The Section is conducting patient-oriented conceptually innovative research about the etiology, pathophysiology, genetics, diagnosis, prognosis, 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. ? ? The Section emphasizes bedside to bench projects and multidisciplinary and multi-institutional collaborations. The studies focus on 3 objectives: (1) development and testing of novel methods and criteria to diagnose and localize pheochromocytoma cost-effectively; (2) development of better treatments for malignant pheochromocytoma; (3) identification of molecular and genetic mechanisms of pheochromocytoma tumorigenesis and clinical manifestations of disease. It is anticipated that studies directed at the last objective will have the most far-reaching consequences by leading to new strategies for diagnosis and therapy of pheochromocytoma, particularly of metastatic disease.? ? Recently, we have summarized new clinical, diagnostic, and localization procedures and approaches for benign and metastatic sporadic and familial pheochromocytomas. Plasma and urinary fractionated metanephrine assays are the most accurate screening procedures for biochemical diagnosis. Initial testing should include measurements of fractionated metanephrines in urine, plasma or both, where these assays are available, and reference intervals should favour high sensitivity over high specificity to avoid a missed diagnosis. We also described that plasma concentrations of free metanephrines are relatively independent of renal function and therefore more suitable for diagnosis of pheochromocytoma among patients with renal failure than measurements of deconjugated metanephrines. We found that measurements of plasma free metanephrines not only provide information about the likely presence or absence of a pheochromocytoma, but when a tumor is present, can also help to predict tumor size and location? ? Localization studies should only be initiated after establishing reasonably compelling clinical evidence for tumor, including signs and symptoms of catecholamine excess, strongly positive biochemical tests, hereditary predisposition or history of previous tumor. Our recent results showed that in patients with pheochromocytoma (including metastatic disease), 6-[18F]-fluorodopamine PET scanning could detect and localize pheochromocytomas with higher sensitivity than other functional imaging modalities. Our findings led to important refinements in the clinical diagnostic approaches in pheochromocytoma which we adopted and are continuing to apply and improve. New imaging algorithms show how to use anatomical imaging studies together with functional imaging in very cost-effective manners together with very high sensitivity to localize benign and metastatic lesions.? ? Since there is no curative treatment of metastatic pheochromocytoma, we are testing the efficacy of radiotoxic treatment of malignant pheochromocytoma using [131I]-metaiodobenzylguanidine ([131I]-MIBG) and, in particular, to evaluate whether pre-treatment with ?enhancer? pharmaceuticals increases the efficacy of experimental [131I]-MIBG treatment in reducing the size and number of tumors.? ? About 50% of patients with metastatic pheochromocytoma die within 5 years due to lack of appropriate therapy. There is a need to search for markers that can identify patients who may develop or have metastatic pheochromocytoma. In addition, these markers can be explored as potential new therapeutic targets. We applied quantitative real-time polymerase chain reaction to 11 metastasis suppressor genes. These genes are known to be involved in the regulation of important cancer-related cell events, such as cell growth regulation and apoptosis (nm23-HI, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TXNIP and CRSP-3), cell-cell communication (BRSM-1), invasion (CRMP-1), and cell adhesion (E-Cad and KiSS1). Following cross-validation, the non-linear rule produced 0 errors in 10 malignant samples and 3 errors in the 15 benign samples, with overall error rate of 12%. These results suggest that down-regulation of metastasis suppressor genes reflect malignant pheochromocytoma with a high degree of sensitivity. In another study we utilized oligonucleotide microarrays to examine gene expression profiles in 98 pheochromocytomas, including 26 malignant tumors, the latter including metastases and primary tumors from which metastases developed. Other subgroups of tumors included those defined by tissue norepinephrine compared to epinephrine contents (i.e., noradrenergic versus adrenergic phenotypes), adrenal versus extra-adrenal locations, and presence of underlying germline mutations of SDHB, RET, and VHL genes. Correcting for the confounding influence of noradrenergic versus adrenergic catecholamine phenotype by analysis of variance revealed a larger and more accurate number of genes that discriminated benign from malignant pheochromocytoma than when the confounding influence of catecholamine phenotype was not considered. Seventy percent of these differentially expressed genes were under-expressed in malignant compared to benign tumors. Similarly, 89% of genes were under-expressed in malignant primary tumors compared to benign tumors, suggesting that malignant potential is largely characterized by a dedifferentiated pattern of gene expression. The present database of differentially expressed genes provides a unique resource for mapping the pathways leading to malignancy and for establishing new targets for treatment and diagnostic and prognostic markers of malignant disease. The database may also be useful for examining mechanisms of tumorigenesis and genotype-phenotype relationships. Further progress based on this database can benefit from application of bioinformatics approaches for data mining and pathways analyses, follow-up confirmatory quantitative PCR and proteomics studies, and testing in pheochromocytoma cell culture and animal model systems.? ? Recently, we have introduced a new model of metastatic pheochromocytoma resulting from tail vein injected mouse pheochromocytoma cells that reproducibly generated multiple tumors. For the first time, we showed that microCT using hepatobillary specific contrast and MRI may reveal liver metastasis as small as 0.35mm and can be detected as early as 4 weeks after initial injection of tumor cells. We also introduced the use of 6-[18F]-fluorodopamine and 6-[18F]-fluoroda PET for the detection of metastatic lesions in this model. We believe that this model may be utilized for studies on the in vivo molecular biology and therapeutic strategies for treatment of malignant pheochromocytoma.
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