RESUMEN
CONTEXT: Although commonly performed, data are lacking regarding efficacy and safety of lymph node dissection (LND) for recurrent/persistent papillary thyroid cancer (PTC). OBJECTIVE: Evaluate the efficacy and morbidity of LND in recurrent/persistent PTC. DESIGN: Retrospective review of central or lateral LND performed for persistent/recurrent PTC between January 2004 and March 2006. SETTING: Multidisciplinary thyroid cancer clinic with a single surgeon at an academic medical center. PARTICIPANTS: Seventy-five patients who underwent 79 LND for persistent/residual PTC. Safety analysis included all 79 resections. Exclusion criteria for the efficacy analysis were factors prohibiting evaluation of thyroglobulin (Tg) response. Forty-one resections were included in the efficacy analysis. INTERVENTION: Selective LND per standard of care. MAIN OUTCOME MEASURE: Primary outcome was the Tg response to LND. Secondary outcomes were surgical complications. RESULTS: Thirty-nine of the 41 evaluable resections also had Tg data allowing classification of Tg response. Of 39 classifiable resections, 16 (41%) resulted in undetectable postoperative stimulated Tg levels. An additional 12 resections resulted in significant (> or =50%) reductions in suppressed or stimulated Tg levels for an overall improvement rate of 72%. Of all 79 resections, 25 (32%) resulted in minor and 7 (9%) resulted in major complications. CONCLUSIONS: LND for persistent/recurrent PTC is a relatively safe procedure in experienced hands. It can lead to an undetectable Tg in 41% of cases and produce a major Tg reduction in an additional 31%. Its efficacy in short-term follow-up is comparable with that reported for I-131, and it should be considered in the management of persistent/recurrent PTC.
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Carcinoma Papilar/cirugía , Escisión del Ganglio Linfático , Recurrencia Local de Neoplasia , Neoplasias de la Tiroides/cirugía , Adolescente , Adulto , Anciano , Algoritmos , Carcinoma Papilar/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Grupo de Atención al Paciente , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Procedimientos Quirúrgicos Operativos/métodos , Tiroglobulina/sangre , Neoplasias de la Tiroides/patología , Resultado del TratamientoRESUMEN
Background: It is unclear whether variations in thyroid status within or near the reference range affect energy expenditure, body mass, or body composition. Methods: 138 subjects treated with levothyroxine (LT4) for hypothyroidism with normal TSH levels underwent measurement of total, resting, and physical activity energy expenditure; thermic effect of food; substrate oxidation; dietary intake; and body composition. They were assigned to receive an unchanged, higher, or lower LT4 dose in randomized, double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). The doses were adjusted every 6 weeks to achieve target TSH levels. Baseline measures were reassessed at 6 months. Results: At study end, the mean LT4 doses and TSH levels were 1.50 ± 0.07, 1.32 ± 0.07, and 0.78 ± 0.08 µg/kg (P < 0.001) and 1.85 ± 0.25, 3.93 ± 0.38, and 9.49 ± 0.80 mU/L (P < 0.001), respectively, in the three arms. No substantial metabolic differences in outcome were found among the three arms, although direct correlations were observed between decreases in thyroid status and decreases in resting energy expenditure for all subjects. The subjects could not ascertain how their LT4 dose had been adjusted but the preferred LT4 dose they perceived to be higher (P < 0.001). Conclusions: Altering LT4 doses in subjects with hypothyroidism to vary TSH levels in and near the reference range did not have major effects on energy expenditure or body composition. Subjects treated with LT4 preferred the perceived higher LT4 doses despite a lack of objective effect. Our data do not support adjusting LT4 doses in patients with hypothyroidism to achieve potential improvements in weight or body composition.
Asunto(s)
Terapia de Reemplazo de Hormonas/métodos , Hipotiroidismo/tratamiento farmacológico , Glándula Tiroides/metabolismo , Tiroxina/administración & dosificación , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Metabolismo Energético/efectos de los fármacos , Femenino , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/fisiopatología , Masculino , Persona de Mediana Edad , Valores de Referencia , Glándula Tiroides/fisiopatología , Tiroxina/sangre , Resultado del TratamientoRESUMEN
Background: The brain is a critical target organ for thyroid hormone, but it is unclear whether variations in thyroid function within and near the reference range affect quality of life, mood, or cognition. Methods: A total of 138 subjects with levothyroxine (L-T4)-treated hypothyroidism and normal thyrotropin (TSH) levels underwent measures of quality of life (36-Item Short Form Health Survey, Underactive Thyroid-Dependent Quality of Life Questionnaire), mood (Profile of Mood States, Affective Lability Scale), and cognition (executive function, memory). They were then randomly assigned to receive an unchanged, higher, or lower L-T4 dose in double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). Doses were adjusted every 6 weeks based on TSH levels. Baseline measures were reassessed at 6 months. Results: At the end of the study, by intention to treat, mean L-T4 doses were 1.50 ± 0.07, 1.32 ± 0.07, and 0.78 ± 0.08 µg/kg (P < 0.001), and mean TSH levels were 1.85 ± 0.25, 3.93 ± 0.38, and 9.49 ± 0.80 mU/L (P < 0.001), respectively, in the three arms. There were minor differences in a few outcomes between the three arms, which were no longer significant after correction for multiple comparisons. Subjects could not ascertain how their L-T4 doses had been adjusted (P = 0.55) but preferred L-T4 doses they perceived to be higher (P < 0.001). Conclusions: Altering L-T4 doses in hypothyroid subjects to vary TSH levels in and near the reference range does not affect quality of life, mood, or cognition. L-T4-treated subjects prefer perceived higher L-T4 doses despite a lack of objective benefit. Adjusting L-T4 doses in hypothyroid patients based on symptoms in these areas may not result in significant clinical improvement.
Asunto(s)
Afecto/efectos de los fármacos , Cognición/efectos de los fármacos , Terapia de Reemplazo de Hormonas , Hipotiroidismo/tratamiento farmacológico , Calidad de Vida , Tiroxina/administración & dosificación , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Terapia de Reemplazo de Hormonas/métodos , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/psicología , Masculino , Persona de Mediana Edad , Calidad de Vida/psicología , Tirotropina/sangre , Resultado del TratamientoRESUMEN
Hypothalamic dopamine inhibits pituitary prolactin secretion and proliferation of prolactin-producing lactotroph cells by activating lactotroph dopamine D2 receptors (D2Rs). Conversely, prolactin (PRL) stimulates hypothalamic dopamine neurons via PRL receptors (PRLRs) in a short-loop feedback circuit. We used Drd2(-/-) and Prlr(-/-) mutant mice to bypass this feedback and investigate possible dopamine-independent effects of PRL on lactotroph function. The absence of either receptor induced hyperprolactinemia and large prolactinomas in females. Small macroadenomas developed in aged Prlr(-/-) males, but only microscopic adenomas were found in Drd2(-/-) male mice. Pharmacologic studies in Prlr(-/-) mice with D2R agonists and antagonists demonstrated a significant loss of endogenous dopamine tone, i.e., constitutive inhibitory signaling by the D2R, in the pituitary. However, Prlr(-/-) mice exhibited more profound hyperprolactinemia and larger tumors than did age-matched Drd2(-/-) mice, and there were additive effects in compound homozygous mutant male mice. In vitro, PRL treatment markedly inhibited the proliferation of wild-type female and male Drd2(-/-) lactotrophs, but had no effect on female Drd2(-/-) lactotrophs, suggesting a downregulation or desensitization of PRLR in response to chronic hyperprolactinemia. We conclude that PRL inhibits lactotrophs by two distinct mechanisms: (a) indirectly by activation of hypothalamic dopamine neurons and (b) directly within the pituitary in a dopamine-independent fashion.
Asunto(s)
Dopamina/fisiología , Hipófisis/patología , Neoplasias Hipofisarias/etiología , Prolactina/metabolismo , Prolactinoma/etiología , Receptores de Prolactina/fisiología , Animales , División Celular , Dihidroxifenilalanina/metabolismo , Femenino , Hipotálamo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Hipófisis/metabolismo , ARN Mensajero/análisis , Receptores de Dopamina D2/fisiología , Tirosina 3-Monooxigenasa/genéticaRESUMEN
OBJECTIVE: Many hypothyroid subjects receiving L-thyroxine (L-T4) complain of psychological symptoms or cognitive dysfunction. However, there is limited validated information on these self-reports. DESIGN: Cross-sectional comparison of 20 euthyroid and 34 treated hypothyroid subjects, aged 20-45 years, with normal thyroid-stimulating hormone (TSH) levels. Subjects underwent the following validated measures: Short Form 36 (SF-36); Symptom Checklist 90-Revised (SCL-90-R); Profile of Mood States (POMS); and tests of declarative memory (Paragraph Recall, Complex Figure), working memory (N-Back, Subject Ordered Pointing, Digit Span Backwards), and motor learning (Pursuit Rotor). MAIN OUTCOMES: L-T4-treated subjects had higher mean TSH and free T4 levels, but free triiodothyronine (T3) levels were comparable to controls. L-T4-treated subjects had decrements on SF-36 and SCL-90-R summary scales and subscales. These subjects performed slightly worse on N-Back and Pursuit Rotor tests. Neither TSH nor thyroid hormone levels were associated with performance on psychological or cognitive measures. CONCLUSIONS: This group of L-T4-treated subjects had decrements in health status, psychological function, working memory, and motor learning compared to euthyroid controls. Higher mean TSH levels suggest this may be related to suboptimal treatment, although there were no correlations between TSH levels and outcomes. These findings are limited by potential selection bias, and randomized studies targeting different TSH levels and memory subdomains would clarify these issues.
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Hipotiroidismo/terapia , Tiroxina/metabolismo , Adulto , Afecto , Estudios de Casos y Controles , Cognición , Femenino , Humanos , Hipotiroidismo/metabolismo , Memoria , Persona de Mediana Edad , Destreza Motora , Pruebas Neuropsicológicas , Glándula Tiroides/metabolismo , Hormonas Tiroideas/metabolismo , Tirotropina/sangreRESUMEN
Purpose: It is not clear whether upper limits of the thyrotropin (TSH) reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. Thyroid hormone plays a critical role in determining energy expenditure, body mass, and body composition, and therefore clinically relevant variations in these parameters may occur across the normal range of thyroid function. Methods: This was a cross-sectional study of 140 otherwise healthy hypothyroid subjects receiving chronic replacement therapy with levothyroxine (L-T4) who had TSH levels across the full span of the laboratory reference range (0.34 to 5.6 mU/L). Subjects underwent detailed tests of energy expenditure (total and resting energy expenditure, thermic effect of food, physical activity energy expenditure), substrate oxidation, diet intake, and body composition. Results: Subjects with low-normal (≤2.5 mU/L) and high-normal (>2.5 mU/L) TSH levels did not differ in any of the outcome measures. However, across the entire group, serum free triiodothyronine (fT3) levels were directly correlated with resting energy expenditure, body mass index (BMI), body fat mass, and visceral fat mass, with clinically relevant variations in these outcomes. Conclusions: Variations in thyroid function within the laboratory reference range have clinically relevant correlations with resting energy expenditure, BMI, and body composition in L-T4-treated subjects. However, salutary effects of higher fT3 levels on energy expenditure may be counteracted by deleterious effects on body weight and composition. Further studies are needed before these outcomes should be used as a basis for altering L-T4 doses in L-T4-treated subjects.
Asunto(s)
Composición Corporal/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Hipotiroidismo/diagnóstico , Hipotiroidismo/tratamiento farmacológico , Tiroxina/administración & dosificación , Absorciometría de Fotón/métodos , Adulto , Anciano , Antropometría , Estudios Transversales , Ejercicio Físico/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Índice de Severidad de la Enfermedad , Pruebas de Función de la Tiroides , Adulto JovenRESUMEN
CONTEXT: Thyroid carcinoma requires lifelong monitoring with serum thyroglobulin, radioactive iodine whole body scanning, and other imaging modalities. Levothyroxine (L-T4) withdrawal for thyroglobulin measurement and whole body scanning increases these tests' sensitivities but causes hypothyroidism. Recombinant human TSH (rhTSH) enables testing without L-T4 withdrawal. OBJECTIVE: Our objective was to examine the impact of short-term hypothyroidism on the health-related quality of life (HRQOL) of patients after rhTSH vs. L-T4 withdrawal. DESIGN, SETTING, AND PATIENTS: In this multicenter study, the SF-36 Health Survey was administered to 228 patients at three time points: on L-T4, after rhTSH, and after L-T4 withdrawal. INTERVENTIONS: INTERVENTIONS included administration of rhTSH on L-T4 and withdrawal from thyroid hormone. MAIN OUTCOME MEASURES: Mean SF-36 scores were compared during the two interventions and with the U.S. general population and patients with heart failure, depression, and migraine headache. RESULTS: Patients had SF-36 scores at or above the norm for the general U.S. population in six of eight domains at baseline on L-T4 and in seven of eight domains after rhTSH. Patients' scores declined significantly in all eight domains after L-T4 withdrawal when compared with the other two periods (P < 0.0001). Patients' HRQOL scores while on L-T4 and after rhTSH were at or above those for patients with heart failure, depression, and migraine in all eight domains. After L-T4 withdrawal, patients' HRQOL scores were significantly below congestive heart failure, depression, and migraine headache norms in six, three, and six of the eight domains, respectively. CONCLUSIONS: Short-term hypothyroidism after L-T4 withdrawal is associated with a significant decline in quality of life that is abrogated by rhTSH use.
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Estado de Salud , Hipotiroidismo/fisiopatología , Calidad de Vida , Hormonas Tiroideas/deficiencia , Neoplasias de la Tiroides/diagnóstico , Tirotropina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor , Radiografía , Proteínas Recombinantes , Neoplasias de la Tiroides/clasificación , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/cirugíaRESUMEN
A paucity of in vitro models has hampered studies of molecular mechanisms of FSH subunit gene expression. Consequently, we used an in vivo transgenic strategy to map the location of regulatory elements in the cloned 10 kb human FSHbeta gene. Analyses of transgenic mouse lines revealed that successive 5' truncations of the hFSHbeta promoter region to -350 bp relative to the transcriptional initiation site retained gonadotroph-specific expression and the sexually dimorphic pattern of male greater than female FSHbeta mRNA levels found normally in rodent pituitary. Truncation of the 3' flanking sequences from positions +3142 to +2138 bp relative to the translational stop codon in exon 3 resulted in a complete loss of transgene expression, suggesting the presence of critical regulatory elements mapping to the 1 kb genomic segment downstream of position +2138, in addition to the proximal 5' promoter elements. In silico phylogenetic comparisons of mammalian FSHbeta genes revealed five islands of highly conserved sequence homology corresponding precisely to the proximal 5' promoter region, exon 2, the 5' translated region of exon 3, and two regions at the 3' untranslated end of exon 3 that include putative polyadenylation and transcriptional termination signals. Sequence analyses of the 5' proximal promoter revealed the presence of several putative homeodomain binding sites as well as GATA, SMAD, AP-1, NF-1, NF-Y and steroid hormone transcription factor binding sites within the highly conserved -350 bp promoter region. Notably absent from these 5' sequences, however, are consensus binding sites for either Egr-1 or Lim-2 transcription factors known to be critical for the gonadotroph-specific expression of the LHbeta gene. These findings support the hypothesis that one of the mechanisms underlying the differential regulation of the LHbeta, FSHbeta, and common alpha-gonadotropin subunits within pituitary gonadotrophs may be differences in sequence-specific binding requirements for distinct combinations of transcription factors.
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Hormona Folículo Estimulante Humana/biosíntesis , Hormona Folículo Estimulante de Subunidad beta/biosíntesis , Hipófisis/metabolismo , Región de Flanqueo 3' , Animales , Secuencia de Bases , Codón de Terminación , Femenino , Hormona Folículo Estimulante Humana/genética , Hormona Folículo Estimulante de Subunidad beta/genética , Humanos , Masculino , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Especificidad de Órganos , Filogenia , Regiones Promotoras Genéticas , ARN Mensajero/biosíntesis , Homología de Secuencia de Ácido Nucleico , Factores SexualesRESUMEN
OBJECTIVE: Perioperative hypocalcemia from temporary parathyroid gland dysfunction is common after thyroid surgery. No reliable cutoff values for parathyroid hormone (PTH) and the subsequent possibility of developing hypocalcemia exist. The purpose of this study is to determine a criterion for predicting hypocalcemia based on different PTH levels as cutoff values. STUDY DESIGN: Retrospective chart review. METHODS: A centralized database of intraoperative PTH levels was analyzed. PTH values approximately 10 minutes after excision of the thyroid gland and in the recovery room were obtained; serial ionized calcium levels were also analyzed. PTH values were then compared using chi-square analysis with significance defined as P < .05. A receiver operator characteristic (ROC) curve was also constructed to define sensitivities and specificities of different PTH levels as potential cutoff values. RESULTS: Eighty patients were identified meeting the study criteria between January 1999 and February 2005. Fourteen of the 80 (17.5%) patients became hypocalcemic during the hospital stay; none experienced permanent hypocalcemia. Patients who became hypocalcemic during their hospitalization were more likely to have a PTH level below 15 pg/mL (P < .01). Patients with a PTH level less than 15 pg/mL were more likely to develop hypocalcemia (P < .01). Finally, an ROC curve was constructed, allowing the surgeon to determine acceptable sensitivities and specificities and various PTH cutoff values. CONCLUSION: Low perioperative PTH levels significantly correlate with the presence of postoperative hypocalcemia but cannot be used to predict it. Using the ROC curve allows different chosen cutoff values to predict hypocalcemia with varying sensitivity and specificity.
Asunto(s)
Hormona Paratiroidea/sangre , Enfermedades de la Tiroides/cirugía , Tiroidectomía , Biomarcadores/sangre , Calcio/sangre , Femenino , Humanos , Hipocalcemia/sangre , Hipocalcemia/diagnóstico , Hipocalcemia/etiología , Masculino , Atención Perioperativa , Pronóstico , Curva ROC , Estudios Retrospectivos , Enfermedades de la Tiroides/sangre , Enfermedades de la Tiroides/complicacionesRESUMEN
BACKGROUND: There has been recent debate within the thyroid field regarding whether current upper limits of the thyrotropin (TSH) reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. One important target organ for thyroid hormone is the brain, but little is known about variations in neurocognitive measures within the reference range for thyroid function. METHODS: This was a cross-sectional study of 132 otherwise healthy hypothyroid subjects receiving chronic replacement therapy with levothyroxine (LT4) who had TSH levels across the full span of the laboratory reference range (0.34-5.6 mU/L). Subjects underwent detailed tests of health status, mood, and cognitive function, with an emphasis on memory and executive functions. RESULTS: Subjects with low-normal (≤2.5 mU/L) and high-normal (>2.5 mU/L) TSH levels did not differ on most tests of health status, mood, or cognitive function, and there were no correlations between TSH, free T4, or free T3 levels and most outcomes. There was, however, a suggestion that thyroid function affected performance on the Iowa Gambling Task, which mimics real life decision-making. Subjects with low-normal TSH levels made more advantageous decisions than those with high-normal TSH levels. CONCLUSIONS: Variations in thyroid function within the laboratory reference range do not appear to have clinically relevant effects on health status, mood, or memory in LT4 treated subjects. However, decision making, which encompasses many executive functions, may be affected. Unless further studies strengthen this finding, these data do not support narrowing the TSH reference range.
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Afecto/fisiología , Cognición/fisiología , Hipotiroidismo/psicología , Glándula Tiroides/fisiopatología , Tiroxina/uso terapéutico , Estudios Transversales , Función Ejecutiva/fisiología , Femenino , Estado de Salud , Terapia de Reemplazo de Hormonas , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/tratamiento farmacológico , Masculino , Memoria/fisiología , Pruebas Neuropsicológicas , Valores de Referencia , Pruebas de Función de la Tiroides , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
BACKGROUND: Thyrotropin (TSH)-suppressive doses of levothyroxine (LT4) have adverse effects on bone and cardiac function, but it is unclear whether metabolic function is also affected. The objective of this study was to determine whether women receiving TSH-suppressive LT4 doses have alterations in energy expenditure or body composition. METHODS: This study was a cross-sectional comparison between three groups of women: 26 women receiving chronic TSH-suppressive LT4 doses, 80 women receiving chronic replacement LT4 doses, and 16 untreated euthyroid control women. Subjects underwent measurements of resting energy expenditure (REE), substrate oxidation, and thermic effect of food by indirect calorimetry; physical activity energy expenditure by accelerometer; caloric intake by 24-hour diet recall; and body composition by dual X-ray absorptiometry. RESULTS: REE per kilogram lean body mass in the LT4 euthyroid women was 6% lower than that of the LT4-suppressed group, and 4% lower than that of the healthy control group (p = 0.04). Free triiodothyronine (fT3) levels were directly correlated with REE, and were 10% lower in the LT4 euthyroid women compared with the other two groups (p = 0.007). The groups of subjects did not differ in other measures of energy expenditure, caloric intake, or body composition. CONCLUSIONS: LT4 suppression therapy does not adversely affect energy expenditure or body composition in women. However, LT4 replacement therapy is associated with a lower REE, despite TSH levels within the reference range. This may be due to lower fT3 levels, suggesting relative tissue hypothyroidism may contribute to impaired energy expenditure in LT4 therapy.
Asunto(s)
Antitiroideos/uso terapéutico , Composición Corporal/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Terapia de Reemplazo de Hormonas , Hipotiroidismo/tratamiento farmacológico , Tirotropina/sangre , Tiroxina/uso terapéutico , Absorciometría de Fotón , Adulto , Antitiroideos/efectos adversos , Biomarcadores/sangre , Calorimetría Indirecta , Estudios de Casos y Controles , Estudios Transversales , Ingestión de Energía , Femenino , Terapia de Reemplazo de Hormonas/efectos adversos , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/diagnóstico , Hipotiroidismo/fisiopatología , Persona de Mediana Edad , Oxidación-Reducción , Encuestas y Cuestionarios , Tiroxina/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) 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.
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Diferenciación Celular , Endocrinología/normas , Oncología Médica/normas , Neoplasias de la Tiroides/terapia , Nódulo Tiroideo/terapia , Consenso , Medicina Basada en la Evidencia/normas , Humanos , Valor Predictivo de las Pruebas , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/epidemiología , Nódulo Tiroideo/patología , Resultado del TratamientoRESUMEN
The diagnosis of Cushing's syndrome is one of the most difficult and yet one of the most important ones a primary care physician can make. The clinical presentation overlaps that of many other common diseases, but more specific signs such as unexplained osteoporosis, muscle weakness, ecchymoses, hypokalemia, and central obesity, the presence of multiple symptoms affecting different body systems, and a demonstrated change over time should prompt the screening evaluation. We recommend a step-wise approach to the diagnostic evaluation. Step 1 involves demonstrating pathologic hypercortisolemia and thus making the diagnosis of Cushing's syndrome. In step 2, distinguishing ACTH-independent disease from ACTH-dependent disease and then adrenal imaging is done. Finally, for patients with ACTH-dependent disease, step 3 entails anatomic localization of the ACTH source by MRI, if unequivocal, or by IPSS or CSS. Only when the evaluation is done in a step-wise fashion can the clinician be assured that appropriate treatment recommendations can be made. Although a fair amount of the testing is complex, requiring special facilities and usually the assistance of an endocrinologist, the most critical step is that done by the primary care physician--considering the diagnosis and initiating the screening algorithm.
Asunto(s)
Síndrome de Cushing/diagnóstico , Guías de Práctica Clínica como Asunto , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/efectos de los fármacos , Hormona Liberadora de Corticotropina/farmacología , Dexametasona/farmacología , Humanos , Hidrocortisona/sangre , Hidrocortisona/orina , Imagen por Resonancia MagnéticaRESUMEN
CONTEXT: TSH-suppressive doses of levothyroxine (L-T4) have adverse effects on bone and cardiac function, but it is unclear whether central nervous system function is also affected. OBJECTIVE: The aim of the study was to determine whether women receiving TSH-suppressive L-T4 doses have decrements in health status, mood, or cognitive function. DESIGN AND SETTING: A cross-sectional comparison was made among three groups of women in an academic medical center research clinic. PATIENTS: Twenty-four women receiving chronic TSH-suppressive L-T4 doses, 35 women receiving chronic replacement L-T4 doses, and 20 untreated control women participated in the study. INTERVENTIONS: Subjects underwent testing at a single outpatient visit. MAIN OUTCOME MEASURES: We measured health status (SF-36), mood (Profile of Mood States, Symptom Checklist 90-R, Affective Lability Scale), and cognitive function (declarative memory [Paragraph Recall], working memory [N-back, Subject Ordered Pointing], motor learning [Pursuit Rotor, Motor Sequence Learning Test], and executive function [Letter Cancellation Test, Trail Making Test, Iowa Gambling Test]). RESULTS: Women receiving TSH-suppressive or replacement L-T4 doses had decrements in health status and mood compared to healthy controls. These decrements were more pronounced in women receiving replacement, rather than suppressive, L-T4 doses. Memory and executive function were not affected in either treated group, compared to healthy controls. CONCLUSIONS: Women receiving TSH-suppressive doses of L-T4 do not have central nervous system dysfunction due to exogenous subclinical thyrotoxicosis, but TSH-suppressed and L-T4-replaced women have slight decrements in health status and mood that may be related to self-knowledge of the presence of a thyroid condition or other uncharacterized factors. These mood alterations do not impair cognitive function.
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Afecto/efectos de los fármacos , Cognición/efectos de los fármacos , Estado de Salud , Terapia de Reemplazo de Hormonas/efectos adversos , Tirotropina/antagonistas & inhibidores , Tiroxina/efectos adversos , Adulto , Estudios de Casos y Controles , Estudios Transversales , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Persona de Mediana Edad , Pruebas de Función de la Tiroides , Tiroxina/administración & dosificación , Adulto JovenRESUMEN
PURPOSE: To respond to increased public and programmatic demand to address underenrollment of clinical translational research studies, the authors examined participant recruitment practices at Clinical and Translational Science Award (CTSA) sites and make recommendations for performance metrics and accountability. METHOD: The CTSA Recruitment and Retention taskforce in 2010 invited representatives at 46 CTSAs to complete an online 48-question survey querying accrual and recruitment outcomes, practices, evaluation methods, policies, and perceived gaps in related knowledge/practice. Descriptive statistical and thematic analyses were conducted. RESULTS: Forty-six respondents representing 44 CTSAs completed the survey. Recruitment conducted by study teams was the most common practice reported (78%-91%, by study type); 39% reported their institution offered recruitment services to investigators. Respondents valued study feasibility assessment as a successful practice (39%); desired additional resources included feasibility assessments (49%) and participant registries (44%). None reported their institution systematically required justification of feasibility; some indicated relevant information was considered prior to institutional review board (IRB) review (30%) or contract approval (22%). All respondents' IRBs tracked study progress, but only 10% of respondents could report outcome data for timely accrual. Few reported written policies addressing poor accrual or provided data to support recruitment practice effectiveness. CONCLUSIONS: Many CTSAs lack the necessary frame work to support study accrual. Recom men dations to enhance accrual include articulating institutional expectations and policy for routine recruitment plan ning; providing recruitment expertise to inform feasibility assessment and recruit ment planning; and developing interdepartmental coordination and integrated informatics infrastructure to drive the conduct, evaluation, and improvement of recruitment practices.
Asunto(s)
Ensayos Clínicos como Asunto/métodos , Selección de Paciente , Evaluación de Programas y Proyectos de Salud/métodos , Investigación Biomédica Traslacional/métodos , Ensayos Clínicos como Asunto/economía , Ensayos Clínicos como Asunto/normas , Recolección de Datos , Humanos , Política Organizacional , Apoyo a la Investigación como Asunto , Responsabilidad Social , Investigación Biomédica Traslacional/economía , Investigación Biomédica Traslacional/normas , Estados UnidosRESUMEN
OBJECTIVE: The objective of this study was to provide recommendations for provision of training for sponsor and investigators at Academic Health Centers. BACKGROUND: A subgroup of the Investigational New Drug/Investigational Device Exemption (IND/IDE) Task Force of the Clinical and Translational Science Award (CTSA) program Regulatory Knowledge Key Function Committee was assembled to specifically address how clinical investigators who hold an IND/IDE and thus assume the role of sponsor-investigators are adequately trained to meet the additional regulatory requirements of this role. METHODS: The participants who developed the recommendations were representatives of institutions with IND/IDE support programs. Through an informal survey, the task force determined that a variety and mix of models are used to provide support for IND/IDE holders within CTSA institutions. In addition, a CTSA consortium-wide resources survey was used. The participants worked from the models and survey results to develop consensus recommendations to address institutional support, training content, and implementation. RECOMMENDATIONS: The CTSA IND/IDE Task Force recommendations are as follows: (1) Institutions should assess the scope of Food and Drug Administration-regulated research, perform a needs analysis, and provide resources to implement a suitable training program; (2) The model of training program should be tailored to each institution; (3) The training should specifically address the unique role of sponsor-investigators, and the effectiveness of training should be evaluated regularly by methods that fit the model adopted by the institution; and (4) Institutional leadership should mandate sponsor-investigator training and effectively communicate the necessity and availability of training.
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Comités Consultivos/normas , Aprobación de Recursos/normas , Drogas en Investigación/normas , Desarrollo de Programa/normas , Investigación Biomédica Traslacional/educación , Investigación Biomédica Traslacional/normas , Educación/métodos , Educación/normas , Humanos , Desarrollo de Programa/métodos , Investigadores/educación , Investigadores/normas , Investigación Biomédica Traslacional/métodosRESUMEN
BACKGROUND: Determining the molecular profile of colon and rectal cancers offers the possibility of personalized cancer treatment. The purpose of this study was to determine whether known genetic mutations associated with colorectal carcinogenesis differ between colon and rectal cancers and whether they are associated with survival. METHODS: The Oregon Colorectal Cancer Registry is a prospectively maintained, institutional review board-approved tissue repository with associated demographic and clinical information. The registry was queried for any patient with molecular analysis paired with clinical data. Patient demographics, tumor characteristics, microsatellite instability status, and mutational analysis for p53, AKT, BRAF, KRAS, MET, NRAS, and PIK3CA were analyzed. Categorical variables were compared using chi-square tests. Continuous variables between groups were analyzed using Mann-Whitney U tests. Kaplan-Meier analysis was used for survival studies. Comparisons of survival were made using log-rank tests. RESULTS: The registry included 370 patients: 69% with colon cancer and 31% with rectal cancer. Eighty percent of colon cancers and 68% of rectal cancers were stages III and IV. Mutational analysis found no significant differences in detected mutations between colon and rectal cancers, except that there were significantly more BRAF mutations in colon cancers compared with rectal cancers (10% vs 0%, P < .008). No differences were seen in 5-year survival rates of patients with colon versus rectal cancers when stratified by the presence of KRAS, PIK3CA, and BRAF mutations. CONCLUSIONS: Stage III and IV colon and rectal cancers share similar molecular profiles, except that there were significantly more BRAF mutations in colon cancers compared with rectal cancers.
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Biomarcadores de Tumor/genética , Neoplasias del Colon/genética , Mutación , Neoplasias del Recto/genética , Fosfatidilinositol 3-Quinasa Clase I , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Análisis Mutacional de ADN , Femenino , GTP Fosfohidrolasas/genética , Genes p53 , Marcadores Genéticos , Humanos , Estimación de Kaplan-Meier , Masculino , Proteínas de la Membrana/genética , Estadificación de Neoplasias , Oregon , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas p21(ras) , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Sistema de Registros , Proteínas ras/genéticaRESUMEN
OBJECTIVE: (1) To investigate the role of chronic lymphocytic thyroiditis (CLT) in central node metastasis of papillary thyroid carcinoma (PTC) and (2) to evaluate the presence of chronic lymphocytic thyroiditis according to PTC-specific molecular markers. STUDY DESIGN: Historical cohort study. SETTING: Academic medical center. SUBJECTS AND METHODS: All patients who underwent total thyroidectomy with central neck dissection for PTC at Oregon Health & Science University between 2005 and 2010 were screened for the presence of CLT and reviewed for clinical prognostic factors. Patients with inadequate central neck dissections were excluded. Molecular markers for PTC were analyzed on archived tumor samples. RESULTS: A total of 139 patients met selection criteria. The rate of CLT was 43.8%. The rate of central node positivity was 63%. Presence of CLT was associated with a significantly lower proportion of central node metastases (49% vs 74%, P = .003) and angiolymphatic invasion (31% vs 15%, P = .03). There was no significant difference in mean age, tumor size, and extracapsular extension. Molecular genotyping did not reveal a significant difference in the types of mutations found in both groups. CONCLUSION: The data indicate a lower incidence of central compartment lymph node metastasis in those with CLT in this patient population, suggesting a potential protective role in tumor spread. The equal distribution of tumor mutations between the carcinomas with and without evidence of CLT argues against a mutation-specific antigen as the immunologic stimulus. Further research is needed to characterize the role of autoimmunity in thyroid cancer.
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Carcinoma Papilar Folicular/patología , Enfermedad de Hashimoto/patología , Metástasis Linfática/patología , Neoplasias de la Tiroides/patología , Adulto , Biomarcadores de Tumor/genética , Biopsia con Aguja Fina , Carcinoma Papilar Folicular/genética , Carcinoma Papilar Folicular/cirugía , Análisis Mutacional de ADN , Femenino , Enfermedad de Hashimoto/genética , Enfermedad de Hashimoto/cirugía , Humanos , Pérdida de Heterocigocidad/genética , Masculino , Persona de Mediana Edad , Disección del Cuello , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/cirugía , TiroidectomíaRESUMEN
PURPOSE: In 2000, the National Center for Research Resources mandated that general research centers create a research subject advocate (RSA) position. In 2008, the Clinical and Translational Science Award (CTSA) consortium endorsed a new advocacy model based on four RSA Best Practice Functions. The authors surveyed CTSA centers to learn about their implementation of programs to fulfill the RSA functions. METHOD: In 2010, the RSA taskforce developed a two-part online survey to examine leadership, organizational structure, governance, scope, collaboration and integration, and funding and evaluation of RSA activities implemented at CTSA centers. RESULTS: Respondents from 45 RSA programs at 43 CTSA centers completed the survey. Senior university or CTSA officials led all programs. Ninety-six percent (43/45) of programs were funded by a CTSA core. Eighty percent (36/45) designated an individual "RSA." Ninety-eight percent (44/45) provided diverse services either in collaboration with or complementary to other departments, including development of data and safety monitoring plans (16/45; 36%), informed consent observation (10/45; 22%), training responsive to audit findings (12/45; 27%), and direct advocacy services to participants (11/45; 24%). Eighty-six percent (24/28) reported qualitative evaluation methods for these activities. CONCLUSIONS: RSA programs conduct both collaborative and unique research protection activities. This survey, an initial step in developing a more robust mechanism for evaluating RSA programs, collected valuable feedback. The authors recommend defining and developing outcome-based evaluation measures that take the heterogeneity of the individual RSA programs into account while advancing their value and effectiveness in protecting human research subject participants.
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Investigación Biomédica , Experimentación Humana , Defensa del Paciente , Investigación Biomédica Traslacional , Humanos , Modelos Organizacionales , Desarrollo de Programa , Evaluación de Programas y Proyectos de Salud , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Prior to human clinical trials, nonclinical safety and toxicology studies are required to demonstrate that a new product appears safe for human testing; these nonclinical studies are governed by good laboratory practice (GLP) regulations. As academic health centers (AHCs) embrace the charge to increase the translation of basic science research into clinical discoveries, researchers at these institutions increasingly will be conducting GLP-regulated nonclinical studies. Because the consequences for noncompliance are severe and many AHC researchers are unfamiliar with Food and Drug Administration regulations, the authors describe the regulatory requirements for conducting GLP research, including the strict documentation requirements, the necessary personnel training, the importance of study monitoring, and the critical role that compliance oversight plays in the process. They then explain the process that AHCs interested in conducting GLP studies should take before the start of their research program, including conducting a needs assessment and a gap analysis and selecting a model for GLP compliance. Finally, the authors identify and analyze several critical barriers to developing and implementing a GLP-compliant infrastructure at an AHC. Despite these challenges, the capacity to perform such research will help AHCs to build and maintain competitive research programs and to facilitate the successful translation of faculty-initiated research from nonclinical studies to first-in-human clinical trials.