Clinically Aggressive Thyroid Cancer: Molecular Basis An

非髓样甲状腺癌(TCA)是最常见的内分泌恶性肿瘤，占内分泌癌死亡的大部分。虽然大多数甲状腺癌通过手术和放射性碘(I-131)治疗(即切除正常的甲状腺术后残留物和治疗转移)得到了成功的治疗，但多年来与这种疾病相关的死亡率一直保持稳定，因为这些治疗对“临床侵袭性”肿瘤无效。后者包括分化较差和未分化的TCA，但也包括分化较好的TCA的某些亚组，这些亚组表现出加速生长的模式和/或未能有效捕获碘。恶性甲状腺细胞对碘的浓缩能力的丧失可能与伴随去分化的其他细胞和分子事件有关。我们的目标是研究伴随临床侵袭性TCA自然病程的分子事件以及各种分子标志物对标准治疗干预的反应(S)，以及通过转译临床研究探索新疗法在试点临床试验中的可行性。术前诊断方法包括抽吸细胞学(细针)、组织芯手术活检、颈部超声等常规X线检查、I-131或I-123全身扫描及其他放射性核素检查，以及L-甲状腺素抑制治疗试验。这项研究的具体目标包括：(I)优化TCA的诊断成像方法(特别是使用非基于RAI的放射性核素，如111In-奥曲肽和18F-氟代脱氧葡萄糖正电子发射断层扫描)和血清甲状腺球蛋白(TG)测量，以诊断残留/复发的转移性疾病；(Ii)改进已建立的I-131治疗方法，以提高风险/效益比(如全身和血液剂量学和皮损剂量学)；(Iii)基于聚合酶链式反应的甲状腺特异性肿瘤mRNAs(例如，甲状腺球蛋白mRNAs和其他肿瘤标记物的mRNAs)的检测和定量(4)分析甲状腺原发灶和转移瘤中促甲状腺激素受体(TSHR)、ras、P53、Fas/Fas配体、ret/PTC、P53、mib1和增殖细胞核抗原等与TCA生长、凋亡和有丝分裂周期调控有关的基因突变情况；(5)建立人TCAs永生化细胞系，用于体外研究。分化标志物的表达水平以及生长相关基因突变与甲状腺癌临床行为之间的关系将有助于进一步明确甲状腺细胞生长和分化的途径。在过去的一年里，我们扩大了我们对NIH(单一机构)30年经验的回顾，这些患者接受了远端和局部转移的广泛二次手术切除，试图更好地确定侵袭性转移切除在TCA患者多模式管理中的作用。此外，与NCI的同事合作，我们目前正在准备一项II期临床试验，研究一种新型、低毒、具有促分化特性的组蛋白脱乙酰酶抑制剂，即去脂肽，在诱导TCA分化(即TG和NIS mRNAs的表达)以及对标准治疗方法无效的TCA患者的杀瘤活性方面的效果。所期望的治疗效果将是诱导/重新出现以前不存在的或增加肿瘤目前不足的碘蓄积，从而使这种肿瘤再次能够通过131-I治疗。我们还计划在一项试点临床试验中研究紫杉醇作为放射增敏剂的作用，该试验结合常规放射治疗或调强放射治疗(IMRT)，用于颈部和上纵隔局部晚期转移性疾病患者，这种转移性疾病威胁到重要的颈部结构，目前还没有有效的治疗方案。

Non-medullary thyroid cancer (TCA), the most common type of endocrine malignancy, accounts for most deaths due to endocrine cancers. Although the majority of TCAs are successfully managed with surgery and radioactive iodine (I-131) therapy (i.e. ablation of normal thyroidal postoperative "remnant" and treatment of metastases), the mortality associated with this disease has remained stable over the years, because these therapies are not effective for "clinically aggressive" tumors. The latter group consists of poorly-differentated and anaplastic TCAs, but also includes certain sub-groups of well-differentiated TCAs, which show accelerated patterns of growth and/or fail to trap iodine efficiently. The loss of iodine concentrating ability by the malignant thyrocytes may be correlated with other cellular and molecular events that accompany de-differentiation. Our goal is to study the molecular events accompanying the natural history of clinically aggressive TCAs and the response of various molecular markers to standard therapeutic intervention(s), as well as investigate the feasibility of new therapies in pilot clinical trials through translational clinical research. Preoperative diagnostic methods include aspiration cytology (fine needle), tissue core surgical biopsy, neck ultrasonography and other conventional radiographic imaging, whole body scanning with I-131 or I-123 -as well as other radionuclides -, and suppression therapy trial with L- thyroxine. Specific aims of this study include: (i) optimization of methods of diagnostic imaging in TCA (especially using non-RAI-based radionuclides, such as 111In-octreotide and 18F-fluorodeoxyglucose positron emmission tomography) and serum thyroglobulin (Tg) measurement to diagnose residual/recurrent metastatic disease, (ii) refinement of already established methods of administering I-131 therapy to improve the risk/benefit ratio (such as whole body and blood dosimetry and lesional dosimetry), (iii) PCR-based detection and quantification of thyroid-specific tumoral mRNAs (e.g. thyroglobulin mRNA and mRNAs for other tumor markers) in thyrocytes circulating in peripheral blood, (iv) analysis of mutations in genes involved in TCA growth, apoptosis, and mitotic cycle regulation, such as the thyrotropin receptor (TSHR), ras, p53, Fas/Fas ligand, ret/PTC, p53, mib1 and PCNA in primary and metastatic thyroid tumors, and, finally, (v) establishment of immortalized cell lines from human TCAs for in vitro studies. The relationship between the level of expression of markers of differentiation, as well as mutations in growth-relevant genes, and the clinical behavior of TCA will help further define the pathways responsible for thyrocyte growth and differentiation. Over the last year, we have expanded on our review of 3 decades of NIH (single institution) experience in 32 patients who underwent extensive secondary surgical resections of distant and locoregional metastases in an attempt to better define the role of aggressive metastatectomies in the multimodality management of patients with TCA. Additionally, in collaboration with our colleagues from the NCI, we are currently preparing a Phase II clinical trial investigating the effects of a novel, low-toxicity histone deacetylase inhibitor with pro-differentiating properties, i.e. depsipeptide, in the induction of differentiation (i.e. expression of Tg and NIS mRNAs), and tumoricidal activity in patients with TCA unresponsive to standard treatment methods. The desired therepeutic effect would be the induction/re-emergence of previously inexistent or the increase in currently insufficient iodine accumulation by the tumor, and thus the ability to render such tumors yet again manageable by 131-I. We are also planning to investigate the role of paclitaxel as a radiosensitizing agent in a pilot clinical trial in conjunction with either conventional radiotherapy or intensity-modulated radiotherapy (IMRT) in patients with locally advanced metastatic disease in the neck and upper mediastinum, which threatens vital neck structures and currently has no effective treatment options.