Consensus on the management of advanced radioactive iodine-refractory differentiated thyroid cancer on behalf of the Spanish Society of Endocrinology Thyroid Cancer Working Group (GTSEEN) and Spanish Rare Cancer Working Group (GETHI)

Thyroid cancer is the single most prevalent endocrine malignancy; differentiated thyroid cancer (DTC) accounts for more than 90 % of all malignancies and its incidence has been rising steadily. For more patients, surgical treatment, radioactive iodine (RAI) ablation, and thyroid-stimulating hormone (TSH) suppressive therapy achieve an overall survival (OS) rate of 97.7 % at 5 years. Nevertheless, locoregional recurrence occurs in up to 20 % and distant metastases in approximately 10 % at 10 years. Two-thirds of these patients will never be cured with radioactive iodine therapy and will become RAI-refractory, with a 3-year OS rate of less than 50 %. Over the last decade, substantial progress has been made in the management of RAI-refractory DTC. Given the controversy in some areas, the Spanish Task Force for Thyroid Cancer on behalf of Spanish Society of Endocrinology Thyroid Cancer Working Group (GTSEEN) and the Spanish Rare Cancer Working Group (GETHI) have created a national joint task force to reach a consensus addressing the most challenging aspects of management in these patients. In this way, multidisciplinary management should be mandatory and nuclear medicine targeted therapy, novel molecular targeted agents, and combinations are currently changing the natural history of RAI-refractory DTC (AU)

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Spanish consensus for the management of patients with anaplastic cell thyroid carcinoma

Anaplastic thyroid cancer (ATC) is the most aggressive solid tumor and almost uniformly lethal in humans. The Boards of the Thyroid Cancer Group of the Spanish Society of Endocrinology and Nutrition and the Grupo Español de Enfermedades Huérfanas e Infrecuentes of the Spanish Society of Oncology requested that an independent task force draft a more comprehensive consensus statement regarding ATC. All relevant literature was reviewed, including serial PubMed searches together with additional articles. This is the first, comprehensive Spanish consensus statement for ATC and includes the characteristics, diagnosis, initial evaluation, treatment goals, recommendations and modalities for locoregional and advanced disease, palliative care options, surveillance, and long-term monitoring. Newer systemic therapies are being investigated, but more effective combinations are needed to improve patient outcomes. Though more aggressive radiotherapy has reduced locoregional recurrences, median overall survival has not improved in more than 50 years (AU)

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Spanish consensus for the management of patients with anaplastic cell thyroid carcinoma.

Anaplastic thyroid cancer (ATC) is the most aggressive solid tumor and almost uniformly lethal in humans. The Boards of the Thyroid Cancer Group of the Spanish Society of Endocrinology and Nutrition and the Grupo Español de Enfermedades Huérfanas e Infrecuentes of the Spanish Society of Oncology requested that an independent task force draft a more comprehensive consensus statement regarding ATC. All relevant literature was reviewed, including serial PubMed searches together with additional articles. This is the first, comprehensive Spanish consensus statement for ATC and includes the characteristics, diagnosis, initial evaluation, treatment goals, recommendations and modalities for locoregional and advanced disease, palliative care options, surveillance, and long-term monitoring. Newer systemic therapies are being investigated, but more effective combinations are needed to improve patient outcomes. Though more aggressive radiotherapy has reduced locoregional recurrences, median overall survival has not improved in more than 50 years.

Consensus on the management of advanced radioactive iodine-refractory differentiated thyroid cancer on behalf of the Spanish Society of Endocrinology Thyroid Cancer Working Group (GTSEEN) and Spanish Rare Cancer Working Group (GETHI).

Thyroid cancer is the single most prevalent endocrine malignancy; differentiated thyroid cancer (DTC) accounts for more than 90 % of all malignancies and its incidence has been rising steadily. For more patients, surgical treatment, radioactive iodine (RAI) ablation, and thyroid-stimulating hormone (TSH) suppressive therapy achieve an overall survival (OS) rate of 97.7 % at 5 years. Nevertheless, locoregional recurrence occurs in up to 20 % and distant metastases in approximately 10 % at 10 years. Two-thirds of these patients will never be cured with radioactive iodine therapy and will become RAI-refractory, with a 3-year OS rate of less than 50 %. Over the last decade, substantial progress has been made in the management of RAI-refractory DTC. Given the controversy in some areas, the Spanish Task Force for Thyroid Cancer on behalf of Spanish Society of Endocrinology Thyroid Cancer Working Group (GTSEEN) and the Spanish Rare Cancer Working Group (GETHI) have created a national joint task force to reach a consensus addressing the most challenging aspects of management in these patients. In this way, multidisciplinary management should be mandatory and nuclear medicine targeted therapy, novel molecular targeted agents, and combinations are currently changing the natural history of RAI-refractory DTC.

Consensus on management of advanced medullary thyroid carcinoma on behalf of the Working Group of Thyroid Cancer of the Spanish Society of Endocrinology (SEEN) and the Spanish Task Force Group for Orphan and Infrequent Tumors (GETHI)

Background: Of all thyroid cancers,< 5 % are medullary (MTC). It is a well-characterized neuroendocrine tumor arising from calcitonin-secreting C cells, and RET gene plays a central role on its pathogeny. Methods: The electronic search was conducted using MEDLINE (PubMed), EMBASE and Cochrane Central Register of Controlled Trials. Quality assessments of selected current articles, guidelines and reviews of MTC were performed. Results: This consensus updates and summarizes biology, treatment and prognostic considerations of MTC. Conclusions: Multidisciplinary teams and specialized centers are recommended for the management of MTC patients. In the metastatic setting, those patients with large volume of disease are candidates to start systemic treatment mainly if they are symptomatic and the tumor has progressed in the last 12-14 months. Wait and see strategy should be offered to patients with: disseminated disease with only high levels of calcitonin and no macroscopic structural disease, low burden and absence of progression (AU)

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Consensus on management of advanced medullary thyroid carcinoma on behalf of the Working Group of Thyroid Cancer of the Spanish Society of Endocrinology (SEEN) and the Spanish Task Force Group for Orphan and Infrequent Tumors (GETHI).

BACKGROUND: Of all thyroid cancers, <5 % are medullary (MTC). It is a well-characterized neuroendocrine tumor arising from calcitonin-secreting C cells, and RET gene plays a central role on its pathogeny. METHODS: The electronic search was conducted using MEDLINE (PubMed), EMBASE and Cochrane Central Register of Controlled Trials. Quality assessments of selected current articles, guidelines and reviews of MTC were performed. RESULTS: This consensus updates and summarizes biology, treatment and prognostic considerations of MTC. CONCLUSIONS: Multidisciplinary teams and specialized centers are recommended for the management of MTC patients. In the metastatic setting, those patients with large volume of disease are candidates to start systemic treatment mainly if they are symptomatic and the tumor has progressed in the last 12-14 months. Wait and see strategy should be offered to patients with: disseminated disease with only high levels of calcitonin and no macroscopic structural disease, low burden and absence of progression.

Comments to SEOM clinical guidelines for the treatment of thyroid cancer

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Molecular biology of thyroid cancer initiation.

Thyroid cancers stand out among solid tumours because many of the tumour-initiating genetic events have been identified. Mutations leading to constitutive activation of MAP kinase effectors -the tyrosine receptor kinase RET and the intracellular signalling effectors RAS and BRAF- are essential for the pathogenesis of papillary thyroid carcinoma (PTC). Similarly, there is increasing evidence demonstrating that mutations leading to activation of the phosphatidylinositol 3- kinase (PI3K)/AKT effectors -PTEN and PI3KCa- are essential for the pathogenesis of follicular thyroid carcinoma (FTC). Besides this strong relationship between the histological phenotype and the pathway predominantly activated, the nature of the genetic event seems to determine the biological behaviour of the tumour and the ultimate clinical outcome of the patient. In this review we will summarise and discuss the main genetic events related to thyroid cancer initiation, the contribution of genomics and the convenience of using a new molecular classification of thyroid cancer, complementary to the clinicopathological classification. This may help us to predict more faithfully the clinical outcome of patients with thyroid cancer and to select more appropriately candidates for targeted therapies.

Molecular biology of thyroid cancer initiation

Thyroid cancers stand out among solid tumours because many of the tumour-initiating genetic events have been identified. Mutations leading to constitutive activation of MAP kinase effectors -the tyrosine receptor kinase RET and the intracellular signalling effectors RAS and BRAF- are essential for the pathogenesis of papillary thyroid carcinoma (PTC). Similarly, there is increasing evidence demonstrating that mutations leading to activation of the phosphatidylinositol 3- kinase (PI3K)/AKT effectors -PTEN and PI3KCa- are essential for the pathogenesis of follicular thyroid carcinoma (FTC). Besides this strong relationship between the histological phenotype and the pathway predominantly activated, the nature of the genetic event seems to determine the biological behaviour of the tumour and the ultimate clinical outcome of the patient. In this review we will summarise and discuss the main genetic events related to thyroid cancer initiation, the contribution of genomics and the convenience of using a new molecular classification of thyroid cancer, complementary to the clinicopathological classification. This may help us to predict more faithfully the clinical outcome of patients with thyroid cancer and to select more appropriately candidates for targeted therapies (AU)

The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I- targeting to the membrane.

The oncogene BRAF(V600E) is the most frequent genetic event in papillary thyroid carcinoma (PTC) but its prognostic impact still remains to be elucidated. We evaluated a representative series of 67 individuals with PTC who underwent total thyroidectomy. BRAF-positive tumours correlated with early recurrences (32% vs 7.6%; P=0.02) during a median postoperative follow-up period of 3 years. Interestingly, within the recurrences, a significant majority had negative radioiodine ((131)I) total body scans, predicting a poorer outcome as treatment with (131)I is not effective. This last observation led us to investigate the role of BRAF(V600E) and the MEK-ERK pathway in thyroid dedifferentiation, particularly in Na(+)/I(-) symporter (NIS) impairment, as this thyroid-specific plasma membrane glycoprotein mediates active transport of I(-) into the thyroid follicular cells. A subset of 60 PTC samples was evaluated for NIS immunoreactivity and, accordingly, we confirmed a significant low NIS expression and impaired targeting to membranes in BRAF-positive samples (3.5% vs 30%; P=0.005). Furthermore, experiments with differentiated PCCl3 thyroid cells demonstrated that transient expression of BRAF(V600E) sharply impaired both NIS expression and targeting to membrane and, surprisingly, this impairment was not totally dependent on the MEK-ERK pathway. We have concluded that BRAF(V600E) is a new prognostic factor in PTC that correlates with a high risk of recurrences and less differentiated tumours due to the loss of NIS-mediated (131)I uptake.

[Severe polymyositis with simvastatin use]. / Polimiositis grave durante el tratamiento con simvastatina.

INTRODUCTION: Myotoxicity is the most common adverse reaction of statins, being its frequency less than 0.5%. Mild myopathy reversible after statin withdrawal is the most common event. We present a case of severe polymyositis which was likely to be induced by simvastatin. CASE REPORT: 75 years old man with hypercholesterolemia treated with simvastatin 20 mg/day for 6 months started previous 2 months with proximal limb weakness, dysphagia and myalgias during exercise that did not release after simvastatin withdrawal. Laboratory findings showed increased creatinin kinase (6,010 UI/L), raised aldolase (51 UI/L) and lactic acid dehydrogenase (1,406 UI/L). Muscular biopsy showed abundant inflammatory cell infiltration in perivascular areas, muscle fibre necrosis with miofagocitosis and considerable variation in fibre size, some of them reaching 210 mm. Treatment with cortico esteroids was started and 4 months later clinical remission and nomalization of creatinin kinase was observed. DISCUSSION: Mechanisms of statins induced myotoxicity are not well known. Studies in rats suggest a muscle membrane defect (increased membrane fluidity) and abundant signs of damage (fiber necrosis, hipercontraction) but no cellular infiltrates were seen, pointing to a non inflammatory myopathy which was dose dependent. In our case, and Giordano s et al, the remission of the disease with cortico esteroid therapy and the finding of abundant inflammatory cell infiltration suggest the implication of immunological mechanism and not only a muscle membrane defect.

Polimiositis grave durante el tratamiento con simvastatina / Severe polymyositis with simvastatin use

Introducción. Los accidentes isquémicos transitorios (AIT), como única manifestación clínica de una malformación arteriovenosa dural, son una forma de presentación clínica muy infrecuente. Caso clínico. Varón de 68 años con episodios recurrentes de hemiparesia derecha, debido a las alteraciones hemodinámicas originadas por una malformación arteriovenosa dural localizada en la fosa media derecha, con un drenaje venoso cortical hacia el seno longitudinal superior, que dificulta el drenaje de las venas corticales parietales izquierdas. En la tomografía computarizada y la resonancia magnética de ingreso se observó sangre en un surco parietal izquierdo, sin lesiones parenquimatosas. Dicha fístula arteriovenosa dural se trató inicialmente por vía endovascular con partículas de polivinil-alcohol de 150-250 µm; pero, tras 11 días, el enfermo volvió a presentar nuevos cuadros de hemiparesia derecha cada vez más frecuentes e intensos, lo que llevó a la búsqueda del tratamiento definitivo de la fístula arteriovenosa dural con cianoacrilatos. En los cinco años de control tras la embolización no se ha vuelto a presentar ningún cuadro similar. Conclusiones. En las fístulas arteriovenosas durales la vena cortical arterializada puede impedir el drenaje de otras venas hacia el seno venoso común. En raras ocasiones, estas fístulas pueden inducir la aparición de cuadros de accidentes isquémicos transitorios en territorios alejados de la localización de dicha malformación arteriovenosa Introducción. La toxicidad muscular es el principal efecto secundario de las estatinas, aunque es muy poco frecuente (menos de un 0,5 por ciento). La mayoría de las veces produce una miopatía leve y transitoria, que cede tras la suspensión del fármaco. Presentamos el caso de una polimiositis grave relacionada con la ingesta de simvastatina. Caso clínico. Varón de 75 años con antecedentes de hipercolesterolemia, en tratamiento con 20 mg/día de simvastatina desde hace seis meses, que presentó un cuadro de dos meses de evolución de disfagia, debilidad muscular progresiva de las cuatro extremidades de predominio proximal y mialgias durante el ejercicio, que no cedió tras la suspensión de simvastatina. En los hallazgos de laboratorio presentó 6.010 UI/L de CPK, 1.406 UI/L de LDH y 51 UI/L de aldolasa. En la biopsia muscular se observó un abundante infiltrado linfocitario que rodeaba las estructuras vasculares, abundante necrosis sarcoplasmática focal con miofagocitosis y una gran variabilidad en los tamaños de las fibras; se apreciaban fibras de hasta 210 µm. Se inició tratamiento con corticoides y presentó una franca mejoría clínica y normalización de la CPK en 4 meses. Discusión. La patogenia de la toxicidad muscular por estatinas no se conoce bien, aunque los estudios con ratas proponen una alteración de la permeabilidad de la membrana muscular con presencia de necrosis de fibras, pero no de infiltrados celulares, lo que apunta a una miopatía no inflamatoria que es dependiente de la dosis y mayor con estatinas lipofílicas. En el caso descrito, junto con el de Giordano et al, la aparición en la biopsia de un abundante infiltrado inflamatorio linfocitario y la remisión de los síntomas tras la administración de corticoesteroides, sugieren la posibilidad de un mecanismo inmunológico mediado por células, y no sólo una alteración de la permeabilidad de la membrana (AU)

Introduction. Myotoxicity is the most common adverse reaction of statins, being its frequency less than 0.5%. Mild myopathy reversible after statin withdrawal is the most common event. We present a case of severe polymyositis which was likely to be induced by simvastatin. Case report. 75 years-old man with hypercholesterolemia treated with simvastatin 20 mg/day for 6 months started previous 2 months with proximal limb weakness, dysphagia and myalgias during exercise that did not release after simvastatin withdrawal. Laboratory findings showed increased creatinin kinase (6,010 UI/L), raised aldolase (51 UI/L) and lactic-acid dehydrogenase (1,406 UI/L). Muscular biopsy showed abundant inflammatory cell infiltration in perivascular areas, muscle fibre necrosis with miofagocitosis and considerable variation in fibre size, some of them reaching 210 µm. Treatment with cortico-esteroids was started and 4 months later clinical remission and nomalization of creatinin kinase was observed. Discussion. Mechanisms of statins-induced myotoxicity are not well-known. Studies in rats suggest a muscle membrane defect (increased membrane fluidity) and abundant signs of damage (fiber necrosis, hipercontraction) but no cellular infiltrates were seen, pointing to a non-inflammatory myopathy which was dose dependent. In our case, and Giordano’s et al, the remission of the disease with cortico-esteroid therapy and the finding of abundant inflammatory cell infiltration suggest the implication of immunological mechanism and not only a muscle membrane defect (AU)