The differential diagnosis and treatment of Cushing's syndrome

库欣综合征的鉴别诊断和治疗

• 批准号: 8351217
• 负责人: Lynnette Nieman
• 金额: $ 18.82万
• 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/8351217
• 关键词: Abdomen; Address; Adrenal Gland Hyperfunction; Adrenalectomy; Bilateral; Chest; Clinical; Clinical Trials; Corticotropin; Corticotropin-Releasing Hormone; Cushing Syndrome; Detection; Diagnosis; Diagnostic; Differential Diagnosis; Discipline of Nuclear Medicine; Discrimination; Disease; Dose; Endocrinologist; Glucocorticoids; Goals; Histologic; Hormones; Hydrocortisone; Image; Imaging Techniques; Immunohistochemistry; Lesion; Levodopa; Magnetic Resonance Imaging; Measures; Medical; Mifepristone; Modality; Neck; Neuroendocrine Tumors; Operative Surgical Procedures; Outcome; Patients; Pentetic Acid; Petrosal Sinus Sampling; Physiological; Pilot Projects; Pituitary Corticotropin Secreting Adenoma; Pituitary Gland; Pituitary Gland Adenoma; Pituitary Neoplasms; Pituitary-dependent Cushing' s disease; Positron-Emission Tomography; Predictive Value; Process; Protocols documentation; Radioisotopes; Reference Values; Replacement Therapy; Research Personnel; Resected; Scanning; Serotonin Production; Serum; Slice; Source; Techniques; Testing; Thick; Time; Tumor Markers; United States National Institutes of Health; Weight; X-Ray Computed Tomography; cost; effective therapy; fluorodeoxyglucose positron emission tomography; high standard; imaging modality; improved; in vivo; oncology; pentetreotide; prospective; tool; tumor

Imaging studies are the cornerstone for tumor localization in patients with Cushing's syndrome caused by ectopic adrenocorticotropin hormone (ACTH) secretion (EAS). Computed tomography (CT) and magnetic resonance imaging (MRI) are used most commonly to localize the source of EAS. However, in 30-50 percent of patients with EAS the source of ACTH secretion cannot be found despite repeated studies over time. Up to half of these patients do not respond to medical therapy of hypercortisolism and must undergo bilateral adrenalectomy with lifelong replacement therapy. Thus, there is a need for improved imaging techniques to identify ACTH-secreting tumors. Nuclear medicine techniques enable in vivo imaging of physiological and pathophysiological processes, and among these techniques, positron emission tomography (PET) studies are increasingly used in oncology. We previously evaluated the utility of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) or 111In-DTPA-D-Phe-pentetreotide (OCT) at higher than standard doses of radionuclide (18 mCi; H-OCT), and found that FDG-PET did not detect tumors that were occult on CT/MRI. H-OCT rarely identified a lesion. Thus, conventional modalities of CT and MRI should be used to image the neck, thorax, and abdomen in these patients. FDG-PET does not provide additional information. H-OCT may be useful when other imaging modalities fail to localize the ACTH-secreting tumor. Currently we are extending these studies to evaluate the utility of 18F- L-3,4-dihydroxyphenylalanine (18F-DOPA) PET to identify these tumors. This compound is a precursor for serotonin production in neuroendocrine tumors, and thus is a good candidate for PET examination since most occult ACTH-secreting tumors are neuroendocrine. We have also evaluated whether serum CgA, CT, ProCT, or NProCT values to distinguish CD from EAS in a prospective pilot study. Serum ProCT, NProCT, and CgA were measured in six patients with occult EAS diagnosed by IPSS, 25 CD patients, and 11 patients with histologically proven EAS. Nine EAS patients (53%) had at least one value above the reference range, including CgA alone (n = 4), ProCT alone (n = 3), CgA and ProCT (n = 1), and NProCT and ProCT (n = 1). Of nine (36%) CD patients with one or two abnormal values, seven had increased ProCT only, one had increased NProCT only, and one had increased CgA and ProCT. CgA had a positive predictive value of 83% and a negative predictive value of 70% for the diagnosis of EAS; other markers showed less discrimination. On pituitary magnetic resonance imaging, no EAS patient had an abnormality, whereas 21 of 25 patients with CD had a mass. These preliminary results suggest that an abnormal CgA and normal pituitary magnetic resonance imaging favor the diagnosis of EAS, but normal tumor markers do not exclude the diagnosis. While detection of pituitary tumors with magnetic resonance imaging (MRI) may reduce diagnostic costs and improve surgical outcomes for patients with Cushing's disease, the optimal T1-weighted spin echo MRI protocol remains unknown. We hypothesized that specific MR scanning parameters influence detection of corticotropinomas. We found that 21 of 84 consecutive patients with Cushing's disease had a falsely negative initial pituitary MRI study and a lesion identified subsequently at the NIH Clinical Center. In 18 patients with available scans, matrix sizes were similar and nearly all had 3 mm slice thickness. Parameters that differed between the NIH and outside scans were: TR (400 ms vs. 492+/-19 ms, P = 0.0002); TE (10.3 +/- 0.5 vs. 17.2 ms +/- 1.2 ms, P = 0.0003); FOV (12x12 cm vs.17+/-0.6 x 18+/-0.7 cm, P<0.0001). Immunohistochemistry of tumors resected at transsphenoidal surgery confirmed all to be corticotropinomas. We conclude that MRI technique, particularly FOV and TR/TE value, influences results and recommend that endocrinologists consider pituitary MRI parameters when interpreting the results. The glucocorticoid antagonist mifepristone blocks cortisol action and thus might be an effective treatment of Cushing's syndrome. This hypothesis is being tested in an ongoing clinical trial of patients with presumed ectopic ACTH secretion.

成像研究是由异位肾上腺皮质激素激素（ACTH）分泌（EAS）引起的库欣综合征患者肿瘤定位的基石。计算机断层扫描（CT）和磁共振成像（MRI）最常用于定位EAS的来源。但是，在30-50％的EAS患者中，尽管随着时间的推移反复进行研究，但仍找不到ACTH分泌的来源。这些患者中有多达一半对过度皮质醇的药物治疗不反应，必须进行双侧肾上腺切除术，并终身替代疗法。因此，需要改进的成像技术来鉴定分泌ACTH的肿瘤。 核医学技术可实现生理和病理生理过程的体内成像，在这些技术中，正电子发射断层扫描（PET）研究越来越多地用于肿瘤学。我们先前评估了18F氟脱氧葡萄糖（FDG）正电子发射层造影（PET）或111in-DTPA-DTPA-DTPA-D-D-D-PHE-PENTETRETIDE（OCT）高于标准剂量的放射性核酸（18 MCI; H-OCT），并发现FDG-PET未检测到CT Ocki occt occt cot cons/Mrigi ct ct ct， H-OCT很少鉴定出病变。因此，在这些患者中，应使用常规的CT和MRI方式来对颈部，胸腔和腹部进行成像。 FDG-PET不提供其他信息。当其他成像方式无法定位分泌ACTH的肿瘤时，H-OCT可能很有用。 目前，我们正在扩展这些研究以评估18F-L-3,4-二羟基苯基丙氨酸（18F-DOPA）PET的实用性，以鉴定这些肿瘤。 该化合物是神经内分泌肿瘤中5-羟色胺产生的前体，因此是宠物检查的良好候选者，因为大多数神秘的acth肿瘤是神经内分泌。 我们还评估了在一项前瞻性初步研究中，血清CGA，CT，PROCT或NPROCT值是否将CD与EAS区分开。在六名由IPS诊断，25名CD患者和11例组织学证明EAS的患者诊断的六名患者中，测量了6例具有神秘EA的患者的血清Proct，NPROCT和CGA。 9名EAS患者（53％）至少高于参考范围，包括单独使用CGA（n = 4），单独使用Proct（n = 3），CGA和Proct（n = 1），NPROCT和Proct（n = 1）。在一个或两个异常值的九名（36％）CD患者中，只有7例仅增加了Proct，其中1例仅增加了NPROCT，而CGA和Proct增加了。 CGA的阳性预测值为83％，而EAS的诊断为70％。其他标记显示出较少的歧视。在垂体磁共振成像上，没有EAS患者有异常，而25例CD患者中有21例具有质量。这些初步结果表明，异常的CGA和正常的垂体磁共振成像有利于EAS的诊断，但正常肿瘤标记不排除诊断。 虽然检测具有磁共振成像（MRI）的垂体肿瘤可以降低诊断成本并改善库欣氏病患者的手术结局，但最佳的T1加权自旋回声ECHO MRI方案仍然未知。我们假设特定的MR扫描参数会影响皮质性瘤的检测。我们发现，在84例库欣氏病患者中，有21例发生了错误的初始垂体MRI研究，随后在NIH临床中心发现了病变。在18例可用扫描的患者中，基质大小相似，几乎所有厚度都具有3毫米的厚度。 NIH和外部扫描之间有所不同的参数为：TR（400毫秒与492 +/- 19 ms，p = 0.0002）； TE（10.3 +/- 0.5对17.2 ms +/- 1.2 ms，p = 0.0003）; FOV（12x12 cm vs.17 +/- 0.6 x 18 +/- 0.7厘米，p <0.0001）。在型苯甲酸手术中切除的肿瘤免疫组织化学证实所有这些都是皮质性瘤。我们得出的结论是，MRI技术，尤其是FOV和TR/TE值会影响结果，并建议内分泌学家在解释结果时考虑垂体MRI参数。 糖皮质激素拮抗剂米非酮可阻止皮质醇作用，因此可能是对库欣综合征的有效治疗方法。 该假设正在正在进行的临床试验中进行了对异位ACTH分泌的患者的临床试验。