Phase I clinical trials in 56 patients with thyroid cancer: the M. D. Anderson Cancer Center experience.

INTRODUCTION: Thyroid cancer is the most common endocrine malignancy. The outcomes of patients with relapsed thyroid cancer treated on early-phase clinical trials have not been systematically analyzed. PATIENTS AND METHODS: We reviewed the records of consecutive patients with metastatic thyroid cancer referred to the Phase I Clinical Trials Program from March 2006 to April 2008. Best response was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: Fifty-six patients were identified. The median age was 55 yr (range 35-79 yr). Of 49 patients evaluable for response, nine (18.4%) had a partial response, and 16 (32.7%) had stable disease for 6 months or longer. The median progression-free survival was 1.12 yr. With a median follow-up of 15.6 months, the 1-yr survival rate was 81%. In univariate analysis, factors predicting shorter survival were anaplastic histology (P = 0.0002) and albumin levels less than 3.5 g/dl (P = 0.05). Among 26 patients with tumor decreases, none died (median follow-up 1.3 yr), whereas 52% of patients with any tumor increase died by 1 yr (P = 0.0001). The median time to failure in our phase I clinical trials was 11.5 months vs. 4.1 months for the previous treatment (P = 0.04). CONCLUSION: Patients with advanced thyroid cancer treated on phase I clinical trials had high rates of partial response and prolonged stable disease. Time to failure was significantly longer on the first phase I trial compared with the prior conventional treatment. Patients with any tumor decrease had significantly longer survival than those with any tumor increase.

Eemian and Holocene sea-surface conditions in the southern Black Sea: organic-walled dinoflagellate cyst record from core 22-GC3

In order to compare the sea-surface conditions in the Black Sea during the Holocene and Eemian, sapropelic parts of marine core 22-GC3 (42°13.53′N/36°29.55′E, 838 m water depth) were studied for organic-walled dinoflagellate cyst content. The record shows a change from freshwater/brackish assemblages (Pyxidinopsis psilata, Spiniferites cruciformis, and Caspidinium rugosum) to more marine assemblages (Lingulodinium machaerophorum and Spiniferites ramosus complex) during each interglacial, due to the inflow of saline Mediterranean water. The lacustrine–marine transitions in 22-GC3 occurred at ~ 8.3 cal kyr BP during the early Holocene and ~ 128 kyr BP during the early Eemian, slightly later compared to the onset of interglacial conditions on the adjacent land. Dinoflagellate cyst assemblages reveal higher sea-surface salinity (~ 28–30) (e.g. Spiniferites pachydermus, Bitectatodinium tepikiense, and Spiniferites mirabilis) around ~ 126.5–121 kyr BP in comparison to the Holocene (~ 15–20) as well as relatively high sea-surface temperature (e.g. Tuberculodinium vancampoae, S. pachydermus, and S. mirabilis) especially at ~ 127.6–125.3 kyr BP. Establishment of high sea-surface salinity during the Eemian correlates very well with reconstructed relatively high global sea-level and is explained as a combined effect of increased Mediterranean supply and high temperatures at the beginning of the last interglacial. The observed changes in the dinocyst record highlight the importance of nutrients for the composition of the Eemian and Holocene dinocyst assemblages.

THE ROLE OF ADRENAL AND THYROID HORMONES IN GASTRIC DEVELOPMENT (THYROXINE, PARIETAL CELL, CORTICOSTERONE)

The role of adrenal and thyroid hormones on the development of chief and parietal cells was studied in the rat. Administration of corticosterone or thyroxine in the first and second postnatal weeks resulted in the precocious appearance of pepsinogen in the oxyntic gland mucosa and an increase in basal acid output. When pups were adrenalectomized or made hypothyroid, both pepsinogen and basal acid secretion were lowed. Corticosterone injection increased pepsinogen content and acid secretion to levels higher than those of control in hypothyroid and adrenalectomized rats while thyroxine had no such effect in adrenalectomized rats. Morphologically, chief cells responded to corticosterone or thyroxine with increases in both zymogen granules and RER. Chief cells, however, contained less zymogen granules and RER in adrenalectomized and hypothyroid rats. Corticosterone was effective in restoring the normal morphological appearance of chief cells in the hypothyroid rats while thyroxine had no effect in the adrenalectomized rats. In response to corticosterone or thyroxine, parietal cells in normal animals appeared to contain more mitochondria, tubulovesicles and intracellular canaliculi than those of control. Unlike chief cells, parietal cells retained normal ultrastructure in the absence of adrenal and thyroid hormones. These data indicate that (1) corticosterone is necessary for the functional and morphological development of chief cells; (2) the morphological development of parietal cells does not appear to depend upon corticosterone, (3) the effect of thyroxine on the development of chief and parietal cells is due to corticosterone. ^

Diagnosis and interdisciplinary treatment of a botryoid odontogenic cyst in the posterior mandible: report of a case.

Botryoid odontogenic cysts (BOC) are considered to be rare polycystic variants of lateral periodontal cysts characterized by a multilocular growth pattern. The most frequent location of BOC is the mandible, predominantly the premolar-canine area, followed by the anterior region of the maxilla. The cyst shows a slight female predilection. This case report of a BOC demonstrates a treatment with initial fenestration and decompression of the cyst in order to prevent damage to adjacent structures such as the inferior alveolar nerve. The present case report emphasizes the importance of accurate clinical, radiographic, and histologic diagnostic procedures of unspecific radiolucent lesions in the jaws to establish a firm diagnosis and avoid inappropriate treatment strategies.

Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas.

Glucagon-like-peptide-1 (GLP1) analogs may induce thyroid or pancreatic diseases in animals, raising questions about their use in diabetic patients. There is, however, controversy regarding expression of GLP1 receptors (GLP1R) in human normal and diseased thyroid and pancreas. Here, 221 human thyroid and pancreas samples were analyzed for GLP1R immunohistochemistry and compared with quantitative in vitro GLP1R autoradiography. Neither normal nor hyperplastic human thyroids containing parafollicular C cells express GLP1R with either method. Papillary thyroid cancer do not, and medullary thyroid carcinomas rarely express GLP1R. Insulin- and somatostatin-producing cells in the normal pancreas express a high density of GLP1R, whereas acinar cells express them in low amounts. Ductal epithelial cells do not express GLP1R. All benign insulinomas express high densities of GLP1R, whereas malignant insulinomas rarely express them. All ductal pancreatic carcinomas are GLP1R negative, whereas 6/20 PanIN 1/2 and 0/12 PanIN 3 express GLP1R. Therefore, normal thyroid, including normal and hyperplastic C cells, or papillary thyroid cancer are not targets for GLP1 analogs in humans. Conversely, all pancreatic insulin- and somatostatin-producing cells are physiological GLP1 targets, as well as most acini. As normal ductal epithelial cells or PanIN 3 or ductal pancreatic carcinomas do not express GLP1R, it seems unlikely that GLP1R is related to neoplastic transformation in pancreas. GLP1R-positive medullary thyroid carcinomas and all benign insulinomas are candidates for in vivo GLP1R targeting.Modern Pathology advance online publication, 12 September 2014; doi:10.1038/modpathol.2014.113.

Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.

CONTEXT Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk. OBJECTIVE The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs). DATA SOURCES AND STUDY SELECTION A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes. DATA EXTRACTION Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events. DATA SYNTHESIS Among 38 274 adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status. CONCLUSIONS CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.

Subclinical thyroid dysfunction and the risk for fractures: a systematic review and meta-analysis.

BACKGROUND Data on the association between subclinical thyroid dysfunction and fractures conflict. PURPOSE To assess the risk for hip and nonspine fractures associated with subclinical thyroid dysfunction among prospective cohorts. DATA SOURCES Search of MEDLINE and EMBASE (1946 to 16 March 2014) and reference lists of retrieved articles without language restriction. STUDY SELECTION Two physicians screened and identified prospective cohorts that measured thyroid function and followed participants to assess fracture outcomes. DATA EXTRACTION One reviewer extracted data using a standardized protocol, and another verified data. Both reviewers independently assessed methodological quality of the studies. DATA SYNTHESIS The 7 population-based cohorts of heterogeneous quality included 50,245 participants with 1966 hip and 3281 nonspine fractures. In random-effects models that included the 5 higher-quality studies, the pooled adjusted hazard ratios (HRs) of participants with subclinical hyperthyroidism versus euthyrodism were 1.38 (95% CI, 0.92 to 2.07) for hip fractures and 1.20 (CI, 0.83 to 1.72) for nonspine fractures without statistical heterogeneity (P = 0.82 and 0.52, respectively; I2= 0%). Pooled estimates for the 7 cohorts were 1.26 (CI, 0.96 to 1.65) for hip fractures and 1.16 (CI, 0.95 to 1.42) for nonspine fractures. When thyroxine recipients were excluded, the HRs for participants with subclinical hyperthyroidism were 2.16 (CI, 0.87 to 5.37) for hip fractures and 1.43 (CI, 0.73 to 2.78) for nonspine fractures. For participants with subclinical hypothyroidism, HRs from higher-quality studies were 1.12 (CI, 0.83 to 1.51) for hip fractures and 1.04 (CI, 0.76 to 1.42) for nonspine fractures (P for heterogeneity = 0.69 and 0.88, respectively; I2 = 0%). LIMITATIONS Selective reporting cannot be excluded. Adjustment for potential common confounders varied and was not adequately done across all studies. CONCLUSION Subclinical hyperthyroidism might be associated with an increased risk for hip and nonspine fractures, but additional large, high-quality studies are needed. PRIMARY FUNDING SOURCE Swiss National Science Foundation.

MicroRNA profile of poorly differentiated thyroid carcinomas: new diagnostic and prognostic insights.

The diagnosis of conventional and oncocytic poorly differentiated (oPD) thyroid carcinomas is difficult. The aim of this study is to characterise their largely unknown miRNA expression profile and to compare it with well-differentiated thyroid tumours, as well as to identify miRNAs which could potentially serve as diagnostic and prognostic markers. A total of 14 poorly differentiated (PD), 13 oPD, 72 well-differentiated thyroid carcinomas and eight normal thyroid specimens were studied for the expression of 768 miRNAs using PCR-Microarrays. MiRNA expression was different between PD and oPD thyroid carcinomas, demonstrating individual clusters on the clustering analysis. Both tumour types showed upregulation of miR-125a-5p, -15a-3p, -182, -183-3p, -222, -222-5p, and downregulation of miR-130b, -139-5p, -150, -193a-5p, -219-5p, -23b, -451, -455-3p and of miR-886-3p as compared with normal thyroid tissue. In addition, the oPD thyroid carcinomas demonstrated upregulation of miR-221 and miR-885-5p. The difference in expression was also observed between miRNA expression in PD and well-differentiated tumours. The CHAID algorithm allowed the separation of PD from well-differentiated thyroid carcinomas with 73-79% accuracy using miR-23b and miR-150 as a separator. Kaplan-Meier and multivariate analysis showed a significant association with tumour relapses (for miR-23b) and with tumour-specific death (for miR-150) in PD and oPD thyroid carcinomas. MiRNA expression is different in conventional and oPD thyroid carcinomas in comparison with well-differentiated thyroid cancers and can be used for discrimination between these tumour types. The newly identified deregulated miRNAs (miR-150, miR-23b) bear the potential to be used in a clinical setting, delivering prognostic and diagnostic informations.

Paediatric thyroid surgery is safe - experiences at a tertiary surgical centre.

PRINCIPLES Thyroidectomy in children is rare and mostly performed because of thyroid neoplasms. The aim of this study based on prospective data acquisition was to evaluate whether thyroid surgery in children can be performed as safely as in adults when undertaken by a team of adult endocrine surgeons and paediatric surgeons. METHODS Between 2002 and 2012, 36 patients younger than 18 years underwent surgery for thyroid gland pathologies. All surgical procedures were performed by an experienced endocrine surgeon and a paediatric surgeon. Baseline demographic data, surgical procedure, duration of operation, length of hospital stay, and postoperative morbidity and mortality were analysed. RESULTS The median age of all patients was 13 years (range 2-17 years), with predominantly female gender (n = 30, 83%). The majority of operations were performed because of benign thyroid disease (n = 27, 75%) and only a minority because of malignancy or genetic abnormality with predisposition for malignant transformation (MEN) (n = 9, 25%). Total thyroidectomy was performed in the majority of the patients (n = 24, 67%). The median duration of the surgical procedure was 153 minutes (range 90-310 minutes). The median hospital stay was 5 days (3-1 days). One patient developed persistent hypoparathyroidism after neck dissection due to cancer. One persistent and two temporary recurrent nerve palsies occurred. CONCLUSION This study demonstrated that paediatric thyroidectomy is safe as performed by this team of endocrine and paediatric surgeons, with acceptable morbidity even when total thyroidectomy was performed in the case of benign disease.

Activating BRAF and PIK3CA mutations cooperate to promote anaplastic thyroid carcinogenesis

UNLABELLED Thyroid malignancies are the most common type of endocrine tumors. Of the various histologic subtypes, anaplastic thyroid carcinoma (ATC) represents a subset of all cases but is responsible for a significant proportion of thyroid cancer-related mortality. Indeed, ATC is regarded as one of the more aggressive and hard to treat forms of cancer. To date, there is a paucity of relevant model systems to critically evaluate how the signature genetic abnormalities detected in human ATC contribute to disease pathogenesis. Mutational activation of the BRAF protooncogene is detected in approximately 40% of papillary thyroid carcinoma (PTC) and in 25% of ATC. Moreover, in ATC, mutated BRAF is frequently found in combination with gain-of-function mutations in the p110 catalytic subunit of PI3'-Kinase (PIK3CA) or loss-of-function alterations in either the p53 (TP53) or PTEN tumor suppressors. Using mice with conditional, thyrocyte-specific expression of BRAF(V600E), we previously developed a model of PTC. However, as in humans, BRAF(V600E)-induced mouse PTC is indolent and does not lead to rapid development of end-stage disease. Here, we use mice carrying a conditional allele of PIK3CA to demonstrate that, although mutationally activated PIK3CA(H1047R) is unable to drive transformation on its own, when combined with BRAF(V600E) in thyrocytes, this leads to development of lethal ATC in mice. Combined, these data demonstrate that the BRAF(V600E) cooperates with either PIK3CA(H1074R) or with silencing of the tumor-suppressor PTEN, to promote development of anaplastic thyroid carcinoma. IMPLICATIONS This genetically relevant mouse model of ATC will be an invaluable platform for preclinical testing of pathway-targeted therapies for the prevention and treatment of thyroid carcinoma.

Subclinical thyroid dysfunction and the risk of stroke: a systematic review and meta-analysis

Subclinical thyroid dysfunction has been associated with coronary heart disease, but the risk of stroke is unclear. Our aim is to combine the evidence on the association between subclinical thyroid dysfunction and the risk of stroke in prospective cohort studies. We searched Medline (OvidSP), Embase, Web-of-Science, Pubmed Publisher, Cochrane and Google Scholar from inception to November 2013 using a cohort filter, but without language restriction or other limitations. Reference lists of articles were searched. Two independent reviewers screened articles according to pre-specified criteria and selected prospective cohort studies with baseline thyroid function measurements and assessment of stroke outcomes. Data were derived using a standardized data extraction form. Quality was assessed according to previously defined quality indicators by two independent reviewers. We pooled the outcomes using a random-effects model. Of 2,274 articles screened, six cohort studies, including 11,309 participants with 665 stroke events, met the criteria. Four of six studies provided information on subclinical hyperthyroidism including a total of 6,029 participants and five on subclinical hypothyroidism (n = 10,118). The pooled hazard ratio (HR) was 1.08 (95 % CI 0.87-1.34) for subclinical hypothyroidism (I (2) of 0 %) and 1.17 (95 % CI 0.54-2.56) for subclinical hyperthyroidism (I (2) of 67 %) compared to euthyroidism. Subgroup analyses yielded similar results. Our systematic review provides no evidence supporting an increased risk for stroke associated with subclinical thyroid dysfunction. However, the available literature is insufficient and larger datasets are needed to perform extended analyses. Also, there were insufficient events to exclude clinically significant risk from subclinical hyperthyroidism, and more data are required for subgroup analyses.

Thyroid signaling in immune organs and cells of the teleost fish rainbow trout (Oncorhynchus mykiss).

Thyroid hormones are involved in modulating the immune system in mammals. In contrast, there is no information on the role played by these hormones in the immune system of teleost fish. Here we provide initial evidence for the presence of active thyroid signaling in immune organs and cells of teleosts. We demonstrate that immune organs (head kidney and spleen) and isolated leukocytes (from head kidney and peripheral blood) of the rainbow trout (Oncorhynchus mykiss) express both thyroid receptor α (THRA) and β (THRB). Absolute mRNA levels of THRA were significantly higher than those of THRB. THRA showed higher expression in immune organs and isolated immune cells compared to the reference organ, liver, while THRB showed the opposite. In vivo exposure of trout to triiodothryronine (T3) or the anti-thyroid agent propylthiouracil (PTU) altered THR expression in immune organs and cells. Effect of T3 and PTU over the relative expression of selected marker genes of immune cell subpopulations was also studied. Treatments changed the relative expression of markers of cytotoxic, helper and total T cells (cd4, cd8a, trb), B lymphocytes (mIgM) and macrophages (csf1r). These findings suggest that the immune system of rainbow trout is responsive to thyroid hormones.