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.

Ultrasound-based clinical prediction rule model for detecting papillary thyroid cancer in cervical lymph nodes: A pilot study.

PURPOSE: To identify sonographic features of cervical lymph nodes (LNs) that are associated with papillary thyroid cancer (PTC) and to develop a prediction model for classifying nodes as metastatic or benign. METHODS: This retrospective study included the records of postthyroidectomy patients with PTC who had undergone cervical ultrasound and LN biopsy. LN location, size, shape, hilum, echopattern, Doppler flow, and microcalcifications were assessed. Model selection was used to identify features associated with malignant LNs and to build a predictive, binary-outcome, generalized linear mixed model. A cross-validated receiver operating characteristic analysis was conducted to assess the accuracy of the model for classifying metastatic nodes. RESULTS: We analyzed records from 71 LNs (23 metastatic) in 44 patients (16 with PTC). The predictive model included a nonhomogeneous echopattern (odds ratio [OR], 5.73; 95% confidence interval [CI], 1.07-30.74; p = 0.04), microcalcifications (OR, 4.91; 95% CI, 0.91-26.54; p = 0.06), and volume (OR, 2.57; 95% CI, 0.66-9.99; p = 0.16) as predictors. The model had an area under the curve of 0.74 (95% CI, 0.60-0.85), sensitivity of 65% (95% CI, 50% to 78%), and specificity of 85% (95% CI, 73% to 94%) at the Youden optimal cut point of 0.38. CONCLUSIONS: Nonhomogeneous echopattern, microcalcifications, and node volume were predictive of malignant LNs in patients with PTC. A larger sample is needed to validate this model.

Histopathology of telomerase reverse transcriptase promoter (TERT) mutated indeterminate thyroid nodules.

Objective: The objective of this study was to analyze the risk of malignancy and the histopathology of telomerase reverse transcriptase promoter (TERT) mutated cytologically indeterminate thyroid nodules (ITN). Methods: A PUBMED search of molecularly tested ITN was conducted and data on TERT mutated ITN with histopathology correlation were extracted. Results: Twenty-six manuscripts (published between 2014 and 2022) reported on 77 TERT mutated ITN. Sixty-five nodules were malignant (84 %), with 16 (25 %) described with high-risk histopathology, 5 (8 %) described as low-risk, and most without any description. Isolated TERT mutations were malignant in 26/30 ITNs (87 %) with 9 (35 %) described as high risk and none described as low risk. TERT + RAS mutated ITNs were malignant in 29/34 ITNs (85 %) with 3 (10 %) described as high risk and 4 (14 %) described as low risk. Finally, all 5 TERT + BRAFV600E mutated nodules were malignant and 3/5 (60 %) were described as high risk. Conclusion: TERT mutated ITNs have a high risk of malignancy (84 %), and the current data does not show a difference in malignancy rate between isolated TERT mutations and TERT + RAS co-mutated ITNs. When described, TERT + RAS co-mutated ITNs did not have a higher rate of high-risk histopathology as compared to isolated TERT mutated lesions. Most TERT mutated ITNs did not have a description of histopathology risk and the oncologic outcomes, including rate of recurrence, metastases, and disease specific survival, are unknown. Further data is needed to determine if TERT mutated ITNs should be subjected to aggressive initial treatment.

Analytical Validation of a Telomerase Reverse Transcriptase (TERT) Promoter Mutation Assay.

CONTEXT: TERT promoter mutated thyroid cancers are associated with a decreased rate of disease free and disease specific survival. High quality analytical validation of a diagnostic test promotes confidence in the results which inform clinical decision making. OBJECTIVE: To demonstrate the analytical validation of the Afirma TERT promoter mutation assay. METHODS: TERT promoter C228T and C250T variant detection in genomic DNA (gDNA) was analyzed by assessing variable DNA input and the limit of detection (LOD) of variant allele frequency (VAF). The negative and positive percent agreement (NPA and PPA) of the Afirma TERT test was examined against a reference primer pair as was the analytical specificity from potential interfering substances (RNA and blood gDNA). Further, the intra-run, inter-run and inter-laboratory reproducibility of the assay were tested. RESULTS: The Afirma TERT test is tolerant to variation in DNA input amount (7-13 ng) and can detect expected positive TERT promoter variants down to 5% VAF LOD at 7ng DNA input with > 95% sensitivity. Both NPA and PPA were 100% against the reference primer pair. The test remains accurate in presence of 20% RNA or 80% blood gDNA for an average patient sample that typically has 30% VAF. The test also demonstrated a 100% confirmation rate when compared with an external NGS-based reference assay executed in a non-Veracyte laboratory. CONCLUSION: The analytical robustness and reproducibility of the Afirma TERT test support its routine clinical use among thyroid nodules with indeterminate cytology that are Afirma GSC suspicious or among Bethesda V/VI nodules.

Molecular diagnostics in the evaluation of thyroid nodules: Current use and prospective opportunities.

Thyroid cancer is the most common endocrine malignancy with an estimated 43,800 new cases to be diagnosed in 2022 and representing the 7th most common cancer in women. While thyroid nodules are very common, being identified in over 60% of randomly selected adults, only 5-15% of thyroid nodules harbor thyroid malignancy. Therefore, it is incumbent upon physicians to detect and treat thyroid malignancies as is clinically appropriate and avoid unnecessary invasive procedures in patients with benign asymptomatic lesions. Over the last 15-20 years, rapid advances have been made in cytomolecular testing to aid in thyroid nodule management. Initially, indeterminate thyroid nodules, those with Bethesda III or IV cytology and approximately a 10-40% risk of malignancy, were studied to assess benignity or malignancy. More recently, next generation sequencing and micro-RNA technology platforms have refined the diagnostic capacity of thyroid nodule molecular testing and have introduced opportunities to glean prognostic information from both cytologically indeterminate and malignant thyroid nodules. Therefore, clinicians can move beyond determination of malignancy, and utilize contemporary molecular information to aid in decisions such as extent of surgery and post-therapy monitoring plans. Future opportunities include molecularly derived information about tumor behavior, neo-adjuvant treatment opportunities and response to thyroid cancer therapies.

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.

Real-World Performance of the Afirma Genomic Sequencing Classifier (GSC)-A Meta-analysis.

CONTEXT: The Afirma® GSC aids in risk stratifying indeterminate thyroid nodule cytology (ITN). The 2018 GSC validation study (VS) reported a sensitivity (SN) of 91%, specificity (SP) of 68%, positive predictive value (PPV) of 47%, and negative predictive value (NPV) of 96%. Since then, 13 independent real-world (RW) postvalidation studies have been published. OBJECTIVE: This study's objective is to compare the RW GSC performance to the VS metrics. METHODS: Rules and assumptions applying to this analysis include: (1) At least 1 patient with molecular benign results must have surgery for that study to be included in SN, SP, and NPV analyses. (2) Molecular benign results without surgical histology are considered true negatives (TN) (as are molecular benign results with benign surgical histology). (3) Unoperated patients with suspicious results are either excluded from analysis (observed PPV [oPPV] and observed SP [oSP]) or assumed histology negatives (false positives; conservative PPV [cPPV] and conservative SP [cSP]) 4. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features is considered malignant. RESULTS: In RW studies, the GSC demonstrates a SN, oSP, oPPV, and NPV of 97%, 88%, 65%, 99% respectively, and conservative RW performance showed cSP of 80% and cPPV of 49%, all significantly higher than the VS except for SN and cPPV. There was also a higher benign call rate (BCR) of 67% in RW studies compared to 54% in the VS (P < 0.05). CONCLUSION: RW data for the Afirma GSC demonstrates significantly better oSP and oPPV performance than the VS, indicating an increased yield of cancers for resected GSC suspicious nodules. The higher BCR likely increases the overall rate of clinical observation in lieu of surgery.

Risk of malignancy in cytologically indeterminate thyroid nodules harboring thyroid stimulating hormone receptor mutations.

Objectives: To evaluate the frequency and risk of malignancy of TSHRpI568T mutations discovered in indeterminate thyroid nodules (ITN) within the Veracyte CLIA laboratory undergoing Afirma® Genomic Sequencing Classifier (GSC) testing, and to evaluate a broader cohort of TSHR variants and their categorization as Afirma GSC benign (GSC-B) or suspicious (GSC-S). Finally, we seek to assess the risk of malignancy (ROM) of this group of TSHR mutated ITN in the GSC-S category. Methods: ITN submitted to Veracyte for Afirma GSC testing between October 2017 and February 2022 were analyzed for TSHR variants and rates of GSC-B and GSC-S were calculated based upon BIII or IV cytology, by TSHR variant codon amino acid (AA) substitution, age, and gender. For GSC-S samples, surgical pathology reports were requested, and the rate of malignancy was calculated. Results: Five percent of the ITN samples harbored an isolated TSHR variant and 5% of those were classified as GSC-S. Among TSHRpI568T samples, 96% were GSC-B and of the GSC-S samples, 21% were malignant. Among an unselected group of TSHR, absent TSHRpI568T mutations, 16.3% of GSC-S samples were malignant, all but one with codon mutations in the transmembrane subdomains of the TSHR. This prompted a dedicated evaluation of transmembrane codons which revealed a malignancy rate of 10.7% among GSC-S nodules. In total, 13/85 (15.3%) TSHR mutated ITN with Afirma GSC-S results were found to be malignant. Conclusions: TSHR variants are rare in ITN, and most are categorized as benign under Afirma GSC testing which carries a < 4% risk of malignancy. For GSC-S ITN with TSHR mutations, the risk of malignancy is ≥= 15%, which is clinically meaningful and may alter treatment or monitoring recommendations for patients.

Preoperative Identification of Medullary Thyroid Carcinoma (MTC): Clinical Validation of the Afirma MTC RNA-Sequencing Classifier.

Background: Cytopathological evaluation of thyroid fine-needle aspiration biopsy (FNAB) specimens can fail to raise preoperative suspicion of medullary thyroid carcinoma (MTC). The Afirma RNA-sequencing MTC classifier identifies MTC among FNA samples that are cytologically indeterminate, suspicious, or malignant (Bethesda categories III-VI). In this study we report the development and clinical performance of this MTC classifier. Methods: Algorithm training was performed with a set of 483 FNAB specimens (21 MTC and 462 non-MTC). A support vector machine classifier was developed using 108 differentially expressed genes, which includes the 5 genes in the prior Afirma microarray-based MTC cassette. Results: The final MTC classifier was blindly tested on 211 preoperative FNAB specimens with subsequent surgical pathology, including 21 MTC and 190 non-MTC specimens from benign and malignant thyroid nodules independent from those used in training. The classifier had 100% sensitivity (21/21 MTC FNAB specimens correctly called positive; 95% confidence interval [CI] = 83.9-100%) and 100% specificity (190/190 non-MTC FNAs correctly called negative; CI = 98.1-100%). All positive samples had pathological confirmation of MTC, while all negative samples were negative for MTC on surgical pathology. Conclusions: The RNA-sequencing MTC classifier accurately identified MTC from preoperative thyroid nodule FNAB specimens in an independent validation cohort. This identification may facilitate an MTC-specific preoperative evaluation and resulting treatment.

Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression.

BACKGROUND: Metastatic melanoma has a high mortality rate and suboptimal therapeutic options. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid x receptor selective agonist, and thiazolidinediones (TZD), PPARgamma selective ligands, as novel treatments. RESULTS: Mouse xenograft models with human melanoma cell lines [A375(DRO) or M14(5-16)] were treated for 4 weeks with daily vehicle, RXR agonist (rexinoid, LGD1069, 30 mg/kg/d), PPARgamma agonist (TZD, rosiglitazone, 10 mg/kg/d) or combination. A375(DRO) tumor growth was significantly inhibited by either ligand alone and the combination had an additive effect. M14(5-16) tumors only responded to LGD1069 100 mg/kg/day. A375(DRO) sublines resistant to rexinoid, TZD and combination were generated and all three sublines had reduced PPARgamma expression but preserved RXR expression. shRNA knockdown of PPARgamma or RXRgamma attenuated the rexinoid, TZD and combination ligand-mediated decreased proliferation in A375(DRO) cells. Rexinoid (LGD1069) and retinoid (TTNPB) treatment of M14(5-16) cells resulted in decreased proliferation that was additive with combination of both rexinoid and retinoid. shRNA knockdown of RXRgamma resulted in a decreased response to either ligand. CONCLUSION: A375 (DRO) melanoma cell growth is inhibited by rexinoid and TZD treatment, and this response is dependent on RXR and PPARgamma receptor expression. M14 (5-16) melanoma cell growth is inhibited by rexinoid and retinoid treatment, and this response is dependent on RXR expression. These findings may help guide molecular-based treatment strategies in melanoma and provide insight for mechanisms of resistance to nuclear receptor targeted therapies in certain cancers.

In vivo and microarray analysis of rexinoid-responsive anaplastic thyroid carcinoma.

PURPOSE: Anaplastic thyroid carcinoma is rare, yet lethal despite aggressive therapy. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid X receptor-selective agonist, as a novel treatment. In this report, we describe the efficacy of LGD1069 in anaplastic thyroid carcinoma in vitro and assess the in vivo treatment effects on a responsive cancer. Additionally, we explore potential mediators of the rexinoid effect on a responsive anaplastic thyroid cancer using comparative microarray analysis. EXPERIMENTAL DESIGN: Anaplastic thyroid cancer cell lines DRO, ARO, and FRO were treated with LGD1069 in vitro. Responsive DRO xenograft tumors were treated with control chow or chow containing a low dose (30 mg/kg/d) or a high dose (100 mg/kg/d) of LGD1069. Comparative microarray analysis of DRO cells treated with LGD1069 compared with volume-equivalent control was assessed after 24 h of treatment to evaluate early gene expression changes. RESULTS: DRO xenograft tumor growth was inhibited by LGD1069 treatment in a dose-dependent manner. Comparative microarray analysis showed that 80 genes had a significant increase in expression and 29 genes had a decrease in expression after 24 h of treatment with LGD1069. Expression of angiopoietin-like 4 (ANGPTL4) mRNA was increased 6.5-fold. A trend towards an increase in ANGPTL4 mRNA (not statistically significant) was seen in treated tumors in vivo and this correlated with decreased tumor vascularity and increased necrosis. CONCLUSIONS: LGD1069 therapy decreases proliferation in an anaplastic thyroid cancer cell line that expresses retinoid X receptor-gamma, and this effect is confirmed with decreased tumor size in vivo in a nude mouse model. ANGPTL4 is increased in DRO in response to LGD1069 and may be a potential mediator of the effects of rexinoid treatment.

Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification.

CONTEXT: Cell lines derived from human cancers provide critical tools to study disease mechanisms and develop novel therapies. Recent reports indicate that up to 36% of cell lines are cross- contaminated. OBJECTIVE: We evaluated 40 reported thyroid cancer-derived cell lines using short tandem repeat and single nucleotide polymorphism array analysis. RESULTS: Only 23 of 40 cell lines tested have unique genetic profiles. The following groups of cell lines are likely derivatives of the same cell line: BHP5-16, BHP17-10, BHP14-9, and NPA87; BHP2-7, BHP10-3, BHP7-13, and TPC1; KAT5, KAT10, KAT4, KAT7, KAT50, KAK1, ARO81-1, and MRO87-1; and K1 and K2. The unique cell lines include BCPAP, KTC1, TT2609-C02, FTC133, ML1, WRO82-1, 8505C, SW1736, Cal-62, T235, T238, Uhth-104, ACT-1, HTh74, KAT18, TTA1, FRO81-2, HTh7, C643, BHT101, and KTC-2. The misidentified cell lines included the DRO90-1, which matched the melanoma-derived cell line, A-375. The ARO81-1 and its derivatives matched the HT-29 colon cancer cell line, and the NPA87 and its derivatives matched the M14/MDA-MB-435S melanoma cell line. TTF-1 and Pax-8 mRNA levels were determined in the unique cell lines. CONCLUSIONS: Many of these human cell lines have been widely used in the thyroid cancer field for the past 20 yr and are not only redundant, but not of thyroid origin. These results emphasize the importance of cell line integrity, and provide the short tandem repeat profiles for a panel of thyroid cancer cell lines that can be used as a reference for comparison of cell lines from other laboratories.

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.

Retinoid X receptor-gamma and peroxisome proliferator-activated receptor-gamma expression predicts thyroid carcinoma cell response to retinoid and thiazolidinedione treatment.

Poorly differentiated, metastatic thyroid cancer is difficult to treat. These tumors often do not concentrate radioactive iodine and may require chemotherapy, which is suboptimal and toxic. Nuclear hormone receptors peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoid X receptor (RXR) are variably expressed in thyroid carcinoma cell lines. Expression of these receptors may predict thyroid cancer cell response to treatment with rexinoids and thiazolidinediones. We studied three thyroid carcinoma cell lines: BHP 5-16 (PPARgamma-/RXRgamma+), BHP 2-7 (PPARgamma+/-/RXRgamma-), and DRO-90 (RXRgamma+/PPARgamma+). BHP 5-16 (RXRgamma+) cells treated with rexinoid had decreased proliferation to 69 +/- 6% growth compared with vehicle. BHP 2-7 (PPARgamma+) cells treated with thiazolidinedione had no decrease in cellular proliferation. DRO-90 (RXRgamma+ and PPARgamma+) cells had 36 +/- 10%, 15 +/- 3%, and 13 +/- 4% growth when treated with rexinoid, thiazolidinedione, or a combination, respectively. We next investigated the role of apoptosis in the ligand-responsive BHP 5-16 and DRO-90 cells. BHP 5-16 cells underwent no significant apoptosis with rexinoid (1 micromol/L). DRO-90 cells, however, had 3.6 +/- 1.3% apoptotic cells with vehicle, 13 +/- 3.5% with rexinoid (1 micromol/L), 18 +/- 4% with thiazolidinedione (1 micromol/L), and 28 +/- 6% with combination treatment (1 micromol/L), suggesting that apoptosis plays a major role in this anaplastic cell line and that the effects of the two ligands are additive. We conclude that receptor expression is necessary for inhibition of thyroid carcinoma growth with ligand treatment but may not be sufficient for response. Additionally, expression of both RXRgamma and PPARgamma may be necessary for maximal growth inhibition by ligands and may be required for the increased apoptosis.

A "safe and effective" protocol for management of post-thyroidectomy hypocalcemia.

BACKGROUND: This study evaluates the outcomes of a protocol to manage hypocalcemia after thyroidectomy (TTX). METHODS: A review of prospectively collected data was performed in 130 patients who underwent TTX after the introduction of a specific protocol. These patients were compared with a control group of 195 patients who underwent TTX the year prior when routine calcium supplementation was utilized and no specific protocol was used. RESULTS: Of the 120 patients in whom the protocol was followed, 44 (37%) patients were classified as high risk, 15 (13%) intermediate risk, and 61 (51%) low risk. The protocol had a sensitivity of 85% and a negative predictive value of 92% for predicting subsequent hypocalcemia. With the implementation of the protocol, there was significant reduction in temporary hypocalcemia events (P = .008) and intravenous calcium drip (P = .49). Also, calcium supplementation was significantly lower in the protocol group (P ≤ .001). CONCLUSIONS: This hypocalcemia protocol identifies patients who do not require additional supplementation and additional monitoring. At the same time, it identifies those who will benefit from supplementation after TTX.

Database and registry research in thyroid cancer: striving for a new and improved national thyroid cancer database.

BACKGROUND: Health registries have become extremely powerful tools for cancer research. Unfortunately, certain details and the ability to adapt to new information are necessarily limited in current registries, and they cannot address many controversial issues in cancer management. This is of particular concern in differentiated thyroid cancer, which is rapidly increasing in incidence and has many unknowns related to optimal treatment and surveillance recommendations. SUMMARY: In this study, we review different types of health registries used in cancer research in the United States, with a focus on their advantages and disadvantages as related to the study of thyroid cancer. This analysis includes population-based cancer registries, health systems-based cancer registries, and patient-based disease registries. It is important that clinicians understand the way data are collected in, as well as the composition of, these different registries in order to more critically interpret the clinical research that is conducted using that data. In an attempt to address shortcoming of current databases for thyroid cancer, we present the potential of an innovative web-based disease management tool for thyroid cancer called the Thyroid Cancer Care Collaborative (TCCC) to become a patient-based registry that can be used to evaluate and improve the quality of care delivered to patients with thyroid cancer as well as to answer questions that we have not been able to address with current databases and registries. CONCLUSION: A cancer registry that follows a specific patient, is integrated into physician workflow, and collects data across different treatment sites and different payers does not exist in the current fragmented system of healthcare in the United States. The TCCC offers physicians who treat thyroid cancer numerous time-saving and quality improvement services, and could significantly improve patient care. With rapid adoption across the nation, the TCCC could become a new paradigm for database research in thyroid cancer to improve our understanding of thyroid cancer management.

Management of recurrent and persistent metastatic lymph nodes in well-differentiated thyroid cancer: a multifactorial decision-making guide for the Thyroid Cancer Care Collaborative.

BACKGROUND: Well-differentiated thyroid cancer (WDTC) recurs in up to 30% of patients. Guidelines from the American Thyroid Association (ATA) and the National Comprehensive Cancer Network (NCCN) provide valuable parameters for the management of recurrent disease, but fail to guide the clinician as to the multitude of factors that should be taken into account. The Thyroid Cancer Care Collaborative (TCCC) is a web-based repository of a patient's clinical information. Ten clinical decision-making modules (CDMMs) process this information and display individualized treatment recommendations. METHODS: We conducted a review of the literature and analysis of the management of patients with recurrent/persistent WDTC. RESULTS: Surgery remains the most common treatment in recurrent/persistent WDTC and can be performed with limited morbidity in experienced hands. However, careful observation may be the recommended course in select patients. Reoperation yields biochemical remission rates between 21% and 66%. There is a reported 1.2% incidence of permanent unexpected nerve paralysis and a 3.5% incidence of permanent hypoparathyroidism. External beam radiotherapy and percutaneous ethanol ablation have been reported as therapeutic alternatives. Radioactive iodine as a primary therapy has been reported previously for metastatic lymph nodes, but is currently advocated by the ATA as an adjuvant to surgery. CONCLUSION: The management of recurrent lymph nodes is a multifactorial decision and is best determined by a multidisciplinary team. The CDMMs allow for easy adoption of contemporary knowledge, making this information accessible to both patient and clinician.

Retinoic acid and retinoid X receptors are differentially expressed in thyroid cancer and thyroid carcinoma cell lines and predict response to treatment with retinoids.

Therapy for patients with advanced thyroid carcinoma is limited. Clinical and in vitro studies suggest that some patients with advanced thyroid cancer may respond to therapy with retinoic acid. mRNA expression of the six retinoic acid (RAR) and retinoid X receptor (RXR) isoforms (RARalpha, -beta, -gamma and RXRalpha, -beta, -gamma) was measured in four human thyroid cell lines, and protein expression was subsequently measured in 10 thyroid cancer cell lines. Two isoforms, RARbeta and RXRgamma, were differentially expressed in the four cell lines. Comparison of 10 thyroid tumors and matched normal thyroid tissue confirmed differential tumor expression of RARbeta and RXRgamma and lack of the RXRgamma isoform in normal thyroid tissue. Cell lines expressing both RARbeta and RXRgamma demonstrated significant growth suppression when treated with retinoids, whereas cell lines lacking these isoforms were unaffected. Expression of RARbeta, the isoform associated with suppression of tumor growth in other cancer types, was not affected by treatment with retinoids in the thyroid cancer cell lines. LG346 increased apoptosis and decreased cells in the S-phase in an anaplastic carcinoma cell line, suggesting that this retinoid causes growth suppression of these cells by multiple mechanisms. In summary, we identified the RARbeta and RXRgamma isoform to be differentially expressed in thyroid cancer cell lines and tumor tissue. These isoforms seem to predict response to retinoid therapy in thyroid cancer cell lines.

Multicenter clinical experience with the Afirma gene expression classifier.

BACKGROUND: Increasingly, patients with thyroid nodule cytology labeled atypical (or follicular lesion) of undetermined significance (AUS/FLUS) or follicular neoplasm (FN) undergo diagnostic analysis with the Afirma gene expression classifier (GEC). No long-term, multisite analysis of Afirma GEC performance has yet been performed. METHODS: We analyzed all patients who had received Afirma GEC testing at five academic medical centers between 2010 and 2013. Nodule and patient characteristics, fine needle aspiration cytology, Afirma GEC results, and subsequent clinical or surgical follow-up were obtained for 339 patients. Results were analyzed for pooled test performance, impact on clinical care, and site-to-site variation. RESULTS: Three hundred thirty-nine patients underwent Afirma GEC testing of cytologically indeterminate nodules (165 AUS/FLUS; 161 FN; 13 suspicious for malignancy) and 174 of 339 (51%) indeterminate nodules were GEC benign, whereas 148 GEC were suspicious (44%). GEC results significantly altered care recommendations, as 4 of 175 GEC benign were recommended for surgery in comparison to 141 of 149 GEC suspicious (P<.01). Of 121 Cyto Indeterminate/GEC Suspicious nodules surgically removed, 53 (44%) were malignant. Variability in site-to-site GEC performance was confirmed, as the proportion of GEC benign varied up to 29% (P=.58), whereas the malignancy rate in nodules cytologically indeterminate/GEC suspicious varied up to 47% (P=.11). Seventy-one of 174 GEC benign nodules had documented clinical follow-up for an average of 8.5 months, in which 1 of 71 nodules proved cancerous. CONCLUSIONS: These multicenter, clinical experience data confirm originally published Afirma GEC test performance and demonstrate its substantial impact on clinical care recommendations. Although nonsignificant site-to-site variation exists, such differences should be anticipated by the practicing clinician. Follow-up of GEC benign nodules thus far confirm the clinical utility of this diagnostic test.