Induction of Contralateral Hepatic Hypertrophy by Unilobar Yttrium-90 Transarterial Radioembolization versus Portal Vein Embolization: An Animal Study.

PURPOSE: To compare hepatic hypertrophy in the contralateral lobe achieved by unilobar transarterial radioembolization (TARE) versus portal vein embolization (PVE) in a swine model. METHODS: After an escalation study to determine the optimum dose to achieve hypertrophy after unilobar TARE in 4 animals, 16 pigs were treated by TARE (yttrium-90 resin microspheres) or PVE (lipiodol/n-butyl cyanoacrylate). Liver volume was calculated based on CT before treatment and during 6 months of follow-up. Independent t-test (P < .05) was used to compare hypertrophy. The relationship between hypertrophy after TARE and absorbed dose was calculated using the Pearson correlation. RESULTS: At 2 and 4 weeks after treatment, a significantly higher degree of future liver remnant hypertrophy was observed in the PVE group versus the TARE group, with a median volume gain of 31% (interquartile range [IQR]: 16%-66%) for PVE versus 23% (IQR: 6%-36%) for TARE after 2 weeks and 51% (IQR: 47%-69%) for PVE versus 29% (IQR: 20%-50%) for TARE after 4 weeks. After 3 and 6 months, hypertrophy converged without a statistically significant difference, with a volume gain of 103% (IQR: 86%-119%) for PVE versus 82% (IQR: 70%-96%) for TARE after 3 months and 115% (IQR: 70%-46%) for PVE versus 86% (IQR: 58%-111%) for TARE after 6 months. A strong correlation was observed between radiation dose (median 162 Gy, IQR: 139-175) and hypertrophy. CONCLUSIONS: PVE resulted in rapid hypertrophy within 1 month of the procedure, followed by a plateau, whereas TARE resulted in comparable hypertrophy by 3-6 months. TARE-induced hypertrophy correlated with radiation absorbed dose.

Chemoembolization with Vascular Disrupting Agent CKD-516 Dissolved in Ethiodized Oil in Combination with Doxorubicin: A VX2 Tumor Model Study.

PURPOSE: To assess feasibility and efficacy of CKD-516, a vascular disrupting agent, in transarterial chemoembolization in a liver tumor model. MATERIALS AND METHODS: A VX2 carcinoma strain was implanted in rabbit liver (n = 40) and incubated for 2 weeks. After confirmation of tumor growth using computed tomography, transarterial chemoembolization was performed. CKD-516 was dissolved in ethiodized oil, and animals were allocated to 4 treatment groups (n = 10 in each): group A, ethiodized oil; group B, ethiodized oil/CKD-516; group C, ethiodized oil + doxorubicin; group D, ethiodized oil/CKD-516 + doxorubicin. To assess hepatic damage, serum aspartate transaminase and alanine transaminase levels were measured on day 1, 3, and 7 after delivery. To assess tumor necrosis, animals were euthanized on day 7, and explanted tumors were stained with hematoxylin and eosin and a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay. Percentage areas of viable tumors were calculated using digitalized histopathologic specimen images. RESULTS: Tumor viability rates were 47.1% ± 11.4%, 27.5% ± 13.6%, 14.4% ± 12.5%, and 0.7% ± 1.0% in groups A, B, C, and D (P < .001). Liver enzyme levels were elevated after drug delivery but recovered during follow-up. Significant between-group differences were observed on days 1, 3, and 7 (aspartate transaminase and alanine transaminase: P = .0135 and P = .0134, P = .0390 and P = .0084, and P = .8260 and P = .0440). CONCLUSIONS: Treatment with a combination of CKD-516 and conventional transarterial chemoembolization showed therapeutic benefit in a liver tumor model.

Preparation and Characterization of Hyaluronic Acid-Polycaprolactone Copolymer Micelles for the Drug Delivery of Radioactive Iodine-131 Labeled Lipiodol.

Micelles, with the structure of amphiphilic molecules including a hydrophilic head and a hydrophobic tail, are recently developed as nanocarriers for the delivery of drugs with poor solubility. In addition, micelles have shown many advantages, such as enhanced permeation and retention (EPR) effects, prolonged circulation times, and increased endocytosis through surface modification. In this study, we measured the critical micelle concentrations, diameters, stability, and cytotoxicity and the cell uptake of micelles against hepatic cells with two kinds of hydrophilic materials: PEG-PCL and HA-g-PCL. We used 131I as a radioactive tracer to evaluate the stability, drug delivery, and cell uptake activity of the micelles. The results showed that HA-g-PCL micelles exhibited higher drug encapsulation efficiency and stability in aqueous solutions. In addition, the 131I-lipiodol loaded HA-g-PCL micelles had better affinity and higher cytotoxicity compared to HepG2 cells.

Transarterial sorafenib chemoembolization: preliminary study of technical feasibility in a rabbit model.

PURPOSE: To test the feasibility of targeted intraarterial administration of the tyrosine kinase inhibitor chemotherapeutic agent sorafenib to inhibit embolotherapy-induced tumor angiogenesis and reduce systemic drug side effects. MATERIALS AND METHODS: The left hepatic lobes of five New Zealand White rabbits (mean weight, 2.7 kg±0.2) were treated with chemoembolization with sorafenib and ethiodized oil emulsion, followed by immediate euthanasia. Postprocedure noncontrast computed tomography (CT) was used to evaluate intrahepatic chemotherapy mixture distribution. Liquid chromatography/tandem mass spectrometry (LC-MS/MS) was then used to directly measure sorafenib concentration in the treated liver tissue. Histopathologic assessment of treated left lobes was performed to identify any immediate toxic effects of the sorafenib solution. RESULTS: Lobar sorafenib chemoembolization was successfully performed in all cases via the left hepatic artery. Sorafenib and ethiodized oil (mean, 6.4 mg±3.8 and 0.95 mL±0.7, respectively) were injected, and CT confirmed targeted left hepatic lobe sorafenib emulsion delivery in all cases. Corresponding LC-MS/MS analysis yielded a mean sorafenib concentration of 94.2 µg/mL±48.3 in treated left lobe samples (n = 5), significantly greater than typical therapeutic drug levels (2-10 µg/mL) achieved with oral sorafenib systemic therapy. Histopathologic assessment showed only mild or moderate nonspecific ballooning degeneration in zone 3 hepatocytes, without tissue necrosis. CONCLUSIONS: Targeted transarterial sorafenib delivery is feasible and results in higher tissue drug levels than reported for systemic sorafenib therapy, without immediate histopathologic tissue toxicity. Future studies should aim to determine the utility of sorafenib chemoembolization in reducing hypoxia-induced vasculogenesis in liver tumors.

Effects of contrast agents on the fallopian tube in a rabbit model.

The authors evaluated the effect of different iodinated contrast agents on the fallopian tube and adnexal tissue in 15 rabbits. Ethiodized oil, an oil-soluble agent, was used in five rabbits. The following water-soluble agents were used: iothalamate meglumine 30% (n = 3), iothalamate meglumine 60% (n = 3), and ioxilan (n = 4). The agents were injected through catheters placed in the fallopian tubes. Fallopian tubes and peritoneal cavities were histologically evaluated. The contralateral tube served as a control. Ioxilan and iothalamate meglumine 30% produced no pathologic response in the tube or peritoneal cavity. Iothalamate meglumine 60% was associated with mild inflammatory infiltrate, mucosal edema, giant cell reaction, and periovarian adhesions that were bilateral but more pronounced on the injected side. Use of ethiodized oil resulted in papillary fibrous adhesions on the ovarian surface, and fat granulomas were seen in the periovarian tissues. The safety of oil-based contrast agents for use in hysterosalpingography is therefore questioned. No significant differences were found among the water-soluble contrast agents.

Peritoneal reaction resulting from iodinated contrast material: comparative study.

A consensus does not exist as to the optimal contrast agent for hysterosalpingography. This study was undertaken to evaluate the early and delayed inflammatory responses of the peritoneal surfaces to various types of iodinated contrast media. Guinea pigs received intraperitoneal injections of lactated Ringer solution, iothalamate meglumine, diatrizoate sodium, ioxilan, or ethiodized oil. The inflammatory response of the peritoneal surfaces was assessed at 1,7, and 30 days. Five animals were studied at each time point for each agent. No animals that received Ringer lactate or iothalamate meglumine had inflammation at any time. Ioxilan produced inflammation in two of five animals at 7 days and no inflammation at 1 or 30 days. Ethiodized oil produced no inflammation at 1 day; however, three animals had inflammation at 7 days, and all five had inflammation at 30 days. The 30-day group showed striking inflammatory response with granulomatous features. The authors recommend the continued use of meglumine-based water-soluble ionic contrast material for hysterosalpingography.

Experimental investigation of a new iodinated lipid emulsion for computed tomography of the liver.

Iodinated lipid emulsions are highly efficient macrophage imaging agents. Nevertheless, none of them has been accepted for clinical use because of adverse reactions. We have tested a new iodinated lipid emulsion, Intraiodol. The size and surface properties of the particles of this emulsion are similar to those of Intralipid which in turn closely resemble the naturally occurring chylomicrons. Using computed tomography (CT) of the rabbit liver as well as vital microscopy and electron microscopy of the rat liver we found that Intraiodol has low efficiency as a liver-specific contrast medium because its particles are predominantly taken up by the hepatocytes and to a less extent by the Kupffer cells, as is Intralipid. The low efficiency of Intraiodol could be fully compensated by an increase in dosage without any significant effect on sinusoidal blood flow. This in turn suggests that the likelihood of release of toxic mediators (and thereby related adverse reactions from activated macrophages) is reduced. We believe that this new way of delivering iodinated lipid particles to the liver represents an important advance in the search for a non-toxic lipid emulsion for CT of the liver.

Effect of intravenously injected iodinated lipid emulsion on the liver. An experimental study correlating computed tomography findings with in vivo microscopy and electron microscopy findings.

Iodinated lipid emulsions have been shown to have great potential as site specific contrast media for the liver and spleen. Because of unacceptable adverse reactions none of these emulsions has been adopted for clinical use. In an attempt to find an explanation for these adverse reactions we tested three iodinated lipid emulsions, EOE-13, AG 60.99 and AG 66.18. The following models were used: Computed tomography (CT) of the rabbit liver, in vivo microscopy and electron microscopy of the rat liver. The emulsions contained particles of different sizes and were used in varying doses. We found that the larger the emulsion particles, the more likely they were to be taken up by the Kupffer cells and thereby the higher the opacification of the liver achieved at CT. We also observed changes in the microcirculation of the liver when the emulsions were given in doses required to secure satisfactory opacification of the liver at CT. The main changes were 1) a marked increase in the size of the Kupffer cells, and 2) damage to the sinusoidal endothelium, both contributing to sinusoidal congestion. These changes strongly suggest activation of the macrophages and this in turn probably results in the release of toxic mediators. We suspect that the adverse reactions observed in patients when using iodinated lipid emulsions are due to these toxic mediators.

Direct infusion of EOE-13 into the hepatic artery. Experimental evaluation of safety in monkeys.

Ethiodized Oil Emulsion 13 (EOE-13) is an intravenous liver-spleen specific CT contrast agent. We infused EOE-13 directly into the hepatic arteries of five rhesus monkeys. Normal saline was administered in the same fashion in two control animals. Serial laboratory studies showed no major toxicity over a seven-day period. Intra-arterial EOE-13 has potential usefulness in the evaluation of hepatic artery infusion chemotherapy.

Hepatomography: an experimental technique using an emulsifier.

Hepatomography was performed by injecting emulsified Ethiodol into the hepatic artery of 9 beagles. The hepatogram was dense and remained long enough for diagnostic tomography. Contrast material was eliminated in part through the kidneys and disappeared from the liver within 24 hours after injection. The dogs were sacrificed 36 hours to 4 months after contrast injection. Longlasting ill effects were observed in only one dog which died of hepatitis. The death of this prompted the use of a more dilute emulsion which was beeter tolerated by all subsequent animals.