Improved cancer risk stratification of isoechoic thyroid nodules to reduce unnecessary biopsies using quantitative ultrasound.

Objective: Gray-scale ultrasound (US) is the standard-of-care for evaluating thyroid nodules (TNs). However, the performance is better for the identification of hypoechoic malignant TNs (such as classic papillary thyroid cancer) than isoechoic malignant TNs. Quantitative ultrasound (QUS) utilizes information from raw ultrasonic radiofrequency (RF) echo signal to assess properties of tissue microarchitecture. The purpose of this study is to determine if QUS can improve the cancer risk stratification of isoechoic TNs. Methods: Patients scheduled for TN fine needle biopsy (FNB) were recruited from the Thyroid Health Clinic at Boston Medical Center. B-mode US and RF data (to generate QUS parameters) were collected in 274 TNs (163 isoechoic, 111 hypoechoic). A linear combination of QUS parameters (CQP) was trained and tested for isoechoic [CQP(i)] and hypoechoic [CQP(h)] TNs separately and compared with the performance of conventional B-mode US risk stratification systems. Results: CQP(i) produced an ROC AUC value of 0.937+/- 0.043 compared to a value of 0.717 +/- 0.145 (p >0.05) for the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) and 0.589 +/- 0.173 (p >0.05) for the American Thyroid Association (ATA) risk stratification system. In this study, CQP(i) avoids unnecessary FNBs in 73% of TNs compared to 55.8% and 11.8% when using ACR TI-RADS and ATA classification system. Conclusion: This data supports that a unique QUS-based classifier may be superior to conventional US stratification systems to evaluate isoechoic TNs for cancer and should be explored further in larger studies.

False-positive Imaging for Papillary Thyroid Cancer Caused by Intraosseous Hemangiomas.

Two patients with papillary thyroid carcinoma and an elevated thyroglobulin had false-positive imaging studies from intraosseous hemangiomas (IH). A 62-year-old man presented with a palpable lytic skull mass suspicious for a bone metastasis after computed tomography (CT) and magnetic resonance imaging (MRI) scans. Surgical excision confirmed an IH. The second patient is a 64-year-old woman whose I-123 whole-body scan with single photon emission computed tomography/CT demonstrated radioiodine uptake in the right frontal bone. Her MRI and CT scans were also consistent with an IH. These cases reveal the limitations of nuclear imaging and of CT and MRI scans in distinguishing metastatic differentiated thyroid cancer from IH in patients with lytic bone lesions. Because no imaging studies are definitive for an IH, bone cranial lesions may warrant resection to establish a diagnosis and avoid potential brain invasion by a malignancy or unnecessary radioiodine treatment.

Thyroglobulin Cutoff Values for Detecting Excellent Response to Therapy in Patients With Differentiated Thyroid Cancer.

Context: Serum thyroglobulin (Tg) is a biochemical marker for detecting persistent or recurrent differentiated thyroid carcinoma (DTC) post-thyroidectomy. Tg can indicate DTC before structural disease (SD) is visible with imaging procedures. Objective: This work aimed to evaluate the clinical performance of the Elecsys® Tg II assay at a Tg cutoff of 0.2 ng/mL for ruling out SD in adults with DTC after total/near-total thyroidectomy, with or without radioiodine ablation (RAI). Methods: Patients were enrolled into 2 cohorts: longitudinal (Tg assessed every 6 months over 2 years under thyroid-stimulating hormone [TSH] suppression therapy following thyroidectomy with or without RAI) and cross-sectional with confirmed SD (Tg assessed once >12 weeks after thyroidectomy). Analyses were performed for both cohorts combined and in the longitudinal cohort. Results: The study included 530 clinically evaluable samples, the majority (n = 424 samples) from patients who had not received RAI treatment. Following correction for SD prevalence (4.97% in the longitudinal cohort), an Elecsys Tg II cutoff of 0.2 ng/mL ruled out SD with a negative predictive value of 99.9% (95% CI, 99.5%-100%). The assay had excellent sensitivity (98.5%-100%) and acceptable specificity (53.4%-53.5%) for detecting SD (Tg ≥ 0.2 ng/mL) for both cohorts combined and in the longitudinal cohort, with similar findings in RAI-treated and non-RAI-treated subgroups. Conclusion: In this cohort of DTC patients post-thyroidectomy, a Tg cutoff of 0.2 ng/mL was highly effective for ruling out the presence of SD under TSH-suppressed conditions, including in patients who had not received RAI treatment.

Pharmacological management of severe Cushing's syndrome: the role of etomidate.

Cushing's syndrome (CS) is an endocrine disease characterized by excessive adrenocortical steroid production. One of the mainstay pharmacological treatments for CS are steroidogenesis enzyme inhibitors, including the antifungal agent ketoconazole along with metyrapone, mitotane, and aminoglutethimide. Recently, osilodrostat was added to this drug class and approved by the US Food and Drug Administration (FDA) for the treatment of Cushing's Disease. Steroidogenesis enzyme inhibitors inhibit various enzymes along the cortisol biosynthetic pathway and may be used preoperatively to lower cortisol levels and reduce surgical risk associated with tumor resection or postoperatively when surgery and/or radiation therapies are not curative. Because their selectivities for steroidogenic enzymes vary, they may even be administered in combination to achieve relatively rapid control of severe hypercortisolemia. Unfortunately, all currently available inhibitors are accompanied by serious adverse side effects that limit dosing and often result in treatment failures. Although more commonly known as a general anesthetic induction agent, etomidate is another member of the steroidogenesis enzyme inhibitor drug class. It suppresses cortisol production primarily by inhibiting 11ß-hydroxylase and is the only inhibitor that may be given parenterally. However, the sedative-hypnotic actions of etomidate limit its use as an acute management option for CS. Thus, some have recommended that it be used only in intensive care settings. In this review, we discuss the initial development of etomidate as an anesthetic agent, its subsequent development as a treatment for CS, and the recent advances in dosing and drug development that dissociate sedative-hypnotic and adrenostatic drug actions to facilitate CS treatment in non-critical care settings.

A Preliminary Study of Quantitative Ultrasound for Cancer-Risk Assessment of Thyroid Nodules.

Background: Gray-scale, B-mode ultrasound (US) imaging is part of the standard clinical procedure for evaluating thyroid nodules (TNs). It is limited by its instrument- and operator-dependence and inter-observer variability. In addition, the accepted high-risk B-mode US TN features are more specific for detecting classic papillary thyroid cancer rather than the follicular variant of papillary thyroid cancer or follicular thyroid cancer. Quantitative ultrasound (QUS) is a technique that can non-invasively assess properties of tissue microarchitecture by exploiting information contained in raw ultrasonic radiofrequency (RF) echo signals that is discarded in conventional B-mode imaging. QUS provides quantitative parameter-value estimates that are a function of the properties of US scatterers and microarchitecture of the tissue. The purpose of this preliminary study was to assess the performance of QUS parameters in evaluating benign and malignant thyroid nodules. Methods: Patients from the Thyroid Health Center at the Boston Medical Center were recruited to participate. B-mode and RF data were acquired and analyzed in 225 TNs (24 malignant and 201 benign) from 208 patients. These data were acquired either before (167 nodules) or after (58 nodules) subjects underwent fine-needle biopsy (FNB). The performance of a combination of QUS parameters (CQP) was assessed and compared with the performance of B-mode risk-stratification systems. Results: CQP produced an ROC AUC value of 0.857 ± 0.033 compared to a value of 0.887 ± 0.033 (p=0.327) for the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) and 0.880 ± 0.041 (p=0.367) for the American Thyroid Association (ATA) risk-stratification system. Furthermore, using a CQP threshold of 0.263 would further reduce the number of unnecessary FNBs in 44% of TNs without missing any malignant TNs. When CQP used in combination with ACR TI-RADS, a potential additional reduction of 49 to 66% in unnecessary FNBs was demonstrated. Conclusion: This preliminary study suggests that QUS may provide a method to classify TNs when used by itself or when combined with a conventional gray-scale US risk-stratification system and can potentially reduce the need to biopsy TNs.

Prognostic Value of Serum Thyroglobulin Measured at 48 Hours Versus 72 Hours after Second Dose of Recombinant Human Thyrotropin in Surveillance of Well-Differentiated Thyroid Cancer.

OBJECTIVE: The sensitivity of thyroglobulin (Tg) to detect differentiated thyroid cancer recurrence increases with the rise of the thyrotropin level. Since 1998, recombinant human thyrotropin (rhTSH) has been commercially available for this purpose. The traditional protocol for using rhTSH calls for 2 daily injections of rhTSH, followed by the measurement of Tg 72 hours after the second dose. In this study, we compared the performance of rhTSH-stimulated Tg (rhTSH-Tg) obtained at 48 versus 72 hours after the second rhTSH. METHODS: A retrospective chart review of 1088 patients with thyroid cancer was conducted. Two hundred forty-nine rhTSH-Tg, without measurable Tg antibody, were identified, 134 of which were obtained at 48 hours (4-day test) and 115 at 72 hours after the second rhTSH (5-day test). The ability of rhTSH-Tg to identify recurrence or persistence of differentiated thyroid cancer and to predict response to therapy at the end of the study period was compared between the 2 groups. RESULTS: The median duration of follow-up was 8 years. When recurrent/persistent cancer was present based on a combination of unstimulated Tg, imaging and procedures, the ratio of rhTSH-Tg ≥ 1 ng/mL was similar in both groups (P value: .153). The negative predictive value of rhTSH-Tg to predict response to therapy over the long term was 95% or higher in 4-day and 5-day tests. CONCLUSION: Tg measured 48 and 72 hours after the second dose of rhTSH may provide a comparable prognostic value. These results encourage further studies to identify new protocols to obtain rhTSH-Tg.

Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: Epidemiology and Long-Term Outcomes in a Strictly Defined Cohort.

Background: A subset of encapsulated/circumscribed follicular variant of papillary thyroid carcinoma (FVPTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in 2016 to reduce overtreatment of a low-risk tumor. Study objectives were to describe the epidemiology and long-term outcomes of NIFTP in a high-volume, urban, tertiary referral center. Methods: Among patients enrolled in the Boston Medical Center (BMC) Thyroid Cancer Registry, 110 cases of FVPTC underwent index thyroid surgery at BMC between 2000 and 2016. Historically, BMC pathologists assess all malignant nodules using sections ≤0.3 cm with evaluation of the entire nodule and capsule. After review of pathology reports to identify potential NIFTPs, slides were rereviewed using criteria established by the NIFTP Working Group in 2016 and 2018. We evaluated interobserver reliability using Cohen's Kappa coefficient. Results: Among 110 FVPTCs, 15 (13%) met NIFTP criteria; 11 women and 4 men, age range 31-64 (mean 47.5) years. Mean tumor diameter was 1.7 cm (compared with 2.2 cm for FVPTC). Among NIFTP cases, there were no lymph node metastases, distant metastases, or tumor recurrences. All NIFTP cases were American Thyroid Association (ATA) low risk compared with only 68% of FVPTC (p = 0.011). Among FVPTCs, 14% had positive lymph nodes at index operation. Four patients (4%) had distant metastases. Mean follow-up time was 46 and 69 months for FVPTC and NIFTP, respectively. Among FVPTCs with an excellent response to therapy (2015 ATA guidelines), there were no recurrences. Just over half (n = 8) of patients with NIFTP received postoperative radioactive iodine (RAI) therapy. Concordance between pathologists was high for ruling out NIFTP (75%), but only 36% for ruling in NIFTP. Overall, for NIFTP designation, Cohen's Kappa was 0.39, which is considered fair. Conclusions: Although this is a relatively small cohort, all NIFTP specimens underwent updated pathology review consistent with current guidelines; mean follow-up was nearly 6 years. NIFTP represents a small fraction of the total papillary neoplasia diagnosed at this tertiary referral center (2.3%). None of the NIFTP cohort experienced an adverse oncologic event, and there were no regional or distant metastases. Over 50% of patients with NIFTP received RAI. Thus, the NIFTP reclassification may substantially reduce the number of patients who require adjuvant therapies, such as completion surgery or RAI.

The real-world performance of ThyroSeqV.2 to diagnose thyroid "neoplasm requiring surgery".

Fine-needle biopsy (FNB) predicts benign or malignant thyroid nodules. For indeterminate (ITN) FNBs, commercial molecular tests may improve the diagnostic accuracy and reduce the number of operations. These tests have had limited independent implementation studies in routine clinical practice. This is a prospective observational study. At Boston Medical Center, the 1,316 consecutive FNBs were classified to one of the six categories in the Bethesda classification system. Those ITN samples were submitted for ThyroSeqV.2 next generation sequencing panel analysis. The performance of ThyroSeqV.2 to predict "neoplasm requiring surgery" (NRS) was evaluated. ThyroSeqV.2 assay was performed in 398 FNBs on 384 cytologically ITN nodules (308 Bethesda III, 47 Bethesda IV and 29 Bethesda V). The first evaluable ThyroSeq result for each nodule was used for final analysis. Seventy-seven (72.0%) of 107 patients with a high risk molecular test underwent thyroid surgery resulting in 41 NRS (53.2%) and 36 benign nodules (46.8%). Of the 249 patients with a low risk or negative molecular analysis, 51 (20.5%) had surgery revealing 47 benign nodules (92.2%) and 4 NRS (7.8%). Based on surgical outcome of 128 ITN with evaluable ThyroSeq results, this molecular test had a sensitivity of 91% (95% CI: 79%-98%), specificity of 56% (45%-67%), positive predictive value (PPV) of 53% (42%-65%), negative predictive value (NPV) of 92% (81%-98%), and an overall accuracy of 69% (55%-85%) with a prevalence of NRS of 35% (27%-44%). ThyroSeqV.2 in this clinical use study in ITN nodules provided a similar NPV but a lower PPV than expected compared to published studies due to the detection of an array of mutations in benign nodules. The NPV of 92.0% for ITN cytology confirmed its utility as a "rule-out" test to exclude NRS.

Thyroid effects of amiodarone: clinical update.

PURPOSE OF REVIEW: Amiodarone-induced thyroid dysfunction is well established and commonly encountered but is associated with several diagnostic and management challenges. The present review discusses recent evidence published related to the effects of amiodarone on the thyroid gland and thyroid function. RECENT FINDINGS: Retrospective studies to evaluate amiodarone-induced thyroid dysfunction in children show the occurrence of potential clinically significant changes within 2 weeks of amiodarone initiation that may not be detected if standard adult guidelines for thyroid hormone monitoring are followed. A small study evaluating beta-glucuronidase activity in amiodarone-induced thyrotoxicosis (AIT) demonstrated higher levels in patients with AIT type 2 compared to type 1. New data have suggested the incidence of agranulocytosis may be higher in patients on thionamides with AIT compared to hyperthyroidism because of other causes. In a small study, investigators demonstrated the use of a combination of intravenous and oral steroids to treat refractory AIT which needs to be evaluated in further controlled trials. Finally, recent data demonstrated a possible mortality benefit of surgery over medical therapy for AIT in patients with moderate to severe reduction in left ventricular ejection fraction. SUMMARY: Recent research regarding the prevalence, diagnosis, and management of amiodarone-induced thyroid dysfunction were reviewed.

Utilities of RAS Mutations in Preoperative Fine Needle Biopsies for Decision Making for Thyroid Nodule Management: Results from a Single-Center Prospective Cohort.

Background: It has been advocated to apply individualized strategies to evaluate thyroid nodules due to the growing awareness that the pathogenesis of thyroid cancer is not uniform. Molecular markers in fine needle biopsies (FNBs) may be helpful for the diagnosis and management decisions. Unlike the detection of BRAF mutations, the clinical utility of rat sarcoma viral oncogene homolog (RAS) mutations has not been fully elucidated. This study aimed at presenting a real-world performance of RAS mutations in identifying thyroid malignancies, at investigating the nature of thyroid tumors carrying RAS mutations, and at providing an additional reference for interpreting how to utilize the presence of RAS mutations in the decision-making process of thyroid nodule management. Methods: Between February 2015 and December 2017, 1400 sequential thyroid biopsies were performed at Boston Medical Center. Of these, 546 FNBs were evaluated for RAS mutations by using a ThyroSeq next-generation sequencing panel. Nodules carrying RAS mutations were prospectively followed, and medical records were collected. Results: ThyroSeq successfully provided molecular information in 504 nodules; 173 with molecular alteration(s); and 80 positive for mutations in the Kirsten-, Neuroblastoma-, or Harvey-RAS genes. RAS gene mutations constituted up to 46.2% of the total molecular alterations found in the study. Fifty-six of the 80 RAS-positive nodules underwent surgery, 33 (58.9%) were confirmed to be benign, 7 (12.5%) were noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), and 16 (28.6%) were thyroid carcinomas. The positive predictive value, negative predictive value, and accuracy of RAS mutations for identifying malignancies among cytologically indeterminate nodules were 25.5%, 89.7%, and 54.0% when NIFTP was not counted as cancer. A combination of RAS and other mutations increased the risk of malignancy. Twelve histopathologically proved RAS-only-positive malignant nodules all showed low-risk features and favorable prognosis. RAS isoforms added little assistance for predicting a malignancy and the response to therapy in our series. Conclusions:RAS mutations represent the most frequently detected genetic alterations in our series. RAS mutations, when occurring alone, are not helpful markers to identify malignancy among Bethesda III/IV cytologies, but may predict favorable behavior, and hence should be considered to guide initial management.

LACK OF A THRESHOLD SIZE FOR AUTONOMOUSLY FUNCTIONING THYROID NODULES THAT EXCLUDES HYPERTHYROIDISM.

Objective: To correlate the size of autonomously functioning thyroid nodules (AFTNs) with thyroid function tests. Methods: A retrospective analysis was performed of data from patients with a diagnosis of a single AFTN who were seen in a university-based endocrinology clinic between January 1, 2003, and December 31, 2015. Patients with a nuclear thyroid scan confirming the presence of an AFTN without significant cystic degeneration were included in the study. Results: The volume of the AFTN and the corresponding thyroid function tests were compared in 32 patients who met inclusion criteria. There was no correlation between the volume of the AFTN and thyroid-stimulating hormone (TSH) levels (r2 = 0.044). There was also no volume threshold below which an AFTN was always associated with a TSH within the reference range. Conclusion: The results agree with the findings of other recent studies comparing the volume of AFTNs with TSH levels, suggesting that smaller nodules can still demonstrate subclinical and overt hyperthyroidism and that a normal TSH level does not preclude the presence of an AFTN. Abbreviations: AFTN = autonomously functioning thyroid nodule; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.

Clinical Significance of Thyroid-Stimulating Hormone Receptor Gene Mutations and/or Sodium-Iodine Symporter Gene Overexpression in Indeterminate Thyroid Fine Needle Biopsies.

Objectives: To examine the prevalence of genetic alterations of thyroid-stimulating hormone receptor (TSHR) gene and sodium-iodine symporter (NIS) in a series of thyroid fine needle biopsy (FNB) specimens with indeterminate cytology, and to assess the correlation of the type of genetic changes with clinical features and follow-up results in the target thyroid nodule. Methods: Between February 2015 and September 2017, 388 consecutive FNBs with indeterminate cytology were evaluated for TSHR mutations and NIS gene overexpression using ThyroSeqV.2 next-generation sequencing (NGS) panel. Medical records were reviewed for target nodules. Results: Among 388 indeterminate FNBs, TSHR mutations and/or NIS overexpression were detected in 25 (6.4%) nodules. Ten nodules (2.6%) harbored TSHR mutations only, 7 nodules (1.8%) over-expressed NIS gene only, and 8 nodules (2.1%) had both alterations. The TSHR mutations were located between codons 281 and 640, with codon 453 being the most frequently affected. The allelic frequency of the mutated TSHR ranged from 6 to 36%. One nodule with NIS overexpression was simultaneously detected EIF1AX mutation and GNAS mutation. Nodules with TSHR mutations and/or NIS overexpression presented hyperfunctioning (n = 4), hypofunctioning (n = 5), and isofunctioning (n = 3) on the available thyroid scintigraphies. Eight cases accompanied with hyperthyroidism in which only 1 was caused by the target nodule. Evidence of co-existing autoimmune thyroid disease (AITD) and multinodular goiter were found in 52% and 52% of cases, respectively. Seven nodules underwent surgeries and all were benign on final pathology. None of 9 nodules with follow-up by ultrasound (3~33 mon, median 12 mon) showed grow in size. Conclusions: TSHR mutations and/or NIS overexpression can be detected in pre-operative FNB specimens using the NGS approach. These genetic alterations occurred in 6.4% thyroid nodules in this consecutive series with indeterminate cytology. They present not only in hyperfunctioning nodules but also in hypo- or iso-functional nodules, indicating their prevalence may be higher than previously expected. Co-existing AITD was common in cases with these molecular alterations. None of our patients with TSHR mutations and/or NIS overexpression manifested malignant outcomes. How to use these two molecular markers in thyroid FNBs to guide our clinical practice warrants further investigation.

Genomic Correlates of Response to Everolimus in Aggressive Radioiodine-refractory Thyroid Cancer: A Phase II Study.

Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine-refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included.Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3-18.5) with a 2-year PFS of 23.6% (95% CI, 10.5-39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8-85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt-mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. Clin Cancer Res; 24(7); 1546-53. ©2018 AACR.

Identification of sex differences in zebrafish (Danio rerio) brains during early sexual differentiation and masculinization using 17α-methyltestoterone.

Sexual behavior in teleost fish is highly plastic. It can be attributed to the relatively few sex differences found in adult brain transcriptomes. Environmental and hormonal factors can influence sex-specific behavior. Androgen treatment stimulates behavioral masculinization. Sex dimorphic gene expression in developing teleost brains and the molecular basis for androgen-induced behavioral masculinization are poorly understood. In this study, juvenile zebrafish (Danio rerio) were treated with 100 ng/L of 17 alpha-methyltestosterone (MT) during sexual development from 20 days post fertilization to 40 days and 60 days post fertilization. We compared brain gene expression patterns in MT-treated zebrafish with control males and females using RNA-Seq to shed light on the dynamic changes in brain gene expression during sexual development and how androgens affect brain gene expression leading to behavior masculinization. We found modest differences in gene expression between juvenile male and female zebrafish brains. Brain aromatase (cyp19a1b), prostaglandin 3a synthase (ptges3a), and prostaglandin reductase 1 (ptgr1) were among the genes with sexually dimorphic expression patterns. MT treatment significantly altered gene expression relative to both male and female brains. Fewer differences were found among MT-treated brains and male brains compared to female brains, particularly at 60 dpf. MT treatment upregulated the expression of hydroxysteroid 11-beta dehydrogenase 2 (hsd11b2), deiodinase, iodothyronine, type II (dio2), and gonadotrophin releasing hormones (GnRH) 2 and 3 (gnrh2 and gnrh3) suggesting local synthesis of 11-ketotestosterone, triiodothyronine, and GnRHs in zebrafish brains which are influenced by androgens. Androgen, estrogen, prostaglandin, thyroid hormone, and GnRH signaling pathways likely interact to modulate teleost sexual behavior.

Intermittent Dosing of Dabrafenib and Trametinib in Metastatic BRAFV600E Mutated Papillary Thyroid Cancer: Two Case Reports.

BACKGROUND: A multi-institutional, randomized phase II trial of continuous dosing of dabrafenib with or without trametinib is ongoing in metastatic thyroid cancer. Preclinical evidence and emerging clinical experience in other cancers support evaluating intermittent dosing of these two agents to achieve more durable response, while being better tolerated and more cost effective. PATIENTS: Two consecutive patients with symptomatic, metastatic radioactive iodine-resistant BRAFV600E mutated papillary thyroid cancer and poor performance status were treated initially with dabrafenib 150 mg twice daily plus trametinib 2 mg once daily, first in continuous daily dosing, then in a five-week-on and three-week-off schedule. RESULTS: Both patients showed rapid clinical improvement upon starting the regimen. They also noted improved tolerance of treatment upon transitioning to the intermittent dosing schedule. They continue to show evidence of antitumor activity 27 and 18 months respectively from the start of treatment and 15 and 13 months respectively from the start of the first break using intermittent dosing. CONCLUSIONS: Achieving durable palliation in these consecutive patients supports evaluating the intermittent dosing schedule of dabrafenib and trametinib in BRAFV600E mutated papillary thyroid cancer. Results of the ongoing phase 3 trial of continuous daily dosing and a subsequent trial of intermittent dosing, as is being tested in other cancers, will be needed to confirm that an intermittent dosing strategy in thyroid cancer can forestall resistant disease, improve tolerability, and decrease the cost of care.

Improving the adoption of thyroid cancer clinical practice guidelines.

OBJECTIVES/HYPOTHESIS: To present an overview of the barriers to the implementation of clinical practice guidelines (CPGs) in thyroid cancer management and to introduce a computer-based clinical support system. DATA SOURCES: PubMed. REVIEW METHODS: A review of studies on adherence to CPGs was conducted. RESULTS: Awareness and adoption of CPGs is low in thyroid cancer management. Barriers to implementation include unfamiliarity with the CPGs and financial concerns. Effective interventions to improve adherence are possible, especially when they are readily accessible at the point of care delivery. Computerized clinical support systems show particular promise. The authors introduce the clinical decision making modules (CDMMs) of the Thyroid Cancer Care Collaborative, a thyroid cancer-specific electronic health record. These computer-based modules can assist clinicians with implementation of these recommendations in clinical practice. CONCLUSION: Computer-based support systems can help clinicians understand and adopt the thyroid cancer CPGs. By integrating patient characteristics and guidelines at the point of care delivery, the CDMMs can improve adherence to the guidelines and help clinicians provide high-quality, evidence-based, and individualized patient care in the management of differentiated thyroid cancer. Laryngoscope, 126:2640-2645, 2016.

ACTIVE SURVEILLANCE FOR PAPILLARY THYROID MICROCARCINOMA: NEW CHALLENGES AND OPPORTUNITIES FOR THE HEALTH CARE SYSTEM.

OBJECTIVE: The dramatic increase in papillary thyroid carcinoma (PTC) is primarily a result of early diagnosis of small cancers. Active surveillance is a promising management strategy for papillary thyroid microcarcinomas (PTMCs). However, as this management strategy gains traction in the U.S., it is imperative that patients and clinicians be properly educated, patients be followed for life, and appropriate tools be identified to implement the strategy. METHODS: We review previous active surveillance studies and the parameters used to identify patients who are good candidates for active surveillance. We also review some of the challenges to implementing active surveillance protocols in the U.S. and discuss how these might be addressed. RESULTS: Trials of active surveillance support nonsurgical management as a viable and safe management strategy. However, numerous challenges exist, including the need for adherence to protocols, education of patients and physicians, and awareness of the impact of this strategy on patient psychology and quality of life. The Thyroid Cancer Care Collaborative (TCCC) is a portable record keeping system that can manage a mobile patient population undergoing active surveillance. CONCLUSION: With proper patient selection, organization, and patient support, active surveillance has the potential to be a long-term management strategy for select patients with PTMC. In order to address the challenges and opportunities for this approach to be successfully implemented in the U.S., it will be necessary to consider psychological and quality of life, cultural differences, and the patient's clinical status.