The Section is conducting patient-oriented research about the etiology, pathophysiology, genetics, diagnosis, and treatment of pheochromocytoma (PHEO) and paraganglioma (PGL). 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. Clinical aspects of PHEO/PGL PHEOs/PGLs show an earlier age of presentation in patients with hereditary rather than sporadic disease. Whether other factors influence age of disease presentation is unclear. We examined age of disease presentation according to different catecholamine phenotypes and locations of PHEOs/PGLs. Patients with PHEOs/PGLs included 172 with and 183 without an identified germ-line mutation or hereditary syndrome. Differences in plasma concentrations of metanephrine, a metabolite of epinephrine, were used to distinguish epinephrine-producing tumors from those lacking epinephrine production. Patients with epinephrine-producing tumors presented with disease 11 years later (P<0.001) than patients with tumors lacking appreciable epinephrine production. Among patients without evidence of a hereditary condition, those with and without epinephrine-producing tumors had respective meanSE ages of 502 and 422 years (P<0.001) at presentation of disease. Patients with multiple endocrine neoplasia type 2 (MEN2) and neurofibromatosis type 1 (NF1), all with epinephrine-producing tumors, similarly presented with disease at a later age than patients with tumors that lacked appreciable epinephrine production secondary to mutations of the von Hippel-Lindau (VHL) and succinate dehydrogenase (SDHx) genes (402 vs 311 years, P<0.001). Among the latter patients, those with multifocal tumors had a younger age of disease presentation than those with solitary tumors (193 vs 342 years, P<0.001). We concluded that the variations in age of disease presentation associated with different tumor catecholamine phenotypes and locations provide useful information for patient management and suggest origins of PHEOs/PGLs from different chromaffin progenitor cells with variable susceptibility to disease causing mutations Hereditary PHEO/PGL We aimed to investigate the rate of SDHB mutations in patients with metastatic PHEO/PGL whose initial tumor presentation began in childhood or adolescence. From 2000 - 2010, 263 PHEO/PGL patients were evaluated. Of those 263 patients, 125 presented with or were found to have metastatic disease;of these 125 patients, 32 presented with a tumor prior to age 20. Genetic testing for mutations in the VHL, MEN, and SDHB/C/D genes was performed on patients without previously identified genetic mutations. Of the 32 patients who presented with metastatic disease and had their primary tumor in childhood or adolescence, sequence analysis of germline DNA found SDHB mutations in 23 (71.9%), SDHD mutations in 3 (9.4%), VHL mutations in 2 (6.3%) and absence of a known mutation in 4 (12.5%). The majority (78.1%) of these 32 patients presented with primary tumors in an extra-adrenal location (retroperitoneum and head and neck). We concluded that the majority of patients with metastatic PHEO/PGL who presented with a primary tumor in childhood or adolescence had primary extra-adrenal tumors and harbored SDHB mutations. Except for primary tumors located in the head and neck where SDHD genetic testing is advised, we recommended that patients presenting with metastatic PHEO/PGL in childhood or adolescence undergo SDHB genetic testing. Another study assessed whether measurements of plasma metanephrine, normetanephrine and methoxytyramine, the O-methylated metabolites of catecholamines, might help distinguish different hereditary forms of the tumor. Plasma concentrations of O-methylated metabolites were measured by liquid chromatography with electrochemical detection in 173 patients with PHEO/PGL, including 38 with MEN2, 10 with NF1, 66 with VHL syndrome and 59 with mutations of the SDHB or D genes. In contrast to patients with VHL and SDH mutations, all patients with MEN2 and NF1 presented with tumors characterized by increased plasma concentrations of metanephrine (indicating epinephrine production). VHL patients usually showed solitary increases in normetanephrine (indicating norepinephrine production), whereas additional or solitary increases in methoxytyramine (indicating dopamine production) characterized 70% of patients with SDH mutations. Patients with NF1 and MEN2 could be discriminated from those with VHL and SDH mutations in 99% of cases by the combination of normetanephrine and metanephrine. Measurements of plasma methoxytyramine discriminated patients with SDH mutations from those with VHL mutations in a further 78% of cases. The distinct patterns of plasma catecholamine O-methylated metabolites in patients with hereditary PHEO/PGL provide an easily utilized tool to guide cost-effective genotyping of underlying disease-causing mutations. Metastatic PHEO/PGL This retrospective study was focused on clinical, genetic, and histopathologic characteristics of primary metastatic versus primary benign PHEOs. We identified 41 subjects with metastatic PHEO and 108 subjects with apparently benign PHEO. We assessed dimension and biochemical profile of the primary tumor, age at presentation, and time to develop metastases. Subjects with metastatic PHEO presented at a significantly younger age (41.414.7 vs. 50.213.7 years;P<0.001), with larger primary tumors (8.383.27 cm vs. 6.182.75 cm;P<0.001) and secreted norepinephrine more frequently (95.1% vs. 83.3%;P=0.046) compared to subjects with apparently benign PHEOs. No significant differences were found in the incidence of genetic mutations in both groups of subjects (25.7% in the metastatic group and 14.7% in the benign group;P=0.13). From available histopathologic markers of potential malignancy, only necrosis occurred more frequently in subjects with metastatic PHEO (27.6% vs. 0%;P<0.001). The median time to develop metastases was 3.6 years, with the longest interval 24 years. In conclusion, regardless of a genetic background, the size of the primary PHEO and age of first presentation are two independent risk factors associated with the development of metastatic disease An animal model of PHEO: Experimental therapeutic approaches For the rapid advancement and preclinical evaluation of novel therapies for PHEO, it is important to develop reliable and sensitive animal models. To this end, we generated two luciferase models: (1) bioluminescent MTT-luc PHEO cells, expressing luciferase, were injected into the tail vein for experimental metastasis and (2) implanted subcutaneously to monitor tumor growth. U.S. Patent Application No. 61/260,991 was filed on November 13, 2009. The title: methods of diagnosis and treatment of cancer using histone deacetylase inhibitors and radiolabeled metaiodobenzylguanidine.

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Jha, Abhishek; Ling, Alexander; Millo, Corina et al. (2018) Superiority of 68Ga-DOTATATE over 18F-FDG and anatomic imaging in the detection of succinate dehydrogenase mutation (SDHx )-related pheochromocytoma and paraganglioma in the pediatric population. Eur J Nucl Med Mol Imaging 45:787-797
Tirosh, Amit; Papadakis, Georgios Z; Millo, Corina et al. (2018) Prognostic Utility of Total 68Ga-DOTATATE-Avid Tumor Volume in Patients With Neuroendocrine Tumors. Gastroenterology 154:998-1008.e1
Taïeb, David; Jha, Abhishek; Guerin, Carole et al. (2018) 18F-FDOPA PET/CT Imaging of MAX-Related Pheochromocytoma. J Clin Endocrinol Metab 103:1574-1582
Wang, Herui; Shepard, Matthew J; Zhang, Chao et al. (2018) Deletion of the von Hippel-Lindau Gene in Hemangioblasts Causes Hemangioblastoma-like Lesions in Murine Retina. Cancer Res 78:1266-1274
Taïeb, David; Sebag, Frédéric; Pacak, Karel (2017) A Large Adrenal Tumor With Marked 18F-Fluorodeoxyglucose Uptake. JAMA 318:84-85
Ross, Alyson; Shamburek, Robert; Wehrlen, Leslie et al. (2017) Cardiometabolic risk factors and health behaviors in family caregivers. PLoS One 12:e0176408
Fishbein, Lauren; Leshchiner, Ignaty; Walter, Vonn et al. (2017) Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. Cancer Cell 31:181-193
Assadipour, Yasmine; Sadowski, Samira M; Alimchandani, Meghna et al. (2017) SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma. Surgery 161:230-239
Taïeb, David; Pacak, Karel (2017) New Insights into the Nuclear Imaging Phenotypes of Cluster 1 Pheochromocytoma and Paraganglioma. Trends Endocrinol Metab 28:807-817
Pamporaki, Christina; Hamplova, Barbora; Peitzsch, Mirko et al. (2017) Characteristics of Pediatric vs Adult Pheochromocytomas and Paragangliomas. J Clin Endocrinol Metab 102:1122-1132

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