Diagnosis, Pathophysiology And Molecular Biology Of Pheochromocytoma

嗜铬细胞瘤的诊断、病理生理学和分子生物学

• 批准号: 7734764
• 负责人: Karel Pacak
• 金额: $ 122.75万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734764
• 关键词: Adrenal Glands; Animal Model; Animals; Basic Science; Benign; Biochemical; Biological Markers; Blood Pressure; Caliber; Cell Count; Cell Line; Cells; Chemistry; Chest; Clinical; Collaborations; Combination Chemotherapy; Consensus; Development; Diagnosis; Disease; Enzymes; Etiology; Excess Mortality; Excision; Functional Imaging; Functional disorder; Gene Mutation; General Population; Genes; Genetic; Genetic Markers; Germ-Line Mutation; Goals; Hypertension; Image; Inherited; Injection of therapeutic agent; Institutes; Interdisciplinary Study; International; Ionizing radiation; Kidney; Knowledge; Laboratories; Length; Lesion; Life; Life Expectancy; Link; Liver; Lung; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Paraganglionic Neoplasm; Malignant Pheochromocytoma; Mediastinal; Medical; Medical center; Metastatic Lesion; Metastatic Neoplasm to the Bone; Metastatic Neoplasm to the Liver; Metastatic Pheochromocytoma; Methods; Minority; Mitochondria; Modality; Modeling; Modification; Molecular; Molecular Biology; Molecular Genetics; Mutation; Neoplasm Metastasis; Neuroendocrinology; Noise; Nuclear; Numbers; Operative Surgical Procedures; Other Finding; Ovary; Paraganglioma; Pathogenesis; Pathway interactions; Patient Participation; Patients; Pelvis; Phenotype; Pheochromocytoma; Physicians; Positron-Emission Tomography; Progressive Disease; RET gene; Radionuclide Imaging; Randomized; Reading; Recurrence; Reporting; Research; Research Personnel; Serial Passage; Site; Staging; Succinate Dehydrogenase; Symptoms; Syndrome; Techniques; Technology; Temperature; Translational Research; Translations; Trypsin; United States National Institutes of Health; Upper arm; VHL mutation; Vertebral column; base; bone; chemotherapy; clinical Diagnosis; clinical application; concept; cyclophosphamide/dacarbazine/vincristine protocol; driving force; follow-up; founder mutation; improved; in vivo; long bone; metastatic process; patient oriented; patient oriented research; programs; response; sacrum; size; symposium; tumor; tumor growth; tumorigenesis

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.

本节正在进行有关病因，病理生理学，遗传学，诊断和治疗嗜铬细胞瘤（PHEO）（PHEO）和Paraganglioma（PGL）的研究。项目不仅包括将基础科学知识应用于临床诊断，病理生理学和治疗，还包括反向翻译研究，对临床发现的欣赏会导致基础研究人员可以在实验室中追求的新概念。 为了实现我们的目标，本节的战略是基于来自多个NIH机构和外部医疗中心的调查人员之间的多学科合作。我们的部分将面向患者的组件与两个基准级组件链接在一起。目前，面向患者的成分（医学神经内分泌学）是我们假设和发现的主要驱动力。两个基准级成分（肿瘤发病机理和化学与生物标志物）首先强调，这是针对途径和目标发现量身定制的基础研究技术，其次是将发现的发展到临床应用中。 遗传性pheo和pgl 遗传性pheo和PGL综合征是由编码线粒体酶琥珀酸酯脱氢酶（SDHB，SDHC和SDHD）的亚基B，C和D的种系突变引起的。 SDHB相关的PGL特别以其高恶性潜力而闻名。然而，最近，还报道了SDHD创始人突变D92Y的少数荷兰载体中的恶性PGL。因此，我们研究了哪些SDHD突变与恶性PGL有关。我们发现转移性PGL的种系SDHD突变为G148D，Y114X，L85X，W43X，D92Y和IVS2+5 g> a。我们还发现，所有纵隔paragangliomas都与SDHB或SDHD基因突变有关。 我们还对71名具有转移性PheO/pGL的受试者进行了回顾性分析（30名受试者SDHB基因突变和41名没有SDHB突变的受试者（包括3名具有RET基因突变的受试者，3名受试者，具有VHL基因突变的VHL基因突变和1名具有SDHD基因突变的受试者。没有SDHB突变的突变和63％的肝脏转移的39％，肺部受累最常见的部位是胸部脊柱（80％），腰椎（78％）（78％），并且骨盆和sacral骨均具有较高的次数。与没有突变的骨头（P = 0.04） Pheo和PGL的成像 在各种Pheos/PGL中比较了不同的成像方法。在任何技术检测到的11个非转移性病变中，在18F-DOPA正电子发射断层扫描（PET）中检测到8个病变，7 by 18f-fda PET/CT，8乘18F-FDG PET/CT和9 by 123i-mibg scintraghy。 CT和/或MRI确定了19例转移性PGL患者的108个病变。功能成像确定了80个其他病变。两位核医生之间的差异通过共识为18F-DOPA PET的7个病变和18F FDA PET的7个病变解决。在188个转移性病变中，在18F-DOPA PET中检测到116个，110乘18F-FDA PET/CT，107乘18F-FDG PET/CT和67乘123i-Mibg Scintigraphy（P <0.001 v 0.001，与所有其他技术相比，P <0.001）。关于CT和/或MRI检测到的病变，18F-DOPA PET的敏感性为52％，18F-FDA PET/CT的敏感性为64％，18F-FDG PET/CT的敏感性为72％（*P <0.05 ving 0.05对所有其他技术，除所有其他技术，除了18F-FDA），而123i-Mibg Scintigrigry除外54％。参考的敏感性18F-DOPA PET检测到的病变总数均为62％，18F-FDA PET/CT的敏感性为59％，18F-FDG PET/CT的敏感性为57％，为123i-Mibg scintigraphy（p <0.001对所有其他技术）的敏感性为59％，为36％。检测骨转移量的最佳总体灵敏度是18F-FDA PET（90％），其次是骨闪烁显像（82％），CT/MRI（78％）和123/131i-Mibg闪烁显像（71％）。在具有SDHB突变的受试者中，对检测骨转移的敏感性最佳的成像方式为CT/MRI（96％），骨闪烁显像（95％）和18F-FDG PET（92％）。在没有SDHB突变的受试者中，对骨转移敏感的最佳敏感性的方式为18F-FDA PET（100％）。我们得出的结论是，骨闪烁显像应用于恶性PHEO/PGL的患者，特别是在SDHB突变患者中。由于PET成像方式，强烈建议在SDHB突变患者中使用18F-FDG PET，而在没有突变的患者中建议使用18F-FDA PET。 其他发现 与普通人群相比，发现接受良性pheo的成功手术的患者的预期寿命降低。死亡率的解释是通过以下事实来解释的：患者在手术后随访期间仍可能患上转移性疾病。三分之二的无复发患者持续存在高血压。因此，这些患者需要终身随访。 我们还对18例患者进行了长期随访，并诊断为用环磷酰胺，长葡萄球菌和达卡巴嗪（CVD化学疗法）的PHEO/PGL诊断。这是一项非随机的单臂试验。与CVD的联合化疗产生了晚期恶性肿/PGL患者的客观肿瘤反应。肿瘤客观地缩减肿瘤和患有稳定或进行性疾病患者的患者之间的总生存率无差异。然而，患者报告说症状的改善，血压的客观改善，肿瘤收缩使手术切除成为可能。我们得出的结论是，在每个转移性PHEO/PGL患者中，并未表明CVD疗法，但应在症状患者的治疗以及肿瘤收缩可能是有益的情况下考虑的。 Pheo动物模型 最近，我们发现MicroCT和MRI在检测350 m尺寸阈值下检测肝转移的能力大致相等。在肺中，MRI比MicroCT更敏感，检测到直径为0.6 mm的病变，而Microct的病变。另外，MRI对肾脏，骨，卵巢和肾上腺的病变更敏感。 MRI比MicroCT表现出更高的对比度比率（CNR）。我们得出的结论是，除了不将动物暴露于电离辐射中的优势外，与MicroCT相比，MRI还对该模型中转移的程度进行了更完整的评估。在另一项研究中，我们通过修改注射的细胞数量，胰蛋白酶处理的长度以及注射前的细胞储存温度以及去除转移性病变，连续通过和转移的重新选择来增强该模型。我们使用体内MRI评估了这些修饰对肿瘤生长的影响。这些结果表明，注射的细胞数量，注射前的细胞储存温度和胰蛋白酶处理的长度是产生更快增长，更具侵略性肿瘤的重要因素，这些因素在其他部位产生了继发性转移性病变。串行培养和转移性肝病的选择产生了保留其生化表型的更具侵略性的Pheo细胞。这些更具侵略性细胞与亲本细胞系的微阵列比较对它们的快速转移过程很重要。 会议 根据我们的计划的精神，该计划强调团队合作，与外部医疗中心的合作以及患者的参与，我们将参加2008年9月在英国剑桥举行的第二届国际嗜铬细胞瘤研讨会组织。

项目成果

Is supine rest necessary before blood sampling for plasma metanephrines?

• DOI: 10.1373/clinchem.2006.076489
• 发表时间: 2007-02-01
• 期刊: CLINICAL CHEMISTRY
• 影响因子: 9.3
• 作者: Lenders, Jacques W. M.;Willemsen, Jacques J.;Sweep, C. G. J. (Fred)
• 通讯作者: Sweep, C. G. J. (Fred)

A new concept of unopposed beta-adrenergic overstimulation in a patient with pheochromocytoma.

嗜铬细胞瘤患者无对抗β-肾上腺素能过度刺激的新概念。

• DOI: 10.7326/0003-4819-142-12_part_1-200506210-00023
• 发表时间: 2005
• 期刊: Annals of internal medicine
• 影响因子: 39.2
• 作者: Kantorovich,Vitaly;Pacak,Karel
• 通讯作者: Pacak,Karel

Comparison of 6-18F-fluorodopamine PET with 123I-metaiodobenzylguanidine and 111in-pentetreotide scintigraphy in localization of nonmetastatic and metastatic pheochromocytoma.

• DOI: 10.2967/jnumed.108.052373
• 发表时间: 2008-10
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Ilias I;Chen CC;Carrasquillo JA;Whatley M;Ling A;Lazúrová I;Adams KT;Perera S;Pacak K
• 通讯作者: Pacak K

The incidentally discovered adrenal mass.

• DOI: 10.1056/nejmc070612
• 发表时间: 2007-05
• 期刊: The New England journal of medicine
• 作者: K. Pacak;G. Eisenhofer;A. Grossman

Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas.

琥珀酸脱氢酶 B 亚基相关嗜铬细胞瘤和副神经节瘤患者的临床表现、生化表型以及基因型-表型相关性。

• DOI: 10.1210/jc.2006-2315
• 发表时间: 2007
• 期刊: The Journal of clinical endocrinology and metabolism
• 作者: Timmers,HenriJLM;Kozupa,Anna;Eisenhofer,Graeme;Raygada,Margarita;Adams,KarenT;Solis,Daniel;Lenders,JacquesWM;Pacak,Karel
• 通讯作者: Pacak,Karel