Effectiveness of peripheral thyrotropin receptor mRNA in follow-up of differentiated thyroid cancer.
ABSTRACT Thyroid cells in peripheral circulation have been linked to thyroid cancer (TC). These cells express thyrotropin receptor (TSHR) messenger RNA (mRNA), which has been studied as a marker of initial TC diagnosis. We examined the utility of TSHR mRNA in long-term follow-up of TC patients. From 2002 to 2007, TSHR mRNA was prospectively measured by quantitative reverse-transcription polymerase chain reaction (RT-PCR) from peripheral blood samples in 259 patients, and those followed > or =3 months since initial thyroidectomy were studied. TSHR mRNA levels were correlated to thyroglobulin (Tg), imaging studies, and disease status during follow-up. Thirty-four patients underwent 20 +/- 14 months median follow-up for papillary (n = 31, 91%), follicular (n = 2) or Hurthle cell (n = 1) TC. Advanced-stage disease occurred in 24% at presentation, and 11 (32%) developed cervical node metastases or recurrence requiring reoperation during follow-up. Of 52 simultaneous TSHR mRNA and serum Tg measurements, 52% were concordant. TSHR mRNA missed disease in 21% patients, but was better than Tg in 27%, including all those with Tg antibodies. TSHR mRNA concurred with whole-body scan detectable disease for 11/14 patients (79%) and accurately predicted overall TC disease status in 77% patients. In discordant cases, TC recurrence was apparent from other imaging modalities [positron emission tomography (PET) scan or ultrasound]. TSHR mRNA in conjunction with Tg diagnosed TC recurrence with 90% sensitivity and 94% specificity. We conclude that TSHR mRNA demonstrates high concordance rates with present methods of detecting TC recurrence, and appears to be more accurate in patients with Tg antibodies. As a novel adjunct, TSHR mRNA may enhance long-term management of TC patients.
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ABSTRACT: Thyroglobulin antibodies (TgAb) are present in approximately 20% of patients with papillary thyroid cancer (PTC) and invalidate the serum thyroglobulin (Tg) level as a tumor marker. We examined whether trends in the TgAb level could serve as a surrogate marker of disease status in the surveillance of patients with PTC. All patients found to have a least one positive post-operative TgAb level (determined by the Beckman-Coulter Access Assay) after undergoing initial surgery for PTC from 2000-2010 at a single institution were included. Log-log transformation and linear regression were applied to longitudinal TgAb levels, yielding patient-specific regression coefficients that categorized as follows: highly negative, moderately negative, and positive/no trend. The recurrence rate in each category was then assessed. Ninety-three of 967 patients with PTC were included. Recurrent disease was detected in 19 patients (20%) after a mean follow up time of 51 months. Regression coefficients in the highly negative and moderately negative groups were not different, and hence these groups were pooled. The proportion of recurrent cases in the negative trend group was similar to that in the positive/no trend group (19.7% vs 21.9%, NS). The mean regression coefficients were similar for recurrent and non-recurrent cases within both the negative trend group (-0.89 vs. -0.80, NS) and the positive/no trend group (0.08 vs. 0.33, NS). Trends in the TgAb level do not predict disease status in PTC in our experience. In the context of most commercially available TgAb assays, surveillance of TgAb-positive patients will hinge on high-quality imaging until a valid alternative serum marker to Tg is identified. This article is protected by copyright. All rights reserved.Clinical Endocrinology 02/2014; · 3.40 Impact Factor
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ABSTRACT: Background: Serum calcitonin is the main tumor marker for medullary thyroid cancer (MTC), but it has certain limitations. Various sCT assays may present an important intra-assay and interassay variation and may yield different and sometimes conflicting results. Pentagastrin or calcium-stimulated calcitonin test may be desirable in some situations. Alternatively, or in the absence of the stimulation test, mRNA detection offers the advantages of being more comfortable and less invasive, being a one-step blood withdrawal, and having no side effects. The objective of this study was to 1) investigate the applicability of measuring CALCA gene transcripts (CT-CALCA and CGRP-CALCA) in patients with MTC and in relatives diagnosed with a RET mutation and 2) test mRNA as an alternative diagnostic tool for the calcitonin stimulation test. Methods: Twenty-three healthy controls and twenty-six individuals evaluated for MTC were selected, including patients with sporadic or hereditary MTC and RET mutation-carrying relatives. For molecular analysis, RNA was extracted from peripheral blood, followed by cDNA synthesis using 3.5 μg of total RNA. RT-qPCR reactions were performed with SYBR Green, 200 nM of each primer for the two specific mRNA targets (CT-CALCA or CGRP-CALCA) and normalized with the ribosomal protein S8 as reference gene. Results: We detected CALCA transcripts in the blood samples and observed a positive correlation between them (r: 0.946 and p <0.0001). Both mRNAs also correlated with sCT (CT-CALCA - r: 0.713, p: <0.0001, and CGRP-CALCA - r: 0.714, p: <0.0001). The relative expression of CT-CALCA and CGRP-CALCA presented higher clinical sensitivity (86.67 and 100, respectively), specificity (97.06 and 97.06), positive predictive value (92.86 and 93.75) and negative predictive value (94.29 and 100), than did sCT (73.33, 82.35, 64.71 and 87.50). In addition, the CALCA transcript measurement mirrors the response to the pentagastrin test. Conclusion: We demonstrated that the measurement of CALCA gene transcripts in the bloodstream is feasible and may refine the management of patients with MTC and RET mutation-carrying relatives. We propose considering the application of this diagnostic tool as an alternative to the calcitonin stimulation test.Thyroid: official journal of the American Thyroid Association 12/2012; · 2.60 Impact Factor
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ABSTRACT: Selecting the best targets is a key challenge for drug discovery, and achieving this effectively, efficiently and systematically is particularly important for prioritizing candidates from the sizeable lists of potential therapeutic targets that are now emerging from large-scale multi-omics initiatives, such as those in oncology. Here, we describe an objective, systematic, multifaceted computational assessment of biological and chemical space that can be applied to any human gene set to prioritize targets for therapeutic exploration. We use this approach to evaluate an exemplar set of 479 cancer-associated genes, reveal the tension between biological relevance and chemical tractability, and describe major gaps in available knowledge that could be addressed to aid objective decision-making. We also propose drug repurposing opportunities and identify potentially druggable cancer-associated proteins that have been poorly explored with regard to the discovery of small-molecule modulators, despite their biological relevance.dressNature Reviews Drug Discovery 12/2012; 12(1):35-50. · 33.08 Impact Factor