Fabián Pitoia

Recommendations of the Latin American Thyroid Society on diagnosis and management of differentiated thyroid cancer.

The aims of these recommendations were to develop clinical guidelines for evaluation and management of patients with differentiated thyroid cancer applicable to Latin American countries. The panel was composed by 13 members of the Latin American Thyroid Society (LATS) involved with research and management of thyroid cancer from different medical centers in Latin America. The recommendations were produced on the basis of the expert opinion of the panel with use of principles of Evidence-Based Medicine. Following a group meeting, a first draft based on evidences and the expert opinions of the panel was elaborated and, later, circulated among panel members, for further revision. After, this document was submitted to the LATS members, for commentaries and considerations, and, finally, revised and refined by the authors. The final recommendations presented in this paper represent the state of the art on management of differentiated thyroid cancer applied to all Latin American countries.

Introducing the Thyroid Gland as Another Victim of the Insulin Resistance Syndrome

BACKGROUND Insulin is a thyroid growth factor that stimulates proliferation of thyroid cells in culture. In order to evaluate the effects of insulin resistance (IR) on the thyroid gland, we developed a prospective study in euthyroid women. METHODS One hundred eleven women (mean age 32.2 +/- 7 years) were evaluated by a thyroid ultrasound (US) and basal and postprandial serum insulin. Subjects were divided into four groups as follows: G1 (n = 42), subjects with IR and obesity; G2 (n = 21), subjects with obesity without IR; G3 (n = 17), subjects with IR and normal weight; and G4 (n = 31) control group (without IR and obesity). RESULTS The thyroid volume (TV), measured by US, showed the following values: G1, 17 +/- 3 mL; G2, 13.8 +/- 2.8 mL; G3, 16.2 +/- 2.1 mL; and G4,12.1 +/- 2.4 mL. There was no significant difference in TV between G1 and G3, but differences between G1 and G2, and between G3 and G4 were significant at p < 0.05. The percentage of nodular thyroid glands observed by US in each group was as follows: G1, 50%; G2, 23.8%; G3, 61%; G4, 16.1%. Again, the differences between G1 and G2 and between G3 and G4 were statistically significant (p < 0.005 and p < 0.001, respectively, for each comparison). CONCLUSIONS It is concluded that the higher circulating levels of insulin cause increased thyroid proliferation. The clinical manifestations are the larger thyroid volume and the formation of nodules. Thus, the thyroid gland appears to be another victim of the insulin resistance syndrome.

Definition and management of radioactive iodine-refractory differentiated thyroid cancer.

356 www.thelancet.com/diabetes-endocrinology Vol 2 May 2014 ALT reduction when liver fat content is reduced, even without improvement in hepatic infl ammation. Finally, although patients with non-alcoholic steatohepatitis can have increased urinary free cortisol, data for increased 11-βHSD1 hepatic expression is confl icting, thus questioning the relevance of this protein as a therapeutic target. Stefan and colleagues’ carefully conducted trial shows benefi cial eff ects of 11-βHSD1 inhibition on body and liver fat in overweight, insulin-resistant patients with liver steatosis. Unfortunately, data suggestive of effi cacy in patients with non-alcoholic steatohepatitis cannot be inferred from this report and need to be obtained from future, liver-oriented trials with relevant histological endpoints.

Outcomes of patients with differentiated thyroid cancer risk-stratified according to the American thyroid association and Latin American thyroid society risk of recurrence classification systems.

OBJECTIVES The aims of this study were to validate the proposed Latin American Thyroid Society (LATS) risk of recurrence stratification system and to compare the findings with those of the American Thyroid Association (ATA) risk of recurrence stratification system. SUBJECTS AND METHODS This study is a retrospective review of papillary thyroid cancer patients treated with total thyroidectomy and radioactive iodine at a single experienced thyroid cancer center and followed according to the LATS management guidelines. Each patient was risk-stratified using both the LATS and ATA staging systems. The primary endpoints were (i) the best response to initial therapy defined as either remission (stimulated thyroglobulin [Tg] <1 ng/mL, negative ultrasonography) or persistent disease (biochemical and/or structural), and (ii) clinical status at final follow-up defined as no evidence of disease (suppressed Tg <1 ng/mL, negative ultrasonography), biochemical persistent disease (suppressed Tg >1 ng/mL in the absence of structural disease), structural persistent disease (locoregional or distant metastases), or recurrence (biochemical or structural disease identified after a period of no evidence of disease). RESULTS One hundred seventy-one papillary thyroid cancer patients were included (mean age 45 ± 16 years, followed for a median of 4 years after initial treatment). Both the ATA and LATS risk stratification systems provided clinically meaningful graded estimates with regard to (i) the likelihood of achieving remission in response to initial therapy, (ii) the likelihood of having persistent structural disease in response to initial therapy and at final follow-up, (iii) the likely locations of the persistent structural disease (locoregional vs. distant metastases), (iv) the likelihood of recurrence, and (v) the likelihood of being no evidence of disease at final follow-up. The likelihood of having persistent biochemical evidence of disease was not significantly different across the staging categories. CONCLUSIONS Both the ATA and LATS risk of recurrence systems effectively risk-stratify patients with regard to multiple important clinical outcomes. When used in conjunction with a staging system that predicts disease-specific mortality, either of these systems can be used to guide risk-adapted individualized initial management recommendations.

Increased Prevalence of Insulin Resistance in Patients With Differentiated Thyroid Carcinoma

BACKGROUND Patients with insulin resistance (IR) have a higher prevalence of thyroid nodules. In the present study, we present original data showing that patients with differentiated thyroid carcinoma (DTC) also have a higher frequency of IR. METHODS Twenty women with DTC (group 1, G1) and 20 euthyroid individuals (control group, CG) were investigated for IR. G1 and CG subjects were matched in pairs by age, gender, and body mass index (BMI). The diagnosis of IR was made when the homeostasis model assesment of insulin resistance (HOMA-IR) index was higher than 2.5. According to the BMI, 20 women (10 with DTC and 10 of the CG) had a BMI < 25, whereas the other 20 had higher BMI values (overweight and obese patients). RESULTS IR was present in the 50% of G1, but only in the 10% of the CG (P < 0.001). In the groups with lower BMI (<25), we found IR in 30% of G1 and no cases in the CG, whereas in those with BMI > 25 the IR was present in 70% of G1 and 20% of CG. There were no differences between the two subgroups regarding the time in which the IR tests were performed. IR was present in 56.3% of patient with papillary anol 25% of follicular thyroid carcinomas, respectively. CONCLUSIONS We conclude that such a high prevalence of IR would be an important risk factor for developing DTC, as it is well known with some other nonthyroid carcinomas.

Metformin treatment for small benign thyroid nodules in patients with insulin resistance.

OBJECTIVE It has been shown that patients with insulin resistance (IR) have a higher prevalence of thyroid nodules and bigger thyroid glands. We evaluated the ability of metformin (M) alone or combined with levothyroxine (L-T₄) to reduce the nodular size in benign thyroid hyperplastic nodules (<2 cm in diameter). METHODS A total of 66 women with IR and nodular hyperplasia, diagnosed by fine needle aspiration biopsy (FNAB), who completed this prospective 6-month duration protocol, were assigned to one of four groups: Group I (GI) (n = 14), patients treated with M; GII (n = 18), patients treated with M plus L-T₄; GIII (n = 19), patients treated with L-T₄; and GIV (n = 15), patients without any treatment. RESULTS All groups of included patients had no statistically significant different mean baseline characteristics. Patients from GII and GIII showed drops in thyroid-stimulating hormone (TSH) levels and GI and GII normalized the homeostasis model assessment (HOMA) index after treatment, as expected. The median baseline size of all included nodules was 298 mm³ ≈0.84 cm in diameter (range, 32-3,616 mm³). After treatment, patients of Group I and II showed significant reductions in their nodule size [median reduction, 108.50 mm³ (30%) and 184.5 mm³ (55%), P < 0.008 and P < 0.0001, respectively]. Patients in GIII and GIV did not have a significant reduction of their nodules [P = not significant (N.S.)]. CONCLUSIONS We conclude that M produced a significant decrease in the nodular size in patients with IR and small thyroid nodules, whereas the combination of M with L-T₄ was the best treatment in these women.

Latin American Thyroid Society recommendations for the management of thyroid nodules

Several guidelines on diagnosis and treatment of thyroid nodules and cancer have recently been published. However, recommended practices are not always appropriate to different settings or countries. The aim of this consensus was to develop Clinical Guidelines for evaluation and management of patients with thyroid nodules applicable to Latin American countries. The panel was composed by 13 members of the Latin American Thyroid Society involved with research and management of thyroid nodules and cancer from different medical centers in Latin America. The consensus was produced based on the expert opinion of the panel with use of principles of evidence-based medicine. Following a group meeting, a first draft based on the expert opinion of the panel was elaborated and later circulated among panel members for further revision. After revision, this document was submitted to all LATS members for commentaries and considerations and finally revised and refined by the authors. The final recommendations represent state of the art on management of thyroid nodules applied to all Latin American countries.

Regional approaches to the management of patients with advanced, radioactive iodine-refractory differentiated thyroid carcinoma

For patients with advanced, radioactive iodine-refractory differentiated thyroid cancer, current treatment guidelines recommend clinical trial enrollment or small-molecule kinase inhibitor therapy. However, details of patient management vary between countries depending on trial availability and national regulatory policies. Insufficient clinical trial data and variable disease characteristics challenge the creation of universal guidelines, and treatment plans often reflect regional influences. A multidisciplinary, multiregional panel of experts met to discuss regional approaches to managing patients with advanced, radioactive iodine-refractory differentiated thyroid cancer and the potential impact of emerging therapies on current treatment strategies. Despite process-oriented regional differences, the decision-making strategies were similar. Multidisciplinary teams used to manage high-risk patients varied in composition across regions, particularly regarding the responsible physician’s specialty. Cytotoxic chemotherapy was viewed as limited in clinical benefit, and targeted agents as attractive, based on promising data. Panel members support clinical trial enrollment as the preferred treatment strategy for managing these patients.

Radioactive iodine-refractory differentiated thyroid cancer: unmet needs and future directions

Approximately 90% of thyroid cancers are differentiated (DTCs) and have papillary, follicular or Hürthle cell morphology. Although treatment with surgery and radioactive iodine (I-131; RAI), as appropriate, is associated with significant cure rates and survival benefits, clonal disease progression with development of refractoriness to RAI poses a major therapeutic challenge in about 15% of patients. Traditional chemotherapeutic agents are relatively ineffective and are associated with significant toxicities. Molecular studies have demonstrated that the development and progression of DTC are associated with a series of consistent abnormalities in pathways such as MAPK/ERK and PI3/Akt, which govern cellular growth, proliferation, apoptosis and angiogenesis. Small molecular inhibitors that target these pathogenic pathways, without many of the impairments associated with cytotoxic chemotherapy, have demonstrated efficacy in a variety of malignancies, including renal cell carcinoma, hepatocellular carcinoma, non-small-cell lung cancer and chronic myelogenous leukemia. Several targeted therapeutic agents are in development for the treatment of RAI-refractory DTC. Sorafenib and lenvatinib are being studied in placebo-controlled Phase III trials based on encouraging efficacy results observed in single-arm Phase II studies.

Selective use of sorafenib in the treatment of thyroid cancer

Sorafenib is a multiple kinase inhibitor (MKI) approved for the treatment of primary advanced renal cell carcinoma and advanced primary liver cancer. It was recently approved by several health agencies around the world as the first available MKI treatment for radioactive iodine-refractory advanced and progressive differentiated thyroid cancer. Sorafenib targets C-RAF, B-RAF, VEGF receptor-1, -2, -3, PDGF receptor-β, RET, c-kit, and Flt-3. As a multifunctional inhibitor, sorafenib has the potential of inhibiting tumor growth, progression, metastasis, and angiogenesis and downregulating mechanisms that protect tumors from apoptosis and has shown to increase the progression-free survival in several Phase II trials. This led to the Phase III trial (DECISION) which showed that there was an improvement in progression-free survival of 5 months for patients on sorafenib when compared to those on placebo. Adverse events with this drug are common but usually manageable. The development of resistance after 1 or 2 years is almost a rule in most patients who showed partial response or stabilization of the disease while on sorafenib, which makes it necessary to think of a plan for subsequent therapies. These may include the use of another MKI, such as lenvatinib, the second approved MKI for advanced differentiated thyroid cancer, or include patients in clinical trials or the off-label use of other MKIs. Given sorafenib’s earlier approval, most centers now have access to its prescription. The goal of this review was to improve the care of these patients by describing key aspects that all prescribers will need to master in order to optimize outcomes.