Paclitaxel-induced arterial wall toxicity and inflammation: tissue uptake in various dose densities in a minipig model.

PURPOSE: Paclitaxel is an antiproliferative agent in drug-eluting stents with largely unknown tissue interaction. Toxicity might result from overdosage and/or accumulation. Part 1 of this two-step study investigated how paclitaxel uptake depends on dose density, coronary drug transfer kinetics, and elution efficacy. MATERIALS AND METHODS: With cobalt chromium stents and Polyzene-F nanoscale coating, low, intermediate, and high paclitaxel dose densities (25 microg, 50 microg, and 150 microg per stent) were investigated in porcine right coronary arteries (RCAs). Coronary and myocardial tissue concentration measurements and determination of on-stent paclitaxel and plasma concentrations were performed at 2, 8, 24, and 72 hours. RESULTS: For all stents, uptake was similar at all time intervals (paclitaxel RCA concentration range, 1,610-33,300 ng). Low- and intermediate-dose stents showed similar RCA concentrations, but those for high-dose stents were three times greater. Residual on-stent paclitaxel concentration was not time-dependent, at 33.3% on low-, 30.6% on intermediate-, and 17.4% on high-dose stents. Paclitaxel was measurable in only the plasma immediately after stent placement, with a linear dose relationship and a timely regression: measurements in high-dose stents were 0.0454-0.656 ng/mL at 1 minute and 0.0329-0.0879 ng/mL at 5 minutes. Untreated control samples of the left coronary artery showed a linear dose-dependent concentration (12.6 ng/g, 21.2 ng/g, and 85.2 ng/g). CONCLUSIONS: Overall coronary paclitaxel uptake is fairly independent from the baseline overall dose density and, hence, depends on immediate binding mechanisms of the arterial wall. This is supported by the fact that, regardless of the applied dose density, the kinetics of paclitaxel uptake did not follow an exposure time pattern.

Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects.

Molecular ultrasound is capable of elucidating the expression of angiogenic markers in vivo. However, the capability of the method for volumetric "multitarget quantification" and for the assessment of antiangiogenic therapy response has rather been investigated. Therefore, we generated cyanoacrylate microbubbles linked to vascular endothelial growth factor receptor 2 (VEGFR2) and alphavbeta3 integrin binding ligands and quantified their accumulation in squamous cell carcinoma xenografts (HaCaT-ras-A-5RT3) in mice with the quantitative volumetric ultrasound scanning technique, sensitive particle acoustic quantification. Specificity of VEGFR2 and alphavbeta3 integrin binding microbubbles was shown, and changes in marker expression during matrix metalloproteinase inhibitor treatment were investigated. In tumors, accumulation of targeted microbubbles was significantly higher compared with nonspecific ones and could be inhibited competitively by addition of the free ligand in excess. Also, multimarker imaging could successfully be done during the same imaging session. Molecular ultrasound further indicated a significant increase of VEGFR2 and alphavbeta3 integrin expression during tumor growth and a considerable decrease in both marker densities after matrix metalloproteinase inhibitor treatment. Histologic data suggested that the increasing VEGFR2 and alphavbeta3 integrin concentrations in tumors during growth are related to an up-regulation of its expression by the endothelial cells, whereas its decrease under therapy is more related to the decreasing relative vessel density. In conclusion, targeted ultrasound appears feasible for the longitudinal molecular profiling of tumor angiogenesis and for the sensitive assessment of therapy effects in vivo.

Pharmacodynamics of streptavidin-coated cyanoacrylate microbubbles designed for molecular ultrasound imaging.

OBJECTIVES: To assess the pharmacodynamic behavior of cyanoacrylate, streptavidin-coated microbubbles (MBs) and to investigate their suitability for molecular ultrasound imaging. MATERIALS AND METHODS: Biodistribution of MBs was analyzed in tumor-bearing mice using gamma-counting, immunohistochemistry, flow cytometry, and ultrasound. Further, vascular endothelial growth factor receptor 2-antibody coupled MBs were used to image tumor neovasculature. RESULTS: After 1 minute >90% of MBs were cleared from the blood and pooled in the lungs, liver, and spleen. Subsequently, within 1 hour a decent reincrease of MB-concentration was observed in the blood. The remaining MBs were removed by liver and spleen macrophages. About 30% of the phagocytosed MBs were intact after 48 hours. Shell fragments were found in the kidneys only. No relevant MB-accumulation was observed in tumors. In contrast, vascular endothelial growth factor receptor 2-specific MBs accumulated significantly within the tumor vasculature (P < 0.05). CONCLUSIONS: The pharmacokinetic behavior of streptavidin-coated cyanoacrylate MBs has been studied. In this context, the low amount of MBs in tumors after >5 minutes is beneficial for specific targeting of angiogenesis.

Assessment of hepatic perfusion in transplanted livers by pharmacokinetic analysis of dynamic magnetic resonance measurements.

OBJECTIVE: The purpose of this study was to validate the assessment of hepatic perfusion by pharmacokinetic analysis of dynamic contrast-enhanced magnetic resonance image series. MATERIALS AND METHODS: Dynamic measurements were performed with a saturation recovery turbo fast low angle shot (ie, FLASH) sequence over the course of approximately 4 minutes in 17 patients with transplanted livers. By pharmacokinetic analysis using an open 2-compartment model, we estimated and correlated an amplitude of signal enhancement, A, and the perfusion rate, kp, with invasive perfusion measurements from implanted thermo-diffusion probes (FTDP). RESULTS: Data analysis for segment IV of the transplanted livers yielded a mean blood flow of 81 +/- 19 mL/min/100g and a mean perfusion rate of 13 +/- 6 minutes. There was a significant correlation between FTDP and kp (rS = 0.64, P = 0.01) but not with A. CONCLUSIONS: Although our open 2-compartment model oversimplifies the complexity of hepatic perfusion, it allows a numerically robust estimation of regional blood flow per unit of blood volume. Thus, dynamic magnetic resonance imaging represents a noninvasive method to assess hepatic perfusion rate which can be visualized in color coded images.

Dynamic contrast-enhanced MRI before and after transcatheter occlusion of patent foramen ovale.

OBJECTIVE: The purpose of this study was threefold: to evaluate the diagnostic accuracy of dynamic contrast-enhanced MRI compared with transesophageal echocardiography (TEE) in the detection of patent foramen ovale (PFO) and of residual shunts after occlusion of PFO, to define cutoff values for semiquantitative analysis of signal intensity-time curves, and to compare the diagnostic accuracy of visual detection with that of semiquantitative analysis. SUBJECTS AND METHODS: Forty-three patients (18 women, 25 men; mean age, 51 +/- 14 years) who underwent TEE for suspicion of PFO (n = 26, 19 patients with and seven without PFO) or for routine assessment for residual shunt after transcatheter PFO occlusion (n = 17, nine patients with and eight without residual shunt) were consecutively enrolled to undergo contrast-enhanced MRI (saturation recovery steady-state free precession sequence). The images were analyzed both visually and semiquantitatively for arrival of contrast agent in the left atrium before arrival in the pulmonary veins during a Valsalva maneuver. TEE results were used as the clinical reference. RESULTS: With an area under the signal intensity-time curve of 0.85, height of the first initial peak in signal intensity in the left atrium proved to be the best discriminator in right-to-left shunt detection. For a cutoff value of 129% (from baseline signal intensity) for this parameter, sensitivity and specificity were 90% (17/19) and 100% (7/7) in patients without PFO devices and 56% (5/9) and 88% (7/8) in patients with PFO devices. The diagnostic accuracy of both visual assessment and semiquantitative analysis was consistently superior before PFO device implantation than after device implantation. The diagnostic accuracy of visual shunt assessment was better than that of semiquantitative shunt assessment in patients with PFO occluders (sensitivity, 67% [6/9] correctly diagnosed; specificity, 88% [7/8]) and those without PFO occluders (sensitivity, 95% [18/19]; specificity, 100% [7/7]). CONCLUSION: At present, MRI cannot replace TEE for the exclusion of potential embolic sources, such as thrombus in the left atrial appendage. However, MRI can be an attractive alternative noninvasive technique if TEE is technically unfeasible or is declined by patients.

CT and endoscopic ultrasound in comparison to endoluminal MRI: preliminary results in staging gastric carcinoma.

PURPOSE: To prospectively compare diagnostic parameters of a newly developed endoluminal MRI (endo-MRI) concept with endoscopic ultrasound (EUS) and hydro-computer tomography (Hydro-CT) in T-staging of gastric carcinoma on one patient collective. MATERIAL AND METHODS: 28 consecutive patients (11 females, 17 males, age range 46-87 years, median 67 years) referred for surgery due to a gastric malignancy were included. Preoperative staging by EUS was performed in 14 cases and by Hydro-CT in 14 cases within a time frame of 2 weeks. Ex vivo endo-MRI examination of gastric specimens was performed directly after gastrectomy within a time interval of 2-3h. EUS data were acquired from the clinical setting whereas Hydro-CT and endo-MRI data were evaluated in blinded fashion by two experienced radiologists and one surgeon well experienced in EUS on gastric carcinomas. RESULTS: Histopathology resulted in 4 pT1, 17 pT2, 3 pT3 and 2 pT4 carcinomas with 2 gastric lymphomas which were excluded. Overall accuracy for endo-MRI was 75% for T-Staging of the 26 carcinomas. EUS achieved 42.9% accuracy; endo-MRI in this subgroup was accurate in 71.4%. Hydro-CT was correct in 28.6%, accuracy for endo-MRI in this subgroup was 71.4%. CONCLUSION: The direct comparison of all three modalities on one patient collective shows that endo-MRI is able to achieve adequate staging results in comparison with clinically accepted methods like EUS and Hydro-CT in classifying the extent of tumor invasion into the gastric wall. However the comparison is limited as we compared in vivo routine clinical data with experimental ex vivo data. Future investigations need to show if the potential of endo-MRI can be transferred into a clinical in vivo setting.

Vessel fractions in tumor xenografts depicted by flow- or contrast-sensitive three-dimensional high-frequency Doppler ultrasound respond differently to antiangiogenic treatment.

High-frequency volumetric Power Doppler ultrasound (HF-VPDU) captures flow-dependent signals in blood vessels and can be used to assess antiangiogenic therapy effects in rodent tumors. However, the sensitivity is limited to vessels larger than capillaries. Contrast-enhanced HF-VPDU reveals all perfused vessels by assessing stimulated acoustic emissions from disintegrating microbubbles. Thus, we investigated whether flow-sensitive and contrast-enhanced HF-VPDU can depict different vessel fractions and assess their early response to antiangiogenic therapy. Mice with A431 tumors were scanned before and after administration of polybutylcyanoacrylate microbubbles by HF-VPDU. Animals received either antiangiogenic treatment (SU11248) or a control substance and were imaged repeatedly over 9 days. At each time point, tumors were removed for immunohistochemical analysis. During growth of untreated tumors, vascularization decreased correspondingly on flow-sensitive and contrast-enhanced scans. Treated tumors showed a significantly (P < 0.05) stronger decline in vascularization than controls, which was more pronounced in contrast-enhanced scans. Surprisingly, whereas vascularization remained low in contrast-enhanced scans, flow-sensitive ultrasound indicated a reincrease after day 6 with a higher vascularization than the controls at day 9. Histologic evaluation indicated that immature vessels degraded markedly on therapy, whereas large mature vessels on the tumor periphery were more therapy resistant and drew closer due to tumor shrinkage. In conclusion, contrast-enhanced HF-VPDU and flow-sensitive HF-VPDU are both capable of assessing the effects of antiangiogenic therapy. Because contrast-sensitive ultrasound is more sensitive for small immature vessels and flow-sensitive ultrasound mostly captures large vessels at the tumor periphery, the combination of both methods can provide evidence of vascular maturity in tumors.

Acute liver failure after a late TIPSS revision.

We report a rare case of late transjugular intrahepatic portosystemic stent shunt (TIPSS) occlusion due to progressive stent protrusion into the periportal liver parenchyma, which was a result of delayed liver shrinkage 2 years after TIPSS. The initial TIPSS procedure had been carried out in a 52-year-old man as a bridge for liver transplantation because of post-alcoholic liver cirrhosis. We describe the applied TIPSS recanalization and revision technique. Immediately after TIPSS revision acute liver failure developed, which required emergency liver transplantation.

Biocompatibility and recanalization characteristics of hydrogel microspheres with polyzene-F as polymer coating.

The objective of this study was to evaluate inflammatory response and recanalization after embolization with a new spherical embolic agent based on a core and shell design with a hydrogel core of polymethylmethacrylate (PMMA) and a Polyzene-F nanoscale coating in a porcine kidney model. Thirty-six minipigs were enrolled for superselective renal embolization. Polyzene-F-coated PMMA particles and uncoated PMMA particles with a diameter of 300-600 mum were used. Either 4 or 12 weeks post-embolization, arteriography of the embolized kidneys was performed and then compared with pre- and immediate post-embolization arteriograms using a specific recanalization score to determine the extent of recanalization. Using a microscopic inflammation score (Banff classification), the embolized organs were examined for local inflammatory effects which occurred in response to the embolic agent. In Polyzene-F-coated particles, the Banff classification showed an average inflammation score of 0.26 +/- 0.58 at 4 weeks and of 0.08 +/- 0.28 at 12 weeks. In uncoated particles, the Banff score measured 0.37 +/- 0.6 at 4 weeks, which was higher, but without a statistically significant difference. According to the recanalization score used in this study, mild angiographic recanalization was evident in all groups, without statistically significant differences (3.0 +/- 0.71 in coated particles, 3.09 +/- 0.81 in uncoated particles; p = 0.74). We conclude that both uncoated hydrogel particles and Polyzene-F-coated embolic agents triggered virtually no inflammatory response and effectively occluded target arteries. This study demonstrates good biocompatibility of the new embolic material. As in other spherical embolic agents, recanalization can occur to some degree.

Preoperative embolization of a tumor-bearing horseshoe kidney via both channels of a concomitant aortic dissection.

Renal cell carcinoma arising in a horseshoe kidney is a rare entity. Preoperative tumor embolization can be performed to prevent massive bleeding complications during organ-preserving surgery. We report the first case of a patient with a tumor-bearing horseshoe-kidney in whom the preoperative embolization, already complex because of the abnormal vascular supply, was additionally complicated by an aortic dissection. An aberrant, horseshoe-kidney-supplying artery originated from the false dissection channel of the aorta, and thus had to be catheterized separately while the other tumor-supplying vessels could be reached via the true aortic lumen. After devascularization of the tumor, organ-preserving surgery was performed without bleeding complications.

Pseudoaneurysms of the common hepatic artery following pancreaticoduodenectomy: successful emergency embolization.

We report a rare case of two communicating pseudoaneurysms of the common hepatic artery 1 month postoperatively following pylorus-preserving pancreaticoduodenectomy due an abscess formation. We describe the superselective transcatheteral embolization technique with deployment of interlocking detachable coils and Histoacryl-Lipiodol in this case and discuss the recent literature. Despite the technical success by achieving hemodynamic stability with initial preservation of liver function, the patient died 23 days postembolization due to multiorgan failure.

Radiofrequency ablation (RFA): development of a flow model for bovine livers for extensive bench testing.

PURPOSE: To develop a flow model for bovine livers for extensive bench testing of technical improvements or procedure-related developments of radiofrequency ablation excluding animal experiments. METHODS: The perfusion of bovine livers directly from the slaughterhouse was simulated in a liver perfusion tank developed for the experimental work. The liver perfusion medium used was a Tyrode solution prepared in accordance with physiologic criteria (as for liver transplants) which was oxygenated by an oxygenator and heated to 36.5 degrees C. Portal vein circulation was regulated via a flow- and pressure-controlled pump and arterial circulation using a dialysis machine. Flow rate and pressure were adjusted as for the physiology of a human liver converted to bovine liver conditions. The fluid discharged from the liver was returned into the perfusion system through the vena cava. Extendable precision swivel arms with the radiofrequency probe attached were mounted on the liver perfusion tank. RFA was conducted with the RF3000 generator and a 2 cm LeVeen needle (Boston Scientific, Ratingen, Germany) in a three-dimensional grid for precise localization of the generated thermolesions. RESULTS: Four bovine livers weighing 8.4 +/- 0.4 kg each were prepared, connected to the perfusion system, and consecutively perfused for the experiments. Mean arterial flow was 569 +/- 43 ml/min, arterial pressure 120 mmHg, portovenous flow 1440 +/- 305 ml/min, and portal pressure 10 mmHg. Macroscopic evaluation after the experiments revealed no thrombi within the hepatic vessels. A total of 136 RF thermolesions were generated with an average number of 34 per liver. Mean RF duration was 2:59 +/- 2:01 min:sec with an average baseline impedance of 28.2 +/- 3.4 ohms. The mean diameter of the thermolesions along the puncture channel was 22.98 +/- 4.34 mm and perpendicular to the channel was 23.27 +/- 4.82 mm. CONCLUSION: Extracorporeal perfusion of bovine livers with consecutive standardized RF ablation was feasible. The bovine liver flow model seems to allow extensive, standardized evaluation of technical or procedure-related developments of RF systems.

New coil concept for endoluminal MR imaging: initial results in staging of gastric carcinoma in correlation with histopathology.

Our aim was to conduct a prospective study to evaluate staging accuracy of a new coil concept for endoluminal magnetic resonance imaging (MRI) on ex vivo gastric carcinomas. Twenty-eight consecutive patients referred to surgery with a clinically proven primary gastric malignancy were included. Surgical specimens were examined with a foldable and self-expanding loop coil (8-cm diameter) at 1.5 Tesla immediately after total gastrectomy. T1- and T2-weighted and opposed-phase sequences (axial, frontal sections; 3- to 4-mm slice thickness) were acquired. Investigators blinded to any patient information analyzed signal intensity of normal gastric wall, gastric tumor, and lymph nodes. Findings were compared with histopathological staging. On surgical specimens, 2-5 gastric wall layers could be visualized. All gastric tumors (26 carcinomas, two lymphomas) were identified on endoluminal MR data (100%). Overall accuracy for T staging was 75% (18/24); sensitivity to detect serosal involvement was 80% and specificity 89%. N staging correlated in 58% (14/24) with histopathology (N+ versus N-). The endoluminal coil concept is feasible and applicable for an ex vivo setting. Endoluminal MR data provided sufficient detail for gastric wall layer differentiation, and therefore, identification of T stages in gastric carcinoma is possible. Further investigations in in vivo settings should explore the potential of our coil concept for endoluminal MR imaging.

Preoperative staging of renal cell carcinoma with inferior vena cava thrombus using multidetector CT and MRI: prospective study with histopathological correlation.

OBJECTIVE: To evaluate the accuracy of multidetector computed tomography (CT) and magnetic resonance imaging (MRI) in staging and estimating renal carcinomas with caval thrombus. METHODS: Initially, 23 patients with suspected caval thrombi were admitted into this prospective study. Triphasic CT imaging was performed using a multidetector CT with a reconstructed slice thickness of 2 mm. 3D CT reconstructions were used to improve surgical planning. MRI protocol included: a transversal T1-weighted GE sequence with and without Gd-DTPA, a transversal T2-weighted respiratory-gated TSE, and a coronal T1-weighted GE sequence with Gd-DTPA and fat saturation. In addition, a multiphase 3D angiography was performed after Gd-DTPA injection. Patients were divided into 3 groups: caval thrombus below the insertion of the hepatic veins, within the intrahepatic vena cava, and intra-atrial extension. The results the tumor thrombus extension and staging results of 2 independent readers were correlated with surgical and histopathological staging. RESULTS: Of the 23 patients admitted, CT and MR scans of 14/13 patients respectively were correlated with histopathological workup. CT thrombus detection sensitivity and specificity for both readers was 0.93 and 0.8 respectively. MRI sensitivity and specificity for both readers was 1.0/0.85 and 0.75. Readers I and II evaluated the uppermost extension of the cranial tumor thrombus by both CT and MRI. CT and MR accuracy was 78% and 72%, 88% and 76% respectively. CONCLUSION: In cases of a suspected tumor thrombus, MRI and multidetector CT imaging showed similar staging results. Consequently, these staging modalities can be used to assess the extension of the tumor thrombus.