分化型甲状腺癌分子靶向治疗进展

分化型甲状腺癌(differentiated thyroid carcinoma,DTC)是最常见的内分泌系统恶性肿瘤。虽然DTC通常有较好的预后,但目前针对那些已经发生局部侵犯、转移和(或)对放射性核素治疗抵抗的患者还没有很好的治疗方法。随着对增殖性肿瘤相关突变分子的深入研究,已经获得了一些新的肿瘤治疗分子靶点。一些蛋白在DTC的致病机制中发挥重要作用,如RET/PTC-RAS-RAF-MAPK途径。此外,血管的异常和再生也与肿瘤的生长有关。尽管这些靶向治疗药物会带来一些不良反应,但靶向治疗的研究进展以及初期较具说服力的实验结论给难治性DTC治疗带来了新的希望。     

Clinical uses of recombinant human thyrotropin

Recombinant human thyroid-stimulating hormone (rhTSH), used to enhance diagnostic radioiodine whole body scanning and thyroglobulin testing, has dramatically altered the management of patients with thyroid cancer. Withdrawal from thyroid hormone suppression therapy and subsequent hypothyroidism is no longer the only safe and effective method for thyroid cancer surveillance. Currently, rhTSH is only approved for the monitoring of low-risk patients with well-differentiated thyroid cancer and radioactive iodine administration, in selected cases. Additional applications of rhTSH include enhancing the sensitivity of positron emission tomography in thyroid cancer, the management of multinodular goiter, and dynamic testing of thyroid reserve. The diagnostic and therapeutic role of rhTSH in these areas is discussed in this review.     

Clinical uses of recombinant human thyrotropin

Recombinant human thyroid-stimulating hormone (rhTSH), used to enhance diagnostic radioiodine whole body scanning and thyroglobulin testing, has dramatically altered the management of patients with thyroid cancer. Withdrawal from thyroid hormone suppression therapy and subsequent hypothyroidism is no longer the only safe and effective method for thyroid cancer surveillance. Currently, rhTSH is only approved for the monitoring of low-risk patients with well-differentiated thyroid cancer and radioactive iodine administration, in selected cases. Additional applications of rhTSH include enhancing the sensitivity of positron emission tomography in thyroid cancer, the management of multinodular goiter, and dynamic testing of thyroid reserve. The diagnostic and therapeutic role of rhTSH in these areas is discussed in this review.     

甲状腺结节与甲状腺癌的临床评估和处理

成人甲状腺结节的发病率相当高,其中大多数为良性病变,无需特殊处理,而恶性病变占5%~15%,需要及时处理。鉴于良恶性甲状腺结节对患者生存质量的影响有显著差异,且临床处理方法不同,所以鉴别结节的良、恶性非常重要。一般可通过病史、体格检查、影像学、核素扫描、细针穿刺、实验室检查等几方面评估甲状腺结节性质。对于分化型甲状腺癌需采取手术、同位素、甲状腺激素抑制治疗等综合手段,预后良好。     

The therapeutic management of differentiated thyroid cancer

Background: The management of thyroid cancer is difficult because the tumors comprise a wide range of biologic behaviors, from small papillary thyroid microcarcinomas that pose little or no threat to survival for the patient, to anaplastic thyroid cancers that are arguably the most lethal tumor. Although it may be difficult initially to determine at which end of the prognostic spectrum a patient resides, one can ordinarily estimate a patient's risk for tumor recurrence and mortality based on a triad of features as simple as the patient's age at the time of diagnosis, the tumor stage at presentation, and its initial response to therapy. While staging systems are available to assist in the management process, all are inexact and leave wide gaps in the treatment plan for a given patient. This is largely because randomized controlled trials are lacking as a result of the low incidence and generally favorable prognosis of the disease. As a practical matter, it may sometimes be difficult to reassure a patient, given the generally favorable prognosis of this group of tumors, knowing that without adequate therapy some become unexpectedly aggressive and recur years after initial management. The treatment of these tumors rests on a fine balance of providing care that reflects the anticipated course of the disease without overtreating the patient or providing reassurance that is unfounded. Objective: To outline the treatment strategy for patients with differentiated thyroid cancer based on the available literature and to guide clinicians through a management algorithm utilizing patient and tumor characteristics. Methods: This review is limited to the treatment of patients with differentiated thyroid cancer – papillary and follicular thyroid cancer – and the standard therapy required for the majority of patients. Results/conclusion: The treatment of differentiated thyroid cancer requires a multidisciplinary approach, involving an experienced surgeon, radiologists and an endocrinologist. There are many unanswered questions in the management algorithm and ongoing research is needed to further define the best treatment strategy for patients with differentiated thyroid cancer.     

The mTOR protein as a target in thyroid cancer

INTRODUCTION: The mammalian target of rapamycin (mTOR) protein is a downstream effector of the phosphatidilinositol-3 kinase (PI3K)/Akt pathway, which regulates not only cell proliferation and viability, but also iodide uptake in thyroid cells. Genetic alterations in the PI3K/Akt/mTOR pathway are common during thyroid cancer progression, and thus, these proteins are attractive targets for cancer therapy. So far, specific mTOR inhibitors, such as rapamycin analogs, have been developed and studied as anti-cancer agents. AREAS COVERED: This review discusses evidence that justifies the potential use of mTOR signaling pathway inhibitors as therapeutic agents for thyroid cancer. EXPERT OPINION: In the near future, mTOR-targeted drugs might represent a new approach for the therapy of thyroid cancer patients; rapamycin analogs have already been developed and are currently being clinically tested. Besides the antiproliferative action of mTOR inhibition, the stimulatory effect on thyroid iodide uptake can also be useful in the treatment of recurrent thyroid cancer. Therefore, if rapamycin analogs are able to increase iodide uptake in thyroid cancer, either alone or in combination with other agents, this will represent a new approach for the treatment of thyroid cancer, which may possibly improve the treatment of patients in which radioiodine therapy is not effective.     

^131碘治疗格雷夫斯病二次治疗的相关因素分析

目的部分格雷夫斯病患者进行1次^131碘治疗后未能完全缓解,需要进行第2次^131碘治疗,分析相关因素的影响。方法182例格雷夫斯病患者进行^131碘治疗,治疗后随访6-12月。临床未治愈者进行第2次^131碘治疗。所有患者根据是否进行第2次治疗分为：A组（一次性临床治愈组,148例）和B组（需要进行第2次治疗组,34例）。采集两组患者基本资料,检测血清甲状腺激素及相关抗体水平、进行核素功能检查。结果 A组和B组在性别、体重、甲状腺质量、甲状腺质量/体重的比值、甲状腺摄锝率、第1次^131碘治疗剂量方面的差异有统计学意义（P〈0.05）,其余指标两组间差异均无统计学意义（P〉0.05）。Logistic回归分析显示,甲状腺质量/体重的比值、甲状腺摄锝率是格雷夫斯病患者在1次^131碘治疗后需要进行第2次^131碘治疗的独立相关因素。结论临床医生应用^131碘治疗格雷夫斯病患者时,综合考虑多个相关因素确定治疗剂量,将有助于一次性临床治愈疾病。     

Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches

INTRODUCTION: Thyroid cancer is an emerging public health concern. In the USA, its incidence has doubled in the past decade, making it the eighth most commonly diagnosed neoplasm in 2010. Despite this alarming increase, most thyroid cancer patients benefit from conventional approaches (surgery, radioiodine, radiotherapy, TSH suppression with levothyroxine) and are often cured. Nevertheless, a minority have aggressive tumors resistant to cytotoxic and other historical therapies; these patients sorely need new treatment options. AREAS COVERED: Herein the biology and molecular characteristics of the common histological types of thyroid cancer are reviewed to provide context for subsequent discussion of recent developments and emerging therapeutics for advanced thyroid cancers. EXPERT OPINION: Several kinase inhibitors, especially those targeting VEGFR and/or RET, have already demonstrated promising activity in differentiated and medullary thyroid cancers (DTC, MTC). Although of minimal benefit in DTC and MTC, cytotoxic chemotherapy with anti-microtubule agents and/or anthracyclines in combination with intensity-modulated radiation therapy appears to extend survival for patients with locoregionally confined anaplastic thyroid cancer (ATC), but to have only modest benefit in metastatic ATC. Further discovery and development of novel agents and combinations of agents will be critical to further progress in treating advanced thyroid cancers of all histotypes.     

Tumour re-differentiation effect of retinoic acid: a novel therapeutic approach for advanced thyroid cancer

Although well-differentiated thyroid carcinomas are usually curable by the combined effects of surgery, radioiodine ablation and thyroid stimulating hormone (TSH) suppressive therapy, recurrence develops in 20-40% of patients. During tumour progression, cellular de-differentiation occurs in up to 30% of cases and is usually accompanied by more aggressive growth, metastasis spread and loss of iodide uptake. The therapeutic options for de-differentiated thyroid cancer are limited and generally not efficient. Retinoic acids (RA) are biologically active metabolites of vitamin A that regulate growth and differentiation of many cell types, by binding to specific nuclear receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Recent studies have shown that RA can induce in vitro re-differentiation of thyroid carcinoma cell lines, as suggested by increased expression of the sodium/iodide symporter (NIS), type I iodothyronine deiodinase, alkaline phosphatase and by the increment of cellular (131)I uptake. In addition to re-differentiating effects, RA also exert anti-proliferative actions, as the inhibition of mitosis and the induction of apoptosis. Previous clinical studies have shown that iodide uptake may be re-stimulated after RA in about 20-50% of patients with radioiodine non-responsive thyroid carcinoma. Longer follow-up of patients demonstrated that, besides iodide uptake increment, RA can induce tumour regression or at least tumour growth stabilisation. The therapy is generally well tolerated and the most frequent side effects are dryness of skin and mucosa, and hypertriglyceridemia. This paper describes the recent advances in the field of thyroid cancer therapy and reviews the use of RA as a promising novel therapeutic tool.     

The mTOR protein as a target in thyroid cancer

Introduction: The mammalian target of rapamycin (mTOR) protein is a downstream effector of the phosphatidilinositol-3 kinase (PI3K)/Akt pathway, which regulates not only cell proliferation and viability, but also iodide uptake in thyroid cells. Genetic alterations in the PI3K/Akt/mTOR pathway are common during thyroid cancer progression, and thus, these proteins are attractive targets for cancer therapy. So far, specific mTOR inhibitors, such as rapamycin analogs, have been developed and studied as anti-cancer agents.

Areas covered: This review discusses evidence that justifies the potential use of mTOR signaling pathway inhibitors as therapeutic agents for thyroid cancer.

Expert opinion: In the near future, mTOR-targeted drugs might represent a new approach for the therapy of thyroid cancer patients; rapamycin analogs have already been developed and are currently being clinically tested. Besides the antiproliferative action of mTOR inhibition, the stimulatory effect on thyroid iodide uptake can also be useful in the treatment of recurrent thyroid cancer. Therefore, if rapamycin analogs are able to increase iodide uptake in thyroid cancer, either alone or in combination with other agents, this will represent a new approach for the treatment of thyroid cancer, which may possibly improve the treatment of patients in which radioiodine therapy is not effective.     

乐伐替尼治疗恶性肿瘤的研究进展

乐伐替尼是一种口服的多靶点酪氨酸激酶受体抑制剂,用于放射性碘难治性分化型甲状腺癌的单药治疗以及与依维莫司联合治疗晚期肾细胞癌。近年越来越多的临床数据展示出了该药在未来抗肿瘤治疗中的巨大潜力。本文将对其作用机制、研究历程、临床试验以及最新研究进展进行综述,以求使读者能够更全面地了解和认识乐伐替尼并且为我国的临床实践提供建议。     

Serum thyroglobulin concentrations and whole-body radioiodine scan in follow-up of differentiated thyroid cancer after thyroid ablation.

Measurement of serum thyroglobulin (Tg) concentrations and whole-body radioiodine scan were performed simultaneously during follow-up of 32 patients with differentiated thyroid cancer who had undergone thyroid ablation by operation and radioiodine. Almost all patients in whom serum Tg was undetectable had normal scans. Concentrations exceeding 50 ng/ml were invariably associated with residual or metastatic tumour uptake in the scan. Out of 21 observations of detectable values below 50 ng/ml, 14 were in patients whose scans showed subclinical or sub-radiological tumour uptake and seven in patients with normal scans. The sensitivity of serum Tg as a tumour marker compared favourably to that of the whole-body scan. A scan is unnecessary when serum Tg is undetectable, but in patients with detectable serum Tg concentrations, particularly if these are below 50 ng/ml, a scan is important to assess and localise tumour uptake of iodine before advising treatmet with iodine-131.     

Platelet-Derived Growth Factor Receptor-α Subunit Targeting Suppresses Metastasis in Advanced Thyroid Cancer In Vitro and In Vivo

Thyroid cancer is the most common endocrine malignancy. Patients with well-differentiated thyroid cancers, such as papillary and follicular cancers, have a favorable prognosis. However, poorly differentiated thyroid cancers, such as medullary, squamous and anaplastic advanced thyroid cancers, are very aggressive and insensitive to radioiodine treatment. Thus, novel therapies that attenuate metastasis are urgently needed. We found that both PDGFC and PDGFRA are predominantly expressed in thyroid cancers and that the survival rate is significantly lower in patients with high PDGFRA expression. This finding indicates the important role of PDGF/PDGFR signaling in thyroid cancer development. Next, we established a SW579 squamous thyroid cancer cell line with 95.6% PDGFRA gene insertion and deletions (indels) through CRISPR/Cas9. Protein and invasion analysis showed a dramatic loss in EMT marker expression and metastatic ability. Furthermore, xenograft tumors derived from PDGFRA gene-edited SW579 cells exhibited a minor decrease in tumor growth. However, distant lung metastasis was completely abolished upon PDGFRA gene editing, implying that PDGFRA could be an effective target to inhibit distant metastasis in advanced thyroid cancers. To translate this finding to the clinic, we used the most relevant multikinase inhibitor, imatinib, to inhibit PDGFRA signaling. The results showed that imatinib significantly suppressed cell growth, induced cell cycle arrest and cell death in SW579 cells. Our developed noninvasive apoptosis detection sensor (NIADS) indicated that imatinib induced cell apoptosis through caspase-3 activation. In conclusion, we believe that developing a specific and selective targeted therapy for PDGFRA would effectively suppress PDGFRA-mediated cancer aggressiveness in advanced thyroid cancers.     

Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches

Introduction: Thyroid cancer is an emerging public health concern. In the USA, its incidence has doubled in the past decade, making it the eighth most commonly diagnosed neoplasm in 2010. Despite this alarming increase, most thyroid cancer patients benefit from conventional approaches (surgery, radioiodine, radiotherapy, TSH suppression with levothyroxine) and are often cured. Nevertheless, a minority have aggressive tumors resistant to cytotoxic and other historical therapies; these patients sorely need new treatment options.

Areas covered: Herein the biology and molecular characteristics of the common histological types of thyroid cancer are reviewed to provide context for subsequent discussion of recent developments and emerging therapeutics for advanced thyroid cancers.

Expert opinion: Several kinase inhibitors, especially those targeting VEGFR and/or RET, have already demonstrated promising activity in differentiated and medullary thyroid cancers (DTC, MTC). Although of minimal benefit in DTC and MTC, cytotoxic chemotherapy with anti-microtubule agents and/or anthracyclines in combination with intensity-modulated radiation therapy appears to extend survival for patients with locoregionally confined anaplastic thyroid cancer (ATC), but to have only modest benefit in metastatic ATC. Further discovery and development of novel agents and combinations of agents will be critical to further progress in treating advanced thyroid cancers of all histotypes.     

Acute promyelocytic leukemia after iodine-131 therapy for Graves' disease

Graves' disease is an autoimmune process in which the thyroid gland is stimulated by autoantibodies, leading to hyperthyroidism. Graves' disease is the most common cause of hyperthyroid function, primarily affecting women in their 40s and 50s. Treatment may involve oral radioiodine, which is taken up by the follicular cells of the thyroid, where it emits ionizing radiation to promote destruction of those cells. Radioiodine therapy is typically safe, effective, and inexpensive. We describe the case of a 51-year-old woman who developed acute promyelocytic leukemia within 27 months of completing a cumulative dose of radioiodine 22.1 mCi (817.7 MBq) for treatment of Graves' disease. Assessment of causality using the Naranjo probability scale showed that a possible relationship existed between this patient's acute promyelocytic leukemia and the use of radioiodine. Strict hematologic follow-up of patients treated with radioiodine may be warranted, along with a high index of suspicion in those with coagulopathy.     

The Adverse Effects of Sorafenib in Patients with Advanced Cancers

Sorafenib is the first multi‐kinase inhibitor (TKI) approved for the treatment of advanced hepatocellular cancer (HCC) and metastatic renal cell cancer (RCC) and is increasingly being used to treat patients with well‐differentiated radioiodine‐resistant thyroid cancer (DTC). Sorafenib demonstrates targeted activity on several families of receptor and non‐receptor tyrosine kinases that are involved in angiogenesis, tumour growth and metastatic progression of cancer. Sorafenib treatment results in long‐term efficacy and low incidence of life‐threatening toxicities. Although sorafenib has demonstrated many benefits in patients, the adverse effects cannot be ignored. The most common treatment‐related toxicities include diarrhoea, fatigue, hand–foot skin reaction and hypertension. Most of these toxicities are considered mild to moderate and manageable to varying degrees; however, cardiovascular events might lead to death. In this MiniReview, we summarize the adverse effects of sorafenib that commonly occur in patients with advanced cancers.     

大剂量131I治疗致分化型甲状腺癌患者睡眠障碍的原因分析及护理体会

目的了解分化型甲状腺癌患者行^131Ⅰ治疗期间的睡眠质量及其影响因素,探讨提高患者睡眠质量的护理措施。方法将106位行大剂量^131Ⅰ治疗的分化型甲状腺癌患者随机分为干预组及对照组,对照组进行常规护理,干预组在对照组基础上进行护理干预,并对两组的睡眠质量及其影响因素采用匹兹堡睡眠质量指数（PSQI）量表和自行设计的睡眠影响因素调查表进行问卷调查。结果调查显示,出院时干预组与对照组睡眠情况比较,差异有统计学意义（P≤0.05）。影响睡眠的主要因素依次为心理因素（对癌症的悲观情绪、对疾病预后的担忧、对放射性治疗畏惧心理、隔离治疗期间孤独寂寞感等）、生理因素（颈部伤口不适、甲状腺功能低下、放射性副作用）、环境因素等。结论接受大剂量^131Ⅰ治疗的甲状腺癌患者普遍存在睡眠障碍,心理、生理和环境因素均可影响其睡眠质量,护理人员应采取针对性措施缓解患者的负性情绪及生理不适,尤其应加强疾病预后及放射性治疗相关知识宣教,同时提供良好的睡眠环境,以提高患者睡眠质量。     

The safety of vandetanib for the treatment of thyroid cancer

ABSTRACT

Introduction: The tyrosine kinase inhibitor vandetanib was approved for use in 2012 for aggressive and symptomatic medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease. As the first effective systemic therapy for MTC, vandetanib is a major step forward and the phase III study suggests an important role for this agent. Trials have also been performed for its use in differentiated thyroid cancer (DTC) though it is not yet approved for use for this indication.

Areas covered: The efficacy and safety of vandetanib is discussed. Studies suggest improvement in progression-free survival (PFS) without clear overall survival benefit but with manageable low grade toxicities and improved quality of life on therapy.

Expert opinion: Vandetanib has an important role in the management of patients with progressive metastatic MTC. The use in patients with stable or asymptomatic disease has no proven benefit. The side effects can usually be managed with dose reduction, interruption, and/or specific symptomatic therapy.     

A study of the role of DIO1 and DIO2 polymorphism in thyroid cancer and drug response to therapy in the Saudi population

BackgroundDeiodinases comprise a group of selenoproteins that regulate the bioavailability of active thyroid hormones (TH) in a time and tissue specific fashion. They increase the hormonal activity by metabolizing their inactive precursors to active forms or terminate their activity by deactivating active hormones. The role of the deiodinase (DIO) gene polymorphisms in thyroid cancer is not fully understood yet. This study evaluated the potential association of the DIO1 and DIO2 genes with differentiated thyroid cancer and differential thyroxine dose requirement in thyroidectomized patients in a Saudi cohort.MethodsWe selected four variants (one DIO1 and three DIO2) for the association studies using Taqman assays in 507 DTC patients undergoing treatment with thyroxin against 560 disease-free individual, all of Saudi Arab origin.ResultsNone of the studied variants was linked to differentiated thyroid cancer. The rs1388378_G > T was initially linked to thyroxine dose requirement (p = 0.035) when all patients were considered together, but this association was lost when the patients were classified into either near suppressed (0.1 ≤ TSH < 0.5) or suppressed (TSH < 0.1) TSH group.DiscussionAlthough the results suggest only a weak relationship with differentiated thyroid cancer, they strongly indicate that the DIO2 polymorphism influences the hormonal dose requirement in patients undergoing treatment with thyroxine. This probably points to a distinction in the way this gene influences disease as compared to therapy thereof.