Thyroid cancer susceptibility polymorphisms: confirmation of loci on chromosomes 9q22 and 14q13, validation of a recessive 8q24 locus and failure to replicate a locus on 5q24.

Five single nucleotide polymorphisms (SNPs) associated with thyroid cancer (TC) risk have been reported: rs2910164 (5q24); rs6983267 (8q24); rs965513 and rs1867277 (9q22); and rs944289 (14q13). Most of these associations have not been replicated in independent populations and the combined effects of the SNPs on risk have not been examined. This study genotyped the five TC SNPs in 781 patients recruited through the TCUKIN study. Genotype data from 6122 controls were obtained from the CORGI and Wellcome Trust Case-Control Consortium studies. Significant associations were detected between TC and rs965513A (p=6.35×10(-34)), rs1867277A (p=5.90×10(-24)), rs944289T (p=6.95×10(-7)), and rs6983267G (p=0.016). rs6983267 was most strongly associated under a recessive model (P(GG vs GT + TT)=0.004), in contrast to the association of this SNP with other cancer types. However, no evidence was found of an association between rs2910164 and disease under any risk model (p>0.7). The rs1867277 association remained significant (p=0.008) after accounting for genotypes at the nearby rs965513 (p=2.3×10(-13)) and these SNPs did not tag a single high risk haplotype. The four validated TC SNPs accounted for a relatively large proportion (∼11%) of the sibling relative risk of TC, principally owing to the large effect size of rs965513 (OR 1.74).

Value of lateral blood pool imaging in patients with suspected stress fractures of the tibia.

AIM: To critically evaluate the use of lateral blood pool imaging in athletes with lower limb pain and with a clinical suspicion of stress fracture. METHODS: Two experienced nuclear medicine physicians evaluated 3-phase bone scans using 99mTc-methylene diphosphonate performed in 50 consecutive patients referred from a specialist sports injury clinic for suspected tibial stress fracture. The vascularity to the tibia as seen on the blood pool (second phase) images in the anterior/posterior views was compared with the lateral/medial view assessments. Stress fractures were presumed to be present when on the delayed images (third phase) there was a focal or fusiform area of increased tracer uptake involving the tibial cortex. Shin splints which are a recognized cause of lower limb pain in athletes mimicking stress fracture were diagnosed if increased tracer uptake was seen extending along the posterior tibial surface with no significant focal or fusiform area of uptake within this. Inter-reviewer agreement for the assessment of vascularity was also assessed using Cohen's Kappa scores. RESULTS: Twenty-four stress fractures in 24 patients and 66 shin splints in 40 patients were diagnosed. In 18 patients stress fracture and shin splints coexisted. In 10 patients no tibial pathology was identified. Of the 24 patients diagnosed with stress fractures, lateral/medial blood pool imaging was superior in the assessment of blood pool activity (P < 0.001) identifying increased vascularity in 21 cases compared with the anterior/posterior views positive in only 11 cases. The inter-reviewer agreement was near perfect for lateral/medial views, κ = 0.86 while very good for anterior/posterior views, κ = 0.68. CONCLUSION: In patients with suspected tibial stress fractures, lateral views of the tibia provide the optimal method for evaluation of vascularity. Prospective studies with quantitative or semi-quantitative assessment of skeletal vascularity could provide supplementary information relating to the pathophysiology of stress fractures, for example, the time scale of vascular changes after a tibial stress fracture, and potentially could have clinical relevance as to the assessment of the severity of stress fractures and their prognosis.

Synthesis and biological evaluation of [(18)F]tetrafluoroborate: a PET imaging agent for thyroid disease and reporter gene imaging of the sodium/iodide symporter.

PURPOSE: The human sodium/iodide symporter (hNIS) is a well-established target in thyroid disease and reporter gene imaging using gamma emitters (123)I-iodide, (131)I-iodide and (99m)Tc-pertechnetate. However, no PET imaging agent is routinely available. The aim of this study was to prepare and evaluate (18)F-labelled tetrafluoroborate ([(18)F]TFB) for PET imaging of hNIS. METHODS: [(18)F]TFB was prepared by isotopic exchange of BF (4) (-) with [(18)F]fluoride in hot hydrochloric acid and purified using an alumina column. Its identity, purity and stability in serum were determined by HPLC, thin-layer chromatography (TLC) and mass spectrometry. Its interaction with NIS was assessed in vitro using FRTL-5 rat thyroid cells, with and without stimulation by thyroid-stimulating hormone (TSH), in the presence and absence of perchlorate. Biodistribution and PET imaging studies were performed using BALB/c mice, with and without perchlorate inhibition. RESULTS: [(18)F]TFB was readily prepared with specific activity of 10 GBq/mg. It showed rapid accumulation in FRTL-5 cells that was stimulated by TSH and inhibited by perchlorate, and rapid specific accumulation in vivo in thyroid (SUV = 72 after 1 h) and stomach that was inhibited 95% by perchlorate. CONCLUSION: [(18)F]TFB is an easily prepared PET imaging agent for rodent NIS and should be evaluated for hNIS PET imaging in humans.

The added value of multislice SPECT/CT in patients with equivocal bony metastasis from carcinoma of the prostate.

PURPOSE: The purpose of this study was to investigate the additional value of single photon emission computed tomography/computed tomography (SPECT/CT) over whole-body planar bone scintigraphy and SPECT in prostate cancer patients in terms of diagnostic confidence, inter-reviewer agreement and the possible impact on the clinical management. METHODS: This was a retrospective review of 40 consecutive prostate cancer patients (mean age 71 years) who underwent (99m)Tc-methylene diphosphonate (MDP) whole-body planar bone scintigraphy, SPECT and SPECT/CT between April 2006 and April 2008. The images were evaluated by two independent reviewers; inter-reviewer agreement was evaluated using a weighted kappa score. Each focus of abnormal increased tracer uptake was recorded using a 4-point diagnostic confidence scale. Institutional Review Board approval was obtained. RESULTS: Fifty lesions on planar bone scintigraphy in the 40 patients were evaluated. On reporting the planar study and SPECT scans, reviewers rated 61% of lesions as equivocal. On reporting the SPECT/CT scans only 8% of lesions were rated as equivocal, 24% were rated as malignant and 68% as benign. Weighted kappa scores for inter-reviewer agreement were 0.43 for bone scintigraphy, 0.56 for SPECT and 0.87 for SPECT/CT. All were significant at p < 0.0001. Follow-up imaging confirmed the SPECT/CT diagnoses in 14 patients. CONCLUSION: The addition of SPECT/CT resulted in a significant reduction of equivocal reports; a definitive diagnosis was given in the majority of the patients due to the improved diagnostic confidence compared to planar or SPECT imaging alone in prostate cancer patients with suspected bone metastases.

Synergistic impact of attenuation correction and gating in routine myocardial SPECT reporting: 2 year follow-up study.

AIM: To look at the combined impact of non-uniform attenuation correction (AC) and gated SPECT in the visual interpretation of myocardial SPECT imaging. This was compared to the individual benefit obtained by adding AC information and gated SPECT information to non-AC image information. MATERIALS: We retrospectively studied a group of 141 patients with a 22-26 month follow-up who underwent myocardial perfusion scintigraphy imaging. All the studies were corrected for attenuation with Gd line source transmission data and were ECG gated. In patients who had abnormal studies, follow-up coronary angiography information was also obtained in addition to medical follow-up information. METHODS: Two experienced nuclear medicine physicians interpreted the images independently and were blinded to the other person's report. Non-attenuation corrected data was first evaluated followed by attenuation corrected data and gated SPECT data. Four approaches to interpretation of images were undertaken: (1) non-AC images only, (2) non-AC+AC images, (3) non-AC+gated images, and (4) non-AC+AC+gated images. Study results were divided into four categories based on how confident the observers were of the diagnosis: (1) normal, (2) borderline normal, (3) borderline abnormal, and (4) abnormal. RESULTS: When results for sensitivity and specificity using the four different interpretation techniques were compared there was a statistically significant improvement in the specificity compared to non-AC image (48%) with the addition of AC (77%) and gating (82%) information (P<0.001). The best improvement in the specificity was noted when both AC and gated information (91%) was used along with non-AC information. The normalcy rates almost doubled following the addition of AC and gated data. There was also a decrease in the number of borderline results, showing an improvement in the reporter confidence in interpreting myocardial SPECT studies. Sensitivity, however, did not show a significant change between the four different approaches to interpretation of the study. CONCLUSION: Attenuation correction and gating when combined have a synergistic impact upon improving the specificity of myocardial SPECT reporting when compared to the use of individual techniques alone to improve the specificity.

Thyroid hormone and parathyroid hormone competing to maintain calcium levels in the presence of vitamin D deficiency.

Weight loss and bone disease in the elderly are very often attributed to malignancy. Rarely, benign treatable conditions may be overlooked. Thyrotoxicosis, a benign treatable condition, needs to be excluded in such patients. The diagnosis may be delayed, since the symptoms are often subtle, and secondary complications including bone disease (osteoporosis) are therefore more frequent at the time of presentation. The case presented here illustrates this well, and also highlights the value of measuring vitamin D levels in such patients. The most interesting aspect of this case was the reciprocal relationship between thyroxine and parathyroid hormone observed in maintaining calcium homeostasis in this thyrotoxic patient with low vitamin D levels.

Risk of non-medullary thyroid cancer influenced by polymorphic variation in the thyroglobulin gene.

Benign thyroid disorders are strong risk factors for non-medullary thyroid cancer (NMTC). Germline variation in Tg (thyroglobulin) and TSHR (thyroid stimulating hormone receptor) confers an increased risk of benign thyroid disorders. To explore the hypothesis that polymorphic variation in these genes affects the risk of NMTC we compared the frequency of TgQ2511R, TSHR-P52T and TSHR-D727E genotypes in two series of NMTC cases and controls (group 1, Canadian 102 cases and 102 controls; group 2, British 202 cases and 298 controls). No significant association was seen with TSHR-P52T and TSHR-D727E genotypes and risk of NMTC. However, the frequency of the R-allele of TgQ2511R was over represented in NMTC cases in both study populations. The odds ratios associated with hetero- and homozygosity for the R-allele were 1.6 (95% confidence interval, 1.1-2.5) and 2.0 (95% confidence interval, 1.2-3.3), respectively. Although the risk of NMTC associated with the TgQ2511R R-allele is modest, its high prevalence in the general population suggests it may make a significant contribution to the incidence of NMTC.