To assess the accuracy, the duration and factors that influence the duration of MRI-guided liver or soft-tissue biopsies.
Purpose: To reduce risk of development of a hepatic abscess in patients with preexisting bilioenteric anastomosis (BEA) undergoing radiofrequency (RF) ablation of hepatic tumors by use of prolonged antibiotic prophylaxis over at least 10 days.Materials and Methods: Between April 2003 and June 2011, 184 patients underwent 206 percutaneous RE ablation procedures for hepatic malignancies. Eight patients presented with BEA and were treated in 10 sessions at 14 tumor locations. These 8 patients were male and ranged in age from 55-73 years. Median follow-up was 34 months. Antibiotic prophylaxis was given before the intervention (n = 9, piperacillin/tazobactam; n = 1, ciprofloxacin). Oral antibiotic prophylaxis after the intervention was continued with ciprofloxacin for at least 10 days. In four cases, prophylaxis after the intervention was extended with additional antibiotics.Results: A liver abscess occurred 22 days after 1 of 10 RE ablation sessions in patients with preexisting BEA. The patient who developed an abscess presented with a large hepatocellular carcinoma (59 mm X 54 mm) and underwent transarterial chemoembolization 8 days before RF ablation. No hepatic abscess occurred after 196 RF ablation sessions in 176 patients without BEA.Conclusions: Preexisting BEA is a risk factor for formation of hepatic abscesses after RE ablation. An antibiotic prophylaxis regimen before the intervention and for a prolonged period after the intervention that covers anaerobic bacteria for at least 10 days is presented. Combined therapy of transarterial chemoembolization and RE ablation increases the risk for complications in patients with known BEA.
JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 9, Issue 10 p. 806-809 ÜbersichtsarbeitFree Access Ulzeroglanduläre Tularämie Christiane Potz-Biedermann, Christiane Potz-Biedermann Universitäts-Hautklinik, Universitätsklinikum TübingenSearch for more papers by this authorLena Schwendemann, Lena Schwendemann Neurologische Universitätsklinik, Universitätsklinikum TübingenSearch for more papers by this authorKlaus Schröppel, Klaus Schröppel Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum TübingenSearch for more papers by this authorKarsten Sönnichsen, Karsten Sönnichsen Universitäts-Hautklinik, Universitätsklinikum TübingenSearch for more papers by this authorDiethard Schmidt, Diethard Schmidt Radiologische Klinik, Universitätsklinikum TübingenSearch for more papers by this authorMartin Schaller, Martin Schaller Universitäts-Hautklinik, Universitätsklinikum TübingenSearch for more papers by this author Christiane Potz-Biedermann, Christiane Potz-Biedermann Universitäts-Hautklinik, Universitätsklinikum TübingenSearch for more papers by this authorLena Schwendemann, Lena Schwendemann Neurologische Universitätsklinik, Universitätsklinikum TübingenSearch for more papers by this authorKlaus Schröppel, Klaus Schröppel Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum TübingenSearch for more papers by this authorKarsten Sönnichsen, Karsten Sönnichsen Universitäts-Hautklinik, Universitätsklinikum TübingenSearch for more papers by this authorDiethard Schmidt, Diethard Schmidt Radiologische Klinik, Universitätsklinikum TübingenSearch for more papers by this authorMartin Schaller, Martin Schaller Universitäts-Hautklinik, Universitätsklinikum TübingenSearch for more papers by this author First published: 28 September 2011 https://doi.org/10.1111/j.1610-0387.2011.07670_suppl.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume9, Issue10October 2011Pages 806-809 RelatedInformation
JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 9, Issue 10 p. 842-843 Clinical Letter Fehldiagnose von Lebermetastasen eines Melanoms durch MRT bei Leberhämagiomen und Hämochromatose Andrea Forschner, Andrea Forschner Universitätshautklinik TübingenSearch for more papers by this authorDiethard Schmidt, Diethard Schmidt Radiologische Klinik des Universitätsklinikums TübingenSearch for more papers by this authorClaus Garbe, Claus Garbe Universitätshautklinik TübingenSearch for more papers by this author Andrea Forschner, Andrea Forschner Universitätshautklinik TübingenSearch for more papers by this authorDiethard Schmidt, Diethard Schmidt Radiologische Klinik des Universitätsklinikums TübingenSearch for more papers by this authorClaus Garbe, Claus Garbe Universitätshautklinik TübingenSearch for more papers by this author First published: 28 September 2011 https://doi.org/10.1111/j.1610-0387.2011.07759_suppl.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume9, Issue10October 2011Pages 842-843 RelatedInformation
JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 9, Issue 10 p. 842-843 Clinical Letter Hepatic hemangioma and hemochromatosis misdiagnosed by MRI as metastatic melanoma Andrea Forschner, Andrea Forschner Department of Dermatology, Tuebingen University Hospital, GermanySearch for more papers by this authorDiethard Schmidt, Diethard Schmidt Department of Radiology, Tuebingen University Hospital, GermanySearch for more papers by this authorClaus Garbe, Claus Garbe Department of Dermatology, Tuebingen University Hospital, GermanySearch for more papers by this author Andrea Forschner, Andrea Forschner Department of Dermatology, Tuebingen University Hospital, GermanySearch for more papers by this authorDiethard Schmidt, Diethard Schmidt Department of Radiology, Tuebingen University Hospital, GermanySearch for more papers by this authorClaus Garbe, Claus Garbe Department of Dermatology, Tuebingen University Hospital, GermanySearch for more papers by this author First published: 25 July 2011 https://doi.org/10.1111/j.1610-0387.2011.07759.x Prof. Dr. med. Claus GarbeUniversitäts-Hautklinik TübingenLiebermeisterstr. 25D-72076 TübingenE-mail: claus.garbe@med.uni-tuebingen.de AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume9, Issue10October 2011Pages 842-843 RelatedInformation
To evaluate the ablation zones created with a gas-cooled bipolar radiofrequency applicator performed on ex vivo bovine liver tissue.
An increasing number of patients with the zoonosis tularemia have been reported in the last few years in Europe. Tularemia can be divided into different forms depending on its appearance. Tularemia must be considered in the differential diagnosis of diseases that present with an ulcer and regional lymphadenopathy. The diagnosis can be confirmed by culturing Francisella tularensis. With effective antibiotic intervention, the prognosis is favorable. Typically tularemia develops after outdoor activities; it is generally transferred by blood-sucking arthropods from infected wild animals to humans.
Due to their adjuvant effect and their ability to chaperone tumor-associated peptides, heat shock proteins constitute a potent alarm signal for the immune system and can lead to activation of anti-tumor T-cell immunity. Radiofrequency ablation has been reported to induce heat shock protein expression especially that of heat shock protein 70 in sublethally damaged tumor cells. In this study, we evaluated the release of heat shock protein 70 into the serum of cancer-bearing patients directly after radiofrequency ablation. Sera of 22 patients undergoing radiofrequency ablation for the treatment of primary and secondary malignancies of the liver, kidney, and lung, as well as control sera of 20 patients undergoing diagnostic liver biopsy were analyzed using a manufactured heat shock protein 70 ELISA. A significant increase in serum levels of heat shock protein 70 was detectable in the patient cohort 1 day after radiofrequency ablation. More than a twofold increase was observed in nine out of 22 patients, which tended to correlate with favorable clinical outcome. No patient of the control group revealed a comparable increase. Radiofrequency ablation can lead to a release of heat shock protein 70 into the serum, which is transiently detectable 1 day after treatment. Elevated heat shock protein 70 serum levels may constitute a biomarker for favorable clinical outcome.
PURPOSE:To evaluate long-term effectiveness of magnetic resonance (MR)-guided radiofrequency (RF) ablation of hepatocellular carcinoma (HCC).MATERIALS AND METHODS:This prospective study was approved by the institutional review board. In 20 patients, 28 HCCs (mean diameter, 28.0 mm; range, 6-58 mm) were treated with 25 sessions of MR-guided RF ablation. Previous chemoembolization had been performed in nine HCCs with diameters greater than 3 cm. The entire RF ablation procedures were carried out on a 0.2-T open MR system. Placement of MR-compatible internally cooled electrodes was performed under MR fluoroscopic imaging with fast gradient-echo sequences. Therapeutic assessment was based on dynamic MR-imaging (1.5 T) at a mean follow-up of 24.2 months (range, 6-52 mo).RESULTS:MR-guided RF ablation was technically successful in all 25 sessions (100%), as assessed at the end of each session. T2-weighted sequences were accurate to monitor the ablation zone and supported guidance of overlapping ablations if necessary. Technique effectiveness, defined as complete ablation confirmed at MR imaging 4 months after RF ablation, was achieved in 27 of 28 HCCs (96.4%). To achieve complete ablation, 25 of 27 tumors (92.6%) were treated in a single session and two tumors were treated twice. In one tumor initially defined as having been treated with technically effective RF ablation, local tumor progression was detected more than 4 months after ablation. Consequently, the available follow-up indicated complete ablation in 26 of 28 HCCs (92.9%). There was one major complication (4.0%) and one minor complication (4.0%).CONCLUSIONS:On a long-term basis, MR-guided RF ablation is an effective therapy option in the treatment of HCC.
Systemic high-dose interleukin-2 (IL-2) treatment achieves long-term survival in a subset of advanced patients with melanoma. As we reported previously, intratumoral IL-2 induced complete local responses in more than 60% of melanoma patients. This study aimed to analyze the long-term outcome of 72 patients treated in two prior trials. Melanoma patients (49 stage III, 23 stage IV) with injectable metastases received intratumoral IL-2 injections thrice weekly at individually escalated doses (median duration, 6.5 weeks; median total IL-2 dose, 72 MIU; median number of injected metastases, 10). The observed 2-year overall survival rates were 95.5% for stage III patients with cutaneous metastases only (stage IIIB), 72% for those with combined cutaneous and lymph node involvement (stage IIIC), 66.7% for stage IV patients with disease limited to distant soft-tissue metastases (stage IV M1a), and 9.1% for those with visceral metastases (stage IV M1b and stage IV M1c). Thirty patients who reported recurrence of unresectable distant metastases subsequently received chemotherapy in the further course of disease and showed an overall response rate of 36.7% (16.7% complete responses, 20% partial responses). A high total dose of IL-2 and a dacarbazine/temozolomide-based chemotherapy regimen were variables correlated with a clinical response. In conclusion, patients with cutaneous metastasis without lymph node involvement in stage III and with soft-tissue metastasis without visceral involvement in stage IV showed unexpected favorable survival rates after intratumoral treatment with IL-2. Furthermore, the intratumoral IL-2 treatment seemed to be associated with increased complete and partial responses in subsequent chemotherapies.
Purpose: To evaluate the relationship between applied energy and volume of coagulation induced by multipolar radiofrequency (RF) ablation.Methods and materials: Multipolar RF ablations (n = 80) were performed in ex vivo bovine liver. Three bipolar applicators with two electrodes located on each applicator shaft were placed in a triangular array. The power-output (75-225 W) and the distance between the different applicators (2, 3, 4, 5 cm) were systematically varied. The volume of confluent white coagulation and the amount of applied energy were assessed. Based on our experimental data the relationship between the volume of coagulation and applied energy was assessed by nonlinear regression analysis. The variability explained by the model was determined by the parameter r(2).Results: The volume of coagulation increases with higher amounts of applied energy. The maximum amount of energy was applied at a power-output of 75 W and an applicator distance of 5 cm. The corresponding maximum volume of coagulation was 324 cm3 and required an application of 453 kJ. The relationship between amount of applied energy (E) and volume (V) of coagulation can be described by the function, V = 4.39E0.7 (r(2) = 0.88). By approximation the volume of coagulation can be calculated by the linear function V = 0.61E + 40.7 (r(2) = 0.87).Conclusion: Ex vivo the relationship between volume of coagulation and amount of applied energy can be described by mathematical modeling. The amount of applied energy correlates to the volume of coagulation and may be a useful parameter to monitor multipolar RF ablation. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
Percutaneous image-guided interventions, such as radiofrequency ablation (RFA), biopsy, seed implantation, and several types of drainage, employ needle shaped instruments which have to be inserted into the patient's body. Precise planning of needle placement is a key to a successful intervention. The planning of the access path has to be carried out with respect to a variety of criteria for all possible trajectories to the selected target. Since the planning is performed in 2D slices, it demands considerable experience and constitutes a significant mental task. To support the process of finding a suitable path for hepatic interventions, we propose a fast automatic method that computes a list of path proposals for a given target point inside the liver with respect to multiple criteria that affect safety and practicability. Prerequisites include segmentation masks of the liver, of all relevant risk structures and, depending on the kind of procedure, of the tumor. The path proposals are computed based on a weighted combination of cylindrical projections. Each projection represents one path criterion and is generated using the graphics hardware of the workstation. The list of path proposals is generated in less than one second. Hence, updates of the proposals upon changes of the target point and other relevant input parameters can be carried out interactively. The results of a preliminary evaluation indicate that the proposed paths are comparable to those chosen by experienced radiologists and therefore are suited to support planning in the clinical environment. Our implementation focuses on RFA and biopsy in the liver but may be adapted to other types of interventions.
Radiofrequency (RF) ablation is a minimally invasive technique routinely applied for the treatment of primary and secondary liver tumors. It induces cell death by thermal coagulative necrosis of tumor tissues, whereas cellular metabolism can still take place in a transition zone surrounding the necrotic area. An increase in heat shock protein expression occurs shortly after treatment, suggesting that the induction of activating signals may stimulate the host immune system. In addition, various effects on immune effectors have also been observed, including stimulation of tumor‐directed T lymphocytes. Here, we prospectively assessed the activation of tumor antigen‐specific antibodies, as well as antigen‐specific CD4+ and CD8+ T cells in patients suffering from primary or secondary malignancies and treated by RF ablation with or without concomitant chemotherapy. An increase of antibodies (in 4 patients of 49), CD4+ T cells or CD8+ T cells (in 2 patients of 49) could be detected several weeks to months following intervention. These findings suggest that in addition to the local control of tumor growth, RF ablation can provide the appropriate conditions for activating tumor‐antigen specific immune responses.
PURPOSE: To determine with comparison of two different monopolar radiofrequency (RF) devices whether a longer duration of energy application has an effect on coagulation necrosis in ex vivo bovine liver tissue.MATERIALS AND METHODS: The volume and short- and long-axis diameters of the coagulation were assessed in ex vivo bovine livers after RF application for 5-60 minutes. A power of 60 W was used for the single perfusion applicator (n = 48), and a power of 200 W was used for the internally cooled cluster applicator (n = 48). Reproducibility and coagulation shape were assessed and compared. For statistical evaluation, the mean values of the dimensions were compared by using analysis of variance with the following factors: applicator, RF duration, and their interaction.RESULTS: RF application up to 60 minutes produced a mean maximum volume of coagulation of 116.8 cm(3) (95% confidence interval [CI]: 98.4 cm(3), 138.8 cm(3)) for the single perfusion device and 89.5 cm(3) (95% CI: 75.4 cm(3), 106.3 cm(3)) for the internally cooled cluster applicator. For both devices, duration of energy application up to 60 minutes showed a significant interaction for the volume and the short- and long-axis diameters of coagulation (P < .0001). The volumes of coagulation necrosis induced with the internally cooled cluster applicator were more reproducible than those induced with the single perfusion applicator (P < .0001). The shape of the lesion was closer to a sphere (mean shape ratio, 0.98) for the internally cooled cluster than for the single perfusion applicator (mean shape ratio, 1.21) (P < .0001).CONCLUSIONS: There is a significant interaction between RF duration and both RF devices influencing the dimensions of coagulation. Longer durations of energy application expand the volume of coagulation with a better reproducibility and more spherical shape of coagulation for the internally cooled cluster device.
Purpose: To evaluate the feasibility of ex vivo ablation implementing a cryo-based internally cooled bipolar radiofrequency (RF) applicator and to determine the influence of power and gas pressure on the size and shape of the resulting ablation zones.Materials and Methods: Two hundred twenty-five ablations were performed using a custom-built internally CO(2)-Cooled bipolar cryo RF applicator in ex vivo bovine livers. The active tip of the applicator was 55 mm long. RF power (32-50 watts) and gas pressure of cooling medium (500-600 psi) were varied independently. Power was applied in continuous mode. Control group experiments were carried out solely using the RF function at 32, 40, and 50 watts. Ablation duration was 15 minutes for all applications. Experiments were repeated 5 times for all parameter combinations. Short and long axes of the induced white ablation zone were macroscopically assessed. The ablation zone was referred to as homogeneous if complete ablation was observed without spots of untreated tissue. The short axis diameters for the simultaneous application of cryo and RF function were analyzed using a multiple linear regression analysis. All impaired Mann-Whitney U test was used to analyze the differences between the short axes with RF alone and RF using cryo cooling.Results: All ablation zones were homogeneous. Using simultaneous RF ablation function and gas cooling with a single applicator, the long axes of the ablation zones ranged between 42 +/- 2 mm (mean +/- SD) and 59 +/- 5 mm, the short axes between 24 +/- 1 and 44 +/- 1 mm, depending on the parameter combination. At it stable gas pressure level, short axes increased with rising power levels and decreased after reaching a maximum. The maxima of the short axis increased with higher gas pressure levels and were shifted to higher power values. Optimal parameter settings were 46 to 50 watts and 600 psi gas pressure, resulting in a short axis of 44 +/- 1 mm. Short axis weakly correlated with gas pressure (r(2) = 0.10) and power (r(2) = 0.34) alone, whereas the correlation was r(2) = 0.76 for the combined factors. Without cooling, short axis diameters were significantly shorter (P < 0.05), ranging between 13 +/- 2 mm at 50 watts and 15 +/- 2 mm at 32 watts.Conclusion: The results of this initial ex vivo study show that the combined cryo RF ablation device allows for large ablation volumes using a single needle, which is superior to RF ablation alone.
Radiofrequency (RF) ablation is an image-guided minimally invasive therapy which destroys a tumor by locally inducing electrical energy into the malignant tissue through a radiofrequency applicator. Treatment success is essentially dependent on the accurate placement of the RF applicator. In the case of CT-guided RF ablation of liver tumors, a central problem during monitoring is the reduced quality and information content in the peri-interventional images compared to the images used for planning. Therefore, the question of how to effectively transfer information from the planning scan into the peri-interventional scan in order to support the interventionalist is of high interest. Key to such an enhancement of peri-interventional scans is an adequate registration of the pre- and peri-interventional image, which also needs to be fast since intervention duration is still a challenge. We present an approach for the fast and automatic registration of a high quality CT volume scan of the liver to a spiral CT scan of lower quality. Our method combines an approximate pre-registration to compensate large displacements and a rigid registration of a liver subvolume for further refinement. The method focuses on the position of the tumor to be ablated and the corresponding access path. Thereby, it achieves both fast and precise results in the region of interest. A preliminary evaluation, on 37 data sets from 20 different patients, shows that the registration is performed within a maximum of 18 seconds, while obtaining high accuracy in the relevant region of the liver comprising tumor and the planned access path.
Abstract 4748 Introduction Radiofrequency (RF) ablation is a safe and effective method to locally treat malignancies of the liver, kidney and more recently lung. For the treatment of small tumors, long term results are comparable with outcome after surgical resection and better than current chemotherapies. RF-ablation has now been reported to induce heat shock protein (HSP) expression on sublethally damaged hepatocytes. HSPs are potent alarm signals for the immune system causing i.e. activation of T cells and dendritic cells. In addition to triggering immune responses directed against HSPs themselves, HSPs can carry antigens derived from those cells of which HSPs originated and thereby elicit specific immune reactions against these cellular epitopes. Patients and Methods We here analyzed serum samples of 22 patients to evaluate the systemic release of HSP70 using a specific HSP70 ELISA. Patients were followed for a median of 30 months until death or three years after the last RF-treatment. As a control group, sera from 20 patients undergoing diagnostic liver biopsy were screened. Results The median increase of HSP70 in serum comparing levels before and one day after the procedures was 1.6-fold in the RF-ablation group, while no soluble HSP-70 could be detected in the control group before and after the biopsy. Nine patients showed a higher than two-fold increase of HSP70 in the serum after ten sessions of RF-ablation compared to levels prior to treatment. No correlation of HSP70 levels with tumor volume, the ablated non-malignant tissue or the total size of the necrosis was observed. In the subgroup of patients with elevated HSP-70 serum levels, 67% (6 out of 9) were alive at the end of follow up with only one suffering from progressive disease. In contrast, 61% (8 out of 13) of the other patients suffered from progressive disease or had deceased at the end of follow-up. Conclusion RF-ablation not only induces cellular HSP expression but also can lead to a systemic release of serum HSP70. Patients with strong increases in HSP-70 serum levels tended to have a better survival than patients without induction of HSP-70 in the serum. Thus, immunomodulation might represent an additional beneficial effect of RF-ablation besides local tumor destruction, since HSPs are strong stimuli for the immune system and can mediate tumor-specific T cell immunity. Disclosures: No relevant conflicts of interest to declare.
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Purpose: To determine, by means of an ex vivo study, the effect of different NaCl concentrations on the extent of coagulation obtained during radiofrequency (RF) ablation performed using a digitally controlled perfusion device.Method: Twenty-eight RF ablations were performed with 40 W for 10 min using continuous NaCl infusion in fresh excised bovine liver. For perfusion, NaCl concentrations ranging from 0 (demineralized water) to 25% were used. Temperature, the amount of energy, and the dimensions of thermal-induced white coagulation were assessed for each ablation. These parameters were compared using the non-parametric Mann-Whitney test. Correlations were calculated according to the Spearman test.Results: RF ablation performed with 0.9% to 25% concentrations of NaCl produced a mean volume of coagulation of 30.7 +/- 3.8 cm(3), with a mean short-axis diameter of 3.6 +/- 0.2 cm. The mean amount of energy was 21,895 +/- 1,674 W and the mean temperature was 85.4 +/- 12.8 degrees C. Volume of coagulation, short-axis diameter, and amount of energy did not differ significantly among NaCl concentrations ( p > 0.5). A correlation was found between the NaCl concentration and the short-axis diameter of coagulation (r = 0.64) and between the NaCl concentration and the mean temperature ( r = 0.67), but not between the NaCl concentration and volume of coagulation.Conclusion: In an ex vivo model, continuous perfusion with high NaCl concentrations does not significantly improve the volume of thermal-induced coagulation. This may be because the use of a low-power generator cannot sufficiently exploit the potential advantage of better tissue conductivity provided by NaCl perfusion.
We present a model for the optimal placement of monoand bipolar probes in radio-frequency (RF) ablation. The model is based on a system of partial differential equations which describe the electric potential of the probe and the steady state of the induced heat distribution. To optimize the probe placement we minimize a temperature based objective function under the constraining system of partial differential equations. Further, the extension of the resulting optimality system for the use of multiple coupled RF probes is discussed. We choose a multi-scale gradient descent approach to solve the optimality system. The paper describes the discretization and implementation of the approach with finite elements on three-dimensional hexahedral grids. Finally, applications of the optimization to artificial test scenarios as well as a comparison to a real RF ablation are presented.
H. O. Peitgen合作论文数Center for Medical Diagnostic Systems and Visualization at the University of Bremen, Bremen, Germany.
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