Thyroid Radioiodine Research Articles

Modulation of sodium iodide symporter expression and function by LY294002, Akti-1/2 and Rapamycin in thyroid cells

The selective increase of Na(+)/I(-) symporter (NIS)-mediated active iodide uptake in thyroid cells allows the use of radioiodine I(131) for diagnosis and targeted treatment of thyroid cancers. However, NIS-mediated radioiodine accumulation is often reduced in thyroid cancers due to decreased NIS expression/function. As PI3K signaling is overactivated in many thyroid tumors, we investigated the effects of inhibitors for PI3K, Akt, or mTORC1 as well as their interplay on NIS modulation in thyroid cells under chronic TSH stimulation. PI3K inhibition by LY294002 increased NIS-mediated radioiodide uptake (RAIU) mainly through upregulation of NIS expression, however, mTORC1 inhibition by Rapamycin did not increase NIS-mediated RAIU despite increased NIS protein levels. In comparison, Akt inhibition by Akti-1/2 did not increase NIS protein levels, yet markedly increased NIS-mediated RAIU by decreasing iodide efflux rate and increasing iodide transport rate and iodide affinity of NIS. The effects of Akti-1/2 on NIS-mediated RAIU are not detected in nonthyroid cells, implying that Akti-1/2 or its derivatives may represent potential pharmacological reagents to selectively increase thyroidal radioiodine accumulation and therapeutic efficacy.

Development of hypothyroidism during long‐term follow‐up of patients with toxic nodular goitre after radioiodine therapy

To investigate the cure rate and incidence of hypothyroidism of radioiodine treatment with a calculated dose regimen and an intended thyroid dose of 150 Gy in patients with toxic nodular goitre during long-term follow-up. A total of 265 consecutive patients with toxic nodular goitre were treated between March 2003 and August 2004 at our institute and followed up for a maximum of 8 years. Preliminary radioiodine testing with volumetric measurement of the thyroid by ultrasound as well as individual thyroidal radioiodine uptake and half-life measurements were performed before radioiodine therapy. The estimated radiation dose to the thyroid was 150 Gy. Follow-up controls with respect to success of therapy and development of hypothyroidism were performed 3 months, 1 and up to 8 years after radioiodine treatment. The relation of the achieved thyroid dose to the success rate of treatment and to the incidence of hypothyroidism was analysed. The cure rates were 85% at 3 months, 98% at 1 year and 98% at the end of follow-up. Above an achieved thyroid dose of more than 120 Gy, there was no significant association between the dose achieved in the thyroid and the cure rate on follow-up. The incidences of hypothyroidism at 3 months, at 1 year and at the end of follow-up were 32%, 55% and 73%, respectively. Radioiodine treatment with a calculated dose regimen is a highly effective treatment option in patients with toxic goitre with an overall success rate of 98%. However, radioiodine treatment with an intended thyroid dose of 150 Gy leads to a high incidence of hypothyroidism on long-term follow-up. This finding supports the suggestion that in future intended thyroid doses could be lowered in patients treated with a calculated dose regimen for toxic nodular goitre.

Radioiodine Thyroid Ablation in Graves′ Hyperthyroidism: Merits and Pitfalls

Ablative approaches using radioiodine are increasingly proposed for the treatment of Graves′ disease (GD) but their ophthalmologic and biological autoimmune responses remain controversial and data concerning clinical and biochemical outcomes are limited. The aim of this study was to evaluate thyroid function, TSH-receptor antibodies (TRAb) and Graves′ ophthalmopathy (GO) occurrence after radioiodine thyroid ablation in GD. We reviewed 162 patients treated for GD by iodine-131 (131I) with doses ranging from 370 to 740 MBq, adjusted to thyroid uptake and sex, over a 6-year period in a tertiary referral center. Collected data were compared for outcomes, including effectiveness of radioiodine therapy (RIT) as primary endpoint, evolution of TRAb, and occurrence of GO as secondary endpoints. The success rate was 88.3% within the first 6 months after the treatment. The RIT failure was increased in the presence of goiter (adjusted odds ratio = 4.1, 95% confidence interval 1.4–12.0, P = 0.010). The TRAb values regressed with time (r = −0.147; P = 0.042) and patients with a favorable outcome had a lower TRAb value (6.5 ± 16.4 U/L) than those with treatment failure (23.7 ± 24.2 U/L, P < 0.001). At the final status, 48.1% of patients achieved normalization of serum TRAb. GO occurred for the first time in 5 patients (3.7%) who were successfully cured for hyperthyroidism but developed early and prolonged period of hypothyroidism in the context of antithyroid drugs (ATD) intolerance (P = 0.003) and high TRAb level (P = 0.012). On the basis the results of this study we conclude that ablative RIT is effective in eradicating Graves’ hyperthyroidism but may be accompanied by GO occurrence, particularly in patients with early hypothyroidism and high pretreatment TRAb and/or ATD intolerance. In these patients, we recommend an early introduction of LT4 to reduce the duration and the degree of the radioiodine-induced hypothyroidism.

Radioiodine Thyroid Remnant Ablation after Recombinant Human Thyrotropin or Thyroid Hormone Withdrawal in Patients with High-Risk Differentiated Thyroid Cancer

To supplement limited relevant literature, we retrospectively compared ablation and disease outcomes in high-risk differentiated thyroid carcinoma (DTC) patients undergoing radioiodine thyroid remnant ablation aided by recombinant human thyrotropin (rhTSH) versus thyroid hormone withdrawal/withholding (THW). Our cohort was 45 consecutive antithyroglobulin antibody- (TgAb-) negative, T3-T4/N0-N1-Nx/M0 adults ablated with high activities at three referral centers. Ablation success comprised negative (<1 μg/L) stimulated serum thyroglobulin (Tg) and TgAb, with absent or <0.1% scintigraphic thyroid bed uptake. “No evidence of disease” (NED) comprised negative unstimulated/stimulated Tg and no suspicious neck ultrasonography or pathological imaging or biopsy. “Persistent disease” was failure to achieve NED, “recurrence,” loss of NED status. rhTSH patients (n = 18) were oftener ≥45 years old and higher stage (P = 0.01), but otherwise not different than THW patients (n = 27) at baseline. rhTSH patients were significantly oftener successfully ablated compared to THW patients (83% versus 67%, P < 0.02). After respective 3.3 yr and 4.5 yr mean follow-ups (P = 0.02), NED was achieved oftener (72% versus 59%) and persistent disease was less frequent in rhTSH patients (22% versus 33%) (both comparisons P = 0.03). rhTSH stimulation is associated with at least as good outcomes as is THW in ablation of high-risk DTC patients.

Treatment room length-of-stay and patient throughput with radioiodine thyroid remnant ablation in differentiated thyroid cancer

We sought to empirically compare treatment room length-of-stay and patient throughput for recombinant human thyroid-stimulating hormone (rhTSH)-aided thyroid remnant ablation with thyroid hormone withdrawal (THW)-aided ablation in patients with differentiated thyroid carcinoma (DTC). We retrospectively reviewed charts of all eligible (near) totally thyroidectomized patients with DTC undergoing ablation and 1-year ablation success evaluation at our tertiary referral centre from January 2003 to February 2009 (N=274). M1 disease caused exclusion unless discovered by a postablation scan or present when rhTSH was the only tolerable stimulation method. We extracted data on the length-of-stay, defined as the time between treatment room admission and discharge, and patient throughput, defined as patients ablated per treatment room per week. The treatment room discharge criterion was a whole-body dose rate of less than 60 μSv/h at 50 cm. The treatment groups (rhTSH, n=187; THW, n=87) had mostly statistically similar characteristics, but differed in primary tumour status distribution. In addition, at ablation, the rhTSH patients had a greater prevalence of prior diagnostic scintigraphy, higher mean serum TSH, and shorter interval since surgery, and received a 5.6% larger mean ablation activity. On average, rhTSH patients had a significantly lower peak whole-body dose rate (57.1 vs. 83.4 μSv/h at 50 cm; P<0.0001) and a significantly shorter treatment room stay than did the THW patients (1.41 vs. 2.02 days; P<0.001). rhTSH use allowed significantly more patients to be ablated per room per week (2.7 vs. 1.2; P<0.001). Relative to THW, rhTSH use to aid ablation reduced mean treatment room length-of-stay by almost one-third and more than doubled the average weekly patient throughput, both of which were significant differences.

Nonclassic TSH Resistance:TSHRMutation Carriers with Discrepantly High Thyroidal Iodine Uptake

Inactivating mutations in the TSH receptor gene (TSHR) cause TSH resistance. Most patients with TSH resistance have low to normal thyroidal radioiodine uptake (RAIU), which is consistent with the physiological knowledge that TSH stimulates iodine uptake. To date, only one TSHR mutation-carrying family with discrepantly high RAIU has been reported. We aimed to test whether TSHR mutation carriers with high RAIU are observed in a cohort of Japanese patients with congenital hypothyroidism (CH). Twenty-four Japanese CH patients with high RAIU were screened for TSHR mutations. The capacities of mutant TSHR to activate Gs- and Gq-coupled signaling pathways were evaluated in vitro. Two patients were found to have biallelic TSHR mutations: p.[T145I]+[R450H] in one and p.[R450H]+[I661fs] in the other. The two subjects had permanent CH with slightly high RAIU (41.8 and 43.0%, reference 8-40) but did not have goiter. One had a slightly high perchlorate discharge rate (10%, reference <10). Expression experiments revealed that T145I-TSHR retained partial ability to transduce both Gs- and Gq-coupled pathways, whereas I661fs-TSHR could transduce neither of them. R450H-TSHR had partial ability to transduce Gs-coupled signaling but had abrogated ability to transduce Gq-coupled signaling, indicating that coupling to Gq was dominantly affected. We show that 8% of Japanese CH patients with high RAIU (two in 24) has inactivating TSHR mutations. Expression of this apparently discrepant phenotype, which we term nonclassic TSH resistance, is presumably associated with the characteristic signaling property of the mutant TSHR, namely the Gq-dominant coupling defect.

A painful cranial bulge

A 56-year-old woman with radio-iodine resistant follicular thyroid carcinoma presented to us with progressive metastatic disease in her lungs, brain, and skull . She had no symptoms apart from a painful cranial bulge. A CT of her head showed a scalp mass with osteolysis of her skull. The parietal, occipital, and temporal bones were aff ected (fi gure A and B). Her thyroglobulin serum concentration was 102 300 μg/L (normal range <55 μg/L). We treated our patient with the tyrosine protein kinase inhibitor, Sorafenib, at a fi xed dose of 400 mg twice daily. She tolerated the treatment well, and after 2 months her cranial bulge was reduced to a painless, softened mass with necrotic areas (fi gure C). Her thyroglobulin serum concentration had decreased to 47 500 μg/L. Further imaging showed a partial response in both her brain and pulmonary metastases. Our patient had a sustained response to sorafenib for 24 months. Sorafenib is not yet licensed for the treatment of thyroid cancer. A phase II trial (NCT00654238) investigating this drug for thyroid cancer is recruiting patients.

A Study of the Etiology of Congenital Hypothyroidism in the Niigata Prefecture of Japan in Patients Born Between 1989 and 2005 and Evaluated at Ages 5–19

The prevalence of congenital hypothyroidism (CH) increased during the period 1994-2002 in Japan. The reasons for these recently described increases in the prevalence of CH remain unclear. Moreover, the proportion of patients with different etiologies CH in the more recently diagnosed patients has not been established. In this study, we determined the etiologies of CH that were detected by neonatal screening in Niigata refecture, Japan. A total of 100 patients having a diagnosis of CH (41 men and 59 women, aged 5-19 years old) were evaluated. To determine the etiology of CH, the patients underwent a ¹²³I thyroidal radioiodine uptake test, a scintigram, a saliva to plasma radioiodine ratio analysis, a perchlorate discharge test, thyroid ultrasonography, measurements of thyroidal function and thyroglobulin, and a thyrotropin (TSH)-releasing hormone tolerance test. Patients with overt CH (n=34, elevated TSH levels with low free thyroxine levels) made up 34% of the total group, 56% of the patients had subclinical CH (n=56, elevated TSH levels with normal free thyroxinelevels), and 10% had normal thyroid function. These were patients who were considered to have transient hypothyroidism or hyperthyrotropinemia. Thyroid dysgenesis was the diagnosis in 73% of patients with overt CH, and the most of these had ectopic thyroid tissue. In contrast, thyroid dysgenesis was the diagnosis in only 36% of the patients with subclinical CH. Only 50% of our patients with CH detected by neonatal screening had thyroid dysgenesis. With an increase in the percentage of patients with subclinical hypothyroidism, the prevalence of thyroid dyshormogenesis has increased. Studies of the frequency and etiology of CH should consider overt and subclinical CH separately.

McCune Albright Syndrome with a Somatolactotroph Pituitary Adenoma Causing Gigantism: Econography and Literature Review

McCune Albright syndrome (MAS) is a rare disease due to a sporadic mutation in Gs protein inducing polyostotic fibrous dysplasia, pigmented skin patches and hyper functioning endocrinopathies. We aimed to report its association with a hot thyroid nodule and gigantism. Case report. A man aged 37, with a history of pigmented skin lesions and lameness was referred for acromegaly. He was giant (height = 1.94 m/ target stature = 1.68 m), and had “cafe au lait” spots. Biological analyses argued for pituitary mixed secretion (random growth hormone = 22 ng/ mL, N<5; prolactin = 27 ng/mL, N<10). Brain CT scan showed a pituitary process of 11x10 mm. Thyroid radioiodine scan revealed a hot nodule. Bone x-ray demonstrated large osteolytic lesions in the right femur and pelvis. He was operated on for endocrine tumours. The thyroid nodule was benign and immunohistochemistry pituitary was positive for GH, prolactin and α subunit. Conclusion. Somatolactotrop adenoma causing gigantism associated with MAS is exceptional. It should be known, diagnosed, and treated early to avoid bone deformations and malignant transformation of osseous

The Role of Routine Diagnostic Radioiodine Whole-Body Scintigraphy in Patients with High-Risk Differentiated Thyroid Cancer

Follow-up diagnostic radioiodine whole-body scintigraphy (DxWBS) is still advised for high-risk patients with differentiated thyroid cancer. The aim of this study was to evaluate the additional value of DxWBS to stimulated thyroglobulin measurement in high-risk patients. The results of DxWBS and thyroglobulin measurements performed 6-12 mo after surgery and radioiodine thyroid remnant ablation in patients with differentiated thyroid cancer were retrospectively evaluated for 112 patients with high-risk features for recurrence (R3/T4 and N1). One patient had an undetectable thyroglobulin level, with DxWBS results suggestive of cervical recurrence. DxWBS was found to be false-positive. Of the patients with detectable thyroglobulin levels, the DxWBS results were negative in 65 and positive in only 8. The 6 patients positive for thyroglobulin antibody had negative DxWBS results. The remaining patients had an undetectable thyroglobulin level and negative DxWBS results. Because undetectable stimulated thyroglobulin levels have a negative predictive value of 100%, DxWBS offers no information additional to recombinant human thyroid-stimulating hormone-stimulated thyroglobulin measurements in patients with high-risk differentiated thyroid cancer.

Qualitative and Quantitative Impact of Protective Glucocorticoid Therapy on the Effective 131I Half-Life in Radioiodine Therapy for Graves Disease

This aim of this retrospective study was to determine the impact of glucocorticoid therapy on the effective (131)I half-life in radioiodine therapy for Graves disease. Three hundred fifteen consecutive Graves disease patients undergoing radioiodine therapy at our institution between August 2004 and January 2009 were enrolled. We investigated the influences of thyroid state (hypothyroidism, euthyroidism, hyperthyroidism), antithyroid drug dose before (131)I therapy, thyroid-stimulating hormone receptor antibody (TRAb) level, and qualitative and quantitative factors of prednisolone therapy on the effective (131)I half-life, applying univariate (paired t test) and multivariate (multiple-regression) analyses. Multivariate analyses revealed independent significant effects of the thyroid metabolic state (P = 0.004), antithyroid drugs (P < 0.001), presence of TRAb (P = 0.004), and glucocorticoids (P = 0.046) on thyroidal radioiodine half-life. Compared with euthyroidism, thyrotoxicosis and hypothyroidism reduced the effective half-life; high doses of antithyroid drugs and high TRAb levels had the same effect. Also, glucocorticoid therapy shortened the effective thyroidal radioiodine half-life in a dose-dependent manner. Pharmacologically, this effect is attributable to the prednisolone-induced increase of renal plasma (131)I clearance and the resulting reduction of plasma (131)I available for reuptake into the thyroid during radioiodine therapy. Oral treatment with prednisolone results in a reduction of effective thyroidal (131)I half-life in Graves disease, especially at higher doses.

Single photon emission computed tomography imaging for temporal dynamics of thyroidal and salivary radionuclide accumulation in 17-allyamino-17-demothoxygeldanamycin-treated thyroid cancer mouse model

Selective iodide uptake and prolonged iodine retention in the thyroid is the basis for targeted radioiodine therapy for thyroid cancer patients; however, salivary gland dysfunction is the most frequent nonthyroidal complications. In this study, we have used noninvasive single photon emission computed tomography functional imaging to quantify the temporal dynamics of thyroidal and salivary radioiodine accumulation in mice. At 60 min post radionuclide injection, radionuclide accumulation in the salivary gland was generally higher than that in thyroid due to much larger volume of the salivary gland. However, radionuclide accumulation per anatomic unit in the salivary gland was lower than that in thyroid and was comparable among mice of different age and gender. Differently, radionuclide accumulation per anatomic unit in thyroid varied greatly among mice. The extent of thyroidal radioiodine accumulation stimulated by a single dose of exogenous bovine TSH (bTSH) in triiodothyronine (T₃)-supplemented mice was much less than that in mice received neither bTSH nor T₃ (nontreated mice), suggesting that the duration of elevated serum TSH level is important to maximize thyroidal radioiodine accumulation. Furthermore, the extent and duration of radioiodine accumulation stimulated by bTSH was less in the thyroids of the thyroid-targeted RET/PTC1 (thyroglobulin (Tg)-PTC1) mice bearing thyroid tumors compared with the thyroids in wild-type (WT) mice. Finally, the effect of 17-allyamino-17-demothoxygeldanamycin on increasing thyroidal, but not salivary, radioiodine accumulation was validated in both WT mice and Tg-PTC1 preclinical thyroid cancer mouse model.

Serum thyroxine and age — rather than thyroid volume and serum TSH — are determinants of the thyroid radioiodine uptake in patients with nodular goiter

Radioiodine (131I) therapy is widely used for treatment of non-toxic goiters. A limitation for this treatment is a low thyroid radioiodine uptake (RAIU), often encountered in these patients. To estimate the impact of various factors on the thyroid RAIU. We examined prospectively 170 patients (146 females; age range: 22-87 yrs) with nodular goiter (median 64 ml, range: 20-464 ml) selected for 131I therapy. Serum TSH was sub-normal in 42.4%. None were treated with anti-thyroid drugs. The thyroid RAIU was determined at 24h and 96 h. The goiter volume was measured by ultrasound (no.=127), or by magnetic resonance imaging (no.=43). The 24h and the 96 h RAIU were 34.2 ± 9.8(SD)% (range: 11.4-66.0%) and 34.0 ± 10.0% (range: 10.5-60.9%), respectively. Sixty-one patients had a 24h RAIU <30% and these individuals were older than patients with a 24h RAIU ≥ 30% (median 58 vs 51 yrs, p=0.02). These two subgroups did not differ significantly in other variables. Overall, the 24h RAIU was positively correlated to the serum (s) free T4-index (r=0.20, p=0.01), and negatively to age (r=-0.18, p=0.02), but not significantly related to serum TSH or thyroid volume. Age correlated positively with thyroid volume (r=0.31, p < 0.001). In a regression analysis, s-free T4-index and age remained as the only determinants of the 24h and the 96 h RAIU. In patients with a symptomatic nodular goiter, serum T4 and age are the major determinants of the thyroid RAIU. A sub-normal serum TSH is not a marker of a compromised thyroid RAIU but reflects that the iodine is confined to a few 'hot spots'.

Retinoic acid modulation of thyroid dual oxidase activity in rats and its impact on thyroid iodine organification

The sodium-iodide symporter (NIS) mediates iodide uptake into the thyrocytes, which is important for the diagnosis and therapy of thyroid disorders. Decreased ability to uptake iodide in thyroid carcinomas reduces the efficacy of radioiodine therapy, and retinoic acid (RA) treatment reinduces iodide uptake. The effectiveness of treatment depends not only on iodide uptake but also on the ability of thyrocytes to organify iodine, which is catalyzed by thyroperoxidase (TPO) in the presence of H(2)O(2). Our goal was to determine the influence of RA on thyroid iodide uptake, iodine organification, and TPO and dual oxidase (DuOx) activities. Normal rats were treated with all-trans-RA or 13-cis-RA (100 or 1500 microg/100 g body weight (b.w.), s.c.) for 14 and 28 days. The 2 h thyroid radioiodine content significantly decreased in rats treated with all-trans-RA (100 microg/100 g b.w.) for 14 days. In this group, NIS function and TPO activity were unchanged, whereas DuOx activity was significantly decreased, which might have contributed to the decrease in iodine organification. Both doses of 13-cis-RA for 28 days increased the 15 min thyroid radioiodine uptake, while the 2 h radioiodide uptake increased only in rats treated with the highest dose of 13-cis-RA. While TPO activity did not change, H(2)O(2) generation was increased in this group, and serum thyroxine levels were normal. Since radioiodine half-life in the thyroid gland is important for treatment efficacy, our results highlight the importance of correctly choosing the RA isomer, the time and the dose of treatment, in order to improve the efficacy of radioiodine therapy.

Radioiodine thyroid remnant ablation in patients with differentiated thyroid carcinoma (DTC): prospective comparison of long-term outcomes of treatment with 30, 60 and 100 mCi

BackgroundThe aim of this study is to compare the effectiveness of 131I therapy between three groups of DTC patients who received 30, 60 or 100 mCi for thyroid remnant ablation after total thyroidectomy and were postoperatively judged with low risk of cancer recurrence.MethodsThe project was designed as a two-stage, prospective randomized clinical trial. In 1998-2001 in a randomized prospective study the early comparison of treatment with 30 mCi vs 60 mCi suggested the lower 131I activity to be less effective, whereas in 2003-2005 the comparison between 60 vs 100 mCi showed no significant differences. The present study comprises the long-term assessment of the disease course in 3 study groups.ResultsA group of 309 DTC patients (285 women and 24 men) with no clinical, histopathological, sonographical or biochemical signs of persistent disease were included after total thyroidectomy and appropriate extent of neck lymph node dissection (265 with papillary and 44 with follicular thyroid cancer). For radioiodine thyroid remnant ablation, 30 mCi of 131I was applied in 86 patients, whereas 60 mCi in 128 and 100 mCi in 95 patients. The median follow-up was 10 years (2-12) for subjects treated with 30 mCi and 60 mCi and 6 years (2-6) for patients treated with 100 mCi of 131I. In the first evaluation, published previously, we observed that because of incomplete thyroid remnant ablation, the second 131I treatment was necessary in 10% patients, without difference between groups treated with 60 and 100 mCi and in 22% patients treated with 30 mCi. All patients entered full remission. To evaluate the long-term outcome of the adjuvant 131I treatment, the course of the follow-up and the most recent disease status were assessed by sonography, radiological examinations and serum Tg estimation (on LT4-suppressive treatment). Within the whole observation period local relapse was stated in 2 (2.4%), 4 (3%) and 3 (3%) patients treated with 131I activities of 30 mCi, 60 mCi and 100 mCi respectively and serum Tg concentration on LT4-suppressive treatment was low, without differences between groups.ConclusionsNo significant differences in the 5 years efficacy of thyroid remnant radioiodine ablation using 30, 60 and 100 mCi were observed in low-risk DTC patients operated by total thyroidectomy and neck lymph node dissection. However, patients treated initially with 30 mCi, required second course of radioiodine in 22%, while this was necessary only in 13,3% and 11,2% of patients treated with 60 mCi and 100 mCi respectively.

Radioiodine Ablation for Differentiated Thyroid Cancer—None, One Dose or Two?

Patients with good prognosis differentiated thyroid cancer are at risk from over-treatment with radioiodine thyroid remnant ablation. Some with unfavourable localised disease might benefit from an elective second dose.

Lithium and thyroid

One in 200 people receive lithium for treatment of bipolar disorder. The common clinical side effects of the drug are goitre in up to 40% and hypothyroidism in about 20%. Lithium increases thyroid autoimmunity if present before therapy. Treatment with levothyroxine is effective and lithium therapy should not be stopped. Lithium may cause hyperthyroidism due to thyroiditis or rarely Graves' disease. As lithium inhibits thyroid hormone release from the thyroid gland it can be used as an adjunct therapy in the management of severe hyperthyroidism. It also increases thyroidal radioiodine retention and may be effective in reducing administered activity in hyperthyroidism. There is no clinical benefit of lithium therapy in thyroid cancer. More research is required on the cellular proliferative effects of lithium as well as its impact on the immune system.

Radioiodine treatment for non-toxic goitre.

There is no ideal treatment for benign multinodular goitre. Besides surgery, which is recommended for large goitres or when malignancy cannot be excluded, the non-surgical treatment options are levothyroxine therapy and radioiodine (131I) therapy. Conventional 131I therapy [without recombinant human thyroid-stimulating hormone (rhTSH)] has been used for more than a decade in symptomatic non-toxic multinodular goitre, and although it does lead to significant thyroid volume reduction, relatively high activities of radioiodine are needed because of a frequent finding of a low thyroid radioiodine uptake. rhTSH, even when used in very small doses in combination with 131I therapy, enhances the thyroid volume reduction at lower 131I activities by doubling the thyroid radioiodine uptake. However, before rhTSH stimulation can be routinely used by clinicians to optimise the 131I therapy in multinodular goitre, aspects of this association, such as the cost-benefit and optimum rhTSH dose and safety, will have to be sufficiently clarified.

Recombinant human TSH and ablation of post-surgical thyroid remnants in differentiated thyroid cancer: the effect of pre-treatment with furosemide and furosemide plus lithium

Recombinant human TSH (rhTSH) can be used for post-surgical radioiodine (I-131) thyroid remnants ablation in differentiated thyroid cancer (DTC) patients after surgery. Debate exists in literature about the optimal amount of I-131 that should be given for obtaining an effective ablation and about the role of iodine pool during treatment. Therefore, the aim of the present study was to assess whether I-131 ablation during rhTSH stimulus can be improved by reducing the circulating iodine pool and by increasing thyroid cell uptake and retention of I-131 obtained by administering furosemide and lithium. A total of 201 consecutive DTC patients were entered in the study: they were treated by total thyroidectomy and I-131 therapy during rhTSH stimulus to ablate thyroid remnants. Patients were divided into two groups according to the TNM stage: group 1 included patients in stage I-II who were treated with a low 30-mCi I-131 dose, while group 2 included patients in stage III-IV who were treated by a high 100-mCi I-131 dose. Moreover, both groups were further subdivided into three subgroups. Subgroup (a) included 45 patients from group 1 and 22 from group 2: they were treated with I-131 under rhTSH stimulus, following a short 4-day withdrawal of L-thyroxine (LT4). Subgroup (b) included 45 patients from group 1 and 22 from group 2: they were treated with I-131 under rhTSH stimulus, following a short 4-day withdrawal of L-T4, and after furosemide administration (25 mg/day orally) during the 3 days before I-131. Subgroup (c) included 45 patients from group 1 and 22 from group 2: they were treated with I-131 under rhTSH stimulus, following a short 4-day L-T4 withdrawal, and after administration of furosemide (25 mg/day orally) during the 3 days prior I-131 and lithium (450 mg/day orally) during the 3 days following I-131. Another group (group 3) of 20 patients characterized by a very low-risk cancer (unifocal tumor <1.0 cm in diameter, without extra-capsular extension, N0) was treated with a 30-mCi I-131 dose under rhTSH stimulus without performing the short 4-day L-4 withdrawal: this group was taken as the control. Follow-up was performed by neck ultrasonography (US), and Tg measurement and I-131 WBS under rhTSH stimulus. Among the patients from group 1, those pre-treated with furosemide or with furosemide plus lithium showed a better outcome of ablation both in terms of undetectable Tg values (97.7% and 95.5 % vs. 79.5%, p < 0.05) and of WBS negativity (97.7% vs. 81.8%, p < 0.05) during the rhTSH stimulus. No similar findings were observed in group 2 patients. Moreover, in patients from group 3 (I-131 30 mCi, without L-T4 withdrawal), the outcome of ablation was significantly lower in comparison to patients from group 1 (I-131 30 mCi, with L-T4 withdrawal) in terms of undetectable Tg during the rhTSH stimulus (55.0%, p < 0.001). rhTSH is highly effective for post-surgical thyroid remnant ablation in low-risk cancer patients using the low 30-mCi dose protocol combined with the short 4-day withdrawal of L-T4. Moreover, in these patients the pre-treatment with furosemide seems to play an important role to further improve the outcome of ablation by reducing the iodine pool.

Chromosome Translocation Frequency after Radioiodine Thyroid Remnant Ablation: A Comparison between Recombinant Human Thyrotropin Stimulation and Prolonged Levothyroxine Withdrawal

Thyroid remnant ablation of differentiated thyroid carcinoma (DTC) patients is traditionally performed after levothyroxine withdrawal. Recombinant human TSH (rhTSH) administration increases serum TSH levels without inducing hypothyroidism. The aim of the study was to investigate the frequency of chromosome translocations in DTC patients after the first (131)I therapeutic dose and compare the frequency of translocations between DTC patients off levothyroxine and those receiving rhTSH. A total of 20 DTC patients were randomly assigned to levothyroxine withdrawal [(30 d) group A; n=10, nine women; mean age 48.5+/- 19.2 yr] or rhTSH injections [(0.9 mg im per 2 consecutive days) group B; n=10, eight women; mean age 50.4+/- 18.8 yr] before undergoing (131)I activity (3.7 GBq). The frequency of translocations in peripheral lymphocytes was analyzed by tricolor fluorescence in situ hybridization with whole-chromosome-specific probes for chromosomes 1, 4, and 8. Lymphocytes were stained routinely (about 500 each time). The two groups showed similar baseline translocation frequency. After (131)I administration, the total chromosomal translocation rate was significantly lower in group B than group A (P = 0.02). The frequency of translocations increased significantly in group A only (P = 0.01 vs. baseline). Rearrangement specifically involved chromosomes 4 and 8 (P = 0.02 vs. baseline). Our preliminary data show that in hypothyroid status (131)I ablation therapy induces a higher translocation rate, especially in chromosomes 4 and 8. This finding, in agreement with previous dosimetric reports, suggests that whereas inducing a low extrathyroid exposure, rhTSH reduces the potential risk of chromosomal aberration associated with blood irradiation.