Publications by authors named "Paul W Ladenson"

90 Publications

Afirma Genomic Sequencing Classifier & Xpression Atlas Molecular Findings in Consecutive Bethesda III-VI Thyroid Nodules.

J Clin Endocrinol Metab 2021 May 19. Epub 2021 May 19.

Department of Medical Affairs, Veracyte, Inc., South San Francisco, California.

Context: Broad genomic analyses among thyroid histologies have been described from relatively small cohorts.

Objective: Investigate the molecular findings across a large, real-world cohort of thyroid fine needle aspiration (FNA) samples.

Design: Retrospective analysis of RNA sequencing data files.

Setting: CLIA laboratory performing Afirma Genomic Sequencing Classifier (GSC) and Xpression Atlas (XA) testing.

Participants: 50,644 consecutive Bethesda III-VI nodules.

Intervention: none.

Main Outcome Measures: Molecular test results.

Results: Of 48,952 Bethesda III/IV FNAs studied, 66% were benign by Afirma GSC. The prevalence of BRAF V600E was 2% among all Bethesda III/IV FNAs and 76% among Bethesda VI FNAs. Fusions involving NTRK, RET, BRAF, and ALK were most prevalent in Bethesda V (10%), and 130 different gene partners were identified. Among small consecutive Bethesda III/IV sample cohorts with one of these fusions and available surgical pathology excision data, the positive predictive value of an NTRK or RET fusion for carcinoma or non-invasive follicular thyroid neoplasm with papillary-like nuclear features was >95%, while for BRAF and ALK fusions it was 81% and 67%, respectively. At least one genomic alteration was identified by the expanded Afirma XA panel in 70% of Medullary Thyroid Carcinoma Classifier positive FNAs, 44% of Bethesda III or IV Afirma GSC suspicious FNAs, 64% of Bethesda V FNAs, and 87% of Bethesda VI FNAs.

Conclusions: This large study demonstrates that almost half of Bethesda III/IV Afirma GSC suspicious and most Bethesda V/VI nodules had at least 1 genomic variant or fusion identified, which may optimize personalized treatment decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgab304DOI Listing
May 2021

The prostate-specific membrane antigen (PSMA)-targeted radiotracer F-DCFPyL detects tumor neovasculature in metastatic, advanced, radioiodine-refractory, differentiated thyroid cancer.

Med Oncol 2020 Oct 9;37(11):98. Epub 2020 Oct 9.

Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Prostate-specific membrane antigen (PSMA; also termed glutamate carboxypeptidase II (GCP II)) is abundantly expressed in prostate cancer. It has been shown recently that PSMA is expressed in neovasculature of differentiated thyroid cancer. In this study, we show that F-DCFPyl might detect neovasculature in advanced, metastatic differentiated thyroid cancer (DTC). We first stained the preserved lymph node samples of three patients with DTC who had undergone total thyroidectomy and neck dissection for cervical lymph node metastatic disease to identify PSMA expression, with the PSMA antibody (DAKO Monoclonal). Then, we performed F-DCFPyl imaging in two other advanced DTC patients with elevated serum thyroglobulin (Tg), indicative of residual disease. We compared the findings with contemporaneous FDG PET/CT scan, conventional Imaging (CT,MRI) and whole-body scan performed with I/I. All the three lymph node samples stained positive for PSMA expression in the neovasculature. In the first imaged patient, F-DCFPyl detected activity within the retropharyngeal CT contrast-enhancing lymph node. Compared to FDG PET/CT, the F-DCFPyl scan showed a greater SUV (3.1 vs 1.8). In the second imaged patient, F-DCFPyl showed intense uptake in the L3 vertebra (not seen on the post treatment I scan or the F-FDG PET/CT). MRI of the lumbar spine confirmed the presence of sclerotic-lytic lesion at the location, consistent with metastatic disease. Our exploratory study is proof of principle, that the prostate cancer imaging agent F-DCFPyl may prove useful for the localization of metastases, in patients with metastatic RAI-refractory DTC by detecting neoangiogenesis within the tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12032-020-01427-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759157PMC
October 2020

Misdiagnosis of Paraganglioma by I-mIBG Without Stable Iodine Blockade of Thyroidal Radioiodine Uptake.

J Endocr Soc 2020 Sep 17;4(9):bvaa099. Epub 2020 Jul 17.

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Iodine-123/iodine-131 (I/I)-metaiodobenzylguanidine (mIBG) scan is an established tool for the localization and treatment of neuroendocrine tumors such as paragangliomas (PGL). To minimize thyroid irradiation by the radioactive iodine in the mIBG preparation, blockade of thyroidal iodine uptake with high doses of stable iodine used to be given routinely as part of all mIBG protocols. As I is now more frequently utilized than I, concern about thyroid radiation has lessened and thyroid blockade is often considered unnecessary. However, in certain situations, the lack of thyroid blockade can significantly impact treatment decisions. This report describes 2 patients who had mediastinal masses incidentally discovered on CT scans, and on further evaluation were found to have symptoms suggesting catecholamine excess with mildly elevated plasma normetanephrine levels. I-mIBG scans were performed without thyroid blockade, which demonstrated accumulation of tracer in the masses that were therefore deemed positive for PGL. Both patients underwent surgical resection of the masses with their surgical pathology revealing ectopic thyroid tissue (ETT). These cases illustrate that if appropriate thyroid blockade is not performed, ETT concentrating radioiodine from mIBG can lead to falsely positive mIBG scans and unnecessary surgical procedures. We conclude that in the setting of a mass suspicious for PGL in a location potentially representing ETT, such as the mediastinum, thyroid blockade should be employed for mIBG protocols to avoid false positive scans caused by ETT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jendso/bvaa099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414919PMC
September 2020

Thyroid and Cardiovascular Disease: Research Agenda for Enhancing Knowledge, Prevention, and Treatment.

Thyroid 2019 06 13;29(6):760-777. Epub 2019 May 13.

8 Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Thyroid hormones have long been known to have a range of effects on the cardiovascular system. However, significant knowledge gaps exist concerning the precise molecular and biochemical mechanisms governing these effects and the optimal strategies for management of abnormalities in thyroid function in patients with and without preexisting cardiovascular disease. In September 2017, The National Heart, Lung, and Blood Institute convened a Working Group with the goal of developing priorities for future scientific research relating thyroid dysfunction to the progression of cardiovascular disease. The Working Group reviewed and discussed the roles of normal thyroid physiology, the consequences of thyroid dysfunction, and the effects of therapy in three cardiovascular areas: cardiac electrophysiology and arrhythmias, the vasculature and atherosclerosis, and the myocardium and heart failure. This report describes the current state of the field, outlines barriers and challenges to progress, and proposes research opportunities to advance the field, including strategies for leveraging novel approaches using omics and big data. The Working Group recommended research in three broad areas: 1) investigation into the fundamental biology relating thyroid dysfunction to the development of cardiovascular disease and into the identification of novel biomarkers of thyroid hormone action in cardiovascular tissues; 2) studies that define subgroups of patients with thyroid dysfunction amenable to specific preventive strategies and interventional therapies related to cardiovascular disease; and 3) clinical trials focused on improvement in cardiovascular performance and cardiovascular outcomes through treatment with thyroid hormone or thyromimetic drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2018.0416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913785PMC
June 2019

Thyroid and Cardiovascular Disease Research Agenda for Enhancing Knowledge, Prevention, and Treatment.

Circulation 2019 May 13. Epub 2019 May 13.

Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD.

Thyroid hormones have long been known to have a range of effects on the cardiovascular system. However, significant knowledge gaps exist concerning the precise molecular and biochemical mechanisms governing these effects and the optimal strategies for management of abnormalities in thyroid function in patients with and without preexisting cardiovascular disease. In September 2017, the National Heart, Lung, and Blood Institute convened a Working Group with the goal of developing priorities for future scientific research relating thyroid dysfunction to the progression of cardiovascular disease. The Working Group reviewed and discussed the roles of normal thyroid physiology, the consequences of thyroid dysfunction, and the effects of therapy in 3 cardiovascular areas: cardiac electrophysiology and arrhythmias, the vasculature and atherosclerosis, and the myocardium and heart failure. This report describes the current state of the field, outlines barriers and challenges to progress, and proposes research opportunities to advance the field, including strategies for leveraging novel approaches using omics and big data. The Working Group recommended research in 3 broad areas: (1) investigation into the fundamental biology relating thyroid dysfunction to the development of cardiovascular disease and into the identification of novel biomarkers of thyroid hormone action in cardiovascular tissues; (2) studies that define subgroups of patients with thyroid dysfunction amenable to specific preventive strategies and interventional therapies related to cardiovascular disease; and (3) clinical trials focused on improvement in cardiovascular performance and cardiovascular outcomes through treatment with thyroid hormone or thyromimetic drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.118.036859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851449PMC
May 2019

Extending expressed RNA genomics from surgical decision making for cytologically indeterminate thyroid nodules to targeting therapies for metastatic thyroid cancer.

Cancer Cytopathol 2019 06 24;127(6):362-369. Epub 2019 Apr 24.

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncy.22132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618055PMC
June 2019

Surveillance for Differentiated Thyroid Cancer Recurrence.

Endocrinol Metab Clin North Am 2019 03;48(1):239-252

Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, MD 21287, USA.

Serum thyroglobulin monitoring along with anatomic and functional imaging play key roles in the surveillance of patients with differentiated thyroid cancer after initial treatment. Among patients with a disease stage justifying thyroid remnant ablation or with suspected metastatic disease, radioiodine whole-body scans are essential in the months after surgery. For patients with low to moderate-risk cancers, ultrasonography of the neck (with measurement of serum thyroglobulin on thyroid hormone replacement) are the best initial diagnostic modalities, and are often the only tests required. In individuals suspected of having distant metastases, CT, MRI, and 18F-FDG PET can make important contributions in localizing residual disease and monitoring its progression and responses to therapy, provided they are used in the appropriate setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ecl.2018.11.008DOI Listing
March 2019

Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy.

Oncologist 2019 06 29;24(6):791-797. Epub 2018 Oct 29.

Foundation Medicine Inc., Cambridge, Massachusetts, USA.

Background: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. We queried whether comprehensive genomic profiling (CGP) of PC might identify genomic alterations (GAs), which would suggest benefit from rationally matched therapeutics.

Methods: We performed hybrid-capture-based CGP to identify GAs and tumor mutational burden (TMB) in tumors from patients with this malignancy.

Results: There were 85 total GAs in 16 cases (5.3 GAs per case), and the median TMB was 1.7 mutations per megabase (m/Mb), with three cases having >20 m/Mb (18.7%). The genes most frequently harboring GA were (38%), (38%), and (31%). All -mutated cases also had loss of heterozygosity at that locus, but in contrast all -mutated cases retained heterozygosity. GAs suggesting potential benefit from matched targeted therapy were identified in 11 patients (69%) and most frequently found in (25%), (12.5%), (12.5%), (12.5%), and (12.5%). A patient whose tumor harbored T668 K and who was treated with cabozantinib experienced a > 50% drop in parathyroid hormone level and radiographic partial response of 5.4 months with duration limited by toxicity.

Conclusion: CGP identified GAs in PC that suggest benefit from targeted therapy, as supported by an index case of response to a matched tyrosine kinase inhibitor. Moreover, the unexpectedly high frequency of high TMB (>20 m/Mb) suggests a subset of PC may benefit from immune checkpoint inhibitors.

Implications For Practice: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. However, its molecular characteristics remain unclear, with few systemic therapeutic options available for this tumor. Hybrid-capture-based comprehensive genomic profiling of 16 primary cancers demonstrated presence of potentially actionable genomic alterations, including , , , , and and a subset of hypermutated cancers with more than 20 mutations per megabase, the latter of which could benefit from immune checkpoint inhibitor therapy. A case benefiting from rationally matched targeted therapy for activating mutation is also presented. These findings should be further investigated for their therapeutic potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2018-0334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656481PMC
June 2019

Performance of a Genomic Sequencing Classifier for the Preoperative Diagnosis of Cytologically Indeterminate Thyroid Nodules.

JAMA Surg 2018 09;153(9):817-824

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: Use of next-generation sequencing of RNA and machine learning algorithms can classify the risk of malignancy in cytologically indeterminate thyroid nodules to limit unnecessary diagnostic surgery.

Objective: To measure the performance of a genomic sequencing classifier for cytologically indeterminate thyroid nodules.

Design, Setting, And Participants: A blinded validation study was conducted on a set of cytologically indeterminate thyroid nodules collected by fine-needle aspiration biopsy between June 2009 and December 2010 from 49 academic and community centers in the United States. All patients underwent surgery without genomic information and were assigned a histopathology diagnosis by an expert panel blinded to all genomic information. There were 210 potentially eligible thyroid biopsy samples with Bethesda III or IV indeterminate cytopathology that constituted a cohort previously used to validate the gene expression classifier. Of these, 191 samples (91.0%) had adequate residual RNA for validation of the genomic sequencing classifier. Algorithm development and independent validation occurred between August 2016 and May 2017.

Exposures: Thyroid nodule surgical histopathology diagnosis by an expert panel blinded to all genomic data.

Main Outcomes And Measures: The primary end point was measurement of genomic sequencing classifier sensitivity, specificity, and negative and positive predictive values in biopsies from Bethesda III and IV nodules. The secondary end point was measurement of classifier performance in biopsies from Bethesda II, V, and VI nodules.

Results: Of the 183 included patients, 142 (77.6%) were women, and the mean (range) age was 51.7 (22.0-85.0) years. The genomic sequencing classifier had a sensitivity of 91% (95% CI, 79-98) and a specificity of 68% (95% CI, 60-76). At 24% cancer prevalence, the negative predictive value was 96% (95% CI, 90-99) and the positive predictive value was 47% (95% CI, 36-58).

Conclusions And Relevance: The genomic sequencing classifier demonstrates high sensitivity and accuracy for identifying benign nodules. Its 36% increase in specificity compared with the gene expression classifier potentially increases the number of patients with benign nodules who can safely avoid unnecessary diagnostic surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamasurg.2018.1153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583881PMC
September 2018

THE RELATIONSHIP OF BRAF MUTATION STATUS TO FDG PET/CT AVIDITY IN THYROID CANCER: A REVIEW AND META-ANALYSIS.

Endocr Pract 2018 Jan 16;24(1):21-26. Epub 2017 Nov 16.

Objective: Papillary thyroid cancer (PTC) harboring a BRAF gene mutation has been shown to exhibit aggressive tumor behavior and carries higher risks of recurrence and disease-specific death. In this systematic review and meta-analysis, we examined published evidence related to the accuracy of fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in detection of residual disease in patients with BRAF mutated thyroid cancer.

Methods: We extracted data from PUBMED/MEDLINE and EMBASE published between January 1995 and March 2017. We included studies that compared FDG PET standardized uptake values (SUVs) between BRAF-positive and BRAF-negative subjects, as well as those that evaluated the odds of having FDG avidity between BRAF-positive and -negative patients with thyroid cancer.

Results: There were a total of 12 studies in the systematic review. Seven studies qualified for the analysis for calculating the pooled odds ratio (OR). The pooled cohort with binary data had 1,144 patients out of which 843 were BRAF positive and 301 were BRAF negative. Those with a BRAF mutation had a significantly greater likelihood of having FDG-avid lesions. The pooled OR was 2.12 (confidence interval [CI] 1.53-3.00, P<.01). The pooled mean SUV (cohort of 315 patients) was significantly higher in BRAF-positive compared to BRAF negative patients, with a pooled mean difference of 5.1 (CI 4.3-5.8).

Conclusion: Our meta-analysis shows that presence of BRAF mutation in PTC confers a higher likelihood of FDG PET avidity and is associated with higher SUV uptake values compared to BRAF-mutation negative status.

Abbreviations: BRAF = B-Raf proto-oncogene, serine/threonine kinase; CI = confidence interval; CT = computed tomography; DTC = differentiated thyroid cancer; FDG = fluorodeoxyglucose; PET = positron emission tomography; PTC = papillary thyroid cancer; SUV = standardized uptake value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4158/EP-2017-0080DOI Listing
January 2018

Unstable Thyroid Function in Older Adults Is Caused by Alterations in Both Thyroid and Pituitary Physiology and Is Associated with Increased Mortality.

Thyroid 2017 11 13;27(11):1370-1377. Epub 2017 Oct 13.

3 National Institute on Aging, National Institutes of Health , Baltimore, Maryland.

Background: Average thyrotropin (TSH) levels are known to be higher in older adults when measured in cross-sectional populations. Possible etiologies include differential survival, neutral aging changes, or increased disease prevalence at older ages. This study aimed to elucidate the mechanisms underlying changing thyroid function during aging, and to determine the association of changes with survival, by analyzing the individual thyroid axis over time.

Methods: Individual patterns of changing TSH and free thyroxine (fT4) were determined in 640 participants in the Baltimore Longitudinal Study of Aging who had at least three measures of serum TSH and fT4, not on medications, over an average of seven years of follow-up. Participants with changing phenotypes were identified based on quintiles for both slopes. Those with alterations in primary thyroid gland function demonstrated intact negative feedback (rising TSH with declining fT4 or declining TSH with rising fT4). Other participants had a parallel rise or fall of TSH and fT4 levels, consistent with pituitary dysfunction. Predictors of phenotype were analyzed by logistic regression. Differential survival between thyroid aging phenotypes was analyzed using multivariate Cox regression.

Results: While the majority of participants at all ages had stable thyroid function, changes were more common among older adults, with 32.3% of those aged >80 years but only 9.5% of those aged <60 years demonstrating thyroid function changes in the highest and lowest quintiles. Regression to the mean accounts for some of the changes, for example increased baseline TSH was associated with a falling TSH pattern (odds ratio = 1.4 [confidence interval 1.1-1.7] per 1 mIU/L). Importantly, changing thyroid function in either the upper or lower quintiles of slope for TSH and fT4 was associated with increased risk of death compared to stable thyroid status (hazard ratio = 5.4 [confidence interval 3.1-9.5]).

Conclusions: Changing thyroid hormone function is increasingly common at older ages and is associated with decreased survival. Nonetheless, the tendency for abnormal thyroid function tests to resolve, along with altered pituitary responsiveness underlying some TSH elevations, suggests that an elevated TSH level should be not assumed to represent subclinical hypothyroidism in older adults. Thus, caution is appropriate when determining the need for thyroid hormone supplements in older adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2017.0211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672620PMC
November 2017

Utility of I-124 PET/CT in identifying radioiodine avid lesions in differentiated thyroid cancer: a systematic review and meta-analysis.

Clin Endocrinol (Oxf) 2017 May 28;86(5):645-651. Epub 2017 Feb 28.

Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Introduction: Diagnostic I-123 scans have been shown to underestimate the disease burden in differentiated thyroid cancer (DTC) when compared to I-131 post-treatment scans, especially in children and patients who have had prior radioiodine (RAI) therapy and/or distant metastasis. I-124 PET/CT has been shown to be highly effective in imaging DTC-related metastatic disease.

Methods: We performed a systematic review and meta-analysis of studies investigating the sensitivity and specificity of I-124 PET/CT in identifying lesions amenable to RAI therapy as confirmed by I-131 post-treatment scanning.

Results: There were 141 patients and 415 lesions of DTC identified altogether. There was significant heterogeneity in the individual studies. The pooled sensitivity of the I-124 PET/CT in detecting lesions of differentiated thyroid cancer amenable to I-131 therapy was 94·2% (91·3-96·4% CI, P < 0·01), and the pooled specificity was 49·0% (34·8-63·4% CI, P < 0·01). The pooled positive likelihood ratio (LR) was 1·43 (1·05-1·94 CI), and the pooled negative LR was 0·28 (0·15-0·53 CI). Overall, the diagnostic odds ratio was 7·90 (3·39-18·48 CI). There were a small but increased number of lesions identified by I-124 PET/CT that was not detected on post-treatment scan.

Conclusion: I-124 PET/CT is a sensitive tool to diagnose RAI avid DTC lesions, but also detects some new lesions that are not visualized on the post-treatment I-131 scan. Further, carefully designed dosimetric studies may be required to fully establish the role of I-124 PET CT for identifying potential lesions for I-131 therapy. I-124 PET/CT in patients with DTC may have other applications in specific clinical situations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cen.13306DOI Listing
May 2017

JOHN BRUTON STANBURY, MD: 1915 - 2015.

Authors:
Paul W Ladenson

Trans Am Clin Climatol Assoc 2016 ;127:cvii-cix

View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216509PMC
February 2017

Mortality Risk Stratification by Combining BRAF V600E and TERT Promoter Mutations in Papillary Thyroid Cancer: Genetic Duet of BRAF and TERT Promoter Mutations in Thyroid Cancer Mortality.

JAMA Oncol 2017 Feb;3(2):202-208

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: BRAF V600E and TERT promoter mutations can coexist in papillary thyroid cancer (PTC). This genetic duet was indicated to be involved in the aggressiveness of PTC, but its prognostic value in PTC-related mortality remains to be specifically established.

Objective: To establish the prognostic power of this genetic duet in PTC-specific mortality.

Design, Setting, And Participants: This genetic-clinical correlation study examined BRAF V600E and TERT promoter mutations (chr5:1,295,228C>T and chr5:1,295,250C>T) and PTC-specific mortality in 1051 patients (764 women and 287 men) with a median (interquartile range [IQR]) age of 46 (36-57) years, with a median (IQR) follow-up time of 89 (48-142) months (7.4 years).

Main Outcomes And Measures: BRAF V600E and TERT promoter mutation patterns and associated patient deaths caused by PTC.

Results: Papillary thyroid cancer-specific mortality occurred in 4 of 629 patients (0.6%) with neither mutation; 7 of 292 (2.4%) with BRAF V600E alone; 4 of 64 (6.3%) with TERT promoter mutation alone; and 15 of 66 (22.7%) with the genetic duet; and deaths per 1000-person years in patients harboring neither mutation, BRAF V600E alone, TERT mutation alone, or both mutations were 0.80 (95% CI, 0.30-2.13), 3.08 (95% CI, 1.47-6.46), 6.62 (95% CI, 2.48-17.64), and 29.86 (95% CI, 18.00-49.52), respectively. Compared with patients harboring neither mutation, HRs (95% CIs) for PTC-specific mortality were 3.08 (0.87-10.84) for BRAF V600E alone; 8.18 (2.04-32.75) with TERT mutation alone; and 37.77 (12.50-114.09) with both mutations. Papillary thyroid cancer-specific mortality for cases with both mutations remained significant (HR, 9.34; 95% CI, 2.53-34.48) after adjustment for clinicopathological factors, and the genetic duet showed a strong incremental and synergistic impact over either mutation alone. Kaplan-Meier analyses revealed a flat PTC-specific patient survival curve with neither mutation, a modest decline in the curve with either mutation alone, and a sharp decline in the curve with coexisting mutations. Even more robust mortality associations of the genetic duet were seen when only conventional-variant PTC (CPTC) was analyzed (HR, 54.46; 95% CI, 12.26-241.82), which remained strongly significant (HR, 18.56; 95% CI, 2.97-116.18) after adjustment for clinicopathological factors.

Conclusions And Relevance: These results demonstrate a simple 4-genotype classification of PTC, particularly CPTC, with a disease-specific mortality risk order of the genetic duet>BRAF V600E alone = TERT promoter mutation alone > wild-type for both genes, representing a powerful molecular prognostic system that can help pinpoint patients with the highest mortality risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2016.3288DOI Listing
February 2017

Response to the Letter to the Editor.

J Clin Endocrinol Metab 2016 08;101(8):L78-9

Division of Health Sciences Informatics (H.L., K.A.R.), Department of Medicine, and Welch Medical Library (B.A.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Divisions of General Internal Medicine (K.A.R., I.J.S.) and Endocrinology and Metabolism (P.W.L.), Departments of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2016-2622DOI Listing
August 2016

The true cost of thyroid surgery determined by a micro-costing approach.

Endocrine 2017 Feb 12;55(2):519-529. Epub 2016 May 12.

Pharmacist, Health Economist, Via Anfossi 10, 35129, Padua, Italy.

Whether the amount of the current DRG tariff for thyroid surgery covers its actual cost has been questioned. We estimated a reliable cost of thyroid surgery for a large Italian hospital. A micro-costing approach is used with data from the University Hospital "Umberto I," a large facility that conducts a high volume of thyroidectomy surgical procedures in the Lazio region. The direct costs of surgery and hospitalization for a total and a hemi-thyroidectomy were €4956 and €4673, respectively. When compared to the DRG tariff of €3340, total thyroidectomy was €1616 (48 %) more per procedure and hemi-thyroidectomy was €1333 (40 %) more per procedure. This DRG shortfall is calculated to generate an annual procedure-specific deficit of approximately €1.38 million for this hospital. Furthermore, when the costs associated with pre-surgical work-up, post-surgical follow-up, and complications management through 12 months are incorporated, the estimated costs of total and hemi-thyroidectomy rose to €5812 and €5277, respectively. The true cost of thyroid surgery in Italy is significantly higher than what has been reported in the literature or reimbursed by the DRG tariff.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12020-016-0980-zDOI Listing
February 2017

Precision Medicine Comes to Thyroidology.

Authors:
Paul W Ladenson

J Clin Endocrinol Metab 2016 Mar 23;101(3):799-803. Epub 2016 Feb 23.

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-0003.

Context: The broad spectrum of thyroid disease severity--from subclinical hypothyroidism to myxedema coma, subclinical thyrotoxicosis to thyroid storm, and microscopic papillary to anaplastic cancers--has always demanded that clinicians individualize their management of thyroid patients. Deepening knowledge of thyroid pathophysiology along with advances in diagnostic, prognostic, and therapeutic technologies applicable to thyroid diseases position this field to ride the wave of precision medicine in the decade ahead.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2015-3695DOI Listing
March 2016

Barriers to optimal diabetes care in Trinidad and Tobago: a health care Professionals' perspective.

BMC Health Serv Res 2015 Sep 19;15:396. Epub 2015 Sep 19.

Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Background: The republic of Trinidad and Tobago (T&T) is a middle income country with a comparatively high prevalence of diabetes mellitus (DM) compared to others in the Caribbean. To date, there have been no studies on health care professionals' (HCP) perspectives regarding the barriers to achieving optimal care of patients with DM in this country and few previous studies in the Caribbean, yet such perspectives are imperative to develop strategies that reduce the global burden of this disease.

Methods: An electronic invitation was sent to prospective HCP in T&T inviting them to attend a symposium on DM and cardiovascular disease. A total of 198 HCP participants attended of whom approximately 100 participants completed an Audience Response Survey at the completion of the conference. The Audience Response Survey included questions regarding access to resources, need for prevention and education, and coordination of care for to diabetes care in T&T. Responses were analyzed in aggregate.

Results: The 198 HCP participants attending the symposium included mostly nurses (40 %) and physicians (43 %). The most common specialty indicated by the 198 HCP participants was Internal and Family Medicine (28 %), followed by Anesthesiology (7 %), Emergency Medicine (6 %), Endocrinology and Diabetes (5 %) and Cardiology (3 %). Among the ~100 HCP who completed the Audience Response Survey, multiple barriers to achieving optimal care of patients with diabetes were reported such as: limited access to blood testing (75 %), ophthalmological evaluations (96 %), ECGs (69 %), and cardiac stress tests (92 %); inadequate time to screen and evaluate DM complications (95 %); poor access to consultants for referral of difficult cases (77 %); and lack of provider education regarding cardiovascular complications of DM (57 %). HCP agreed that nurses could potentially be considered to have a more active role in the care and prevention of cardiovascular disease and diabetes through leading patient education efforts (98 %), screening patients for complications (91 %), coordinating care efforts (99 %) and educating family members (98 %).

Conclusions: The HCP in our study reported significant barriers to achieving optimal diabetes care in T&T. In the future, such barriers to care will need to be addressed in order to respond to the projected growth of diabetes in developing countries both within the Caribbean and globally.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12913-015-1066-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575420PMC
September 2015

Reassessing the NTCTCS Staging Systems for Differentiated Thyroid Cancer, Including Age at Diagnosis.

Thyroid 2015 Oct 24;25(10):1097-105. Epub 2015 Aug 24.

14 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center , Houston, Texas.

Background: Thyroid cancer is unique for having age as a staging variable. Recently, the commonly used age cut-point of 45 years has been questioned.

Objective: This study assessed alternate staging systems on the outcome of overall survival, and compared these with current National Thyroid Cancer Treatment Cooperative Study (NTCTCS) staging systems for papillary and follicular thyroid cancer.

Methods: A total of 4721 patients with differentiated thyroid cancer were assessed. Five potential alternate staging systems were generated at age cut-points in five-year increments from 35 to 70 years, and tested for model discrimination (Harrell's C-statistic) and calibration (R(2)). The best five models for papillary and follicular cancer were further tested with bootstrap resampling and significance testing for discrimination.

Results: The best five alternate papillary cancer systems had age cut-points of 45-50 years, with the highest scoring model using 50 years. No significant difference in C-statistic was found between the best alternate and current NTCTCS systems (p = 0.200). The best five alternate follicular cancer systems had age cut-points of 50-55 years, with the highest scoring model using 50 years. All five best alternate staging systems performed better compared with the current system (p = 0.003-0.035). There was no significant difference in discrimination between the best alternate system (cut-point age 50 years) and the best system of cut-point age 45 years (p = 0.197).

Conclusions: No alternate papillary cancer systems assessed were significantly better than the current system. New alternate staging systems for follicular cancer appear to be better than the current NTCTCS system, although they require external validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2015.0148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589102PMC
October 2015

Thyroid Hormone Therapy and Risk of Thyrotoxicosis in Community-Resident Older Adults: Findings from the Baltimore Longitudinal Study of Aging.

Thyroid 2015 Sep 13;25(9):979-86. Epub 2015 Aug 13.

4 National Institute on Aging, National Institutes of Health , Baltimore, Maryland.

Background: Both endogenous and exogenous thyrotoxicosis has been associated with atrial fibrillation and low bone mineral density. Therefore, this study investigated the risk factors associated with prevalent and incident thyrotoxicosis and the initiation of thyroid hormone therapy in a healthy, aging cohort.

Methods: A total of 1450 ambulatory community volunteer participants in the Baltimore Longitudinal Study of Aging examined at the NIA Clinical Research Unit in Baltimore, MD, have undergone longitudinal monitoring of serum thyrotropin (TSH) and thyroid hormone (free thyroxine and free triiodothryonine) levels as well as medication use every one to four years, depending on age, between 2003 and 2014.

Results: The prevalence of low TSH was 9.6% for participants on thyroid hormone and 0.8% for nontreated individuals (p < 0.001). New cases occurred at a rate of 17.7/1000 person-years of exposure to thyroid hormone therapy [CI 9-32/1000] and 1.5/1000 person-years in the unexposed population [CI 0.7-2.9/1000]. Women were more likely to be treated and more often overtreated than men were. The adjusted hazard ratio (HR) for thyrotoxicosis between treated and untreated women was 27.5 ([CI 7.2-105.4]; p < 0.001) and 3.8 for men ([CI 1.2-6.3]; p < 0.01). White race/ethnicity and older age were risk factors for thyroid hormone therapy but not overtreatment. Body mass index was not associated with starting therapy (HR = 1.0). Thyroid hormone initiation was highest among women older than 80 years of age (3/100 person-years). For one-third of treated participants with follow-up data, overtreatment persisted at least two years.

Conclusions: Iatrogenic thyrotoxicosis accounts for approximately half of both prevalent and incident low TSH events in this community-based cohort, with the highest rates among older women, who are vulnerable to atrial fibrillation and osteoporosis. Physicians should be particularly cautious in treating subclinical hypothyroidism in elderly women in light of recent studies demonstrating no increased risk of cardiovascular morbidity or death for individuals with elevated TSH levels <10 mIU/L.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2015.0180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560848PMC
September 2015

Long-Term Outcomes Following Therapy in Differentiated Thyroid Carcinoma: NTCTCS Registry Analysis 1987-2012.

J Clin Endocrinol Metab 2015 Sep 14;100(9):3270-9. Epub 2015 Jul 14.

Department of Endocrine Neoplasia and Hormonal Disorders (A.A.C., D.R.L., S.I.S.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Thyroid Unit (D.S.R.), Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology (J.J.), Department of Medicine, Georgetown University Medical Center, Washington, DC 20057; Division of Endocrinology and Metabolism (D.S.C., P.W.L., M.X.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Radiation Oncology (J.D.B.), Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada; Department of Internal Medicine (K.B.A.), Veterans Affairs Medical Center and University of Kentucky, Lexington, Kentucky 40502; Division of Endocrinology and Metabolism (H.G.F.), Sinai Hospital, Baltimore, Maryland 21215; Division of Endocrinology, Metabolism, and Diabetes (B.R.H.), University of Colorado School of Medicine, Aurora, Colorado 80045; Genzyme (J.M.), a Sanofi Company, Cambridge, Massachusetts 02142; Diabetes, Endocrinology, Obesity Branch (M.C.S.), National Institutes of Health, Bethesda, Maryland 20892; Departments of Head and Neck Surgery (D.L.S.) and Nuclear Medicine (H.R.M.), University of Cincinnati Medical Center, Cincinnati, Ohio 45219.

Context: Initial treatments for patients with differentiated thyroid cancer are supported primarily by single-institution, retrospective studies, with limited follow-up and low event rates. We report updated analyses of long-term outcomes after treatment in patients with differentiated thyroid cancer.

Objective: The objective was to examine effects of initial therapies on outcomes.

Design/setting: This was a prospective multi-institutional registry.

Patients: A total of 4941 patients, median follow-up, 6 years, participated.

Intervention: Interventions included total/near-total thyroidectomy (T/NTT), postoperative radioiodine (RAI), and thyroid hormone suppression therapy (THST).

Main Outcome Measure: Main outcome measures were overall survival (OS) and disease-free survival using product limit and proportional hazards analyses.

Results: Improved OS was noted in NTCTCS stage III patients who received RAI (risk ratio [RR], 0.66; P = .04) and stage IV patients who received both T/NTT and RAI (RR, 0.66 and 0.70; combined P = .049). In all stages, moderate THST (TSH maintained subnormal-normal) was associated with significantly improved OS (RR stages I-IV: 0.13, 0.09, 0.13, 0.33) and disease-free survival (RR stages I-III: 0.52, 0.40, 0.18); no additional survival benefit was achieved with more aggressive THST (TSH maintained undetectable-subnormal). This remained true, even when distant metastatic disease was diagnosed during follow-up. Lower initial stage and moderate THST were independent predictors of improved OS during follow-up years 1-3.

Conclusions: We confirm previous findings that T/NTT followed by RAI is associated with benefit in high-risk patients, but not in low-risk patients. In contrast with earlier reports, moderate THST is associated with better outcomes across all stages, and aggressive THST may not be warranted even in patients diagnosed with distant metastatic disease during follow-up. Moderate THST continued at least 3 years after diagnosis may be indicated in high-risk patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/JC.2015-1346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393522PMC
September 2015

Race/Ethnicity and the prevalence of thyrotoxicosis in young Americans.

Thyroid 2015 Jun 8;25(6):621-8. Epub 2015 May 8.

2Population Health Department, QIMR Berghofer Medical Research Institute, Herston, Australia.

Background: Race/ethnicity may be a newly recognized risk factor for Graves' disease.

Objective: The aim of this study was to examine the prevalence of thyrotoxicosis by race/ethnicity in Americans aged 12-49 years using three National Health and Nutritional Examination Surveys (NHANES).

Methods: Data were analyzed from 17,939 participants in NHANES III (1988-1994), NHANES 1999-2002, and NHANES 2007-2010 with available thyroid function test results. Thyrotoxicosis was defined as a serum thyrotropin (TSH) of ≤0.1 mIU/L or subjects taking methimazole or propylthiouracil, and overt thyrotoxicosis was defined as high serum thyroxine and a serum TSH of ≤0.1 mIU/L. Logistic regression was performed accounting for the complex sampling design of NHANES, and the results from all three NHANES surveys were combined using a random-effects model.

Results: There were 75 study participants with point prevalent thyrotoxicosis, representing a pooled prevalence of 0.4% for Americans aged 12-49 years. Prevalent thyrotoxicosis was nearly three times more likely in non-Hispanic black subjects compared with non-Hispanic whites (OR=2.9 [CI 1.5-5.7]), while there was no difference between the prevalence of thyrotoxicosis in Mexican Americans compared to non-Hispanic whites (OR=1.2 [CI 0.6-2.4]; I2 for heterogeneity=0% for both). Among 27 patients with overt thyrotoxicosis, the odds ratio was 8.7 [CI 0.7-112.6] for non-Hispanic blacks and 4.6 [CI 0.4-59.3] for Mexican Americans compared with non-Hispanic whites.

Conclusions: The results suggest there are race/ethnicity differences in the prevalence of thyrotoxicosis. Future studies should address whether these differences are due to heritable factors, environmental exposures, or a combination of both.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2014.0504DOI Listing
June 2015

The clinical endocrinology workforce: current status and future projections of supply and demand.

J Clin Endocrinol Metab 2014 Sep 18;99(9):3112-21. Epub 2014 Jun 18.

Diabetes Institute (R.A.V.), Walter Reed National Military Medical Center, Bethesda, Maryland 20889; Hennepin County Medical Center (L.F.), Minneapolis, Minnesota 55425; The Lewin Group (P.H.), Falls Church, Virginia 22042; Diabetes, Obesity, and Metabolism Institute (A.S.), Mt Sinai School of Medicine, New York, New York 10029; The Endocrine Society (S.K.), Washington, DC 20036; Division of Endocrinology and Metabolism (P.W.L.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Endocrinology and Diabetes Practice (M.M.), University of Colorado Hospital, Denver, Colorado 80045; and Division of Endocrinology, Diabetes, and Metabolism (K.H.H.), Nassau University Medical Center, East Meadow, New York 11554.

Context: Many changes in health care delivery, health legislation, and the physician workforce that affect the supply and demand for endocrinology services have occurred since the first published workforce study of adult endocrinologists in 2003.

Objective: The objective of the study was to assess the current adult endocrinology workforce data and provide the first analysis of the pediatric endocrinology workforce and to project the supply of and demand for endocrinologists through 2025.

Design: A workforce model was developed from an analysis of proprietary and publicly available databases, consultation with a technical expert panel, and the results of an online survey of board-certified endocrinologists.

Participants: The Endocrine Society commissioned The Lewin Group to estimate current supply and to project gaps between supply and demand for endocrinologists. A technical expert panel of senior endocrinologists provided context, clinical information, and direction.

Main Outcome Measures: The following were measured: 1) the current adult and pediatric endocrinology workforce and the supply of and demand for endocrinologists through 2025 and 2) the number of additional entrants into the endocrinology work pool that would be required to close the gap between supply and demand.

Results: Currently there is a shortage of approximately 1500 adult and 100 pediatric full-time equivalent endocrinologists. The gap for adult endocrinologists will expand to 2700 without an increase in the number of fellows trained. An increase in the prevalence of diabetes mellitus further expands the demand for adult endocrinologists. The gap can be closed in 5 and 10 years by increasing the number of fellowship positions by 14.4% and 5.5% per year, respectively. The gap between supply and demand for pediatric endocrinologists will close by 2016, and thereafter an excess supply over demand will develop at the current rate of new entrants into the work force.

Conclusions: There are insufficient adult endocrinologists to satisfy current and future demand. A number of proactive strategies need to be instituted to mitigate this gap.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2014-2257DOI Listing
September 2014

Defining, assessing, and certifying procedural competency in endocrinology, diabetes, and metabolism.

J Clin Endocrinol Metab 2014 Aug 13;99(8):2651-3. Epub 2014 May 13.

Division of Endocrinology, Diabetes, and Metabolism (P.W.L.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Division of Diabetes, Endocrinology, and Metabolism (A.B.), Baylor College of Medicine, Houston, Texas 77030; Division of Endocrinology (A.D.), Veterans Affairs New York Harbor Health Care System and New York University Langone Medical Center, New York, New York 10016; and Research Program in Men's Health: Aging and Metabolism (S.B.), Brigham and Women's Hospital, Boston, Massachusetts 02115.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2014-1555DOI Listing
August 2014

Reductions in serum levels of LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver-selective thyroid hormone receptor agonist eprotirome.

J Intern Med 2015 Mar 16;277(3):331-342. Epub 2014 May 16.

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Liver-selective thyromimetic agents could provide a new approach for treating dyslipidaemia.

Methods: We performed a multicentre, randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of eprotirome, a liver-selective thyroid hormone receptor agonist, in 98 patients with primary hypercholesterolaemia. After previous drug wash-out and dietary run-in, patients received 100 or 200 μg day(-1) eprotirome or placebo for 12 weeks. The primary end-point was change in serum LDL cholesterol; secondary end-points included changes in other lipid parameters and safety measures.

Results: Eprotirome treatment at 100 and 200 μg daily reduced serum LDL cholesterol levels by 23 ± 5% and 31 ± 4%, respectively, compared with 2 ± 6% for placebo (P < 0.0001). Similar reductions were seen in non-HDL cholesterol and apolipoprotein (apo) B, whereas serum levels of HDL cholesterol and apo A-I were unchanged. There were also considerable reductions in serum triglycerides and lipoprotein(a), in particular in patients with elevated levels at baseline. There was no evidence of adverse effects on heart or bone and no changes in serum thyrotropin or triiodothyronine, although the thyroxine level decreased. Low-grade increases in liver enzymes were evident in most patients.

Conclusion: In hypercholesterolaemic patients, the liver-selective thyromimetic eprotirome decreased serum levels of atherogenic lipoproteins without signs of extra-hepatic side effects. Selective stimulation of hepatic thyroid hormone receptors may be an attractive way to modulate lipid metabolism in hyperlipidaemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/joim.12261DOI Listing
March 2015

Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study.

Lancet Diabetes Endocrinol 2014 Jun 18;2(6):455-63. Epub 2014 Feb 18.

Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands. Electronic address:

Background: Eprotirome is a liver-selective thyroid hormone receptor agonist that has been shown to lower plasma LDL cholesterol concentrations in previous phase 1 and 2 studies of patients with dyslipidaemia. We aimed to assess the long-term safety and efficacy of 50 μg and 100 μg eprotirome in patients with familial hypercholesterolaemia.

Methods: For this randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial, we enrolled patients between Oct 3, 2011, and Feb 14, 2012, at 53 sites in 11 countries in Europe, Africa, and south Asia. Patients were eligible for enrolment if they were aged 18 years or older, diagnosed with heterozygous familial hypercholesterolaemia, and had not reached target LDL cholesterol concentrations after at least 8 weeks of statin therapy with or without ezetimibe. We used a computer-generated randomisation sequence to allocate patients to one of three groups: 50 μg eprotirome, 100 μg eprotirome, or placebo. This trial was planned for 52-76 weeks, with primary efficacy analysis at 12 weeks, but it was prematurely terminated when another study found that eprotirome causes cartilage damage in dogs. Although it was impossible to meet the predefined study outcomes, we analysed changes in the concentrations of LDL cholesterol and other lipids, liver parameters, thyroid hormone concentrations, and adverse effects of treatment with eprotirome versus placebo at 6 weeks of treatment. Analysis was done in all patients who received 6 weeks of treatment. This study is registered with ClinicalTrials.gov, number NCT01410383.

Findings: We enrolled 236 patients, randomly allocating 80 to receive placebo, 79 to receive 50 μg eprotirome, and 77 to receive 100 μg eprotirome. 69 patients reached the 6 week timepoint (23 given placebo, 24 given 50 μg eprotirome, and 22 given 100 μg eprotirome). Mean LDL cholesterol concentrations increased by 9% (95% CI -2 to 20) in the placebo group, decreased by 12% (-28 to 4%; p=0.0677 vs placebo) in the 50 μg eprotirome group, and decreased by 22% (-32 to -13%; p=0.0045 vs placebo) in the 100 μg eprotirome group. We noted statistically significant increases between both eprotirome groups and placebo in aspartate aminotransferase (AST; p<0.0001), alanine aminotransferase (ALT; p<0.0001), conjugated bilirubin (p=0.0006), and gamma-glutamyltranspeptidase (p<0.0001). Four patients had to discontinue or interrupt study treatment before trial termination due to AST increases between the upper limit of normal (ULN) and six times ULN, and ALT concentrations between three and seven times ULN. Although we detected no changes in serum concentrations of thyroid-stimulating hormone or free tri-iodothyronine, free tetra-iodothyronine decreased by 19% (23 to 16) in the 50 μg eprotirome group and 27% (30 to 23) in the 100 μg eprotirome group (p<0.0001 vs placebo for both groups).

Interpretation: Our findings show that eprotirome can lower LDL cholesterol concentrations in patients with familial hypercholesterolaemia when added to conventional statin treatment with or without ezetimibe, but that it has the potential to induce liver injury. These findings, along with findings of cartilage damage in dogs, raise serious doubts about selective thyroid hormone mimetics as a therapeutic approach to lower LDL cholesterol concentrations.

Funding: Karo Bio AB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-8587(14)70006-3DOI Listing
June 2014

Prognosis of differentiated thyroid cancer in relation to serum thyrotropin and thyroglobulin antibody status at time of diagnosis.

Thyroid 2014 Jan 4;24(1):35-42. Epub 2013 Sep 4.

1 Department of Internal Medicine & Aged Care, Royal Brisbane and Women's Hospital , Herston, Australia .

Background: Serum thyrotropin (TSH) concentration and thyroid autoimmunity may be of prognostic importance in differentiated thyroid cancer (DTC). Preoperative serum TSH level has been associated with higher DTC stage in cross-sectional studies; data are contradictory on the significance of thyroid autoimmunity at the time of diagnosis.

Objective: We sought to assess whether preoperative serum TSH and perioperative antithyroglobulin antibodies (TgAb) were associated with thyroid cancer stage and outcome in DTC patients followed by the National Thyroid Cancer Treatment Cooperative Study, a large multicenter thyroid cancer registry.

Methods: Patients registered after 1996 with available preoperative serum TSH (n=617; the TSH cohort) or perioperative TgAb status (n=1770; the TgAb cohort) were analyzed for tumor stage, persistent disease, recurrence, and overall survival (OS; median follow-up, 5.5 years). Parametric tests assessed log-transformed TSH, and categorical variables were tested with chi square. Disease-free survival (DFS) and OS was assessed with Cox models.

Results: Geometric mean serum TSH levels were higher in patients with higher-stage disease (Stage III/IV=1.48 vs. 1.02 mU/L for Stages I/II; p=0.006). The relationship persisted in those aged ≥45 years after adjusting for sex (p=0.01). Gross extrathyroidal extension (p=0.03) and presence of cervical lymph node metastases (p=0.003) were also significantly associated with higher serum TSH. Disease recurrence and all-cause mortality occurred in 37 and 38 TSH cohort patients respectively, which limited the power for survival analysis. Positive TgAb was associated with lower stage on univariate analysis (positive TgAb in 23.4% vs. 17.8% of Stage I/II vs. III/IV patients, respectively; p=0.01), although the relationship lost significance when adjusting for age and sex (p=0.34). Perioperative TgAb was not an independent predictor of DFS (hazard ratio=1.12 [95% confidence interval=0.74-1.69]) or OS (hazard ratio=0.98 [95% confidence interval=0.56-1.72]).

Conclusions: Preoperative serum TSH level is associated with higher DTC stage, gross extrathyroidal extension, and neck node metastases. Perioperative TgAb is not an independent predictor of DTC prognosis. A larger cohort is required to assess whether preoperative serum TSH level predicts recurrence or mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2013.0062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887423PMC
January 2014

Clinical significance of discordant findings between pre-therapy (123)I and post-therapy (131)I whole body scan in patients with thyroid cancer.

Int J Clin Exp Med 2013 22;6(5):320-33. Epub 2013 May 22.

Division of Nuclear Medicine, Department of Radiology, Johns Hopkins University Baltimore, MD, USA.

Radioactive therapy with (131)I (RAI) is commonly used during the management of patients with differentiated thyroid cancer (DTC). The aim of this study was to determine the clinical significance of discordant findings between pre-RAI whole body scan (WBS) with (123)I and post-RAI WBS in the management of DTC. We retrospectively evaluated 342 individuals between 2002 and 2008 who had a diagnosis of DTC and underwent RAI. All had WBS one day before RAI and WBS one week after RAI. Patients were divided into 3 groups: 1) RAI-naive subjects without known distant metastatic disease (M1); 2) patients with history of prior RAI and persistent disease (except M1); and 3) patients with known M1. In Group 1 (n=311), 7% of patients (n=22) had discordant scans, but in only 4 of these cases did this represent true disease (3 unsuspected lung and 1 mediastinal node metastasis). In the remaining 18 patients, discordant findings corresponded to physiologic or other benign causes. In group 2 (n=23), 7 subjects (30%) had discordant findings and all of the discrepant sites consisted of loco-regional nodal disease in the neck/upper mediastinum (n=6) and M1 in lung (n=1). In group 3 (n=8), 5 patients (62%) showed discordant uptake in lung and bone which corresponded to the locations of known M1. A total of 12 patients with iodine-avid M1 were identified on post-RAI WBS (3.5% of entire cohort). Pre-RAI WBS was only concordant in 3 of these cases (25%). In conclusion, the significance of pre and post-RAI WBS is highly influenced by the clinical setting. Unsuspected distant metastatic disease is infrequent in RAI-naive patients without known M1, where most discordant findings are usually due to benign explanations, and represent false positive findings in this group. In contrast, in patients with history of previous RAI or known M1, discordant results likely correspond to true disease. In our study, pre-RAI scans showed a low yield to detect iodine-avid distant metastatic disease when compared to post-RAI scans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663998PMC
June 2013

Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer.

JAMA 2013 Apr;309(14):1493-501

Laboratory for Cellular and Molecular Thyroid Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Importance: BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established.

Objective: To investigate the relationship between BRAF V600E mutation and PTC-related mortality.

Design, Setting, And Participants: Retrospective study of 1849 patients (1411 women and 438 men) with a median age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011.

Main Outcomes And Measures: Patient deaths specifically caused by PTC.

Results: Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001) in BRAF V600E-positive vs mutation-negative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]).

Conclusions And Relevance: In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2013.3190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791140PMC
April 2013

Patterns of interferon-alpha-induced thyroid dysfunction vary with ethnicity, sex, smoking status, and pretreatment thyrotropin in an international cohort of patients treated for hepatitis C.

Thyroid 2013 Sep 3;23(9):1151-8. Epub 2013 Aug 3.

1 Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine , Baltimore, Maryland.

Background: Interferon-alpha (IFNα)-induced thyroid dysfunction occurs in up to 20% of patients undergoing therapy for hepatitis C. The diversity of thyroid disease presentations suggests that several different pathological mechanisms are involved, such as autoimmunity and direct toxicity. Elucidating the relationships between risk factors and disease phenotype provides insight into the mechanisms of disease pathophysiology.

Methods: We studied 869 euthyroid patients from the ACHIEVE 2/3 trial, a randomized international clinical trial comparing pegylated-IFNα2a weekly or albumin-IFNα2b every 2 weeks for up to 24 weeks in patients with hepatitis C, genotype 2 or 3, from 136 centers. The study population was 60% male and 55% white. Serum thyrotropin (TSH) and free thyroxine were measured before therapy, monthly during treatment from week 8, and at 4- and 12-week follow-up visits.

Results: Overall, 181 (20.8%) participants had at least one abnormal TSH during the study. Low TSH occurred in 71 (8.2%), of whom 30 (3.5%) had a suppressed TSH below 0.1 mU/L. Hypothyroidism occurred in 53 patients (6.1%), with peak TSH above 10 mU/L in 12 patients (1.4%). Fifty-seven patients had a biphasic thyroiditis (6.6%), with extreme values for the nadir and/or peak TSH in all but one. Medical therapy was given to one thyrotoxic patient, four hypothyroid patients, and 26 biphasic thyroiditis patients. Multivariate logistic regression analysis demonstrated that biphasic thyroiditis is associated with being female and higher pretreatment serum TSH, whereas being Asian or a current smoker decreased the risk of thyroiditis. Hypo- and hyperthyroidism are most strongly predicted by the pretreatment TSH.

Conclusions: Biphasic thyroiditis accounted for the majority (58%) of clinically relevant IFNα-induced thyroid dysfunction. We confirmed our recent findings in a related cohort that female sex is a risk factor for thyroiditis but not hypothyroidism. Further, in this large multiethnic study, the risk of thyroiditis is dramatically increased, specifically for white women. Smoking was found to be protective of thyroiditis. These results support closer monitoring of women and those with a serum TSH at the extremes of the normal range during therapy so that prompt intervention can mitigate the consequences of thyroid dysfunction associated with IFNα treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2012.0565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770239PMC
September 2013