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Colorectal cancer is one of the most common cancers in the United States and treatment options are limited for patients who develop liver metastases. Several chemotherapeutic regimens have been used for transvascular liver-directed therapy in the treatment of colorectal liver metastases without clear evidence of superiority of one therapy over another. We describe the development of a novel nanoemulsion through combining irinotecan (IRI), a first line systemic agent used for the treatment of colon cancer, with lipiodol, an oily contrast medium derived from poppy seed oil, and evaluated its pharmacokinetic and biodistribution profile as a function of portal venous chemoembolization (PVCE) versus transarterial chemoembolization (TACE) delivery. The Tessari technique was used to create a stable emulsion (20 mg IRI mixed with 2 mL lipiodol) with resultant particle size ranging from 28.9 nm to 56.4 nm. Pharmacokinetic profile established through venous sampling in Buffalo rats demonstrate that the area under the curve (AUC 0-∞ ) of IRI was significantly less after PVCE with IRI-lipiodol as compared to IRI alone (131 vs. 316 µg*min/mL, p -value = .023), suggesting significantly higher amounts of IRI retention in the liver with the IRI-lipiodol nanoemulsion via first-pass extraction. Subseqent biodistribution studies in tumor-bearing WAG/Rjj rats revealed more IRI present in the tumor following TACE versus PVCE (29.19 ± 12.33 µg/g versus 3.42 ± 1.62; p -value = .0033) or IV (29.19 ± 12.33 µg/g versus 1.05 ± 0.47; p -value = .0035). The IRI-lipiodol nanoemulsion demonstrated an acceptable hepatotoxicity profile in all routes of administration. In conclusion, the IRI-lipiodol nanoemulsion via TACE showed promise and warrants further investigation as an option for the treatment of metastatic colorectal cancer.

Purpose: To compare Lipiodol uptake and tumor response in intermediate-stage hepatocellular carcinoma (HCC) with and without pre-embolization vascular lake phenomenon (VLP) and to identify the incidence and predictive factors of this phenomenon, in patients treated by conventional transarterial chemoembolization (cTACE)., Materials and Methods: This retrospective study included 151 consecutive patients with intermediate HCC totaling 232 nodules, who underwent cTACE from June 2015 to October 2018. Patients were divided into two groups according to the presence of VLP before embolization. Initial Lipiodol uptake was assessed using post-cTACE computed tomography (CT) within 1-1.5 months after cTACE. Enhanced CT or magnetic resonance imaging was performed at 6 months after the procedure to assess local recurrence and distant metastasis., Results: The VLP was demonstrated in 21.85% (33/151) patients and 16.81% (39/232) nodules on the super-selective angiography. On nodule-based analysis, significantly better Lipiodol uptake (p < 0.001) and higher ORR (60.61% vs. 26.49%, p < 0.001) and DCR (87.88% vs. 51.66%, p < 0.001) were observed in the VLP group compared to the non-VLP group. The multivariate logistic regression analysis showed that the presence of VLP (OR 6.431, 95% CI 2.495-16.579) might be a predictive factor for better Lipiodol uptake. Univariate and multivariate logistic regression analysis showed that poor differentiation of tumor (OR 6.397, 95% CI 2.804-19.635) remained predictive for the VLP., Conclusion: The incidence of VLP before embolization is 21.19%. The presence of VLP is well correlated with tumor Lipiodol uptake after cTACE and may be a new predictive factor for evaluation of cTACE efficacy and prognosis of intermediate HCC.

The benefit of chemotherapy as a constituent of transcatheter arterial chemoembolization (TACE) is still in debate. Recently we have developed arsenic trioxide nanoparticle prodrug (ATONP) as a new anticancer drug, but its systemic toxicity is a big issue. In this preclinical TACE study, ATONP emulsified in lipiodol behaved as drug-eluting bead manner. Sustained release of arsenic from ATONP within occluded tumor caused very low arsenic level in plasma, avoiding the "rushing out" effect as ATO did. Correspondingly, intratumoral arsenic accumulation and inorganic phosphate deprivation were simultaneously observed, and arsenic concentration was much higher as ATONP was transarterially administered than ATO, or intravenously injected. Tumor necrosis and apoptosis were remarkably more severe in ATONP group than ATO, but no significant hepatic and renal toxicity was perceived. In brief, ATONP alleviated arsenic toxicity and boosted the therapeutic effect of TACE via Pi-activated drug sustainable release., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To evaluate physiochemical characteristics of emulsions formed by a modified emulsification device and to compare in vitro drug release properties of ethiodized oil (Lipiodol)-drug solution emulsion formed by the device and a 3-way-stopcock for conventional transarterial chemoembolization., Materials and Methods: A V-shaped pumping emulsification device with a 100-μm-micropore glass membrane was developed to reduce the resistance of pumping. Epirubicin solution was mixed with Lipiodol (ratio 1:2) with pumping exchanges through the device. The percentage of water-in-oil (W/O) and droplet size distribution and viscosity were evaluated. The in vitro drug release properties were compared between using the device and a 3-way-stopcock., Results: Percentage of W/O was 98.45 ± 0.03%. The median droplet size was 22.58 ± 1.70 μm, and the viscosity was 143.70 ± 12.36 cP. The released epirubicin at 0 min was 1.73 ± 1.05% in the device, whereas 41.02 ± 7.27% in a 3-way-stopcock (P < 0.001). The half-life of release (t 50% ) of the device was significantly longer than that of a 3-way-stopcock (175 ± 25 vs. 8 ± 6 min, P < 0.001)., Conclusion: The V-shaped emulsification device with a 100-μm-micropore glass membrane can form nearly 100% W/O emulsion with homogenous droplet sizes. Emulsion formed by the device showed a slower epirubicin release property compared with that of a 3-way-stopcock.

Purpose: Transcatheter arterial chemoembolization (TACE) is the first-line therapy for unresectable hepatocellular carcinoma (HCC). However, its therapeutic effects are hampered by the poor distribution of anticancer drugs in tumors. iRGD, a novel tumor-penetrating peptide, enhances the penetration distance and therapeutic efficacy of anticancer drugs. Herein, we evaluated the therapeutic effects of iRGD coupled with TACE in the rabbit VX2 liver tumor model., Subjects and Methods: This study had two stages: tumor permeability assay and anticancer efficacy evaluation. In the tumor permeability assay, we coadministered TACE with either iRGD + lipiodol-doxorubicin emulsion (LDE) or LDE in the rabbit VX2 liver tumor model. We evaluated the doxorubicin (DOX) distribution at predetermined times by immunofluorescence microscopy. To evaluate anticancer efficacy, we administered saline, LDE, or iRGD + LDE to tumor-grafted rabbits. We measured tumor volume using magnetic resonance scanning. We quantified the expression levels of Bax, Bcl-2, and cleaved caspase-3 using Western blot (WB) analysis and determined the apoptosis rate in tumor cells using transferase-mediated dUTP nick-end labeling assay., Results: The iRGD + LDE infusion significantly increased the DOX concentration and DOX penetration in tumors compared with the LDE infusion (P < 0.05). The antitumor efficacy of the iRGD + LDE in tumor inhibition was higher than that of the other treatments (P < 0.05). Besides, iRGD + LDE induced more apoptosis (P < 0.05)., Conclusions: We demonstrated that iRGD coadministered with TACE is effective against HCC., Competing Interests: None

Objectives: To evaluate the diagnostic value of Lipiodol distribution in angiography and CT to differentiate between hepatocellular carcinoma (HCC) and benign nodules of LI-RADS 3 and 4 lesions observed in MRI of liver cirrhosis., Methods: This retrospective study included all patients with liver cirrhosis who had diagnosis of LI-RADS 3 or 4 lesions by MRI who underwent a Lipiodol-based angiography and post-interventional unenhanced CT- and liver biopsy. Two independent radiologists evaluated appearance, contrast enhancement, Lipiodol uptake in angiography, and morphological parameters (size, form, and density) of the lesions in unenhanced post-angiography CT. α-Fetoprotein (AFP) levels and pre-existing liver conditions were additionally taken into consideration. Differences between HCC lesions and benign nodules were analyzed. Sensitivity and specificity were calculated. P < 0.05 was considered as statistically significant., Results: Of 60 patients (men, n = 42 [70.0%]; women, 18 [30.0%]; mean age, 61 ± 9.1 years) 36 (60.0%) had HCC and 24 (40.0%) benign nodules. Clear visibility in angiography (sensitivity [se], 100%; specificity [sp], 87.5%) with homogeneous or lacunar Lipiodol enhancement (se, 86.1%; sp, 100%) in consecutive CT can be diagnosed as HCC lesions in cirrhotic liver. Lesion form (p < 0.001), round or oval, and intense contrast (p < 0.001) are minor features which can facilitate the findings. Furthermore, patients with HCC showed a larger lesion size in CT (p = 0.026)., Conclusion: Clearly detectable lesions in Lipiodol-based angiography and a homogeneous or lacunar enhancement in post-angiographic non-contrast CT allow for differentiation of intrahepatic lesions classified as LI-RADS 3 or 4 into benign vs. malign liver lesions with high sensitivity and specificity in patients with liver cirrhosis. Definite diagnosis may not require an additional biopsy., Key Points: • Combination of clear visibility in Lipiodol-based angiography and homogeneous or lacunar enhancement in following native CT scan is HCC-defining. • In lesions classified with MRI as LI-RADS 3 or 4, evaluation based on Lipiodol angiography and following plain CT performed is highly sensitive and specific for the differentiation between HCC and benign nodules in a cirrhotic liver. • The results lead to an alternative pathway in the diagnosis of HCC in cirrhotic liver without the need of an additional liver biopsy.

Background: To evaluate the predictive value of the lipiodol retention pattern for local progression of HCC with a complete response (CR) on CT according to mRECIST criteria after a first session of conventional chemoembolization (cTACE)., Methods: From January 2014 to May 2016 all consecutive patients undergoing a first cTACE session for HCC were identified. Inclusion criteria were the presence of ≤3 HCCs and available pre- and post-cTACE CT. Tumor response was classified according to mRECIST criteria. The analysis focused on tumors with a CR. The lipiodol retention pattern in these tumors was classified as complete (C-Lip, covering the entire tumor volume), or incomplete (I-Lip). Local progression was defined as the reappearance of areas of enhancement on arterial-phase images with washout on portal/delayed phase images within 2 cm from treated tumors on follow-up CT., Results: The final population included 50 patients with 82 HCCs. A total of 46 (56%) HCCs were classified with a CR, including 16 (35%) with I-Lip, and 30 (65%) with C-Lip. After a median follow-up of 14 months (3.2-35.9 months), 15/16 (94%) and 10/30 (30%) of I-Lip and C-Lip HCCs showed local progression on CT, respectively (p < 0.001), with no significant difference in the time to progression (mean 11.1 ± 2 vs. 13.4 ± 3 months for I-Lip and C-Lip, respectively p = 0.51)., Conclusions: HCCs with incomplete lipiodol retention after a first cTACE session have a high risk of local progression even when there is a CR according to mRECIST, and should be considered to be incompletely treated.

Objective: To study lipiodol deposition in portal vein tumour thrombus (PVTT) in predicting the treatment outcome of hepatocellular carcinoma (HCC) patients after transarterial chemoembolisation (TACE)., Methods: We retrospectively reviewed data from 379 HCC patients with PVTT who underwent TACE as the initial treatment at Sun Yat-Sen University Cancer Center from January 2008 to December 2015. Patients were grouped by positive and negative lipiodol deposition based on the extent of lipiodol deposition in PVTT. The overall survival (OS) and progression-free survival (PFS) were compared between negative and positive lipiodol deposition groups; furthermore, the value of the combinatorial evaluation of tumour responses and lipiodol deposition in PVTT in predicting prognosis was analysed in subgroup patients with stable disease (SD) after TACE., Results: Of the 379 patients, 264 (69.7%) had negative and 115 (30.3%) had positive lipiodol deposition in PVTT after TACE. Multivariate analysis identified positive lipiodol deposition in PVTT as an independent prognostic factor for favourable OS (p = 0.001). The median OS and PFS of negative and positive lipiodol deposition groups were 4.70 vs. 8.97 months (p = 0.001) and 3.1 months vs. 5.8 months (p < 0.001). In subgroup patients, the median OS and PFS of negative and positive lipiodol deposition groups were 4.7 months vs. 10.5 months (p < 0.001) and 3.5 months vs. 7.0 months (p < 0.001), respectively., Conclusions: The patients with positive lipiodol deposition in PVTT had a longer OS than those with negative lipiodol deposition. Furthermore, the positive lipiodol deposition in PVTT can further differentiate HCC patients with favourable prognosis from SD patients., Key Points: • Lipiodol deposition in PVTT is a prognostic indicator for HCC patients after TACE treatment. • Positive lipiodol deposition in PVTT is associated with a better prognosis.

Water-in-oil (W/O) Lipiodol emulsions remain the preferable choice for local delivery of chemotherapy in the treatment of hepatocellular carcinoma. However, their low stability severely hampers their efficiency. Here, remarkably stable W/O Lipiodol emulsion stabilized by biodegradable particles was developed thanks to Pickering technology. The addition of poly(lactide-co-glycolide) nanoparticles (NPs) into the aqueous-phase of the formulation led to W/O Pickering emulsion by a simple emulsification process through two connected syringes. Influence of nanoparticles concentration and water/oil ratio on emulsion stability and droplet size were studied. All formulated Pickering emulsions were W/O type, stable for at least one month and water droplets size could be tuned by controlling nanoparticle concentration from 24 µm at 25 mg/mL to 69 µm at 5 mg/mL. The potential of these emulsions to efficiently encapsulate chemotherapy was studied through the internalization of doxorubicin (DOX) into the aqueous phase with a water/oil ratio of 1/3 as recommended by the medical community. Loaded-doxorubicin was released from conventional emulsion within a few hours whereas doxorubicin from stable Pickering emulsion took up to 10 days to be completely released. In addition, in vitro cell viability evaluations performed on the components of the emulsion and the Pickering emulsion have shown no significant toxicity up to relatively high concentrations of NPs (3 mg/mL) on two different cell lines: HUVEC and HepG2. STATEMENT OF SIGNIFICANCE: We present an original experimental research in the field of nanotechnology for biomedical applications. In particular, we have formulated, thanks to Pickering technology, a new therapeutic emulsion stabilized with biodegradable PLGA nanoparticles. As far as we know, this is the first therapeutic Pickering emulsion reported in the literature for hepatocellular carcinoma. Such a new emulsion allows to easily prepare a predictable and stable lipiodolized emulsion having all the required characteristics for optimum tumor uptake. As demonstrated throughout our manuscript, emulsions stabilized with these nanoparticles have the advantage of being biodegradable, biocompatible and less toxic compared to usual emulsions stabilized with synthetic surfactants. These findings demonstrate the plausibility of the use of Pickering emulsions for chemoembolization as a therapeutic agent in extended release formulations., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: To compare the stability of stable and unstable water-in-oil emulsions and the efficacy and safety of these emulsions in a single-center, prospective double-blind trial of transarterial chemoembolization for hepatocellular carcinoma (HCC)., Materials and Methods: A total of 812 patients with inoperable HCC were randomized (stable emulsion, n = 402; unstable emulsion, n = 410). The 2 emulsions were prepared by using the same protocol except that different solvents were used for chemotherapy agents, including epirubicin, lobaplatin, and mitomycin C. The solvent in the stable emulsion arm was contrast medium and distilled water, and the solvent in the unstable emulsion arm was distilled water. The primary endpoint was overall survival (OS), and secondary endpoints were time to progression (TTP), tumor response, adverse events (AEs), and plasma epirubicin concentrations., Results: In vitro, stable emulsions did not occur until 1 day, and unstable emulsions, with a lower peak plasma concentration (P = .001) in vivo, exhibited rapid separation of the oil and aqueous phases after 10 minutes. Median OS times in the stable and unstable emulsion arms were 17.7 and 19.2 months, respectively (P = .81). No differences were found in TTP, tumor response, and AEs except for myelosuppression (anemia, 3.5% vs 7.6%; thrombocytopenia, 11.5% vs 17.7%), which was significantly more severe and frequent in the unstable emulsion arm (P = .013)., Conclusions: Chemoembolization is equally effective with the use of stable and unstable emulsions, but the use of a stable emulsion has the advantage of less myelosuppression and a favorable pharmacokinetic profile., (Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: To systematically review mechanism of action, pharmacokinetics (PKs), efficacy, and safety of ethiodized oil-based locoregional therapy (LRT) for liver cancer in preclinical models., Materials and Methods: A MEDLINE search was performed from 1988 to 2016. Search terms included hepatocellular carcinoma (HCC), HCC, liver-cell carcinoma, liver, hepatic, hepatocarcinoma, transarterial or chemoembolization, TACE, animal, Lipiodol, Ethiodol, iodized oil, and/or poppy-seed oil. Inclusion criteria were: publication in a peer-reviewed journal, an accepted animal model, and PK/safety/efficacy data reported. Exclusion criteria were: inadequate PK, safety, or efficacy data; anticancer drug name/dose not available; and article not in English. Outcomes included intratumoral anticancer drug uptake, PKs, tolerance, tumor response, and survival., Results: Of 102 identified articles, 49 (49%) met the inclusion criteria. Seventeen, 35, and 2 articles used rat, rabbit, and pig models. Mechanism of action was investigated in 11 articles. Eleven articles reported drug uptake, PK, and tolerance data, showing 0.5%-9.5% of injected chemotherapy dose in tumor. Tumor-to-liver drug distribution ratios were 2-157. Toxicology data across 6 articles showed transient liver laboratory level elevations 1 day after LRT. There was no noteworthy liver or extrahepatic histologic damage. Nine articles reported tumor response, with 0%-30% viable tumor and -10% to -38% tumor growth at 7 days after LRT. Two articles reported survival, showing significantly longer survival after LRT vs untreated controls (56/60 d vs 33/28 d). Several articles described ethiodized oil mixed with radiopharmaceutical (n = 7), antiangiogenic (n = 6), gene (n = 6), nanoembolic (n = 5), immune (n = 2), or other novel (n = 1) agents., Conclusions: Animal studies show preferential tumor uptake of anticancer agent, good hepatic/systemic tolerance, high tumor response, and enhanced survival after ethiodized oil-based LRT., (Copyright © 2017 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare the response to transcatheter arterial chemoembolization (TACE) between hepatocellular carcinoma (HCC) with paradoxical uptake on the hepatobiliary phase (HBP) (HCC para ) and HCC with defect on the HBP (HCC def ), and to identify some imaging features that can differentiate between two groups., Materials and Methods: Ninety-three HCCs from 54 patients who underwent gadoxetic acid-enhanced liver magnetic resonance imaging (MRI) prior to TACE were included. HCCs were classified into two groups according to the signal intensity (SI) on the HBP: HCC para and HCC def . Using post-TACE computed tomography (CT) as a reference standard, initial compact lipiodol uptake was assessed and compared between groups. The arterial enhancement ratio (AER), SI ratios of the arterial phase and HBP, and presence of the capsule appearance were compared between groups. After initial response, local tumor recurrence within 6 and 18 months was evaluated based on follow-up CT or MRI., Results: Fifteen HCC para and 78 HCC def were included. Compared to HCC def , HCC para showed more frequent initial compact lipiodol uptake (p=0.009), larger mean size (p=0.019), lower AER (p=0.005), higher SI ratio of the HBP (p<0.0001), and more frequent capsule appearance (p<0.0001). Local tumor recurrence rate within 6 months was also significantly lower in HCC para than in HCC def (p=0.008)., Conclusion: Despite larger size and lower AER, HCC para showed more frequent initial compact lipiodol uptake and lower early local recurrence rate after TACE than did HCC def ., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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 131 I 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 131 I-lipiodol loaded HA-g-PCL micelles had better affinity and higher cytotoxicity compared to HepG2 cells., Competing Interests: The authors declare no conflict of interests.

Background: To investigate accuracy of intraprocedural cone beam computed tomography (CBCT) compared to fluoroscopy for detection of lipiodol retention pattern during conventional transarterial chemoembolization (cTACE) of hepatocellular carcinoma (HCC) and its correlation with short-term response., Methods: Between September 2013 and July 2014, 29 patients with HCC underwent chemoembolization of 51 tumors (mean diameter 28.1 mm, range 10.0-136.3 mm). Lipiodol retention pattern was assessed by CBCT at the endpoint of cTACE compared by fluoroscopy. Depending on the pattern of tumor covered by lipiodol three classes were defined: complete (more than 90 %, no peripheral defects), moderate (50-90 %, some with or without peripheral defects), and poor (less than 50 %). Tumor response was assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST) based on follow-up contrast enhanced (CE) computed tomography (CT) or magnetic resonance imaging (MRI) obtained 4-6 weeks post-cTACE. Correlations between lipiodol retention patterns on CBCT and fluoroscopy as well as tumor response were assessed using multivariate logistic regression., Results: Of 51 hepatic tumors, 40 (78.4 %) had complete response (CR); 8 (15.7 %) had partial response (PR); 1 (2.0 %) had stable disease (SD); and 2 (3.9 %) had progressive disease (PD). The degree of lipiodol retention scored excellent, moderate, and poor, in fluoroscopic images vs CBCT images were 23 (45.1 %) vs 39 (76.5 %), 19 (37.3 %) vs 11 (21.6 %), and 9 (17.6 %) vs 1 (2.0 %), respectively. Lipiodol retention assessment with CBCT (A z  = 0.75) is more accurate than fluoroscopy (A z  = 0.54) in predicting target tumor response. Other than lipiodol retention pattern assessed with CBCT (p = 0.01), tumor size (p = 0.04) is an independent predictors of CR., Conclusion: CBCT is more accurate than fluoroscopy in classification of lipiodol retention pattern in HCC tumors at the time of cTACE. CBCT could be used as a reliable intra precedural monitoring modality of cTACE.

Purpose: Image-guided radiotherapy (IGRT) based on bone matching can produce large target-positioning errors because of expiration breath-hold reproducibility during stereotactic body radiation therapy (SBRT) for liver tumors. Therefore, the feasibility of diaphragm-based 3D image matching between planning computed tomography (CT) and pretreatment cone-beam CT was investigated., Methods: In 59 liver SBRT cases, Lipiodol uptake after transarterial chemoembolization was defined as a tumor marker. Further, the relative isocenter coordinate that was obtained by Lipiodol matching was defined as the reference coordinate. The distance between the relative isocenter coordinate and reference coordinate, which was obtained from diaphragm matching and bone matching techniques, was defined as the target positioning error. Furthermore, the target positioning error between liver matching and Lipiodol matching was evaluated., Results: The positioning errors in all directions by the diaphragm matching were significantly smaller than those obtained by using by the bone matching technique (p < 0.05). Further, the positioning errors in the A-P and C-C directions that were obtained by using liver matching were significantly smaller than those obtained by using bone matching (p < 0.05). The estimated PTV margins calculated by the formula proposed by van Herk for diaphragm matching, liver matching, and bone matching were 5.0 mm, 5.0 mm, and 11.6 mm in the C-C direction; 3.6 mm, 2.4 mm, and 6.9 mm in the A-P direction; and 2.6 mm, 4.1 mm, and 4.6 mm in the L-R direction, respectively., Conclusions: Diaphragm matching-based IGRT may be an alternative image matching technique for determining liver tumor positions in patients., (Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: This study was performed to evaluate the accumulation of lipiodol emulsion (LE) and adverse events during our initial experience of balloon-occluded trans-catheter arterial chemoembolization (B-TACE) for hepatocellular carcinoma (HCC) compared with conventional TACE (C-TACE)., Methods: B-TACE group (50 cases) was compared with C-TACE group (50 cases). The ratio of the LE concentration in the tumor to that in the surrounding embolized liver parenchyma (LE ratio) was calculated after each treatment. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Effects (CTCAE) version 4.0., Results: The LE ratio at the level of subsegmental showed a statistically significant difference between the groups (t test: P < 0.05). Only elevation of alanine aminotransferase was more frequent in the B-TACE group, showing a statistically significant difference (Mann-Whitney test: P < 0.05). While B-TACE caused severe adverse events (liver abscess and infarction) in patients with bile duct dilatation, there was no statistically significant difference in incidence between the groups. Multivariate logistic regression analysis suggested that the significant risk factor for liver abscess/infarction was bile duct dilatation (P < 0.05)., Conclusion: The LE ratio at the level of subsegmental showed a statistically significant difference between the groups (t test: P < 0.05). B-TACE caused severe adverse events (liver abscess and infarction) in patients with bile duct dilatation.

Background & Aims: The amount of drug-loaded lipiodol in an HCC tumor post-transarterial chemoembolization (TACE) correlates with the risk of local tumor recurrence. Lipiodol enhancement of a tumor on conventional CT, measured in Hounsfield units (HU), can predict tumor response. Here we investigate whether cone-beam CT (CBCT) can also be used to predict tumor response, providing the benefit of being able to optimize the patient's treatment plan intra-procedurally., Methods: A total of 82 HCC nodules (82 patients), ≤5 cm in diameter, were treated with balloon-occluded TACE using miriplatin between December 2013 and November 2014. For each patient, both CBCT and conventional CT images were obtained post-TACE. The degree of correlation between CBCT and conventional CT was determined by comparing identical regions of interest for each imaging modality using pixel values., Results: The pixel values from conventional CT and CBCT were highly correlated, with a Pearson correlation coefficient of 0.912 (p<0.001). The location of the nodules within the liver did not affect the results; the correlation coefficient was 0.891 (p<0.001) for the left lobe and 0.926 (p<0.001) for the right lobe. The mean pixel value for conventional CT was 439 ± 279 HU, and the mean pixel value for CBCT was 416 ± 311 HU., Conclusions: CBCT may be used as a substitute for conventional CT to quantitatively evaluate the amount of drug-loaded lipiodol within an HCC nodule and, hence, the efficacy of TACE treatment. The major benefit of using CBCT is the ability to predict the likelihood of local recurrence intra-procedurally, enabling subsequent treatment optimization.

Purpose: To validate the usefulness of a newly developed tracer for preoperative gastric sentinel lymph node (LN) (SLN) mapping and intraoperative navigation after a single preoperative submucosal injection in rat and beagle models., Materials and Methods: This study was approved by the Experimental Animal Ethical Committee of Yonsei University College of Medicine according to the eighth edition of the Guide for the Care and Use of Laboratory Animals published in 2011. An emulsion was developed that contained indocyanine green in iodized oil, which can be visualized with both computed tomography (CT) and near-infrared (NIR) optical imaging and has the property of delayed washout. This emulsion was injected into the footpad of rats (n = 6) and the gastric submucosa of beagles (n = 8). CT lymphography was performed. The degree of enhancement of popliteal LNs was measured in rats, and the enhancing LNs were identified and the degree of enhancement of the enhancing LNs was measured in beagles. Next, NIR imaging was performed in beagles during open, laparoscopic, and robotic surgery to identify LNs containing the fluorescent signals of indocyanine green. The enhanced LNs detected with CT lymphography and NIR imaging were matched to see if they corresponded., Results: Preoperative CT lymphography facilitated SLN mapping, and 26 SLNs were identified in eight beagles. NIR imaging enabled high-spatial-resolution visualization of both SLNs and the intervening lymphatic vessels and was useful for intraoperative SLN navigation., Conclusion: SLN mapping with fluorescent iodized oil emulsion is effective and feasible for both CT and NIR imaging., (© RSNA, 2014 Online supplemental material is available for this article.)

In many studies for chemoembolization of hepatocellular carcinoma, the Lipiodol emulsion preparation protocols, especially the mixing steps, were unclear or even unrevealed at all. However, doxorubicin (DOX) release may depend on the composition and volume ratio (Lipiodol to DOX solution) of a Lipiodol emulsion. Therefore, we conducted a preclinical study to compare in-vitro drug release and in-vivo pharmacokinetics of DOX from diverse Lipiodol emulsions and drug-eluting beads (DEBs) and to compare the tumor response in a rabbit VX2 carcinoma model. DOX release profiles of four types of Lipiodol emulsions with different media (normal saline or Pamiray as an iodinated contrast medium), volume ratio (Lipiodol to DOX solution), and DEBs were investigated in-vitro. For the in-vivo study, 15 rabbits bearing VX2 carcinoma in the liver were treated with 4∶1 volume ratio Lipiodol emulsion (group A), 1∶1 volume ratio Lipiodol emulsion (group B), and DEBs (group C) chemoembolization. Blood and tissue sampling was conducted to evaluate DOX concentration in plasma and tissues, histological changes, and liver toxicity. The most stable emulsion was formed with Pamiray (including DOX) at a 4∶1 volume ratio. The AUC value of group A was significantly lower than that of group B (p = 0.003) but comparable to that of group C (p = 0.071). The Cmax value of group A was significantly different compared with those of group B (p = 0.004) and C (p = 0.015). The tissue drug concentration in group A was comparable to that in group C (p = 0.251). No viable tumor was detected in rabbits of group A and B. In group C, viable tumor less than 10% was seen in two of the five rabbits. There were no significant differences in liver enzyme levels after the procedure. In conclusion, DOX release and pharmacokinetics of presented emulsion systems depend substantially on their composition. Therefore, Lipiodol emulsion type should be considered when interpreting data and designing new studies dealing with chemoembolization.

The effects of warming or emulsification with the water-soluble contrast medium, Iomeron (IOM), on reducing the viscosity of miriplatin-lipiodol (MPT-LPD) suspension were studied. Reduction in the viscosity of MPT-LPD suspension was ob- served upon increasing the temperature. Although the O/W MPT-LPD emulsion with a low ratio of MPT-LPD to IOM reduced the viscosity, the effect was lesser than that achieved with the warming treatment. Radiographic images of the liver obtained after administration of the emulsion into the rat portal vein showed that warming resulted in improved intrahepatic distribution of the formulation, which was dependent on the reduction of viscosity. Emulsification also led to better intrahepatic distribution, but this distribution did not depend on the viscosity of the formulation. The MPT-LPD emulsion showed different distribution properties from the MPT-LPD suspension, and it was difficult to estimate the intrahepatic distribution property from the viscosity of the emulsion. Thus, we suggest that emulsification and warming of MPT-LPD are effective methods for improving the intrahepatic distribution of the MPT formulation.

Purpose: To assess the usefulness of intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) for predicting lipiodol uptake in patients with hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE)., Materials and Methods: The institutional review board approved this study. 44 HCC patients underwent IVIM-DWI and Gd-EOB-DTPA-enhanced MRI prior to TACE. Using post-TACE CT as a reference standard, each HCC was classified into either lipiodol good uptake (LGU) or poor uptake (LPU) group. Apparent diffusion coefficient (ADC), true diffusion coefficient (D), perfusion coefficient (D*), and perfusion fraction (f) in HCC were calculated. Arterial enhancement ratio (AER) and IVIM parameters were compared between those two groups using the Mann-Whitney U test., Results: Of the 51 HCCs, 37 (72.5%) were LGU group and 14 (27.5%) were LPU group. AER of HCC was significantly higher in LGU than LPU (0.99±0.54 and 0.67±0.45; P=.034). ADC, D, and f values were not significantly different (P=.073, .059, and .196, respectively) between these two groups. D* was significantly elevated in LGU than LPU (48.10±15.33 and 26.75±9.55; P=.001)., Conclusion: Both AER derived from contrast enhanced MRI and D* values derived from IVIM-DWI for HCC were significantly higher in LGU than in LPU. These parameters would be helpful for predicting the lipiodol uptake., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Rationale and Objectives: To evaluate the capability of cone-beam computed tomography (CBCT) acquired immediately after transcatheter arterial chemoembolization (TACE) in determining lipiodol retention quantitatively and volumetrically when compared to 1-day postprocedure unenhanced multidetector computed tomography (MDCT)., Materials and Methods: From June to December 2012, 15 patients met the inclusion criteria of unresectable hepatocellular carcinoma (HCC) that was treated with conventional TACE (cTACE) and had intraprocedural CBCT and 1-day post-TACE MDCT. Four patients were excluded because the lipiodol was diffuse throughout the entire liver or lipiodol deposition was not clear on both CBCT and MDCT. Eleven patients with a total of 31 target lesions were included in the analysis. A quantitative three-dimensional software was used to assess complete, localized, and diffuse lipiodol deposition. Tumor volume, lipiodol volume in the tumor, percent lipiodol retention, and lipiodol enhancement in Hounsfield units (HU) were calculated and compared between CBCT and MDCT using two-tailed Student's t test and Bland-Altman plots., Results: The mean value of tumor volume, lipiodol-deposited regions, calculated average percent lipiodol retention, and HU value of CBCT were not significantly different from those of MDCT (tumor volume: 9.37 ± 11.35 cm(3) vs 9.34 ± 11.44 cm(3), P = .991; lipiodol volume: 7.84 ± 9.34 cm(3) vs 7.84 ± 9.60 cm(3), P = .998; lipiodol retention: 89.3% ± 14.7% vs. 90.2% ± 14.9%, P = .811; HU value: 307.7 ± 160.1 HU vs. 257.2 ± 120.0 HU, P = .139). Bland-Altman plots showed only minimal difference and high agreement when comparing CBCT to MDCT., Conclusions: CBCT has a similar capability, intraprocedurally, to assess lipiodol deposition in three dimensions for patients with HCC treated with cTACE when compared to MDCT., (Copyright © 2014 AUR. Published by Elsevier Inc. All rights reserved.)

Background: This study examined the safety, pharmacokinetics, and efficacy of transarterial chemoembolization of hepatocellular carcinoma (HCC) using a newly developed size of a superabsorbent polymer drug-eluting embolic material., Methods: Forty-five patients with documented HCC (Child-Pugh score A/B: 55.5 %/44.5 %) were embolized with HepaSphere microspheres 30-60 μm with escalation of lesion, dose, and frequency of re-embolization. Local response was evaluated with modified response evaluation criteria in solid tumors (mRECIST). Plasma levels of doxorubicin were measured in 24 patients at baseline and at 5, 20, 40, 60, and 120 min, at 6, 24, and 48 h, and at 7 days, respectively, to determine doxorubicin in plasma (Cmax) and area under the curve (AUC). Measurements of three patients who underwent lipiodol-based conventional chemoembolization (c-TACE) were also performed., Results: TACE with HepaSphere was well tolerated with an acceptable safety profile and no 30-day mortality. Response rates were calculated on intention-to-treat basis with complete response (CR) in 17.8 % reaching 22.2 % for the target lesion. Overall partial response (PR) was seen in 51.1 %, stable disease in 20 %, and progressive disease in 11.1 % of patients. Overall objective response (CR + PR), including patients treated at all dosages of doxorubicin, was seen in 68.9 % of cases. After a median follow-up of 15.6 months, 1-year survival is 100 %. Doxorubicin AUC was significantly lower in patients with HepaSphere 30-60 μm (35,195 ± 27,873 ng × min/ml) than in patients with conventional TACE (103,960 ± 16,652 ng × min/ml; p = 0.009). Cmax was also significantly lower with HepaSphere 30-60 μm (83.9 ± 32.1 ng/ml) compared with c-TACE (761.3 ± 58.8 ng/ml; p = 0.002)., Conclusion: HepaSphere 30-60 μm is an effective drug-eluting embolic material with a favourable pharmacokinetic profile.

Purpose: Thrombin inhibits cadherin on vascular endothelial cells, rapidly and reversibly increasing endothelial permeability. The purpose of this study was to evaluate the feasibility of trans-arterial infusion with thrombin., Material and Methods: Ten rabbits with right thigh tumor were randomly divided into two groups: A thrombin group and a control group. In the thrombin group, a suspension of thrombin (300 IU), cisplatin (3 mg), lipiodol (0.3 ml) and iopamidol (0.3 ml) was infused into the right femoral artery. In the control group, a suspension of cisplatin, lipiodol and iopamidol was infused. Platinum concentrations in plasma were measured five and ten minutes after administration. Platinum concentrations were also measured in tumor specimens excised 30 minutes after infusion., Results: At both five and ten minutes after infusion, platinum concentrations in plasma were significantly lower for the thrombin group than for the control group. Platinum concentration in tumor tissue was significantly higher for the thrombin group than for the control group., Conclusion: The present results suggest that transarterial infusion with thrombin may offer a number of pharmacological advantages.

Hepatocellular carcinoma (HCC) remains a major public health problem. Transarterial chemoembolization (TACE) is recognized as the standard of care for patients with unresectable, asymptomatic, noninvasive and multinodular HCC. This procedure is based on percutaneous administration of a cytotoxic drug emulsified with Lipiodol followed by embolization of the tumour-feeding arteries. The standard procedure involves Lipiodol, an oily contrast medium which consists of a mixture of long-chain di-iodinated ethyl esters of poppy seed fatty acids. The aim of this review is to discuss the physical properties, tumour uptake behaviour and drug delivery effects of Lipiodol, the parameters influencing tumour uptake and future prospects. Lipiodol has a unique place in TACE as it combines three specific characteristics: drug delivery, transient and plastic embolization and radiopacity properties. Substantial heterogeneity in the physicochemical characteristics of Lipiodol/cytotoxic agent emulsions might reduce the efficacy of this procedure and justifies the current interest in Lipiodol for drug delivery., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To reveal the mechanism of dense accumulation of lipiodol emulsion (LE) in hepatocellular carcinoma (HCC) during selective balloon-occluded transarterial chemoembolization (B-TACE)., Methods: Balloon-occluded arterial stump pressure (BOASP) at the embolization portion was measured during selective B-TACE for 43 nodules in 42 patients. Fluoroscopy and digital subtraction angiography were prospectively observed during selective B-TACE to note whether dense LE accumulation in HCC occurred. The LE concentration ratio of HCC to embolized liver parenchyma (LECHL ratio) was also calculated for each treatment on the basis of the computed tomographic scan obtained immediately after selective B-TACE. The relationships between degree of LE accumulation and the BOASP, as well as the LECHL ratio, were analyzed., Results: Arterial flow beyond the catheter tip was maintained even after balloon inflation. In 39 of 43 treatments, LE inflow into the nontumorous liver parenchyma ceased immediately after LE droplets were filled in arteries of the nontumorous liver parenchyma while LE inflow into the HCC nodule continued (group 1). More dense LE accumulation in HCC nodule was obtained in these 39 treatments. In four treatments, LE inflow both into the nontumorous liver parenchyma and into the HCC nodule continued, and no dense LE accumulation in HCC nodule was observed (group 2). In these four treatments, thick anastomotic vessels with collateral artery were noted. The BOASP in group 1 was (mean ± SD) 33.8 ± 12.8 mmHg (range 13-64 mmHg) and that in group 2 was 92.3 ± 7.4 mmHg (range 83-100 mmHg). There was a statistically significant difference in BOASP between groups (p = 0.00004, Welch's t test). The LECHL ratio in group 1 was 18.3 ± 13.9 (range 2.9-54.2) and that in group 2 was 2.6 ± 1.1 (range 1.7-4.2). There was a statistically significant difference in the LECHL ratio between the groups (p = 0.000034, Welch's t test)., Conclusion: Selective B-TACE induced dense LE accumulation in HCC nodules in 39 (91 %) of 43 treatments in which BOASP was 64 mmHg or less.

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., (Copyright © 2013 SIR. Published by Elsevier Inc. All rights reserved.)

Because liver cancer is rarely suitable for surgery, transcatheter arterial chemoembolization (TACE) is used for palliative therapy. In this procedure, an emulsion of doxorubicin in iodized oil is injected directly into liver tumors through a catheter positioned within the artery supplying blood flow to the tumor. At present, there is limited understanding of factors affecting the delivery and dispersion of doxorubicin within treated tumors during TACE. This study addresses the development and application of an ultrahigh-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS-MS) method for rapid confirmation of drug delivery after TACE in a rabbit VX2 liver cancer model. Doxorubicin levels in liver tumors were measured using UHPLC-MS-MS and compared with computed tomography measured levels of iodized oil, a metric used clinically to indicate drug delivery. We found that tissue drug levels determined using UHPLC-MS-MS did not correlate with the regional iodized oil concentration (vehicle) within tumors following TACE, suggesting that chemotherapeutic drugs like doxorubicin spread throughout tumors, and that lack of iodized oil staining in portions of a tumor does not necessarily indicate inadequate therapy during TACE., (Copyright © 2012 John Wiley & Sons, Ltd.)

The aim of this study was to develop new Lipiodol formulations with increased viscosities to augment Lipiodol embolic effect and optimize efficiency of radiolabeled Lipiodol in hepatocarcinoma treatments. New Lipiodol formulations consist of Lipiodol mixtures with different stearic acid concentrations (0.8%, 1.3%, and 1.8%). These formulations were fully characterized in vitro (viscosity, rheologic profiles) and labeled with 99mTc. Their viscosities at 20°C are 54, 60, and 67cP respectively, versus 45cP for Lipiodol ultra-fluide. Second, their biodistribution profiles were studied in vivo, at 24 and 72 hours, in hepatoma-bearing rats, and compared to control group (99mTc-Lipiodol). Biodistribution at 24 hours show a Gaussian tumor uptake profile with a maximum obtained with 1.3% stearic acid, and a tumor uptake superior to control group (+67%) (p<0.05). At 72 hours, optimal tumor uptake is reached with the 0.8% formulation, with 89% increase compared with control group (p<0.05). Moreover, we show a tendency to the decrease of pulmonary uptake for the new formulations at 24 hours and 72 hours. These results suggest a correlation between viscosity and Lipiodol tumor uptake. The new 0.8% stearic acid/Lipiodol formulation appears to be the optimized formulation for Lipiodol treatments of hepatocarcinoma, since it leads to a significant increase of tumor uptake at 72 hours and possibly to a decrease of undesirable pulmonary effects.

Purpose: To investigate the feasibility of using lipiodol as a direct surrogate for target localization using cone-beam CT (CBCT) image guidance in radiotherapy (RT) of patients with unresectable liver tumors after transarterial chemoembolization., Methods and Materials: Forty-six patients with an unresectable solitary liver tumor were enrolled for RT using active breathing control (ABC) and CBCT image guidance after transarterial chemoembolization. Each patient had pre- and posttreatment CBCT in the first 10 fractions of treatment. Lipiodol retention was evaluated using daily CBCT scans, and volume of lipiodol retention in the liver was calculated and compared between planning CT and post-RT CT. Influence of lipiodol on dosimetry was evaluated by measuring doses using an ion chamber with and without the presence of lipiodol. Margin analysis was performed on the basis of both inter- and intrafractional target localization errors., Results: Twenty-eight patients successfully completed the study. The shape and size of lipiodol retention did not vary substantially during the course of treatment. The mean Dice similarity coefficient for the lipiodol volume in pretreatment CT and that in posttreatment CT was 0.836 (range, 0.817-0.885). The maximum change (ratio of the lipiodol volume in pretreatment CT to that in posttreatment CT) was 1.045. The mean dose changes with the presence of <10 mL lipiodol were -1.44% and 0.13% for 6 MV and 15 MV, respectively. With ABC and online CBCT image guidance, clinical target volume-planning target volume margins were determined to be 2.5 mm in the mediolateral direction, 2.9 mm in the anteroposterior direction, and 4.0 mm in the craniocaudal direction., Conclusions: Lipiodol could be used as a direct surrogate for CBCT image guidance to improve the localization accuracy for RT of liver tumors. Combination of ABC and CBCT image guidance with lipiodol can potentially reduce the clinical target volume-planning target volume margin., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background/aims: To elucidate the prognostic factors for hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE)., Methodology: We studied 85 TACE-treated HCC patients, including 117 lesions, who fulfilled the Milan criteria. The area of iodized poppy-seed oil (lipiodol) accumulation on CT immediately after TACE was classified into three groups, by comparing with the area of HCC detected by CT during hepatic arteriography; accumulation surrounding the HCC lesion (group I), accumulation involving the entire area of the HCC lesion (group II), and accumulation that covered a portion of the HCC lesion (group III)., Results: Among 85 patients, the 1- and 2-year disease free survival (DFS) rates were 67% and 50% in group I, 49% and 29% in group II and 29% and 15% in group III. DFS rate was higher in group I than in groups II and III (p=0.016 and p<0.001). Difference in DFS by lipiodol accumulation pattern was evident in patients aged 75 or younger., Conclusions: Lipiodol accumulation pattern as evaluated by CT immediately after TACE may be a powerful indicator of the therapeutic efficacy of TACE in HCC patients.

Objective: The purpose of our study was to assess the feasibility of using C-arm CT to detect incomplete accumulation of iodized oil in hepatocellular carcinoma immediately after transarterial chemoembolization (TACE)., Materials and Methods: This retrospective study included 80 hepatocellular carcinoma lesions in 55 patients (41 men and 14 women; mean age, 69.2 years; mean tumor size, 18.1 mm [range, 5-55 mm]) who underwent TACE with a flat-detector C-arm angiographic system. C-arm CT images were acquired at the end of each session, and unenhanced MDCT images were obtained 7 days later. Two independent observers scored both sets of images, using a predefined detection scale for incomplete iodized oil accumulation. The accuracy for predicting residual lesions was compared using the area under the receiver-operating characteristic curve (A(z)). Contrast-enhanced CT findings obtained 1 month after TACE served as reference standards., Results: Viable lesions were observed in 18 of the 80 study lesions by contrast-enhanced CT. The accuracy of the C-arm CT (A(z) = 0.816) was not significantly different (p = 0.449) from that of the MDCT (A(z) = 0.841). Sensitivity, specificity, and positive and negative predictive values for C-arm CT (80.5%, 74.2%, 47.5%, and 92.9%, respectively) and MDCT (86.1%, 75.0%, 50.0%, and 94.9%, respectively) did not differ significantly., Conclusion: C-arm CT is nearly equivalent to MDCT for detecting incomplete iodized oil accumulation after TACE, suggesting that the immediate assessment of iodized oil accumulation with C-arm CT without the need to perform follow-up unenhanced MDCT is likely feasible.

Objective: Linear measurements, such as those described by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, may be limited for assessment of response after transarterial chemoembolization (TACE). The purpose of this pilot study was to show intra- and interobserver reproducibility of volumetric measurements of Ethiodol (ethiodized oil) seen within tumor 24 hours after TACE and of necrotic and viable tumor 1 month after treatment. Volumetric measurements are compared with linear measurements and survival outcomes., Materials and Methods: Between 2006 and 2009, 37 consecutive TACE procedures were performed in 27 patients with hepatic malignancies. CT images obtained 24 hours and 1 month after TACE were retrospectively analyzed. Three observers measured volumes twice. Intraoperator reproducibility was determined using Wilcoxon's signed rank test to assess whether the difference in each volumetric measurement approaches zero. The intraclass correlation coefficient (ICC) and Bland-Altman plots were used to determine interoperator reproducibility. Survival data were retrospectively obtained from the electronic medical record., Results: Good intraobserver reproducibility and interobserver reproducibility (p > 0.05, ICC > 0.9, respectively) were shown for Ethiodol, whole tumor, and necrotic tumor volumes. The volume of Ethiodol correlated with subsequent necrotic tumor volume (p = 0.009), reduction in whole tumor volume (p = 0.004), and patient survival (p = 0.029). Kaplan-Meier curves suggest that Ethiodol accumulation in more than 50% of the tumor and a 10% or greater increase in the volume of necrotic tumor correlated with survival (p = 0.028 and 0.047, respectively)., Conclusion: Semiautomated volumetric analysis can be performed with good intra- and interobserver reproducibility. The volume of Ethiodol accumulated in the tumor after TACE correlates with subsequent necrosis. These early measurements may predict survival outcomes.

Introduction: Lipiodol is used as a vector for chemoembolization or internal radiotherapy in unresectable hepatocellular carcinomas (HCCs). The aim of this study is to improve the tumoral uptake of Lipiodol by modulating membrane fluidizing agents to optimize the effectiveness of Lipiodol vectorized therapy., Methods: The effect of dexamethasone and tamoxifen on membrane fluidity was studied in vitro by electron paramagnetic resonance applied to rat hepatocarcinoma cell line N1S1. The tumoral uptake of Lipiodol was studied in vivo on rats with HCC, which had been previously treated by dexamethasone and/or tamoxifen, after intra-arterial administration of (99m)Tc-SSS-Lipiodol., Results: The two molecules studied here exhibit a fluidizing effect in vitro which appears dependent on time and dose, with a maximum fluidity obtained after 1 hr at concentrations of 20 μM for dexamethasone and 200 nM for tamoxifen. In vivo, while the use of dexamethasone or tamoxifen alone tends to lead to increased tumoral uptake of Lipiodol, this effect does not reach levels of significance. On the other hand, there is a significant increase in the tumoral uptake of (99m)Tc-SSS-Lipiodol in rats pretreated by both dexamethasone and tamoxifen, with a tumoral uptake (expressed in % of injected activity per g of tumor) of 13.57 ± 3.65% after treatment, as against 9.45 ± 4.44% without treatment (P<.05)., Conclusions: Dexamethasone and tamoxifen fluidify the N1S1 cells membrane, leading to an increase in the tumoral uptake of Lipiodol. These drugs could be combined with chemo-Lipiodol-embolization or radiolabeled Lipiodol, with a view to improving the effectiveness of HCCs therapy., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the most prevalent forms of cancer with high morbidity. (131)I-lipiodol is used clinically and has been found to be effective for the treatment of HCC. However, this preparation has its limitations, including compromised yield and stability of exchange labeling and unnecessary dose burden from gamma emissions. In the present study, (177)Lu-oxine in lipiodol was considered as a possible alternative for radioiodinated lipiodol. Oxine or 8-hydroxyquinoline was labeled with (177)Lu obtained by neutron irradiation of natural lutetium. Under optimized conditions, the radiolabeled complex was obtained with yields >98% and adequate in vitro stability. (177)Lu-oxine dispersed in lipiodol showed appreciable uptake into rat liver cells (normal and HCC-induced) in vitro. (177)Lu-oxine-lipiodol showed initial localization in the liver, but subsequent leakage of radioactivity with deposition in the skeletal tissue was seen. The studies suggest that (177)Lu-oxine dispersed in lipiodol might not be suitable for treatment of HCC.

Ethiodol (or lipiodol) is selectively retained in hepatocellular carcinoma and is used as a vehicle to deliver radioactive agents following intraarterial hepatic infusion. We prepared the lipophilic complex 90Y-oxine with a radiolabeling efficiency of 97.6+/-1.1%. After extraction into ethiodol, a stability test in serum at 37 degrees C showed that 87.8% of the 90Y remained ethiodol-bound for 7 days. Bremsstrahlung imaging of a rabbit for 48 h confirmed that the homogeneous mixture of radiolabeled 90Y-oxine and ethiodol stayed in the targeted liver lobe. This radiopharmaceutical is thus a potential candidate for the treatment of non-resectable liver cancer.

Rationale and Objectives: The authors' purpose was to define the stability and drug-carrying and drug-releasing capacity of ethiodized oil emulsions in the hepatic circulation., Methods: Emulsions prepared in various ratios of a nonionic contrast material containing doxorubicin to ethiodized oil were injected into the hepatic arteries of normal and tumor-bearing livers in rats or mice. In vivo microscopy was used to observe the dynamic distribution of the emulsions in the hepatic circulation., Results: A solution of less water mixed with more oil formed water-in-oil (w/o) phase emulsions, whereas oil with more water formed oil-in-water (o/w) emulsions. The oil in the emulsions carried the water in the blood circulation. The w/o emulsions exhibited significantly higher carriage capacity and longer release time for the drug solution than did the o/w emulsions (P < .01)., Conclusion: The delivery of w/o emulsions is superior to that of o/w emulsions. Further studies about preparation methods and delivery capability of emulsions in the liver are warranted.

Purpose: The distribution of different ethiodized oil-doxorubicin mixtures within and around hypovascular liver metastases in athymic nude mice was compared following either intraarterial or intraportal injections., Materials and Methods: Six different mixtures of doxorubicin and ethiodized oil in water-soluble contrast material, shaken for 5, 10, 15, and 30 minutes, respectively, were prepared and the size of the oil droplets in the mixtures evaluated. Intraarterial and intraportal injections of mixtures shaken for 10 and 15 minutes were performed in mice bearing hypovascular hepatic colorectal metastases. In vivo video microscopy was used to evaluate microvascular flow and the biodistribution and the size of the oil droplets within and around the tumors., Results: Oil droplets smaller than 20 microns in diameter were taken up by tumor nodules. There was no significant difference in oil droplet accumulation within the tumor between intraarterial and intraportal injections. Oil droplets larger than 20 microns occluded small and medium portal branches. The optimum combination was 0.1 mL of ethiodized oil in 2 mL of diatrizoate sodium meglumine (Renografin-76) shaken for 15 minutes at 800 rpm, which formed droplets smaller than 20 microns (92%)., Conclusion: Avascular regions of hepatic metastases may be embolized with ethiodized oil-anticancer drug mixtures containing oil droplets smaller than 20 microns. Since these droplets penetrate to the tumor interstitium with either intraarterial or intraportal injections, chemoembolization via the arterial route seems preferable for treatment of unresectable hypovascular hepatic metastases since it is easier to perform. The conclusions drawn from this study are limited to the animal model for experimental hypovascular hepatic metastases.

Purpose: To evaluate the efficacy and safety of selective chemoembolization in patients with colorectal metastases to the liver., Materials and Methods: Forty-six patients underwent the regimen, which involved use of doxorubicin and ethiodized oil, with 75% selectively administered to different subsegments and 25% into the respective main hepatic artery., Results: In eight patients, the lesions disappeared and carcinoembryonic antigen levels returned to normal. Eleven patients showed no disease progression for 12 months; two others, for 24 months. Thirteen patients died; three were lost to follow-up in the 1st year. Six patients were followed up for 5 years, seven for 3 years, 16 for 2 years, and 30 for 1 year. Five of seven patients who survived 3 years or more exhibited homogeneous distribution of the chemoembolic agent throughout the metastatic tumor., Conclusion: Selective chemoembolization is recommended for treatment of patients with colorectal metastases to the liver, a resectable primary tumor, and no evidence of other metastatic disease.

The in vivo distribution and kinetics of [131I]Ethiodol injected through the hepatic artery have been measured on a group of four patients with hepatocellular carcinoma. The [131I]Ethiodol was distributed predominantly in the liver (70-90%) and lungs (10-20%) and was selectively concentrated and retained in the patients with massive and multinodular hepatomas with approximately 10% of the administered activity localizing in tumor. The radioactivity in the blood 2 hr postinjection was less than 0.1% and was never higher than 0.9% of the administered activity. The radioactivity cleared from normal liver tissue with an effective half-life of approximately 4 days while the clearance time from the tumor was 20-25% longer. Activity in the lungs initially increased and then cleared with a 5-day effective half-life. Based on these measurements, the estimated dose per mCi of [131I]Ethiodol administered is 31 rad to the liver, 22 rad to the lungs, 1.9 rad to the total body and 239 rad to a 4-cm diameter tumor. These results suggest that [131I]Ethiodol has the potential to deliver curative radiation doses to hepatomas with acceptable radiation burdens to normal tissues.

Iodinated oil (Ethiodol, 1 or 2 ml) was administered po or by im administration to adult women and older children in rural highland Ecuador who were either well nourished or malnourished to determine the effect of nutritional status on the disposal rate of iodine. These subjects resides in a region previously severely deficient in iodine, but this had been corrected in these subjects by prior administration of iodinated oil or by use of iodized salt or both. Malnutrition as determined by the conventional standards of height for age was associated with a significantly shortened retention time of the administered iodine, whether given po or im. The half life of retention was approximately half in the malourished of that in the well nourished. If these findings can be extrapolated to chronically iodine deficient subjects, then malnourished populations in need of iodine supplementation should either receive higher dosages than those conventionally employed or more frequent dosage.