Elizabeth H. Holt

Association Between BRAF V600E Mutation and Recurrence of Papillary Thyroid Cancer

PURPOSE To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). PATIENTS AND METHODS This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). RESULTS The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation-positive and 11.6% (125 of 1,082) of BRAF V600E mutation-negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation-positive versus -negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation-positive versus -negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. CONCLUSION This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.

Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer

The role of aberrant tumor suppressor gene methylation in the aggressiveness of papillary thyroid cancer (PTC) has not been documented. By showing promoter methylation‐induced gene silencing in PTC‐derived cell lines, we first demonstrated the functional consequence of methylation of several recently identified tumor suppressor genes, including those for tissue inhibitor of metalloproteinase‐3 (TIMP3), SLC5A8, death‐associated protein kinase (DAPK) and retinoic acid receptor β2 (RARβ2). We then investigated the role of methylation of these genes in the aggressiveness of PTC by examining the relationship of their aberrant methylation to clinicopathological characteristics and BRAF mutation in 231 primary PTC tumors. Methylation of TIMP3, SLC5A8 and DAPK was significantly associated with several aggressive features of PTC, including extrathyroidal invasion, lymph node metastasis, multifocality and advanced tumor stages. Methylation of these genes was also significantly associated with BRAF mutation in PTC, either individually or collectively in various combinations. Methylation of these genes, either individually or collectively, occurred more frequently in more aggressive classical and tall‐cell PTC subtypes than in less aggressive follicular‐variant PTC, with the latter known to infrequently harbor BRAF mutation. Several other tumor suppressor genes investigated were not methylated. These results suggest that aberrant methylation and hence silencing of TIMP3, SLC5A8, DAPK and RARβ2, in association with BRAF mutation, may be an important step in PTC tumorigenesis and progression.

Differential Clinicopathological Risk and Prognosis of Major Papillary Thyroid Cancer Variants

CONTEXT Individualized management, incorporating papillary thyroid cancer (PTC) variant-specific risk, is conceivably a useful treatment strategy for PTC, which awaits comprehensive data demonstrating differential risks of PTC variants to support. OBJECTIVE This study sought to establish the differential clinicopathological risk of major PTC variants: conventional PTC (CPTC), follicular-variant PTC (FVPTC), and tall-cell PTC (TCPTC). METHODS This was a retrospective study of clinicopathological outcomes of 6282 PTC patients (4799 females and 1483 males) from 26 centers and The Cancer Genome Atlas in 14 countries with a median age of 44 years (interquartile range, 33-56 y) and median follow-up time of 37 months (interquartile range, 15-82 mo). RESULTS The cohort consisted of 4702 (74.8%) patients with CPTC, 1126 (17.9%) with FVPTC, and 239 (3.8%) with TCPTC. The prevalence of high-risk parameters was significantly different among the three variants, including extrathyroidal invasion, lymph node metastasis, stages III/IV, disease recurrence, mortality, and the use (need) of radioiodine treatment (all P < .001), being highest in TCPTC, lowest in FVPTC, and intermediate in CPTC, following an order of TCPTC > CPTC ≫ FVPTC. Recurrence and mortality in TCPTC, CPTC, and FVPTC were 27.3 and 6.7%, 16.1 and 2.5%, and 9.1 and 0.6%, corresponding to events per 1000 person-years (95% confidence interval [CI]) of 92.47 (64.66-132.26) and 24.61 (12.31-49.21), 34.46 (30.71-38.66), and 5.87 (4.37-7.88), and 24.73 (18.34-33.35) and 1.68 (0.54-5.21), respectively. Mortality hazard ratios of CPTC and TCPTC over FVPTC were 3.44 (95% CI, 1.07-11.11) and 14.96 (95% CI, 3.93-56.89), respectively. Kaplan-Meier survival analyses showed the best prognosis in FVPTC, worst in TCPTC, and intermediate in CPTC in disease recurrence-free probability and disease-specific patient survival. This was particularly the case in patients at least 45 years old. CONCLUSION This large multicenter study demonstrates differential prognostic risks of the three major PTC variants and establishes a unique risk order of TCPTC > CPTC ≫ FVPTC, providing important clinical implications for specific variant-based management of PTC.

Parathyroid Hormone-related Peptide Is Produced by Cultured Cerebellar Granule Cells in Response to L-type Voltage-sensitive Ca2+ Channel Flux via a Ca2+/Calmodulin-dependent Kinase Pathway

Parathyroid hormone (PTH)-related peptide (PTHrP) is expressed in the adult mammalian brain, but its function is unknown. Here we show that PTHrP and the PTH/PTHrP receptor are products of cerebellar granule cells in primary culture. Granule cells maintained under depolarizing conditions (25 mM K+) make and release PTHrP. Further, PTHrP-(1-36) stimulates cAMP accumulation in granule neurons in a dose-dependent manner with half-maximal activation at ∼16 nM. Granule cell PTHrP mRNA is activity-dependent, and the pathway of regulation depends absolutely on the flux of Ca2+ ions through the L-type voltage-sensitive Ca2+ channel and the Ca2+/calmodulin kinase cascade. PTHrP is therefore a neuropeptide whose regulation depends upon L-type voltage-sensitive Ca2+ channel activity, and the gene is expressed under conditions that promote granule cell survival.

Regulation of Parathyroid Hormone-Related Peptide Gene Expression by Estrogen in GH4C1 Rat Pituitary Cells Has the Pattern of a Primary Response Gene

The parathyroid hormone‐related peptide (PTHrP) gene has been reported to be subject to a wide variety of physiological and pharmacological controls. Two distinct patterns of PTHrP mRNA response have been recognized, one characterized by a prolonged or plateau response lasting many hours to days and the second characterized by rapid induction‐deinduction kinetics and lasting 1 to several hours. The kinetics of the second pattern are similar to those displayed by primary response genes like nuclear protooncogenes, cytokines, and growth factors. In GH4C1, rat pituitary cells, 17β‐estradiol induced a rapid and transient increase in PTHrP mRNA expression, with a peak response at 1–2 h. This response appeared to be due to a rapid and transient burst in gene transcription, which by runoff analysis was maximal at 20–40 min and declined thereafter. PTHrP mRNA half‐life was 30 min in these cells and was unaltered by estradiol. Cy‐cloheximide did not block the 17β‐estradiol‐induced response but rather prolonged it, and runoff analysis revealed that this effect was due to a prolongation or persistence of PTHrP gene transcription. These findings suggest that the transient nature of the native response reflects the effects of an estrogen‐inducible represser. All of these features are characteristic of a prototypical primary response gene.

Risk stratification in follicular neoplasm: A cytological assessment using the modified bethesda classification

The 2007 Bethesda classification for thyroid cytology defines follicular neoplasm as a category of cases with cellular specimens demonstrating abundant follicular cells arranged in a microfollicular pattern with little or no colloid. The current recommendation for the management of these cases is diagnostic lobectomy. There has been great difficulty and variability in triaging and reporting follicular neoplasm. To increase diagnostic accuracy, at the study institution, this category is subclassified further into 3 categories: 1) microfollicular‐patterned neoplasm (MN); 2) Hürthle cell neoplasm (HN); and 3) follicular lesion with some features suggestive of but not diagnostic of the follicular variant of papillary thyroid carcinoma (FL). The authors reviewed the cases of follicular neoplasm observed over a period of 5 years to document the follow‐up trend using this modified classification.

Care of the pregnant thyroid cancer patient.

Purpose of review Thyroid cancer is the fastest rising type of cancer among women in North America. Care of the pregnant patient with thyroid cancer is, therefore, of concern to obstetricians, internists and endocrine specialists. Guidelines for the care of the pregnant patient with thyroid disease were released by the Endocrine Society in late 2007, and a symposium on thyroid dysfunction and pregnancy was hosted by the American Thyroid Association in April 2009. With this increasing interest in thyroid disease and pregnancy, a variety of important studies have been published recently. Recent findings In addition to guidelines published by the Endocrine Society, recent research has focused on detection and management of hypothyroidism in pregnancy, and consequences of hypothyroidism for the fetus and child. Impact of radioactive iodine therapy on subsequent fertility has been described. The risk of adverse outcomes due to thyroid surgery during pregnancy was evaluated in analysis of a large inpatient database. Summary Identification of hypothyroidism during pregnancy continues to be challenging due to the need for well established trimester-specific normal ranges. Physicians may reassure patients about the effects of radioactive iodine therapy on fertility, although men may wish to cryopreserve sperm prior to treatment. Thyroid surgery during pregnancy was associated with a two-fold increased risk of surgical complications.

Controversies in the surveillance of patients with well differentiated thyroid cancer.

Purpose of review Thyroid cancer incidence is rising in the USA, likely due to increased surveillance. Over the past several years, new approaches have developed for the long-term monitoring of differentiated thyroid cancer patients. The most recent developments in this area, as well as interesting data on molecular genetics of thyroid cancer will be discussed. Recent findings The introduction of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging in the follow-up of patients with differentiated thyroid cancer is an important development in the last few years. Recent research has helped improve understanding of how 18F-FDG PET can best be applied. There is now improved understanding of the use of serum thyroglobulin levels to predict future risk of recurrence of differentiated thyroid cancer. Guidelines from the American Thyroid Association for management of thyroid neoplasia were updated in 2006 for the first time in a decade, helping physicians navigate the published data and provide evidence-based care. Ongoing advances in thyroid cancer genetics may help predict aggressiveness of individual thyroid cancers. Summary Better tools are becoming available for physicians caring for thyroid cancer patients. Recent developments in thyroid cancer research will help physicians better anticipate a patients future disease course and select appropriate surveillance testing.

Physiology and Pathophysiology of the Parathyroid Glands and Preoperative Evaluation

Calcium homeostasis is of critical importance to living organisms. In man, a complex hormonal system exists to finely regulate the extracellular calcium concentration. A common aberration of this system is primary hyperparathyroidism, the leading cause of chronic hypercalcemia. While usually presenting with few symptoms, this disease is a frequent explanation for osteoporosis and nephrolithiasis. If undiagnosed, it may progress with severe sequelae. It is therefore useful for the surgeon to have a general understanding of the regulation of calcium metabolism as well as the clinical features, diagnostic strategies, and the accepted surgical indications for this common endocrine condition.

Parathyroid Hormone, Parathyroid Hormone–Related Protein, and Calcitonin

Publisher Summary This chapter provides information on mechanism, structure, and function of parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), and Calcitonin. The observations that intermittent administration of PTH induces anabolic responses in the skeleton have led to the development of PTH analogs for the treatment of osteoporosis. Like many growth factors or cytokines, PTHrP has been suggested to have many functions, such as in the skeleton, mammary gland, placenta, smooth muscle and the cardiovascular system, teeth, and bone homeostatis. Finally, as far as calcitonin is concerned, it is a convenient serum tumor marker for medullary thyroid carcinoma, and can be used in longitudinal monitoring of patients for signs of recurrence or progression after surgery. There is considerable variability in the ability of individual medullary thyroid cancers to produce calcitonin, so baseline levels drawn prior to surgery are needed to interpret results. The effects of calcitonin on the osteoclast have made it a useful agent in treatment of bone and calcium disorders.