Diagnosis, Pathophysiology And Molecular Biology of Pheochromocytoma and Paraganglioma

嗜铬细胞瘤和副神经节瘤的诊断、病理生理学和分子生物学

• 批准号: 10685192
• 负责人: Karel Pacak
• 金额: $ 233.26万
• 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/10685192
• 关键词: Adrenal Gland Neoplasms; Adrenergic Receptor; Age; Agreement; Anti-CD40; Antibodies; Basic Science; Bilateral; Biochemical; Biological Markers; Bladder Paraganglioma; CD4 Positive T Lymphocytes; Carotid Body; Catecholamines; Cells; Chemistry; Clinical; Clinical Trials; Collaborations; Comparative Study; Consensus; Cystectomy; Data; Development; Diagnosis; Diagnostic; Disseminated Malignant Neoplasm; Distal; Distant; Dopamine; Endocrinologist; Enzymes; Epidemiology; Etiology; Evaluation; Event; Excision; Flow Cytometry; Functional disorder; Future; Genes; Genetic; Germ-Line Mutation; Goals; Growth; Guidelines; Head and Neck Paraganglioma; Health Professional; Hematuria; Hypertension; Image; Image Analysis; Immune; Immunologic Markers; Immunologic Memory; Immunotherapy; Infiltration; Injections; Institutes; Institution; Interdisciplinary Study; International; Intraoperative Complications; Knowledge; Laboratories; Lesion; Ligands; Link; Liver; Location; Magnetic Resonance Imaging; Mannans; Measurement; Medical; Medical Genetics; Medical center; Metastatic Pheochromocytoma; Methods; MicroRNAs; Modality; Modeling; Molecular; Molecular Biology; Molecular Genetics; Monitor; Multicenter Studies; Mus; Mutation; Neoplasm Metastasis; Neuroendocrine Tumors; Neuroendocrinology; Operative Surgical Procedures; Outcome; PET/CT scan; Paraganglioma; Pathogenesis; Pathway interactions; Patients; Pheochromocytoma; Plasma; Primary Neoplasm; Production; Professional Organizations; Reporting; Research Personnel; Residual Tumors; Resistance; Secondary to; Sex Differences; Solid; Spleen; Succinate Dehydrogenase; Surgical Management; Technology; Testing; Therapeutic Intervention; Tracer; Translational Research; Transurethral Resection; United States National Institutes of Health; Visualization; Woman; analytical method; anti-tumor immune response; associated symptom; base; cancer therapy; clinical application; clinical diagnosis; driving force; fluorodeoxyglucose positron emission tomography; genetic disorder diagnosis; imaging modality; improved; meetings; men; metabolomics; mutation carrier; patient oriented; patient oriented research; recruit; subcutaneous; symposium; tumor; tumor diagnosis; tumorigenesis

The Section is conducting patient-oriented research about the etiology, epidemiology, pathophysiology, genetics, diagnosis, and treatment of pheochromocytoma and paraganglioma (PPGL). 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 NIH investigators and outside medical centers/institutions. 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, Genetics, Chemistry & Biomarkers and Experimental Immunotherapies) emphasize first, technologies of basic research tailored for pathway and target discovery and second, the development of the discoveries into clinical applications. Clinical and genetic aspects of PPGLs Head and neck paragangliomas (HNPGLs) are tumors of parasympathetic origin that occur at variable locations and are often secondary to germline mutations in succinate dehydrogenase (SDH) subunit genes. We assessed whether different locations of HNPGLs relate to the presence of SDHx mutations, catecholamine production and other presentations. In this multicenter study, we collected clinical and biochemical data from 244 patients with HNPGLs and 71 patients without HNPGLs. We clarified that jugulotympanic HNPGLs have distinct features. In particular, 88% of jugulotympanic HNPGLs arose in women, among whom only 24% occurred due to SDHx mutations compared to 55% in men. Jugulotympanic HNPGLs were also rarely bilateral, were of a smaller size and were less often metastatic compared to carotid body and vagal HNPGLs. Furthermore, we showed that plasma concentrations of methoxytyramine (MTY) were higher (P < 0.0001) in patients with HNPGL than without HNPGL, whereas plasma normetanephrine did not differ. Only 3.7% of patients showed strong increases in plasma normetanephrine. Plasma MTY was positively related to tumor size but did not relate to the presence of SDHx mutations or tumor location. Our findings confirm that increases in plasma MTY represent the main catecholamine-related biochemical feature of patients with HNPGLs. We expect that more sensitive analytical methods will make biochemical testing of HNPGLs more practical in the future and enable more than the current 30% of patients to be identified with dopamine-producing HNPGLs. The sex-dependent differences in the development of HNPGLs may have relevance to the diagnosis, management and outcomes of these tumors. Paraganglioma of the urinary bladder (UBPGL) is a rare neuroendocrine tumor diagnosed in many patients only after surgery. We, therefore, assessed clinical clues relevant to presurgical diagnosis and clinical consequences in patients with a missed presurgical diagnosis of UBPGL based on international collaboration. We included 177 articles reporting 194 cases. In 90 (46.4%) patients, the UBPGL was diagnosed before and in 104 (53.6%) after surgery. In presurgically diagnosed UBPGL, hypertension and catecholamine-associated symptoms were 2- to 3-fold (p < 0.001) more frequent than in postsurgically diagnosed patients whereas hematuria was twofold (p = 0.003) more prevalent in those with postsurgical diagnosis. Hypertension was an independent factor for presurgical biochemical testing (OR 4.45, 95% CI 1.66-11.94) while hematuria (OR 0.23, 95% CI 0.09-0.60) was an independent factor for not performing presurgical biochemical testing. Most patients diagnosed after surgery were not pretreated with alpha-adrenoceptor blockade (95.2%), underwent more frequently transurethral resection instead of cystectomy (70.2% vs. 23.1%) and had more frequent peroperative complications and residual tumor mass. We concluded that in nearly half of all patients with a UBPGL, the diagnosis was not established before surgery. Hypertension and hematuria contributed independently to a presurgical diagnosis. Postsurgical diagnosis, which was associated with suboptimal presurgical and surgical management, resulted in more peroperative complications and incomplete tumor resections. We also identified candidate miRNA and lncRNAs associated with metastasis-free survival in PCPGs (e.g. USP3-AS1, LINC00877, and AC009312.1). Imaging aspects of PPGLs The purpose of this study was to perform an intraindividual comparison of 68Ga-DOTATATE PET/CT, FDG PET/CT, 18F-FDOPA PET/CT, 18F-FDA PET/CT, CT, and MRI in visualization of sporadic primary PHEO. The analysis included 14 patients (eight women, six men; mean age, 52.4 16.8 SD years) with PHEO. Both 68Ga-DOTATATE PET/CT and FDG PET/CT were completed in all 14 patients, 18F-FDOPA PET/CT in 11, 18F-FDA PET/CT in 7, CT in 12, and MRI in 12. Mean conspicuity score for PHEO was 5.0 0.0 for 18F-FDOPA PET/CT, 4.7 0.5 for MRI, 4.6 0.8 for 18F-FDA PET/CT, 4.4 1.0 for 68Ga-DOTATATE PET/CT, 4.3 1.0 for CT, and 4.1 1.5 for FDG PET/CT. The positivity rate for PHEO was 100.0% (11/11) for 18F-FDOPA PET/CT, 100.0% (12/12) for MRI, 85.7% (6/7) for 18F-FDA PET/CT, 78.6% (11/14) for FDG PET/CT, 78.6% (11/14) for 68Ga-DOTATATE PET/CT, and 66.7% (8/12) for CT. Lesion-to-liver SUVmax was 10.5 for 18F-FDOPA versus 3.0-4.2 for the other tracers. Interreader agreement across modalities ranged from 85.7% to 100.0% for lesion positivity with ICCs of 0.55-1.00 for SUVmax measurements. CONCLUSION. Findings from this small intraindividual comparative study support 18F-FDOPA PET/CT as a preferred first-line imaging modality in evaluation of sporadic PHEO. CLINICAL IMPACT. This study provides data supporting current guidelines for imaging evaluation of suspected PHEO. Immune aspects of PPGLs Immunotherapy has become an essential component in cancer treatment. However, the majority of solid metastatic cancers, such as pheochromocytoma, are resistant to this approach. Therefore, understanding immune cell composition in primary and distant metastatic tumors is important for therapeutic intervention and diagnostics. Combined mannan-BAM, TLR ligand, and anti-CD40 antibody-based intratumoral immunotherapy (MBTA therapy) previously resulted in the complete eradication of murine subcutaneous pheochromocytoma and demonstrated a systemic antitumor immune response in a metastatic model. Here, we further evaluated this systemic effect using a bilateral pheochromocytoma model, performing MBTA therapy through injection into the primary tumor and using distant (non-injected) tumors to monitor size changes and detailed immune cell infiltration. MBTA therapy suppressed the growth of not only injected but also distal tumors and prolonged MBTA-treated mice survival. Our flow cytometry analysis showed that MBTA therapy led to increased recruitment of innate and adaptive immune cells in both tumors and the spleen. Moreover, adoptive CD4+ T cell transfer from successfully MBTA-treated mice (i.e., subcutaneous pheochromocytoma) demonstrates the importance of these cells in long-term immunological memory. In summary, this study unraveled further details on the systemic effect of MBTA therapy and its use for tumor and metastasis reduction or even elimination. PPGL guidelines/consensus Approximately 20% of patients diagnosed with PPGLs carry a mutation in one of the succinate dehydrogenase genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. This International Consensus Statement focused on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed clinical guidan

该科正在开展以患者为导向的关于嗜铬细胞瘤和副神经节瘤（PPGL）的病因学、流行病学、病理生理学、遗传学、诊断和治疗的研究。项目不仅包括转化研究——将基础科学知识应用于临床诊断、病理生理学和治疗——还包括反向转化研究，即对临床发现的欣赏导致基础研究人员可以在实验室中追求的新概念。