Iodized oil uptake assessment with cone-beam CT in chemoembolization of small hepatocellular carcinomas.

AIM: To evaluate the utility of assessing iodized oil uptake with cone-beam computed tomography (CT) in transarterial chemoembolization (TACE) for small hepatocellular carcinoma (HCC). METHODS: Cone-beam CT provided by a biplane flat-panel detector angiography suite was performed on eighteen patients (sixteen men and two women; 41-76 years; mean age, 58.9 years) directly after TACE for small HCC (26 nodules under 30 mm; mean diameter, 11.9 mm; range, 5-28 mm). The pre-procedural locations of the tumors were evaluated using triphasic multi-detector row helical computed tomography (MDCT). The tumor locations on MDCT and the iodized oil uptake by the tumors were analyzed on cone-beam CT and on spot image directly after the procedures. RESULTS: All lesions on preprocedural MDCT were detected using iodized oil uptake in the lesions on cone-beam CT (sensitivity 100%, 26/26). Spot image depicted iodized oil uptake in 22 of the lesions (sensitivity 85%). The degree of iodized oil uptake was overestimated (9%, 2/22) or underestimated (14%, 3/22) on spot image in five nodules compared with that of cone-beam CT. CONCLUSION: Cone-beam CT is a useful and convenient tool for assessing the iodized oil uptake of small hepatic tumors (< 3 cm) directly after TACE.

Lipiodol and dye at the site of ablation decreases during RFA.

OBJECTIVES: Intrahepatic metastasis is one of the serious complications of radiofrequency ablation (RFA) therapy for hepatocellular carcinoma. The aim of this study was to investigate how liver tissue could be disseminated during the RFA procedure with different devices and protocols in an in vivo porcine model. METHODS: Three pigs underwent RFA procedures using 2 different devices: needles that could be expanded (LeVeen needle) and those that could not (cool-tip needle). A LeVeen needle was used with a single-step full extension method or a stepwise extension method. Before RFA, a mixture of lipiodol and blue dye was injected intrahepatically into a precoagulated area. After the ablation procedure, the specimen was cut to evaluate the amount of dye remaining in the ablated region and the distribution of the dye outside the ablated area. RESULTS: The stepwise extension method resulted in the disappearance of the smallest amount of the dye and lipiodol at the ablation site, compared with the full extension method and cool-tip needle. Dye was found at sites distant from the ablated area in all cases using the cool-tip needle, but in none with the stepwise extension method. CONCLUSIONS: The stepwise procedure using the expandable needle can reduce tumor cell scattering, which can cause intrahepatic metastasis, compared with other methods.

Effect of stabilized iodized oil emulsion on experimentally induced hepatocellular carcinoma in rats.

PURPOSE: Previous studies have shown that the use of Lipiodol UltraFluid (LUF) emulsified with water leads to an increase in the tumoral uptake of iodine I 131-labeled LUF and reduced pulmonary uptake. Although emulsions containing LUF are currently used for chemoembolization of hepatocellular carcinomas (HCCs), this approach is impossible with intraarterial radiation therapy (RT) because of the problems of radiation protection linked to instability of the emulsions. The aims of this study were to develop stabilized emulsions of radiolabeled LUF of different particle sizes and viscosities and to study its biodistribution in rats with HCC. MATERIALS AND METHODS: An emulsifier made of polyethylene glycol and hydrogenated castor oil was used to stabilize emulsions containing water and technetium Tc 99m-labeled Super Six Sulfur LUF. The various emulsions were injected in the hepatic arteries of rats with HCC. Twenty-four hours after injection, the rats were killed and the liver, tumor, and lungs were removed to perform ex-vivo gamma-counting to quantify tumoral, hepatic, and pulmonary uptake. RESULTS: Emulsions of oil in water and water in oil of different viscosities (0.68-1.06 Pa.S) and particle size distributions (21-45 mum) were prepared and kept stable for more than 24 hours. Whatever the type of emulsion, the observed effect on tumoral uptake was the opposite of that expected. Indeed, a decrease in tumoral activity was observed (P < .05 in three of five cases) and a tendency toward increased pulmonary activity was observed (P < .05 in two of five cases) rather than any significant decrease. CONCLUSIONS: This study made it possible to develop emulsions of radiolabeled iodized oil that remain stable for more than 24 hours. However, studies of biodistribution in rats with HCC failed to demonstrate any improvement in tumoral targeting, but rather showed a decrease in tumoral uptake that renders this approach impractical for intraarterial radiolabeled iodized oil RT as well as for intraarterial iodized oil chemoembolization. These results may possibly be explained by the use of an emulsifier containing lipophilic and hydrophilic components that modify the properties of LUF.

Lipiodol UF retention in dental sialography.

Lipiodol is a lipid based contrast medium and is very useful in sialography. It gives very fine images and clearly shows the details of the gland. It is viscous and has a relatively high iodine content. However, lipiodol UF drops sometimes remain in the salivary gland and in the adjacent tissues for a long time and may cause irritation. We report a case where lipiodol UF leaked from Stensen's duct and was not resorbed after a period of 70 months.

Gigantic cavernous hemangioma of the liver treated by intra-arterial embolization with pingyangmycin-lipiodol emulsion: a multi-center study.

PURPOSE: To evaluate the therapeutic effect and safety of pingyangmycin-lipiodol emulsion (PLE) intra-arterial embolization for treating gigantic cavernous hemangioma of the liver (CHL). METHODS: Three hospitals (Nanfang Hospital, Inner Mongolia Autonomous Region's Hospital and Huai He Hospital) participated in the study during 1997-2001. A total of 98 patients with CHL were embolized with PLE via the hepatic artery. The therapeutic effects including changes in tumor diameter, symptomatic improvement and occurrence of complications were evaluated for a period of 12 months after the procedure. RESULTS: The tumor diameters decreased significantly from 9.7 +/- 2.3 cm to 5.6 +/- 1.6 cm 6 months after the treatment ( P < 0.01), and then to 3.0 +/- 1.2 cm at 12 months ( P < 0.01). Transient impairment of liver function was found in 77 cases after embolization, 69 cases of which returned to normal in 2 weeks, and the other eight cases of which recovered 1 month later. The clinical symptoms were significantly relieved in all 53 symptomatic patients. Persistent pain in the hepatic region was found in two cases, and these two patients resorted to surgery eventually. CONCLUSION: Intra-arterial PLE embolization proves to be effective and safe in treating patients with CHL.

[Magnetic resonance behavior of lipiodol--an experimental study].

OBJECTIVE: To describe the characteristics of magnetic resonance (MR) signals generated by lipiodol and to assess the influence on MR imaging of hepatoma nodule. METHODS: Pure lipiodol and lipiodol emulsions mixed with 76% urografin in different ratio were imaged by both CT and MR; quantitative T(1) and T(2) measurements of lipiodol were performed. Fourty-one SD rats with transplanted walker-256 sarcoma in liver were randomly divided into six groups: 0.4-0.6 ml lipiodol emulsion was infused via hepatic artery in experimental groups by means of laparotomy under celiac anesthesia. The changes in MRI signal of hepatoma nodule were observed. RESULT: In vitro, iodized oil demonstrated high signal on T(1)-weighted images when performed at 37 degree, but all could be suppressed by the fat saturation sequence, and showed very low signal on T(2)-weighted images. The characteristic of MR signal with ultra fluid lipiodol was different from that of iodized oil (P<0.01), showing short T(1) and long T(2) signal; the high signal on T(1)-weighted images was only partially suppressed by the fat saturation sequence. With descending ratio of lipiodol in emulsion, the signal behavior was gradually similar to urografin (r -0.958, P<0.01). When rats were transarterially infused with emulsion, the intensity of the signal on MRI was nearly the same as that in the control rats, but when lipiodol was injected out of the hepatic artery and accumulated in lymphadenopathy, it demonstrated a signal similar to fat; the high intensity signal was maintained on T(1)-weighted images and T(2)-weighted images. CONCLUSION: There are little changes in MR signal intensity when the lipiodol is accumulated in the tumor nodules. MR behavior of lipiodol is determined by its deposit area.

Supplemental transcatheter arterial chemoembolization through a collateral omental artery: treatment for hepatocellular carcinoma.

PURPOSE: To evaluate the therapeutic efficacy and safety of supplemental transcatheter arterial chemoembolization (TACE) through the extrahepatic collateral omental artery (OA) for the treatment of hepatocellular carcinoma (HCC). METHODS: We studied 21 patients with extrahepatic collaterals of the OA, among 1,512 patients with HCC who had undergone angiography. HCCs supplied by collateral OAs were located at: segment IV in seven, segment V in five, segment III in three, segment VI in three and segment VIII in three patients (Couinaud classification of segments). On preoperative CT scans, every HCC was abutting the liver surface. Adjacent omental infiltration or engorgement was noted in 11 patients. Celiac and hepatic arteriograms showed hypertrophy of the feeding OA in all patients. TACE of the OA was performed in 19 patients with an emulsion of iodized oil and doxorubicin hydrochloride. Embolization with gelatin sponge particles was added in five patients. RESULTS: Collaterals of the OA to the HCC were found on the first to seventeenth sessions of TACE. On follow-up CT scans, five patients showed complete uptake of iodized oil in the tumor. Partial uptake of iodized oil was noted in 13 patients and no uptake in one patient. There was no serious complication that related to the omental embolization, such as omental or bowel ischemia. The cumulative survival rates from the time of the TACE of the OA were 81% at 6 months and 68% at 12 months. CONCLUSION: TACE of the OA is safe and has a potential therapeutic effect in the treatment of HCC.

In-vitro uptake of radioactive lipiodol I-131 and I-125 by hepatoblastoma: implications for targeted radiotherapy.

Lipiodol, a stable iodine addition product of fatty ethyl esters derived from poppyseed oil, has been used as a vehicle for targeted cytotoxic or radiotherapeutic treatment in adults with unresectable hepatocellular carcinoma and in a few children with advanced hepatoblastoma (HB). Prolonged retention of lipiodol by the cancer cells might enable more effective targeted therapy to advanced, multifocal, or metastatic HB. To investigate the uptake and cytotoxic efficacy of beta and Auger electron-emitting radioconjugates on HB cells, monolayers of HB (C3a, Hep Tow1) and normal human hepatocyte cell lines were exposed to lipiodol131 (L131), lipiodol125 (L125), or a cocktail of both isotopes. Uptake of radioactivity was assessed autoradiographically using phosphoimages and the cytotoxicity assessed by trypan blue exclusion and clonogenic assay. The uptake of the different radioconjugates was identical in both HB cell lines. The "cocktail" of both radioactive lipiodols caused the greatest cytotoxicity to HB C3a, and HepTow1. L125 alone had a similar level of uptake and cytotoxicity as L131. Radioactive iodine alone did not show any cytotoxicity on any of the liver cell lines in culture for up to 72 h. These experimental results provide support for a clinical strategy of combinations ("cocktails") of radioconjugates in targeted radiotherapy in patients with HB.

Serum thyroglobulin and urinary iodine concentration are the most appropriate indicators of iodine status and thyroid function under conditions of increasing iodine supply in schoolchildren in Benin.

Iodine deficiency control programs have greatly reduced iodine deficiency disorders worldwide. For monitoring changes in iodine status, different indicators may be used. The aim of this study was to evaluate the suitability of indicators of iodine status and thyroid function, thyroglobulin (Tg), thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in serum, thyroid volume and urinary iodine concentration, in iodine-deficient schoolchildren under conditions of increasing iodine supply. The study was established as a double-blind, placebo-controlled oral administration of a single dose of iodized oil to schoolchildren (7-10 y old), living in an iodine-deficient area of Benin, with an observation period of 10 mo. However, 3-4 mo after supplementation, iodized salt became available in the area. The study population therefore comprised an iodized oil-supplemented group and a nonsupplemented group, both of which had variable, uncontrolled intakes of iodized salt during the last 6 mo of the study. Initial mean serum concentrations of TSH and FT4 were within the normal range, whereas serum Tg concentration, urinary iodine concentration and thyroid volume were indicative of moderate-to-severe iodine deficiency. At the end of the study, all indicators had improved significantly, except thyroid volume, which had decreased only in the supplemented group. The supplemented group also still had significantly lower serum Tg and higher urinary iodine concentrations than the nonsupplemented group. Serum Tg and urinary iodine concentrations are the indicators most influenced by a changing iodine supply. Current normal reference ranges of serum concentrations of TSH and FT4 are too wide for detecting iodine deficiency in this age group.

Lipiodol avid liver metastases from adrenocortical carcinoma; prospects for therapy?

A young lady with liver metastases from adrenocortical carcinoma was given a tracer dose of lipiodol into the hepatic artery and her liver metastases were shown to be extremely lipiodol avid. A therapeutic dose of lipiodol I131 was then given. There was not, however, any evidence of response to this treatment.

Efficacy of oral iodised oil is associated with anthropometric status in severely iodine-deficient schoolchildren in rural Malawi.

The effect of anthropometric status on the efficacy of an oral supplement of iodised oil (1 ml Lipiodol Ultrafluide, 490 mg I; Laboratoire Guerbet, Aulnay-sous-Bois, France) was examined in 8-10-year-old schoolchildren (n 197) of Ntcheu, a severely I-deficient district of Malawi. The study was a controlled trial using the I concentration of casual urine samples to monitor the I status. The median urinary I concentration increased from 0.15 micromol/l at baseline (51.3 % of children < 0.16 micromol/l, 89.7 % < 0.40 micromol/l, 95.7 % 0.79 micromol/l) to 0.32 micromol/l at 40 weeks (29.1 % of the children < 0.16 micromol/l, 71.0 % < 0.40 micromol/l, 96.1 % < 0.79 micromol/l) while the total goitre prevalence fell from 63 % to 21 %. Variables of efficacy were estimated from a hyperbolic function describing the longitudinal pattern of urinary I excretion after the dose. The I retention and I elimination rate, and the periods of protection from mild (< 0.79 micromol/l) or moderate (< 0.40 micromol/l) I deficiency were obtained for groups of children with differing anthropometric status at baseline. Initial height-for-age and mid upper-arm circumference were not significantly related to efficacy. However, both the I retention and I elimination rate were reduced in children with lower initial weight-for-height. Children with lower skinfold thickness at baseline also had reduced I retention, which resulted in shorter protection periods from recurrent moderate and mild I deficiency. The efficacy of the oral iodised-oil supplement was not related to changes in anthropometric status during follow-up, nor was it related to the consumption of a food supplement of 1610 kJ immediately before the iodised-oil dose. Very low (< 0.16 micromol/l) urinary I concentration, and the presence of goitre at baseline were both associated with higher I retention and elimination rate. Children with goitre at baseline were found to have a prolonged duration of protection against recurrent moderate I deficiency. We conclude that in apparently healthy schoolchildren in I-deficient areas, general anthropometric status has a little influence on the efficacy of oral iodised oil for correcting I deficiency.

Human liver cancer cells and endothelial cells incorporate iodised oil.

Iodised oil (lipiodol) administered via the hepatic artery localises selectively in primary liver cell cancers (hepatocellular carcinomas or HCCs) for prolonged periods and has been used as a vehicle for cytotoxic agents. Despite clinical use, the mechanism of lipiodol retention by tumours has remained unclear, embolisation of oil droplets in the tumour vasculature being the prevailing hypothesis. We have investigated the role of tumour and endothelial cells in lipiodol retention. Human liver tumour (Hep G2) cells and human umbilical vein endothelial cells in culture were exposed to lipiodol. Light microscopy using selective silver impregnation stains and transmission electron microscopy revealed lipiodol incorporation by both cell types, probably by pinocytosis. This was not associated with cellular injury in terms of cell lysis, cell replication or radio-labelled leucine uptake. Histological analysis of 24 HCCs either surgically resected or discovered incidentally at liver transplantation (with prior arterial injection of lipiodol) revealed vesicles of lipiodol in the cytoplasm of tumour cells and endothelial cells lining tumour vessels. Thus, lipiodol is likely to deliver cytotoxic agents directly into tumour cells and endothelial cells, both in vitro and in vivo. This may also apply to other lipids and to other human tumours. These findings have significant therapeutic implications.

Lipiodol accumulation in hepatic hemangioma. Detection with osmium postfixation.

Lipiodol has been used to increase the detectability of small primary neoplasms in the liver. We report a patient who was found to have lipiodol deposits in the liver one month after intra-arterial injection. The region was resected, under ultrasound control, because of the impression that the lesion was malignant. The specimen contained two small hemangiomas as well as many small dysplastic nodules (adenomatous hyperplasia) in a noncirrhotic parenchyma. To locate the lipiodol deposit in this case, the tissue was radiographed, postfixed in osmium tetroxide, and embedded in paraffin. Black osmium-stained deposits were found within the cavities of the hemangiomas but not in the dysplastic nodules. Most of the deposits were extracellular multivesiculated bodies with a small focus of lipid droplets engulfed by multinucleated foreign-body type giant cells. This report reinforces that hepatic lipiodol retention is not specific for hepatocellular carcinoma. We present, for the first time, the histologic appearance of lipiodol accumulation in an hemangioma. The value of osmium tetroxide postfixation for the detection of lipiodol is also demonstrated.

New model for describing urinary iodine excretion: its use for comparing different oral preparations of iodized oil.

Iodine excretion in urine after oral dosing with iodized oil is influenced by various factors involved in the retention and elimination of iodine by the body. In a study comparing different treatments of severely iodine-deficient schoolchildren from Malawi, a hyperbolic function was found to describe changes in urinary iodine concentration over time more adequately than a simple exponential function. Compared with oil A, comprising ethyl esters of iodized fatty acids, the retention and elimination of iodine from oil B, comprising triacylglycerol esters of iodized fatty acids, were significantly greater. The mean duration of effectiveness of oral iodized oil, based on urinary iodine concentrations > 0.40 mumol/L, was estimated to be 13.7, 9.9, and 52.5 wk for a single dose of iodized oil A (490 mg I), a split dose of iodized oil A (2 x 245 mg I), and a single dose of iodized oil B (675 mg I), respectively. Dividing the dose of oil A into two equal amounts given on consecutive days did not improve its efficacy.

Iodized oil in the treatment of hepatocellular carcinoma.

When injected into the hepatic artery the contrast agent Lipiodol (iodized poppy seed oil) is selectively retained by hepatocellular carcinoma (HCC) for a prolonged period of time. Liver computed tomography (CT) performed after Lipiodol angiography is more sensitive than ordinary CT at imaging HCC. Arterial administration of cytotoxic drugs and radioisotopes conjugated to Lipiodol has been shown to be reasonably safe in patients with irresectable HCC. These therapies, often combined with embolization, provide effective palliation, better tumour response and improved survival compared with other available treatments. Their use as a preoperative adjunct to surgical resection of HCC is controversial.

P-31 MR spectrum and histologic changes after intrahepatic arterial injection of iodized oil in normal and cirrhotic rat liver.

Injection of iodized oil (Lipiodol) into the hepatic artery is widely used in the diagnosis and treatment of hepatocellular carcinoma. However, no reports have yet appeared concerning temporal changes in hepatic metabolism following Lipiodol injection. In the present study, Lipiodol was injected into the hepatic arteries of normal and cirrhotic rats, successive P-31 MR measurements were performed, and temporal changes in metabolism were compared with histologic findings. Both normal and cirrhotic rats displayed minimum levels of beta-ATP/PME and beta-ATP/Pi 5 days after hepatic arterial injection of Lipiodol. However, 10 days after injection these values had reverted to the preinjection levels. The metabolic dysfunction observed in the liver following hepatic arterial injection of 0.3 ml/kg b.w. Lipiodol was transient. Moreover, no distinct differences were observed between P-31 MR changes in normal and cirrhotic rats. Conversely, histologic impairment assessed on the basis of hepatic necrosis ratios was most severe 2 days after hepatic arterial injection in both normal and cirrhotic rats, and this did not coincide with the time of the most pronounced metabolic impairment as inferred from P-31 MR changes.

Distribution of Lipiodol and evidence for tumor necrosis in hepatocellular carcinoma.

To study the distribution and thromboembolic effect of Ultrafluid Lipiodol, 15 surgically removed hepatocellular carcinomas with selective intraarterial Lipiodol injection 7 to 10 days before surgery and 15 noninjected controls were studied radiologically and histologically. Tissue blocks were processed with an en bloc silver impregnation technique for Lipiodol localization in histologic sections. Lipiodol was distributed evenly in tumors measuring less than 5 cm in diameter and peripherally in tumors measuring 10 cm or more. Lipiodol droplets were mainly extracellular. There was no difference in tumor architecture or in hemorrhage and necrosis scores between Lipiodol-injected cases and negative controls (1.18 versus 0.92). Similarly, in injected cases, no differences were observed between Lipiodol-positive and Lipiodol-negative areas (scores of x-ray Lipiodol-positive versus Lipiodol-negative areas: 1.17 versus 1.36; scores of microscopic Lipiodol-positive versus Lipiodol-negative areas: 1.18 versus 1.14). Lipiodol-negative but hypodense areas examined by x-ray proved to be necrosis or fibrosis with or without viable tumor islands. Lipiodol has no thromboembolic effects. The uneven Lipiodol distribution may account for its failure as a carrier for chemotherapeutic agents in large tumors.

Clinicopathological study on combination therapy consisting of arterial infusion of lipiodol-dissolved SMANCS and transcatheter arterial embolization for hepatocellular carcinoma.

Combination therapy (LpTAE) consisting of arterial infusion of a lipophilic anticancer drug, SMANCS, dissolved in an oily lymphographic agent, lipiodol (LPD), and transcatheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) was studied with special reference to the pathological findings. A total of 32 patients were subjected to surgical resection after LpTAE. The pattern of LPD deposition in the tumor was examined by CT scan (Lipiodol CT, LpCT) at 7 days and/or 1 month after LpTAE. The resected materials were examined radiographically with soft X-rays and histologically. LPD was deposited in tiny daughter nodules with a diameter of less than 5 mm and in tumor thrombi as well as in the main tumors, which showed necrotic change. Part of the LPD flowed out from the main tumor via the drainage vein and was deposited in the capsular invasion, resulting in necrosis. LPD accumulated almost exclusively within the blood spaces of trabecular-type HCC, creating a pattern corresponding to a cast of the tumor vessels, which showed prominent necrosis. On the other hand, LPD was not deposited in scirrhous, compact, or well-differentiated HCC, which showed little or no necrosis. It was demonstrated that LpCT images, which accurately depicted the existence and the extent of LPD deposition and necrosis in the tumor, were useful for precise evaluation of the therapeutic effect. Our findings indicate that LpTAE and LpCT are valuable for the diagnosis and treatment of HCC and should play a central role in systemic therapeutic approaches to this disease.

Case report: persistence of lipiodol for 13 months in metastatic deposits in the liver on computed tomography.

The computed tomography (CT) findings in a 17-year-old male student with liver metastases from a primary adenocarcinoma of the rectum are presented. Lipiodol-enhanced CT 4 days after lipiodol infusion demonstrated several metastases not visible on conventional CT. A repeat CT 13 months later showed lipiodol to have been retained within the original lesions and also demonstrated new metastatic deposits free of lipiodol. Although persistence of lipiodol for up to a year has been reported by workers in Japan imaging hepatocellular carcinoma (Yumoto et al., 1985) this experience has not been confirmed in the UK (Raby et al., 1989). There are relatively few reports investigating metastatic adenocarcinoma (Nakakuma et al., 1985), none of which refers to persistence of lipiodol over 1 year. This case report demonstrates the ability of lipiodol-enhanced CT to detect occult metastases and also to facilitate their follow-up and differentiation from newer lesions.