 Tumor types, n (%) Colorectal cancer Mamma cancer Pancreatic cancer Other cancer Previous chemotherapy regimens, n (%) Any 1–3 4–5 ‡5
51.5 (31–72) 8 (40) 12 (60) 4 (20) 14 (70) 2 (10) 10 3 3 4
(50) (15) (15) (20)
20 5 12 3
(100) (25) (60) (15)
ECOG, Eastern Cooperative Oncology Group.
Table 2. Adverse events reported in more than three patients overall Adverse eventa
EndoTAG-1 (n = 20), n (%)
Abdominal pain Diarrhea Dyspepsia Nausea Vomiting Constipation Fatigue Pyrexia Edema peripheral Hypersensitivity Anorexia Bone pain Dizziness Headache Epistaxis Dyspnea Hyperhidrosis
10 4 4 11 10 4 14 4 5 8 7 4 4 6 5 6 8
a
(50) (20) (20) (55) (50) (20) (70) (20) (25) (40) (30) (20) (20) (30) (25) (30) (40)
Medical Dictionary for Regulatory Activities-preferred term.
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last dose. For clinical chemistry, hematology and urinalysis parameter, laboratory evaluations showed no marked changes during treatment compared with baseline. There was no consistent trend in mean blood pressure either.
pharmacokinetics Blood samples for PK analysis were available from 17 patients on day 1 (visit 1) and 15 patients on day 25 (visit 8). Singledose and steady-state PK profiles were generated for paclitaxel, 6a-OH paclitaxel and the cationic liposomal constituent DOTAP. Since no considerable sex differences were observed, the PK profiles of all patients were combined. The key PK parameters for paclitaxel and DOTAP are presented in Tables 3 and 4. Paclitaxel displayed a bi- or triphasic PK profile in plasma. The mean maximum plasma concentration Cmax was comparable at both visits. Cmax was reached at the end of infusion, followed by a rapid decrease (Figure 1A). AUCinf (area under the curve from time zero up to infinity) showed a slight increase of 7% from the first to the last dose. A small decrease for systemic clearance was observed from visit 1 to visit 8 and the volume of distribution slightly decreased at steady state. For DOTAP, Cmax increased by 10%. Time to reach Cmax exceeded the time of infusion due to further increasing DOTAP levels after the end of infusion (Figure 1B). AUCinf values increased by 22% after repeated doses. In comparison with paclitaxel, a distinctively lower volume of distribution and a much lower clearance were observed. For 6aOH-paclitaxel, highly variable profiles were obtained, which showed clearly lower exposure (8 weeks. For this patient, two additional MRI examinations were carried out after day 29. Contrast media was injected into an antecubital vein 36 s after start of measurement. A continuous decrease of contrast agent uptake from screening to the second follow-up after 8 weeks could be observed for this patient. MRI, magnetic resonance imaging.
Figure 1. Arithmetic mean concentration (+SD) versus time for paclitaxel (A) and DOTAP (B). SD, standard deviation; DOTAP, N-[1-(2,3dioleoyloxy)]-N,N,N-trimethylammonium propane methylsulfate.
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patient showed a continuous decrease of CM uptake during the first 8 weeks of therapy. Ktrans and/or iAUC60 decreased at least once during the 4week treatment cycle in 68% of the patients. The relative change of iAUC60 and Ktrans of all patients at day 4, 15 and 29 compared with baseline is displayed in Figure 3. At day 4, 53% (47%) of the patients showed a decrease in iAUC60 (Ktrans) values. After 4 weeks of treatment, decreased iAUC60 and Ktrans were observed for 65% of the patients. Comparing day 29 with day 4, 80% (13 of 16) of the patients revealed a decrease of iAUC60 and 73% (11 of 15) of Ktrans. The median change at day 29 compared with baseline was 24% for Ktrans and 210% for
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iAUC60. Taking all patients into account, no uniform trend could be observed over the 4-week treatment phase.
(Figure 4). Relative change of Ktrans and of DCmaxk showed a correlation of R = 0.70 (data not shown).
contrast-enhanced ultrasound CEUS scans were carried out in 16 patients. Reference lesions used for assessment by CEUS measured 31 6 9 mm (mean 6 standard deviation) at screening and 37 6 11 mm at day 29 (Table 5). Appearance of CM in liver and tumor lesions followed approximately a saturation kinetic and measurements at different locations produced similar results. The mean contrast enhancement (DCmax) in tumor lesions showed a decreasing trend between screening and day 29 (Table 5). The rate constant k did not change significantly.
discussion
approach for a comparison of CEUS and MRI results For 14 patients, reference lesions in the liver have been examined with DCE-MRI and CEUS. The correlation between the CEUS parameters DCmax and k and the DCE-MRI parameters Ktrans and iAUC60 was checked. The highest correlation of R = 0.87 was found between the relative change of the product of DCmaxk and the relative change of iAUC60 at day 29 compared with screening
The antivascular effect of cationic liposomal paclitaxel has been demonstrated in preclinical studies using DCE-MRI, showing significant impairment of tumor vasculature properties [23, 24]. ET has been shown to work via antivascular mechanisms by targeting endothelial cells and antitumor effects have been observed in various tumor models [4–7]. Clinical phase I and II studies provided encouraging evidence of antitumor activity of ET [25] but clinical investigations on its effect on the tumor vascular system are still lacking. In this study, the effect of ET on tumor vasculature was evaluated by measurement of DCE-MRI parameters Ktrans and iAUC60 in patients with advanced cancer and liver metastasis. Valid data could be acquired for 19 patients and in all of them, effects could be revealed. Interestingly, patients with low Ktrans values at baseline tended to high increases during the course of the study. Thus, it might be only supposed that the high increases in Ktrans observed for these patients might be due to increases in permeability whereas decreases in Ktrans in patients with high baseline Ktrans might be based predominantly on decreases in vessel density. Even though no statistically significant relative changes in mean Ktrans and iAUC60 were found and no clear perfusion Table 5. Size of reference tumor lesions, maximal contrast agent uptake (DCmax) and rate constant (k) at different times during the study DCmax/DCmax(liver) k(s21) Diameter of reference lesions (mm) Screening (N = 16) Day 4 (N = 16) Day 15 (N = 16) Day 29 (N = 15)
30.9 30.8 34.2 37.2
6 6 6 6
8.7 9.9 10.8 11.0
0.73 0.72 0.69 0.62
6 6 6 6
0.25 0.19 0.19 0.24
0.25 0.23 0.26 0.28
6 6 6 6
0.11 0.12 0.13 0.13
Data are given as means 6 SD. SD, standard deviation.
rel. change of iAUC60 [%]
160 data
120
linear regression (R=0.87)
80 40 0 -40 -80 -80
-40
0
40
80
120
160
200
relative change of Cmax *k [%]
Figure 3. Relative change of iAUC60 (A) and Ktrans (B) compared with baseline measurement of all 19 patients. The area of negative values is highlighted in gray. The dashed black line shows the median of all values. iAUC60, initial area under concentration curve for the first 60 s after the bolus reached the tissue.
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Figure 4. Relative change of iAUC60 measured by DCE-MRI compared with DCmaxk obtained with CEUS at day 29 to screening. The correlation coefficient is R = 0.87. iAUC60, initial area under concentration curve for the first 60 s after the bolus reached the tissue; DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; CEUS, contrast-enhanced ultrasound.
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Annals of Oncology
characteristics could be elaborated, our observations may suggest that the effect of ET on perfusion parameters potentially follows different timescales in individual patients. In contrast to preclinical findings with untreated tumors at start of treatment [23, 24], it can be assumed that in this study the initial tumor microvessel function before start of treatment differed with respect to tumor histology, pathophysiology and previous treatment, which may have affected ET response. Drug efficacy has been demonstrated with DCE-MRI in several clinical trials with antiangiogenic and antivascular drugs [11, 13, 26, 27]. Most of the studies comprise a great variety of tumor types, stage, dose of experimental drug and previous treatment. Although changes in DCE-MRI parameters can occur as early as 24 h after initiation of the therapy, vascular collapse using anti-VEGF strategies is most reliably detected after 2 weeks [28]. Remarkably, in a combined sorafenib– bevacizumab study, no significant changes were found after 4 weeks of single-agent therapy, while DCE-MRI parameters decreased after the following combination therapy [29]. VEGFR-2 receptor inhibitor SU5416 was reported to decrease tumor perfusion in metastatic melanoma 8 weeks after start of treatment [30]. In our study, reductions in Ktrans and iAUC60 were most pronounced after 4 weeks of treatment with ET. In one patient who continued treatment, a further reduction in uptake of CM was observed. This may indicate a delayed beneficial vascular effect of ET for longer treatment periods, which has to be confirmed in future studies. Tumor assessment using modified RECIST criteria showed stable disease in half of the patients after 4 weeks of treatment with ET. Four patients showed neither evidence of objective progression nor signs of clinical progression. A correlation of DCE parameter changes to clinical outcome could not be demonstrated. Only a few clinical trials with angiogenesis inhibitors have demonstrated a relationship between DCE-MRI biomarker and clinical outcome measure [10]. Conventional tumor size measurement may be inadequate for early detection of the antitumor mechanism of ET [28]. Otherwise, the heterogeneity of the heavily pretreated last-line patient population, included in the current study, may have masked subtle effects on tumor microvasculature and/or tumor size. CEUS data did not detect any significant changes in the inflow rate of the CM into tumor lesions. However, CEUS did show a trend to decrease in CM uptake. This pattern might indicate a decrease of vascular fractional volume in growing tumors, possibly due to inadequate angiogenesis or incipient necrosis. Several differences have to be considered, comparing DCEMRI and CEUS. Since the CM of CEUS is located intravascular, but that one used for DCE-MRI also passes to the extravascular space, it is not possible to compare directly the curves of enhancing signal. By technical reasons, the slice orientations of the scans were not the same for both imaging modalities and the reference lesion examined was not identical for all patients at both modalities. Nevertheless, the response to the therapy should concern all lesions of an individual patient, even though not all of them in exactly the same extent. Evaluated parameters, DCmaxk (CEUS) [22] and Ktrans (DCE-MRI) [19], are expected to be related to the blood flow.
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original articles There are a few publications about comparison of CEUS and DCE-MRI data. For example, Yankeelov et al. [31] compared the two modalities in a tumor animal model and found a correlation of R = 0.75 between DCmaxk and Ktrans. Analysis of the data within the current study reveals a correlation of R = 0.70 (R = 0.87) between the relative change of DCmaxk and that of Ktrans (iAUC60). The higher correlation between iAUC60 and DCmaxk is probably due to the fact, that to obtain iAUC60 is more robust. So, DCE-MRI and CEUS results seem to be well correlated. But looking into detail, not all patients show the same trend in both modalities. This might be caused by the differences between CEUS and DCE-MRI concerning CM, performance and analysis. Whereas for DCEMRI, standards for application in drug studies were published [19], CEUS is a relative new technique [32] and standards have to be developed. A detailed comparison of DCE-MRI and CEUS is out of the scope of this article. The PK profiles of ET were similar to those observed in previous studies. Our findings from PK analysis support the hypothesis of a rapid disaggregation of ET liposomes, allowing fast targeting and rapid release of paclitaxel to tumor tissues. The nominal ratio of paclitaxel and DOTAP in plasma was immediately altered toward approximately 1 : 1000 after the end of infusion (ET infusion solution: 1 : 13.5). This is obviously driven by opposite distribution kinetics since paclitaxel levels dropped rapidly within minutes after the end of infusion, whereas DOTAP levels further increased up to 2 h. The accumulation indices, calculated by Cmax and AUCinf, indicate a minimal accumulation following multiple dosing of ET 22 mg/m2. ET doses of 22 mg/m2 were generally well tolerated with no unknown toxic effects reported. In conclusion, in most of the patients, changes in the perfusion parameters were observed after treatment with ET. A slight trend toward decrease in Ktrans and iAUC60 was observed; iAUC60 showed the trend a bit more distinct, perhaps because it is the more robust parameter. This slight decrease might support the hypothesis of a vascular-targeting mode of action for ET. No correlation between DCE-MRI parameter changes and clinical outcome could be established. Marked variation in tumor type and previous treatment regimens impede data evaluation and may have masked subtle drug effects. Furthermore, the time course of vascular effects may be variable for different tumors and antiangiogenic effect induced by short-term treatment of 4 weeks may be difficult to acquire. Longer treatment with ET and a more homogenous patient population could shed light on the potential correlation between changing DCE-MRI parameters and clinical outcome. As demonstrated by analysis of PK properties of ET with 22 mg/m2 twice weekly doses, a relevant accumulation of paclitaxel and the cationic liposomal constituent DOTAP is not expected to occur in the course of longer treatment periods. Additional studies in a larger trial with a homogenous patient population (e.g. in metastatic breast cancer) should be carried out to confirm our findings.
acknowledgements We thank C. Adam, M. Studen and U. Elsasser for close collaboration in preparing this paper. We thank R. Angerer and M. Reil for their
doi:10.1093/annonc/mdr300 | 1035
original articles excellent work for study documentation and study organisation in the Clinical Trial Unit of the Tumor Biology Center. We also thank the team of technicians at the MR Development and Application Center for the organisation and perfomance of the MR examinations and organizing all the associated documentation. EndoTAG-1 is a trademark of MediGene AG, Germany.
funding MediGene AG, Germany.
disclosure The authors declare no conflict of interest.
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