Modified-release recombinant human TSH (MRrhTSH) augments the effect of (131)I therapy in benign multinodular goiter: results from a multicenter international, randomized, placebo-controlled study.

BACKGROUND: Recombinant human TSH (rhTSH) can be used to enhance (131)I therapy for shrinkage of multinodular goiter (MG). OBJECTIVE, DESIGN, AND SETTING: The objective of the study was to compare the efficacy and safety of 0.01 and 0.03 mg modified-release (MR) rhTSH as an adjuvant to (131)I therapy, vs. (131)I alone, in a randomized, placebo-controlled, international, multicenter study. PATIENTS AND INTERVENTION: Ninety-five patients (57.2 ± 9.6 yr old, 85% females, 83% Caucasians) with MG (median size 96.0, range 31.9-242.2 ml) were randomized to receive placebo (group A, n = 32), MRrhTSH 0.01 mg (group B, n = 30), or MRrhTSH 0.03 mg (group C, n = 33) 24 h before a calculated activity of (131)I. MAIN OUTCOME MEASURES: The primary end point was a change in thyroid volume (by computerized tomography scan, at 6 months). Secondary end points were the smallest cross-sectional area of the trachea; thyroid function tests; Thyroid Quality of Life Questionnaire; electrocardiogram; and hyperthyroid symptom scale. RESULTS: Thyroid volume decreased significantly in all groups. The reduction was comparable in groups A and B (23.1 ± 8.8 and 23.3 ± 16.5%, respectively; P = 0.95). In group C, the reduction (32.9 ± 20.7%) was more pronounced than in groups A (P = 0.03) and B. The smallest cross-sectional area of the trachea increased in all groups: 3.8 ± 2.9% in A, 4.8 ± 3.3% in B, and 10.2 ± 33.2% in C, with no significant difference among the groups. Goiter-related symptoms were effectively reduced and there were no major safety concerns. CONCLUSION: In this dose-selection study, 0.03 mg MRrhTSH was the most efficacious dose as an adjuvant to (131)I therapy of MG. It was well tolerated and significantly augmented the effect of (131)I therapy in the short term. Larger studies with long-term follow-up are warranted.

[Guideline 'Differentiated thyroid carcinoma', including diagnosis of thyroid nodules]. / Richtlijn 'Gedifferentieerd schildkliercarcinoom', inclusief de diagnostiek van de schildkliernodus.

Differentiated thyroid carcinoma is a rare disease. Appropriate diagnosis, treatment and follow-up are complex but greatly influence treatment outcomes and patient quality of life. Patients with differentiated thyroid carcinoma present in many hospitals throughout the Netherlands, underscoring the need for uniformity in diagnosis and treatment. This prompted the Dutch Society of Nuclear Medicine and the Dutch Endocrine Society to develop an evidence-based guideline that emphasises not only new scientific developments but also the organisation of care. Thyroid-stimulating hormone (TSH) assessment and fine needle aspiration cytology play a central role in the diagnostic assessment of a patient with a thyroid nodule. Ablation of residual thyroid tissue with radioiodine (1-131) is recommended for all patients who have undergone total thyroidectomy. Follow-up protocols distinguish between patients with a low risk of thyroid-carcinoma recurrence and those with a non-low risk of recurrence.

Pretreatment with recombinant human TSH changes the regional distribution of radioiodine on thyroid scintigrams of nodular goiters.

In a recent study, we demonstrated that pretreatment with a single, low dose of recombinant human TSH (rhTSH) doubles 24-h thyroid radioactive iodine uptake in patients with nodular goiter. The purpose of the present study was to investigate whether rhTSH pretreatment induces changes in the regional distribution of radioiodine as visualized on thyroid scintigrams in these patients. Anterior planar thyroid 123I scintigrams were obtained in 26 patients with a nodular goiter (23 women and 3 men; age, 62 +/- 9 yr, mean +/- SD; thyroid weight, 165 +/- 72 g) 24 h after administration of a diagnostic dose of radioiodine. All patients were studied twice: first, without rhTSH pretreatment (baseline study), and second, after an im injection of 0.01 mg (n = 10) or 0.03 mg rhTSH (n = 16), given 24 h before radioiodine administration (rhTSH study). For quantification of regional differences in radioiodine uptake, a region of interest method was used. Upon visual inspection, baseline scintigrams showed a heterogeneous uptake of radioiodine. In general, rhTSH scintigrams also showed heterogeneous radioiodine uptake. In some patients, the distribution of radioiodine in the rhTSH scintigram was considerably more homogeneous than in the baseline scintigram. In a few patients, originally "cold" areas had changed into "hot" ones, whereas originally hot areas had changed into cold ones. Quantification of regional radioiodine uptake showed that pretreatment with rhTSH caused a larger increase in radioiodine uptake in relatively cold areas and a smaller increase in radioiodine uptake in relatively hot areas, compared with the increase in radioiodine uptake in the entire thyroid. In patients with a baseline serum TSH level of 0.5 mU/liter or lower, the increase in radioiodine uptake in relatively cold areas was significantly larger than in patients with a baseline serum TSH level higher than 0.5 mU/liter. In conclusion, a single, low dose of rhTSH not only doubled 24-h radioactive iodine uptake but also caused a more homogeneous distribution of radioiodine within the thyroid gland in patients with a nodular goiter by stimulating radioiodine uptake in relatively cold areas more than in relatively hot areas. This was most marked in patients with a low baseline serum TSH level. Our data suggest that pretreatment with rhTSH may improve the efficacy of radioiodine treatment for volume reduction of nodular goiters, especially in patients with a low baseline serum TSH level.

Administration of a single low dose of recombinant human thyrotropin significantly enhances thyroid radioiodide uptake in nontoxic nodular goiter.

Radioiodine (131I) is increasingly used as treatment for volume reduction of nontoxic, nodular goiter. A high dose of 131I is often needed because of low thyroid radioiodide uptake (RAIU). We investigated whether pretreatment with a single, low dose of recombinant human TSH (rhTSH; Thyrogen, Genzyme Transgenics Corp.) enhances RAIU in 15 patients with nontoxic, nodular goiter (14 women and 1 man; aged 61+/-11 yr). Four patients were studied twice, and 1 patient was studied 3 times. RAIU was measured both under basal conditions and after pretreatment (im) with rhTSH, given either 2 h (0.01 mg; n = 7) or 24 h [0.01 mg (n = 7) or 0.03 mg (n = 7)] before 131I administration (20-40 microCi). Serum levels of TSH, free T4 (FT4), and total T3 were measured at 2, 5, 8, 24, 48, 72, 96, and 192 h after rhTSH administration. After administration of 0.01 mg rhTSH, serum TSH rose from 0.7+/-0.5 to a peaklevel of 4.4+/-1.1 mU/L (P < 0.0001), FT4 rose from 16.0+/-2.6 to 18.5+/-3.7 pmol/L (P < 0.0001), and T3 rose from 2.10+/-0.41 to 2.63 - 0.66 nmol/L (P < 0.0001). After administration of 0.03 mg rhTSH, TSH rose from 0.6+/-0.4 to 15.8+/-2.3 mU/L (P < 0.0001), FT4 rose from 15.2+/-1.5 to 21.7+/-2.9 pmol/L (P < 0.0001), and T3 rose from 1.90+/-0.43 to 3.19+/-0.61 nmol/L (P < 0.0001). Peak TSH levels were reached at 5-8 h and peak FT4 and T3 levels at 8-96 h after rhTSH administration. Administration of 0.01 mg rhTSH 2 h before 131I increased 24-h RAIU from 30+/-11% to 42+/-10% (P < 0.02), 0.01 mg rhTSH administered 24 h before 131I increased 24-h RAIU from 29+/-10% to 51+/-10% (P < 0.0001), and 0.03 mg rhTSH administered 24 h before 131I increased 24-h RAIU from 33+/-11% to 63+/-9% (P < 0.0001). After administration of 0.01 mg rhTSH 2 h before 131I, 24-h RAIU did not increase in 1 patient, whereas the increase in 24-h RAIU was less than 10% in 2 other patients. In contrast, administration of rhTSH 24 h before 131I increased 24-h RAIU by more than 10% in all 14 patients (by >20% in 10 and by >30% in 6). In conclusion, pretreatment with a single, low dose of rhTSH in patients with nontoxic, nodular goiter increased RAIU considerably. Our observations hold promise that administration of rhTSH before 131I therapy for nontoxic, nodular goiter will allow treatment with lower doses of 131I in these patients.

[Diagnosis and therapy of patients with euthyroid goiter]. / Diagnostiek en therapie bij patiënten met euthyreotisch struma.

Nontoxic goitre is common, even in areas where iodine intake is sufficient. The most important symptoms and signs of nontoxic goitre are caused by compression of vital structures in the neck or upper thoracic cavity. In any patient with goitre the serum concentration of thyroid-stimulating hormone (TSH) should be measured to detect or exclude clinically inapparent (subclinical) hyper- or hypothyroidism. CT and MRI are expensive but very sensitive methods to identify tracheal compression and to determine intrathoracic extension. Thyroid ultrasonography and scintigraphy are not routinely indicated. Fine-needle aspiration biopsy is indicated in patients with fast-growing nodules and nodules that have a firmer consistency than other nodules within the gland. Thyroidectomy is standard therapy for young and otherwise healthy patients, especially when prompt decompression of vital structures is required. Radioiodine therapy is an attractive alternative to surgery in older patients, in those with cardiopulmonary disease, and in those with recurrent goitre. Thyroxin therapy may be tried in young patients with small, diffuse goitres who have normal serum TSH concentrations.

Evaluation of surgical gamma probes for radioguided sentinel node localisation.

By using a surgical gamma probe after peritumoral injection of a radioactive tracer, the surgeon can identify the sentinel, or first, nodal site of regional metastasis in clinically node-negative patients. In the near future, the pathological status of this node will have an important impact on the treatment strategy in breast cancer and melanoma patients. This article reviews the necessary requirements for the instrument, such as: absolute sensitivity, spectral resolution, angular sensitivity and response ratio to the radioactive source at depth. In addition, ergonomic characteristics are important. The surgeon must consider the above characteristics, as they influence operational handling. Four commercially available surgical gamma probes were subjected to laboratory tests to appraise the extent to which they fulfilled these criteria. The results for each gamma probe are summarised and discussed.<

Radioiodine for nontoxic multinodular goiter.

Surgery is considered standard therapy for nontoxic goiter. However, surgical treatment of large goiters is not without risk, especially in elderly patients and in those with cardiopulmonary diseases. Therefore, in recent years interest in 131I treatment of nontoxic goiter has increased. Studies, using ultrasonography and magnetic resonance imaging (MRI) for accurate measurements of thyroid volume, have shown that 131I treatment of nontoxic nodular goiter results in a mean thyroid volume reduction of 40% after 1 year of 50-60% after 3-5 years. Moreover, an improvement of compressive symptoms can be achieved. This has been objectified by a significant decrease in tracheal compression as measured by MRI. Early side effects due to radiation thyroiditis usually are mild. The development of autoimmune hyperthyroidism occurring several months after 131I therapy in approximately 5% of patients is the most important complication of 131I therapy for nontoxic goiter. The incidence of post-treatment hypothyroidism appears to be approximately 20-30% at 5 years. For elderly people, the lifetime risk of fatal and nonfatal cancer induced by this therapy (administered activity 1.9 +/- 0.9 GBq of 131I) was estimated to be approximately 0.5%. In all patients with nontoxic multinodular goiter the estimated risks of both surgery and radioiodine therapy should be weighed carefully. In younger patients surgery still is to be preferred, especially when the amount of 131I to be administered is high. However, for elderly patients, especially those with cardiopulmonary disease, the profits of radioiodine treatment will outweigh the lifetime risk of this mode of therapy.

Dosimetry and risk estimates of radioiodine therapy for large, multinodular goiters.

UNLABELLED: In patients with a large, multinodular goiter (> 100 g), radiation absorbed doses in the thyroid, surrounding tissues and remainder of the body were estimated after therapeutic administration of 131I(3.7 MBq or 100 microCi/g of thyroid tissue retained at 24 hr). METHODS: Thermoluminescent dosimeter (TLD) measurements were performed on 23 patients (12 euthyroid and 1I hyperthyroid; thyroid weight 222 +/- 72 g; 2.1 +/- 0.9 GBq 131I) on the skin over the thyroid, over the submandibular gland and over the parotid gland. Thyroid radioactivity measurements were done daily in 6 euthyroid and 6 hyperthyroid patients (thyroid weight 204 +/- 69 g; 1.9 +/- 0.9 GBq 131I). An iodine biokinetic model and the MIRD methodology were used to estimate absorbed doses in organs. Cancer risks were calculated using ICRP Publication 60. RESULTS: Cumulated absorbed doses on the skin (TLD measurements) were 4.2 +/- 1.4 Gy (thyroid), 1.2 +/- 0.6 Gy (submandibular) and 0.4 +/- 0.2 Gy (parotid). All these values were significantly correlated with the amount of radioiodine retained in the thyroid at 24 hr (euthyroid versus hyperthyroid not significant). Absorbed doses in the thyroid of 94 +/- 25 Gy for euthyroid and 93 +/- 17 Gy for hyperthyroid patients were calculated (thyroid radioactivity measurements). Extrathyroidal absorbed doses (means of 12 patients) were 0.88 Gy in the urinary bladder, 0.57 Gy in the small intestine, 0.38 Gy in the stomach, and ranged from 0.05 to 0.30 Gy in other organs (euthyroid versus hyperthyroid not significant). A 1.6% life-time risk of development of cancer outside the thyroid gland was calculated. When applied to people of 65 yr and older the estimated risk is approximately 0.5%. CONCLUSION: These data may help in choosing the treatment regimen for individual patients with a large, multinodular goiter, who have to be treated for hyperthyroidism or compressive problems. In younger patients, surgery may be preferred. However, for elderly patients and patients with cardiopulmonary disease, the advantages of noninvasive radioiodine treatment will outweight the life-time risk of this mode of therapy.

Mortality, reinfarction, left ventricular ejection fraction and costs following reperfusion therapies for acute myocardial infarction.

The comparative efficacy of thrombolytic drugs and primary angioplasty for acute myocardial infarction have recently been studied, but long-term follow-up data have not yet been reported. We conducted a randomized trial involving 301 patients with acute myocardial infarction; 152 patients were randomized to primary angioplasty and 149 to intravenous streptokinase. Left ventricular function was assessed with a radionuclide technique both at hospital discharge and at the end of the follow-up period. Follow-up data were collected after a mean (+/-SD) of 31 +/- 9 months. Total medical costs were calculated. At the end of the follow-up period, 5% of the angioplasty patients had died from a cardiac cause compared to 11% of the patients randomized to intravenous streptokinase, P = 0.031. Cardiac death or a non-fatal reinfarction occurred in 7% of angioplasty patients compared to 28% of streptokinase patients, P < 0.001. There was a sustained benefit of angioplasty compared to streptokinase on left ventricular function. The total medical costs in the two groups were similar. Coronary anatomy (patency and single or multivessel disease), infarct location and previous myocardial infarction were important determinants of clinical outcome and costs. After 31 +/- 9 months of follow-up, primary angioplasty compared to intravenous streptokinase results in a lower rate of cardiac death and reinfarction, a better left ventricular ejection fraction, and no increase in total medical costs.

Bone mineral density and bone turnover before and after surgical cure of Cushing's syndrome.

We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry in 20 patients with Cushing's syndrome (CS) (14 pre- and 2 postmenopausal women, 4 men) before and in 18 of them also at regular intervals after surgical cure (median duration of follow-up, 36 months). In addition, in the premenopausal women with CS, fasting blood samples and 2-h fasting urine samples for measurement of biochemical parameters of bone and collagen metabolism were collected before and in 9 of them also at regular intervals during the first 2 yr after surgery. Marked osteopenia was present in most patients with active CS (Z-scores: lumbar spine -1.45 +/- 1.44 and femoral neck -1.50 +/- 1.02; mean +/- SD). No consistent change in BMD was observed at 3 and 6 months after surgery. Thereafter BMD increased considerably in almost all patients. For the 15 patients with a follow-up of at least 1 yr, Z-scores at the last evaluation were -0.65 +/- 1.27 for the lumbar spine and -0.98 +/- 1.02 for the femoral neck (both P < 0.002 compared with pretreatment values). In the premenopausal patients, the increase in BMD both in the lumbar spine and in the femoral neck at 24 months was inversely correlated with age (r = -0.733, P < 0.03, and r = -0.667, P < 0.05, respectively). Serum levels of osteocalcin, bone alkaline phosphatase, carboxyterminal propeptide of type I procollagen, aminoterminal propeptide of type III procollagen, and the cross-linked telopeptide of type I collagen were not significantly different between the group of 14 premenopausal patients with active CS and a control group of 18 age-matched healthy premenopausal women. However, the urinary hydroxyproline/creatinine ratio was significantly higher in patients with CS (24.6 +/- 9.6 vs. 16.2 +/- 3.5 mumol/mmol, P < 0.01). In all 9 premenopausal patients, serum levels of osteocalcin increased considerably between 0 and 3 months (from 1.04 +/- 0.20 to 3.82 +/- 0.30 nmol/L) (mean +/- SEM, P < 0.0001), indicating a prompt increase of osteoblast activity. Also serum levels of carboxyterminal propeptide of type I procollagen, aminoterminal propeptide of type III procollagen, and cross-linked telopeptide of type I collagen, and the urinary hydroxyproline/creatinine ratio increased significantly between 0 and 3 months. Thereafter these levels decreased gradually. We conclude that marked osteopenia in the lumbar spine and femoral neck is present in most patients with active Cushing's syndrome.(ABSTRACT TRUNCATED AT 400 WORDS)

Large, compressive goiters treated with radioiodine.

OBJECTIVE: To evaluate the effectiveness of radioiodine therapy as an alternative for surgery in elderly patients with a large, compressive goiter using objective methods for measuring thyroid volume and tracheal compression. DESIGN: Prospective study. SETTING: University hospital in the Netherlands. PATIENTS: 19 patients (mean age +/- SD, 66 +/- 14 years) with a large, compressive multinodular goiter who had a high operative risk or refused to have thyroid surgery. INTERVENTION: A single intravenous dose of 131I at 2.6 +/- 1.0 GBq (70 +/- 28 mCi) (3.7 MBq or 100 microCi/g of thyroid tissue), followed by daily administration of L-thyroxine in doses that did not suppress thyroid-stimulating hormone. MEASUREMENTS: Clinical evaluation and measurements of thyroid volume, maximal tracheal deviation, and the smallest cross-sectional area of the tracheal lumen with magnetic resonance imaging before and 1 year after 131I treatment. RESULTS: No exacerbation of compressive symptoms after 131I therapy was observed. Thyroid volume was 269 +/- 153 mL before treatment and 154 +/- 73 mL 1 year after treatment (P < 0.001). Thyroid volume was reduced 40% +/- 15% (range, 19% to 68%). Maximal tracheal deviation (1.9 +/- 0.8 cm before and 1.5 +/- 0.7 cm 1 year after therapy) had decreased by 20% +/- 20% (range, -4% to 73%; P < 0.001), and the smallest cross-sectional area of tracheal lumen (0.78 +/- 0.38 cm2 before and 1.04 +/- 0.48 cm2 1 year after therapy) had increased by 36% +/- 38% (range, -3% to 125%; P < 0.001). Clinical signs and symptoms improved in 8 of 12 patients with dyspnea and inspiratory stridor and in both patients with compression of the superior vena cava. CONCLUSIONS: Therapy with 131I is an effective alternative to surgery for elderly patients with a large, compressive multinodular goiter.

Magnetic resonance imaging for volume estimation of large multinodular goitres: a comparison with scintigraphy.

As a result of increasing interest in non-surgical treatment for the reduction of goitre size the use of magnetic resonance (MR) imaging for volume estimation of large multinodular goitres was evaluated in 20 patients (three males and 17 females; age 61 +/- 21 years) with a multinodular goitre larger than 100 ml. In addition, MR measurements were compared with scintigraphic (SC) volume estimations. Intraobserver coefficient of variation (CV) of MR measurements was 2.2 +/- 2.0% (Observer 1) and interobserver CV 4.1 +/- 2.2% (Observers 1 and 2). In all 20 patients signs of mechanical complications were shown on MR images. For SC measurements intraobserver CV was 7.5 +/- 5.7% (Observer 3) and 5.4 +/- 5.1% (Observer 4). Interobserver CV was 10.1 +/- 6.1%. The correlation between measurements with both methods was not strong (r = 0.665) and the resulting CV was 17.3 +/- 14.2%. Underestimation of SC volumes could not be explained by the presence of cysts on the surface of the thyroid. It is concluded that MR imaging can be used for in vivo thyroid volume estimation in large multinodular goitres. The high precision of MR measurements makes this technique potentially useful for the evaluation of thyroid growth and non-surgical treatment for reducing goitre size. Scintigraphic volume measurements do not suffice for this purpose. An additional advantage of MR imaging is the detailed anatomical information it provides with regard to mechanical complications of large goitres.

Long-term results of two schedules of radioiodine treatment for toxic multinodular goitre.

The long-term effects of two schedules of radioiodine therapy in patients with toxic multinodular goitre were evaluated. Forty-five patients (group A) were treated with low doses and 58 patients (group B) with calculated doses adjusted for thyroid weight (1.85-3.70 MBq/g) and radioactive iodine uptake. Follow-up (mean +/- SEM) was 4.3 +/- 0.2 years and 5.2 +/- 0.3 years, respectively (P > 0.1). At the end of follow-up, hyperthyroidism was successfully reversed in 73% (group A) and 88% (group B). In each group, hypothyroidism was present in 7%. The total dose per gram of thyroid tissue was not significantly different in groups A and B (2.1 +/- 0.2 vs 2.7 +/- 0.2 MBq/g). However, for patients treated with calculated doses the number of 131I administrations was significantly lower (1.3 +/- 0.1) than for patients treated with low doses (2.2 +/- 0.2), and the percentage of patients who were adequately treated with a single dose was more than twice as high (66% in group B versus 27% in group A). Euthyroidism was reached within a significantly shorter time after treatment with calculated doses (median time 0.6 years in group B vs 1.5 years in group A; life table analysis). It is concluded that radioiodine is an effective treatment for toxic multinodular goitre with a low risk of post-treatment hypothyroidism and that calculated (higher) doses appear to be preferable to low doses.

Long-term follow-up in toxic solitary autonomous thyroid nodules treated with radioactive iodine.

The long-term effects of radioiodine treatment on thyroid function in patients with a toxic solitary autonomous thyroid nodule were evaluated. Fifty-two patients received a therapeutic dose of 20 mCi of iodine-131 (131I). Duration of follow-up was 10 +/- 4 yr. Follow-up data included a biochemical evaluation of thyroid function. The failure rate (recurrent hyperthyroidism) was 2%. The incidence of hypothyroidism was 6% and was not related to the dose per gram of nodular tissue. Oral administration of 20 mCi of radioiodine is a simple and highly effective method for the treatment of patients with a toxic autonomous thyroid nodule. The risk of development of hypothyroidism is low if extranodular uptake of 131I is prevented. This can be achieved by not treating euthyroid patients, by no longer using injections of exogenous thyroid stimulating hormone in the diagnostic work-up of the patients and by always performing radioiodine imaging shortly before treatment.

Thallium-201 scintigraphy of the suppressed thyroid: an alternative for iodine-123 scanning after TSH stimulation.

Thallium-201 scintigraphy of the thyroid gland suppressed by autonomous nodule was compared with 123I scintigraphy after TSH stimulation. In all patients, similar images were obtained by both methods. In 20 patients, the contralateral lobe was visualized on both scans and in 14 of these, the upper pole of the ipsilateral lobe was also visualized. In one patient, neither 123I scanning after TSH nor 201TI scintigraphy showed any extranodular tissue. This study suggests that 201TI scintigraphy is a reliable alternative for scanning after TSH. It is a relatively simple method, not inducing any TSH-related allergic reactions. Iodine uptake in extranodular tissue is not stimulated and therefore, 201TI scintigraphy and radioiodine therapy can be combined on one day, without increasing the risk of radiation damage to the normal thyroid tissue with a resultant post-treatment hypothyroidism.