Coordinated expression of galectin-3 and caveolin-1 in thyroid cancer.

Galectin-3 (Gal3) is the single most accurate marker for the diagnosis of differentiated thyroid cancer (DTC). Gal3 overrides the tumour suppressor activity of caveolin-1 (Cav1) and functions in concert with Cav1 to promote focal adhesion turnover and tumour cell migration and invasion. To study their coordinated role in progression of a human cancer, we investigated the expression of Gal3 and Cav1 in specimens of human benign thyroid lesions, DTC and anaplastic thyroid cancer (ATC). Gal3 and Cav1 expression is significantly associated with DTC and ATC, but not benign nodules. Essentially all Cav1-positive DTC cancers express Gal3, supporting the synergistic activity of these two proteins in DTC progression. Similarly, coordinated elevated Gal3/Cav1 expression was observed in three DTC-derived cell lines (papillary TCP1 and KTC1 and follicular FTC133) but only one (ACT1) of five ATC-derived cell lines. Using siRNA knockdown, Gal3 and Cav1 were shown to be required for RhoA GTPase activation, stabilization of focal adhesion kinase (FAK; a measure of focal adhesion signalling and turnover) and increased migration of the DTC cell lines studied, but not the ATC cell lines, including ACT1, which expresses elevated levels of Gal3 and Cav1. Co-expression of Gal3 and Cav1 in the T238 anaplastic cell line stabilized FAK-GFP in focal adhesions. Gal3 and Cav1 therefore function synergistically to promote focal adhesion signalling, migration and progression of DTC.

Limited adequacy of thyroid cancer patient follow-up at a Canadian tertiary care centre.

BACKGROUND: We sought to evaluate the adequacy of follow-up of thyroid cancer patients at a Canadian centre. METHODS: We mailed a survey to the family physicians of thyroid cancer patients and analyzed the findings relative to follow-up guidelines published by the American Thyroid Association (ATA). Statistical significance between early and late follow-up patterns was analyzed using the χ(2) test. RESULTS: Our survey response rate was 56.2% (91 of 162). The time from operation ranged from 1.24-7.13 (mean 3.96) years, and 87.9% of patients had undergone a physical exam within the previous year. Only 37.4% and 14% of patients had a serum thyroglobulin measurement within 6 and between 6 and 12 months before the survey, respectively. Thyroid simulating hormone (TSH) levels were measured within the prior 6 months in 67% of patients and between 6 and 12 months in 13.2%. The TSH levels were suppressed (< 0.1 µIU/L) in 24.2% of patients, 0.1-2 µIU/L in 44% and greater than 2 µIU/L in 17.6%. Ultrasonography was the most common imaging test performed. CONCLUSION: There is significant variation in the follow-up patterns of patients with thyroid cancer, and there is considerable deviation from current ATA guidelines.

CONTEXTE: Nous avons évalué la pertinence du suivi des patients atteints d'un cancer de la thyroïde dans un centre canadien. MÉTHODES: Nous avons posté un questionnaire aux médecins de famille de patients atteints d'un cancer de la thyroïde et analysé les résultats en regard des lignes directrices concernant le suivi publiées par l'American Thyroid Association (ATA). Nous avons utilisé le test du χ2 pour comparer la portée statistique des modes de suivi précoce et tardif. RÉSULTATS: Le taux de réponse à notre sondage a été de 56,2 % (91 sur 162). Le temps écoulé depuis l'intervention variait de 1,24 à 7,13 (moyenne 3,96) ans et 87,9 % des patients avaient subi un examen physique au cours de l'année écoulée. Seulement 37,4 % et 14 % des patients avaient eu un dosage de leur thyroglobuline sérique dans les derniers 6 mois et entre les 6e et 12e mois précédant le sondage, respectivement. Les taux de thyréostimuline (TSH) avaient été contrôlés au cours des 6 mois précédents chez 6 % des patients et entre les 6e et 12e mois chez 13,2 %. Les taux de TSH étaient supprimés (< 0,1 µUI/L) chez 24,2 % des patients, à 0,1­2 µUI/L chez 44 % et à plus de 2 µUI/L chez 17,6 %. L'échographie a été la technique d'ima gerie la plus utilisée. CONCLUSION: On note une variation significative dans le mode de suivi des patients atteints d'un cancer de la thyroïde et on note un écart considérable par rapport aux lignes directrices courantes de l'ATA.

Incremental value and clinical impact of neck sonography for primary hyperparathyroidism: a risk-adjusted analysis.

BACKGROUND: Despite the different preoperative imaging modalities available for parathyroid adenoma localization, there is currently no uniform consensus on the most appropriate preoperative imaging algorithm that should be routinely followed prior to the surgical management of primary hyperparathyroidism (PHPT). We sought to determine the incremental value of adding neck ultrasonography to scintigraphy-based imaging tests. METHODS: In a single institution, surgically naive patients with PHPT underwent the following localization studies before parathyroidectomy: 1) Tc-99m sestamibi imaging with single photon emission computed tomography/computed tomography (SPECT/CT) or Tc-99m sestamibi imaging with SPECT alone, or 2) ultrasonography in addition to those tests. We retrospectively collected data and performed a multivariate analysis comparing group I (single study) to group II (addition of ultrasonography) and risk of bilateral (BNE) compared with unilateral (UNE) neck exploration. RESULTS: Our study included 208 patients. Group II had 0.45 times the odds of BNE versus UNE compared with group I (unadjusted odds ratio [OR] 0.45, 95% confidence interval [CI] 0.25-0.81, p = 0.008). When adjusting for patient age, sex, preoperative calcium level, use of intraoperative PTH monitoring, preoperative PTH level, adenoma size, and number of abnormal parathyroid glands, Group II had 0.48 times the odds of BNE versus UNE compared with group I (adjusted OR 0.48, 95% CI 0.23-1.03, p = 0.06). In a subgroup analysis, only the addition of ultrasonography to SPECT decreased the risk of undergoing BNE compared with SPECT alone (unadjusted OR 0.40, 95% CI 0.19-0.84, p = 0.015; adjusted OR 0.38, 95% CI 0.15-0.96, p = 0.043). CONCLUSION: The addition of ultrasonography to SPECT, but not to SPECT/CT, has incremental value in decreasing the extent of surgery during parathyroidectomy, even after adjusting for multiple confounding factors.

CONTEXTE: Malgré l'existence de diverses modalités d'imagerie préopératoire pour la localisation de l'adénome parathyroïdien, on déplore actuellement l'absence de consensus en ce qui concerne l'algorithme le plus approprié à suivre au chapitre de l'imagerie préalable à une prise en charge chirurgicale de l'hyperparathyroïdie primaire (HPTP). Nous avons voulu vérifier si l'ajout de l'échographie du cou aux tests d'imagerie scintigraphique offrait une valeur ajoutée. MÉTHODES: Dans un établissement, des patients atteints d'HPTP n'ayant jamais subi d'intervention chirurgicale ont été soumis à des examens de localisation préparathyroïdectomie : 1) imagerie au moyen du sestamibi marqué au Tc-99m avec tomographie par émission monophotonique/tomodensitométrie (SPECT/CT), ou imagerie au moyen du sestamibi marqué au Tc-99m avec SPECT seule, our 2) échographie en plus de ces tests. Nous avons recueilli les données rétrospectivement et effectué une analyse multivariée pour comparer le Groupe I (examen seul) au Groupe II (ajout de l'échographie) et la probabilité qu'ils subissent une exploration cervicale bilatérale (ECB) plutôt qu'unilatérale (ECU). RÉSULTANTS: Notre étude a recruté 208 patients. Le Groupe II s'est trouvé exposé à un risque 0,45 fois plus grand d'être soumis à une ECB plutôt qu'à une ECU, comparativement au Groupe I (rapport des cotes [RC] non ajusté 0,45, intervalle de confiance [IC] de 95 % 0,25­0,81, p = 0,008). Après ajustement pour tenir compte de l'âge et du sexe des patients, de leur taux préopératoire de calcium, de la surveillance peropératoire de l'HPT, du taux préopératoire de l'HPT, de la taille de l'adénome et du nombre de ganglions parathyroïdiens anormaux, le Groupe II s'est révélé exposé à un risque 0,48 fois plus grand à l'égard de l'ECB plutôt que de l'ECU comparativement au Groupe I (RC ajusté 0,48, IC de 95 % 0,23­1,03, p = 0,06). Selon une analyse de sous-groupe, seul l'ajout de l'échographie à la SPECT a réduit le risque de subir une ECB comparativement à la SPECT seule (RC non ajusté 0,40, IC de 95 % 0,19­0,84, p = 0,015; RC ajusté 0,38, IC de 95 % 0,15­0,96, p = 0,043). CONCLUSIONS: L'ajout de l'échographie à la SPECT, mais non à la SPECT/CT, a offert une valeur ajoutée pour ce qui est de réduire l'étendue de l'opération durant la parathyroïdectomie, même après ajustement pour tenir compte de plusieurs facteurs de confusion.

Hemithyroidectomy is the preferred initial operative approach for an indeterminate fine needle aspiration biopsy diagnosis.

BACKGROUND: Fine needle aspiration biopsy represents the critical initial diagnostic test used for evaluation of thyroid nodules. Our objectives were to determine the cytological distribution, the utility of clinicopathologic characteristics for predicting malignancy and the true proportion of cancer among individuals who presented with indeterminate cytology and had undergone thyroid surgery for suspicion of cancer. METHODS: We retrospectively reviewed 1040 consecutive primary thyroid operations carried out over an 8-year period at a tertiary care endocrine referral centre. Follicular neoplasm (FN), Hürthle cell neoplasm (HN), neoplasms suspicious for but not diagnostic of papillary carcinoma (IP) and neoplasms with cellular atypia (IA) were reviewed. RESULTS: In all, 380 individuals presented with cytologically indeterminate thyroid nodules. Of these, 252 (66%) patients had FN, 47 (12%) HN, 44 (12%) IP, 26 (7%) IA and 11 (4%) had mixed diagnoses. Biopsied lesions were found to be malignant on pathological evaluation in 102 (27%) patients: 49 (19%) with FN, 11 (23%) HN, 28 (64%) IP and 9 (35%) with IA. Hemithyroidectomy was adequate definitive treatment in 196 of 225 (87%) patients with FN and 39 of 42 (93%) with HN. Significant associations with a cancer diagnosis were identified for smaller tumour size in patients with FN (p = 0.004) and right thyroid lobe location in patients with IP (p = 0.012), although these factors were nonsignificant in the corrected analyses for multiple comparisons. CONCLUSION: In a review of the experience at a Canadian centre, 4 operations were carried out to identify each cancer, and hemithyroidectomy was the optimal initial and definitive surgical approach for most patients.

Diagnostic utility of galectin-3 in thyroid cancer.

Galectin-3 (Gal-3), which has received significant recent attention for its utility as a diagnostic marker for thyroid cancer, represents the most well-studied molecular candidate for thyroid cancer diagnosis. Gal-3 is a protein that binds to beta-galactosidase residues on cell surface glycoproteins and has also been identified in the cytoplasmic and nuclear compartment. This marker has been implicated in regulation of normal cellular proliferation and apoptosis, as well as malignant transformation and the metastasis of cancer cells. We here present a mechanistic review of Gal-3 and its role in cancer development and progression. Gal-3 expression studies in thyroid tissue and cytologic tumor specimens and their methodological considerations are also discussed in this article. Despite great variance in their methodology, the majority of immunohistochemical studies found that Gal-3 was differentially expressed in thyroid carcinoma compared with benign and normal thyroid specimens, suggesting that Gal-3 is a good diagnostic marker for thyroid cancer. Recent studies have also demonstrated improved methodological reliability. On the other hand, Gal-3 genomic expression studies have shown inconsistent results for diagnostic utility and are not recommended. Overall, the development of Gal-3 as a diagnostic marker for thyroid cancer represents a promising avenue for future study, and its clinical application could significantly reduce the number of diagnostic thyroid operations performed for cases of indeterminant fine needle aspiration biopsy cytology, and thus positively impact the current management of thyroid nodular disease.

Synoptic pathology reporting for thyroid cancer: a review and institutional experience.

Thyroid cancer surgical pathology reports contain information that is critical for diagnosis, determining completeness of resection, staging and guiding postoperative management. Traditional narrative pathology reporting is prone to errors and omissions with variability in content and completeness. The objective of this review was to evaluate the impact of synoptic reporting on thyroid cancer pathology reporting. Our institutional study of pathology reporting of differentiated thyroid cancers at a Canadian tertiary care institution relative to the College of American Pathologists checklists is also presented and critically evaluates deficiencies in the narrative pathology reporting format.

Phosphocaveolin-1 is a mechanotransducer that induces caveola biogenesis via Egr1 transcriptional regulation.

Caveolin-1 (Cav1) is an essential component of caveolae whose Src kinase-dependent phosphorylation on tyrosine 14 (Y14) is associated with regulation of focal adhesion dynamics. However, the relationship between these disparate functions remains to be elucidated. Caveola biogenesis requires expression of both Cav1 and cavin-1, but Cav1Y14 phosphorylation is dispensable. In this paper, we show that Cav1 tyrosine phosphorylation induces caveola biogenesis via actin-dependent mechanotransduction and inactivation of the Egr1 (early growth response-1) transcription factor, relieving inhibition of endogenous Cav1 and cavin-1 genes. Cav1 phosphorylation reduces Egr1 binding to Cav1 and cavin-1 promoters and stimulates their activity. In MDA-231 breast carcinoma cells that express elevated levels of Cav1 and caveolae, Egr1 regulated Cav1, and cavin-1 promoter activity was dependent on actin, Cav1, Src, and Rho-associated kinase as well as downstream protein kinase C (PKC) signaling. pCav1 is therefore a mechanotransducer that acts via PKC to relieve Egr1 transcriptional inhibition of Cav1 and cavin-1, defining a novel feedback regulatory loop to regulate caveola biogenesis.

Anaplastic thyroid cancer: a comprehensive review of novel therapy.

Thyroid carcinomas are the most common cancer of the human endocrine system and are typically classified as papillary, follicular, anaplastic or medullary carcinomas. Although epidemiological studies have suggested an increased incidence of anaplastic thyroid carcinomas (ATCs) worldwide, there has been little evidence to suggest that, with current treatment, there has been any improvement in patient survival over the past two decades. Anaplastic thyroid carcinoma is one of the most aggressive human malignancies and is responsible for a disproportionate number of thyroid cancer-related deaths. Currently, available therapy for ATCs includes: chemotherapy, radiotherapy and surgery. Due to the poor treatment outcomes for individuals diagnosed with ATCs who undergo conventional therapy, novel therapeutic strategies for the treatment of ATCs are urgently needed. In this article, we review the existing management of ATCs, with a focus on novel molecular-targeted approaches as described in preclinical studies and in early human clinical trials.

Gender differences in thyroid cancer: a critical review.

It has long been known that the incidence of thyroid cancer in women is significantly higher than that in men. The objective of this article is to review gender differences in thyroid cancer, as well as epidemiological, clinical and experimental research on the role of sex hormones, their receptors and other molecular factors in this well-established thyroid cancer gender discrepancy. Although more common in women, thyroid cancer typically presents at a more advanced stage and with a worse disease prognosis in men. Clinical evidence on the impact of estrogen and other sex hormones on thyroid cancer has remained inconclusive, although numerous experimental studies have suggested that these hormones and their receptors may play a role in tumorigenesis and tumor progression. Studies of thyroid cancer cell lines suggest that an imbalance between the two estrogen receptor (ER) isoforms, α and ß, may be responsible for the cell proliferation seen with estrogen treatment. Expression studies on thyroid tumors indicate that they express ER and possibly progesterone receptors and androgen receptors, but there is conflicting evidence as to whether or not there is a difference in receptor status between thyroid cancers, benign thyroid lesions and normal thyroid tissue. There have been few studies evaluating the ERα/ERß profiles in thyroid tumors and normal thyroid tissue. Our understanding of the underlying basis for sex differences in thyroid cancer has improved over the last few decades, but the relationship between gender and thyroid cancer risk has remained elusive. Areas for future research include ERα/ERß profiling of normal and neoplastic thyroid tissue, association between ER status and tumor dedifferentiation, and evaluation of the signaling pathways by which estrogen and other sex steroids exert their effects on thyroid cancer cells. Sex steroid receptors, and then downstream signaling pathways, represent promising future therapeutic targets for thyroid cancer treatment, and further study is required.

Concerted regulation of focal adhesion dynamics by galectin-3 and tyrosine-phosphorylated caveolin-1.

Both tyrosine-phosphorylated caveolin-1 (pY14Cav1) and GlcNAc-transferase V (Mgat5) are linked with focal adhesions (FAs); however, their function in this context is unknown. Here, we show that galectin-3 binding to Mgat5-modified N-glycans functions together with pY14Cav1 to stabilize focal adhesion kinase (FAK) within FAs, and thereby promotes FA disassembly and turnover. Expression of the Mgat5/galectin lattice alone induces FAs and cell spreading. However, FAK stabilization in FAs also requires expression of pY14Cav1. In cells lacking the Mgat5/galectin lattice, pY14Cav1 is not sufficient to promote FAK stabilization, FA disassembly, and turnover. In human MDA-435 cancer cells, Cav1 expression, but not mutant Y14FCav1, stabilizes FAK exchange and stimulates de novo FA formation in protrusive cellular regions. Thus, transmembrane crosstalk between the galectin lattice and pY14Cav1 promotes FA turnover by stabilizing FAK within FAs defining previously unknown, interdependent roles for galectin-3 and pY14Cav1 in tumor cell migration.

Phosphorylated caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion.

Rho/ROCK signaling and caveolin-1 (Cav1) are implicated in tumor cell migration and metastasis; however, the underlying molecular mechanisms remain poorly defined. Cav1 was found here to be an independent predictor of decreased survival in breast and rectal cancer and significantly associated with the presence of distant metastasis for colon cancer patients. Rho/ROCK signaling promotes tumor cell migration by regulating focal adhesion (FA) dynamics through tyrosine (Y14) phosphorylation of Cav1. Phosphorylated Cav1 is localized to protrusive domains of tumor cells and Cav1 tyrosine phosphorylation is dependent on Src kinase and Rho/ROCK signaling. Increased levels of phosphorylated Cav1 were associated with elevated GTP-RhoA levels in metastatic tumor cells of various tissue origins. Stable expression and knockdown studies of Cav1 in tumor cells showed that phosphorylated Cav1 expression stimulates Rho activation, stabilizes FAK association with FAs, and promotes cell migration and invasion in a ROCK-dependent and Src-dependent manner. Tyrosine-phosphorylated Cav1, therefore, functions as an effector of Rho/ROCK signaling in the regulation of FA turnover and, thereby, tumor cell migration and invasion. These studies define a feedback loop between Rho/ROCK, Src, and phosphorylated Cav1 in tumor cell protrusions, identifying a novel function for Cav1 in tumor metastasis that may contribute to the poor prognosis of some Cav1-expressing tumors.