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chromaffin tissue [keywords]
- Combination chemotherapy regimen in a patient with metastatic malignant pheochromocytoma and neurofibromatosis type 1. [Journal Article]
- Am J Case Rep 2014.:123-7.
Patient: Female, 55 Final Diagnosis: Metastatic malignant pheochromocytoma Symptoms: Chest pain • tachycardia • tachypnea Medication: - Clinical Procedure: - Specialty: Oncology.Rare disease.Malignant pheochromocytoma is defined as the occurrence of the tumor in an area that is normally devoid of chromaffin tissue, direct tumor invasion, and/or metastasis. Metastatic malignant pheochromocytoma is very rare. Malignant pheochromocytoma carries a poor prognosis with a 5-year survival rate of 44%. The majority of pheochromocytoma cases are sporadic, but a small portion (10%) can be associated with hereditary syndromes such as neurofibromatosis type 1 (NF1).A 55-year-old Hispanic woman presented to our care with chest pain. Her past medical problems included hypertension, neurofibromatosis type 1 (NF1), and pheochromocytoma status after right laparoscopic adrenalectomy, which was converted to open procedure about 19 months ago. Initial vital signs were significant for tachycardia, tachypnea, and hypertension. Computed tomography (CT) angiography of the chest was performed to rule out a pulmonary embolism, but instead revealed multiple bilateral lung nodules measuring up to 8 mm, consistent with metastasis. CT of the abdomen and pelvis revealed a lytic lesion in the posterior aspect of the left pedicle and transverse process of L4, and the neck/greater trochanter of the left femur. MIBG scan revealed widespread metastatic disease. She received an outpatient chemotherapy regimen of cyclophosphamide, dacarbazine, and vincristine.Metaiodobenzylguanidine (MIBG) is an alkyl-guanidine derivative similar to noradrenaline, which accumulates in tissue derived from neural crest cells. Current medical literature suggests that therapeutic 131I MIBG has a response rate of 50-75%. Combination chemotherapy using cyclophosphamide, vincristine, and dacarbazine has been the most widely used regimen for malignant pheochromocytoma. This combination of chemotherapy has been shown to have a high response rate and symptomatic improvement. Numerous therapeutic regimens exist for metastatic malignant pheochromocytoma; however, no regimen has been shown to have a benefit significantly superior to the others.
- Reversible catecholamine-induced cardiomyopathy due to pheochromocytoma:Case report. [JOURNAL ARTICLE]
- Rev Port Cardiol 2014 Mar; 33(3):177.e1-177.e6.
Pheochromocytoma is a tumor originating from chromaffin tissue. It commonly presents with symptoms and signs of catecholamine excess, such as hypertension, tachycardia, headache and sweating. Cardiovascular manifestations include catecholamine-induced cardiomyopathy, which may present as severe left ventricular dysfunction and congestive heart failure. We report a case of pheochromocytoma which was diagnosed following investigation of dilated cardiomyopathy. We highlight the dramatic symptomatic improvement and reversal of cardiomyopathy, with recovery of left ventricular function after treatment.
- The Genetic Basis of Pheochromocytoma and Paraganglioma: Implications for Management. [REVIEW]
- Urology 2014 Mar 15.
Chromaffin cells are catecholamine-producing cells derived from neural crest tissue. Chromaffin tumors are rare tumors arising from these cells and are divided into pheochromocytoma arising from adrenal tissue and paraganglioma arising from extra-adrenal ganglia. Previously, ∼10% were believed to be hereditary, but advances in genome sequencing have shown that roughly 35% of apparently sporadic tumors have a hereditary component. In this review, we describe both classic and newly discovered hereditary chromaffin tumors syndromes and provide recommendations for genetic testing. In many cases, the genes associated with these conditions are linked to common kidney cancer pathways familiar to urologic oncologists.
- [Pheochromocytoma: update on diagnosis and therapy]. [English Abstract, Journal Article, Review]
- Dtsch Med Wochenschr 2014 Mar; 139(10):486-90.
Pheochromocytomas (P) are rare catecholamine producing neuroendocrine tumors originating from the chromaffin cells of the adrenal medulla or in 15 % of cases from extra adrenal chromaffin tissue and termed paragangliomas (PGL). Because of secretion of the catecholamines - adrenaline, noradrenaline and dopamine - the tumors are dangerous with a risk of life threating hypertensive crises. Measurements of plasma metanephrine, normetanephrine and methoxytyramine by liquid chromatography with tandem mass spectrometry provides the most accurate and precise method for biochemical diagnosis. Approximately 30-40 % of the tumors have a hereditary background due to mutations of 11 known susceptibility genes, with identification facilitated by targeted genetic testing according to clinical presentation. Apart from syndrome-dependent clinical stigmata, other hints to an underlying mutation can be provided by biochemical profiles of the catecholamine metabolites, tumor location, patient age and presence of metastatic disease. Surgery with minimal invasive procedures is the recommended therapeutic way after pretreatment with an alpha receptor blocking medication.
- [Pheochromocytoma can be an insidious disease]. [English Abstract, Journal Article, Review]
- Duodecim 2013; 129(22):2375-8.
Pheochromocytoma is a tumor of the chromaffin tissue, originating from the suprarenal medulla and secreting cathecolamines, adrenalin and noradrenalin. Because the symptoms of this rare disease may deceptively resemble those of other diseases, its diagnosis may be delayed. Episodic symptoms are characteristic of pheochromocytoma. In most cases the tumor is curable with surgery, but untreated may lead to sudden death of the patient, or have time to spread. Alpha-blockade is started before the operation. The operations should be concentrated to units specialized in endocrine surgery.
- Succinate-to-fumarate ratio as a new metabolic marker to detect the presence of SDHB/D-related paraganglioma: initial experimental and ex vivo findings. [Journal Article]
- Endocrinology 2014 Jan; 155(1):27-32.
Pheochromocytomas (PHEOs) and paragangliomas (PGLs; extra-adrenal tumors) are rare neuroendocrine chromaffin cell tumors with a hereditary background in about 30%-35%. Those caused by succinate dehydrogenase subunit B (SDHB) germline mutations are associated with a high metastatic potential and ultimately higher patient mortality. Succinate dehydrogenase converts succinate to fumarate, uniquely linking the Krebs cycle and oxidative phosphorylation. SDH mutations result in the accumulation of succinate associated with various metabolic disturbances and the shift to aerobic glycolysis in tumor tissue. In the present study, we measured succinate and fumarate levels in mouse pheochromocytoma (MPC) and mouse tumor tissue (MTT) cells and in 10 apparently sporadic, 10 SDHB-, 5 SDHD-, and 2 neurofibromatosis 1-related PHEOs/PGLs and plasma samples using mass spectrometry. We found that the succinate-to-fumarate ratio was significantly higher in the SDHB- and SDHD-related PGLs than in apparently sporadic and neurofibromatosis 1-related PHEOs/PGLs (P = .0376). To further support our data, we silenced SDHB expression in MPC and MTT cells and evaluated the succinate and fumarate levels. Compared with control samples, SDHB-silenced MTT cells also showed an increase in the succinate-to-fumarate ratio (MTT cells: 2.45 vs 7.53), similar to the findings in SDHB-related PGLs. The present findings for the first time demonstrate a significantly increased succinate-to-fumarate ratio in SDHB/D-related PGLs and thus suggest this ratio may be used as a new metabolic marker for the detection of SDHB/D-related PHEOs/PGLs.
- Doc2b synchronizes secretion from chromaffin cells by stimulating fast and inhibiting sustained release. [Journal Article, Research Support, Non-U.S. Gov't]
- J Neurosci 2013 Oct 16; 33(42):16459-70.
Synaptotagmin-1 and -7 constitute the main calcium sensors mediating SNARE-dependent exocytosis in mouse chromaffin cells, but the role of a closely related calcium-binding protein, Doc2b, remains enigmatic. We investigated its role in chromaffin cells using Doc2b knock-out mice and high temporal resolution measurements of exocytosis. We found that the calcium dependence of vesicle priming and release triggering remained unchanged, ruling out an obligatory role for Doc2b in those processes. However, in the absence of Doc2b, release was shifted from the readily releasable pool to the subsequent sustained component. Conversely, upon overexpression of Doc2b, the sustained component was largely inhibited whereas the readily releasable pool was augmented. Electron microscopy revealed an increase in the total number of vesicles upon Doc2b overexpression, ruling out vesicle depletion as the cause for the reduced sustained component. Further experiments showed that, in the absence of Doc2b, the refilling of the readily releasable vesicle pools is faster, but incomplete. Faster refilling leads to an increase in the sustained component as newly primed vesicles fuse while the [Ca(2+)]i following stimulation is still high. We conclude that Doc2b acts to inhibit vesicle priming during prolonged calcium elevations, thus protecting unprimed vesicles from fusing prematurely, and redirecting them to refill the readily releasable pool after relaxation of the calcium signal. In sum, Doc2b favors fast, synchronized release, and limits out-of-phase secretion.
- Neurobiological consequences of acute footshock stress: effects on tyrosine hydroxylase phosphorylation and activation in the rat brain and adrenal medulla. [Journal Article, Research Support, Non-U.S. Gov't]
- J Neurochem 2014 Feb; 128(4):547-60.
Stress activates selected neuronal systems in the brain and this leads to activation of a range of effector systems. Our aim was to investigate some of the relationships between these systems under basal conditions and over a 40-min period in response to footshock stress. Specifically, we investigated catecholaminergic neurons in the locus coeruleus (LC), ventral tegmental area and medial prefrontal cortex (mPFC) in the brain, by measuring tyrosine hydroxylase (TH) protein, TH phosphorylation and TH activation. We also measured the effector responses by measuring plasma adrenocorticotrophic hormone, corticosterone, glucose and body temperature as well as activation of adrenal medulla protein kinases, TH protein, TH phosphorylation and TH activation. The LC, ventral tegmental area and adrenal medulla all had higher basal levels of Ser19 phosphorylation and lower basal levels of Ser31 phosphorylation than the mPFC, presumably because of their cell body versus nerve terminal location, while the adrenal medulla had the highest basal levels of Ser40 phosphorylation. Ser31 phosphorylation was increased in the LC at 20 and 40 min and in the mPFC at 40 min; TH activity was increased at 40 min in both tissues. There were significant increases in body temperature between 10 and 40 min, as well as increases in plasma adrenocorticotropic hormone at 20 min and corticosterone and glucose at 20 and 40 min. The adrenal medulla extracellular signal-regulated kinase 2 was increased between 10 and 40 min and Ser31 phosphorylation was increased at 20 min and 40 min. Protein kinase A and Ser40 phosphorylation were increased only at 40 min. TH activity was increased between 20 and 40 min. TH protein and Ser19 phosphorylation levels were not altered in any of the brain regions or adrenal medulla over the first 40 min. These findings indicate that acute footshock stress leads to activation of TH in the LC, pre-synaptic terminals in the mPFC and adrenal medullary chromaffin cells, as well as changes in activity of the hypothalamic-pituitary-adrenal axis.
- Identification of unique release kinetics of serotonin from guinea-pig and human enterochromaffin cells. [Journal Article, Research Support, Non-U.S. Gov't]
- J Physiol 2013 Dec 1; 591(Pt 23):5959-75.
The major source of serotonin (5-HT) in the body is the enterochromaffin (EC) cells lining the intestinal mucosa of the gastrointestinal tract. Despite the fact that EC cells synthesise ∼95% of total body 5-HT, and that this 5-HT has important paracrine and endocrine roles, no studies have investigated the mechanisms of 5-HT release from single primary EC cells. We have developed a rapid primary culture of guinea-pig and human EC cells, allowing analysis of single EC cell function using electrophysiology, electrochemistry, Ca(2+) imaging, immunocytochemistry and 3D modelling. Ca(2+) enters EC cells upon stimulation and triggers quantal 5-HT release via L-type Ca(2+) channels. Real time amperometric techniques reveal that EC cells release 5-HT at rest and this release increases upon stimulation. Surprisingly for an endocrine cell storing 5-HT in large dense core vesicles (LDCVs), EC cells release 70 times less 5-HT per fusion event than catecholamine released from similarly sized LDCVs in endocrine chromaffin cells, and the vesicle release kinetics instead resembles that observed in mammalian synapses. Furthermore, we measured EC cell density along the gastrointestinal tract to create three-dimensional (3D) simulations of 5-HT diffusion using the minimal number of variables required to understand the physiological relevance of single cell 5-HT release in the whole-tissue milieu. These models indicate that local 5-HT levels are likely to be maintained around the activation threshold for mucosal 5-HT receptors and that this is dependent upon stimulation and location within the gastrointestinal tract. This is the first study demonstrating single cell 5-HT release in primary EC cells. The mode of 5-HT release may represent a unique mode of exocytosis amongst endocrine cells and is functionally relevant to gastrointestinal sensory and motor function.
- Granins and catecholamines: functional interaction in chromaffin cells and adipose tissue. [Journal Article, Research Support, Non-U.S. Gov't]
- Adv Pharmacol 2013.:93-113.
Catecholamines (CAs) and granin peptides are costored in dense-core vesicles within the chromaffin cells of the adrenal medulla and in other endocrine organs and neurons. Granins play a major functional and structural role in chromaffin cells but are ubiquitous proteins, which are present also in secretory cells of the nervous, endocrine, and immune systems, where they regulate a number of cellular functions. Furthermore, recent studies also demonstrate that granin-derived peptides can functionally interact with CA to modulate key physiological functions such as lipolysis and blood pressure. In this chapter, we will provide a brief update on the interaction between CA and granins at the cellular and organ levels. We will first discuss recent data on the regulation of exocytosis of CA and peptides from the chromaffin cells by the sympathetic nervous system with a specific reference to the prominent role played by splanchnic nerve-derived pituitary adenylate cyclase-activating peptide (PACAP). Secondly, we will discuss the role of granins in the storage and regulation of exocytosis in large dense-core vesicles. Finally, we will provide an up-to-date review of the roles played by two granin-derived peptides, the chromogranin A-derived peptide catestatin and the VGF-derived peptide TLQP-21, on lipolysis and obesity. In conclusion, the knowledge gathered from recent findings on the role played by proteins/peptides in the sympathetic/target cell synapses, discussed in this chapter, would contribute to and provide novel mechanistic support for an increased appreciation of the physiological role of CA in human pathophysiology.