Recurrent and/or metastatic thyroid cancer: therapeutic options

Thyroid cancer is relatively rare, accounting for 0.5 - 10 cases per 100,000 individuals per year. Despite their generally favourable prognosis, patients with differentiated thyroid cancer are at risk of tumour recurrence for decades after diagnosis. The optimal management remains controversial even in the low-risk patients because of the high cure rates, long natural history and rarity of these tumours. Therapeutic interventions in recurrent and metastatic differentiated thyroid cancer depend on the type of initial treatment, the site and the extent of disease. Surgical excision of the amenable-to-surgery lesions and radioiodine administration remain the first approach. External radiotherapy may be given to patients with inoperable lesions or those not concentrating radioiodine. Chemotherapy has not provided consistently successful results. Various therapeutic approaches for anaplastic carcinoma give poor results, making the development of novel treatments necessary. Innovative strategies, including recombinant human thyroid stimulating hormone, retinoic acid redifferentiation therapy and gene therapy, may lead to further improvement in the management of thyroid cancer arising from follicular cells.     

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。     

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.     

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.     

New molecular targeted therapies in thyroid cancer

Carcinoma of the thyroid gland is the most common malignancy of the endocrine system. Differentiated tumors are often curable with surgical resection and radioactive iodine. A small percentage of such patients, however, do not undergo remission and need new therapeutic approaches. Both anaplastic and medullary thyroid carcinomas exhibit aggressive behavior and are usually resistant to current therapeutic modalities. Thyroid carcinoma represents a fascinating model and a particularly promising paradigm for targeted therapy because some of the key oncogenic events are activating mutations of genes coding for tyrosine kinases, and these occur early in cancer development. A prototype is the RET proto-oncogene, a receptor tyrosine kinase, which is a key regulator of development and a 'hotspot' for oncogenic mutations. Mutations in the RET proto-oncogene have been identified as causative for papillary carcinoma and familial medullary thyroid carcinoma, making it an attractive target for selective inhibition in these subtypes. ZD 6474 has shown promising activity in preclinical models against RET kinase, and its contemporary inhibition of vascular endothelial growth factor and epidermal growth factor pathways renders it a very attractive drug for clinical trials in thyroid cancer. Activating point mutation of B-RAF can occur early in the development of papillary carcinoma. Moreover, papillary carcinomas with these mutations have more aggressive properties and are diagnosed more often at an advanced stage. Clinical evaluation of B-RAF-targeting drugs is undergoing and trials in thyroid cancer are planned. Agents that restore radioiodine uptake, such as histone deacetylase inhibitors and retinoids, represent another exciting field in new drug development in thyroid cancer.     

The flavonoid quercetin inhibits thyroid-restricted genes expression and thyroid function

Quercetin is the most abundant flavonoid present in a broad range of fruit and vegetables. Furthermore, quercetin is available as dietary supplements that are based on its antioxidant, antiproliferative and anti-inflammatory properties. However, concerns have been raised about the potential toxic effects of excessive intake of quercetin, and several studies have demonstrated that flavonoids, included quercetin, can interfere with thyroid function. In a previous report, we showed that quercetin inhibits thyroid-cell growth and iodide uptake. The latter effect was associated with down-regulation of sodium/iodide symporter gene expression. In the present study, we have evaluated the effects of quercetin on the expression of other thyroid-restricted genes, and we show that quercetin decreases the expression of the thyrotropin receptor, thyroid peroxidase and thyroglobulin genes. We further investigated the inhibitory effects of quercetin on thyroid function in vivo through evaluation of radioiodine uptake in the Sprague–Dawley rat, which was significantly decreased after 14 days of quercetin treatment. These data confirm that quercetin can act as a thyroid disruptor, and they suggest that caution is needed in its supplemental and therapeutic use.     

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.     

Impact of flavonoids on thyroid function

Flavonoids are polyphenolic compounds of natural occurrence produced by plants that are largely consumed both for therapeutic purposes and as food. Experimental data have shown that many flavonoids could inhibit thyroperoxidase activity, decreasing thyroid hormones levels thus increasing TSH and causing goiter. In humans, infants fed with soy formula have been shown to develop goiter. However, in post-menopausal women soy intake did not affect thyroid function. In thyroid tumor cell line, flavonoids were shown to inhibit cell growth, but they can also decrease radioiodine uptake, that could reduce the efficacy of radioiodine therapy. Flavonoids could also affect the availability of thyroid hormones to target tissues, by inhibiting deiodinase activity or displacing T4 from transthyretin. Thus, flavonoids have been shown to interfere with many aspects of the thyroid hormones synthesis and availability in in vivo and in vitro models. In the present article, we review and synthesize the literature on the effects of flavonoids on thyroid and discuss the possible relevance of these effects for humans.     

^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。     

Graves disease in childhood: a review of the options for diagnosis and treatment

While diagnosing Graves disease in childhood and adolescence does not usually present specific problems, the treatment of hyperthyroidism is still controversial. In particular, with regard to the use of radioiodine therapy, strategies vary between many European and North American pediatric endocrinology centers. After the diagnosis is made, antithyroid drug treatment with methimazole (thiamazole), carbimazole, or propylthiouracil should be performed with caution, in particular, because of severe adverse effects, such as agranulocytosis or hepatitis, that are found in up to 1% of patients. Antithyroid drug treatment should not be continued long-term, particularly since definitive remission cannot be expected in more than 30-40% of patients. In contrast, the risk of severe adverse effects is still present, and the risk of thyroid carcinoma increases with time and appears to be considerably higher than after radioiodine treatment. To a great extent, the success of surgery depends on the skills of a trained surgeon. The question of whether to perform total or subtotal thyroidectomy is yet to be resolved. Surgery should be considered in patients with a large thyroid gland (>80g), severe ophthalmopathy, and a lack of remission on antithyroid drug treatment. Success rates have increased to up to 97%, while severe adverse effects (laryngeal nerve palsy, hypoparathyroidism) occur in approximately 4% of patients. Mortality is below 0.1%. Radioiodine treatment in children >5 years of age does not appear to be associated with an increased risk of thyroid carcinoma; however, long-term data are lacking. Compared with the surgical approach, success rates are lower, particularly if low doses of radioiodine are used. In general, adverse effects are less prevalent than in patients who have undergone surgery.     

IL-1 inhibitors: novel agents in the treatment of rheumatoid arthritis

IL-1 is a pleiotropic cytokine shown to play a major role in synovitis and in the mechanisms that lead to the progressive joint destruction of rheumatoid arthritis (RA). IL-1 receptor antagonist (IL-1Ra), a member of the IL-1 family, binds IL-1 receptors but does not induce a cellular response. IL-1Ra competitively inhibits the binding of IL-1 to its cell surface receptors and thus acts as an endogenous anti-inflammatory mediator. In different experimental animal models of arthritis systemic administration of IL-1Ra, or local delivery into the joints by gene therapy attenuated the severity of the inflammatory response and reduced articular destruction. In addition, treatment of RA patients with IL-1Ra led to an improvement in different clinical and biological parameters and to a reduction in the radiological signs of joint erosions. Recently, interesting results were obtained using IL-1Ra in combination with methotrexate, a well-known antirheumatic drug, or in combination with other strategies designed to block the effects of tumour necrosis factor (TNF)-alpha. Encouraging results also have been reported in both in vitro and in vivo experimental models of arthritis by using other strategies designed to block the effects of IL-1.     

Applications of gene transfer to targeted radiotherapy

For targeted radionuclide therapy to succeed as a single modality treatment, schemes must be devised which will enable the deposition in malignant cells of sterilising doses of radiation. Until such methods have been perfected, it is necessary to combine targeted radiotherapy in a rational manner with conventional anti-cancer treatments. Several means of delivery of therapeutic radionuclides are being evaluated but none of these yet appears to be as powerful as the simplest and most effective example, viz: sodium [131I]iodide treatment of disseminated thyroid carcinoma. The radiopharmaceutical [131I]meta-iodobenzylguanidine ([131I]MIBG) is an effective single agent for the treatment of neuroblastoma. However, uptake of the drug in malignant sites is heterogeneous, suggesting that this therapy alone is unlikely to cure disease. A growing body of experimental evidence indicates exciting possibilities for the integration of gene transfer with radionuclide targeting. This review covers aspects of the combination of gene manipulation and targeted radiotherapy, emphasising the potential of gene transfer to facilitate tumour targeting with low molecular weight radiopharmaceuticals.     

碘对甲状腺冷热结节细胞生长的调节特点

研究碘对以冷或热结节为表现的甲状腺腺瘤细胞生长的调节特征,探讨碘在甲状腺结节发病机理中的作用。方法手术切取甲状腺腺瘤及腺瘤旁正常组织,采用单层细胞培养技术和非同位素标记的细胞增殖分析法,检测不同浓度碘化钠经过不同作用时间对甲状腺细胞生长的影响。     

The effects of ammonium perchlorate on thyroid homeostasis and thyroid-specific gene expression in rat

Perchlorate, a kind of inorganic chemical, is mainly used in defense industry and widely used in other civilian areas. It was well known that perchlorate exerts its thyrotoxicant effect on thyroid homeostasis via competitive inhibition of iodide uptake. However, some details of mechanism by which perchlorate disturb thyroid homeostasis are unknown and remain to be elucidated. The present study aimed to investigate if iodide insufficiency in the thyroid is the main mechanism by which perchlorate exerts its effect on the thyroid gland. We highlighted and measured the gene expression of NIS, Tg, and TPO which involved in thyroid hormone biosynthesis. Thyroid effects of perchlorate were identified by assessing different responses of these genes at the treatments of perchlorate and iodine deficiency. The results indicated that high dose perchlorate (520 mg kg(-1) b.wt.) can induce a significant decrease in body weight and cause hypertrophy of thyroid gland, with a decreased level of FT3, FT4 and a remarkable increased level of TSH. In addition, the significant decreased gene expression of Thyroglobulin (Tg) and thyroperoxidase (TPO) were both observed at the treatment of high dose perchlorate. These results suggested that perchlorate can suppress gene expression of Tg and TPO which directly involved in biosynthesis of thyroid hormones, and may therefore aggravate the perturbation of thyroid homeostasis in addition to competitive inhibition of iodide uptake.     

碘对比剂诱发甲状腺功能减退的病因及临床特点研究进展

应用碘对比剂（ICM）可诱发甲状腺功能减退（IIHypo）。新近研究发现ICM可独立于游离碘而特异性抑制甲状腺对碘化物摄取,其作用机制与传统的Wolff-Chaikoff效应并不一致。目前关于IIHypo发病率、相关危险因素及监测ICM诱发事件的适应证等问题尚未完全确定。认识发生IIHypo的潜在风险因素、及时评估在碘暴露时间窗内发生的碘诱导事件,对优化ICM诱发甲状腺功能障碍诊断和管理程序具有重要临床意义。