Thyroid-stimulating Hormone Suppressive Therapy Research Articles

Low versus high radioiodine dose in postoperative ablation of residual thyroid tissue in patients with differentiated thyroid carcinoma

Radioiodine ablation of thyroid tissue remains the cornerstone of treatment for patients with differentiated thyroid carcinoma after thyroidectomy. Selecting an optimal dose of radioiodine for successful ablation is a continuous challenge in these patients. We compared the treatment response of 341 patients with thyroidectomy randomly allocated to the high-dose group, 3700 MBq (170 patients), versus the low-dose group, 1110 MBq (171 patients), for radioiodine ablation therapy in a double-blind randomized clinical trial. The response to treatment was defined as successful or unsuccessful according to post-therapy ultrasonography of the neck, serum thyroglobulin (Tg), anti-Tg, and functioning residual tissue after 6-month and 12-month intervals. The major criteria of successful ablation were Tg<2 ng/ml, anti-Tg<100 IU/ml, and absent remnant in the off-levothyroxine state. Additional radioiodine doses were administered in cases showing no significant response to the first therapy. Finally, the initial outcome, the total hospitalization time, and the cumulative I-131 doses during the 12-month course of the study were compared between the subgroups. The rate of initial successful ablation was 51.6% in all patients, 39.2% in the low-dose group, and 64.1% in the high-dose group. The corresponding success rates at the end of the 12-month follow-up without additional treatment were 55.1, 41.5, and 68.8%, respectively. The relative risk (RR) of unsuccessful ablation for the low-dose versus the high-dose group was 1.695 [95% confidence interval (CI), 1.34-2.14]. In the low-dose group, more patients needed a second dose of I-131, resulting in a higher cumulative activity (median, 4810 vs. 3700 MBq, P<0.0001) and more inpatient time (median 4 vs. 3 days) in comparison with the high-dose group. The covariate factors predicting the treatment response, in order of significance, were radioiodine dose, baseline Tg, baseline thyroid stimulating hormone (TSH) level, efficiency of TSH suppressive therapy, and sex. The higher dose of I-131 (3700 MBq) resulted in successful ablation more often than the low dose (1110 MBq).

Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumor with lymph node metastasis: A case report

IntroductionPapillary thyroid carcinoma and medullary thyroid carcinoma are two different thyroid neoplasia. The simultaneous occurrence of medullary thyroid carcinoma and papillary thyroid carcinoma as a collison tumor with metastases from both lesions in the regional lymph nodes is a rare phenomenon.Case presentationA 32-year-old Iranian man presented with a fixed anterior neck mass. Ultrasonography revealed two separate thyroid nodules as well as a suspicious neck mass that appeared to be a metastatic lesion. The results of thyroid function tests were normal, but the preoperative calcitonin serum value was elevated. Our patient underwent a total thyroidectomy with neck exploration. Two separate and ill-defined solid lesions grossly in the right lobe were noticed. Histological and immunohistochemical studies of these lesions suggested the presence of medullary thyroid carcinoma and papillary thyroid carcinoma. The lymph nodes isolated from a neck dissection specimen showed metastases from both lesions.ConclusionsThe concomitant occurrence of papillary thyroid carcinoma and medullary thyroid carcinoma and the exact diagnosis of this uncommon event are important. The treatment strategy should be reconsidered in such cases, and genetic screening to exclude multiple endocrine neoplasia 2 syndromes should be performed. For papillary thyroid carcinoma, radioiodine therapy and thyroid-stimulating hormone suppressive therapy are performed. However, the treatment of medullary thyroid carcinoma is mostly radical surgery with no effective adjuvant therapy.

Effect of postoperative thyrotropin suppressive therapy on bone mineral density in patients with papillary thyroid carcinoma: A prospective controlled study

The influence of thyrotropin (thyroid-stimulating hormone [TSH]) suppressive therapy on bone mineral density (BMD) remains contentious. We have conducted a randomized controlled trial evaluating the effects of postoperative TSH suppressive therapy on disease-free survival for papillary thyroid carcinoma (PTC) since 1996, while prospectively verifying the effects of TSH suppression on BMD. Lumbar spine BMD as expressed by T-score was examined annually in female patients randomly assigned to receive TSH suppressive therapy (group A; n = 144) or no therapy (group B; n = 127). The mean TSH level was 0.07 ± 0.10 mU/L in group A and 3.14 ± 1.69 mU/L in group B. Group B did not show any significant decrease in T-score until 5 years postoperatively, whereas group A had a significant deterioration from 1 year postoperatively. Among group A patients, significant decreases in T-score within 1 year were seen in patients ≥ 50 years of age, but not in those <50 years of age. After 5 years of TSH suppression, 20 patients had T-scores below -2.0 and 100 patients did not. These former patients were significantly older and had lower preoperative BMD measurements than the latter. This prospective controlled trial suggests that TSH suppression after surgery for PTC has adverse effects on BMD in women ≥ 50 years of age.

Individualized thyrotropin suppression in patients with differentiated thyroid cancers

The epidemic characteristics of differentiated thyroid cancer(DTC)are changing, thyrotropin(TSH)suppressive therapy is also improving in recent years. The risks of recurrence and the death of patients, as well as the adverse effects of levothyroxine sodium treatment should be fully considered during thyroid hormone administration for patients of DTC. Hence, the degree of TSH suppression should be individualized in patients with DTC. Key words: Differentiated thyroid cancers; Thyrotropin suppressive therapy; Thyrotropin; Individualization

Effects of Physical Activity on Body Composition and Fatigue Perception in Patients on Thyrotropin-Suppressive Therapy for Differentiated Thyroid Carcinoma

Subclinical thyrotoxicosis (scTox) may be associated with alterations in body composition and fatigue that can be possibly reversed with physical activity. The aim of the present study was to evaluate whether the systematic practice of physical activity improves lower extremity muscle mass and fatigue perception in patients with scTox. We studied 36 patients (2 men) with median age of 48.0 (43.0-51.0) years, body mass index of 27.4 (22.1-30.2) kg/m(2), thyrotropin <0.4 mU/L, and free thyroxine between 0.8 and 1.9 ng/dL and 48 control subjects (C group; 7 men). Patients were randomly divided in two groups according to the adherence to the exercise training: scTox-Tr (n = 19)-patients who adhered to the exercise intervention and scTox-Sed (n = 17)--patients who did not adhere to it. The C group did not participate in the randomization. The exercise training was supervised by a physical education instructor, and it was composed of 60 minutes of aerobic activity and stretching exercises, twice a week, during 12 weeks. In both groups, body composition was assessed (anthropometric method), and the Chalder Fatigue Scale was determined at baseline and after 3 months of intervention (scTox-Tr group) or observation (scTox-Sed group). At baseline, patients with scTox had lower muscle mass and mid-thigh girth and more fatigue on the Chalder Fatigue Scale than euthyroid control subjects. The scTox-Tr group had an increase in muscle mass, reduction in the variables reflecting whole body fat, and lesser perception of fatigue during the exercise training period (p ≤ 0.05 for these parameters at the start and end of the exercise training period). scTox is associated with lower muscle mass and mid-thigh girth and more fatigue. Physical activity training can partially ameliorate these characteristics. More studies are needed to determine what training program would be optimum, both in terms of beneficial effects and for avoiding potential adverse responses.

Antiproliferation and Redifferentiation in Thyroid Cancer Cell Lines by Polyphenol Phytochemicals

Thyroid carcinogenesis is accompanied by loss of thyroid-specific functions and refractory to radioiodine and thyroid stimulating hormone (TSH) suppression therapy. Redifferentiating agents have been shown to inhibit tumor growth and improve the response to conventional therapy. Polyphenol phytochemicals (PPs) in fruits and vegetables have been reported to inhibit cancer initiation, promotion, progression and induce redifferentiation in selected types. In this study we examined PPs induce redifferentiation in thyroid cancer cell lines. We investigated the effects of genistein, resveratrol, quercetin, kaempferol, and resorcinol on the F9 embryonal carcinoma cell differentiation model. The thyroid cancer cell lines, TPC-1, FTC-133, NPA, FRO, and ARO, displayed growth inhibition in response to genistein, resveratrol, quercetin. We further demonstrated that genistein decreased the dedifferention marker CD97 in NPA cells and resveratrol decreased CD97 in FTC-133, NPA, FRO cells and quercetin decreased CD97 in all cell lines. We observed increased expression of differentiation marker NIS in FTC-133 cells in response to genistein, and resveratrol but no change in NPA, FRO, ARO cells. Quercetin increased or induced NIS in FTC-133, NPA, FRO cells. These findings suggest that PPs may provide a useful therapeutic intervention in thyroid cancer redifferentiation therapy.

Low bone turnover and increase of bone mineral density in a premenopausal woman with postoperative hypoparathyroidism and thyroxine suppressive therapy

We report the case of a 36-year-old woman who developed permanent hypoparathyroidism after thyroidectomy for differentiated thyroid carcinoma. A 6-year follow-up showed an increase of 11% in absolute bone mineral density at the spine and 6% at the hip accompanied by low bone turnover despite thyroid-stimulating hormone suppressive thyroxine therapy.

Management of Differentiated Thyroid Cancer with Rising Thyroglobulin and Negative Diagnostic Radioiodine Whole Body Scan

BackgroundDifferentiated thyroid carcinoma (DTC) with rising thyroglobulin (Tg) level and negative radioiodine whole body scan results has been observed in follow-up studies. The management of this condition remains controversial. Most studies support blind 131I treatment while others oppose this approach. AimsTo assess the effects of 131I therapy for DTC with rising Tg and negative scan results. Selection criteriaRandomised controlled clinical trials, prospective controlled clinical trials and any trials using 131I treatment or no treatment for Tg-positive and radioiodine-negative disease were included in this review. ResultsDue to the lack of any suitable randomised or prospective controlled trials in this area, it was not possible to undertake a meta-analysis. Eighteen trials were retrieved for further overall assessment. Of 438 patients from 16 studies who were treated empirically with 131I for Tg-positive and radioiodine-negative disease, 267 (62%) displayed pathological uptake in the thyroid bed, lungs, bone, mediastinum and lymph nodes. In studies in which data were available for serum Tg levels during thyroid-stimulating hormone (TSH) suppression therapy or TSH withdrawal, 188 of 337 patients (56%) showed a decrease in serum Tg. Of 242 patients from five studies who received no specific treatment for Tg-positive and radioiodine-negative disease, 106 (44%) showed spontaneous normalisation and a significant decrease in serum Tg. ConclusionsThe currently available evidence is insufficient for reliable assessment of the potential of 131I treatment for DTC with elevated Tg and negative scan results. A decrease in serum Tg in 62% of patients with DTC with elevated Tg and negative scan results suggests that 131I therapy has a therapeutic effect for more than one-half of patients when the Tg level is considered an index of tumour burden. However, considering that 44% of patients with DTC with elevated Tg and negative scan results showed spontaneous normalisation and a significant reduction in serum Tg without any specific treatment, 131I therapy should be individualised according to clinical characteristics. Other diagnostic techniques are strongly recommended for patients with Tg-positive and radioiodine-negative disease. If these diagnostic results are positive, treatment options such as surgery, external radiotherapy and tumour embolisation should be considered. If diagnostic results are negative, one course of 131I treatment may be considered in high-risk patients with serum Tg >10ng/mL after TSH withdrawal or >5ng/mL under recombinant human TSH stimulation. No further 131I therapy is indicated for patients with a negative post-therapy radioiodine scan.

Percepción de los endocrinólogos clínicos sobre los potenciales efectos perjudiciales del tratamiento supresor de la TSH en el carcinoma diferenciado de tiroides

Objective To explore the opinion of clinical endocrinologists as to the deleterious effects of thyrotropin (TSH) suppressive therapy in patients with differentiated thyroid carcinoma (DTC). Materials and methods A self-administered survey was sent by e-mail to a group of endocrinologists with expertise in the treatment of patients with differentiated thyroid carcinoma. The questionnaire consisted of three questions related to: 1) the possible adverse effects of this therapy on different organ systems, 2) the clinical significance of these effects and 3) the usefulness of treatment guidelines for DTC. Results A total of 91 endocrinologists responded with a wide divergence of opinions. No question had more than 80% of answers in a particular option. Of the possible side effects of suppressive therapy, a high degree of ignorance to three of them (increased left ventricular mass, reentrant tachycardia and diastolic dysfunction). Most respondents felt that the seven items, dementia and Alzheimer, decreased quality of life, decreased bone mineral density (BMD) in premenopausal women and men, thromboembolic disease, signs and symptoms of hyperthyroidism and increased risk of fractures were not affected by suppressive therapy, while most responded positively to two items (increased heart rate and decreased BMD in postmenopausal women). Eighty percent of the respondents felt that in any case these effects were not clinically significant and 33% considered that treatment guidelines should be reviewed. Conclusions Clinical endocrinologists seem to have a very heterogeneous opinion regarding the potential harmful effects of TSH-suppressive therapy for DTC

Renal Metastasis from Hurthle Cell Thyroid Carcinoma and Its Evaluation with Hybrid Imaging

In general, thyroid carcinomas, when they behave aggressively, metastasize to lungs and occasionally to bone and brain. Metastases to other organs are distinctly unusual. Renal metastases have been reported in only 10 patients. Here we report, to the best of our knowledge, the first patient with Hurthle cell thyroid cancer and renal metastasis. The evaluation of this patient was enhanced by utilizing a variety of imaging techniques. The patient was a 75-year-old man who had a history of a total thyroidectomy 9 years previously for a right thyroid lobe Hurthle cell carcinoma. He postoperatively received 150 mCi (5550 MBq) of 131-I therapy and was maintained on thyrotropin suppressive therapy with levothyroxine. He presented to us with a recent history of a progressively enlarging left neck mass. The serum thyroglobulin was elevated to 1183 ng/mL. Multimodality imaging with fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging, and Somatostatin receptor scintigraphy with single photon emission computed tomography (SPECT)-computed tomography revealed numerous foci in the skeleton and right kidney. Anatomic imaging characteristics favored a primary renal cell cancer with the additional evidence of renal vein invasion and thrombosis. Histology later revealed a metastatic renal Hurthle cell cancer with positive thyroglobulin stains. Several of the skeletal foci responded partially to cryoablative therapy. The patient refused noncurative Somatostatin analog therapy. He is alive and doing well clinically. The management of thyroid cancers in high-risk groups, such as our patient, frequently requires expert management by the use of novel multimodality imaging and therapeutic techniques.

Osteoporosis and Thyrotropin-Suppressive Therapy: Reduced Effectiveness of Alendronate

Many reports of the effect of exogenous thyroxine therapy on bone mineral density (BMD) show a relationship between excess thyroid hormone administration and osteoporosis. The aim of this study was to evaluate the effect of antibone resorptive agents, in particular alendronate (ALN) on BMD in postmenopausal osteoporotic women with thyroid carcinoma who were receiving long-term thyrotropin (TSH)-suppressive therapy with thyroxine. Seventy-four postmenopausal women with low BMD (T-score < or =-2.5) and differentiated thyroid carcinoma on long-term TSH-suppressive therapy (TSH > or =0.05 and < or =0.1 microU/mL) for about 3-9 years were selected for the study. The patients were divided into three groups according to the length of levothyroxine (LT(4)) treatment prior to the beginning of the study: group A (TSH-suppressive therapy for about 3 years), group B (for about 6 years), and group C (for about 9 years). These patients were compared with 74 matched women not taking LT(4). All patients and controls were treated with bisphosphonates, calcium, and vitamin D for 2 years and evaluated. After 24 months of treatment group A showed a 7.8% increase in lumbar BMD; group B, a 4.6% increase; and group C, a 0.86% increase. In the control group BMD increased 8.2%. A significant difference was found in both lumbar and femoral BMD increase among the three groups: group C had a lower BMD increase than group A (p < 0.001) and B (p < 0.001). In postmenopausal women who were receiving adequate amounts of calcium and vitamin D in their diet ALN was less effective for those who were also receiving TSH-suppressive doses of LT(4) for either 6 or 9 years. The positive effect of ALN on BMD was less for longer periods of LT(4) treatment. It seems likely that other bisphosphonates would also be less effective in increasing BMD in postmenopausal women receiving TSH-suppressing doses of LT(4).

The Successful Use of Sorafenib to Treat Pediatric Papillary Thyroid Carcinoma

Pediatric papillary thyroid cancer (PTC) typically presents with more advanced disease as compared with adults, yet the prognosis, even in the presence of distant metastatic disease, is usually excellent. Systemic therapies other than radioactive iodine (RAI) are rarely required. Sorafenib is an orally administered multi-kinase inhibitor that has shown promise in the treatment of adults with advanced thyroid cancer, but it has not yet been studied in children with this disease. Our objective is to present an adolescent with a progressive RAI-resistant PTC who was successfully treated with sorafenib. A 14-year-old girl had progressive lung metastases from PTC despite previous therapies with almost 400 mCi (131)I. Sorafenib was initiated at a starting dose of 200 mg twice daily and decreased to a maintenance dose of 200 mg daily due to side effects that developed within 3 weeks of treatment. After 67 days on the lower dose, there was a dramatic improvement in the lung metastases. The patient was monitored while continuing thyrotropin-suppressive therapy only. Minimal regrowth of the pulmonary metastases was observed, and a second treatment course of sorafenib 200 mg every other day was equally successful in achieving a clinical response. Thyroglobulin autoantibodies declined over the course of therapy and observation. In the very rare case of the pediatric patient with progressive RAI-refractory PTC, for which no good systemic therapy exists, sorafenib may play an important role in the management of this disease.

New therapeutic advances in the management of progressive thyroid cancer

The spectrum of thyroid cancers ranges from one of the most indolent to one of the most aggressive solid tumors identified. Conventional therapies for thyroid cancers are based on the histologic type of thyroid cancers such as papillary or follicular thyroid cancer (differentiated thyroid cancer (DTC)), medullary thyroid cancer (MTC), or anaplastic thyroid cancer (ATC). While surgery is one of the key treatments for all such types of thyroid cancers, additional therapies vary. Effective targeted therapy for DTC is a decades-old practice with systemic therapies of thyroid stimulating hormone suppression and radioactive iodine therapy. However, for the iodine-refractory DTC, MTC, and ATC there is no effective systemic standard of care treatment. Recent advances in understanding pathogenesis of DTC and development of molecular targeted therapy have dramatically transformed the field of clinical research in thyroid cancer. Over the last five years, incredible progress has been made and phases I-III clinical trials have been conducted in various types of thyroid cancers with some remarkable results that has made an impact on lives of patients with thyroid cancer. Such history-making events have boosted enthusiasm and interest among researchers, clinicians, patients, and sponsors and we anticipate ongoing efforts to develop more effective and safe therapies for thyroid cancer.

Thyrotropin Suppressive Therapy in Thyroid Carcinoma: What Are the Targets?

Published guidelines on the treatment of thyroid carcinoma support TSH suppressive therapy as the standard of care for long-term follow-up after initial surgery and sequential radioiodine application (1, 2). This guidance based on large retrospective studies may be criticized on several grounds; in particular, they were not uniformly performed to current standards of surgical intervention, postoperative radioactive iodine treatment, standardized thyroxine preparations, or tailored TSH suppression using sensitive TSH assays (3). However, recent findings have largely resolved these uncertainties and confirm the beneficial effects of TSH suppressive treatment in patients with thyroid cancer (4, 5). Another important finding of these newer studies was that high-risk patients appear to respond better than patients carrying a low risk (5).

Cognitive dysfunctions during chronic Thyrotropin-suppressive therapy with levothyroxine in patients with differentiated thyroid carcinoma

Cognitive dysfunctions during chronic Thyrotropin-suppressive therapy with levothyroxine in patients with differentiated thyroid carcinoma

Practical Management of Well Differentiated Thyroid Carcinoma in Korea

The optimal extent of surgery and postoperative management of patients with well differentiated thyroid carcinoma (WDTC) vary among countries and institutions. We assessed the practical management of WDTC in Korea by questionnaire and compared these results with those obtained in similar surveys of members of the Japanese Society of Thyroid Surgery (JSTS) and the International Association of Endocrine Surgeons (IAES). Questionnaires were sent by mail or e-mail to 266 members of the Korean Association of Endocrine Surgeons (KAES). Ninety members (33.8%) completed the questionnaire; their responses were compared with those of the JSTS and IAES surveys. Total thyroidectomy was more prevalent in the KAES and IAES than in the JSTS, irrespective of tumor size in the low-risk group. Patients with papillary microcarcinoma were more likely to undergo aggressive central compartment node dissection in the KAES than in the IAES or JSTS. Thyroid stimulating hormone suppression therapy was administered to a higher proportion of patients and for longer times in the KAES and IAES than in the JSTS. Postoperative radioactive iodine treatment was more prevalent in the KAES than in the JSTS. There were no differences between the KAES and the JSTS in the treatment of patients with locally advanced thyroid carcinoma. External irradiation and radioactive iodine treatment for recurrent papillary thyroid carcinoma were favored more by the KAES than the IAES and JSTS. The actual practices of members of the KAES were almost similar to those of the IAES, but differed from those in Japan in some aspects. In general, however, members of the KAES favored more aggressive treatment of WDTC than did physicians in other countries.

The Effects of Thyrotropin-Suppressive Therapy on Bone Metabolism in Patients with Well-Differentiated Thyroid Carcinoma

Patients with differentiated thyroid carcinoma (DTC) are commonly treated long-term with thyrotropin (TSH)- suppressive thyroxine replacement therapy resolving in a state of subclinical hyperthyroidism. The relationship between subclinical hyperthyroidism and osteoporosis is not clear. In this review, we systematically selected and analyzed 21 studies addressing this issue. Although multiple methodological differences between studies prevented a structured meta-analysis, our data suggest that postmenopausal women with subclinical hyperthyroidism are most at risk, whereas no increased risk was observed in men and premenopausal women. Based on these findings we believe that measurement of bone mineral density is recommended in postmenopausal women with DTC starting TSH suppressive therapy. This should be subsequently regularly measured to enable timely intervention with bone protective agents.

Long-Term Thyrotropin-Suppressive Therapy with Levothyroxine Impairs Small and Large Artery Elasticity and Increases Left Ventricular Mass in Patients with Thyroid Carcinoma

Exogenous subclinical hyperthyroidism, caused by long-term thyrotropin (TSH)-suppressive treatment with levothyroxine (LT(4)), is associated with several cardiovascular abnormalities. In order to assess the effect of long-term thyroid hormone-suppressive therapy on the blood vessels and myocardium, we determined the arterial elasticity, using the pulse wave contour analysis. Twenty-six athyreotic patients receiving TSH-suppressive LT(4) therapy for periods ranging from 3 to 21 years at a mean daily dose of 2.25 +/- 0.5 microg/kg per day were included in the study. Twenty six age- and gender-matched healthy subjects served as controls. Arterial elasticity of large and small arteries was evaluated using pulse wave contour analysis method (HDI CR 200, Eagen, MN). Cardiac structure was assessed by two-dimensional echocardiography. We found decreased large artery elasticity in subclinical hyperthyroidism (sHT) patients compared to controls (14.14 +/- 3.38 versus 10.53 +/- 2.43 L/mm Hg x 100, p < 0.000). Small artery elasticity was also lower in patients than in controls (5.42 +/- 1.82 versus 4.30 +/- 1.75 mL/mm Hg x 100, p < 0.056). The echocardiographic data showed significantly increased left ventricular (LV) mass index (101.90 +/- 18.61 versus 88.03 +/- 22.01 g/m(2), p < 0.049) and interventricular septum thickness (10.61 +/- 1.46 versus 9.11 +/- 1.13 mm, p < 0.002) in LT(4)-treated patients compared to controls. We found impaired vascular elasticity of large and small arteries and increased LV mass in patients receiving long-term TSH-suppressive therapy with LT(4).

Radio-guided surgery of differentiated thyroid cancer using 131I or 99mTc-Sestamibi

The classical therapeutic approach to patients with differentiated thyroid cancer (DTC) is based on total or near-total thyroidectomy, followed by (131)I treatment and thyroid-stimulating hormone suppressive therapy. This approach allows complete cure in many patients, especially when the tumour is diagnosed at an early stage; it also allows long-term survival in patients with locoregional recurrences or distant metastases if they can be treated with (131)I. In contrast, when metastatic DTC deposits lose their ability to trap (131)I (non-functioning metastases), a worse prognosis is expected. Nevertheless, in patients with locoregional non-functioning recurrences, an early diagnosis and prompt surgical extirpation can lead to a favourable prognosis. In these cases, radical surgery is needed. This can be achieved with radio-guided surgery using a hand-held gamma probe and a tumour-seeking radiotracer to detect, intraoperatively, the smallest metastatic lesions. In this paper, we discuss the two principal techniques proposed in the literature for radio-guided surgery of non-functioning DTC metastatic recurrences, the first using high doses of (131)I and the second using low doses of 99mTc-Sestamibi.

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.