Biomedical subjects

Karel Pacak

Publications and source records attributed to Karel Pacak.

65 records · Page 4Linked to original sources

PubMed2002

Diagnostic localization of pheochromocytoma: the coming of age of positron emission tomography.

Pheochromocytoma is a rare but clinically important tumor of catecholamine-secreting chromaffin cells. This tumor constitutes a surgically curable cause of hypertension. Therefore, correct localization of pheochromocytoma is essential for effective management of this tumor. Several conventional and nuclear imaging modalities are currently available to localize pheochromocytoma. Computed tomography (CT) and magnetic resonance imaging (MRI) have good sensitivity but poor specificity for detecting pheochromocytoma, and nuclear imaging approaches such as (131)I-metaiodobenzylguanidine scintigraphy or [(111)In]-DTPA-D-Phe-pentetreotide (Octreoscan) have limited sensitivity. However, specificity of (131)I-metaiodobenzylguanidine scintigraphy is very good and this means of imaging provides a method for confirming that a tumor is a pheochromocytoma and rules out metastatic disease. Recently, we introduced a new imaging method, 6-[(18)F]fluorodopamine positron emission tomography, that can be used successfully for the detection of solitary and metastatic pheochromocytomas. Our preliminary data suggest that this method is superior to other nuclear imaging methods including metaiodobenzylguanidine and octreotide scintigraphy. In this report we provide an update regarding nuclear imaging of primary and metastatic pheochromocytoma, particularly using 6-[(18)F]fluorodopamine positron emission tomographic scanning.

3-Iodobenzylguanidine↗

PubMed2002

Genomic medicine: exploring the basis of a new approach to endocrine hypertension.

Recent improvements in defining the molecular basis of disease have encouraged scientists worldwide to develop new therapeutic strategies based on engineered genes and cells. Genomic medicine has the potential to revolutionize diagnosis and therapy of a variety of human diseases, including endocrine disorders. Hypertension is the presenting feature of some of these disorders, such as congenital adrenal diseases, and adrenal and pituitary tumors. Preclinical data indicate that gene transfer to both the adrenal gland and the pituitary is not only feasible but also quite efficient. Research in this field is only in its infancy, but with the ever-increasing advances in DNA technologies, genomic therapies for endocrine hypertension may become available within the next few decades.

Endocrine Glands↗

PubMed2002

Chronic hypercortisolemia inhibits dopamine synthesis and turnover in the nucleus accumbens: an in vivo microdialysis study.

Over 60% of patients with Cushing's syndrome suffer from major depression, which frequently abates after correction of the hypercortisolism. The mesolimbic and mesocortical dopaminergic (DAergic) systems are thought to participate in psychiatric disorders. In this study, we investigated whether hypercortisolemia affects indices of DAergic activity in the nucleus accumbens (NAc) and the prefrontal cortex (PFC) of freely moving rats. Cortisol (CORT, 25 mg/kg/day) was infused subcutaneously for 7 days via an osmotic minipump. Microdialysate collection (30-min periods, 2 microl/min) began 24 h after probe placement. Concentrations of dihydroxyphenylalanine (DOPA) in interstitial fluid in the nucleus accumbens (NAc) and perifrontal cortex (PFC) were measured before and after local perfusion with NSD-1015, an irreversible inhibitor of L-aromatic amino acid decarboxylase, to assess local dopamine (DA) biosynthesis. The sum of microdialysate DA, dihydroxyphenylacetic acid, and homovanillic acid was used as an index of local DA turnover. DOPA accumulation after NSD-1015 was markedly attenuated in CORT-treated compared with saline-treated animals (5,703 +/- 1,849 vs. 10,902 +/- 2,454 pg/ml; p < 0.01). In contrast, the two groups did not differ in DOPA accumulation in the PFC. Values for the turnover index of DA were also significantly lower in CORT-treated animals in the NAc but not in the PFC. The results indicate that CORT inhibits DA synthesis and turnover in the NAc but not in the PFC. Region-specific CORT-induced inhibition of DAergic activity may help to explain depressive symptoms in patients with chronic hypercortisolemia and normalization after medical or surgical correction of hypercortisolism.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors.

Modern imaging modalities lead to frequent detection of adrenal masses, most of them incidental findings. Although the majority of adrenocortical and adrenomedullary tumors are benign, there are no reliable clinical and laboratory markers to distinguish most of them from malignant neoplasms. The molecular mechanisms underlying the pathogenesis of these tumors have recently begun to be unraveled. A fruitful avenue for the elucidation of tumorigenesis has been the study of adrenal tumors that are manifestations of hereditary or postzygotic genetic syndromes, because one knows the "first hit", i.e. the primary gene defect. In contrast, in sporadic adrenal tumors the first hit, possibly a somatic mutation of a tumor-related gene, is unknown, and therefore the sequence of genetic alterations is difficult to establish. In this article we review in addition to our own work the literature on molecular aspects of adrenocortical and adrenomedullary tumorigenesis.

Adrenal Cortex Neoplasms↗

PubMed2002

Utility of plasma free metanephrines for detecting childhood pheochromocytoma.

Measurements of plasma free metanephrines, normetanephrine (NMN) and metanephrine (MN), provide a sensitive test for diagnosis of pheochromocytoma in adults but have not been evaluated in children. We therefore established reference ranges for plasma and urinary metanephrines and the catecholamines, norepinephrine (NE) and epinephrine (E), in 86 healthy children (age 5-17). A group of 158 healthy adults (age 18-72) served as a comparison group. Pediatric reference ranges were applied to examine the diagnostic utility of the various tests in 45 children evaluated for pheochromocytoma (age 8-17; 38 with von Hippel-Lindau syndrome), with tumors found on 12 occasions. Upper reference limits for E and MN were higher and those for NE and NMN lower in children than in adults. Boys had higher plasma levels of E and MN and higher urinary excretion of all four amines than girls. Plasma free metanephrines provided a diagnostic test with values for sensitivity (100%) and specificity (94%) that were equal to or higher than those of other tests. In two children screened for pheochromocytoma on multiple occasions, use of pediatric reference ranges for plasma free metanephrines indicated the tumor a year earlier than indicated using adult reference ranges. The findings indicate that plasma free metanephrines provide a sensitive tool for detection of pheochromocytoma in children. Age appropriate reference ranges should be used and gender differences should be considered.

Adolescent↗

PubMed2002

Pheochromocytoma in von hippel-lindau disease: distinct histopathologic phenotype compared to pheochromocytoma in multiple endocrine neoplasia type 2.

Pheochromocytomas are rare neuroendocrine tumors that arise from chromaffin tissue. In a small subset of patients, pheochromocytomas occur as a manifestation of von Hippel- Lindau (VHL) disease. The histology of VHL-associated pheochromocytomas has not been reported in detail. In this article, we describe histopathologic features of 14 pheochromocytomas in eight patients with VHL disease and demonstrate that VHL-associated pheochromocytomas have a distinct histologic phenotype as compared with pheochromocytomas in patients with multiple endocrine neoplasia type 2 (MEN 2). VHL tumors are characterized by a thick vascular tumor capsule; myxoid and hyalinized stroma; round, small to medium tumor cells intermixed with small vessels; predominantly amphophilic and clear cytoplasm; absence of cytoplasmic hyaline globules; and lack of nuclear atypia or mitoses. In contrast to MEN 2, there is no extratumoral adrenomedullary hyperplasia in the VHL adrenal gland. Our findings of a distinct histologic phenotype of VHL pheochromocytoma may further help in subdividing patients who clinically present with multiple, bilateral pheochromocytomas.

Adrenal Gland Neoplasms↗

PubMed2002

Survivin: a novel neuroendocrine marker for pheochromocytoma.

OBJECTIVE: To study survivin expression in human adrenal medulla and in benign and malignant pheochromocytoma tissue as a tool to predict tumor metastatic potential and prognosis. DESIGN: Blinded study to assess the role of the anti-survivin antibody in chromaffin cells. METHODS: We performed immunohistochemistry with a purified rabbit-polyclonal anti-survivin antibody on 39 formalin-fixed and paraffin-embedded pheochromocytoma/paraganglioma specimens, and on 10 normal adrenal medulla samples from patients unaffected by a chromaffin cell tumor. Fourteen samples were from 14 patients with benign pheochromocytoma (<8 year follow-up, mean 5.2 years), 18 specimens were from 12 patients with malignant pheochromocytoma (<13 year follow-up, mean 6.3 years), 5 samples were from 2 patients with malignant paraganglioma (<6 year follow-up, mean 4 years), and 2 specimens from 2 patients with benign paraganglioma (<7 year follow-up, mean 5.5 years). Malignancy was defined by metastases in non-chromaffin tissues. Staining intensity with the anti-survivin antibody was scored from 0 (none) to 3+ (heavy). Tissues from human kidney, breast, and melanoma served as controls. RESULTS: All pheochromocytoma/paraganglioma specimens stained either 2+ or 3+. By analysis of variance (ANOVA), there was no statistically significant difference between the staining intensity of benign and malignant samples. All normal adrenal medulla specimens stained positively with anti-survivin but to a lesser degree than the chromaffin cell tumors (P<0.01). CONCLUSIONS: Based on these findings, we conclude that (i) survivin may represent a novel neuroendocrine marker for chromaffin cell tumors, and (ii) survivin does not appear to reliably distinguish benign from malignant pheochromocytomas/paragangliomas and thus does not identify patients at risk of recurrent disease.

Adolescent↗

PubMedDate not supplied

Phaeochromocytoma.

Phaeochromocytomas are rare neuroendocrine tumours with a highly variable clinical presentation but most commonly presenting with episodes of headaches, sweating, palpitations, and hypertension. The serious and potentially lethal cardiovascular complications of these tumours are due to the potent effects of secreted catecholamines. Biochemical testing for phaeochromocytoma is indicated not only in symptomatic patients, but also in patients with adrenal incidentalomas or identified genetic predispositions (eg, multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and mutations of the succinate dehydrogenase genes). Imaging techniques such as CT or MRI and functional ligands such as (123)I-MIBG are used to localise biochemically proven tumours. After the use of appropriate preoperative treatment to block the effects of secreted catecholamines, laparoscopic tumour removal is the preferred procedure. If removal of phaeochromocytoma is timely, prognosis is excellent. However, prognosis is poor in patients with metastases, which especially occur in patients with large, extra-adrenal tumours.

Humans↗

PubMedDate not supplied

Ectopic Cushing's syndrome caused by an esthesioneuroblastoma.

OBJECTIVE: To report a case of florid Cushing's hormone (ACTH) secretion related to the presence of an esthesioneuroblastoma (ENB). METHODS: We present clinical, laboratory, and pathologic findings in a 36-year-old Caucasian man presenting with Cushing's syndrome. Results of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) scanning, and somatostatin receptor scintigraphy are presented, along with tumor pathology findings. RESULTS: After initial biochemical studies suggestive of ectopic Cushing's syndrome, CT of the chest and abdomen revealed multiple cavitated pulmonary lesions, an ischiorectal mass, and bilateral adrenal hyperplasia. MRI of the pituitary gland revealed normal findings. Both PET scanning with [18 F]-flurodeoxyglucose (FDG) and somatostatin receptor scintigraphy with 111 indium-penetetreotide (Octreoscan) revealed strong tracer uptake in the ethmoid region. CT and MRI of the sinuses and brain subsequently localized a 5-cm mass in the ethmoid sinuses with intracranial extension. On biopsy, pathology results were consistent with a diagnosis of ENB, and immunohistochemical analysis revealed that tumor cells were strongly positive for ACTH, synaptophysin, and S-100, providing definitive diagnosis of ACTH-producing ENB. Hypercortisolemia was initially controlled by metyrapone, then by external beam radiation therapy (RT). CONCLUSION: This case illustrates the usefulness of nuclear imaging in the diagnosis of ENB, and the importance of prompt control of hypercortisolemia in Cushing's syndrome.

ACTH Syndrome, Ectopic↗

PubMedDate not supplied

Utility of plasma free metanephrines in diagnosis of factitious pheochromocytoma.

OBJECTIVE: To report a case of epinephrine-induced factitious pheochromocytoma in a young woman with a past medical history of Conn's syndrome. METHODS: We present a case report with clinical and laboratory details, review related reports in the literature, and demonstrate the usefulness of plasma free metanephrine levels in facilitating the diagnosis of factitious pheochromocytoma. RESULTS: A 34-year-old woman was admitted to our hospital for confirmation and localization of an occult pheochromocytoma. After thorough investigation, we discovered that the patient was surreptitiously injecting epinephrine in order to induce symptoms and signs consistent with a pheochromocytoma. Analysis of the patient's biochemical profile during and between her catecholaminergic crises revealed plasma epinephrine and free metanephrine levels that would be highly unusual for a patient with a pheochromocytoma. CONCLUSION: This case illustrates the utility of implementing the ratio of plasma epinephrine to free metanephrine levels in distinguishing factitious from organic pheochromocytoma.

Adult↗

PubMedDate not supplied

Hypotension in a woman with a metastatic dopamine-secreting carotid body tumor.

OBJECTIVE: To describe a woman with metastatic carotid body tumor in whom hypotension occurred in the setting of exceedingly high plasma dopamine levels. METHODS: We present a case report and review the literature on the topic of dopamine-secreting paraganglioma or pheochromocytoma. RESULTS: A previously healthy 40-year-old Asian woman noted difficulty with swallowing and hoarseness. No neck mass was visible, and she had no symptoms of catecholamine excess and no family history of endocrine disorders or malignant disease. Indirect laryngoscopy revealed a paralyzed left vocal cord and a nonulcerating mass in the left parapharyngeal space. An initial needle biopsy was interpreted as undifferentiated carcinoma. After a second biopsy, this mass was diagnosed as a neuroendocrine tumor, consistent with paraganglioma. The patient underwent surgical resection and radiation therapy (total dose, 40 Gy), after which she remained asymptomatic for 11 years. Then loss of weight, fatigue, nausea, and hypotensive episodes (blood pressures as low as 70/35 mm Hg) prompted whole-body imaging with bone scans, computed tomography, and magnetic resonance imaging, which disclosed several lesions in the liver, lungs, and spine, suggestive of metastatic disease. The adrenal glands were unremarkable. A metaiodobenzylguanidine scan with use of (131)I was negative. Liver biopsy of a hypodense lesion revealed a neuroendocrine tumor by histologic and immunohistochemical studies. Because of the patient's history, malignant paraganglioma was diagnosed. The tumor secreted predominantly dopamine at extraordinary levels (plasma concentration 27,942 pg/mL; normal, <30). The patient died before further treatment could be initiated. CONCLUSION: Carotid body tumors usually do not secrete catecholamines but frequently metastasize. During progression, these neuroendocrine tumors may become able to produce and secrete selected catecholamines such as dopamine. Dopamine can lower the blood pressure rather than causing hypertension, even though hypertension is one of the main symptoms of a pheochromocytoma.

3-Iodobenzylguanidine↗