In 2015, the American Thyroid Association (ATA) published evidence-based guidelines for the manag... more In 2015, the American Thyroid Association (ATA) published evidence-based guidelines for the management and follow-up of patients with differentiated thyroid cancer (DTC) [1]. While many of the updated recommendations can be easily integrated into clinical practice, appropriate implementation of several of the major management recommendations will require additional training and education for most clinicians involved in the care of patients with DTC. One of the major changes with regard to the evaluation of thyroid nodules is the shift toward much greater emphasis on pattern recognition (ultrasonographic characteristics of the thyroid nodule) in the selection of nodules for fine needle aspiration biopsy, rather than relying strictly on the size of thyroid nodules [1]. The new guidelines also note that an active surveillance management approach can be considered as an alternative to immediate biopsy and surgery in subcentimeter thyroid nodules with highly suspicious ultrasonographic characteristics and in cytologically confirmed very low-risk thyroid cancer [1]. Appropriate application of these guideline recommendations will require strong skills in the use of ultrasonography. Unfortunately, many endocrinology fellowship programs lack formal training in diagnostic thyroid ultrasound. As a result, clinicians practicing outside of academic medical centers will probably find it very challenging to implement the new ATA guidelines that rely on systematic ultrasonographic evaluations. On the other side, the classification of patients with thyroid cancer according to their risk of recurrence was initially introduced by ATA and Latin American Thyroid Society in 2009 [2, 3]. This categorization was developed to help physicians to predict initial and long-term outcomes, mainly to estimate the frequency of excellent response or structural persistent disease. However, in our experience, it seems that many physicians in the United States and Latin America are adopting a risk-adapted management approach rather slowly and as a result many patients continue to be subjected to a “one size fits all” model of management, which may lead to either unnecessary treatments and close follow-up in low risk patients, or inadequate treatments in high-risk patients. Some physicians may argue that the available information at diagnosis could be insufficient to accurately determine the ATA initial or dynamic risk of recurrence. This is usually related to: (i) the absence of complete information about the surgical procedure; (ii) the inadequate description of the pathological report, (iii) the absence of a reliable neck ultrasonographic report; and/or (iv) the absence of reliable thyroglobulin or anti-thyroglobulin antibodies measurements. One of the authors of this letter (FP) has compared the absence of complete risk stratification information with a “broken chair”; when one or more of these “legs” are missing, it is very difficult to correctly risk stratify patients. We firmly believe that we do not need to quickly make decisions in the presumed low/intermediate-risk group of patients regarding remnant ablation. As the current evidence was carefully reviewed by Lamartina and Cooper [4], we agree that there are several cost-effective tools for staging * Amanda La Greca [email protected]
Arquivos Brasileiros de Endocrinologia & Metabologia, 2014
Objective: To investigate the efficacy of sorafenib in progressive radioiodine resistant metastat... more Objective: To investigate the efficacy of sorafenib in progressive radioiodine resistant metastatic thyroid carcinoma. Subjects and methods: Off-label observational study. Sorafenib 400 mg twice daily was evaluated. Therapy duration was 12 ± 3 months (range 6-16 months). Results: Eight patients were included (seven papillary, one insular variant). The eight patients meeting study criteria received sorafenib 400 mg orally twice a day until disease progression or unacceptable toxicity developed. One patient showed a partial response with tumor regression of -35%, six months after the beginning of the treatment; five patients exhibited stable disease and two patients had progressive disease and died. Thyroglobulin decreased within 4 weeks in all patients by 50% ± 23%. Adverse events: one patient had heart failure, and recovered after sorafenib withdrawal. However, she died five months later of sudden death. Conclusion: These data suggest a possible role for sorafenib in the treatment of progressive metastatic DTC. Adverse event are usually manageable, but severe ones may appear and these patients should be strictly controlled. Arq Bras Endocrinol Metab. 2014;58(1):37-41 Objetivo: Investigar a eficácia do sorafenibe no carcinoma de tireoide metastático progressivo e refratário à iodoterapia. Sujeitos e métodos: Estudo observacional do efeito do sorafenibe off-label administrado 400 mg duas vezes ao dia. A duração da terapia foi de 12 ± 3 meses (variação de 6-16 meses). Resultados: Oito pacientes foram incluídos (sete com variante papilífera e um com variante insular). Os oito pacientes que preencheram os critérios do estudo receberam o sorafenibe 400 mg por via oral duas vezes por dia até progressão da doença ou toxicidade inaceitável. Um paciente apresentou uma resposta parcial com regressão tumoral da lesão alvo de 35% seis meses após o início do tratamento; cinco pacientes apresentaram doença estável e dois pacientes progrediram e morreram. A tireoglobulina diminuiu 50% ± 23% em 4 semanas em todos os pacientes. Eventos adversos: um paciente teve insuficiência cardíaca e morreu por morte súbita cinco meses após a retirada do sorafenibe. Conclusão: Esses dados sugerem um possível papel para sorafenibe para o tratamento do CDT metastático progressivo. Arq Bras Endocrinol Metab. 2014;58(1):37-41 Descritores
The transcription factor Pitx2 is required for the morphogenesis of anterior structures such as t... more The transcription factor Pitx2 is required for the morphogenesis of anterior structures such as the eye, teeth, and anterior pituitary. We investigated the functional properties of Pitx2 missense mutants previously reported in Axenfeld-Rieger syndrome, using reporter genes under the control of pituitary target gene [human (h)PRL, hGH, hPit-1] promoters transfected in nonpituitary and pituitary cell lines. The five mutants appeared to be transcriptionally defective despite conserved DNA-binding in CV1 cells. In addition, one mutation, R91P, almost completely blocked the wt-Pitx2-induced activation of the target promoters, prevented the Pitx2/Pit-1 synergistic activation of the hPRL promoter, and was able to counteract the Pitx1-driven transactivation effects. The dominant negative properties of this mutant were further estab-lished in cells endogenously expressing Pitx2 because transfection of R91P in GH4C1 somatolactotroph cells resulted in a dose-dependent inhibition of basal activities of the pituitary promoters. These results, which show that Pitx2 mutants are defective in activating pituitary target genes, confirm the critical role of this homeodomain factor in the differentiated functions of the pituitary somatolactotroph cells. Furthermore, these results might form the basis for future experiments because dominant negative forms of Pitx2 such as R91P might provide instructive tools to further delineate the detailed mechanisms mediating Pitx2 functions in cell proliferation and differentiation. (Endocrinology 143: 2839 -2851, 2002)
The transcription factor Pitx2 is required for the morphogenesis of anterior structures such as t... more The transcription factor Pitx2 is required for the morphogenesis of anterior structures such as the eye, teeth, and anterior pituitary. We investigated the functional properties of Pitx2 missense mutants previously reported in Axenfeld-Rieger syndrome, using reporter genes under the control of pituitary target gene [human (h)PRL, hGH, hPit-1] promoters transfected in nonpituitary and pituitary cell lines. The five mutants appeared to be transcriptionally defective despite conserved DNA-binding in CV1 cells. In addition, one mutation, R91P, almost completely blocked the wt-Pitx2-induced activation of the target promoters, prevented the Pitx2/Pit-1 synergistic activation of the hPRL promoter, and was able to counteract the Pitx1-driven transactivation effects. The dominant negative properties of this mutant were further estab-lished in cells endogenously expressing Pitx2 because transfection of R91P in GH4C1 somatolactotroph cells resulted in a dose-dependent inhibition of basal activities of the pituitary promoters. These results, which show that Pitx2 mutants are defective in activating pituitary target genes, confirm the critical role of this homeodomain factor in the differentiated functions of the pituitary somatolactotroph cells. Furthermore, these results might form the basis for future experiments because dominant negative forms of Pitx2 such as R91P might provide instructive tools to further delineate the detailed mechanisms mediating Pitx2 functions in cell proliferation and differentiation. (Endocrinology 143: 2839 -2851, 2002)
Thyroid : official journal of the American Thyroid Association, 2013
This analysis was performed to determine the effect of initial therapy on the outcomes of thyroid... more This analysis was performed to determine the effect of initial therapy on the outcomes of thyroid cancer patients. The study setting was a prospectively followed multi-institutional registry. Patients were stratified as low risk (stages I and II) or high risk (stages III and IV). Treatments employed included near-total thyroidectomy, administration of radioactive iodine, and thyroid hormone suppression therapy. Outcome measures were overall survival, disease-specific survival, and disease-free survival. Near-total thyroidectomy, radioactive iodine, and aggressive thyroid hormone suppression therapy were each independently associated with longer overall survival in high-risk patients. Near-total thyroidectomy followed by radioactive iodine therapy, and moderate thyroid hormone suppression therapy, both predicted improved overall survival in stage II patients. No treatment modality, including lack of radioactive iodine, was associated with altered survival in stage I patients. Based on our overall survival data, we confirm that near-total thyroidectomy is indicated in high-risk patients. We also conclude that radioactive iodine therapy is beneficial for stage II, III, and IV patients. Importantly, we show for the first time that superior outcomes are associated with aggressive thyroid hormone suppression therapy in high-risk patients, but are achieved with modest suppression in stage II patients. We were unable to show any impact, positive or negative, of specific therapies in stage I patients.
Arquivos brasileiros de endocrinologia e metabologia, 2013
To establish the frequency of U Tg (undetectable pre-ablation thyroglobulin) in TgAbnegative pati... more To establish the frequency of U Tg (undetectable pre-ablation thyroglobulin) in TgAbnegative patients and to evaluate the outcome in the follow-up. Subjects and methods: We retrospectively reviewed 335 patients' records. Twenty eight patients (9%) had U Tg. Mean follow--up was 42 ± 38 months. All subjects had undergone total thyroidectomy, and lymph nodes were positive in 13 (46%) patients. Tg and TgAb levels were measured 4 weeks after surgery by IMA technology in hypothyroid state. No evidence of disease (NED) status was defined as undetectable (< 1 ng/mL) stimulated Tg and negative Tg-Ab and/or negative WBS, together with normal imaging studies. Results: Seventeen patients (61%) were considered with NED. Four patients (14%) had persistent disease (mediastinum, n = 1, lung n = 2, unknown n = 1), and 7 (25%) had detectable TgAb by other method during their follow-up. Conclusions: U Tg levels usually is associated to a complete surgery. However, in a low percentage of patients, this may be related to false negative Tg or TgAb measurement. Arq Bras Endocrinol Metab. 2013;57(4):300-6
ABSTRACT For some patients with metastatic disease from differentiated thyroid cancer, remarkable... more ABSTRACT For some patients with metastatic disease from differentiated thyroid cancer, remarkable results can be achieved with eradication of tumour cells through radioactive iodine ( 131 I) uptake. However, even after an adequate stimulation by thyroid-stimulating hormone and in the absence of excess iodine, only two thirds of patients with metastases show substantial radioactive iodine uptake, and only 42% of them achieve a cure. 1 Patients who are not responsive to radioactive iodine treatment have a life ...
ObJEctIVE: some extra-thyroid actions of thyroid stimulating hormone (tsH), such as an in vitro a... more ObJEctIVE: some extra-thyroid actions of thyroid stimulating hormone (tsH), such as an in vitro action on bone, have been described. Our aim was to evaluate in vivo the acute effect of a recombinant human tsH (rhtsH)-induced tsH surge on Osteoprotegerin (OPG) and receptor activator of the nuclear factor-κb (rANK-L) levels in patients under levo-thyroxine (L-t4) therapy. DEsIGN: 24 patients with differentiated thyroid carcinoma (Dtc) were studied. standard rhtsH testing was performed. OPG, rANK-L, tsH, thyroid hormones, thyroglobulin and several parameters of bone metabolism were evaluated. rEsuLts: baseline OPG and rANK-L levels were in the range of our reference population. An inverse correlation between OPG and spinal Z-score (p=0.029) and between rANK-L and age (p=0.018) or urinary calcium/creatinine ratio (p=0.011) was detected. After rhtsH administration, a significant (p<0.001) increase in tsH was found. No significant increase in OPG or rANK-L levels after rhtsH was observed. No correlation was detected between tsH peak value after rhtsH and maximal percentage change in OPG or rANK-L. A slight increase in urinary cross-links after rhtsH was found. cONcLusIONs: In a small group of subjects with a history of Dtc on L-t4 regimen, our study did not support an acute direct effect of tsH on OPG and rANK-L.
The objective of this study was to evaluate the initial response to treatment and the long-term o... more The objective of this study was to evaluate the initial response to treatment and the long-term outcome of patients with papillary thyroid cancer (PTC), according to the modified 2014 risk of recurrence classification of the American Thyroid Association and the presence or absence of insulin resistance (IR). We retrospectively reviewed our database of 636 records and selected 171 patients in whom we had previously validated the ATA risk of recurrence (RR) classification. From these patients, 38 non-diabetic subjects were included for analysis according to the following criteria: age older than 18 years, classic papillary thyroid carcinoma, stable body mass index 5 years previous to PTC diagnosis and during the entire time of follow-up, low and intermediate RR, follow-up after initial treatment at least for 3 years, and absence of any drug treatment for the metabolic syndrome. The IR was evaluated through the homeostasis model assessment (HOMA) index. When equal or higher than 2.5, patients were considered as harboring IR. The initial response to treatment was classified as remission or persistent disease (biochemical and/or structural). The clinical status at final follow-up was defined as no evidence of disease, biochemical persistent disease, structural persistent disease, or recurrence (biochemical or structural disease identified after a period of no evidence of disease). RR was as follows: low: n = 15, intermediate: n = 23. The median follow-up of this patient cohort was 5.5 years (range 3-22 years). We found no statistically significant differences when the response to initial treatment was considered in low-risk patients with or without IR. However, remission was more frequently found in those patients without IR when the intermediate RR was considered (36 vs. 11 %, p = 0.01). When considering the status at final follow-up, we found more frequency of structural persistent disease in both, low and intermediate RR patients with IR (10 vs. 0 %, p = 0.02 and 45 vs.7 %, p = 0.01, respectively). In this series of patients with PTC, the state of IR was associated with increased frequency of structural persistent disease at final follow-up. The IR could have a deleterious effect on the outcome of patients with PTC.
Objective: It has been shown that patients with insulin resistance (IR) have a higher prevalence ... more 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-T 4 ) 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 ¼ 14), patients treated with M; GII (n ¼ 18), patients treated with M plus L-T 4 ; GIII (n ¼ 19), patients treated with L-T 4 ; and GIV (n ¼ 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 mm 3 &0.84 cm in diameter (range, 32-3,616 mm 3 ). After treatment, patients of Group I and II showed significant reductions in their nodule size [median reduction, 108.50 mm 3 (30%) and 184.5 mm 3 (55%), P < 0.008 and P < 0.0001, respectively]. Patients in GIII and GIV did not have a significant reduction of their nodules [P ¼ 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-T 4 was the best treatment in these women.
Recombinant Human TSH Versus Thyroid Hormone Withdrawal TO THE EDITOR: With considerable interest... more Recombinant Human TSH Versus Thyroid Hormone Withdrawal TO THE EDITOR: With considerable interest we have read the recent report by Van Nostrand et al. in which the authors compared the proportion of patients with positive scans and the number of lesions detected during diagnostic 131 I whole-body scintigraphy and 124 I PET/CT in patients prepared with either recombinant human thyroid-stimulating hormone (rhTSH) or conventional thyroid hormone withdrawal (THW) (1). The authors reported that considerably more patients were "positive" both on diagnostic 131 I whole-body scintigraphy and on 124 I PET/CT after THW than after rhTSH.
For patients with advanced, radioactive iodine-refractory differentiated thyroid cancer, current ... more 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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;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.
and Introduction Abstract Objective: To evaluate serum thyrotropin (TSH) concentrations after con... more and Introduction Abstract Objective: To evaluate serum thyrotropin (TSH) concentrations after conventional (0.9 mg) or half-dose (0.45 mg) administration of recombinant human TSH (rhTSH) injections intramuscularly in patients with end-stage renal disease and differentiated thyroid cancer. Methods: In this case series, we administered 2 doses of 0.9-mg rhTSH or 2 doses of 0.45-mg rhTSH to 3 patients with renal failure and differentiated thyroid cancer who were receiving hemodialysis. Basal serum TSH concentrations were assessed while the patients were taking thyroid hormone therapy. Serum TSH was measured on days 2, 3, 5, 8, 10, 14, and 17 of the study. Thyroglobulin and thyroglobulin antibodies were also measured on days 5 and 7. Patients were asked to report any adverse effects. Results: Patient 1, who received 2 injections of 0.9-mg rhTSH administered on days 1 and 3, had persistently elevated serum TSH levels for approximately 11 days. Peak serum TSH measured on day 5 was 644 mIU/L. Self-limited diarrhea was the only reported adverse effect. Patients 2 and 3 received 0.45 mg of rhTSH on 2 consecutive days (days 1 and 2), and both exhibited persistently elevated serum TSH levels for 12 days. The peak serum TSH values on day 3 were 402 mIU/L in Patient 2 and 386 mIU/L in Patient 3. No adverse events were observed in these 2 patients. Patient 2 received thyrotropin alfa for injection to confirm disease status. Patient 3 also received a radioiodine dose because of presumed persistent disease. Conclusion: High serum TSH levels achieved after conventional and half-dose administration of rhTSH suggest that a dose adjustment might be considered in patients with end-stage renal disease. (Endocr Pract. 2008;14:961-966) Abbreviation Notes rhTSH = recombinant human thyrotropin; TSH = thyrotropin Endocrine Practice. 2008;14(8):961-966.
C uando hablamos de cáncer de tiroides e hipertiroidismo, es necesario hacer una diferenciación c... more C uando hablamos de cáncer de tiroides e hipertiroidismo, es necesario hacer una diferenciación clara de las dos situaciones principales a las cuales podemos referirnos. Por un lado, la asociación de hipertiroidismo por enfermedad de Graves y cáncer de tiroides, y por el otro, la presencia de un cáncer de tiroides con hiperproducción autónoma de hormonas tiroideas. Una tercera causa de hipertiroidismo en pacientes con cáncer de tiroides, aunque extremadamente poco frecuente, puede ser la producción hormonal por metástasis masivas de un cáncer de tiroides.
In 2015, the American Thyroid Association (ATA) published evidence-based guidelines for the manag... more In 2015, the American Thyroid Association (ATA) published evidence-based guidelines for the management and follow-up of patients with differentiated thyroid cancer (DTC) [1]. While many of the updated recommendations can be easily integrated into clinical practice, appropriate implementation of several of the major management recommendations will require additional training and education for most clinicians involved in the care of patients with DTC. One of the major changes with regard to the evaluation of thyroid nodules is the shift toward much greater emphasis on pattern recognition (ultrasonographic characteristics of the thyroid nodule) in the selection of nodules for fine needle aspiration biopsy, rather than relying strictly on the size of thyroid nodules [1]. The new guidelines also note that an active surveillance management approach can be considered as an alternative to immediate biopsy and surgery in subcentimeter thyroid nodules with highly suspicious ultrasonographic characteristics and in cytologically confirmed very low-risk thyroid cancer [1]. Appropriate application of these guideline recommendations will require strong skills in the use of ultrasonography. Unfortunately, many endocrinology fellowship programs lack formal training in diagnostic thyroid ultrasound. As a result, clinicians practicing outside of academic medical centers will probably find it very challenging to implement the new ATA guidelines that rely on systematic ultrasonographic evaluations. On the other side, the classification of patients with thyroid cancer according to their risk of recurrence was initially introduced by ATA and Latin American Thyroid Society in 2009 [2, 3]. This categorization was developed to help physicians to predict initial and long-term outcomes, mainly to estimate the frequency of excellent response or structural persistent disease. However, in our experience, it seems that many physicians in the United States and Latin America are adopting a risk-adapted management approach rather slowly and as a result many patients continue to be subjected to a “one size fits all” model of management, which may lead to either unnecessary treatments and close follow-up in low risk patients, or inadequate treatments in high-risk patients. Some physicians may argue that the available information at diagnosis could be insufficient to accurately determine the ATA initial or dynamic risk of recurrence. This is usually related to: (i) the absence of complete information about the surgical procedure; (ii) the inadequate description of the pathological report, (iii) the absence of a reliable neck ultrasonographic report; and/or (iv) the absence of reliable thyroglobulin or anti-thyroglobulin antibodies measurements. One of the authors of this letter (FP) has compared the absence of complete risk stratification information with a “broken chair”; when one or more of these “legs” are missing, it is very difficult to correctly risk stratify patients. We firmly believe that we do not need to quickly make decisions in the presumed low/intermediate-risk group of patients regarding remnant ablation. As the current evidence was carefully reviewed by Lamartina and Cooper [4], we agree that there are several cost-effective tools for staging * Amanda La Greca [email protected]
Arquivos Brasileiros de Endocrinologia & Metabologia, 2014
Objective: To investigate the efficacy of sorafenib in progressive radioiodine resistant metastat... more Objective: To investigate the efficacy of sorafenib in progressive radioiodine resistant metastatic thyroid carcinoma. Subjects and methods: Off-label observational study. Sorafenib 400 mg twice daily was evaluated. Therapy duration was 12 ± 3 months (range 6-16 months). Results: Eight patients were included (seven papillary, one insular variant). The eight patients meeting study criteria received sorafenib 400 mg orally twice a day until disease progression or unacceptable toxicity developed. One patient showed a partial response with tumor regression of -35%, six months after the beginning of the treatment; five patients exhibited stable disease and two patients had progressive disease and died. Thyroglobulin decreased within 4 weeks in all patients by 50% ± 23%. Adverse events: one patient had heart failure, and recovered after sorafenib withdrawal. However, she died five months later of sudden death. Conclusion: These data suggest a possible role for sorafenib in the treatment of progressive metastatic DTC. Adverse event are usually manageable, but severe ones may appear and these patients should be strictly controlled. Arq Bras Endocrinol Metab. 2014;58(1):37-41 Objetivo: Investigar a eficácia do sorafenibe no carcinoma de tireoide metastático progressivo e refratário à iodoterapia. Sujeitos e métodos: Estudo observacional do efeito do sorafenibe off-label administrado 400 mg duas vezes ao dia. A duração da terapia foi de 12 ± 3 meses (variação de 6-16 meses). Resultados: Oito pacientes foram incluídos (sete com variante papilífera e um com variante insular). Os oito pacientes que preencheram os critérios do estudo receberam o sorafenibe 400 mg por via oral duas vezes por dia até progressão da doença ou toxicidade inaceitável. Um paciente apresentou uma resposta parcial com regressão tumoral da lesão alvo de 35% seis meses após o início do tratamento; cinco pacientes apresentaram doença estável e dois pacientes progrediram e morreram. A tireoglobulina diminuiu 50% ± 23% em 4 semanas em todos os pacientes. Eventos adversos: um paciente teve insuficiência cardíaca e morreu por morte súbita cinco meses após a retirada do sorafenibe. Conclusão: Esses dados sugerem um possível papel para sorafenibe para o tratamento do CDT metastático progressivo. Arq Bras Endocrinol Metab. 2014;58(1):37-41 Descritores
The transcription factor Pitx2 is required for the morphogenesis of anterior structures such as t... more The transcription factor Pitx2 is required for the morphogenesis of anterior structures such as the eye, teeth, and anterior pituitary. We investigated the functional properties of Pitx2 missense mutants previously reported in Axenfeld-Rieger syndrome, using reporter genes under the control of pituitary target gene [human (h)PRL, hGH, hPit-1] promoters transfected in nonpituitary and pituitary cell lines. The five mutants appeared to be transcriptionally defective despite conserved DNA-binding in CV1 cells. In addition, one mutation, R91P, almost completely blocked the wt-Pitx2-induced activation of the target promoters, prevented the Pitx2/Pit-1 synergistic activation of the hPRL promoter, and was able to counteract the Pitx1-driven transactivation effects. The dominant negative properties of this mutant were further estab-lished in cells endogenously expressing Pitx2 because transfection of R91P in GH4C1 somatolactotroph cells resulted in a dose-dependent inhibition of basal activities of the pituitary promoters. These results, which show that Pitx2 mutants are defective in activating pituitary target genes, confirm the critical role of this homeodomain factor in the differentiated functions of the pituitary somatolactotroph cells. Furthermore, these results might form the basis for future experiments because dominant negative forms of Pitx2 such as R91P might provide instructive tools to further delineate the detailed mechanisms mediating Pitx2 functions in cell proliferation and differentiation. (Endocrinology 143: 2839 -2851, 2002)
The transcription factor Pitx2 is required for the morphogenesis of anterior structures such as t... more The transcription factor Pitx2 is required for the morphogenesis of anterior structures such as the eye, teeth, and anterior pituitary. We investigated the functional properties of Pitx2 missense mutants previously reported in Axenfeld-Rieger syndrome, using reporter genes under the control of pituitary target gene [human (h)PRL, hGH, hPit-1] promoters transfected in nonpituitary and pituitary cell lines. The five mutants appeared to be transcriptionally defective despite conserved DNA-binding in CV1 cells. In addition, one mutation, R91P, almost completely blocked the wt-Pitx2-induced activation of the target promoters, prevented the Pitx2/Pit-1 synergistic activation of the hPRL promoter, and was able to counteract the Pitx1-driven transactivation effects. The dominant negative properties of this mutant were further estab-lished in cells endogenously expressing Pitx2 because transfection of R91P in GH4C1 somatolactotroph cells resulted in a dose-dependent inhibition of basal activities of the pituitary promoters. These results, which show that Pitx2 mutants are defective in activating pituitary target genes, confirm the critical role of this homeodomain factor in the differentiated functions of the pituitary somatolactotroph cells. Furthermore, these results might form the basis for future experiments because dominant negative forms of Pitx2 such as R91P might provide instructive tools to further delineate the detailed mechanisms mediating Pitx2 functions in cell proliferation and differentiation. (Endocrinology 143: 2839 -2851, 2002)
Thyroid : official journal of the American Thyroid Association, 2013
This analysis was performed to determine the effect of initial therapy on the outcomes of thyroid... more This analysis was performed to determine the effect of initial therapy on the outcomes of thyroid cancer patients. The study setting was a prospectively followed multi-institutional registry. Patients were stratified as low risk (stages I and II) or high risk (stages III and IV). Treatments employed included near-total thyroidectomy, administration of radioactive iodine, and thyroid hormone suppression therapy. Outcome measures were overall survival, disease-specific survival, and disease-free survival. Near-total thyroidectomy, radioactive iodine, and aggressive thyroid hormone suppression therapy were each independently associated with longer overall survival in high-risk patients. Near-total thyroidectomy followed by radioactive iodine therapy, and moderate thyroid hormone suppression therapy, both predicted improved overall survival in stage II patients. No treatment modality, including lack of radioactive iodine, was associated with altered survival in stage I patients. Based on our overall survival data, we confirm that near-total thyroidectomy is indicated in high-risk patients. We also conclude that radioactive iodine therapy is beneficial for stage II, III, and IV patients. Importantly, we show for the first time that superior outcomes are associated with aggressive thyroid hormone suppression therapy in high-risk patients, but are achieved with modest suppression in stage II patients. We were unable to show any impact, positive or negative, of specific therapies in stage I patients.
Arquivos brasileiros de endocrinologia e metabologia, 2013
To establish the frequency of U Tg (undetectable pre-ablation thyroglobulin) in TgAbnegative pati... more To establish the frequency of U Tg (undetectable pre-ablation thyroglobulin) in TgAbnegative patients and to evaluate the outcome in the follow-up. Subjects and methods: We retrospectively reviewed 335 patients' records. Twenty eight patients (9%) had U Tg. Mean follow--up was 42 ± 38 months. All subjects had undergone total thyroidectomy, and lymph nodes were positive in 13 (46%) patients. Tg and TgAb levels were measured 4 weeks after surgery by IMA technology in hypothyroid state. No evidence of disease (NED) status was defined as undetectable (< 1 ng/mL) stimulated Tg and negative Tg-Ab and/or negative WBS, together with normal imaging studies. Results: Seventeen patients (61%) were considered with NED. Four patients (14%) had persistent disease (mediastinum, n = 1, lung n = 2, unknown n = 1), and 7 (25%) had detectable TgAb by other method during their follow-up. Conclusions: U Tg levels usually is associated to a complete surgery. However, in a low percentage of patients, this may be related to false negative Tg or TgAb measurement. Arq Bras Endocrinol Metab. 2013;57(4):300-6
ABSTRACT For some patients with metastatic disease from differentiated thyroid cancer, remarkable... more ABSTRACT For some patients with metastatic disease from differentiated thyroid cancer, remarkable results can be achieved with eradication of tumour cells through radioactive iodine ( 131 I) uptake. However, even after an adequate stimulation by thyroid-stimulating hormone and in the absence of excess iodine, only two thirds of patients with metastases show substantial radioactive iodine uptake, and only 42% of them achieve a cure. 1 Patients who are not responsive to radioactive iodine treatment have a life ...
ObJEctIVE: some extra-thyroid actions of thyroid stimulating hormone (tsH), such as an in vitro a... more ObJEctIVE: some extra-thyroid actions of thyroid stimulating hormone (tsH), such as an in vitro action on bone, have been described. Our aim was to evaluate in vivo the acute effect of a recombinant human tsH (rhtsH)-induced tsH surge on Osteoprotegerin (OPG) and receptor activator of the nuclear factor-κb (rANK-L) levels in patients under levo-thyroxine (L-t4) therapy. DEsIGN: 24 patients with differentiated thyroid carcinoma (Dtc) were studied. standard rhtsH testing was performed. OPG, rANK-L, tsH, thyroid hormones, thyroglobulin and several parameters of bone metabolism were evaluated. rEsuLts: baseline OPG and rANK-L levels were in the range of our reference population. An inverse correlation between OPG and spinal Z-score (p=0.029) and between rANK-L and age (p=0.018) or urinary calcium/creatinine ratio (p=0.011) was detected. After rhtsH administration, a significant (p<0.001) increase in tsH was found. No significant increase in OPG or rANK-L levels after rhtsH was observed. No correlation was detected between tsH peak value after rhtsH and maximal percentage change in OPG or rANK-L. A slight increase in urinary cross-links after rhtsH was found. cONcLusIONs: In a small group of subjects with a history of Dtc on L-t4 regimen, our study did not support an acute direct effect of tsH on OPG and rANK-L.
The objective of this study was to evaluate the initial response to treatment and the long-term o... more The objective of this study was to evaluate the initial response to treatment and the long-term outcome of patients with papillary thyroid cancer (PTC), according to the modified 2014 risk of recurrence classification of the American Thyroid Association and the presence or absence of insulin resistance (IR). We retrospectively reviewed our database of 636 records and selected 171 patients in whom we had previously validated the ATA risk of recurrence (RR) classification. From these patients, 38 non-diabetic subjects were included for analysis according to the following criteria: age older than 18 years, classic papillary thyroid carcinoma, stable body mass index 5 years previous to PTC diagnosis and during the entire time of follow-up, low and intermediate RR, follow-up after initial treatment at least for 3 years, and absence of any drug treatment for the metabolic syndrome. The IR was evaluated through the homeostasis model assessment (HOMA) index. When equal or higher than 2.5, patients were considered as harboring IR. The initial response to treatment was classified as remission or persistent disease (biochemical and/or structural). The clinical status at final follow-up was defined as no evidence of disease, biochemical persistent disease, structural persistent disease, or recurrence (biochemical or structural disease identified after a period of no evidence of disease). RR was as follows: low: n = 15, intermediate: n = 23. The median follow-up of this patient cohort was 5.5 years (range 3-22 years). We found no statistically significant differences when the response to initial treatment was considered in low-risk patients with or without IR. However, remission was more frequently found in those patients without IR when the intermediate RR was considered (36 vs. 11 %, p = 0.01). When considering the status at final follow-up, we found more frequency of structural persistent disease in both, low and intermediate RR patients with IR (10 vs. 0 %, p = 0.02 and 45 vs.7 %, p = 0.01, respectively). In this series of patients with PTC, the state of IR was associated with increased frequency of structural persistent disease at final follow-up. The IR could have a deleterious effect on the outcome of patients with PTC.
Objective: It has been shown that patients with insulin resistance (IR) have a higher prevalence ... more 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-T 4 ) 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 ¼ 14), patients treated with M; GII (n ¼ 18), patients treated with M plus L-T 4 ; GIII (n ¼ 19), patients treated with L-T 4 ; and GIV (n ¼ 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 mm 3 &0.84 cm in diameter (range, 32-3,616 mm 3 ). After treatment, patients of Group I and II showed significant reductions in their nodule size [median reduction, 108.50 mm 3 (30%) and 184.5 mm 3 (55%), P < 0.008 and P < 0.0001, respectively]. Patients in GIII and GIV did not have a significant reduction of their nodules [P ¼ 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-T 4 was the best treatment in these women.
Recombinant Human TSH Versus Thyroid Hormone Withdrawal TO THE EDITOR: With considerable interest... more Recombinant Human TSH Versus Thyroid Hormone Withdrawal TO THE EDITOR: With considerable interest we have read the recent report by Van Nostrand et al. in which the authors compared the proportion of patients with positive scans and the number of lesions detected during diagnostic 131 I whole-body scintigraphy and 124 I PET/CT in patients prepared with either recombinant human thyroid-stimulating hormone (rhTSH) or conventional thyroid hormone withdrawal (THW) (1). The authors reported that considerably more patients were "positive" both on diagnostic 131 I whole-body scintigraphy and on 124 I PET/CT after THW than after rhTSH.
For patients with advanced, radioactive iodine-refractory differentiated thyroid cancer, current ... more 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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;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.
and Introduction Abstract Objective: To evaluate serum thyrotropin (TSH) concentrations after con... more and Introduction Abstract Objective: To evaluate serum thyrotropin (TSH) concentrations after conventional (0.9 mg) or half-dose (0.45 mg) administration of recombinant human TSH (rhTSH) injections intramuscularly in patients with end-stage renal disease and differentiated thyroid cancer. Methods: In this case series, we administered 2 doses of 0.9-mg rhTSH or 2 doses of 0.45-mg rhTSH to 3 patients with renal failure and differentiated thyroid cancer who were receiving hemodialysis. Basal serum TSH concentrations were assessed while the patients were taking thyroid hormone therapy. Serum TSH was measured on days 2, 3, 5, 8, 10, 14, and 17 of the study. Thyroglobulin and thyroglobulin antibodies were also measured on days 5 and 7. Patients were asked to report any adverse effects. Results: Patient 1, who received 2 injections of 0.9-mg rhTSH administered on days 1 and 3, had persistently elevated serum TSH levels for approximately 11 days. Peak serum TSH measured on day 5 was 644 mIU/L. Self-limited diarrhea was the only reported adverse effect. Patients 2 and 3 received 0.45 mg of rhTSH on 2 consecutive days (days 1 and 2), and both exhibited persistently elevated serum TSH levels for 12 days. The peak serum TSH values on day 3 were 402 mIU/L in Patient 2 and 386 mIU/L in Patient 3. No adverse events were observed in these 2 patients. Patient 2 received thyrotropin alfa for injection to confirm disease status. Patient 3 also received a radioiodine dose because of presumed persistent disease. Conclusion: High serum TSH levels achieved after conventional and half-dose administration of rhTSH suggest that a dose adjustment might be considered in patients with end-stage renal disease. (Endocr Pract. 2008;14:961-966) Abbreviation Notes rhTSH = recombinant human thyrotropin; TSH = thyrotropin Endocrine Practice. 2008;14(8):961-966.
C uando hablamos de cáncer de tiroides e hipertiroidismo, es necesario hacer una diferenciación c... more C uando hablamos de cáncer de tiroides e hipertiroidismo, es necesario hacer una diferenciación clara de las dos situaciones principales a las cuales podemos referirnos. Por un lado, la asociación de hipertiroidismo por enfermedad de Graves y cáncer de tiroides, y por el otro, la presencia de un cáncer de tiroides con hiperproducción autónoma de hormonas tiroideas. Una tercera causa de hipertiroidismo en pacientes con cáncer de tiroides, aunque extremadamente poco frecuente, puede ser la producción hormonal por metástasis masivas de un cáncer de tiroides.
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