Mixed-ligand complexes of yttrium-90 dialkyldithiocarbamates with 1,10-phenanthroline as a possible agent for therapy of hepatocellular carcinoma.

Yttrium-90 is a radioelement which has found wide use in targeted radionuclide therapy because of its attractive physical and chemical properties. Radioembolisation of hepatocellular carcinoma with radiolabelled Lipiodol is a method of choice. We have synthesised a series of alkyldithiocarbamate yttrium complexes, easily extracted into Lipiodol due to their high lipophilicity. Among the prepared series, a new radioconjugate, which is stable over an extended period of time, has been prepared, and could represent a potential treatment procedure for hepatocellular carcinoma.

[Radioembolisation for hepatocellular carcinoma]. / Traitement des carcinomes hépatocellulaires par injection intra-artérielle de radio-isotopes.

Hepatocellular carcinoma is now a major public health concern. In intermediate stages (one third of hepatocellular carcinoma patients), chemoembolization is the standard of care despite a poor tolerance and a moderate efficacy. Moreover, despite recent improvements, this technique seems in a dead end. Radioembolization could be an excellent tool for such patients. Currently (131)I-Lipiodol, (188)Re-Lipiodol, (90)Y-glass or resin microspheres are available. More recent and promising data come from microspheres, but phase II and III studies are needed before drawing any conclusion. In the future, the combination of radioembolization with systemic chemotherapy or targeted agents (particularly antiangiogenic drugs) seems very promising.

131-iodine Lipiodol therapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major health concern worldwide. Several therapeutic options are available, but transplantation is the only curative option; for the vast majority of patients, the remaining alternative is palliative care. There is some hope however with Lipiodol which, when injected into the hepatic artery remains concentrated in the liver and specifically within the malignant tumor for a long period of time. This feature has been used for internal radiation therapy using (131)Iodine-labeled Lipiodol. Phase III studies with (131)I-Lipiodol have demonstrated, in an adjuvant setting improved recurrence-free and overall survival compared with surgery alone and in a palliative setting improved survival among patients with portal thrombosis. Comparison with chemoembolization has shown similar results in terms of efficacy but with better tolerance for (131)I-lipiodol. The method would also be useful for small nodules not amendable to surgery or percutaneous treatment. The use of another radionuclide, (188)Re, could probably improve the current method by reducing the need for radioprotection. New perspectives will be forthcoming with the advent of targeted drugs using combinations in sequential or concomitant regimens.

Description and technical pitfalls of a hepatoma model and of intra-arterial injection of radiolabelled lipiodol in the rat.

Intra-arterial metabolic radiotherapy (using lipiodol labelled with iodine-131 or rhenium-188) is a therapeutic approach that can be used for the treatment of hepatocellular carcinomas (HCC). We propose a detailed description of the tumoral model using the N1-S1 cell line as well as a technique for intra-arterial injection of radiolabelled lipiodol in order to undertake preclinical studies necessary for the evaluation of a new molecule. We also report the principal technical pitfalls that were faced. The speed of injection of the tumoral cells is a key factor in the tumoral induction since slow injections lead to a tumoral induction rate of 36.3% compared with 76.6% (P<0.01) when using very slow injections. This parameter should thus be controlled carefully during the subcapsular injection of the tumoral cells. In addition, when injecting radiolabelled lipiodol, anaesthesia should not be performed with isoflurane since this leads to a reduction in tumoral uptake. Indeed, we found a 'tumour/healthy liver' uptake ratio of only 2.1+/-0.7 with isoflurane as against 4.4+/-2.6 (P<0.05) when anaesthesia was carried out by intraperitoneal injection of ketamine. Lastly, we show that the tumour size has an influence on the tumoral uptake of radiolabelled lipiodol; therefore, this parameter must also be carefully controlled.

Development and biodistribution of 188Re-SSS lipiodol following injection into the hepatic artery of healthy pigs.

Although intra-arterial radiotherapy with (131)I-labelled lipiodol is a useful therapeutic approach in the treatment of hepatocellular carcinomas, various disadvantages limit its use. Here we describe the development of (188)Re-SSS lipiodol, as well as its biodistribution in the healthy pig after injection into the hepatic artery. The (188)Re-SSS lipiodol was obtained after dissolving a chelating agent, previously labelled with (188)Re, in cold lipiodol. The radiochemical purity (RCP) of the labelling was checked immediately and at 24 and 48 h. The (188)Re-SSS lipiodol was injected into the hepatic artery of six healthy pigs. They were killed 1, 24 and 48 h post injection, for ex vivo counting. An autoradiographic study was performed in three cases. (188)Re-SSS lipiodol was obtained with a yield of 87%+/-9.1%. The immediate RCP was 93%+/-3.4%. This radiolabelling was reproducible and stable at 48 h in plasma: 90.6%+/-1.5% of the activity remained in the lipiodol with an RCP of 91%+/-4%. Ex vivo counting confirmed the predominantly hepatic uptake and revealed weak lung and intestinal uptake. There was very weak urinary elimination (2.3%+/-0.5% at 48 h) and a slightly higher level of intestinal elimination (4.8%+/-1.9% at 48 h). The autoradiographic studies showed (188)Re-SSS lipiodol to be located mainly in sinusoids, like (131)I-lipiodol. By using the method described here, (188)Re-SSS lipiodol can be obtained with a very high yield and a satisfactory RCP. Its biodistribution in the healthy pig is in agreement with data published elsewhere concerning other types of radiolabelling used for lipiodol, except for the very weak urinary and intestinal elimination, which probably indicates better stability of (188)Re-SSS labelling.

Safe radiation exposure of medical personnel by using simple methods of radioprotection while administering 131I-lipiodol therapy for hepatocellular carcinoma.

The intra-arterial administration of 131I-lipiodol is a therapeutic approach increasingly used for the treatment of inoperable hepatocellular carcinomas. This technique has even become the reference treatment for hepatocellular carcinomas with portal thrombosis and is the only effective treatment to reduce the risk of recurrence among patients who could benefit from surgical operation. Currently, few data have been published concerning the levels of exposure for personnel carrying out this type of treatment. We undertook a dosimetric study targeted mainly on the exposure of the person performing the injection of 131I-lipiodol to show that this treatment can be carried out with an exposure at the extremities distinctly lower than the regulatory annual threshold by using simple means of radioprotection. The point of puncture was carried out at the level of left femoral artery, the preparation and injection of the therapeutic dose was carried out extemporaneously by the nuclear medicine specialist using a 10 ml syringe (for an injected volume of 4 ml) fitted with an adapted syringe protector. The injection was carried out as rapidly as possible under scopic control while avoiding reflux, with compression carried out by the radiologist. This study comprises 52 intra-arterial injections of 131I-lipiodol (2016+/-92 MBq). For the nuclear medicine specialists, 52 measurements were carried out at the level of the thorax and 41 on the fingers. For the radiologists, 22 measurements were carried out at the level of the thorax and six on their index fingers; nine measurements were carried out at the level of the thorax for the technologist and four at the level of the thorax for the stretcher bearer. For the nuclear medicine specialists, the average dose received at the level of the fingers varies between 140 and 443 microSv (according to the fingers) and the average dose at the thorax is 17 microSv. For the radiologists, the average dose received is 215 microSv at the level of the fingers and 15 microSv at the thorax. These results show that the administration of high therapeutic activities of 131I-lipiodol can be carried out for the exposed personnel with a dose at the level of the fingers much lower than the European regulatory limit of 500 mSv.

Therapy of renal anemia in children and adolescents with recombinant human erythropoietin (rHuEPO).

Eleven anemic children and adolescents with a median age of 14 years (range six months-20 years) on chronic hemodialysis were treated with recombinant human erythropoietin (rHuEPO) intravenously three times a week for an average of 9.2 months. After eight weeks of therapy, hematocrit rose from 20.3 +/- 1.4% to 31.7 +/- 0.7% (0.20 +/- 0.01 to 0.31 +/- 0.007, p less than 0.001, mean +/- SEM). After reaching the target hematocrit of 30% to 33% (0.30 to 0.33), doses were adjusted individually. Blood transfusions were eliminated in all but one patient. All patients experienced an increase in appetite and energy level. Serum ferritin concentrations decreased in all patients who reached target hematocrit and seven required iron supplementation. Hypertension worsened in two patients and developed in two others. One patient's vascular access clotted. Dialysis efficiency and heparin requirements during dialysis did not change significantly. We conclude that rHuEPO is safe, effective, and should be recommended as treatment for anemia in children and adolescents on hemodialysis, but close monitoring for the development of hypertension and/or iron deficiency is necessary.