The frequency of change in five-point scale score with a Bayesian penalised likelihood PET reconstruction algorithm on interim FDG PET-CT and its potential implications for therapy decisions in Hodgkin's lymphoma.

AIM: To assess the effect of a Bayesian penalised likelihood (BPL) reconstruction algorithm on the five-point scale (5-PS) score, response categorisation, and potential implications for therapy decisions after interim 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)-computed tomography (CT) (iPET-CT) to guide treatment in classical Hodgkin's lymphoma (HL). MATERIALS AND METHODS: The present study included new patients with HL undergoing iPET-CT from 2014-2019 after two cycles of doxorubicin (Adriamycin), bleomycin, vincristine, and dacarbazine (ABVD). Two reporters categorised response using the 5-PS and measured maximum standardised uptake values (SUVmax) of the most avid tumour residuum, mediastinal blood pool, and normal liver with ordered subset expected maximisation (OSEM) and BPL reconstructions. RESULTS: Eighty-one iPET-CT examinations were reviewed. Compared with OSEM, BPL increased the 5-PS score by a single score in 18/81 (22.2%) patients. The frequency of potential treatment intensification by changing a score of 3-4 was 13.6% (11/81) and represented 25% (11/44) of patients with a score of 3 on OSEM. All 11 patients remained in remission without a change in therapy (mean 63 months) except one who required second-line treatment for refractory disease. Median SUVmax of tumour residuum was significantly higher with BPL compared with OSEM (2.7 versus 2.4, p<<0.0001), whilst liver SUVmax was significantly lower for both reporters (up to 6.6%, p<0.0001). CONCLUSION: BPL PET reconstruction increased the 5-PS score on iPET-CT in 22% of HL patients and can potentially result in unnecessary treatment escalation in over half of these patients.

Detecting and estimating head motion in brain PET acquisitions using raw time-of-flight PET data.

Head motion during brain PET imaging is not uncommon and can negatively affect image quality. Motion correction techniques typically either use hardware to prospectively measure head motion, or they divide the acquisition into short fixed-frames and then align and combine these to produce a motion free image. The aim of this work was to retrospectively detect when motion occurred in PET data without the use of motion detection hardware, and then align the frames defined by these motion occurrences. We describe two methods that use either principal component analysis or the motion induced spatial displacements over time to detect motion in raw time-of-flight PET data. The points in time of motion then define the temporal boundaries of frames which are reconstructed without attenuation correction, aligned and combined. Phantom and [18F]-Fallypride patient acquisitions were used to validate and evaluate these approaches, which were compared with motion estimation using 60 s fixed-frames. Both methods identified all motion occurrences in phantom data, and unlike the fixed-frame approach did not exhibit intra-frame motion. With patient acquisitions, images corrected with the motion detection methods increased the average image sharpness by the same amount as the fixed-frame approach, but reduced the number of reconstructions and registrations by a factor of 3.4 on average. Detecting head motion in raw PET data alone is possible, allowing retrospective motion estimation of any listmode brain PET acquisition without additional hardware, subsequently decreasing data processing and potentially reducing intra-frame motion.

Differential changes in brain glucose metabolism during hypoglycaemia accompany loss of hypoglycaemia awareness in men with type 1 diabetes mellitus. An [11C]-3-O-methyl-D-glucose PET study.

AIMS/HYPOTHESIS: Hypoglycaemia unawareness in type 1 diabetes increases the risk of severe hypoglycaemia and impairs quality of life for people with diabetes. To explore the central mechanisms of hypoglycaemia awareness, we used [11C]-3-O-methyl-D-glucose (CMG) positron emission tomography (PET) to measure changes in global and regional brain glucose metabolism between euglycaemia and hypoglycaemia in aware and unaware diabetic subjects. MATERIALS AND METHODS: Twelve men with type 1 diabetes, of whom six were characterised as aware and six as unaware of hypoglycaemia, underwent two CMG-PET brain scans while plasma glucose was controlled by insulin and glucose infusion either at euglycaemia (5 mmol/l) or at hypoglycaemia (2.6 mmol/l) in random order. RESULTS: With hypoglycaemia, symptoms and sweating occurred only in the aware group. Brain glucose content fell in both groups (p=0.0002; aware, 1.18+/-0.45 to 0.02+/-0.2 mmol/l; unaware, 1.07+/-0.46 to 0.19+/-0.23 mmol/l), with a relative increase in tracer uptake in prefrontal cortical regions, including the anterior cingulate. No detectable differences were found between groups in global brain glucose transport parameters (K1, k2). The cerebral metabolic rate for glucose (CMRglc) showed a relative rise in the aware subjects (11.839+/-2.432 to 13.958+/-2.372) and a fall in the unaware subjects (from 12.457+/-1.938 to 10.16+/-0.801 micromol 100 g(-1) min(-1), p=0.043). CONCLUSIONS/INTERPRETATION: Hypoglycaemia is associated with reduced brain glucose content in aware and unaware subjects, with a relative preservation of metabolism in areas associated with sympathetic activation. The relative rise in global glucose metabolic rate seen in aware subjects during hypoglycaemia contrasted with the relative fall in the unaware subjects and suggests that cortical neuronal activation is a necessary correlate of the state of hypoglycaemia awareness.

Update on intrathyroidal iodine metabolism.

The thyroid concentrates iodide from the serum and oxidizes it at the apical membrane, attaching it to tyrosyl residues within thyroglobulin (Tg) to make diiodotyrosine and monoiodotyrosine. Major players in this process are Tg, thyroperoxidase (TPO), hydrogen peroxide, pendrin, and nicotinamide adenine dinucleotide phosphate (NADPH). Further action of TPO, hydrogen peroxide (H2O2), and iodinated Tg produce thyroxine (T4) and triiodothyronine (T3). Hormone-containing Tg is stored in the follicular lumen, then processed, most commonly by micropinocytosis. The lysosomal enzymes cathepsins B, L, and D are active in Tg proteolysis. Tg digestion leaves T4 and T3 intact, to be released from the cell, while the 3,5'-diiodotyrosine (DIT) and 3-iodotyrosine (MIT) are retained and deiodinated for recycling within the thyroid. Some areas of especially active recent research include: (1) the role of molecular chaperones in directing properly folded TPO and Tg to the apical membrane; (2) details of proteolytic pathways; (3) modulation of iodine metabolism, not only by thyrotropin (TSH) but by iodine supply and by feedback effects of Tg, glutathione, and inhibitory elements in the N-terminal region of Tg; and (4) details of Tg structure and iodotyrosyl coupling. Despite general agreement on the major steps in intrathyroidal iodine metabolism, new details of mechanisms are constantly being uncovered and are greatly improving understanding of the overall process.

Iodine deficiency in the world: where do we stand at the turn of the century?

Iodine deficiency is the leading cause of preventable mental retardation. Universal salt iodization (USI), calling for all salt used in agriculture, food processing, catering and household to be iodized, is the agreed strategy for achieving iodine sufficiency. This article reviews published information on programs for the sustainable elimination of the iodine deficiency disorders and reports new data on monitoring and impact of salt iodization programs at the population level. Currently, 68% of households from areas of the world with previous iodine deficiency have access to iodized salt, compared to less than 10% a decade ago. This great achievement, a public health success unprecedented in the field of noncommunicable diseases, must be better recognized by the health sector, including thyroidologists. On the other hand, the managers and sponsors of programs of iodized salt must appreciate the continuing need for greatly improved monitoring and quality control. For example, partnership evaluation of iodine nutrition using the ThyroMobil model in 35,223 schoolchildren at 378 sites of 28 countries has shown that many previously iodine deficient parts of the world now have median urinary iodine concentrations well above 300 microg/L, which is excessive and carries the risk of adverse health consequences. The elimination of iodine deficiency is within reach but major additional efforts are required to cover the whole population at risk and to ensure quality control and sustainability.

Iodine nutrition and the risk from radioactive iodine: a workshop report in the chernobyl long-term follow-up study.

The major fallout of radionuclides from the nuclear power station accident at Chernobyl on 26 April, 1986, occurred in regions of Ukraine and Belarus that are believed to be moderately deficient in dietary iodine. On 17 November, 2000, in conjunction with the Ukraine-Belarus-USA study of developing thyroid disease in a cohort of individuals exposed as children, a workshop was held to review what is known about iodine nutrition in the region, how this might influence the risk of thyroid tumor formation from radioiodine, and whether and how iodine nutrition should be monitored in this long-term project. This report is a summary of the workshop proceedings. Although no precise information about iodine intake in 1986 was found, the prevalence of mild goiter in the region's children suggested iodine deficiency and urinary iodine measurements begun in 1990 indicated that mild to moderate deficiency existed. Increased thyroid iodine uptake and increased thyroid size in 1986 resulting from iodine deficiency would have had counteracting influence on the thyroid radiation dose and knowledge of these parameters is required for dose reconstruction. More problematic is the possible role of iodine deficiency in the years following the accident. Theoretically, the resulting increase in thyroid cellular activity might increase the risk of tumorigenesis but experimental or clinical evidence supporting this hypothesis is meager or absent. Despite this limitation it was considered important to monitor iodine nutrition in the cohort subjects in relation to their place of residence and over time. Methods to accomplish this were discussed.

Endemic goiter and cretinism: an update on iodine status.

Iodine deficiency is the most prevalent correctable cause of brain damage in the world. Over the past 15 years, great progress has been made towards the elimination of iodine deficiency, principally through universal salt iodization. Much more needs to be done for countries that are lagging in the effort or that have weak systems for sustaining it. The key to maintaining optimal iodine intake is regular monitoring, usually by the measurement of urinary iodine concentration, linked to a prompt response in the event of abnormal results. If the present momentum continues then global iodine sufficiency is possible and, in a landmark achievement, iodine deficiency will be the first major non-infectious disorder to be eliminated.

Thyroid function changes related to use of iodinated water in the U.S. Space Program.

BACKGROUND: The National Aeronautics and Space Administration (NASA) has used iodination as a method of microbial disinfection of potable water systems in U.S. spacecraft and long-duration habitability modules. A review of thyroid function tests of NASA astronauts who had consumed iodinated water during spaceflight was conducted. METHODS: Thyroid function tests of all past and present astronauts were reviewed. Medical records of astronauts with a diagnosis of thyroid disease were reviewed. Iodine consumption by space crews from water and food was determined. Serum thyroid-stimulating hormone (TSH) and urinary iodine excretion from space crews were measured following modification of the Space Shuttle potable water system to remove most of the iodine. RESULTS: Mean TSH significantly increased in 134 astronauts who had consumed iodinated water during spaceflight. Serum TSH, and urine iodine levels of Space Shuttle crewmembers who flew following modification of the potable water supply system to remove iodine did not show a statistically significant change. There was no evidence supporting association between clinical thyroid disease and the number of spaceflights, amount of iodine consumed, or duration of iodine exposure. CONCLUSIONS: It is suggested that pharmacological doses of iodine consumed by astronauts transiently decrease thyroid function, as reflected by elevated serum TSH values. Although adverse effects of excess iodine consumption in susceptible individuals are well documented, exposure to high doses of iodine during spaceflight did not result in a statistically significant increase in long-term thyroid disease in the astronaut population.

Monomorphic teratoma of the ovary: a rare cause of triiodothyronine toxicosis.

A case of low thyroid radioactive iodine uptake (RAIU) thyrotoxicosis due to a large struma ovarii comprising pure thyroid tissue is presented, including a detailed diagnostic evaluation, histopathology, and demonstration of rapid recovery of native thyroid function after surgical excision. In addition, the first comprehensive analysis of thyroglobulin obtained from an ovarian struma is reported.

The oral administration of human thyroglobulin does not affect the incidence of lymphocytic thyroiditis in the biobreeding Worcester rat.

Oral tolerization with the appropriate antigen(s) to ameliorate autoimmune diseases in humans and in experimentally induced animal models, including experimentally autoimmune thyroiditis in mice, has been reported to be efficacious. Spontaneous and iodine induced (0.05% iodine in the drinking water) lymphocytic thyroiditis (LT) occurs in the diabetes mellitus (DM)-prone BioBreeding/Worcester (BB/Wor) rat. The present study was carried out to determine whether the oral administration of human thyroglobulin (hTg) would decrease the incidence of spontaneous and iodine-induced LT in the BB/Wor rat. Low iodine content hTg or bovine serum albumin (BSA) were given orally every 2 days for six doses beginning at age 50 days to BB/W rats, half of whom also received iodine in their drinking water. No effect or orally administered hTg was observed on thyroid weight, the incidence of LT or DM, or on serum thyroglobin antibodies (TgAb), thyrotropin (TSH), thyroxine (T4), and triiodothyronine (T3) concentrations when rats were killed at 100 days of age. In a second experiment, the oral administration of iodine rich hTg or BSA every 2 days for six doses beginning at 30 days of age to iodine-treated BB/Wor rats again did not affect the high incidence of LT or DM or serum TgAb, TSH, T4, and T3 concentrations. The present study suggests that oral tolerization with hTg does not affect spontaneous or iodine-induced lymphocytic thyroiditis or serum thyroglobulin antibodies in the BB/Wor rat.

Persistence of iodine deficiency 25 years after initial correction efforts in the Khumbu region of Nepal.

AIMS: To assess the current status of, and understanding about iodine deficiency disorders among Sherpa residents of the Khumbu region of Nepal, 25 years after the introduction of iodised oil injections. METHODS: Several groups of Khumbu Sherpas were studied and goitre rate, urinary iodine level and cretinism prevalence were measured as indicators of iodine deficiency. Subjects were also questioned in detail about their food consumption, with particular reference to salt use, and about their understanding of the causes and treatment of iodine deficiency disorders. RESULTS: The prevalences of goitre, deaf-mutism and cretinism were 21%, 1.3% and 0.5% respectively (compared to 92%, 4.7% and 5.9% in 1966). No cretins had been born since 1966. The median urine iodine concentration was 35 microg/L. Most people preferred uniodised Tibetan rock salt, although 44% regularly consumed iodised salt. All granulated salt tested from the local market contained adequate amounts of iodine. Only 11% of those surveyed knew that goitre was caused by iodine deficiency CONCLUSIONS: Although prevalences of iodine deficiency disorders are much less than 30 years ago, iodine deficiency continues to be a major problem in Khumbu and demands a clear control strategy, combining ongoing iodine supplementation and education. Iodised salt is usually the best approach to control of iodine deficiency disorders for most regions of the world but the Khumbu experience shows that local cultural and commercial factors can severely limit its impact. To be successful, control programme for iodine deficiency disorders also needs assessment of the salt trade, monitoring, education and occasional targeted interventions with iodised oil or other supplements.

The importance of thyroglobulin structure for thyroid hormone biosynthesis.

Thyroglobulin (Tg) is the most important protein in the thyroid because it provides the matrix for thyroid hormone biosynthesis. Here we review experimental work, principally from our laboratory, on the relationship between Tg structure and hormonogenesis. Early work showed that Tg's most important hormonogenic site was located in a fragment of approximately 26 kDa obtained on chemical reduction. With the establishment of the cDNA sequence of Tg, this and other major sites could be localized within Tg's polypeptide chain. The four major hormonogenic sites, designated A, B, C, and D, are located respectively at tyrosyls 5, 2553, 2746, and 1290. In most species, site A accounts for about 40% of Tg's hormone, and site B for about 25%. Site C is associated with increased T3, at least in some species. Site D is prominent in guinea pigs and rabbits, and TSH favors hormonogenesis at it in these species. Sequential iodination of low iodine human Tg shows three consensus sequences associated with early iodination and with T4 formation. Recent work has identified Tyr130 in beef Tg as donor of an outer iodothyronine ring, most likely to Tyr5, the most important hormonogenic site. In addition to its biochemical importance, Tg has clinical interest in familial goiter and autoimmune thyroid disease. Further elucidation of Tg structure and its relation to thyroid hormone synthesis will contribute to thyroid physiology and to its clinical application.

Simple methods for assessing urinary iodine, including preliminary description of a new rapid technique ("Fast B").

The urinary iodine is the best laboratory measure of iodine nutrition. Several simple methods are suitable for developing countries. The present article reviews these briefly. It also presents preliminary information on "Fast B", a rapid method that puts samples into convenient ranges rather than giving absolute values for individuals. This grouping by ranges is satisfactory for many epidemiological purposes and is considerably more rapid than other approaches. The choice among methods depends on the intended application, the number of samples, the cost and the technical capability. Having several different methods available allows the user to select the one best suited to specific needs. Further development of simple methods and appropriate combinations of steps from different ones deserve encouragement as a means of improving monitoring in the campaign to achieve sustainable elimination of iodine deficiency.

Preoperative evaluation and predictive value of fine-needle aspiration and frozen section of thyroid nodules.

BACKGROUND: We sought to evaluate the predictive value of preoperative fine-needle aspiration (FNA) on surgical decision making by evaluating the final pathologic diagnosis and comparing it to the preoperative diagnosis. Further, we wished to calculate the predictive accuracy of each of several types of preoperative FNA diagnosis. STUDY DESIGN: A retrospective chart review of 151 thyroid resections between July 1990 and April 1996 at the University of Virginia was undertaken. The mean age was 45 years (range, 11 to 85 years). Preoperative laboratory values, presenting symptoms, imaging studies, and predictive values of preoperative FNA and intraoperative frozen section were analyzed. RESULTS: Symptomatology was poorly predictive of a benign versus malignant postoperative final pathologic diagnosis. Sensitivity, specificity, and accuracy of frozen section versus FNA was 86% versus 86%; 99% versus 93%, and 96% versus 92%, respectively, if the reading "cancer" or "suspicious" were predicted as positive for malignancy and "benign" or "follicular" were predicted as negative for malignancy. If only the reading "cancer" was predicted as positive for malignancy and only "benign" was predicted as negative for malignancy, sensitivity and specificity for FNA were 100% and 96%, respectively, and 100% and 99%, respectively, for frozen section. Forty-nine "follicular" lesions obtained by preoperative FNA resulted in 46 benign diagnoses after surgical resection. CONCLUSIONS: The use of preoperative FNA is a powerful diagnostic tool in the hands of skilled pathologists. There is increasing evidence that intraoperative frozen section adds little to intraoperative decision making in patients diagnosed with thyroid cancer by preoperative FNA. Less definitive interpretations decrease the sensitivity, specificity, and accuracy of the FNA diagnosis.

Tyrosine 130 is an important outer ring donor for thyroxine formation in thyroglobulin.

The thyroid couples two iodotyrosine molecules to produce thyroid hormone at the acceptor site in thyroglobulin, leaving dehydroalanine or pyruvate at the donor position. Previous work has located the acceptors but not the principal iodotyrosine donors. We incorporated [14C]tyrosine into beef thyroid slices, isolated and iodinated the [14C]thyroglobulin (Tg I), separated its N-terminal approximately 22-kDa hormone-rich peptide, and digested the latter with trypsin and endoproteinase Glu-C (EC 3.4.21.19). Nonlabeled thyroglobulin (Tg II) was isolated from the same glands and processed similarly, without iodination in vitro. Tg I was used to initially recognize pyruvate in peptide fractions, and Tg II was used to then identify its location in the thyroglobulin polypeptide chain. Sequencing of a tryptic peptide by mass spectrometry and Edman degradation showed a cleavage after Val129. An endoproteinase Glu-C-generated peptide had the predicted molecular mass of a fragment containing residues 130-146 with Tyr130 replaced by pyruvate; the identification of this peptide was supported by obtaining the expected shortened fragment after tryptic digestion. 14C-labeled pyruvate was identified in the same fraction as this peptide. We conclude that Tyr130 is an important donor of the outer iodothyronine ring. Its likely acceptor is Tyr5, the most important hormonogenic site of thyroglobulin, because Tyr5 and Tyr130 are proximate, because they are the most prominent early iodination sites in this part of thyroglobulin, and because the N-terminal region was previously found capable of forming T4 by itself.

Intermittent oral administration of potassium iodide solution for the correction of iodine deficiency.

Iodized salt and iodized oil are the main methods used to prevent iodine deficiency, but sometimes alternative approaches are needed. We tested the efficacy of various regimens for the intermittent administration of potassium iodide in Hwedza, Zimbabwe, an area of known severe iodine deficiency. We divided 304 schoolchildren aged 7-13 y into five equal groups that received iodine as a 10% solution of potassium iodide as follows: 8.7 mg every 2 wk (group A), 29.7 mg every month (group B), 148.2 mg every 3 mo (group C), 382 mg every 6 mo (group D), or 993 mg once (group E). The follow-up period was 13 mo. No adverse effects were encountered with any of these doses. After 6 mo, the median blood spot thyroglobulin concentration had decreased in all groups and had normalized in groups A and B to values found in iodine-sufficient populations. The number of children with elevated thyroid-stimulating hormone concentrations decreased in groups A-C, but the changes were not significant. Urine iodine concentration generally remained low in all groups but increased in group A. After 13 mo, mean thyroid volume measured by ultrasound had decreased in groups A and B to values comparable with those in iodine-sufficient areas, and was unchanged in the other groups. We conclude that oral potassium iodide is effective for the prophylaxis of iodine deficiency if given as a dose of 30 mg I monthly or 8 mg biweekly.