Patient dosimetry after 131I-MIBG therapy for neuroblastoma and carcinoid tumours.

AIM: The aim of the study was to determine the equivalent total body dose (ETBD) using the cytokinesis-blocked micronucleus assay in 22 131 I-meta-iodobenzylguanidine (131 I-MIBG) therapies (18 neuroblastoma, mean 5097 MBq, SD 1591; and four carcinoid tumours, mean 7681 MBq, SD 487). The results are correlated with the total body radiation dose according to the Medical Internal Radiation Dosimetry (MIRD) formalism. METHODS: For each patient, blood samples were taken immediately before and 1 week after 131I-MIBG therapy. The first blood sample was irradiated in vitro with 60Co gamma-rays to determine the dose-response curve. Micronuclei were scored in 1000 binucleated cells. By using the dose-response curve the ETBD was derived from the increase in micronuclei after 131I-MIBG therapy (second blood sample). Based on three consecutive biplanar scans taken at 3, 6 and 9 days post-administration respectively, the total body dose following the MIRD formalism was calculated. RESULTS: The micronucleus assay was evaluable in only 14 out of 22 131I-MIBG therapies due to cell division inhibition caused by previous chemotherapy treatments and lymphocyte dilution due to blood transfusions given shortly after 131I-MIBG therapy. For these 14 therapies, the mean micronucleus yield after 131I-MIBG therapy was significantly increased (P < 0.01) with a mean of 92 (SD 77) for neuroblastoma patients and with a mean of 35 (SD 8) for carcinoid patients. The increase observed in the present study is greater than previously observed after 131I therapy and 89Sr therapy but much lower than after external beam radiotherapy. For all patients treated with multiple therapies, the initial increase in micronucleus yield had at least partially recovered by the time of the next therapy. This might be explained by an increased turnover of lymphocytes. A mean ETBD of 0.95 Gy (SD 0.55) for neuroblastoma patients and a mean of 0.46 Gy (SD 0.09) for carcinoid patients was calculated. A reasonable correlation (R = 0.87) between the ETBD and the MIRD dose was obtained. The slope value of 0.75 can be explained by the low dose rate effect. CONCLUSIONS: The observation in the present study of important inter-individual variability in the total body dose, with the possibility of high dose values, suggests the necessity of individual dosimetry when administering 131I-MIBG therapy, especially considering that generally more than one therapy is given to each patient.

Dosimetry from organ to cellular dimensions.

While the conventional Medical Internal Radiation Dose (MIRD) approach is useful for estimating approximate organ absorbed doses in diagnostic applications of isotopes, this strategy is suited neither to the exacting requirements of targeted radionuclide therapy nor to radiopharmaceuticals with a non-uniform activity distribution. For the individual treatment planning of patients treated with common radionuclides emitting high energy betas, the individual activity distribution has to be obtained from CT-SPECT images and the doses to the target organs and critical tissues have to be calculated by point-kernel methods. Due to the stochastic nature, alpha-radioimmunotherapy (alpha-RIT) requires microdosimetric calculations with Monte Carlo on a realistic model of the source and target tissue at the micrometer level. For a prediction of the biological effects of intracellular labelling with Auger electron emitters an accurate subcellular modelling including the DNA structure at the nanometre level with knowledge of the target for the considered biological effect is necessary.

Adaptive response in patients treated with 131I.

UNLABELLED: The aim of this study was to investigate whether an adaptive response (defined as the induction of radiation tolerance after a small dose of radiation) could be observed in peripheral blood lymphocytes of patients treated with 1311 for thyroid disease. METHODS: For each patient, blood samples were taken immediately before and 1 wk after 131I administration. Each blood sample was divided into 3 fractions and the fractions were subsequently irradiated in vitro with 0, 0.5, and 1.0 Gy 60Co gamma-rays. After blood culture for 70 h, cells were harvested and stained with Romanowsky-Giemsa and micronuclei were counted in 1000 binucleated cells. The increase in micronuclei by the in vitro irradiation of the blood samples taken before and after therapy was compared. In this setup, an adaptive response is represented by a significant decrease of the in vitro induced micronucleus yield after therapy compared with that before therapy. The iodine therapy can be considered as an in vivo adaptation dose, after which the subsequent in vitro irradiation acts as a challenge dose. To investigate the reproducibility of the method, 2 subsequent blood samples of healthy volunteers were taken 7 d apart. Irradiation and cell culture were performed as described. RESULTS: In 8 of 20 patients, a significant (P = 0.0002) decrease was found in the in vitro induced micronucleus yield in the blood sample taken 1 wk after 1311 administration compared with that of the blood sample taken before therapy. No significant (P > 0.1) differences were observed between these 8 patients and the other patients when the number of micronuclei induced in vivo by the iodine treatment and the resulting equivalent total body dose were compared. None of the control subjects showed a significant change in micronucleus yield after in vitro irradiation between both blood samples taken 1 wk apart. CONCLUSION: The iodine treatment can act as an in vivo adaptation dose and can induce an adaptive response that is observed by a decrease of the cytogenetic damage in peripheral blood lymphocytes after in vitro irradiation as a challenge dose. A large interindividual difference was observed.

Estimation of risk based on biological dosimetry for patients treated with radioiodine.

A multicentre study was undertaken to assess the cytogenetic damage to peripheral blood lymphocytes in 31 patients treated with 131I for thyrotoxicosis using the cytokinesis-blocked micronucleus assay. The results were compared to those for eight thyroid carcinoma patients using the same method. For each patient, blood samples were taken immediately before and 1 week after iodine administration. The first blood sample was divided into three fractions and each fraction was subsequently irradiated in vitro with 0, 0.5 and 1 Gy 60Co gamma rays, respectively. After blood culture for 70 h, cells were harvested, stained with Romanowsky-Giemsa and the micronuclei scored in 1000 binucleated cells. For both patient groups, a linear-quadratic dose-response curve was fitted through the data set of the first blood sample by a least squares analysis. The mean increase in micronuclei after 131I therapy (second blood sample) was fitted to this curve and the mean equivalent total body dose (ETBD) calculated. Surprisingly, in view of the large difference in administered activity between thyroid carcinoma patients and thyrotoxicosis patients, the increase in micronuclei after therapy (mean +/- S.D.: 32 +/- 30 and 32 +/- 23, respectively) and the equivalent total body dose (0.34 and 0.32 Gy, respectively) were not significantly different (P > 0.1). The small number of micronuclei induced by 131I therapy (32 +/- 29), compared with external beam radiotherapy for Hodgkin's disease (640 +/- 381) or cervix carcinoma (298 +/- 76) [1], gave a cancer mortality estimate of less than 1%. This also explains why late detrimental effects in patients after 131I treatment have not been reported in the literature.

Characteristics of creatine release during acute myocardial infarction, unstable angina, and cardiac surgery.

Creatine release was compared in various conditions of muscle damage: acute myocardial infarction (AMI), unstable angina, and cardiac surgery. After AMI, serum and urine creatine concentrations increased transiently. After cardiopulmonary resuscitation, serum creatine values were significantly higher because of impaired renal function, whereas urinary creatine concentrations were comparable. In 38 patients with unstable angina, no significant changes in serum and urine creatine concentrations were seen. In 37 of 92 AMI patients, secondary creatine peaks were observed 20.9 +/- 8.1 h after onset of symptoms. The magnitudes of the first and second peaks were correlated: Spearman r = 0.66. In 24 patients who underwent cardiac surgery, the changes in creatine concentration in serum during surgery were very small, despite the presence of muscle trauma.

Acute myocardial infarction size and myoglobin release into serum.

The kinetics of myoglobin release after acute myocardial infarction were studied. Various algorithms for calculation of infarct size, based on immunonephelometric determination of myoglobin and cumulative myoglobin release into the circulation were compared. The cumulative myoglobin release and maximal serum myoglobin concentration were compared with various measures of infarct size: cumulative release of creatine kinase, electrocardiographic changes, and left ventricular ejection fraction. After acute myocardial infarction, time to peak for myoglobin in serum was correlated with time to peak for creatine kinase (r = 0.645). On average, the myoglobin concentration peaked 8.8 h earlier than creatine kinase activity. The rate of elimination of myoglobin showed a large variation (0.041-0.628 h-1) and was not correlated with the elimination rate of creatine kinase. The elimination rate of myoglobin after acute myocardial infarction was shown to depend on the patient's age and infarct size. The elimination constant of myoglobin is preferably estimated on an individual basis in large and complicated infarctions. Cumulative myoglobin release correlated with algorithms based on the cumulative release of creatine kinase (r = 0.622) and its isoenzyme MB (r = 0.660), and to a lesser extent with the residual left ventricular ejection fraction (r = 0.513) and the sum of ST-segment deviations on electrocardiography (r = 0.469). Maximal myoglobin values in serum correlated moderately with the calculated infarct size (r = 0.488; based on creatine kinase-MB) and electrocardiographic changes (r = 0.554). In combination with fast immunological methods for myoglobin determination, myoglobin peak height offers the advantage of providing reliable results within 12 h after onset of symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphocyte labeling with technetium-99m-HMPAO: a radiotoxicity study using the micronucleus assay.

The cytogenetic radiation damage to lymphocytes after in-vitro labeling of mixed leukocytes and isolated lymphocytes with 99mTc-hexamethylpropyleneamine oxime (HMPAO) was evaluated using the cytokinesis-blocked micronucleus assay. A direct assessment of the radiation damage to the lymphocytes after a labeling procedure of leukocytes separated from 46 ml blood with 740 MBq of 99mTc-HMPAO was not possible due to an almost complete impairment of the proliferative capacity. By starting with isolated lymphocytes, the number of micronuclei was studied versus the intracellular activity concentration in the range 0-3 MBq/10(7) lymphocytes for three donors. A comparison of these results with the dose response of the micronucleus incidence in lymphocytes after in-vitro irradiation with x-rays allowed an individual assessment of the x-ray dose, inducing the equivalent amount of clastogenic damage as the intracellular activity after 99mTc-HMPAO labeling. Based on an extrapolation of these data, the radiation damage of the lymphocytes due to self-irradiation in a labeling procedure of leukocytes with 740 MBq of 99mTc-HMPAO was estimated to be equivalent to 26 Gy of x-rays. Due to the observed almost complete inhibition of the proliferative capacity at this high dose level, the increased risk for a lymphoid malignancy after administration of isolated lymphocytes or mixed leukocytes labeled with 99mTc-HMPAO activities sufficient for scintigraphy can be regarded as small.