CLINICALLY AGGRESSIVE THYROID CANCER: MOLECULAR BASIS AND TREATMENT OUTCOME

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TCA通过手术和放射性碘(I-131)消融治疗获得了成功，但多年来与这种疾病相关的死亡率一直保持稳定，因为这些治疗方法对临床侵袭性肿瘤无效。后一类包括分化较差和间变性的三氯乙酸，但也包括某些分化较好的三氯乙酸亚群，它们加速了生长模式和/或未能有效捕获碘。恶性甲状腺细胞捕捉碘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甲状腺癌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)。术前诊断方法包括抽吸细胞学、B超、I-131和/或其他放射性核素甲状腺扫描及L-甲状腺素抑制治疗。具体问题包括：(I)优化TCA的诊断扫描方法和血清甲状腺球蛋白测定以诊断肿瘤复发；(Ii)改进已建立的I-131治疗方法以提高风险/收益比；(Iii)基于聚合酶链式反应(PCR)检测和量化外周血中甲状腺细胞中的甲状腺特异性mRNAs(例如，甲状腺球蛋白mRNAs和其他标记物的mRNAs)；(Iv)分析与TCA生长、凋亡和有丝分裂周期调节有关的基因突变，如促甲状腺激素受体、ras、p53、Fas/Fas配体和ret/PTC，以及原发和转移性甲状腺肿瘤中的ret/PTC。以及(V)建立用于体外研究的人TCA永生化细胞系。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确定甲状腺细胞生长和分化的途径。这些数据将指导新的临床治疗试验的发展，以评估通过使用分化药物将侵袭性TCA逆转为更良性的分化表型的策略。-甲状腺，癌症，低分化，放射性碘，剂量学，治疗，癌基因，肿瘤抑制基因，分化，细胞凋亡，聚合酶链式反应-人类受试者

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) ablative therapy, 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 have accelerated patterns of growth and/or fail to trap iodine efficiently. The loss of iodine trapping ability by the malignant thyrocyte 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 TCA and the response of various molecular markers to standard therapeutic intervention(s). Preoperative diagnostic methods include aspiration cytology, ultrasonography, thyroid scanning with I-131 and/or other radionuclides, and suppression therapy with L-thyroxine. Specific issues include: (i) optimization of methods of diagnostic scanning in TCA and serum thyroglobulin measurement to diagnose tumor recurrence, (ii) refinement of already established methods of administering I-131 therapy to improve the risk/benefit ratio, (iii) PCR-based detection and quantification of thyroid-specific mRNAs (e.g. thyroglobulin mRNA and mRNAs for other 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, ras, p53, Fas/Fas ligand, and ret/PTC in primary and metastatic thyroid tumors, and (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 define the pathways responsible for thyrocyte growth and differentiation. These data will guide the development of novel clinical therapy trials to evaluate strategies of attacking aggressive TCAs by reverting them to a more benign differentiated phenotype by using differentiating agents. - thyroid, cancer, poorly-differentiated, radioiodine, dosimetry, therapy, oncogenes, tumor-suppressor genes, differentiation, apoptosis, PCR - Human Subjects