Mario Vaisman

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.

Spontaneous remission in thyroid cancer patients after biochemical incomplete response to initial therapy

To validate the American Thyroid Association (ATA) initial risk of recurrence scheme and the Memorial Sloan Kettering Cancer Center (MSKCC) response to therapy re‐stratification approach in a large cohort of patients with differentiated thyroid cancer (DTC) treated outside of the United States.

Glucagon stimulation test for the diagnosis of GH deficiency in adults

The insulin tolerance test (ITT) is considered the test of choice for the diagnosis of GH deficiency (GHD). However, in patients with contraindications to ITT, alternative provocative tests must be used with appropriate cut-offs. The glucagon stimulation test has proved to be a safe, low-cost and effective means of stimulating GH secretion, and therefore can be considered as a suitable alternative to the ITT. We have studied the GH response to the glucagon test in 33 patients with known pituitary disease, 12 males and 21 females, aged between 21 and 60 yr (41.18±9.47 yr); 5 had isolated GHD and 28 had panhypopituitarism. We also evaluated a control group of 25 individuals, matched for age and sex (8 males and 17 females), aged between 20 and 60 yr (39.28±12.10 yr). They were selected via the ITT if their peak GH response was >5.0 ng/ml. GH peak after glucagon was significantly lower in the group of patients compared to the control group (0.49±0.85 vs 8.69±5.85 ng/ml, p=0.0001). Receiver-operating characteristic (ROC) plot analyses of the control and GHD group showed an area under the curve of 0.982 for GH peak response to glucagon. The response value of 3.0 ng/ml showed the best pair of sensitivity (97%)/specificity (88%), and was chosen as the cut-off defining GHD. After evaluation of positive predictive values (PPV) and negative predictive values (NPV) through simulation of different prevalences of the disease, we concluded that the cut-off point of 3.00 ng/ml maximizes both PPV and NPV (100%). In conclusion, we have shown that the glucagon stimulation test has a good performance and great diagnostic accuracy for the diagnosis of GHD.

Retinoic acid in patients with radioiodine non-responsive thyroid carcinoma

De-differentiated thyroid carcinoma is characterized by loss of thyroid-specific functions and properties. The therapeutic options for this type of thyroid cancer are limited and generally not efficient. Recent studies with retinoic acid (RA) have shown that this drug can induce re-differentiation of the thyrocyte and tumor regression after 131I therapy. The aim of the present study was to assess the effects of RA therapy in patients with extensive thyroid tumor involvement, which lost radioiodine uptake ability. A total of 5 patients (1 follicular carcinoma, 3 papillary carcinomas and 1 poorly differentiated carcinoma) were treated with isotretinoin (1.0 to 1.5 mg/kg/day) for 5 weeks and then submitted to radioiodine therapy. Three parameters for assessment of RA effects were established: a) reduction of serum thyroglobulin levels; b) increment of the post-therapeutic dose radioiodine uptake; c) tumor size regression after therapy. All patients completed the treatment and the most frequent side effects were dry skin and lips and hypertriglyceridemia. One patient showed satisfactory response (2 or more of the 3 criteria were reached) and a new cycle of RA was given. In two, just a partial response (1 criterion) was seen and the other patients did not respond. Based on these results, isotretinoin might be an option for de-differentiated thyroid cancer, with low rate of severe side effects, especially when compared with cytotoxic drugs. Aggressive thyroid cancer frequently needs multimodal adjuvant therapy.

Lipid profile in different degrees of hypothyroidism and effects of levothyroxine replacement in mild thyroid failure

The aim of this study was to evaluate the lipid profile of patients with different degrees of hypothyroidism and the effect of levothyroxine replacement in subclinical hypothyroidism (SH). Initially, a cross-sectional study was performed with 226 participants [SH = 133 participants, manifest hypothyroidism (MH) = 23 participants, and euthyroidism (EU) = 70 participants]. The mean levels of atherogenic lipid variables were greater in MH than in SH and were greater in SH than in EU, although the differences between SH and EU did not reach statistical significance. The SH subgroup with greater serum thyrotropin (TSH) levels and that with positive antithyroperoxidase antibodies (TPO-Ab) had greater levels of triglycerides and of the atherogenic index Apo B/Apo A. A positive correlation exists between serum TSH and total cholesterol (rs = 0.167; P = 0.006), triglycerides (rs = 0.219; P < 0.001), and ApoB levels (rs = 0.205; P < 0.001). Eleven patients who received levothyroxine (L-T4) treatment and 15 patients who received placebo were reevaluated 1 year after TSH adjusted intervention. A fall in atherogenic variables was observed in the L-T4-treated group, with significance for total cholesterol (-20.0 vs +16.1 mg/dL in the placebo group) and LDL-c (-21.7 vs +17.2 mg/dL). We concluded that SH leads to an intermediary lipid profile between euthyroid individuals and that found in manifest hypothyroidism and that a significant lipid profile improvement occurred 1 year after L-T4 replacement therapy.

Incidência e mortalidade por câncer de tireóide no Brasil

In this study we evaluated the incidence and mortality due to thyroid cancer (TC) in Brazil using incidence data provided by seven Brazilian cancer registries and mortality data from the Brazilian Mortality Information System. Five-year age-adjusted mortality rates were calculated over a 20-year period (1980-1999) for the country as a whole. We have calculated a 3-year age-adjusted incidence rate using data available since 1993. Age-adjusted mortality rates decreased from 0.22/100,000 to 0.28/100,000 (-21%) among males, and from 0.42/100,000 to 0.51/100,000 (-17%) among females. Among males, age-adjusted incidence rates varied from 0.7/100,000 in Belém to 3.0/100,000 in São Paulo. These cities also presented the lowest (0.8/100,000) and the highest (10.9/100,000) age-adjusted incidence rates among females. The downward tendency of mortality is probably explained by an improvement in diagnosis and treatment of TC over the study period, whereas geographical variations in incidence are probably related to availability of medical care resources in the different regions and the quality of cancer registers data.

Dynamic Risk Stratification in Patients with Differentiated Thyroid Cancer Treated Without Radioactive Iodine

CONTEXT Although response to therapy assessment is a validated tool for dynamic risk stratification in patients with differentiated thyroid cancer (DTC) treated with total thyroidectomy (TT) and radioactive iodine therapy (RAI), it has not been well studied in patients treated with lobectomy or TT without RAI. Because these responses to therapy definitions are heavily dependent on serum thyroglobulin (Tg) levels, modifications of the original definitions were needed to appropriately classify patients treated without RAI. OBJECTIVE This study aimed to validate the response to therapy assessment in patients with DTC treated with lobectomy or TT without RAI. DESIGN AND SETTING This was a retrospective study, which took place at a referral center. PATIENTS A total of 507 adults with DTC were treated with lobectomy (n = 187) or TT (n = 320) without RAI. They had a median age of 43.7 y, 88% were female, 85.4% had low risk, and 14.6% intermediate risk. MAIN OUTCOME MEASURE Main outcome measured was recurrent/persistent structural evidence of disease (SED) during a median followup period of 100.5 months (24-510). RESULTS Recurrent/persistent SED was observed in 0% of the patients with excellent response to therapy (nonstimulated Tg for TT < 0.2 ng/mL and for lobectomy < 30 ng/mL, undetectable Tg antibodies [TgAb] and negative imaging; n = 326); 1.3% with indeterminate response (nonstimulated Tg for TT 0.2-5 ng/mL, stable or declining TgAb and/or nonspecific imaging findings; n = 2/152); 31.6% of the patients with biochemical incomplete response (nonstimulated Tg for TT > 5 ng/mL and for lobectomy > 30 ng/mL and/or increasing Tg with similar TSH levels and/or increasing TgAb and negative imaging; n = 6/19) and all (100%) patients with structural incomplete response (n = 10/10) (P < .0001). Initial American Thyroid Association risk estimates were significantly modified based on response to therapy assessment. CONCLUSIONS Our data validate the newly proposed response to therapy assessment in patients with DTC treated with lobectomy or TT without RAI as an effective tool to modify initial risk estimates of recurrent/persistent SED and better tailor followup and future therapeutic approaches. This study provides further evidence to support a selective use of RAI in DTC.

Influence of Thyroid Autoimmunity and Maternal Age on the Risk of Miscarriage

Objectives:  Recently, studies have shown an association between antiperoxidase for the detection of thyroid autoimmunity (TAI) and abortion. Another point to be considered is the association of high risk of abortion and maternal age. The aim of the present study was to evaluate if the association between TAI and miscarriage could also be verified whether a population of unselected pregnant young women who normally present a low risk of miscarriage.

Modified-Release Recombinant Human TSH (MRrhTSH) Augments the Effect of 131I Therapy in Benign Multinodular Goiter: Results from a Multicenter International, Randomized, Placebo-Controlled Study

BACKGROUND Recombinant human TSH (rhTSH) can be used to enhance (131)I therapy for shrinkage of multinodular goiter (MG). OBJECTIVE, DESIGN, AND SETTING The objective of the study was to compare the efficacy and safety of 0.01 and 0.03 mg modified-release (MR) rhTSH as an adjuvant to (131)I therapy, vs. (131)I alone, in a randomized, placebo-controlled, international, multicenter study. PATIENTS AND INTERVENTION Ninety-five patients (57.2 ± 9.6 yr old, 85% females, 83% Caucasians) with MG (median size 96.0, range 31.9-242.2 ml) were randomized to receive placebo (group A, n = 32), MRrhTSH 0.01 mg (group B, n = 30), or MRrhTSH 0.03 mg (group C, n = 33) 24 h before a calculated activity of (131)I. MAIN OUTCOME MEASURES The primary end point was a change in thyroid volume (by computerized tomography scan, at 6 months). Secondary end points were the smallest cross-sectional area of the trachea; thyroid function tests; Thyroid Quality of Life Questionnaire; electrocardiogram; and hyperthyroid symptom scale. RESULTS Thyroid volume decreased significantly in all groups. The reduction was comparable in groups A and B (23.1 ± 8.8 and 23.3 ± 16.5%, respectively; P = 0.95). In group C, the reduction (32.9 ± 20.7%) was more pronounced than in groups A (P = 0.03) and B. The smallest cross-sectional area of the trachea increased in all groups: 3.8 ± 2.9% in A, 4.8 ± 3.3% in B, and 10.2 ± 33.2% in C, with no significant difference among the groups. Goiter-related symptoms were effectively reduced and there were no major safety concerns. CONCLUSION In this dose-selection study, 0.03 mg MRrhTSH was the most efficacious dose as an adjuvant to (131)I therapy of MG. It was well tolerated and significantly augmented the effect of (131)I therapy in the short term. Larger studies with long-term follow-up are warranted.

MTOR downregulates iodide uptake in thyrocytes.

Phosphoinositide-3-kinase (PI3K) inhibition increases functional sodium iodide symporter (NIS) expression in both FRTL-5 rat thyroid cell line and papillary thyroid cancer lineages. In several cell types, the stimulation of PI3K results in downstream activation of the mechanistic target of rapamycin (MTOR), a serine-threonine protein kinase that is a critical regulator of cellular metabolism, growth, and proliferation. MTOR activation is involved in the regulation of thyrocyte proliferation by TSH. Here, we show that MTOR inhibition by rapamycin increases iodide uptake in TSH-stimulated PCCL3 thyroid cell line, although the effect of rapamycin was less pronounced than PI3K inhibition. Thus, NIS inhibitory pathways stimulated by PI3K might also involve the activation of proteins other than MTOR. Insulin downregulates iodide uptake and NIS protein expression even in the presence of TSH, and both effects are counterbalanced by MTOR inhibition. NIS protein expression levels were correlated with iodide uptake ability, except in cells treated with TSH in the absence of insulin, in which rapamycin significantly increased iodide uptake, while NIS protein levels remained unchanged. Rapamycin avoids the activation of both p70 S6 and AKT kinases by TSH, suggesting the involvement of MTORC1 and MTORC2 in TSH effect. A synthetic analog of rapamycin (everolimus), which is clinically used as an anticancer agent, was able to increase rat thyroid iodide uptake in vivo. In conclusion, we show that MTOR kinase participates in the control of thyroid iodide uptake, demonstrating that MTOR not only regulates cell survival, but also normal thyroid cell function both in vitro and in vivo.