Furio Pacini

Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer

BACKGROUND Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Associations guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. METHODS Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. RESULTS The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, and suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound and serum thyroglobulin as well as those related to management of recurrent and metastatic disease. CONCLUSIONS We created evidence-based recommendations in response to our appointment as an independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer

BACKGROUND Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Associations (ATAs) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. METHODS The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members. RESULTS The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research. CONCLUSIONS We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial

BACKGROUND Patients with radioactive iodine ((131)I)-refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis because of the absence of effective treatment options. In this study, we assessed the efficacy and safety of orally administered sorafenib in the treatment of patients with this type of cancer. METHODS In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (DECISION), we investigated sorafenib (400 mg orally twice daily) in patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria In Solid Tumors (RECIST); Eastern Cooperative Oncology Group performance status 0-2; adequate bone marrow, liver, and renal function; and serum thyroid-stimulating hormone concentration lower than 0·5 mIU/L. An interactive voice response system was used to randomly allocate participants in a 1:1 ratio to either sorafenib or matching placebo. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival, assessed every 8 weeks by central independent review. Analysis was by intention to treat. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Archival tumour tissue was examined for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit. This study is registered with ClinicalTrials.gov, number NCT00984282, and with the EU Clinical Trials Register, number EudraCT 2009-012007-25. FINDINGS Patients were randomly allocated on a 1:1 basis to sorafenib or placebo. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group) and the safety population was 416 patients (207 in the sorafenib group and 209 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10·8 months) than in the placebo group (5·8 months; hazard ratio [HR] 0·59, 95% CI 0·45-0·76; p<0·0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98·6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87·6%) patients receiving placebo. Most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand-foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash or desquamation (50·2%). INTERPRETATION Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer. FUNDING Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).

Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma

INTRODUCTION The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. METHODS The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document. RESULTS The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. CONCLUSIONS The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendations to represent current, rational, and optimal medical practice.

Medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) accounts for 5-8% of all thyroid cancers. MTC is mainly sporadic in nature, but an hereditary pattern [multiple endocrine neoplasia type 2 (MEN 2)] is present in 20-30% of cases, transmitted as an autosomal-dominant trait due to germline mutations of the RET proto-oncogene. About 98% of patients with MEN 2 have germline mutations in exons 5, 8, 10, 11, 13, 14, 15 or 16 of the RET gene. The primary treatment of both hereditary and sporadic forms of MTC is total thyroidectomy and removal of all neoplastic tissue present in the neck. The therapeutic option for lymph node surgery should be dictated by the results of presurgical evaluation. After total thyroidectomy, measurements of serum calcitonin (CT) and carcinoembryonic antigen are of paramount importance in the postsurgical follow-up of patients with MTC as they reflect the presence of persistent or recurrent disease. Complete remission is demonstrated by undetectable and stimulated serum CT measurement. On the contrary, if serum CT is detectable under basal conditions or becomes detectable after stimulation, the patient is probably not cured, but imaging techniques will not demonstrate any disease until serum CT approaches levels >150 pg/ml. The tumour metastasises early to both paratracheal and lateral cervical lymph nodes. Metastases outside the neck may occur in the liver, lungs, bones and, less frequently, brain and skin. Surgery is the main treatment for local and distant metastases whenever feasible. Systemic chemotherapy with dacarbazine, 5-fluorouracil and doxorubicin (alone or in combination) has shown very limited efficacy, achieving only partial responses in the range of 10-20% and of short duration. Several kinase inhibitors are currently under evaluation and preliminary results are promising. Familial cases must be identified by searching for RET proto-oncogene mutations in the proband and in family members. Carriers of the RET gene are candidates for prophylactic thyroidectomy at different ages depending on the risk associated with the specific RET mutations.

Phase II Study of Safety and Efficacy of Motesanib in Patients With Progressive or Symptomatic, Advanced or Metastatic Medullary Thyroid Cancer

PURPOSE This phase II study investigated the efficacy and tolerability of motesanib, an investigational, highly selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit in advanced medullary thyroid cancer (MTC). PATIENTS AND METHODS Patients with locally advanced or metastatic, progressive or symptomatic MTC received motesanib 125 mg/d orally for up to 48 weeks or until unacceptable toxicity or disease progression. The primary end point was objective response by independent review. Other end points included duration of response, progression-free survival, safety, pharmacokinetics, and changes in tumor markers. RESULTS Of 91 enrolled patients who received motesanib, two (2%) achieved objective response (95% CI, 0.3% to 7.7%); their duration of response was 32 weeks (censored) and 21 weeks (disease progressed). Eighty-one percent of patients had stable disease (48% had durable stable disease > or = 24 weeks), 8% had disease progression as best response, and 9% were not evaluated; 76% experienced a decrease from baseline in target lesion measurement. Median progression-free survival was 48 weeks (95% CI, 43 to 56 weeks). Among patients with tumor marker analysis, 69 (83%) of 83 and 63 (75%) of 84 had decreased serum calcitonin and carcinoembryonic antigen during treatment, respectively, compared with baseline. The most common treatment-related adverse events were diarrhea (41%), fatigue (41%), hypothyroidism (29%), hypertension (27%), and anorexia (27%). In pharmacokinetic analyses, motesanib trough concentrations were lower compared with differentiated thyroid cancer patients from the same study. CONCLUSION Although the objective response rate was low, a significant proportion of MTC patients (81%) achieved stable disease while receiving motesanib.

Decreased levels of helper T cells: a possible cause of immunodeficiency in pregnancy.

DECREASED maternal immune responsiveness during pregnancy may partly explain the survival of the fetus as an allograft. It may also account for changes in disease activity and antibody production i...

Disappearance of humoral thyroid autoimmunity after complete removal of thyroid antigens.

RiassuntoLe malattie autoimmuni della tiroide sono caratterizzate dalla presenza di anticorpi diretti contro la tireoperossidasi (TPO), la tireoglobulina (Tg) e il recettore per l’ormone tireotropo (TSH-R). Questo studio ha valutato se la rimozione completa degli antigeni tiroidei fosse in grado di indurre la scomparsa dei segni di autoimmunità tiroidea circolante. Lo studio è basato su una revisione retrospettiva delle cartelle cliniche di pazienti che erano stati seguiti e trattati secondo un protocollo standard. Sono stati studiati 182 pazienti affetti da tumore differenziato della tiroide i quali, per la coesistenza di una tiroidite cronica autoimmune, di un morbo di Basedow o di una tiroidite focale autoimmune, risultavano positivi per anticorpi anti-TPO (TPOAb), anti-Tg (TgAb) o anti-TSH-R (TRAb). Dei 182 soggetti, 151 erano di sesso femminile e 31 di sesso maschile; l’età media era di 39,7±13,7 anni, con un range da 6 a 81 anni. Tutti i pazienti sono stati sottoposti a tiroidectomia totale e a trattamento con iodio radioattivo allo scopo di ablare il tessuto tiroideo residuo o metastatico. Il follow-up è stato effettuato mediante scintigrafie corporee totali con radioiodio e dosaggio della Tg circolante. La media del follow-up era di 10,1±4,1 anni, con un range di 4–20 anni. A seguito del trattamento con tiroidectomia totale e iodio radioattivo, si è verificata la scomparsa dei TgAb, TPOAb e TRAb. La mediana di scomparsa è stata di 6,3 anni per iTPOAb e di 3,0 anni per i TgAb. La scomparsa del tessuto tiroideo e quella degli anticorpi antitiroide erano correlate in modo statisticamente significativo. La persistenza di TPOAb e TgAb non veniva influenzata dal sesso, dall’età e dalla concomitanza della tiroidite autoimmune o del morbo di Basedow.

Impact of Proto-Oncogene Mutation Detection in Cytological Specimens from Thyroid Nodules Improves the Diagnostic Accuracy of Cytology

CONTEXT Fine-needle aspiration cytology (FNAC) is the gold standard for the differential diagnosis of thyroid nodules but has the limitation of inadequate sampling or indeterminate lesions. OBJECTIVE We aimed to verify whether search of thyroid cancer-associated protooncogene mutations in cytological samples may improve the diagnostic accuracy of FNAC. STUDY DESIGN One hundred seventy-four consecutive patients undergoing thyroid surgery were submitted to FNAC (on 235 thyroid nodules) that was used for cytology and molecular analysis of BRAF, RAS, RET, TRK, and PPRgamma mutations. At surgery these nodules were sampled to perform the same molecular testing. RESULTS Mutations were found in 67 of 235 (28.5%) cytological samples. Of the 67 mutated samples, 23 (34.3%) were mutated by RAS, 33 (49.3%) by BRAF, and 11 (16.4%) by RET/PTC. In 88.2% of the cases, the mutation was confirmed in tissue sample. The presence of mutations at cytology was associated with cancer 91.1% of the times and follicular adenoma 8.9% of the time. BRAF or RET/PTC mutations were always associated with cancer, whereas RAS mutations were mainly associated with cancer (74%) but also follicular adenoma (26%). The diagnostic performance of molecular analysis was superior to that of traditional cytology, with better sensitivity and specificity, and the combination of the two techniques further contributed to improve the total accuracy (93.2%), compared with molecular analysis (90.2%) or traditional cytology (83.0%). CONCLUSIONS Our findings demonstrate that molecular analysis of cytological specimens is feasible and that its results in combination with cytology improves the diagnostic performance of traditional cytology.

Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update

CONTEXT Over the last decade, our knowledge of the multiple endocrine neoplasia (MEN) type 2 syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has expanded greatly. In this manuscript, we summarize how recent discoveries have enhanced our understanding of the molecular basis of these diseases and led to improvements in the diagnosis and management of affected patients. EVIDENCE ACQUISITION We reviewed the English literature through PubMed from 2000 to the present, using the search terms medullary thyroid carcinoma, multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma, RET proto-oncogene, and calcitonin. EVIDENCE SYNTHESIS Over 70 RET mutations are known to cause MEN2A, MEN2B, or FMTC, and recent findings from studies of large kindreds with these syndromes have clouded the relationship between genotype and phenotype, primarily because of the varied clinical presentation of different families with the same RET mutation. This clinical variability has also confounded decisions about the timing of prophylactic thyroidectomy for MTC, the dominant endocrinopathy associated with these syndromes. A distinct advance has been the demonstration through phase II and phase III clinical trials that molecular targeted therapeutics are effective in the treatment of patients with locally advanced or metastatic MTC. CONCLUSIONS The effective management of patients with MEN2A, MEN2A, and FMTC depends on an understanding of the variable behavior of disease expression in patients with a specific RET mutation. Information gained from molecular testing, biochemical analysis, and clinical evaluation is important in providing effective management of patients with either early or advanced-stage MTC.