The Section is conducting patient-oriented research about the etiology, pathophysiology, genetics, diagnosis, and treatment of pheochromocytoma. Projects include not only translational research-applying basic science knowledge to clinical diagnosis, pathophysiology, and treatment-but also reverse translation research where appreciation of clinical findings leads to new concepts that basic researchers can pursue in the laboratory.? ? In order to achieve our goals, the strategy of the Section is based on the multidisciplinary collaborations among investigators from multiple NIH Institutes and outside medical centers. Our Section links together a patient-oriented component with two bench-level components. The patient-oriented component (Medical Neuroendocrinology) is currently the main driving force for our hypotheses and discoveries. The two bench-level components (Tumor Pathogenesis and Chemistry & Biomarkers) emphasize first, technologies of basic research tailored for pathway and target discovery and second, the development of the discoveries into clinical applications.? ? SDHB-related pheochromocytoma and paraganglioma? ? SDHB mutations appear to be associated with more aggressive tumor behavior and a higher rate of malignancy. In our initial study of this area, we examined the frequency of SDHB mutations in patients with malignant pheochromocytomas/paragangliomas. Pathogenic SDHB mutations were found in 30% of these patients. In those patients who presented initially with primary abdominal paragangliomas, mutations of the SDHB gene were associated with about one half of all malignancies justifying a high priority for SDHB germline mutation testing in these patients. ? In a further study, we aimed to gain more detailed insight into the clinical and biochemical characteristics of SDHB-associated paragangliomas. Thirty patients with abdominal or thoracic paragangliomas and SDHB mutations were studied. At presentation, 21% of patients lacked any symptoms of catecholamine excess. Family history was positive for paraganglioma in only 10% of patients. Primary tumors were found in extra-adrenal locations in 97% of patients and had a mean diameter of about 8 cm. In 30% of patients, metastatic disease was already apparent at the initial diagnosis and 97% of patients eventually developed metastases after 2.64.1 years. The biochemical phenotype indicated hypersecretion of both NE and DA in about half of the patients. There was no correlation between the particular SDHB gene mutation type and clinical presentations, including malignant potential.? The importance of functional imaging was demonstrated by an additional study. SDHB gene mutations carry a high malignant potential; thus, timely and accurate localization of SDHB related pheochromocytomas and paragangliomas is critical for implementing optimal treatment. Sensitivities for detection of metastases were compared between 18F-fluorodopamine (18F-FDA) and 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), 123I- and 131I-metaiodobenzylguanidine (MIBG), 111In-Pentetreotide (Octreoscan) and Tc-99m-methylene diphosphonate (MDP) bone scintigraphy in 30 patients with SDHB-associated paragangliomas. Lesions detected by CT and MRI were used as a standard of reference. Sensitivity according to patient/body region were as follows: 123/131I-MIBG 57/68; Octreoscan: 59/81; 18F-FDA: 70/99; FDG: 97/100. At least 90% of regions that were false negative on 123I-MIBG scintigraphy or 18F-FDA PET were detected by FDG PET. We concluded that FDG PET is the preferred functional imaging modality for staging and treatment monitoring of SDHB-related metastatic paraganglioma.? ? VHL- and MEN-related pheochromocytoma ? ? Pheochromocytomas in MEN 2 produce EPI; those in VHL syndrome produce NE. Patients with MEN 2 pheochromocytomas have a high incidence of paroxysmal attacks and have a higher prevalence of hypertension and other cardiovascular problems than do patients with VHL pheochromocytomas. Therefore, we hypothesized that these distinctions relate to differences in expression of the transporters responsible for uptake and storage of catecholamines, namely neuropeptide Y (NPY), a vasoactive peptide with influences on blood pressure, and of chromogranin A and B (CGA, CGB), major secretory proteins of chromaffin granules. We demonstrated that MEN 2-related pheochromocytomas expressed more cell membrane noradrenergic transporter mRNA and protein than tumors from VHL patients. This difference was associated with larger numbers of storage vesicles and higher tissue content of catecholamines in MEN 2 than in VHL tumors. In another study we found that tumor NPY levels in VHL patients were significantly lower than in those from MEN 2 patients for both mRNA and the peptide. We also showed that pheochromocytomas from MEN 2 patients expressed substantially more CGA and CGB than tumors from VHL patients at both the mRNA and protein level. We concluded that the differences in tumor CGA expression could contribute to differences in secretory vesicle formation and secretion in the two types of tumors. This may contribute, for example, to the lower prevalence of hypertension in VHL patients than in patients with MEN 2-related pheochromocytoma.? We also evaluated seven VHL patients with adrenal pheochromocytomas using CT, MRI, 123/131I-MIBG scintigraphy, and 18F-FDA PET. We concluded that 18F-FDA PET in conjunction with CT/MRI should be considered an effective method for the proper localization of VHL-related adrenal pheochromocytoma.? ? An animal model of pheochromocytoma? ? As a continuation of our first anatomical studies, we have further optimized the use of microCT and MRI to localize organ and bone metastatic lesions in the mouse model of pheochromocytoma. To improve localization of liver lesions using microCT, we combined two time points of scanning. The first microCT scan was performed immediately after FenestraTMLC injection where both liver lesions and vessels were detected. The second scan was performed 3 hours after FenestraTMLC injection when the contrast disappeared from the vessels and allowed detection of the liver metastatic lesions. By combining these two scans we were able to precisely localize liver lesions at sizes of 300-500 ?m in diameter. To detect other organ lesions, we used MRI. To optimize the signal-to-noise ratio, we used a small animal dedicated radiofrequency coil on 3T MRI; and to reduce the motion artifacts, we applied respiratory triggering on anesthetized mice while scanning.? ? In addition to developing and optimizing methods for tumor imaging in mice, we have also used the mouse model of metastatic pheochromocytoma to study the gene expression profile of hepatic and subcutaneous lesions derived from mouse pheochromocytoma cells. It is of great interest to develop biomarkers or genomic screens that may predict the aggressiveness of pheochromocytoma. We therefore used the mouse model of metastatic pheochromocytoma to study the gene expression profile of hepatic and subcutaneous lesions. Comparison of subcutaneous and liver tumors revealed 8 genes (Pten, Mdm2, Metap2, Rb1, Reck, S100a4, Timp2 and Timp3) with 2-fold increases in expression in the liver compared to subcutaneous tumors. QT-PCR analysis confirmed 5 of these genes. This study provides initial information about which genes could play an important role in the aggressive behavior of metastatic pheochromocytoma cells. This study provides initial information about which genes could play an important role in the aggressive behavior of metastatic pheochromocytoma cells.? ? In 2006, we organized the 1st SDHB Related Pheochromocytoma conference as a series of interactive sessions for health professionals and patients. This year we are organizing the Pheochromocytoma 2007 conference.
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