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.

Preparation with recombinant humanized thyroid-stimulating hormone before radioiodine ablation after thyroidectomy: a systematic review.

BACKGROUND: Standard treatment for differentiated thyroid cancer is thyroidectomy followed in selected cases by radioiodine ablation (RA). Recombinant humanized thyroid-stimulating hormone (rhTSH) is an exogenous source of tsh that can be administered to obviate the need for hormone withdrawal. In this systematic review, we analysed the evidence for the therapeutic use of (rhTSH for RA preparation. METHOD: A systematic review of the MEDLINE and EMBASE databases from 1996 through January 2008 selected articles reporting randomized controlled trials, cohort studies, and retrospective studies published in English that compared ra using rhTSH with standard hormone withdrawal. RESULTS AND INTERPRETATION: Stimulation by rhTSH is equivalent to thyroid hormone withdrawal in achieving ablation while avoiding detrimental symptoms of hypothyroidism and significantly lowering the whole-body radiation dose. Furthermore, rhTSH may be the only option for patients who either cannot raise endogenous tsh or who would be at risk from the morbidity of hypothyroidism. Based on the results of validated instruments of physical and mental performance, there is agreement that rhTSH maintains a better quality of life. Studies of cost-effectiveness found that rhTSH-prepared patients lost less time from work and required fewer encounters with health care providers.

Follow-up of low-risk differentiated thyroid cancer patients who underwent radioiodine ablation of postsurgical thyroid remnants after either recombinant human thyrotropin or thyroid hormone withdrawal.

BACKGROUND: We previously demonstrated comparable thyroid remnant ablation rates in postoperative low-risk thyroid cancer patients prepared for administration of 3.7GBq (131)I (100 mCi) after recombinant human (rh) TSH during T(4) (L-T4) therapy vs. withholding L-T4 (euthyroid vs. hypothyroid groups). We now compared the outcomes of these patients 3.7 yr later. PATIENTS AND METHODS: Fifty-one of the 63 original patients (28 euthyroid, 23 hypothyroid) participated. Forty-eight received rhTSH and serum thyroglobulin (Tg) sampling. A (131)I whole-body scan was performed in 43 patients, and successful ablation was defined by criteria from the previous study. Based on the criterion of uptake less than 0.1% in thyroid bed, 100% (43 of 43) remained ablated. When no visible uptake instead was used, five patients (four euthyroid, one hypothyroid) had minimal visible activity. When the TSH-stimulated Tg criterion was used, only two of 45 (one euthyroid, one hypothyroid) had a stimulated Tg level greater than 2 ng/ml. RESULTS: No patient in either group died, and no patient declared disease free had sustained tumor recurrence. Nine (four euthyroid, five hypothyroid) had received additional (131)I between the original and current studies due to detectable Tg or imaging evidence of disease; with follow-up, all now had a negative rhTSH-stimulated whole-body scan and seven (three euthyroid, four hypothyroid) had a stimulated serum Tg less than 2 ng/ml. CONCLUSIONS: In conclusion, after a median 3.7 yr, low-risk thyroid cancer patients prepared for postoperative remnant ablation either with rhTSH or after L-T4 withdrawal were confirmed to have had their thyroid remnants ablated and to have comparable rates of tumor recurrence and persistence.

Accuracy of quantitative reconstructions in SPECT/CT imaging.

The goal of this study was to determine the quantitative accuracy of our OSEM-APDI reconstruction method based on SPECT/CT imaging for Tc-99m, In-111, I-123, and I-131 isotopes. Phantom studies were performed on a SPECT/low-dose multislice CT system (Infinia-Hawkeye-4 slice, GE Healthcare) using clinical acquisition protocols. Two radioactive sources were centrally and peripherally placed inside an anthropometric Thorax phantom filled with non-radioactive water. Corrections for attenuation, scatter, collimator blurring and collimator septal penetration were applied and their contribution to the overall accuracy of the reconstruction was evaluated. Reconstruction with the most comprehensive set of corrections resulted in activity estimation with error levels of 3-5% for all the isotopes.

Does preoperative positron emission tomography with computed tomography predict nodal status in endometrial cancer? A pilot study.

Fewer than 20% of women with endometrial cancer have positive nodes, and an accurate noninvasive imaging modality to assess lymph node status would be helpful in selecting those who need lymphadenectomy. The objective of this pilot study was to evaluate positron emission tomography with computed tomography (pet-ct) in predicting nodal status before surgery for endometrial cancer. Twelve patients were enrolled at a single tertiary care centre. The sensitivity and specificity of preoperative pet-ct in predicting nodal status were 53.3% and 99.6% respectively. Using pet-ct, all metastatic nodes may not necessarily be detected, especially nodes with microscopic disease. The sensitivity of this imaging modality has to be improved before it can routinely be used in the preoperative evaluation of endometrial cancer.

A pragmatic protocol for I-131 rhTSH-stimulated ablation therapy in patients with renal failure.

PURPOSE: Ablation of thyroid remnants in patients with differentiated thyroid carcinoma and renal failure can be challenging because of the altered and variable clearance rates of iodine from the blood secondary to variations in dialysis protocols, which complicate the selection of the appropriate I-131 dose. The advent of recombinant human TSH allows a simpler approach to dosimetry and ablation without rendering the patient hypothyroid. Avoidance of hypothyroidism may be an important consideration for patients who are experiencing various morbidities from conditions associated with renal failure. METHOD: Three patients on dialysis, who had undergone total thyroidectomy and were euthyroid on L-thyroxine replacement, were given diagnostic doses of I-131 followed by blood and whole-body retention measurements through serial dialyses to determine individual blood clearance rates. After administration of rhTSH, each patient received an ablative dose of I-131 calculated to keep total body dose below 1 Gy. RESULTS: The treatments were administered without complications, and in follow-up imaging of 2 available patients, the ablations were demonstrated to be complete. CONCLUSION: Dosimetry performed on euthyroid dialysis patients permits I-131 dose selection and avoids the additional morbidity of hypothyroidism.

Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study.

CONTEXT: After surgery for differentiated thyroid carcinoma, many patients are treated with radioiodine to ablate remnant thyroid tissue. This procedure has been performed with the patient in the hypothyroid state to promote endogenous TSH stimulation and is often associated with hypothyroid symptoms and impaired quality of life. OBJECTIVE AND INTERVENTION: This international, randomized, controlled, multicenter trial aimed to compare the efficacy and safety of recombinant human TSH (rhTSH) to prepare euthyroid patients on L-thyroxine therapy (euthyroid group) to ablate remnant thyroid tissue with 3.7 GBq (100 mCi) 131I, compared with that with conventional remnant ablation performed in the hypothyroid state (hypothyroid group). Quality of life was determined at the time of randomization and ablation. After the administration of the 131-I dose, the rate of radiation clearance from blood, thyroid remnant, and whole body was measured. RESULTS: The predefined primary criterion for successful ablation was "no visible uptake in the thyroid bed, or if visible, fractional uptake less than 0.1%" on neck scans performed 8 months after therapy and was satisfied in 100% of patients in both groups. A secondary criterion for ablation, an rhTSH-stimulated serum thyroglobulin concentration less than 2 ng/ml, was fulfilled by 23 of 24 (96%) euthyroid patients and 18 of 21 (86%) hypothyroid patients (P = 0.2341). Quality of life was well preserved in the euthyroid group, compared with the hypothyroid group, as demonstrated by their lower pretreatment scores on the Billewicz scale for hypothyroid signs and symptoms, 27 +/- 7 vs. 18 +/- 4 (P < 0.0001) and their significantly higher Short Form-36 Health Assessment Scale scores in five of eight categories. Euthyroid patients had a statistically significant one third lower radiation dose to the blood, compared with patients in the hypothyroid group. CONCLUSIONS: This study demonstrates comparable remnant ablation rates in patients prepared for 131I remnant ablation with 3.7 GBq by either administering rhTSH or withholding thyroid hormone. rhTSH-prepared patients maintained a higher quality of life and received less radiation exposure to the blood.

A case of bronchopulmonary carcinoid tumor: the role of octreotide scanning in localization of an ectopic source of ACTH.

BACKGROUND: Bronchopulmonary carcinoids are neuroendocrine tumors. They can present with Cushing's syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) secretion. Curative resection is possible only after adequate localization of the ectopic source. OBJECTIVE: To describe a case that illustrates the role of octreotide scanning in the management of a bronchopulmonary carcinoid. RESULTS: The use of preoperative and postoperative octreotide scanning aided in performing a limited resection, thereby preserving the lung parenchyma. CONCLUSIONS: We propose that octreotide scanning can be a very important and informative test in the management of carcinoid tumors. In situations when conventional imaging is not conclusive, octreotide scanning may be of help in determining the source of ectopic ACTH syndrome.

Two cases of thyroid carcinoma that were not stimulated by recombinant human thyrotropin.

Recombinant human TSH (rhTSH) is being widely used to monitor patients who were previously treated for differentiated thyroid cancers for evidence of recurrence. Its value lies in the avoidance of recurrent episodes of hypothyroidism in the follow-up protocols. rhTSH is also being evaluated as a potential therapeutic adjunct that would spare patients the experience of becoming hypothyroid when undergoing thyroid remnant ablation or treatment for metastases. In some centers, rhTSH is also used to support compassionate care of patients with advanced disease who cannot safely become hypothyroid. The (131)I uptake response to rhTSH, presently an off-label application, is expected to be similar to that of endogenously raised TSH levels. The two cases presented here are cautionary tales in which (131)I uptake by metastases was present under hypothyroid conditions, but absent in one patient and present in only a portion of the lesions in the other, with rhTSH stimulation.

Inactivation of Bacillus subtilis spores and formation of bromate during ozonation.

Inactivation of B. subtilis spores with ozone was investigated to assess the effect of pH and temperature, to compare the kinetics to those for the inactivation of C. parvum oocysts, to investigate bromate formation under 2-log inactivation conditions, and to assess the need for bromate control strategies. The rate of B. subtilis inactivation with ozone was independent of pH, decreased with temperature (activation energy of 42,100 Jmol(-1)), and was consistent with the CT concept. B. subtilis was found to be a good indicator for C. parvum at 20-30 degrees C, but at lower temperatures B. subtilis was inactivated more readily than C. parvum. Bromate formation increased as both pH and temperature increased. For water with an initial bromide concentration of 33 microgl(-1), achieving 2-logs of inactivation, without exceeding the 100 microg l(-1) bromate standard, was most difficult at 30 degrees C for B. subtilis and at midrange temperatures (10-20 degrees C) for C. partum. pH depression and ammonia addition were found to reduce bromate formation without affecting B. subtilis inactivation, and may be necessary for waters containing more than 50 microgl(-1) bromide.

Inactivation of Cryptosporidium parvum oocysts with sequential application of ozone and combined chlorine.

Single-step inactivation experiments with ozone and monochloramine revealed the presence of a CT lag followed by pseudo-first order inactivation kinetics. Sequential disinfection experiments with ozone followed by monochloramine revealed that ozone pretreatment resulted in the removal of a more prominent CT lag observed for monochloramine. In addition, the rate of inactivation for ozone-pretreated oocysts was approximately 2.5x greater than that observed for the post-lag phase portion of the monochloramine primary inactivation curve.

By-products formation during drinking water disinfection: a tool to assess disinfection efficiency?

In drinking water treatment, the inactivation of microorganisms increases with increasing disinfectant exposure (product of concentration and contact time, CT). Also, the formation of undesired (toxic) disinfection by-products increases with CT. The present study proposes a new concept that uses this undesired side effect of chemical water disinfection for a fast and reliable test of treatment efficiency. In laboratory systems, bromate formation during ozonation and the formation of trihalomethanes during chlorination were used to calculate the disinfectant exposure, which is a measure for the achieved degree of disinfection.

Inactivation of Cryptosporidium parvum oocysts with ozone and monochloramine at low temperature.

The rate of Cryptosporidium parvum inactivation decreased with decreasing temperature (1-20 degrees C) for ozone and for monochloramine applied alone as well as after pre-treatment with ozone. Synergy was observed at all temperatures studied for the ozone/monochloramine sequential disinfection scheme. The synergistic effect was found to increase with decreasing temperature. The inactivation rate with monochloramine after ozone pre-treatment was 5 times faster at 20 degrees C and 22 times faster at 1 degree C than the corresponding post-lag phase rates of inactivation with monochloramine at these temperatures when no ozone pre-treatment was applied. The CT required for achieving 2-logs of inactivation ranged from 11,400 mg min l-1 at 20 degrees C to 64,600 mg min l-1 at 1 degree C when monochloramine was applied alone. In contrast, the CT required for an overall sequential inactivation of 2-logs ranged from 721 mg min l-1 at 20 degrees C to 1350 mg min l-1 at 1 degree C when applying monochloramine after ozone pre-treatment. The presence of excess ammonia in the monochloramine solutions was not responsible for the synergy observed in ozone/monochloramine sequential disinfection.

FDG PET of recurrent or metastatic 131I-negative papillary thyroid carcinoma.

UNLABELLED: This study reports on the use of FDG PET in the follow-up of papillary thyroid cancer patients with negative findings on 131I total body scans and elevated levels of thyroglobulin after total thyroidectomy. METHODS: Eleven asymptomatic patients with previous papillary thyroid cancer, total thyroidectomy, 131I ablation, and treatment of all known metastases had negative findings on 131I total body scans after therapy but persisting elevations of thyroglobulin when not receiving thyroid hormone. All imaging before PET failed to show persisting tumor. FDG PET was performed on all patients while receiving full thyroid hormone replacement, except for the repeated scan of 1 patient (patient 6). After the PET scan, all patients were referred for supplementary CT, sonography, or biopsy of lesions in the neck. RESULTS: All 11 patients showed FDG uptake in the neck or upper mediastinum-in the initial scan in 10 and in a repeated scan in 1. Sonographically guided biopsy confirmed malignancy in 6, was nondiagnostic in 2, and showed normal findings in 1. In 2 patients, the sonographic results were normal and no biopsy was attempted. FDG imaging redirected the treatment of 7 patients, resulting in surgery and external beam radiotherapy in 3, surgery in 1, and external beam radiotherapy in 2. One patient declined further recommended surgery. The other 4 patients remain under observation. Surgical histopathology confirmed thyroid tumor in all 4 surgically treated patients. Retrospective review of the original histopathology slides showed no preponderance of aggressive histology. CONCLUSION: FDG PET is able to guide further evaluation of thyroid cancer patients who have elevated thyroglobulin levels and normal findings on 131I whole-body scanning.

Review of the toxicologic properties of medium-chain triglycerides.

Medium chain triglycerides (MCTs) are a family of triglycerides, containing predominantly, caprylic (C(8)) and capric (C(10)) fatty acids with lesser amounts of caproic (C(6)) and lauric (C(12)) fatty acids. MCTs are widely used for parenteral nutrition in individuals requiring supplemental nutrition and are being more widely used in foods, drugs and cosmetics. MCTs are essentially non-toxic in acute toxicity tests conducted in several species of animals. In ocular and dermal irritation testing MCTs exhibit virtually no potential as ocular or dermal irritants, even with prolonged eye or skin exposure. MCTs exhibit no capacity for induction of hypersensitivity. Ninety-day toxicity tests did not result in notable toxicity, whether the product was administered in the diet up to 9375mg/kg body weight/day or by intramuscular (im) injection (up to 0. 5ml/kg/day, rabbits). There was no evidence that intravenous (iv) or dietary administration of MCTs adversely affected the reproductive performance of rats or resulted in maternal toxicity, foetal toxicity or teratogenic effects at doses up to 4.28g/kg body weight/day (iv) or 12,500mg/kg body weight/day (dietary). There was no evidence that dietary administration of MCTs adversely affected the reproductive performance of pigs or resulted in maternal toxicity, foetal toxicity or teratogenic effects at doses up to 4000mg/kg body weight/day in the diet. In rabbits, following iv administration, the maternal and foetal no-observed-adverse-effect levels (NOAELs) were between 1.0 and 4.28g/kg body weight/ day. A 2-year study in rats, conducted with a closely related compound (tricaprylin, a triglyceride with C(8) fatty acids), provided no evidence of a carcinogenic effect when the material was administered by oral gavage at levels up to 10ml/kg (9.54g/kg) per day. Although tricaprylin was found to be positive in one of five strains of Salmonella typhimurium in the presence of metabolic activation in an Ames mutagenicity assay, the results of the carcinogenicity test with tricaprylin and mutagenicity tests with caprylic acid indicate that MCTs do not have the potential to be carcinogenic or mutagenic. The safety of human dietary consumption of MCTs, up to levels of 1g/kg, has been confirmed in several clinical trials.

Java-based remote viewing and processing of nuclear medicine images: toward "the imaging department without walls".

UNLABELLED: In nuclear medicine practice, images often need to be reviewed and reports prepared from locations outside the department, usually in the form of hard copy. Although hard-copy images are simple and portable, they do not offer electronic data search and image manipulation capabilities. On the other hand, picture archiving and communication systems or dedicated workstations cannot be easily deployed at numerous locations. To solve this problem, we propose a Java-based remote viewing station (JaRViS) for the reading and reporting of nuclear medicine images using Internet browser technology. METHODS: JaRViS interfaces to the clinical patient database of a nuclear medicine workstation. All JaRViS software resides on a nuclear medicine department server. The contents of the clinical database can be searched by a browser interface after providing a password. Compressed images with the Java applet and color lookup tables are downloaded on the client side. This paradigm does not require nuclear medicine software to reside on remote computers, which simplifies support and deployment of such a system. To enable versatile reporting of the images, color tables and thresholds can be interactively manipulated and images can be displayed in a variety of layouts. Image filtering, frame grouping (adding frames), and movie display are available. Tomographic mode displays are supported, including gated SPECT. RESULTS: The time to display 14 lung perfusion images in 128 x 128 matrix together with the Java applet and color lookup tables over a V.90 modem is <1 min. SPECT and PET slice reorientation is interactive (<1 s). JaRViS could run on a Windows 95/98/NT or a Macintosh platform with Netscape Communicator or Microsoft Intemet Explorer. The performance of Java code for bilinear interpolation, cine display, and filtering approaches that of a standard imaging workstation. CONCLUSION: It is feasible to set up a remote nuclear medicine viewing station using Java and an Internet or intranet browser. Images can be made easily and cost-effectively available to referring physicians and ambulatory clinics within and outside of the hospital, providing a convenient alternative to film media. We also find this system useful in home reporting of emergency procedures such as lung ventilation-perfusion scans or dynamic studies.

Radiation safety when a patient dies after therapy.

OBJECTIVE: When a patient dies a short time after radionuclide therapy, several issues arise due to the shifting of responsibility from patient care to protection of the public, while respecting societal values and rites. Such a situation occurred in our institution after administering a large therapeutic dose of 131I for metastatic thyroid cancer. The requirements of safe practice, the shift accountability, the ethical aspects and forthcoming changes in the regulatory constraints are discussed.

Early detection of cancer cachexia in the rat using 31P magnetic resonance spectroscopy of the liver and a fructose stress test.

The dynamic metabolic effects of a fructose infusion challenge on hepatic intracellular levels of adenosine 5'-triphosphate (ATP), inorganic phosphate (Pi) and phosphomonoesters (PME) were monitored noninvasively by 31P MRS in a remote tumour-bearing rat model. Fisher male rats were inoculated with a methylcholanthrene-induced sarcoma. Seventeen rats were randomized into three groups: control (n = 6), low tumour burden (LTB, n = 6), or moderate tumour burden (MTB, n = 5). The LTB group had tumour burdens of 0.2-2.0% while the MTB group had tumour burdens of 2.6-5.7%. All rats were in the pre-clinical phase of cancer cachexia as determined by food intake and body weight. Rats were infused with 1.2 g/kg of fructose i.v. and the metabolic response of the liver was monitored with time over 1 h via 31P MRS. In all groups an immediate increase in hepatic levels of PME was noted, which returned to baseline values over the course of the experiment, reflecting the phosphorylation of fructose to fructose 1-phosphate. For the MTB rats, the return to baseline levels was more rapid than in the control or LTB group. All groups experienced a 20% decrease in hepatic ATP levels which did not return to baseline over the 1 h observation period. As well, all groups experienced an initial fall in Pi, which recovered to prefructose levels or greater. MTB rats demonstrated a 30-40% increase in Pi concentration and a 60-70% increase in Pi/ATP ratio after infusion with fructose as compared to LTB and control rats (ANOVA;p<0.05). This is consistent with cachexia-induced enhancement of hepatic gluconeogenic activity, and hence more rapid release of Pi from the phosphorylated metabolites in the MTB rats. Thus fructose infusion and hepatic 31P MRS permit pre-clinical detection of cancer cachexia as reflected by increased Pi generation and more rapid removal of PME.