Thomas E. Hilditch

Investigation of factors affecting adhesion of 99Tcm labelled colloids to glass vials.

Factors which may possibly influence the adhesion of 99Tcm labelled colloid to glass vials were investigated. Of five colloids studied, two protein-free tin colloids were affected most by the problem, some 12–18% being lost by adhesion to the glass vial when the colloid was left resting on the bench, or 60–87% when it was rotated for a period of 4 h. The proportion of activity which adhered to the vial was dependent on the time the product had been contained within it, whether on the bench or rotated. Two of the colloids, both of which contained protein, were affected only slightly by the problem one being a tin colloid and the other a sulphur colloid. An antimony sulphide colloid, which contained no added protein, was virtually unaffected by the problem. The degree of adhesion was not related to the pH of the product, nor to the temperature at which the product was stored, nor to the tendency of the colloidal particles to grow in size upon vigorous agitation.

The significance of bone islands, cystic areas and sclerotic areas in dysbaric osteonecrosis

Dysbaric osteonecrosis is a major hazard to compressed air workers and an increasing hazard to divers. Symptomless osteonecrosis is best recognised by radiology and it is of fundamental importance that interpretation be reliable and accurate. There is much controversy concerning the significance of bone islands and cystic areas; several authors report bone islands and cystic areas to be up to eight times more frequent in compressed air workers and divers and believe that these represent positive evidence of osteonecrosis. Skeletal radiographs of 100 Royal Navy divers, all of whom were at risk to osteonecrosis were matched for age and rank with 100 controls, none of whom had been exposed to high pressures. The radiographs were interpreted by three radiologists working independently without knowing whether the radiographs were in the diving or control group. It is concluded that bone islands, cystic areas and sclerotic areas, as described in this text, occur with equal frequency in divers as in the normal population and do not represent positive evidence of osteonecrosis. The report includes autopsy studies of the proximal femur and proximal humerus in six diving fatalities. Five bone islands in the proximal humerus and one in the femoral neck were studied in bones removed from five divers. In the sixth case a cyst was seen to develop radiologically in the femoral neck and then reduce in size over 3 years and 10 months. Slab radiographs and histological section in all cases show no evidence of osteonecrosis.

Formation of large particles in a 99Tcm-tin colloid preparation.

The effect of prolonged continuous movement on particle size within a 99Tcm-tin colloid preparation was investigated, making use of photon correlation spectroscopy for size estimation.No increase in particle size was found when the preparation was left undisturbed for up to 7 h, the mean (±S.D.) size being found to be 239±24 nm. When the preparation was placed in a laboratory rotator for the same period of time, there was a gradual increase in mean particle size to 404±127 nm. The increase in size was much greater, however, after 7 h of continuous agitation in a laboratory shaker, a mean value of 2260±746 nm being observed. An antimony sulphide colloid was subjected to continuous agitation for the same period of time but there was no evidence of aggregation.It is supposed that continuous movement of reconstituted 99Tcm-tin colloid, leading to a marked increase in particle size, may explain occasional instances of significant lung intake.

Re: The So-Called Stunning of Thyroid Tissue

TO THE EDITOR: In a recent report, Sisson et al. (1) hypothesized that so-called stunning of thyroid tissue results from the early effects of the ablation dose of 131I in the form of accelerated disappearance of the therapeutic radionuclide from thyroid tissue. It was argued that initial uptake of the therapeutic dose within the first day (determined in their study by extrapolation of observed data back to time zero) was not impaired by the diagnostic dose of 131I. So-called stunning—that is, reduced uptake of the therapeutic dose observed from day 1 onward— results from more rapid clearance of the therapeutic radioiodine than of the diagnostic radioiodine. This hypothesis is somewhat at variance with our postulate (2) that the process of ablation begins with radiation damage to the iodine uptake mechanism of the cells within the thyroid remnant. In other words, there is a degree of self-stunning as the therapeutic radionuclide is being taken up by thyroid tissue, leading to a relative reduction in initial uptake. Their hypothesis (1) is based on observations on 10 patients in whom the time course of radionuclide in thyroid tissue was studied after the administration of diagnostic and therapeutic 131I. The intention was to measure thyroid uptake of both diagnostic (37 MBq [1 mCi]) and therapeutic (1,110 MBq [30 mCi] or 5,550 MBq [150 mCi]) radionuclide daily for the first 7 d. In fact, this daily measurement was achieved in only 3 patients because of difficulties with patient compliance after administration of the diagnostic dose. Visual inspection of their data indicates that in 2 of this small subgroup of patients, clearance of the therapeutic radionuclide was indeed more rapid. In the third patient, the clearance curves for both doses of radionuclide were similar. In the remaining 7 patients, the data were insufficient to draw any conclusions on the comparative clearance of 131I after administration of diagnostic and therapeutic radionuclide. However, the main basis for their hypothesis is their model of iodine kinetics for an ablative dose of radioiodine. In 5 patients, the disappearance of 131I was biexponential, with a rapid first phase, but the fact that only 5 data points were used (from either day 1 or day 2 onward) imposes some uncertainty on the derived curve parameters. Furthermore, 2 outlier points were excluded in 2 of the 5 patients. In the remaining patients, the disappearance was either monoexponential or followed an unusual pattern of late acceleration. The best-fit curves were then extrapolated back to time zero, and a ‘‘reasonable assumption’’ was made that the ‘‘near-maximum uptakes of radioiodine are between 6 and 24 h after ingestion.’’ It would be interesting to know the basis for this assumption. In normal thyroid tissue, the half-time of iodine uptake is usually taken to be 8 h (3), implying that maximal uptake does not occur before 24 h, albeit in the presence of normal thyroid-stimulating hormone levels. The limited diagnostic uptake data (only 2 data points in 7/10 patients) were also extrapolated back to time zero, and therapeutic or diagnostic uptake ratios were calculated at 2, 1, 0.25, and 0 d, the mean ratios at these time points being 0.65, 1.01, 1.63, and 2.26, respectively. From analysis of these data, the authors (1) concluded that only 1 patient showed a pattern that could reflect a substantial impairment of uptake of 131I by thyroid tissue. An alternative conclusion from their published data is that, compared with diagnostic radioiodine, therapeutic radioiodine showed unexpectedly enhanced uptake in 5 of 10 patients. This conclusion raises doubts about the validity of their assumption with respect to the time of maximal uptake and the use of limited data for extrapolation purposes. In our work (2), we quantitatively compared 131I and 123I as diagnostic agents. Our results in the case of 131I were broadly similar to those reported by Sisson et al. (1) in that the thyroid content of therapeutic radioiodine (a 4,000-MBq [108-mCi] dose) was substantially less that that of diagnostic radioiodine (a 120MBq [3.2-mCi] dose) 1–3 d after dose administration. In the case of 123I, we compared the uptake of a diagnostic dose of 131I (200 MBq [5.4 mCi]) and an ablative dose of 131I (4,000 MBq [108 mCi]) at 24 h after administration in 16 patients. We took care to ascertain the response of our g-camera system to high counting rates and to allow for the different absorption characteristics of photon emissions from the 2 radionuclides. For measurement of therapeutic uptake, we preset the g-camera to a high counting-rate mode and corrected for any count losses, as detailed in our paper. Some other camera systems do not allow the operator to preset a high counting-rate mode; the system automatically switches over depending on counting rate, potentially leading to anomalies in serial studies of uptake, in which the counting rate is decreasing daily. Sisson et al. (1) give little detail on the counting-rate response of the g-camera systems used in their study. The results for 123I were unexpected in that stunning was still observed, albeit to a lesser extent than with 131I (58.8% and 32.8%, respectively, for the ratio of median therapeutic uptake to diagnostic uptake). This finding led us to conclude that the ablative dose itself, on being taken up by thyroid tissue, caused radiation damage to the iodine-trapping function of the cells, thus inhibiting uptake. We calculated that a substantial radiation dose could be delivered to thyroid tissue within the first 8 h of administration of the ablative radioiodine. Comparison of 2 uptake measurements (% dose) 1–3 d after therapy in 15 patients revealed some loss of radionuclide due to biologic turnover, but the result did not achieve statistical significance in the group as a whole. It is difficult to compare this finding with the data published by Sisson et al. (1) because their disappearance curves included radioactive decay. Both papers raise the possibility that so-called stunning is partly due to injury to thyroid tissue by the ablative dose. We suggested that the observed reduction in uptake is due in part to early damage to the iodine uptake process by the ablative dose (2), whereas Sisson et al. have suggested that the primary cause of ‘‘stunning’’ is early destruction of thyroid tissue (1). In their hypothesis, initial uptake of the ablative dose is not impaired.

Technetium-99m-tetrofosmin: retention of nitrogen atmosphere in kit vial as a cause of poor quality material.

Technetium-99m (99Tcm)-tetrofosmin was prepared using four different reconstitution methods. The radiochemical purity (RCP) of these products was assessed 8 h later using thin layer chromatography (TLC). Material produced using the original method supplied by the manufacturer and using an newer method, which involves the use of a vent needle and the addition of air, had acceptable RCP (mean±SD 94.2±1.1% and 94.7±1.7%, respectively) and similar chromatograms. In addition, both products showed good clinical efficacy and exhibited normal biodistribution behaviour. Preparing 99Tcm-tetrofosmin using the two other methods, one using a high radioactive concentration and the other maintaining the nitrogen content of the kit vial, gave rise to chromatograms with reduced RCP (63.5±10.9% and 61.9±7.6%, respectively) and greater levels of impurities. Although neither of these last two preparations was used clinically, we suggest that reports of poor quality images may be the result of administration of materials similar to these. Results for the high radioactive concentration method were as expected and are consistent with the restrictions imposed by the manufacturer. However, results using the last method are surprising and would suggest that the production of good quality 99Tcm-tetrofosmin is dependent on the quantity of nitrogen in the kit vial. We believe that the amount of nitrogen removed from the kit vial during the process of reconstitution is critical. If too much nitrogen is present this will result in poor quality material. In practice it is conceivable that there could be occasions when insufficient nitrogen is removed when following the manufacturers original guidance, thereby leading to low RCP material. To ensure adequate nitrogen is removed during reconstitution, adoption of the manufacturers revised method, involving the deliberate introduction of air, is therefore appropriate.

The design and construction of a central radiopharmacy

Following an inspection by the Medicines Control Agency (MCA) of the existing radiopharmacy, it was necessary to design and build a new facility at the Western Infirmary to supply radiopharmaceuticals for patient use throughout the West of Scotland. This is one of the largest radiopharmacies in Europe, supplying some 40 000 patient doses per year prepared using both closed and open procedures. The design parameters and construction details of the new facility are presented.

Formation of labelled colloid in 99Tcm-DMSA due to the presence of bactericidal fluid

The possibility that traces of bactericidal fluid in 99Tcm-DMSA could lead to the formation of labelled colloid, was explored. In vitro investigations were undertaken using ultracentrifugation techniques and photon correlation spectroscopy. The latter showed that both contaminated and uncontaminated DMSA contained colloidal (or particulate) material. However the presence of 10 μl bactericidal fluid as contaminant was shown by ultracentrifugation to result in labelling of this colloidal material when 99Tcm was added to DMSA.Studies in a normal volunteer confirmed the results of the in vitro studies, in that significant liver and spleen uptake was observed after the administration of contaminated 99Tcm-DMSA.

Long-lived radiopharmaceuticals: dispensing from multidose vials.

We report the use of broth simulation as a means of validating the practice of sub-dispensing from stock vials of long-lived sterile radiopharmaceuticals. ‘Matched’ vials of nutrient broth accompanied the stock vials of long-lived sterile radiopharmaceuticals during their time in use and were subject to the same handling and storage procedures. At the end of the life of each radiopharmaceutical stock vial, the matching broth residue was sent for incubation and reporting. The results to date have yielded no reports of microbial contamination in any of the simulated broths (0 in 256).

Automated radiopharmaceutical dispensing.

An automated workstation, developed for clinical biochemistry, has been evaluated for potential use in preparing radiopharmaceuticals. It was found that substantial modifications, both hardware and software, would be required but the approach seemed feasible.