Biomedical subjects
Publications and source records attributed to B L Shulkin.
Gallium-67 citrate has been useful in providing scintigraphic evidence for pericarditis and myocarditis. However, the differentiation between pericardial and myocardial localization is difficult with planar images alone. SPECT can be valuable in making these distinctions, and a case of myocarditis is presented in which uptake of Gallium is shown to lie within the heart, correlating with the histologic proof.
Iodine-131 MIBG scintigraphy may be used to determine the presence or absence of metastases to the appendicular skeleton in malignant pheochromocytoma and neuroblastoma. Normal bones show no uptake of [131I]MIBG and the joints are seen as photon-deficient areas surrounded by background muscle activity. Discrete concentrations of radioactivity in bone are often seen in patients with malignant pheochromocytoma and neuroblastoma. Bone marrow involvement in neuroblastoma may be indicated by diffuse uptake of [131I]MIBG or focal accumulation at the metaphyses. Uncommonly, bone involvement may not be displayed by the [131I]MIBG images. Since conventional bone scanning agents may also fail to detect these tumors, skeletal scintigraphy with both [131I]MIBG and [99mTc]MDP is necessary to reliably stage malignant pheochromocytoma and neuroblastoma.
I-131 metaiodobenzylguanidine (I-131 MIBG) is a well established imaging agent that reliably detects pheochromocytoma. In some patients, however, I-131 MIBG may fail to localize pheochromocytoma. I-123 MIBG has several potential advantages over I-131 MIBG, and these advantages may enable locating pheochromocytomas which have eluded other techniques, including I-131 MIBG imaging. A patient with primary extra-adrenal pheochromocytoma is described who illustrates the superiority of I-123 MIBG for the imaging of pheochromocytoma.
99mTc-DTPA scintigraphy was evaluated in seven patients as a technique to assess perfusion of the transplanted pancreas and kidney. Such scans provide high-quality images of both organs in both the flow phase and later phases. The radionuclide is readily available and its brief effective half-life allows repeated evaluations at short intervals. 131I-hippuran, the major radiopharmaceutical for renal transplant scintigraphy, does not allow visualization of the transplanted pancreas or evaluation of its blood supply. Although the blood glucose is a gross indicator of the function of the pancreatic allograft, pancreatic scintigraphy with 99mTc-DTPA in one case was capable of detecting graft dysfunction before elevation of the blood glucose occurred. While additional studies will be necessary to determine the predictive value of this test, 99mTc-DTPA is valuable for pancreatic-renal transplant evaluation.
Iodine-123-4-amino-3-iodobenzylguanidine ([123I]AIBG), an analog of 123I metaiodobenzylguanidine ([123I]MIBG), has an advantage in having a more rapid and simple synthesis. This, combined with animal data that suggested a greater affinity of the new radiopharmaceutical for the autonomic innervation of the myocardium led us to study the biodistribution of [123I]AIBG in three men with metastatic pheochromocytoma. In all instances, [123I]AIBG revealed the same metastatic deposits shown by [123I]MIBG. Iodine-123 AIBG uptake, however, was greater than [123I]MIBG in lung, gut, and spleen. These higher backgrounds may pose diagnostic problems in some cases.
The effect of caloric restriction, as a model of nonthyroid illness, on serum thyroid hormone and TSH concentrations in hypothyroid patients was studied to determine if pituitary-thyroid function is altered in such patients, as it is in euthyroid subjects. Serum T4, T3, and TSH concentrations and serum TSH responses to TRH were measured in 5 untreated hypothyroid patients and 10 hypothyroid patients receiving T4 replacement therapy before and after restriction of caloric intake to 500 cal daily for 7 days. In 5 untreated hypothyroid patients, the mean serum T3 concentration declined 17%, from 75 +/- 14 (+/- SE) to 62 +/- 11 ng/dl. The mean basal serum TSH concentrations were 154 +/- 67 (+/- SE) microU/ml before and 161 +/- 75 microU/ml at the end of the period of caloric restriction, and the serum TSH responses to TRH were similar on both occasions. In 10 T4-treated hypothyroid patients, the mean serum T3 concentration declined 35%, from 110 +/- 8 to 71 +/- 8 ng/dl. In this group, mean basal serum TSH concentrations were 17 +/- 5.1 microU/ml before and 18.2 +/- 7.0 microU/ml at the end of the period of caloric restriction, and as in the untreated hypothyroid patients, the serum TSH responses to TRH were similar on both occasions. Mean serum T4 concentrations and serum free T4 index values did not change in either group. These results indicate that caloric restriction in both untreated and T4-treated hypothyroid patients is accompanied by 1) reduced serum T3 concentrations, as it is euthyroid subjects, and 2) no alterations in basal or TRH-stimulated TSH secretion.
beta-Adrenergic antagonists provide moderate symptomatic relief for most hyperthyroid patients, although these agents have no direct antithyroid effects. Propranolol administration results in modest declines in serum T3 concentrations in both hyperthyroid and normal subjects and also inhibits T4 to T3 conversion in various tissue preparations in vitro. Other beta-adrenergic antagonists have not been shown to consistently alter serum T3 concentrations in vivo or T3 production in vitro. To evaluate the ability of beta-adrenergic antagonists to inhibit T4-5'-deiodination, we measured T3 production from T4 in rat liver homogenates (10,000 X g supernatant) using 1 microM T4 in the presence of varying concentrations of the beta-adrenergic antagonists available in the United States. Each drug inhibited T3 production, and the dose-dependent responses were linear and parallel when plotted as percent inhibition vs. log dose concentration. The calculated drug concentrations required to produce 50% inhibition were: propranolol, 1.7 mM; pindolol, 6.7 mM; timolol, 11.5 mM; atenolol, 23.2 mM; metoprolol, 30.5 mM, and nadolol, 106.1 mM. The IC50 values were similar in the presence of 4 mM dithiothreitol. In separate studies, the ability of D- and L-propranolol to inhibit T3 production was compared with that of D,L-propranolol, the common form. Both D- and L-propranolol were as effective as the racemic mixture. The propranolol metabolites 4-hydroxypropranolol, 4-methylpropranolol, propranolol glycol, and N-desisopropyl propranolol were also effective inhibitors. Thus, beta-adrenergic antagonists inhibit T3 production in vitro. This inhibition is not related to beta-adrenergic antagonism per se, but is correlated with the lipid solubility of the drugs, which may explain the effects of propranolol on serum T3 in vivo.
Serum rT3 concentrations are often increased in patients with nonthyroid illness. Such elevations could be responsible for some of the alterations in pituitary-thyroid function that occur in such patients, particularly since rT3 is a potent inhibitor of extrathyroidal T3 production in vitro. To evaluate the role of serum rT3 elevations in the regulation of the hypothalamic-pituitary-thyroid axis, 10 normal subjects were given 3 mg rT3, orally, in divided doses for 4 days. Serum rT3 concentrations were elevated at least 10-fold by the end of the first day of treatment. Mean serum T4 and T3 concentrations did not change, nor was there any change in basal or TRH-stimulated serum TSH concentrations. There was, likewise, no change in serum binding of T3 or T4. These results show that rT3, given orally, has no detectable activity in normal subjects, and hence, elevations in serum rT3 concentrations per se do not contribute to other abnormalities in thyroid function found in patients with nonthyroid illness.
Two women who presented with amenorrhea-galactorrhea and hyperprolactinemia associated with x-ray evidence of pituitary enlargement and suprasellar extension were found to have primary hypothyroidism. Resolution of the pituitary enlargement and galactorrhea occurred after thyroid hormone replacement. Both women spontaneously ovulated and conceived, and normal pregnancies resulted. Amenorrhea, galactorrhea, and/or pituitary enlargement may be the principal manifestations of primary hypothyroidism. In such patients, it is imperative that primary hypothyroidism be excluded before drug or surgical therapy for presumed prolactinoma is undertaken. When these findings are due to primary hypothyroidism, thyroid hormone replacement alone is adequate therapy.
Sulfhydryl reagents stimulate enzymatic conversion of T4 to T3 and rT3. A recent study suggested that such reagents stimulated T4 5'-deiodination by a direct interaction with T4. We therefore tested the ability of dithiothreitol (DTT) and other sulfhydryl reagents to enhance the susceptibility of T4 and rT3 to 5'-deiodination by liver homogenates and of T4 to 5-deiodination by placental homogenates. Preincubation of T4 with DTT in concentrations ranging from 0.5-80 mM did not result in increased T3 production from T4 in rat liver homogenates, nor was T3 production increased by preincubation of T4 with reduced glutathione or mercaptoethanol. Preincubation of rT3 with DTT also did not result in increased rT3 degradation by liver homogenates. T4 5-deiodination to rT3 by rat and human placental homogenates was not consistently increased by preincubation of T4 with DTT in concentrations ranging from 2.25-450 mM. These results do not support the hypothesis that sulfhydryl stimulation of T4 deiodination occurs as a result of sulfhydryl-T4 interaction.
PURPOSE: Wilms tumor is the most common renal neoplasm in children. The diagnosis is usually suggested by anatomic imaging and established by biopsy or resection. The principal roles of functional imaging have been the search for skeletal metastases and evaluation of renal function. We hypothesized that, like many tumors, Wilms tumors could concentrate 18F-FDG and that evaluation of the metabolic activity of these neoplasms might prove clinically useful. MATERIALS AND METHODS: Three patients with known or suspected Wilms tumors underwent positron emission tomography (PET) with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) scanning (four scans). A patient with a single Wilms tumor was studied once at the time of diagnosis. The two patients with bilateral Wilms tumors were studied during therapy. RESULTS: Uptake of FDG was present in the Wilms tumor studied at diagnosis, and in one of the tumors in each of the patients with bilateral disease studied during therapy. In all three cases, the results of the PET scans influenced therapeutic decisions. CONCLUSION: PET FDG scanning may be useful for the management of selected patients with Wilms tumors.
Fourteen patients with advanced neuroblastoma, which was unresponsive to or had relapsed despite conventional therapy, were entered into a phase I/II trial of [131I]metaiodobenzylguanidine (131I-MIBG). Doses ranged from 1.85-8.14 GBq each (50-220 mCi), with cumulative doses of 1.85-24.20 GBq (50-654 mCi) in one to three doses. Side effects included mild nausea and vomiting and moderate myelosuppression which occurred in nine patients. Subjective responses occurred in five patients. Four patients had objective responses (one partial, two minor and one mixed). Two of these patients remain alive 80 and 60 months after beginning 131I-MIBG therapy. Comparison of the 131I-MIBG treated patients with 11 carefully matched control patients treated with an advanced current chemotherapy protocol (CCG 8605) was performed by means of Kaplan-Meier life table analysis. The 14% four-year survival with 131I-MIBG compared favorably with the 6% achieved by salvage chemotherapy. We thus believe 131I-MIBG may have a role in the management of neuroblastoma.