A preliminary animal study of thermal rheology fluid as a new temperature-dependent liquid intravascular embolic material.

PURPOSE: Thermal rheology (TR) fluid, which comprises polyethylene (PE) particles, their dispersant, and solvent, is a material that increases in viscosity to various degrees depending on the type and ratio of these constituents when its temperature rises. The viscosity of type 1 (TRF-1) increases more than that of type 2 (TRF-2) near rabbit body temperature. This preliminary animal study aimed to determine the basic characteristics and embolic effect of TR fluid by comparing TRF-1 and TRF-2. MATERIALS AND METHODS: Twenty-four Japanese white rabbits underwent unilateral renal artery embolization using TRF-1 or TRF-2 and follow-up angiography at 7 or 28 days (4 subgroups, n = 6 each). Subsequently, the rabbits were euthanized, and the embolized kidneys were removed for pathological examination. The primary and final embolization rates were defined as the ratio of renal artery area not visible immediately after embolization and follow-up angiography, respectively, to visualized renal artery area before embolization. The final embolization rate and maximum vessel diameter filled with PE particles were compared between materials. Moreover, the embolic effect was determined to be persistent when a two-sided 95% confidence interval (CI) for the difference in means between the embolization rates was < 5%. RESULTS: The final embolization rate was significantly higher for the TRF-1 than for the TRF-2 at both 7 (mean 80.7% [SD 18.7] vs. 28.4% [19.9], p = 0.001) and 28 days (94.0% [3.5] vs. 37.8% [15.5], p < 0.001). The maximum occluded vessel diameter was significantly larger for TRF-1 than for TRF-2 (870 µm [417] vs. 270 µm [163], p < 0.001). The embolic effect of TRF-1 was persistent until 28 days (difference between rates - 3.3 [95% CI - 10.0-3.4]). CONCLUSION: The embolic effect of TRF-1 was more persistent than that of TRF-2, and the persistency depended on the type and ratio of TR fluid constituents.

Change in hepatic hemodynamics assessed by hepatic arterial blood pressure and computed tomography during hepatic angiography with the double balloon technique.

PURPOSE: To assess the change in hepatic arterial blood pressure (HABP) and computed tomography during hepatic arteriography (CTHA) using the double balloon technique. MATERIALS AND METHODS: Nine patients with hepatocellular carcinoma (HCC) were enrolled. We inserted a 5.2-Fr balloon catheter into the common or proper hepatic artery and a 1.8-Fr microballoon catheter into the lobar or segmental artery feeding the HCC. HABPs were measured with the 1.8-Fr microballoon catheter (usual-HABP), with the 1.8-Fr balloon inflated (B-HABP), and with both the 5.2-Fr and 1.8-Fr balloons inflated (BB-HABP). CTHAs were performed via a 1.8-Fr microcatheter (usual-CTHA), with the 1.8-Fr balloon inflated (B-CTHA selective), with both the 5.2-Fr and 1.8-Fr balloons inflated (BB-CTHA selective), and via the 5.2-Fr catheter with the 1.8-Fr balloon inflated (B-CTHA whole) and with both the 5.2-Fr and 1.8-Fr balloons inflated (BB-CTHA whole). RESULTS: In all cases, B-HABP was lower than usual-HABP. There was a decrease in BB-HABP in comparison with B-HABP in cases with occlusion of the proper hepatic artery. The contrast effect of B-CTHA selective increased in four cases. The contrast effect on B-CTHA whole remained in all cases. CONCLUSION: This technique can be useful in decreasing HABP and collateral blood flow from the adjacent hepatic segment.

Transcatheter Arterial Embolization for Postoperative Bleeding Following Abdominal Surgery.

PURPOSE: We aimed to estimate the usefulness of transcatheter arterial embolization (TAE) in patients with postoperative abdominal hemorrhage and to evaluate the effects of pancreatic fistula on clinical outcomes and angiographic findings. MATERIALS AND METHODS: We enrolled 22 patients (20 males and 2 females; mean age 63 years; range 25-86 years), who underwent transarterial angiography for postoperative hemorrhage after abdominal surgery. This group corresponded to 28 procedures. Technical and clinical success rates were calculated, and clinical findings and outcomes were compared between patients with and without a pancreatic fistula. RESULTS: Pre-interventional CT was performed in all patients before first angiography, and the location of the bleeding was identified in all but one patient. Active arterial bleeding, identified by extravasation of contrast agent (n = 12), pseudoaneurysm formation (n = 12), and arterial wall irregularity (n = 2) were detected in 28 angiographic procedures, and embolization was performed in 26 instances. Various embolization techniques such as isolation, packing, embolization, and stentgraft implantation were performed. The technical and clinical success rates were 96% (25/26 procedures) and 82% (18/22 patients), respectively. In hemodynamically unstable patients (shock index: heart rate/systolic blood pressure > 1), a 92% (12/13 cases) technical success rate was achieved. There were no significant differences in any evaluated parameters between patients with and without pancreatic fistula. CONCLUSION: TAE is a safe and effective for treating postoperative hemorrhage even in patients with hemodynamic instability and pancreatic fistula. Additionally, pre-interventional CT is useful for effective, consecutive interventions.

Anti-tumor Effects of Sorafenib Administered at Different Time Points in Combination with Transarterial Embolization in a Rabbit VX2 Liver Tumor Model.

OBJECTIVE: To investigate the most suitable timing parameters when using sorafenib to enhance the anti-tumor effects of transarterial embolization (TAE) in a rabbit VX2 liver tumor model. MATERIALS AND METHODS: Twenty-five Japanese white rabbits were randomly assigned to five equal groups two weeks after VX2 tumor transplantation to the liver. We then performed the combination treatment with sorafenib and TAE in the according ways; Group 1 (TAE just before consecutive 7-day administration of sorafenib), Group 2 (TAE on second day of the administration period), Group 3 (TAE on fourth day of the administration period), and Group 4 (TAE after the administration period). Group 5 underwent TAE only. The anti-tumor effects were assessed by the tumor growth rates and by the immunohistochemical analysis of the density of intratumoral vessels. RESULTS: The tumor size increased by 103 ± 23% in Group 1, 126 ± 50% in Group 2, 177 ± 44% in Group 3 196 ± 78% in Group 4, and 211 ± 20% in Group 5. The difference between Group 1 and Group 5 and Group 2 and Group 5 was significant. The ratio of areas positive for CD31 in specimens was 2.06 ± 0.90% in Group 1, 1.86 ± 0.59% in Group 2, 3.51 ± 2.10% in Group 3, 3.67 ± 0.79% in Group 4, and 4.84 ± 0.81% in Group 5. The difference between Group 1 and Group 5, Group 2 and Group 5, and Group 2 and Group 4 was significant. CONCLUSION: We suggest that the ideal time of TAE is prior to or early after commencement of sorafenib administration.

Adrenal obliteration by balloon-occluded retrograde venous ethanol injection in a swine model.

PURPOSE: To evaluate the effects of adrenal obliteration by balloon-occluded retrograde venous ethanol injection. MATERIAL AND METHODS: We inserted a micro-balloon catheter into the left adrenal vein of six pigs and retrogradely injected absolute ethanol (0.06 ml/kg) under balloon occlusion. Two pigs were sacrificed on day 3, 7, and 14 after the procedure, respectively. We evaluated adrenal cortical and medullary hormones of the left renal vein, venograms, magnetic resonance imaging scans obtained before and after the procedure, autopsy and microscopic findings, and the weight of the bilateral adrenal glands. RESULTS: The hormone levels were extremely high on day 3 after the procedure. Post-procedure, partially-enhanced parenchyma and shaggy veins were observed. On the post-mortem examination, the left adrenal glands showed hemorrhage and adhesion on the third and seventh day and fatty proliferation 14 days after the procedure. Microscopic examination revealed hemorrhagic necrosis on day 3, inflammatory cell infiltration on day 7, and partial fibrosis 14 days after the procedure. The weight of the left adrenal gland on day 14 was lower than that of the right gland. CONCLUSIONS: This procedure elicited partial adrenal infarction with a high catecholamine concentration in the left renal vein.

An Attempt to Shorten Loading Time of Epirubicin into DC Beads® Using Vibration and a Sieve.

PURPOSE: We investigated the possibility of shortening the time required for loading epirubicin into calibrated polyvinyl alcohol-based hydrogel beads (DC Beads®) to be used for transarterial chemoembolization. METHOD: After separating the beads suspended in phosphate-buffered saline (PBS) solution by the use of a sieve (clearance 75 µm), epirubicin hydrochloride (EH) was loaded for 20, 30, or 60 s under vibration into DC beads. The EH loading rate into conventionally prepared (control) beads, i.e., beads loaded for 30 min without vibration, and vibration-loaded beads were calculated from the residual EH concentration in the bead-depleted EH solution. The amount of EH eluted from conventionally and vibration-loaded samples into a PBS solution (pH 7.0) was measured at 15 and 30 min and 1, 2, 6, 12, and 24 h. We also recorded the inhibitory effect of the PBS solution on the loading time. Using frozen sections, the EH load in the beads was evaluated visually under a fluorescence microscope. RESULTS: Spectrophotometry (495 nm) showed that the loading rate was 98.98 ± 0.34, 99.02 ± 0.32, and 99.50 ± 0.11 % with 20-, 30-, and 60-s vibration, respectively. The eluted rate was statistically similar between vibration- and statically loaded (control) beads. The PBS solution hampered EH loading into the beads. Visually, the distribution of EH in conventionally and vibration-loaded DC beads was similar. DISCUSSION: The use of vibration and the removal of PBS solution when epirubicin hydrochloride was loaded into DC beads dramatically shortened the loading time of epirubicin hydrochloride into DC beads.

Asialoerythropoietin ameliorates bleomycin-induced acute lung injury in rabbits by reducing inflammation.

Acute lung injury, a critical illness characterized by acute respiratory failure with bilateral pulmonary infiltrates, remains unresponsive to current treatments. The condition involves injury to the alveolar capillary barrier, neutrophil accumulation and the induction of proinflammatory cytokines followed by lung fibrosis. In the present study, a rabbit model of bleomycin-induced acute lung injury was established to examine the effects of asialoerythropoietin (AEP), an agent with tissue-protective activities, on pulmonary inflammation. Six Japanese white rabbits were randomly divided into two equal groups. Acute lung injury was induced in all rabbits by intratracheally injecting bleomycin. The control group was injected with bleomycin only; the experimental (AEP) group was injected intravenously with AEP (80 µg/kg) prior to the bleomycin injection. Computed tomography (CT) studies were performed seven days later. The CT inflammatory scores of areas exhibiting abnormal density and the pathological inflammatory scores were recorded as a ratio on a 7×7 mm grid. The CT and pathological inflammatory scores were significantly different between the control and AEP groups [122±10 and 16.3±1.5 (controls) vs. 71±8.5 and 9.7±1.4 (AEP), respectively; P<0.01]. Thus, the present study revealed that AEP prevents bleomycin-induced acute lung injury in rabbits.

Inhibition of fibrosis and inflammation by triple therapy with pirfenidone, edaravone and erythropoietin in rabbits with drug-induced lung injury: comparison of CT imaging and pathological findings.

In a rabbit model of bleomycin-induced lung injury, computed tomography (CT) and pathological studies were conducted to investigate whether the progression of this injury is inhibited by pirfenidone and by triple therapy with pirfenidone, edaravone and erythropoietin. We divided nine rabbits with bleomycin-induced lung injury into three equally sized groups. Group 1 served as the control, group 2 received pirfenidone alone and group 3 was treated with pirfenidone, edaravone and erythropoietin. Multidetector CT (MDCT) scans were acquired immediately after the administration of bleomycin, and further scans were performed on days 14 and 28. The area of abnormal opacity was calculated. The rabbit lungs were removed and the size of abnormal areas in macroscopic specimens was calculated and the degree of fibrosis and inflammation in microscopic specimens was scored. In order, the average size of the area of abnormal opacity on CT scans was largest in group 1, followed by groups 2 and 3. On day 28, the area of opacity was significantly smaller in group 3 than in group 1 (P=0.071). The average size of the area of abnormal opacity on macroscopic findings was largest in group 1, followed in order by groups 2 and 3; the difference between group 1 and 3 was significant (P<0.05). The average fibrosis score was highest in group 3 followed by groups 2 and 1. By contrast, the average inflammation score was highest in group 2 followed by groups 1 and 3. Although the administration of pirfenidone alone slowed the progression of bleomycin-induced lung injury, the triple-drug combination was more effective.

Antitumor effect of miriplatin-lipiodol suspension/emulsion using a VX2 liver tumor model.

OBJECTIVE: To evaluate the antitumor effects of miriplatin-lipidol suspension and emulsion. MATERIALS AND METHODS: Fifty rabbits with VX2 liver tumors were randomly assigned to ten groups. Then, we prepared four types of mixtures: a suspension of lipiodol and miriplatin (ML), an emulsion of miriplatin dissolved with lipiodol and contrast medium (MLC) or saline (MLS), and saline alone (S). Ratios between lipiodol and contrast medium/saline volumes were 1:1/4, 1:1/2, 1:1, and 1:2 respectively. We used the same dose of miriplatin (2 mg/kg) and lipiodol (0.1 ml/kg) in each emulsion and suspension group. After intra-arterial infusion, the tumor growth rate was calculated, and sequential change of the plasma platinum concentration, the platinum concentration in the tumor and in surrounding normal liver tissue was also measured. RESULTS: Among the ten groups, the tumor growth rate was lower in MLC and MLS groups, and the difference between tumor treated with MLS emulsion (ratio 1:1/2) and ML suspension was significant (p = 0.02). The platinum concentration in the normal liver tissue was lower in MLS and MLC groups than in the ML group, and that in the tumor was higher in the MLS and MLC emulsion (ratio 1:1/2) groups. CONCLUSION: We suggest that miriplatin-lipiodol emulsion may be more effective than suspension.

Evaluation of the embolic effect and degradability of gelatin microspheres and Gelpart particles.

PURPOSE: To evaluate the embolic effect and degradability of gelatin microspheres (GMS) and Gelpart particles (GPS) in dogs subjected to hepatic embolization. MATERIAL AND METHODS: We subjected 20 beagles to embolization of the hepatic artery (HA) and assessed the embolic effects of GMS measuring 500 µm in dry and 1 mm in wet state and of 1-mm GPS, porous gelatin embolic particles. We obtained celiac angiographs before and immediately after embolization and two, 14, and 28 days later; the livers were histopathologically evaluated. Reperfusion of HA was assessed by inspecting the arterial branches. We checked the liver specimens for residual GMS, injury to surrounding tissues, and inflammatory changes, and investigated embolic formation in the HA. RESULTS: The mean amount of injected GMS and GPS was 15.5 and 14.5 mg, respectively. While none of the dogs manifested HA reperfusion two days post-embolization, there was angiographic evidence of complete reperfusion 28 days after embolization. In all dogs, histopathological study showed arterial inflammatory changes and injury of surrounding tissues irrespective of the embolization materials used. These findings were pronounced on day 28 in dogs injected with GMS. CONCLUSION: There was no difference in the embolic effects of GMS and GPS nor in their degradability in dogs subjected to hepatic embolization.

Gelatin microspheres: correlation between embolic effect/degradability and cross-linkage/particle size.

PURPOSE: To evaluate the embolic effect and degradability of gelatin microspheres (GMS) using various degrees of cross-linkage and particle sizes in rabbit renal artery embolization. METHODS: Four types of GMS were used, as follows: 2 types of cross-linkage and 2 types of particle size. Twenty-four rabbits (6 in each group) were used for the renal artery embolization. Renal angiography was performed before and after embolization of right renal artery. Follow-up renal angiography was performed 2 days (n = 2), 5 days (n = 2), and 15 days (n = 2) after embolization in each group, and then kidneys were removed for histopathological evaluation. Vascular areas of the angiography were measured by Image J software, and the reperfusion rate was calculated. In renal specimens, residual GMS were checked and the degree of degradation was classified according to a 4-point scale. RESULTS: The mean amounts of large- and small-particle-size GMS injected were 15.0 and 34.3 mg, respectively. Tissue necrosis was confirmed in each group; however, no difference was observed among groups. Renal reperfusion was observed more with small GMS than with large GMS. Renal reperfusion was also observed more with low cross-linked GMS than with high cross-linked GMS. In histopathological specimens, large GMS were confirmed in lobar artery, and small GMS were confirmed in lobular artery. Low cross-linked GMS completely degraded 15 days after embolization. In contrast, high cross-linked GMS were persistent 15 days after embolization. CONCLUSION: Degree of cross-linkage and particle size affected degradability and reperfusion.

Vascular regeneration by pinpoint delivery of growth factors using a microcatheter reservoir system in a rabbit hind-limb ischemia model.

The purpose of this study was to compare the results of delivering low doses of growth factor iteratively (20 µg x5) via a reservoir system with results obtained following a single administration of 100 µg of growth factor. The delivery systems using gelatin microspheres (GMS) facilitate the controlled release of drugs. The controlled release of growth factors at specific sites is essential for vascular regeneration. An ischemic hind-limb model was established in nine rabbits. A reservoir system was implanted in each rabbit. GMS impregnated with basic fibroblast growth factor (bFGF) through an indwelling 2-Fr catheter was infused in the reservoir system. The rabbits were divided into three equal groups: group 1 received 20 µg iteratively (x5) via the reservoir, a single dose of 100 µg growth factor was administered to group 2 and group 3 was the saline control. The therapeutic effects were evaluated by measuring the thigh temperature, blood pressure and blood flow. An immunohistological analysis was also performed for CD31. No significant difference was observed between preand post-treatment (4 weeks following bFGF infusion) in the thigh temperature, blood pressure and blood flow results from each group. Pathological analysis revealed that the number of regenerated vessels was significantly higher in the group treated iteratively with low-dose bFGF.

Comparison of the anti-tumor effects of two platinum agents (miriplatin and fine-powder cisplatin).

PURPOSE: This study was designed to evaluate the anti-tumor effects of miriplatin-lipidol and fine-powder cisplatin-lipiodol suspensions. METHODS: Assessment of the cytotoxicity of two drugs was performed: a soluble derivative of miriplatin (DPC) and fine-powder cisplatin. We randomly divided 15 rabbits with transplanted VX2 liver tumors into three equal groups. They were infused via the proper hepatic artery with a miriplatin-lipiodol suspension (ML), a fine-powder cisplatin-lipiodol suspension (CL), or saline (control) and the tumor growth rate was determined on MR images acquired before and 7 days after treatment. The concentration of platinum (PCs) in blood was assayed immediately, and 10, 30, and 60 min, and 24 h and 7 days after drug administration. Its concentration in tumor and surrounding normal liver tissues was determined at 7 days postadministration. RESULTS: At high concentrations, fine-powder cisplatin exhibited stronger cytotoxicity than DPC. At low concentrations, both agents manifested weak cytotoxicity. While there was no difference between the tumor growth rate of the ML and the CL groups, the difference between the controls and ML- and CL-treated rabbits was significant. The blood PCs peaked at 10 min and then gradually decreased over time. On the other hand, no platinum was detected at any point after the administration of ML. There was no difference between the ML and CL groups in the PCs in tumor tissues; however, in normal hepatic tissue, the PCs were higher in ML- than CL-treated rabbits. CONCLUSIONS: We confirmed the anti-tumor effect of ML and CL. There was no significant difference between the anti-tumor effect of ML and CL at 7 days postadministration.