User:Lexiholroyd/new sandbox

= Iobenguane =

Introduction
Iobenguane, or MIBG, is an aralkylguanidine analog of the adrenergic neurotransmitter norepinephrine and a radiopharmaceutical. It acts as a blocking agent for adrenergic neurons. When radiolabeled, it can be used in nuclear medicinal diagnostic techniques as well as in neuroendocrine antineoplastic treatments. It localizes to adrenergic tissue and thus can be used to identify the location of tumors such as pheochromocytomas and neuroblastomas. With I-131 it can also be used to eradicate tumor cells that take up and metabolize norepinephrine.

Usage/mechanism

MIBG gets absorbed by and accumulated in granules of adrenal medullary chromaffin cells, as well as in pre-synaptic adrenergic neuron granules. The process in which this occurs is closely related to the mechanism employed by norepinephrine and its transporter in vivo. The norepinephrine transporter (NET) is necessary for norepinephrine uptake at the synaptic terminals and adrenal chromaffin cells. MIBG targets NET, permitting its properties in imaging and therapy.

Metabolites/Excretion

Less than 10% of the administered dose gets metabolized into m-iodohippuric acid (MIHA), but the mechanism for how this metabolite is produced is unknown.

Imaging Procedures/Neoplasm Treatments

MIBG radiolabeled with iodine 131 or 123 concentrates in endocrine tumors, most commonly neuroblastomas, paragangliomas, and pheochromocytomas. It also accumulates in norepinephrine transporters in adrenergic nerves in the heart, lungs, adrenal medulla, salivary glands, liver, and spleen, as well as in tumors that originate in the neural crest. MIBG serves as a whole-body, non-invasive scintigraphic screening for germ-line, somatic, benign, and malignant neoplasms originating from the adrenal glands. It is able to detect both intra and extra-adrenal disease. The imaging is highly sensitive and specific. Iobenguane concentrates in presynaptic terminals of the heart and other autonomically innervated organs. This enables the possible non-invasive use as an in vivo probe to study these systems. Large doses of the compound have been used in trials to selectively administer radiotherapy to malignant pheochromocytomas as well as neuroblastomas.

Side effects

Common side effects post imaging includes lymphopenia, neutropenia, anemia, thrombocytopenia, and fatigue. Nausea, vomiting, hypertension, and dizziness have also been observed. 6.8% of patients in a study who received therapeutic dosing of iobenguane developed acute leukemia or myelodysplastic syndrome.

= Pheochromocytoma = Introduction

Pheochromocytomas are tumors arising from chromaffin cells of the adrenal medulla that synthesize, store, metabolize and usually but not always secrete catecholamines. Extra-adrenal paragangliomas (often described as extra-adrenal pheochromocytomas) are closely related, though less common, tumors that originate in the ganglia of the sympathetic nervous system and are named based upon the primary anatomical site of origin. The term is from the Greek phaios (dark), chroma (color), kytos (cell), and -oma (tumor).

Causes

The hereditary implications of pheochromocytoma are still being investigated, however, genes have been identified as genomic biomarkers to aid in the identification of inherited disease. Of these genes studied, the most well-known include VHL, RET, and NF1. Aberrations of these genes are associated with bilateral disease.

The RET protein is a tyrosine kinase receptor that plays an integral role in development of sympathetic neurons. Mutations in the gene via germ-line (MEN-2) or somatic acquisition activate multiple signaling pathways involved in PCC, as well as other neuroendocrine tumors in humans. MEN-2 generally results from a gain-of-function variant of this RET gene, and MEN-2 is commonly associated with pheochromocytoma and amyloid producing medullary thyroid carcinoma.

Mutations in two subunits of the succinate dehydrogenase gene, SDHB and SDHD, have been strongly associated with cancer presenting at a younger age as well as extra-adrenal location, multiple tumors/metastasis, and poor prognosis.

Complications: Endocrine Implications

A common clinical presentation of pheochromocytoma includes hypertension, due to increased total peripheral resistance. Most heochromocytomas secrete norepinephrine, which is a vasoconstrictor via α-adrenergic receptor stimulation, however research has yet to significantly correlate the increase in peripheral resistance with increased circulating norepinephrine. Theories behind the inability to correlate the two variables include simultaneous dopamine release, which has the opposing effect of norepinephrine in terms of vasodilation. Other mechanisms propose the down-regulation of α-adrenergic receptors or the release of other hormones that have opposing effects to norepinephrine. Due to increased catecholamine production, cardiovascular complications upon presentation and throughout the course of the disease are common. Complications that arise from these cardiovascular disturbances include blood pressure changes as well as possible sudden death, heart attach despite no prior history, noncardiogenic pulmonary shock/edema, and arrhythmias.

Pheochromocytoma is also capable of causing, at presentation, pseudo-obstruction of bowels, diabetic ketoacidosis, or multisystem crisis involving lactic acidosis. These symptoms may be in part due to the co-secretion of other hormones associated with norepinephrine, such as corticotropin-releasing hormone, adrenocorticotropin, and interleukin six.

Complications: Diagnosis

Pheochromocytoma may go undiagnosed or undetected for multiple reasons. The main reason is the fact that the tumors are rare. Hypertension may not clinically present itself right away due to the fact that catecholamines can convert into their biologically inactive forms in the tumor, suppressing symptoms. Lastly, the symptoms of the disease are non-specific and common to stress neuronal release of catecholamines. Lag in diagnosis averages about three years. Presymptomatic diagnosis is most possible in patients with germ-line inheritance.

Pre-excision testing via imaging:

Testing prior to tumor excision helps ascertain whether the tumor is a singular tumor or if there are multiple, if it is ectopic or adrenal originating, malignant or benign, and isolated or present with other tumors in context of inherited disease. CT is the most commonly used imaging technique, however MRI is preferred. MIBG scanning should be used when possible, as it is the most accurate way to locate cancer in catecholamine producing cancers, as catecholamine plasma membrane and vesicular transport systems are especially abundant in pheochromocytoma cells. Imaging using MIBG would yield specific and sensitive results compared to CT and MRI, as the latter two are non-specific generalized imaging techniques.