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.? ? Hereditary PHEO and PGL? ? Hereditary PHEO and PGL syndromes result from germline mutations in genes encoding subunits B, C and D of the mitochondrial enzyme succinate dehydrogenase (SDHB, SDHC and SDHD). SDHB-related PGLs are known in particular for their high malignant potential. Recently, however, malignant PGLs were also reported among a small minority of Dutch carriers of the SDHD founder mutation D92Y. Therefore, we investigated which SDHD mutations are associated with malignant PGL. We found that germline SDHD mutations underlying metastatic PGL were G148D, Y114X, L85X, W43X, D92Y, and IVS2+5 G>A. We also found that all mediastinal paragangliomas are related to either SDHB or SDHD gene mutations.? ? We also performed a retrospective analysis of 71 subjects with metastatic PHEO/PGL (30 subjects SDHB gene mutation and 41 subjects without SDHB mutation (including 3 subjects with mutation of the RET gene, 3 subjects with mutation of the VHL gene and 1 subjects with mutation of the SDHD gene). Sixty nine percent presented with bone metastases (77% of those with SDHB mutation and 63% of those without SDHB mutation), 39% with liver metastases and 32% with lung metastases. The most common sites of bone involvement were thoracic spine (80%), lumbar spine (78%), and pelvic and sacral bones (78%). Subjects with SDHB mutation showed significantly higher involvement of long bones (P=0.007) and pelvic and sacral bones (P=0.04) than those without the mutation? ? ? Imaging of PHEO and PGL ? ? Different imaging methods were compared in various PHEOs/PGLs. Out of 11 non-metastatic lesions detected by any technique, 8 lesions were detected by 18F-DOPA positron emission tomography (PET), 7 by 18F-FDA PET/CT, 8 by 18F-FDG PET/CT, and 9 by 123I-MIBG scintigraphy. CT and/or MRI identified 108 lesions in 19 patients with metastatic PGL. Functional imaging identified 80 additional lesions. Discrepant readings between the two nuclear physicians were solved by consensus for 7 lesions on 18F-DOPA PET and 7 lesions on 18F-FDA PET. Out of 188 metastatic lesions, 116 were detected by 18F-DOPA PET, 110 by 18F-FDA PET/CT, 107 by 18F-FDG PET/CT, and 67 by 123I-MIBG scintigraphy (P<0.001 versus all other techniques). In reference to lesions detected by CT and/or MRI, sensitivities were 52% for 18F-DOPA PET, 64% for 18F-FDA PET/CT, 72% for 18F-FDG PET/CT (*P<0.05 versus all other techniques, except 18F-FDA), and 54% for 123I-MIBG scintigraphy. Sensitivities in reference the total number of lesions detected by any technique were 62% for 18F-DOPA PET, 59% for 18F-FDA PET/CT, 57% for 18F-FDG PET/CT, and 36% for 123I-MIBG scintigraphy (P<0.001 versus all other techniques). The best overall sensitivity in detecting bone metastases was 18F-FDA PET (90%), followed by bone scintigraphy (82%), CT/MRI (78%) and 123/131I-MIBG scintigraphy (71%). In subjects with SDHB mutation, imaging modalities with best sensitivities for detecting bone metastases were CT/MRI (96%), bone scintigraphy (95%) and 18F-FDG PET (92%). In subjects without SDHB mutation, the modality with the best sensitivity for bone metastases was 18F-FDA PET (100%). We concluded that bone scintigraphy should be used in the staging of patients with malignant PHEO/PGL, particularly in patients with SDHB mutation. As PET imaging modality, 18F-FDG PET was highly recommended in SDHB mutation patients, whereas 18F-FDA PET was recommended in patients without the mutation.? ? Other findings? ? Patients who undergo successful surgery for apparently benign PHEO were found to have a reduced life expectancy as compared to the general population. The excess mortality was explained by the fact that patients may still develop metastatic disease during post-surgical follow-up. Hypertension persisted in two-thirds of recurrence-free patients. Life-long follow-up is therefore warranted in these patients. ? ? We also conducted a long-term follow up of the 18 patients with a diagnosis of PHEO/PGL treated with a combination of cyclophosphamide, vincristine and dacarbazine (CVD chemotherapy). This was a non-randomized, single arm trial. Combination chemotherapy with CVD produced objective tumor responses in patients with advanced malignant PHEO/PGL. No difference in overall survival between patients whose tumors objectively shrank and those with stable or progressive disease. However, patients reported improvement in symptoms, had objective improvements in blood pressure and had tumor shrinkage that made surgical resection possible. We concluded that CVD therapy was not indicated in every patient with metastatic PHEO/PGL, but should be considered in the management of patients with symptoms and where tumor shrinkage might be beneficial.? ? An animal model of PHEO? ? Recently, we have found that microCT and MRI were approximately equal in their ability to detect hepatic metastases at a size threshold of 350 m. In the lungs, MRI was more sensitive than microCT, detecting lesions 0.6 mm in diameter vs 1mm for microCT. Additionally, MRI was more sensitive for lesions in the kidneys, bone, ovaries and adrenal glands. MRI demonstrated higher contrast-to-noise ratio (CNR) than microCT. We concluded that in addition to the advantage of not exposing the animal to ionizing radiation, MRI provided a more complete assessment of the extent of metastases in this model, compared to microCT. In another study, we have enhanced this model by modifying the number of cells injected, length of trypsin treatment, and temperature for cells storage before injection and by removal of metastatic lesions, serial passage and re-selection of metastases. We evaluated the effect of these modifications on tumor growth using in vivo MRI. These results show that number of cells injected, temperature for cell storage before injection and length of trypsin treatment are important factors to produce faster-growing, more aggressive tumors that yielded secondary metastatic lesions at other sites. Serial culture and selection of metastatic liver lesions produced even more aggressive PHEO cells that retained their biochemical phenotype. Microarray comparison of these more aggressive cells to the parental cell line identified genes important for their rapid metastatic process.? ? Conferences? ? In line with the spirit of our Program which emphasizes teamwork, collaboration with outside medical centers and patient participation, we are participating in the organization of the 2nd International Symposium on Pheochromocytoma that will be held in Cambridge, UK in September 2008.
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