Plasma 3,4-dihydroxyphenylalanine (dopa) and catecholamines in neuroblastoma or pheochromocytoma.
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Adrenal Gland Neoplasms↗
Biomedical subjects
J C Sisson
Publications and source records attributed to J C Sisson.
Familial partial peripheral and pituitary resistance to thyroid hormone: a frequently missed diagnosis?
The diagnosis of partial peripheral and pituitary resistance to thyroid hormone was ultimately made in two boys, 7 and 9 years of age, and a 10-year-old girl who had goiters and hyperthyroxinemia. The boys were treated with propythiouracil and/or thyroidectomy or iodine 131 for suspected thyrotoxicosis but had poorly suppressible serum thyroid-stimulating hormone (TSH) post treatment in spite of the usual L-thyroxine replacement. The girl had increasing goiter size while receiving propylthiouracil, 100 mg every eight hours. These findings led to reevaluation of thyroid hormone dynamics in these children and their families. Twelve additional family members, 3 to 38 years of age, compatible with an autosomal dominant inheritance, were also found to have peripheral and pituitary resistance to thyroid hormone. All affected individuals had elevated serum thyroxine and triiodothyronine levels, normal to slightly elevated triiodothyronine resin uptakes, and a nonsuppressed serum TSH. The five individuals who were given thyrotropin-releasing hormone showed exaggerated TSH responses, which normalized on L-thyroxine therapy. Misdiagnosis in six of 15 family members led to significant morbidity (hypothyroidism, delayed growth, and therapy risk). A nonsuppressed serum TSH in a patient with suspected thyrotoxicosis should lead to suspicion of this disorder. Appropriate management for this condition includes L-thyroxine therapy to decrease goiter size and normalize TSH responses to thyrotropin-releasing hormone.
Child↗
Radiolabeled meta-iodobenzylguanidine: pharmacology and clinical studies.
Much was known of the pharmacology of meta-iodobenzylguanidine (MIBG) before its clinical use, but we have since learned a good deal more about the metabolic distribution and fate of this radiopharmaceutical. And, as is the nature of science, more is yet to be discovered. This communication reviews what is known about the pharmacology of radiolabeled MIBG and how this pharmacology affects the clinical studies that use the agent.
3-Iodobenzylguanidine↗
Iodine-123-4-amino-3-iodobenzylguanidine, a new sympathoadrenal imaging agent: comparison with iodine-123 metaiodobenzylguanidine.
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.
3-Iodobenzylguanidine↗
Recurrent medullary carcinoma of the thyroid demonstrated by thallium-201 scintigraphy.
Thallium-201 scintigraphy has been used in the evaluation of thyroid neoplasms, but uptake in recurrent or persistent medullary thyroid cancer has not been reported. We present two cases where focal 201TI activity localized superior mediastinal recurrences which were subsequently resected. Postoperative 201TI scans in both cases showed elimination of the focal uptake seen before surgery, as well as return of previously elevated serum calcitonin levels to normal. Scanning with 201TI may be useful in the preoperative localization of recurrent medullary thyroid cancer.
Adult↗
Determination of iodine-131 diagnostic dose for imaging metastatic thyroid cancer.
The dose of radioiodine (131I) used to survey patients for metastatic functioning thyroid cancer varies from 0.2 mCi to 30.0 mCi. Higher doses have occasionally revealed more tumors, but deliver more radiation to the patient. We asked which dose would be sufficient to detect metastatic deposits. Using a water tank with small-source phantoms, we sought to determine: the minimum volume and concentration of activity capable of being imaged, effects of background and source depth on detectability, and a practical 131I tracer dose based on these findings. Two gamma cameras affixed with high-energy collimators of different design were used to evaluate the capabilities of two instrument systems. The lowest activity detectable at the water surface was 0.03 microCi, in volumes of 10 to 300 microliters. Background activity at 0.01 microCi/ml resulted in a three to tenfold loss of detectability; computer subtraction of background did not improve results. We assumed that the minimum beneficial treatment would be 4,500 rad, a dose delivered by 200 mCi of 131I to a tumor with 0.05% uptake of the dose per gram. From these assumptions, our data show that a 2 mCi diagnostic dose would detect 10 and 30 microliter lesions containing 0.05% or more of the dose per per gram, but only at the surface and in the absence of background radioactivity. Moreover, assuming patient motion and background activity, some potentially treatable lesions probably cannot be detected even with a 30 mCi diagnostic dose, using present-day equipment. Selection of a diagnostic dose should therefore acknowledge the limitations of scintigraphic detection and take into account the radiation burden incurred by studies repeated over years.
Humans↗
Immunohistochemical localization of epinephrine, norepinephrine, catecholamine-synthesizing enzymes, and chromogranin in neuroendocrine cells and tumors.
The immunohistochemical localization of epinephrine (E), norepinephrine (NE), and chromogranin was analyzed in normal and neoplastic neuroendocrine cells. The immunohistochemical detection of tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) was used to distinguish between uptake and biosynthesis of catecholamines. E, NE, chromogranin, TH, DBH, and PNMT were found in the normal human adrenal medulla and in pheochromocytomas. Although many neuroendocrine tissues outside of the adrenal gland contained immunoreactive NE, only a small percentage of these tissues contained DBH. E was found in a few neuroendocrine tissues outside of the adrenal, including cardiac paragangliomas, and the enzyme PNMT was localized in some of these neoplasms. There was very close agreement between the localization of chromogranin and of catecholamines in normal and neoplastic neuroendocrine tissues. These results indicate that the presence of catecholamines and chromogranin in neuroendocrine cells and tumors within the adrenal medulla and in many other sites may be closely related.
Adrenal Medulla↗
Metabolism of iodine-131 metaiodobenzylguanidine in patients with metastatic pheochromocytoma.
Iodine-131 metaiodobenzylguanidine ([131I]MIBG) is used to image and treat human pheochromocytoma. As part of a pharmacodynamic study of this agent, we have evaluated its excretion and metabolism in nine pheochromocytoma patients undergoing MIGB therapy. Following diagnostic doses of [131I]MIBG given prior to therapy, 40 to 55% of the administered radioactivity generally appeared in the urine within 24 hr and 70 to 90% was recovered within 4 days. Reverse-phase high performance liquid chromatography was used to identify radioactive metabolites following therapeutic doses of [131I]MIBG. Unaltered [131I]MIBG was the major radioactive urinary component found, representing 75 to 90% of the total in all but one of the nine patients examined. The urine samples from the patient, whose rate of urinary excretion was the lowest of the group, contained [131I]-m-iodohippuric acid ([131I]MIHA) in amounts equal to that of [131I]MIBG, as well as small amounts of [131I]iodide and [131I]-m-iodobenzoic acid ([131I]MIBA). Iodine-131 MIHA and [131I]iodide were also minor components in the urine samples from the other eight patients. Trace quantities of [131I]MIBA and 131I-4-hydroxy-3-iodobenzylguanidine ([131I]HIBG) were also detected in a few of the patient urine samples examined. The 4- to 5-day metabolism profiles varied from patient to patient but were similar for the same patient following therapy doses given 4 mo apart. There was no obvious correlation between the presence of metabolites and the location of the tumors or the plasma or urinary catecholamine levels. Extraction of radioactivity from two pheochromocytomas removed from patients was determined to be primarily MIBG. These studies suggest that [131I]MIBG is a rapidly excreted, relatively stable radiopharmaceutical agent.
3-Iodobenzylguanidine↗
Radio-iodobenzylguanidine for the scintigraphic location and therapy of adrenergic tumors.
Radioiodinated meta-iodobenzylguanidine, a recently developed radiopharmaceutical, has been shown to permit safe, noninvasive, sensitive, and specific scintigraphic location of pheochromocytomas of all types. The technique is especially efficacious in the case of extraadrenal primary lesions and locally recurrent and metastatic tumors. In addition to being taken up by pheochromocytomas, meta-iodobenzylguanidine may be used to image neuroblastomas, nonfunctioning paragangliomas, and carcinoid tumors. Lesions with high 131I-meta-iodobenzylguanidine uptake may respond to treatment with large doses of this radiopharmaceutical.
3-Iodobenzylguanidine↗
Pheochromocytoma and the normal adrenal medulla: improved visualization with I-123 MIBG scintigraphy.
The radiopharmaceutical iodine 131 metaiodobenzylguanidine (I-131 MIBG) has been shown to locate pheochromocytomas scintigraphically with a false-negative rate of approximately 13%. To improve image quality and reduce the false-negative rate, I-123 was examined as a radioactive label for MIBG, as it has many advantages over I-131, including superior dosimetry and better detection efficiency. Diagnostic doses of 0.5 mCi (18.5 MBq) I-131 MIBG and 10.0 mCi (370.0 MBq) I-123 MIBG with nearly equivalent radiation dosimetries were compared in 18 patients with known or suspected pheochromocytomas. Images of superior quality were obtained with I-123 MIBG in 18 of 18 patients, and in eight cases lesions not visualized on I-131 MIBG scintigraphy were portrayed. A further advantage of I-123 MIBG is that it permits single photon emission computed tomography (SPECT). This was performed in six cases and provided additional information in three cases. The adrenal medullae were definitely visualized using I-123 scintigraphy in eight of 14 patients still possessing adrenal glands, whereas I-131 MIBG images portrayed the adrenal medulla in only one of 14 cases. Five remaining patients had multiple abdominal tumor deposits that were difficult to differentiate from normal adrenal medullae.
3-Iodobenzylguanidine↗
131I-MIBG--a new agent in diagnosis and treatment of pheochromocytoma.
The newly developed radiopharmaceutical, 131I-metaiodobenzylguanidine (131I-MIBG), has been shown to be efficacious for the location of intra- and extra-adrenal, primary pheochromocytomas and metastatic, malignant pheochromocytomas (11.4% false-negative and 1.8% false-positive in patients with proven pheochromocytomas). Preliminary experience in selected patients with malignant pheochromocytoma suggest that therapy using large doses of 131I-MIBG results in partial tumor regression and improvement in catecholamine hypersecretion in some cases.
3-Iodobenzylguanidine↗
Iodine-131 metaiodobenzylguanidine for the locating of suspected pheochromocytoma: experience in 400 cases.
The efficacy of the newly developed pheochromocytoma-seeking radiopharmaceutical, [131I]MIBG, was examined in the first 400 patients (441 studies) investigated for suspected pheochromocytoma at our institution. The results of [131I]MIBG scintigraphy were classified as true positive, false positive, true negative, and false negative. Using this classification the sensitivity was found to be 78.4% in primary, sporadic pheochromocytoma, 92.4% in malignant pheochromocytoma, and 94.3% in familial pheochromocytoma giving an overall sensitivity of 87.4%. The specificity was 98.9% in primary, sporadic pheochromocytoma, 100% in malignant pheochromocytoma, and 100% in familial pheochromocytoma. The overall specificity was 98.9%. Iodine-131 MIBG scintigraphy was thus found to be a safe, noninvasive, and efficacious technique for the location of pheochromocytomas, especially for those arising from nonadrenal sites, recurring postoperatively, and exhibiting malignant metastatic disease. We find that, where available, [131I]MIBG scintigraphy is the study of choice to initiate the location of suspected pheochromocytoma.
3-Iodobenzylguanidine↗
Limitations of 131I-MIBG scintigraphy in locating pheochromocytomas.
131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy for the location of pheochromocytomas has proved to be a major advance in patient management. In combination with computerized tomographic scanning, nearly all pheochromocytomas can be located before surgery and invasive investigations are now indicated only in exceptional cases. However, there are still lessons to be learned concerning the optimal administration and interpretation of 131I-MIBG scintigraphy. With careful attention to detail and an awareness of isotope distribution, false positive studies should be extremely rare. While the incidence of false negative studies is uncommon, these certainly occur. A patient with sporadic bilateral adrenal medullary hyperplasia, bilateral pheochromocytomas, and additional benign pheochromocytomas arising in paraganglia tissue anterior to the abdominal aorta is presented. The right adrenal pheochromocytoma was not identified on 131I-MIBG imaging. We conclude that even with current locating techniques, the traditional surgical approach to pheochromocytoma should not be abandoned. This involves transabdominal exploration of both adrenal glands and careful examination of all possible sites of extra-adrenal pheochromocytomas.
3-Iodobenzylguanidine↗
What causes uptake of technetium-99m methylene diphosphonate by tumors? A case where the tumor appeared to secrete a hypercalcemia-causing substance.
A patient exhibited an unusual constellation of findings: His extraosseous lymphoma sequestered [99mTc]MDP, a bone-seeking agent, while at the same time it appeared to produce a factor that caused hypercalcemia. The dispersed lymphoma cells took up more [99mTc]MDP in vitro than did cultured lymphoblasts suggesting that the in vivo sequestration may have been, at least in part, an active intracellular process.
Cells, Cultured↗
Effect of uptake-one inhibitors on the uptake of norepinephrine and metaiodobenzylguanidine.
The mechanisms underlying the uptake of the radiopharmaceutical metaiodobenzylguanidine (MIBG) and the catecholamine norepinephrine (NE) were studied using cultured bovine adrenomedullary cells as an in vitro model system. Sodium-dependent and sodium-independent uptake systems have been identified and characterized for both MIBG and NE. The sodium-dependent uptake of NE and MIBG was inhibited by the selective Uptake-one inhibitors, desmethylimipramine (DMI) and cocaine, whereas the sodium-independent uptake for NE and MIBG was much less sensitive to inhibition by these agents. The sodium-dependent uptake system fulfills the criteria for the neuronal Uptake-one system, and the sodium-independent uptake system fulfills the criteria for a passive diffusion mechanism. Both NE and MIBG were transported into cultured bovine adrenomedullary cells by both uptake systems; the relative role of each uptake system was dependent upon the concentration of NE and MIBG in the media. Arterial concentrations proximal to the dog adrenal were very small suggesting that the sodium-dependent (Uptake-one) system is predominant in vivo. Consistent with the in vitro observations, the in vivo uptake of MIBG and NE into dog adrenal medullae was effectively blocked by pretreatment with DMI or cocaine. Therefore, iodine-131 MIBG scintigraphy of the adrenal appears to reflect uptake by way of the Uptake-one system.
3-Iodobenzylguanidine↗
Detection of HLA-DR antigens in paraffin-embedded thyroid epithelial cells with a monoclonal antibody.
The human Class II major histocompatibility (MHC) antigens, or Ia antigens, which are thought to regulate immune cell interaction, can be detected in paraffin-embedded tissues by immunoperoxidase staining with a recently developed monoclonal antibody (LK8D3). HLA-DR antigens were observed in lymphoid tissues, Langerhans cells of the skin, some epithelial cells, and pulmonary alveolar macrophages. The expression of HLA-DR antigens was analyzed in formalin-paraffin sections by immunoperoxidase in 86 normal and abnormal thyroid epithelial tissues. All patients with Hashimoto's disease (8/8) and most patients with Graves' disease (6/8) expressed HLA/DR antigens in the thyroid epithelial cells and in adjacent inflammatory cells. Most papillary carcinomas (12/18), including 3 of 5 follicular variant of papillary thyroid carcinomas, had HLA-DR antigens detected in epithelial cells; whereas medullary thyroid carcinomas (0/5), follicular carcinomas (0/5), and multinodular goiters (0/4) did not have detectable HLA-DR immunoreactivity. A few other thyroid lesions had HLA-DR antigens detected in epithelial cells, including anaplastic carcinomas (2/5), Hurthle-cell tumors (1/16), and thyroid lymphomas (2/2). Monoclonal antibody LK8D3 and two other commercially available monoclonal antibodies against HLA-DR-stained tissues equally well in cryostat sections, but only antibody LK8D3 was effective in formalin-fixed paraffin-embedded tissue sections. These results indicate that epithelial cells from thyroids of patients with autoimmune diseases commonly express HLA-DR antigens. The presence of HLA-DR antigens in most papillary thyroid carcinomas may be helpful diagnostically in cases of follicular variants of papillary carcinomas. The role of HLA-DR expression in autoimmune thyroid disease and in papillary thyroid carcinoma remains to be determined.
Antibodies, Monoclonal↗
Cardiac paragangliomas. A clinicopathologic and immunohistochemical study of four cases.
Cardiac paragangliomas are extremely rare neoplasms. Four surgically resected tumors were examined by immunohistochemistry and electron microscopy. The patients ranged in age from 18 to 36 years. All patients had hypertension and elevated urine catecholamine levels. Three tumors were located on the posterior left atrium, and one tumor was located in the interventricular groove at the aortic root. The tumors ranged in size from 5 to 7 cm, and they displayed a prominent Zellballen pattern without significant necrosis or mitosis. The tumors were mostly unencapsulated and infiltrated adjacent cardiac tissue in two cases. Immunoperoxidase staining showed that all tumors were positive for chromogranin and neuron-specific enolase. Three tumors were positive for methionine enkephalin. Positive staining for S-100 protein was seen in the sustentacular cells of all tumors but was negative in chromaffin cells. All tumors were negative for insulin, glucagon, gastrin, vasoactive intestinal polypeptide, somatostatin, adrenocorticotropic hormone, calcitonin, serotonin, pancreatic polypeptide, and rat atrial peptide. Ultrastructural studies of all four tumors showed moderate numbers of predominantly norepinephrine-type granules and a few epinephrine-type granules. These results show that cardiac paragangliomas are commonly found in close proximity to the left atrium and have immunohistochemical and ultrastructural features similar to other paragangliomas.
Adolescent↗
Familial extra-adrenal pheochromocytoma. A new syndrome.
Pheochromocytomas in the same anatomic site, the right renal hilum, occurred in a family over three successive generations. For two patients in the latter two generations, scintigraphy with iodine 131-tagged metaiodobenzylguanidine (MIBG) showed tumors only in the region of the right renal hilum, thus indicating that they were primary lesions. At surgery, except for lymph node metastases noted microscopically in one patient, tumors were found only near the right renal hilum. The adrenal glands seemed normal on inspection, palpation, and computed tomography. In another family, a mother and son had primary pheochromocytomas arising from the urinary bladder. We suggest that primary extra-adrenal pheochromocytoma is a syndrome in which specific genetic abnormalities determine sites of tumor development.
Adolescent↗