Enterohepatic circulation and distribution of 131I-6 beta-iodomethyl-19-norcholesterol (NP-59)

The enterohepatic circulation and distribution of 131I-6 beta-iodomethyl-19-norcholesterol (NP-59) was assessed in a rabbit model to examine the relative distribution of NP-59 and its metabolites. Adrenal, bile and serum samples were obtained from seven rabbits at 48 h following NP-59 administration (240 to 570 microCi) and the distribution of 131I radioactivity examined using thin layer chromatography. In serum 71% of the radioactivity circulated as NP-59 and 20% as NP-59 esters. In contrast greater than 90% of the adrenal radioactivity was in the form of NP-59 esters while in bile 70% of the activity was NP-59 with the remainder in the form of bile acids. In another group of animals, adrenal activity was observed 5 days after intragastric administration of NP-59. Thus, we have demonstrated a significant enterohepatic circulation of NP-59 that may have the potential to influence the distribution of and resultant adrenal imaging with NP-59.     

Positive iodine-131 6 beta-iodomethyl-19-norcholesterol (NP-59) adrenal images can precede return of adrenocortical function after o,p' DDD treatment

A patient with bilateral adrenal hyperplasia, due to the ectopic adrenocorticotrophic hormone (ACTH) syndrome, received a 3-month course of treatment with 1,1 dichloro-2(o-chlorophenyl)-2-(p-chlorophenyl)ethane (o,p' DDD), which caused adrenal hypofunction requiring steroid therapy. Eleven months later, Cushing's syndrome recurred. His CT scan showed a left adrenal gland that was enlarged and a normal-sized right adrenal gland. However, the NP-59 image showed increased uptake by both glands. Venous effluent was sampled from each adrenal vein. The plasma cortisol level from the left gland was 1392 ng/ml, and that from the right gland was 667 ng/ml. The latter value was not significantly different from the values obtained at peripheral sites (517-744 ng/ml). In the course of recovery from o,p' DDD damage, the ability of the adrenal gland to take up NP-59 may be restored before the return of its biosynthetic and secretory functions. Serial NP-59 adrenal images can anticipate the recurrence of Cushing's syndrome after adrenolytic therapy, thereby permitting early retreatment.     

Clinical application of SPECT in adrenal imaging with iodine-131 6 beta-iodomethyl-19-norcholesterol

Forty-one patients with or without adrenocortical disorders were studied to evaluate the clinical usefulness of SPECT in adrenal imaging with I-131 Adosterol. In the SPECT images from this study, all glands with either normally functioning or hyperfunctioning adrenal cortices could be detected, while those glands with hypofunctioning adrenal cortices could not be detected. Particularly in transaxial and sagittal slices, the adrenal gland was identified posteriorly and was clearly distinguished from the gallbladder. In preliminary results using SPECT by a standard method, uptake in 68 detectable glands ranged from 1.7% to 4.9% in four glands with Cushing's syndrome, from 1.1% to 1.3% in seven glands with primary aldosteronism, and were distributed below 1.0% in the remaining glands with normally functioning adrenal cortices. These data show that it is possible to evaluate the adrenocortical functioning status simply by analyzing the SPECT images of the adrenal.     

Diagnostic accuracy and pitfalls of [iodine-131]6-beta-iodomethyl-19-norcholesterol (NP-59) imaging

NP-59 concentrates in steroid hormone synthesizing tissues, enabling scintigraphic localization and characterization of endocrine dysfunction in the adrenal cortex and ovary. Studying 108 consecutive cases from 1982 to 1985 and using clinical, biochemical, radiographic, and pathologic data, we performed a rigorous assessment of the accuracy and pitfalls of NP-59 scintigraphy. The evaluation was divided into categories of abnormal hormone secretion: Cushing's syndrome, primary aldosteronism, and hyperandrogenism. Additional categories included euadrenal tumors (without detectable hormone dysfunction) and sites of residual adrenal cortical tissue. The accuracy of NP-59 scintigraphy ranged from 71% in primary aldosteronism and 75% in euadrenal tumors, to 100% for Cushing's syndrome and hyperandrogenism. However, more than in most nuclear medicine studies, NP-59 imaging requires well-defined indications to be met for it to be efficacious, including the fulfillment of clear clinical, biochemical, and radiographic criteria. The high reproducibility of NP-59 scintigraphic interpretation was demonstrated when 40 random cases underwent interinstitutional exchange and through interobserver evaluation at the University of Michigan. Responses of 85/126 medical centers to questionnaires revealed the high level of NP-59 safety.     

Absorbed dose to the human adrenals from lodomethylnorcholesterol (I-131) "NP-59": concise communication.

During the past 2 years, adrenal uptake percentage values were measured in more than 40 patients, using an external counting technique. They suggest that the absorbed dose to the adrenals is significantly less than 150 rads/mCIi previously estimated using concentration values from animal adrenals. The measured combined uptake percentage for both adrenals ranged from 0.15% to 0.52% in 21 patients without evidence of adrenal disease, with a mean of 0.33% +/- 0.1%; also from 0.22% to 1.5% in 22 patients with Cushing's disease, with a mean uptake of 0.78% +/- 0.35%. The absorbed dose to the adrenals was estimated to be 25 rads/mCi for patients without evidence of adrenal disease, and 57 rads/mCi for patients with Cushing's disease. Both values are calculated for the respective mean uptake percentages by using MIRD formalism.     

Visualization of adrenocortical carcinoma lung metastases with iodine-131 labeled 6B-iodomethylnorcholesterol (NP-59)

This case report describes visualization of lung metastases secondary to adrenocortical carcinoma using I-131 labeled 6B-iodomethyl-19-norcholesterol (NP-59) in a 26-year-old woman with a recurrence of Cushing's syndrome one year following surgical removal of the primary tumor.     

The influence of I-131 therapy on FDG uptake in differentiated thyroid cancer

OBJECTIVE: 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) [or PET/computed tomography (CT)] is more likely to show false-negative results when it is performed shortly after chemotherapy and/or radiotherapy because of "metabolic stunning". The present study aimed to evaluate the influence of I-131 therapy on FDG uptake and the detection of recurrence or metastasis of differentiated thyroid cancer (DTC). METHODS: We retrospectively enrolled 16 consecutive FDG-PET/CT studies which had been performed in patients with DTC with elevated thyroglobulin (TG) but negative I-131 whole-body scan. All studies were performed under L: -thyroxine suppression. The patients were divided into groups A and B for PET/CT performed within 4 months of I-131 therapy or no such therapy, respectively. Each lesion identified on PET/CT was characterized using a 5-point scale by visual analysis: 0 = definitely benign, 1 = probably benign, 2 = equivocal, 3 = probably malignant, and 4 = definitely malignant. The maximum standardized uptake value (SUV max) in each lesion was also measured for semiquantitative analysis. We compared the visual grading and SUV max of the lesion of highest FDG uptake between groups A and B. RESULTS: For visual analysis, group B had significantly more patients with an uptake score of 3 or 4 than group A (80% vs. 17%, P = 0.01). In addition, there were significantly more equivocal results from group A than from group B (67% vs. 10%, P = 0.02). If the patients with the highest uptake scores of 2, 3, and 4 were considered to be positive for local recurrence or metastasis, there would be no significant difference between the positive rates of groups A and B (83% vs. 90%, P = 0.7). However, the mean SUV max of positive results was significantly lower for group A than for group B (3.1 +/- 0.9 and 6.6 +/- 3.5, respectively, P = 0.02). CONCLUSIONS: The preliminary results suggested that FDG uptake in DTC may be negatively influenced by I-131 therapy within 4 months, resulting in lower FDG uptake and more equivocal results. Further studies are necessary to determine whether it is secondary to "metabolic stunning" caused by I-131 therapy.     

SPECT semiquantitative analysis of adrenocortical (131)I-6 beta iodomethyl-norcholesterol uptake to discriminate subclinical and preclinical functioning adrenal incidentaloma.

The goal of this study was to evaluate the clinical reliability of the (131)I-6 beta-iodomethyl-norcholesterol ((131)I-NP-59) uptake semiquantitative evaluation method we propose for the characterization of adrenocortical masses in a selected population of patients with disease clinically classified as subclinical (SC) and preclinical (PC) Cushing's syndrome (CS) according to Reincke's definition. METHODS: Forty-seven consecutive patients with incidentally discovered unilateral adrenal masses were examined by a triple-head SPECT system after intravenous injection of (131)I-NP-59. Abdominal SPECT was performed at 24, 48, 72, and, in selected cases, 96 h after tracer injection. Connected with adrenals and liver, a standard elliptic region of interest (ROI) was manually drawn, taking care to avoid the gallbladder region. The adrenal ROI integral count, obtained by summing the 24-, 48-, and 72-h counting values, was normalized by the hepatic integral count. Subsequently, the adrenal percentage of relative uptake (UPT%) was computed. RESULTS: Discriminant analysis was performed on the variables UPT%, adrenocorticotropic hormone (ACTH) serum concentration, and CT mass dimension (CTMD) to determine the variable, or combination thereof, best discriminating between the SC-CS and PC-CS groups. Compared with both ACTH and CTMD variables, univariate analysis confirmed the UPT% variable as the most significant to discriminate between these 2 clinical groups. In fact, UPT% alone correctly classified 8 of 9 patients in the SC-CS group and 20 of 22 patients in the PC-CS group with 95% positive and 80% negative predictive values and with overall accuracy, sensitivity, and specificity equal to 90%, 91%, and 89%, respectively. When all 3 variables were submitted to stepwise discriminant analysis, the derived classification matrix, after cross-validation, correctly classified 9 of 9 patients in the SC-CS group and 18 of 22 patients in the PC-CS group with 100% positive and 69% negative predictive values and with overall accuracy, sensitivity, and specificity equal to 87%, 82%, and 100%, respectively. CONCLUSION: According to these initial results, use of the proposed semiquantitative approach associated with both laboratory screening for cortisol production and CTMD measure seems to be able to increase the clinical diagnostic accuracy of PC-CS. This approach could be used in the follow-up of adrenal mass function every time hormonal or clinical features are suggestive of adrenocortical hyperfunction.     

Efficacy of iodine-131 6beta-methyl-iodo-19-norcholesterol scintigraphy and computed tomography in patients with primary aldosteronism.

In order to define the role of scintigraphy in determining the aetiology of primary aldosteronism, 41 patients were examined by computed tomography (CT) scan and adrenal scintigraphy using iodine-131 6beta-methyl-iodo-19-norcholesterol with the dexamethasone suppression test. Hormonal and scintigraphic examinations were conducted while avoiding interference by medical treatment. The aetiological diagnosis was established by taking account of the clinical context, the endocrine profile, and CT scan and scintigraphic data, as well as possible hormone assays after catheterization of the adrenal veins (12 cases) and postoperative pathology data (14 cases). The aetiological diagnoses established were Conn's adenoma (insensitive to angiotensin II) in 12 cases, idiopathic hyperplasia in 11 and macronodular hyperplasia (with functional autonomy of the nodules) in 18. Unilateral and bilateral lesions were correctly distinguished by scintigraphy in 92% of cases as compared with only 58% using CT scan alone; this was because the CT scan appearance was normal in 3/12 cases of adenoma and because a single nodule was visible in 2/11 cases of idiopathic hyperplasia and in 12/18 cases of macronodular hyperplasia. It is concluded that scintigraphy using noriodocholesterol with the dexamethasone suppression test should be performed systematically in conjunction with hormonal tests and adrenal CT scan in all cases of primary aldosteronism, as part of a strategy aimed not only at detecting adenoma but also at determining whether the hyperfunctional lesions are bilateral.     

Effect of large doses of 131I-19-iodocholesterol on metapyralone-induced adrenal cortical hyperplasia in dogs.

The potential use of 131I-19-iodocholesterol to treat ACTH excess Cushing's disease was evaluated in the dog. Three normal female dogs were given LD50 radiation doses of 131I-19-iodocholesterol without producing gross or histopathologically demonstrable change of the adrenals at autopsy 3 months later. The adrenal cortices of three dogs were made hyperplastic (to simulate the adrenal cortex in Cushing's disease) with ACTH and three with Metapyralone. In addition these six dogs were given KD50 doses of 131I-19-iodocholesterol. Three months after treatment, the adrenal glands of the ACTH-treated dogs were not enlarged, the cortex was thicker than normal, and there were no changes attributable to irradiation. At 3 months, the Metapyralone-treated dogs had enlarged adrenals, widening of the adrenal cortex, and no necrosis or other changes attributable to irradiation. It is concluded that a therapeutic trial of 131I-19-iodocholesterol in the treatment of Cushing's disease is not indicated.     

Adrenal scintigraphy with 131I-19-iodocholesterol in the diagnosis of Cushing's syndrome associated with adrenal tumor

Seven patients with Cushing's syndrome secondary to adrenocortical tumors were studied using ¹³¹I-19-iodocholesterol. The diagnosis of all cases were verified histologically. In three cases with adenoma the uptake of the tracer was in the tumor only, while the two patients with adrenocortical carcinoma failed to show adrenal accumulation of the labelled compound.In two patients there was a hyperplasia-like scintigraphic pattern, while the stimulation and suppression biochemical tests suggested adrenal tumor. One of these cases was verified as a mixed form (adenoma plus hyperplasia), and the tumor bearing gland was significantly larger on the scan which helped the preoperative localization. In the other case, verified as bilateral multiple adrenocortical adenomas, the autonomus function of both adrenals was proved by dexamethasone suppression scanning. It seens reasonable to use the latter as an adjunctive diagnostic procedure in patients where there is a discrepancy between the standart scintiscan and the biochemical indexes of adrenal hyperfunction.     

Adrenal scintigraphy with 131I-19-iodochlesterol in the diagnosis of Cushing's syndrome associated with adrenal tumor

Seven patients with Cushing's syndrome secondary to adrenocortical tumors were studied using 131I-19-iodocholesterol. The diagnosis of all cases were verified histologically. In three cases with adenoma the uptake of the tracer was in the tumor only, while the two patients with adrenocortical carcinoma failed to show adrenal accumulation of the labelled compound. In two patients there was a hyperplasia-like scintigraphic pattern, while the stimulation and suppression biochemical tests suggested adrenal tumor. One of these cases was verified as a mixed form (adenoma plus hyperplasia), and the tumor bearing gland was significantly larger on the scan which helped the preoperative localization. In the other case, verified as bilateral multiple adrenocortical adenomas, the autonomus function of both adrenals was proved by dexamethasone suppression scanning. It seens reasonable to use the latter as an adunctive diagnostic procedure in patients where there is a discrepancy between the standart scintiscan and the biochemical indexes of adrenal hyperfunction.     

Radioimmunodetection of cancer of gastrointestinal tract and liver metastasis with I-131 anti-CEA and I-131 anti-CA19-9 monoclonal antibody cocktail (IMACIS-1)

We evaluated the intravenous infusion of a cocktail of I-131 anti-CEA and anti-C A19-9 monoclonal antibody F(ab’)2 (IMACIS-1) in patients with gastrointestinal neoplasm and liver metastases in order to assess its efficacy in detecting the presence of cancer. Seven patients with primary or recurrent gastrointestinal cancer in whom liver metastases were also detected were studied. Accumulation of radioactivity in the primary tumor was seen in only one patient. Visualization of the liver metastases was achieved in all patients. Thus detection of liver metastasis was better than in primary or recurrent tumors. While tumor visualization was most often seen in the 3 day image, optimal visualization of the tumor was seen at 5–7 days. There was no correlation between the serum concentration of CEA or CA19-9 and the visualization of tumors. Serum kinetics of I-131IMACIS-1 showed biexponential components with a 1st phase T_1/2 of 5.0 hours and 2nd phase T_1/2 of 34.7 hours. The mean whole body (I-131) half-life determined from the whole-body scans was 1.95 days. The mean urinary excretion of I-131 in 7 days was 85%. This value agreed closely with total radioactivity retention detected by scanning. This series of studies demonstrated the potential utility of a cocktail of antibodies consisting of an anti-CEA and an anti-CA19-9 monoclonal F(ab’)₂.