Radiation synovectomy using 165Dy ferric-hydroxide and oxidative DNA damage in patients with different types of arthritis.

UNLABELLED: Radiation synovectomy is an effective treatment for chronic synovitis refractory to pharmacological treatment in patients with rheumatoid or seronegative arthritis. Concerns persist about possible radiation-induced cytogenetic damage after radiation synovectomy leading to recommendations to use this technique only in the elderly. Micronucleus (MN) frequency in lymphocytes and urinary excretion of 8-hydroxy-2'-deoxyguanosine (8OHdG) as an indicator of cellular oxidative DNA base damage are biomarkers of radiation-induced cytogenetic damage. The course of both biomarkers was studied in patients with different types of chronic synovitis undergoing radiation synovectomy with very short-lived 165Dy-ferric-hydroxide (DFH). METHODS: Radiation synovectomy of the knee was performed in 13 men and 12 women (mean age, 44+/-15 y) using a mean activity of 9.48+/-1.65 GBq 165Dy-DFH in 27 consecutive treatments. MN frequency in lymphocytes and urinary excretion of 8OHdG, measured by high-performance liquid chromatography, were assessed before and 4 (MN only) and 20 h after radiation synovectomy. RESULTS: Urinary excretion of 8OHdG in patients (in micromol/mol creatinine; pretreatment mean, 3.1+/-3.4; median, 2.27) was not significantly different from that in healthy volunteers (mean, 2.0+/-1.2; median, 1.87) and not altered by radiation synovectomy (post-treatment mean, 2.5+/-1.5; median, 2.04, NS). An increase in 8OHdG levels after radiation synovectomy of more than 1 SD was found in only 1 patient, who experienced leakage to the lymph nodes but who already had elevated urinary 8OHdG levels before treatment. The frequency of MN/500 binucleated cells (BNCs) was slightly lower in patients (pretreatment mean, 4.3+/-2.6; median, 4.25) than in healthy volunteers (mean, 5.4+/-2.3; median, 5.3) and did not significantly change after therapy, either (4-h post-treatment mean, 3.9+/-2.1, median, 3.8; 20-h post-treatment mean, 4.1+/-2, median 3.8 MN/500 BNC). In 22 of 27 treatments, no leakage to nontarget organs could be monitored, whereas leakage to the local lymph nodes and the liver was detected after 5 treatments. CONCLUSION: Radiation synovectomy using 165Dy-DFH causes no significant radiation burden to most patients as indicated by the absence of adverse changes in levels of biomarkers of cytogenetic damage and a low incidence of leakage. These data suggest that the risk of malignancy may not be elevated.

Modeling radioprotective mechanisms in the dose effect relation at low doses and low dose rates of ionizing radiation.

A new model (Random Coincidence Model--Radiation Adapted (RCM-RA)) is proposed which explains a possible pseudo threshold for stochastic radiation effects. It describes the formation of cancer in the case of multistep fixation of lesions in the critical regions of tumor associated genes such as proto-oncogenes or tumor-suppressor genes. The RCM-RA contains two different possibilities of DNA damage to complementary nucleotides. The damage may be caused either by radiation or by natural processes such as cellular radicals or thermal damage or by chemical cytotoxins. The model is based on the premise that radiation initially is bionegative, damaging organisms at their different levels of organization. The radiation, however, also induces various cellular radioprotective mechanisms which decrease the damage by natural processes. Considering both effects together, the theory explains apparent thresholds in the dose-response relation for radiation carcinogenesis without contradiction to the classical assumption that radiation is predominantly bionegative at doses typically found in occupational exposures.

Monitoring of the biodistribution and biokinetics of dysprosium-165 ferric hydroxide with a shadow-shield whole-body counter.

Radiation synovectomy is indicated when conventional pharmacological treatment of chronic synovitis has proved insufficient. In these cases dysprosium-165 ferric hydroxide (DFH) has been demonstrated to be clinically effective. After application of the agent, blood activity measurements and monitoring of activity distribution by gamma camera imaging over the local lymph nodes and the liver are commonly performed for control of possible leakage. In addition, we have used a shadow-shield whole-body counter with a profile facility to evaluate the biokinetics and biodistribution of 165Dy-DFH. Fifteen intra-articular injections were performed in 13 patients who received a median activity of 6.8 GBq (range 0.5-9.9 GBq) 165Dy-DFH. Activity profiles were obtained with the whole-body counter 2, 4 and 6 h after injection of 165Dy-DFH. The doses to non-target organs were calculated using the software MIRDOSE 3. In 10 of 15 treatments, absence of any leakage could be demonstrated. The effect of scattered rays could be observed in 14 measurements. In three patients small amounts of activity could be detected in the urinary bladder and in three patients activity was detected in the local inguinal lymph nodes, while no leakage could be detected by camera imaging. In these cases the individual doses to the bladder were 15 Gy, 65 mGy and 50 mGy, and those to the lymph nodes, 0.54 Gy, 0.89 Gy and 2.41 Gy. The whole-body counter also enabled the monitoring of activity profiles related to more complex pathological structures. In conclusion, using a whole-body counter activity leakage could be detected with much higher sensitivity than by using a gamma camera. The biodistribution of 165Dy-DFH could be determined, and leakage could be localised and related to organs. These results encourage the use of a whole-body counter to identify the site and extent of activity leakage.