Investigational drugs in early stage clinical trials for thyrotoxicosis with hyperthyroidism.

INTRODUCTION: Thyrotoxicosis with hyperthyroidism is treated with these classical approaches (i) antithyroid drugs to blockade thyroid hormone release and normalize thyroid hormone production and (ii) destruction of the thyroid using radioiodine or surgical removal of the thyroid. The optimal medical therapy, especially for Graves´ disease, remains a subject of debate and there has been little progress in Graves' disease therapeutics over the last decade. AREAS COVERED: Novel treatments of thyrotoxicosis with hyperthyroidism. This includes (i) small molecules such as synthetic thyroid hormone receptor antagonists and environmental molecules and (ii) molecules with interaction between thyroid stimulating hormone (TSH) receptor and TSH receptor antibodies such as M22, ANTAG3, org274179-0, 5C9, and K1-70. Other approaches to Graves´ disease treatment includes immunosuppressive treatment, glucocorticosteroids, rituximab, and intrathyroid injection of dexamethasone. Optimal iodine and selenium supplementation can also be considered. EXPERT OPINION: Clinical trials results suggest that novel thyroid treatments involving small molecule therapy, may predict a good future in Graves' disease treatment; however, a greater understanding of these antagonists is needed. Other treatments comprising immunosuppressives have demonstrated a significant reduction of relapse of the disease, but are not recommended by international guidelines.

Sunitinib for the treatment of thyroid cancer.

INTRODUCTION: Sunitinib is an oral oxindol derivative and a potent inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor and a multitargeted tyrosine-kinase inhibitor, which has antitumor and antiangiogenic activity due to the selective inhibition that can stabilize progressive metastatic disease. The aim of this review is to expose whether the drug could be considered as a new promising therapy compared with other tyrosine-kinase inhibitors. Areas covered: In seven open-label studies carried out with sunitinb, the drug showed its anti-tumoral activity in advanced differentiated thyroid carcinoma and in medullary thyroid carcinoma. The reported objectives in advanced differentiated thyroid carcinoma, partial response ranges 13% to 55.5%, stable disease ranges 44.4% to 68%, progressive disease ranges 10% to 21% of patients, progression free survival ranges 3 to 13.3% months. In medullary thyroid carcinoma, PR ranges 0% to 55%, SD ranges 44.4% to 87.5%, PD ranges 7% to 18.8% and progression free survivalranges seven to 21 months. Expert opinion: Sunitinib has demonstrated a potent anti-tumoral activity in differentiated thyroid carcinoma and in medullary thyroid carcinoma, but the results of the open-label trials single arm are limited. Further investigations with this agent with randomized trials are warranted.

Spanish consensus for the management of patients with advanced radioactive iodine refractory differentiated thyroid cancer.

BACKGROUND: Approximately one third of the patients with differentiated thyroid cancer (DTC) who develop structurally-evident metastatic disease are refractory to radioactive iodine (RAI). Most deaths from thyroid cancer occur in these patients. The main objective of this consensus is to address the most controversial aspects of management of these patients. METHODS: On behalf of the Spanish Society of Endocrinology & Nutrition (SEEN) and the Spanish Group for Orphan and Infrequent Tumors (GETHI), the Spanish Task Force for Thyroid Cancer, consisting of endocrinologists and oncologists, reviewed the relevant literature and prepared a series of clinically relevant questions related to management of advanced RAI-refractory DTC. RESULTS: Ten clinically relevant questions were identified by the task force. In answering to these 10 questions, the task force included recommendations regarding the best definition of refractoriness; the best therapeutic options including watchful waiting, local therapies, and systemic therapy (e.g. kinase inhibitors), when sodium iodide symporter (NIS) restoration may be expected; and how recent advances in molecular biology have increased our understanding of the disease. CONCLUSIONS: In response to our appointment as a task force by the SEEN and GHETI, we developed a consensus to help in clinical management of patients with advanced RAI-refractory DTC. We think that this consensus will provide helpful and current recommendations that will help patients with this disorder to get optimal medical care.

[Update of recommendations for evaluation and treatment of osteoporosis associated to endocrine and nutritional conditions. Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology]. / Actualización de las recomendaciones para la evaluación y tratamiento de la osteoporosis asociada a enfermedades endocrinas y nutricionales. Grupo de trabajo de osteoporosis y metabolismo mineral de la SEEN.

OBJECTIVE: To update previous recommendations developed by the Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology and Nutrition for the evaluation and treatment of osteoporosis associated to different endocrine and nutritional diseases. PARTICIPANTS: Members of the Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology and Nutrition. METHODS: Recommendations were formulated according to the GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) to describe both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (Pubmed) using the following terms associated to the name of each condition: AND "osteoporosis", "fractures", "bone mineral density", and "treatment". Papers in English with publication date between 18 October 2011 and 30 October 2014 were included. The recommendations were discussed and approved by all members of the Working Group. CONCLUSIONS: This update summarizes the new data regarding evaluation and treatment of osteoporosis associated to endocrine and nutritional conditions.

Consensus on the 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: In Spain medullary thyroid carcinoma (MTC) would not exceed 80 new cases per year and less than half of them would be good candidates for systemic treatment with novel agents. METHODS: Relevant literature was reviewed, including PubMed searches supplemented with additional articles. RESULTS: The consensus summarizes the clinical outcomes in terms of activity and toxicity of each of the available drugs. A brief summary of the minimum requirements in terms of follow up and genetic counseling around MTC is also included. CONCLUSIONS: Only those patients with objective imaging progression in the last 12-14 months with large volume of disease are clear candidates to start systemic treatment. However, those patients with low disease volume should be considered for 'wait and see' strategy until symptoms of the disease appear. Multidisciplinary approach for the management of MTC patient is mandatory nowadays.

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

Anaplastic thyroid cancer (ATC) is the most aggressive solid tumour known and is a rare but highly lethal form of thyroid cancer that requires a multidisciplinary team approach. No Spanish consensus exists for management of patients with ATC. The Thyroid Cancer Group of the Spanish Society of Endocrinology and Nutrition and the GETHI (Grupo Español de Enfermedades Huérfanas e Infrecuentes) of the Spanish Society of Oncology, in agreement with the Boards of these Societies, commissioned an independent task force to develop a wide consensus on ATC. The relevant literature was reviewed, including serial PubMed searches supplemented with additional articles. The consensus includes the characteristics, diagnosis, initial evaluation, establishment of treatment goals, approaches to locoregional disease (surgery, radiotherapy, systemic therapy, supportive care during active treatment), approaches to advanced/metastatic disease, palliative care options, monitoring, and long-term follow-up of ATC. For operable disease, a combination of radical surgery with adjuvant radiotherapy or chemotherapy, using agents such as doxorubicin, cisplatin and paclitaxel, is the best treatment strategy. Cytotoxic drugs are poorly effective for advanced/metastatic ATC. On the other hand, targeted agents may represent a viable therapeutic option. Patients with stage IVA/IVB resectable disease have the best prognosis, particularly if a multimodal approach is used, and some stage IVB unresectable patients may respond to aggressive therapy. Patients with stage IVC disease should be considered for clinical trials or for hospice/palliative care depending on their preference. This is the first Spanish consensus for ATC, and provides recommendations for management of this extremely aggressive malignancy. Novel systemic therapies are being tested, and more effective combinations are needed to improve patient outcomes. Although more aggressive radiotherapy has reduced locoregional recurrence, mean overall survival has not improved in the past 50 years.

Primary Hyperparathyroidism Focused on Molecular Pathogenesis.

Primary hyperparathyroidism (PHPT) is a common cause of hypercalcaemia. The most common lesion found in patients is the solitary benign parathyroid adenoma. Multiple parathyroid adenomas have also been reported. Parathyroid carcinomas are an uncommon cause of PHPT. In 15% of patients, all four parathyroid glands are involved and it may be associated with a familial hereditary syndrome, such as multiple endocrine neoplasia, types 1, 2A and 4. PHPT jaw tumour syndrome is associated with fibromas in the mandible and tumours can also be present in the kidneys and the uterus. No predisposing germline DNA variants in parathyroid adenomas have been demonstrated and only a few clonally altered genes that drive parathyroid tumorigenesis have been identified. Frequently parathyroid adenomas have HRPT2 gene mutations that are likely to be of pathogenetic importance. Mutations in the MEN1 gene (localised to 11q13) are responsible for multiple endocrine neoplasia 1. Multiple endocrine neoplasia 2A, which can be associated with medullary thyroid cancer, is due to a germline mutation of the RET proto-oncogene located on chromosome 10. In MEN1-like negative patients some of the germline mutations in this new susceptibility gene were due to gene CDKN1B (12p13). This new syndrome was classified as multiple endocrine neoplasia 4. In PHPT jaw tumour syndrome, HRPT2, the gene on the long arm of chromosome 1, is responsible for the syndrome. It is suggested to perform genetic testing in patients with PHPT below the age of 30 years, but at any age in patients presenting with multigland parathyroid disease.

[Normocalcemic primary hyperparathyroidism: recommendations for management and follow-up]. / Hiperparatiroidismo primario normocalcémico: recomendaciones acerca del manejo y seguimiento.

OBJECTIVE: To provide practical recommendations for evaluation and follow-up of patients with normocalcemic primary hyperparathyroidism. PARTICIPANTS: Members of the Bone Metabolism Working Group of the Spanish Society of Endocrinology. METHODS: A systematic search was made in MEDLINE (PubMed), using the terms normocalcemic primary hyperparathyroidism and primary hyperparathyroidism, for articles in English published before 22 November 2012. Literature was reviewed by 2 members of the Bone Metabolism Working Group of the Spanish Society of Endocrinology, and after development of recommendations, the manuscript was reviewed by all other members of the Group, and their suggestions were incorporated. CONCLUSIONS: The document provides practical recommendations for evaluation and follow-up of patients with normocalcemic primary hyperparathyroidism. There is however little evidence available about different aspects of this disease, mainly progression rate and clinical impact. More data are therefore needed before definite recommendations may be made.

Current and Future Perspectives in Thyroid Carcinoma Treatment.

Thyroid nodules are a common clinical problem and evaluation with neck and thyroid ultrasound and fine-needle aspiration biopsy are the most accurate methods for evaluating and identifying those that require surgical resection. The surgical treatment of differentiated thyroid carcinoma is the most common and recommended approach. Post-operative 131I remnant ablation is used to eliminate the post-surgical thyroid remnant and may facilitate the early detection of recurrence. The conclusion of two important recent studies is that the use of recombinant human thyrotropin and low 131I dose, 30 mCi, for post-operative ablation may be sufficient for the management of low-risk thyroid cancer. Recently, multi-targeted kinase inhibitors have emerged as promising treatments for metastatic differentiated thyroid cancers based on mutation detection in samples from thyroid cancer. Motesanib, sorafenib, vandetanib, sunitinib, lenvatinib, imatinib and cabozantinib are multi-kinase inhibitors that have the ability of inhibiting the rearranged during transection (RET) and vascular endothelial growth factor receptor (VEGFR), and other kinases, and have been used in advanced differentiated thyroid carcinoma. By contrast, axitinib and pazopanib seem to act only as anti-angiogenic agents. Anaplastic thyroid carinoma is often advanced and metastatic at diagnosis. Patients with localised disease not amenable to surgical resection can be treated with adjuvant chemoradiotherapy.

[Clinical practice guidelines for evaluation and treatment of osteoporosis associated to endocrine and nutritional conditions. Bone Metabolism Working Group of the Spanish Society of Endocrinology]. / Guías de práctica clínica para la evaluación y tratamiento de la osteoporosis asociada a enfermedades endocrinas y nutricionales. Grupo de Metabolismo Mineral de la Sociedad Espa˜nola deEndocrinología y Nutrición.

OBJECTIVE: To provide practical recommendations for evaluation and treatment of osteoporosis associated to endocrine diseases and nutritional conditions. PARTICIPANTS: Members of the Bone Metabolism Working Group of the Spanish Society of Endocrinology, a methodologist, and a documentalist. METHODS: Recommendations were formulated according to the GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) to describe both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (Pubmed), using the following terms associated to the name of each condition: AND "osteoporosis", "fractures", "bone mineral density", and "treatment". Papers in English with publication date before 18 October 2011 were included. Current evidence for each disease was reviewed by two group members, and doubts related to the review process or development of recommendations were resolved by the methodologist. Finally, recommendations were discussed in a meeting of the Working Group. CONCLUSIONS: The document provides evidence-based practical recommendations for evaluation and management of endocrine and nutritional diseases associated to low bone mass or an increased risk of fracture. For each disease, the associated risk of low bone mass and fragility fractures is given, recommendations for bone mass assessment are provided, and treatment options that have shown to be effective for increasing bone mass and/or to decreasing fragility fractures are listed.

[Is our approach to thyroid nodules and differentiated thyroid carcinoma in agreement with the American guideline and European consensus?]. / ¿Está de acuerdo nuestra conducta ante el nódulo tiroideo y cáncer diferenciado de tiroides con la guía norteamericana y el consenso europeo?

INTRODUCTION: The aim of this study was to assess the approaches of specialists in Spain to patients with thyroid nodules and differentiated thyroid carcinoma and to compare them with the American guideline and European consensus. MATERIAL AND METHODS: We performed a cross-sectional study based on a questionnaire addressed to clinical endocrinologists specialized in thyroid cancer and specialists in nuclear medicine throughout Spain. RESULTS: A total of 177 questionnaires were completed, representing an overall response rate of 85%; 74% of responses were from endocrinologists and 24% from physicians active in nuclear medicine; 82% of respondents worked in third-level hospitals, 10% in second level hospitals and the remainder in private practice. Most used ultrasonography and cytology to assess thyroid nodules and collaborated with a group of surgeons expert in thyroid surgery. The majority preferred total or subtotal thyroidectomy in tumors with a diameter of 1 cm or more, and systematic lymph node dissection. Only 43 (24%) preferred prophylactic central lymph node dissection. Eighty-one respondents (45%) would still use whole body scan with ¹³¹I or ¹²³I before ¹³¹I ablation. Follow-up was based on cervical echography and thyroglobulin determination; however, 101 (57%) respondents continued to use diagnostic whole body scan in the follow-up. CONCLUSION: The approaches of the respondents were mainly in accordance with the guideline and consensus, although some variations were found, especially in the use of whole body scan with ¹³¹I before ablation and in follow-up.

Diagnostic usefulness of tumor markers in the thyroid cytological samples extracted by fine-needle aspiration biopsy.

Thyroid nodules are quite common and present approximately in 10% of the population. Fine-needle aspiration biopsy has become the mainstay of thyroid nodule evaluation and the overall accuracy is excellent; however, some aspirates demonstrating indeterminate cytology results do not permit definitive diagnosis of malignancy, and in addition, there are no clear guidelines for the management of these lesions because the incidence of malignancy in indeterminate aspirates varies in the different studies published. In order to find molecular markers in an attempt to predict malignancy based on cytology, at least 70 molecular or cellular and genetic markers have been studied in thyroid nodules. This review focuses on some potential markers such as thyroid peroxidase, thyroglobulin, telomerase, galectin-3, RET/PTC and protein p53; some of them, such as thyroid peroxidases, thyroglobulin and galectin-3, can be studied in a routine pathology laboratory and are promising, but do not yet fulfil criteria required for their use in clinical practice. The American guidelines and the European consensus for the management of thyroid nodules and differentiated thyroid cancer do not recommend their systematic use because the evidence that they have provided is insufficient. On the other hand, information obtained through cytological smears permits the study of complex metabolic or genetic pathways, providing researchers with a high throughput tool to elucidate changes in the global expression patterns seen in tumour cells. This ability to take tumour biology into account would allow the selection of different drugs, considering the predominant altered pathways observed in these samples. Finally, all these data may provide the molecular groundwork for permitting future preoperative discrimination of follicular adenomas from hyperplastic nodules, and may ultimately guide therapeutic strategies.

[Clinical manifestations and asymptomatic forms of primary hyperparathyroidism]. / Manifestaciones clínicas y formas asintomáticas del hiperparatiroidismo primario.

The clinical profile of primary hyperparathyroidism (PHPT) has changed considerably, especially since the introduction of autoanalyzers in the laboratory, allowing calcium to be determined more frequently and a large number of cases of hypercalcemia to be detected. The most frequent causes are PHPT and cancer-related hypercalcemia. All of these factors have modified the prevalence of the clinical manifestations and currently the presence of recurrent kidney stones is observed in 20% of patients, while bone lesions, even the most subtle, are infrequent. Differentiating and establishing the limits between symptomatic and asymptomatic PHPT is difficult and many asymptomatic cases will never show disease progression, such as severe hypercalcemia, bone disease, hypercalciuria and/or kidney stones. An important question is whether patients not showing the classical manifestations of PHPT will benefit from surgery. This question is all the more important since, among patients not surgically treated, many are lost to follow-up after 5 to 10 years and the cost of follow-up exceeds that of surgery. Those against intervention base their arguments on the lack of progression in many patients and the possibility of alternative treatments.