Search

Background: Combination therapy with lenvatinib plus programmed death-1 (PD-1) immune checkpoint blockades (ICBs) is under investigation in many solid tumors, including thyroid cancer. Lenvatinib is known to reduce angiogenesis and may overturn the immunosuppressive effects of vascular endothelial growth factor in the tumor microenvironment. Previous studies investigating the effects of VEGF receptor inhibition on the immune response were performed in rapidly growing tumor models where immune equilibrium is not established before treatment. We hypothesize that physiologically relevant preclinical models are necessary to define mechanisms of resistance to immune-targeted combination therapies. Methods: We utilized the TPO-CreER/Braf(V600E)(/wt)/Trp53(Δex2–10/Δex2–10) inducible transgenic model of advanced thyroid cancer to investigate lenvatinib treatment in the context of an anti-PD-1 ICB. Following tumor establishment, 3.5 months postinduction, mice were treated with high- (10 mg/kg) or low-dose (2 mg/kg) lenvatinib, anti-PD-1, or combination of lenvatinib with anti-PD-1. Tumor volume and lung metastases were assessed in each group. Immune infiltrate was characterized by flow cytometry and immunohistochemistry, and TCRß sequencing was performed to further investigate the T cell response. Results: Both low- and high-dose lenvatinib reduced tumor volume, while anti-PD-1 had no effect, alone or in combination. Although both low- and high-dose lenvatinib reduced vascular density, low-dose lenvatinib was superior in controlling tumor size. Lung metastases and survival were not improved with therapy despite the effects of lenvatinib on primary tumor size. Low-dose lenvatinib treatment led to a subtle reduction in the dominant Ly6G(+)CD11b(+) myeloid cell population and was associated with increased CD4(+) T cell infiltrate and enrichment in 4–1BB(+) and granzyme B(+) CD4(+) T cells and FoxP3(+) regulatory T cells. Polyclonal T cell expansion was evident in the majority of mice, suggesting that a tumor-specific T cell response was generated. Conclusions: The effects of lenvatinib on the immune response were most pronounced in mice treated with low-dose lenvatinib, suggesting that dose should be considered in clinical application. While the immune-modulating potential of lenvatinib is encouraging, alterations in the immune milieu and T cell activation status were insufficient to sustain durable tumor regression, even with added anti-PD-1. Additional studies are necessary to develop more effective combination approaches in low-mutation burden tumors, such as thyroid cancer.

Background: Little is known about the role of emotions in treatment decisions for thyroid cancer. We aimed to characterize the emotional content of patient–surgeon communication during decision-making about low-risk thyroid cancer treatment. Methods: We audio-recorded conversations about treatment for clinically low-risk thyroid cancer or biopsy suspicious for thyroid cancer between patients (n = 30) and surgeons (n = 9) in two diverse, academic hospitals in the United States. Inductive and deductive content analyses were used to characterize the emotional content in verbatim transcripts. Results: Patients' expression of emotion focused on primarily on their diagnosis and treatment outcomes. Patients commonly expressed negative emotions like fear and anxiety about “the C-word” and worried about the cancer growing or spreading. In response, most surgeons used education, as opposed to empathy or validation, to reassure patients, often highlighting low probabilities of adverse events. Surgeons emphasized the “slow-growing” nature and excellent prognosis of thyroid cancer compared with other malignancies. When discussing treatment options, surgeons often described alternatives in terms of their emotional outcomes. Some described total thyroidectomy as providing “peace of mind” or a “sense of completeness,” warning that cancer or thyroid tissue remaining in the body with active surveillance or lobectomy might “worry” or “bother” patients. Surgeons supported deliberation by reassuring patients that there are “two right answers” and “no rush” to decide. Conclusions: Patients express negative emotions during treatment decision-making. In response, surgeons often miss opportunities to provide empathy in addition to education. Surgeons and patients both acknowledge patient fear and anxiety as a reason to choose thyroidectomy instead of active surveillance. Peace of mind gained by patients and surgeons as a result of thyroidectomy may lead to overtreatment of patients with low-risk thyroid cancer.

Background: Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab. Patients and Methods: In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14–24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1–90%). Results: Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%. Conclusions: Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.

BACKGROUND: Prior studies evaluating thyroid fine needle aspiration biopsies (FNABs) have limited the calculation of risk of malignancy (ROM) to cytologic specimens with corresponding histologic specimens, and clinical follow-up for those patients who do not undergo immediate surgery has been largely disregarded. Moreover, there is marked variability in how researchers have approached thyroid FNAB statistical analyses. This study addresses the urgent need for information from a large cohort of patients with long-term clinical follow-up to more accurately determine the performance of thyroid FNAB and ROM for each diagnostic category. METHODS: A retrospective review of the University of California, San Francisco (UCSF), pathology database for thyroid FNABs from January 1, 1997, to December 31, 2004, was performed. Diagnoses were coded using the 2017 The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), and patients were matched to both the UCSF cancer registry and California Cancer Registry. Data were analyzed using the Kaplan–Meier method, and stratified by TBSRTC diagnostic category. Kaplan–Meier curves were used to estimate incidence rates of malignancy, stratified by FNAB category. Cox proportional hazards models were used to determine the instantaneous ROM. RESULTS: Initial FNABs from 2207 patients were included. Median follow-up period after the first thyroid FNAB was 13.9 years (range: 10.5–18.4 years). During follow-up, there were 279 confirmed diagnoses of thyroid malignancy. Estimates derived from Kaplan–Meier curves demonstrated that the risk of having a thyroid malignancy was low for nondiagnostic and benign categories, intermediate for atypia of undetermined significance (AUS), follicular lesion of undetermined significance (FLUS), AUS/FLUS combined, and follicular neoplasm, and high for suspicious and malignant categories. A total of 52/1575 false-negative cases (3.2%) were identified. Excluding papillary microcarcinomas, the false-negative rate was 1.5% (23/1575). No patients with a false-negative diagnosis died of thyroid cancer during the follow-up period. CONCLUSIONS: Asymptomatic patients with low-risk clinical and radiologic features and initially benign or unsatisfactory biopsy are unlikely to develop thyroid malignancy and highly unlikely to die of thyroid cancer. FNAB is highly accurate in detecting malignancy. Additional studies evaluating similar large data sets after the adoption of TBSRTC and the integration of molecular testing are needed.

Background: Little is known about financial hardship among Hispanic women with thyroid cancer. The goal of this study was to determine the prevalence of financial hardship and to identify correlates of financial hardship in this understudied patient group. Methods: We surveyed Hispanic women who had diagnoses of thyroid cancer reported to the Los Angeles Surveillance Epidemiology and End Results (SEER) registry in 2014–2015, and who had previously completed our thyroid cancer survey in 2017–2018 (N = 273; 80% response rate). Acculturation was assessed with the Short Acculturation Scale for Hispanics (SASH). Patients were asked about three outcome measures since their thyroid cancer diagnosis: (i) financial status, (ii) insurance status, and (iii) material measures of financial hardship, collapsed into a single composite measure of financial hardship. We used multivariable logistic regression to identify correlates of financial hardship. Results: Patients' median age at diagnosis was 47 years (range 20–79 years); 49% were low-acculturated and 47% reported financial hardship. Since their thyroid cancer diagnosis, 31% and 12% of the cohort reported being worse off regarding financial and insurance status, respectively. In multivariable analysis, high-acculturated older women were less likely to experience financial hardship compared with high-acculturated 20-year-old women. While financial hardship decreased with age for high-acculturated women (p = 0.002), financial hardship remained elevated across all age groups for low-acculturated women (p = 0.54). Conclusions: Our findings suggest that across all age groups, low-acculturated Hispanic women with thyroid cancer are vulnerable to financial hardship, emphasizing the need for tailored patient-focused interventions.

Background: Incidence of differentiated thyroid cancer has increased in the United States and globally with disproportionate increases observed among women. Recent data suggest that factors other than increased detection may underlie this increase. To understand incidence and survival patterns in differentiated thyroid cancer during a time period of increasing imaging, we examined data from a contemporary population-based sample of U.S. reproductive-aged women. Methods: Women aged 20–49 years (N = 61,552) diagnosed with papillary thyroid cancer (PTC) or follicular thyroid cancer (FTC) during 2000–2016 were identified from the U.S. National Cancer Institute Surveillance, Epidemiology, and End Results 18 registries database. For each age decade (20–29, 30–39, 40–49 years), we estimated age-adjusted average annual percentage changes in incidence using segmented and unsegmented regression models and 15-year survival. Results were stratified by race/ethnicity and cancer stage. Results: The estimated incidence of PTC increased during 2000–2016 among women aged 20–29 years and during 2000–2012 among women aged 30–49 years. During 2012–2016, incidence stabilized among women aged 30–39 years and decreased among women aged 40–49 years. For FTC, incidence decreased slightly among women aged 20–29 years and was rather stable among those aged 30–49 years during 2000–2016, although increases were observed among non-Hispanic black women aged 30–49 years. By stage, the percentage increase in PTC incidence was largest for regional disease. Fifteen-year estimated survival was generally high but somewhat lower among women aged 40–49 years than those aged 20–39 years. Survival was similar for PTC and FTC except among women aged 20–29 years, for whom survival was modestly lower with FTC than PTC. Conclusions: Our findings confirm increasing incidence of PTC among U.S. women aged 20–29 years, a recent stabilization of PTC incidence in women 30–49 years, and stable to decreasing incidence of FTC. Increased detection based on imaging is unlikely to fully explain the continued increase in PTC incidence, given the increasing incidence of regional disease and routine imaging occurring less often among premenopausal than postmenopausal women. Although survival is generally high, treatment often requires surgery and lifelong medications. Further investigations into contributors to these trends are warranted to reduce future morbidity in reproductive-aged women.

Background: Active surveillance is accepted as a first-line management for patients with low-risk papillary thyroid microcarcinoma (PTMC) without metastasis or extrathyroid extension. While the lung is the most frequent site of distant metastasis of papillary thyroid carcinomas (PTCs), it is unclear if chest computed tomography (CT) is necessary at the initiation of active surveillance. In our institution, we usually did not perform chest CT for candidates identified for active surveillance. However, routine preoperative chest CT for patients with thyroid cancers, including PTMCs, was standard practice. The present study aimed to evaluate the clinical value of chest CT for patients with PTMCs. Methods: We retrospectively reviewed preoperative chest CT images from 1000 consecutive patients (88.5% women; median age, 55 years) with cT1aN0 PTC who underwent surgery between January 2006 and May 2012 in our hospital. The median maximum size of PTMCs was 8 mm. Results: Abnormal findings were detected in 326 (32.6%) of the 1000 patients. Of these, 290 patients had presumed benign or inflammatory lesions of no clinical importance. In total, 36 patients (3.6%) were referred to specialized departments for further evaluation of the lesions, and 9 patients (0.9%) received invasive tests and/or treatments. Five patients (0.5%) benefited from the chest CT (lung cancer was detected in four, and a cardiac lesion was detected and treated in one), while the lesions in the other four patients were benign, not necessarily requiring treatment. The remaining 27 patents were followed for presumed benign or inflammatory lesions. Thus, none of the present 1000 patients was found with distant metastasis of thyroid cancer. Conclusions: Routine chest CT did not detect thyroid cancer lung metastasis in patients with PTMC. Thus, routine chest CT at the time of presentation is not required for patients with cT1aN0 PTCs.

Background: The success of an active surveillance management approach to low-risk papillary thyroid cancer (PTC) is heavily dependent on proper patient selection. For example, primary tumors located in a subcapsular position immediately adjacent to the trachea or a recurrent laryngeal nerve (RLN) are considered to be inappropriate for active surveillance. Since preoperative imaging cannot reliably rule out extrathyroidal extension or reveal the full course of the RLN relative to the thyroid gland, it is important for clinicians to understand subcapsular tumor locations and minimum tumor sizes that are most likely to be associated with gross invasion of the RLNs. Methods: We assessed the medical records of 123 patients treated at Memorial Sloan Kettering Cancer Center (MSK) between 1986 and 2015 who had a primary PTC tumor demonstrating gross extrathyroidal extension to either the right or left RLN. Thirty patients with a primary tumor ≤2 cm in diameter demonstrating extrathyroidal extension into an RLN were included in the analysis. Results: Gross invasion of an RLN by tumors ≤2 cm is a rare event that was seen in only 0.8% (35/4334) of patients with PTC who underwent initial thyroid surgery at MSK between 1986 and 2015. Gross RLN invasion was associated with subcapsular PTC tumors located in either the right paratracheal area (60%), left paratracheal area (36.7%), or right lateral posterior lobe area not adjacent to the trachea (3.3%). Only a quarter of the patients had imaging findings suggestive of extrathyroidal extension and only 30% had clinically apparent vocal paresis/paralysis on preoperative examination. Invasion of the RLN was not observed for primary tumors

Background: The prevalence and clinical significance of de novo detection of anti-thyroglobulin antibodies (TgAbs) during the follow-up of patients with differentiated thyroid cancer (DTC) is unknown. Methods: We utilized the National Thyroid Cancer Treatment Cooperative Study registry (1987–2012). Patients registered after 1996 (n = 3318) were analyzed. We identified 1545 subjects who had available TgAb status (TgAb cohort) between years 1996 and 2012, of whom 1325 were TgAb negative at first postoperative follow-up testing. From this initial TgAb-negative group, we excluded 513 patients: 423 patients who had less than 3 years of follow-up and/or fewer than three follow-up visits, 86 patients with persistent disease after initial treatment, and 4 patients with data entry errors. The remaining 812 patients were included for analysis, comprising the TgAb persistently negative group (defined as TgAb negative for at least 3 consecutive follow-up visits and at least 3 years of follow-up) (n = 772) and the de novo TgAb-positive group in whom TgAbs became detectable (n = 40). We then assessed whether de novo appearance of TgAb was associated with DTC structural recurrence by using the Kaplan–Meier method. Results: The de novo detection of TgAb occurred in 5% of DTC patients. Recurrence of DTC in the TgAb persistently negative group compared with the de novo TgAb-positive group did not differ significantly (9.6% vs. 15.0%, p = 0.23). Baseline characteristics, histology, history of radiation exposure, staging, and median duration of follow-up were similar between the two groups. Interestingly, in all six patients who suffered a recurrence in the de novo TgAb-positive group, the TgAbs were negative at the time of recurrence detection and became positive at a median of 2.1 (0.7–8.7) years after the structural recurrence. Conclusions: Utilizing a large North American DTC registry, we found the prevalence of de novo TgAb detection to be 5% among initially TgAb-negative patients. We did not find a statistically significant association between de novo TgAb development and DTC structural recurrence. Larger prospective studies are required to confirm these findings and further assess the significance of de novo TgAb detection in the follow-up of DTC.

Purpose: To evaluate the impact of structural disease progression of metastatic lesions after initial surgery on overall survival (OS) of patients presenting with metastatic medullary thyroid cancer (MTC). We used tumor volume doubling time (TVDT) as a marker of structural disease progression and aimed to correlate the average structural tumor volume doubling time (midDT) with OS in MTC patients after initial surgery. Methods: In this retrospective study, we examined the clinical characteristics; average tumor volume doubling times of neck, lung, and liver metastasis; and disease-specific survival of patients with metastatic MTC. Results: Tumor growth is constant in MTC metastasis, irrespective of location of the metastasis. The median correlation coefficient (r) and the coefficient of determination (r(2)) were similar in lung metastasis (r = 0.91, r(2) = 0.95) and liver metastasis (r = 0.88, r(2) = 0.94), and comparable in neck metastasis (r = 0.73, r(2) = 0.85). Patients with metastatic MTC with a midDT ≤1 year have a worse prognosis than those with higher midDT (p = 0.002). Those with midDT ≤1 year had a median OS of 11.1 years [confidence interval (CI) 7.4–14.8 years]. In contrast, patients with midDT 1–3 years had a median OS of 16.5 years [CI 10.3–22.6 years]. All patients with midDT ≥3 survived by the end of the follow-up period. Preliminary results suggest that measurement of midDT can predict response to molecular targeted therapies. Conclusions: In conclusion, TVDT is a strong predictor of OS in patients with recurrent or metastatic MTC, can be used as a marker of progression, and potentially can help select patients who may benefit from molecular targeted therapy.

Background: Active surveillance (AS) of small, low-risk papillary thyroid cancers (PTCs) is increasingly being considered. There is limited understanding of why individuals with low-risk PTC may choose AS over traditional surgical management. Methods: We present a mixed-methods analysis of a prospective observational real-life decision-making study regarding the choice of thyroidectomy or AS for management of localized, low-risk PTCs

Introduction: The optimal management for patients with small, low-risk thyroid cancer is often debated. We aimed to characterize the attitudes and beliefs of providers and patients about management of small, low-risk thyroid cancer and how they relate to overtreatment. Methods: We conducted 34 semi-structured interviews with surgeons (n = 12), endocrinologists (n = 12), and patients with

Background: Distant metastasis is a rare occurrence in thyroid cancer, and it can be associated with poor prognosis. The genomic repertoires of various solid malignancies have previously been reported but remain underexplored in metastatic papillary thyroid cancer (PTC). Furthermore, whether distant metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. Methods: We performed whole-exome sequencing on 14 matched distant metastases, primary PTC tumors, and normal tissues. Point mutations, copy number alterations, cancer cell fractions, and mutational signatures were defined using the state-of-the-art bioinformatics methods. All likely deleterious variants were validated by orthogonal methods. Results: Genomic differences were observed between primary and distant metastatic deposits, with a median of 62% (range 21-92%) of somatic mutations detected in metastatic tissues, but absent from the corresponding primary tumor sample. Mutations in known driver genes including BRAF, NRAS, and HRAS were shared and preferentially clonal in both sites. However, likely deleterious variants affecting DNA methylation and transcriptional repression signaling genes including SIN3A, RBBP1, and CHD4 were found to be restricted in the metastatic lesions. Moreover, a mutational signature shift was observed between the mutations that are specific or enriched in the metastatic and primary lesions. Conclusions: Primary PTC and distant metastases differ in their range of somatic alterations. Genomic analysis of distant metastases provides an opportunity to identify potentially clinically informative alterations not detected in primary tumors, which might influence decisions for personalized therapy in PTC patients with distant metastasis.

Background: Gene panels are routinely used to assess predisposition to hereditary cancers by simultaneously testing multiple susceptibility genes and/or variants. More recently, genetic panels have been implemented as part of solid tumor malignancy testing assessing somatic alterations. One example is targeted variant panels for thyroid nodules that are not conclusively malignant or benign upon fine-needle aspiration (FNA). We systematically reviewed published studies from 2009 to 2018 that contained genetic data from preoperative FNA specimens on cytologically indeterminate thyroid nodules (ITNs) that subsequently underwent surgical resection. Pooled prevalence estimates per gene and variant, along with their respective positive predictive values (PPVs) for malignancy, were calculated. Summary: Our systematic search identified 540 studies that were supplemented by 18 studies from bibliographies or personal files. Sixty-one studies met all inclusion criteria and included >4600 ITNs. Overall, 26% of nodules contained at least 1 variant or fusion. However, half of them did not include details on the specific gene, variant, and/or complete fusion pair reported for inclusion toward PPV calculations. The PPVs of genomic alterations reported at least 10 times were limited to BRAFV600E (98%, 95% confidence interval [CI 96–99%]), PAX8/PPARG (55% [CI 34–78%]), HRASQ61R (45% [CI 22–72%]), BRAFK601E (42% [CI 19–68%]), and NRASQ61R (38% [CI 23–55%]). Excluding BRAFV600E, the pooled PPV for all other specified variants and fusions was 47%. Multiple variants within the same nodule were identified in ∼1% of ITN and carried a cumulative PPV of 77%. Conclusions: The chance that a genomic alteration predicts malignancy depends on the individual variant or fusion detected. Only five alterations were reported at least 10 times; BRAFV600E had a PPV of 98%, while the remaining four had individual PPVs ranging from 38% to 55%. The small sample size of most variants and fusion pairs found among ITNs, however, limits confidence in their individual PPV point estimates. Better specific reporting of genomic alterations with cytological category, histological subtype, and cancer staging would facilitate better understanding of cancer prediction, and the independent contribution of the genomic profile to prognosis.

Background: Molecular testing (MT) is commonly used to refine cancer probability in thyroid nodules with indeterminate cytology. Whether or not ultrasound (US) patterns and clinical parameters can further inform the risk of thyroid cancer in nodules predicted to be positive or negative by MT remains unknown. The aim of this study was to test if clinical parameters, including patient age, sex, nodule size (by US), Bethesda category (III, IV, V), US pattern (American Thyroid Association [ATA] vs. American College of Radiology Thyroid Image Reporting and Data System [TI-RADS] systems), radiation exposure, or family history of thyroid cancer can modify the probability of thyroid cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) predicted by MT. Methods: We studied 257 thyroid nodules in 232 patients from 10 study centers with indeterminate fine needle aspiration cytology and informative MT results using the ThyroSeq v3 genomic classifier (TSv3). Univariate and multivariate logistic regression was used for data analysis. Results: The presence of cancer/NIFTP was associated with positive TSv3 results (odds ratio 61.39, p

Background: The approach for surgical treatment of patients with low-/intermediate-risk T1T2N0/Nx well-differentiated thyroid cancer (WDTC)—total thyroidectomy (TT) versus thyroid lobectomy (TL)—remains a controversial topic. Conducting a randomized controlled trial (RCT) would be the gold standard to address this issue. However, this is challenging due to excellent survival outcomes, and therefore, high number of patients and long-term follow-up would be required. As an alternative to RCT, we have used propensity score (PS) matching to determine if T1T2N0/Nx patients selected to have TL had equivalent outcomes to a similar group treated with TT. Methods: After institutional review board approval, a database of 6259 patients with WDTC treated with primary surgery at our institution between 1985 and 2016 was analyzed to identify patients with T1T2N0/Nx cancers. Of 3756 patients identified, 943 were managed by TL and 2813 by TT. To control for possible confounders and reduce potential bias, we selected age, sex, histology, (131)I therapy, American Thyroid Association risk, and American Joint Committee Cancer stage as our PS matching criteria. Subsequently, 918 TL patients were successfully matched with 918 TT patients. The Pearson χ(2) test or Fisher's exact test was used to compare categorical covariates, and Student's t-test was used for comparison of continuous variables between the two groups. Disease-specific survival (DSS), overall survival (OS), and recurrence-free survival (RFS) were calculated using the Kaplan–Meier method and compared using the log-rank test. Results: After PS matching, there were no significant differences between TL and TT patients for OS (10-year OS: 92.2% vs. 91.3%, p = 0.9668), DSS (10-year DSS: 100% vs. 99.1%, p = 0.1967), or RFS (10-year RFS: 99.5% vs. 98.3%, p = 0.079). Conclusions: For low-/intermediate-risk patients with intrathyroidal thyroid cancer

Background: Anaplastic thyroid cancer (ATC) is a rare cancer with poor prognosis and few treatment options. The objective of this study was to investigate new immune-associated therapeutic targets by identifying ATC-derived, human leukocyte antigen (HLA) class II-presenting peptides. One protein that generated multiple peptides in ATC was chondroitin sulfate-proteoglycan-4 (CSPG4), a transmembrane proteoglycan with increased expression in multiple aggressive cancers, but not yet investigated in ATC. Methods: We applied autologous peripheral blood T cells to ATC patient-derived xenografted mice to examine whether ATC induces a tumor-specific T cell response. We then identified peptide antigens eluted from the HLA-DQ complex in ATC patient-derived cells using mass spectrometry, detecting abundant CSPG4-derived peptides specific to the ATC sample. Next, we analyzed the surface expression level of CSPG4 in thyroid cancer cell lines and primary cell culture using flow cytometry. In addition, we used immunohistochemistry to compare the expression level and localization of the CSPG4 protein in ATC, papillary thyroid cancer, and normal thyroid tissue. We then investigated the correlation between CSPG4 expression and clinicopathological features of patients with thyroid cancer. Results: We found that ATC tissue had a high level of HLA-DQ expression and that the patient's CD4(+) T cells showed activation when exposed to ATC. By eluting the HLA-DQ complex of ATC tissue, we found that CSPG4 generated one of the most abundant and specific peptides. CSPG4 expression at the cell surface of thyroid cancer was also significantly high when determined by flow cytometry, with the majority of ATC cell lines exhibiting ∼10-fold higher mean fluorescence intensity. Furthermore, most ATC patient cases expressed CSPG4 in the cytoplasm or membrane of the tumor cells. CSPG4 expression was correlated with tumor size, extrathyroidal extension, and intercellular adhesion molecule-1 (ICAM-1) circumferential expression. CSPG4 mRNA overexpression was associated with worse overall survival in patients with ATC and poorly differentiated thyroid cancer. Conclusions: CSPG4 expression is significantly elevated in aggressive thyroid cancers, with a strong correlation with a poor prognosis. The vast number of HLA-DQ eluted CSPG4 peptides was identified in ATC, demonstrating the potential of CSPG4 as a novel immunotherapeutic target for ATC.

Background: The Afirma Gene Expression Classifier (GEC) has been used to further characterize cytologically indeterminate (cyto-I) thyroid nodules into either benign or suspicious categories. However, its relatively low positive predictive value (PPV) limited its use as a classifier for patients with suspicious results. The Afirma Gene Sequencing Classifier (GSC) was developed to improve PPV while maintaining a high negative predictive value (NPV), yet real-world assessment of its performance is lacking. Methods: We analyzed all patients who had cyto-I nodules and molecular testing with either GEC or GSC between 2011 and 2018 at a single academic medical center. Clinical information was obtained for 343 GEC-tested nodules and 164 GSC-tested nodules. Results: The GSC had a statistically significant higher benign call rate (76.2% vs. 48.1%, p

Background: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) is used to interpret fine-needle aspiration (FNA) cytology of thyroid nodules in children and adults. Nodule management is guided by the implied malignancy risk of each cytological category, which has been derived from adult populations. Whether these implied risks are applicable to pediatric thyroid nodules remains uncertain. We compared malignancy rates between pediatric and adult thyroid nodules within each cytological category. Methods: We evaluated consecutive thyroid nodules ≥1 cm that underwent FNA at the Boston Children's Hospital and Brigham and Women's Hospital from 1998 to 2016. All cytology was interpreted by a single cytopathology group according to the BSRTC. Malignancy rates were compared between pediatric (

Background: Thyroid cancer patients with radioiodine-refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. It was hypothesized that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment, and/or immune surveillance are associated with RAI-R disease. Methods: Whole-genome genotyping data analysis was performed on 1145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, nine of whom were RAI-R. Germline-variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (n = 7), who were later determined to be AA patients of >80% African ancestry (n = 37). This led to the study focusing on germline single nucleotide polymorphisms uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of the common somatic mutations BRAF(V600E), NRAS(Q61R), and HRAS(Q61R) in AA patients whose primary tumor samples were available (28/55). Results: TG, BRCA1, and NSMCE2 haplotypes were identified as being uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (n = 4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (n = 4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in three out of four patients with the NSMCE2 haplotype. The incidence of BRAF(V600E) appears lower in papillary thyroid carcinomas from AA patients of >80% African ancestry (3/14; 21%) than in AA patients of

Background: Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid cancer that requires a rapid diagnosis and treatment to achieve disease control. Gene mutation profiling of circulating cell-free DNA (cfDNA) in peripheral blood may help to facilitate early diagnosis and treatment selection. The relatively rapid turnaround time compared with conventional tumor mutation testing is a major advantage. The objectives of this study were to examine the concordance of ATC-related mutations detected in cfDNA with those detected in the corresponding tumor tissue, and to determine the prognostic significance of cfDNA mutations in ATC patients. Methods: The ATC patients who were diagnosed and treated at The University of Texas MD Anderson Cancer Center between January 2015 and February 2018 and who had cfDNA testing were included in this study. cfDNA was collected by blood draw and was analyzed by next-generation sequencing (NGS) using the Guardant360-73 gene platform. Results: A total of 87 patients were included in the study. The most frequently mutated genes detected in cfDNA were TP53, BRAF, and PIK3CA. In 28 treatment naive ATC patients, the concordance rate of detected mutations in TP53, BRAF(V600E), and PIK3CA between cfDNA and matched tissue NGS was 82.1%, 92.9%, and 92.9%, respectively. Patients with a PIK3CA mutation detected on cfDNA had worse overall survival (OS) (p = 0.03). This association was observed across various treatment modalities, including surgery, cytotoxic chemotherapy, radiation, and BRAF inhibitor (BRAFi) therapy. With regard to treatment, BRAFi therapy significantly improved ATC OS (p = 0.003). Conclusions: cfDNA is a valuable tool to evaluate a tumor's molecular profile in ATC patients. We identified high concordance rates between the gene mutations identified via cfDNA analysis and those identified from the NGS of the corresponding tumor tissue sequencing. Identified mutations in cfDNA can potentially provide timely information to guide treatment selection and evaluate the prognosis in patients with ATC.

Background: Molecular testing (MT) refines risk stratification for thyroid nodules that are indeterminate for cancer by fine needle aspiration (FNA) cytology. Criteria for selecting nodules for MT vary and remain largely untested, raising questions about the best strategy for maximizing the usefulness of MT while minimizing the harms of overtesting. We used a unique data set to examine the effects of repeat FNA cytology-based criteria for MT on management decisions and nodule outcomes. Methods: This was a study of adults (age 25–90 years; 281 women and 72 men) with cytologically indeterminate (Bethesda III/IV) thyroid nodules who underwent repeat FNA biopsy and Afirma Gene Expression Classifier (GEC) testing (N = 363 nodules from 353 patients) between June 2013 and October 2017 at a single institution, with follow-up data collected until December 2019. Subgroup analysis was performed based on classification of repeat FNA cytology. Outcomes of GEC testing, clinical/sonographic surveillance of unresected nodules, and histopathologic diagnoses of thyroidectomies were compared between three testing approaches: (i) Reflex (MT sent on the basis of the initial Bethesda III/IV FNA), (ii) SemiRestrictive (MT sent if repeat FNA is Bethesda I–IV), and (iii) Restrictive (MT sent only if repeat FNA is Bethesda III/IV) testing approaches. Results: Restricting MT to nodules that remain Bethesda III/IV on repeat FNA would have missed 4 low-risk cancers and 3 noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) (collectively 2% of the test population) but would have avoided diagnostic surgery for 42 benign nodules (12% of the test population). The Restrictive testing strategy was more specific (delta 0.126 confidence interval [CI 0.093 to 0.159] and 0.129 [CI 0.097 to 0.161], respectively) but less sensitive (delta −0.339 [CI −0.424 to −0.253] and −0.340 [CI −0.425 to −0.255], respectively) than the Reflex and SemiRestrictive approaches for detecting NIFTP or cancer. Conclusions: Repeat FNA cytology can guide the selection of cytologically indeterminate thyroid nodules that warrant MT. The Restrictive model of performing Afirma GEC only on nodules with two separate biopsies showing Bethesda III/IV cytology would reduce the rate of diagnostic surgery for histologically benign nodules while missing only rare low-risk tumors. Given the low but nontrivial risks of thyroidectomy, the higher specificity of the Restrictive testing approach disproportionately outweighs the potential harms.

Background: Incidence rates of thyroid cancer in children and young adults (age 0-19 years) have nearly doubled over a recent 15-year period in the United States. Children with thyroid cancer may require long-term therapy and surveillance and are at greater risk for second primary malignancies. High-dose exposure to ionizing radiation is the only known nongenetic risk factor; the vast majority of cases have an unknown etiology. Methods: We conducted a population-based nested case-control study to evaluate the relationship between a range of birth characteristics and the risk of pediatric thyroid cancer. Using linked birth records and cancer registry data from California, we included 1012 cases who were diagnosed with first primary thyroid cancer at the age of 0-19 years from 1988 to 2015 and 50,600 birth-year matched controls (1:50 case to control ratio). We estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) by using multivariable logistic regression models applied to the full population and stratified by thyroid cancer subtypes (papillary and follicular), race/ethnicity (white and Hispanic), and age at diagnosis (0-14 and 15-19 years). Results: Hispanic ethnicity (OR: 1.20 [CI 1.01-1.42]), higher birth weight (OR: 1.11 [CI 1.04-1.18] per 500g), and higher maternal education (13-15 years OR: 1.35 [CI 1.09-1.68], 16+ years OR: 1.35 [CI 1.07-1.71]) were associated with an increased risk of pediatric thyroid cancer, while male sex (OR: 0.21 [CI 0.18-0.25]) and higher birth order (third or higher OR: 0.81 [CI 0.68-0.98]) were associated with a decreased risk. Some heterogeneity was observed across subtype, most notably an elevated OR with higher birth order for follicular thyroid cancer, in contrast to the reduced risk for this category among papillary thyroid cancer cases (p-value for interaction = 0.01). Hispanic ethnicity was a risk factor for papillary, but not follicular thyroid cancer (p-value for interaction = 0.07). Conclusions: In this population-based study of birth characteristics and pediatric thyroid cancer, we identified several important risk factors for pediatric thyroid cancer, including female sex, Hispanic ethnicity, higher birth weight, higher maternal educational attainment, and lower birth order. Our data provide new areas for replication and investigation of biological mechanisms for this poorly understood malignancy.

Background: Current guidelines recommend against thyrotropin (TSH) suppression in low-risk differentiated thyroid cancer patients; however, physician practices remain underexplored. Our objective was to understand treating physicians' approach to TSH suppression in patients with papillary thyroid cancer. Methods: Endocrinologists and surgeons identified by thyroid cancer patients from the Surveillance, Epidemiology, and End Results registries of Georgia and Los Angeles were surveyed in 2018–2019. Physicians were asked to report how likely they were to recommend TSH suppression (i.e., TSH 40 patients per year, OR = 0.53 [CI 0.30–0.96]; OR = 0.49 [CI 0.24–0.99], respectively, compared with 0–20 patients per year). Physicians who estimated higher likelihood of recurrence were more likely to suppress TSH in a patient with very low-risk papillary thyroid cancer (OR = 2.34 [CI 1.91–4.59]). Conclusions: Many patients with low-risk thyroid cancer continue to be treated with suppressive doses of thyroid hormone, emphasizing the need for more high-quality research to guide thyroid cancer management, as well as better understanding of barriers that hinder guideline adoption.

Background: Understanding the impact of comorbidities and competing risks of death when caring for older adults with thyroid cancer is key for personalized management. The objective of this study was to determine whether older adults with thyroid cancer are more likely to die from thyroid cancer or other etiologies, and determine patient factors associated with each. Methods: The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify patients aged ≥66 years diagnosed with thyroid cancer (papillary, follicular, Hurthle cell, medullary, anaplastic, and other) between 2000 and 2015 (median follow-up, 50 months). We analyzed time to event (i.e., death from other causes or death from thyroid cancer) using cumulative incidence functions. Competing risk hazards regression was used to determine the association between patient (e.g., age at diagnosis and specific comorbidities) and tumor characteristics (e.g., SEER stage) with two competing mortality outcomes: death from other causes and death from thyroid cancer. Results: Of 21,509 patients with a median age of 72 years (range 66-106), 4168 (19.4%) died of other causes and 2644 (12.3%) died of thyroid cancer during the study period. For differentiated thyroid cancer patients, likelihood of dying from other causes exceeds likelihood of dying from thyroid cancer, whereas the opposite is true for anaplastic thyroid cancer. For medullary thyroid cancer, after 6.25 years patients are more likely to die from other etiologies than thyroid cancer. Using competing risks hazards regression, male sex (hazards ratio [HR] 1.47; 95% confidence interval [CI 1.37-1.57]), black race (HR 1.30; CI [1.16-1.46]), and comorbidities (e.g., heart disease, HR 1.34; CI [1.25-1.44]; chronic lower respiratory disease, HR 1.25; CI [1.17-1.34]) were associated with death from other causes. Tumor characteristics such as histology, tumor size, and stage correlated with death from thyroid cancer (e.g., distant SEER stage compared with localized, HR 12.65; CI [10.91-14.66]). Conclusions: The clinical context, including patients' specific comorbidities, should be considered when diagnosing and managing thyroid cancer. Our findings can be used to develop decision models that account for competing causes of death, as an aid for clinical decision making.

Background: RAS gene family mutations are the most prevalent in thyroid nodules with indeterminate cytology and are present in a wide spectrum of histological diagnoses. We evaluated differentially expressed genes and signaling pathways across the histological/clinical spectrum of RAS-mutant nodules to determine key molecular determinants associated with a high risk of malignancy. Methods: Sixty-one thyroid nodules with RAS mutations were identified. Based on the histological diagnosis and biological behavior, the nodules were grouped into five categories indicating their degree of malignancy: non-neoplastic appearance, benign neoplasm, indeterminate malignant potential, low-risk cancer, or high-risk cancer. Gene expression profiles of these nodules were determined using the NanoString PanCancer Pathways and IO 360 Panels, and Angiopoietin-2 level was determined by immunohistochemical staining. Results: The analysis of differentially expressed genes using the five categories as supervising parameters unearthed a significant correlation between the degree of malignancy and genes involved in cell cycle and apoptosis (BAX, CCNE2, CDKN2A, CDKN2B, CHEK1, E2F1, GSK3B, NFKB1, and PRKAR2A), PI3K pathway (CCNE2, CSF3, GSKB3, NFKB1, PPP2R2C, and SGK2), and stromal factors (ANGPT2 and DLL4). The expression of Angiopoietin-2 by immunohistochemistry also showed the same trend of increasing expression from non-neoplastic appearance to high-risk cancer (p

© Julia Ramírez-Moya and Pilar Santisteban, 2020., [Background]: DICER1 plays a central role in microRNA biogenesis and functions as a tumor suppressor in thyroid cancer, which is the most frequent endocrine malignancy with a rapidly increasing incidence. Thyroid cancer progression is associated with loss of cell differentiation and reduced expression of thyroid differentiation genes and response to thyrotropin (TSH). Here we investigated whether a molecular link exists between DICER1 and thyroid differentiation pathways. [Methods]: We used bioinformatic tools to search for transcription factor binding sites in the DICER1 promoter. DICER1, NKX2-1, PAX8, and CREB expression levels were evaluated by gene and protein expression in vitro and by interrogation of The Cancer Genome Atlas (TCGA) thyroid cancer data. Transcription factor binding and activity were assayed by chromatin immunoprecipitation, band-shift analysis, and promoter–reporter gene activity. Gene-silencing and overexpression approaches were used to elucidate the functional link between DICER1 and differentiation. [Results]: We identified binding sites for NKX2-1 and CREB within the DICER1 promoter and found that both transcription factors are functional in thyroid cells. TSH induced DICER1 expression in differentiated thyroid cells, at least in part, through the cAMP/PKA/CREB pathway. TCGA analysis revealed a significant positive correlation between CREB and DICER1 expression in human thyroid tumors. NKX2-1 overexpression increased DICER1 promoter activity and expression in vitro, and this was significantly greater in the presence of CREB and/or PAX8. Gain- and loss-of-function assays revealed that DICER1 regulates NKX2-1 expression in thyroid tumor cells and vice versa, thus establishing a positive feedback loop between both proteins. We also found a positive correlation between NKX2-1 and DICER1 expression in human thyroid tumors. DICER1 silencing decreased PAX8 expression and, importantly, the expression and activity of the sodium iodide symporter, which is essential for the diagnostic and therapeutic use of radioiodine in thyroid cancer. [Conclusions]: The differentiation transcription factors NKX2.1, PAX8, and CREB act in a positive feedback loop with DICER1. As the expression of these transcription factors is markedly diminished in thyroid cancer, our findings suggest that DICER1 downregulation in this cancer is mediated, at least partly, through impairment of its transcription., This work was supported by grants SAF2016-75531-R, Fondo Europeo de Desarrollo Regional, and PID2019-1053 03RB-I00/AEI/10.13039/501100011033 from Ministerio de Ciencia e Innovacio´n (MICIN), Spain, B2017/BMD-3724 from Comunidad de Madrid, and GCB14142311CRES from Fundacio´n Espan˜ola Contra el Ca´ncer (AECC). J.R.-M. holds an FPU fellowship from MECD (Spain).

Background: We examined the changes in glucose metabolites of papillary thyroid cancer (PTC) and identified phosphoglycerate dehydrogenase (PHGDH) as a potential target. The role of PHGDH in the proliferation and tumorigenesis of thyroid cancer cells and its clinical significance were analyzed. Methods: Glucose metabolites of various thyroid tissues were analyzed via targeted metabolomics analysis. In vitro experiments using shPHGDHs, inhibitor (NCT503), or PHGDH overexpression in thyroid cell lines (BCPAP, 8505C, and Nthy-Ori) were performed. In vivo experiments were performed by using shPHGDH. Human tissue samples and The Cancer Genome Atlas (TCGA) data were used to validate the experimental findings. Results: PHGDH knockdown in BCPAP and 8505c cell lines significantly inhibited cell viability, colony formation, and tumor spheroid formation compared with the control. In addition, treatment with NCT503 showed similar results. PHGDH inhibition by both knockdown and treatment with NCT503 significantly inhibited the expression of embryonic cancer stemness markers (Oct4, Sox2, KLF4, and Nanog). PHGDH overexpression in Nthy-Ori cells significantly increased cell viability and colony formation. The stemness markers were significantly increased after PHGDH overexpression. PHGDH knockdown significantly inhibited tumor growth in an in vivo mouse xenograft study using 8505c cells. The protein expression of Oct4 in tumors was significantly reduced after PHGDH knockdown. The associations between PHGDH expression and stemness markers were confirmed in the TCGA data and human thyroid tissue samples. Positive PHGDH protein expression was associated with metastases of PTC. Conclusions: PHGDH expression is induced in thyroid cancer and is associated with stemness and aggressiveness of PTC.

Introduction: Little is known about the experiences and concerns of patients recently diagnosed with thyroid cancer or an indeterminate thyroid nodule. This study sought to explore patients' reactions to diagnosis with papillary thyroid cancer (PTC) or indeterminate cytology on fine needle aspiration. Methods: We conducted semistructured interviews with 85 patients with recently diagnosed PTC or an indeterminate thyroid nodule before undergoing thyroidectomy. We included adults with nodules ≥1 cm and Bethesda III, IV, V, and VI cytology. The analysis utilized grounded theory methodology to create a conceptual model of patient reactions. Results: After diagnosis, participants experienced shock, anxiety, fear, and a strong need to “get it out” because “it's cancer!” This response was frequently followed by a sense of urgency to “get it done,” which made waiting for surgery difficult. These reactions occurred regardless of whether participants had confirmed PTC or indeterminate cytology. Participants described the wait between diagnosis and surgery as difficult, because the cancer or nodule was “still sitting there” and “could be spreading.” Participants often viewed surgery and getting the cancer out as a “fix” that would resolve their fears and worries, returning them to normalcy. The need to “get it out” also led some participants to minimize the risk of complications or adverse outcomes. Education about the slow-growing nature of PTC reassured some, but not all patients. Conclusions: After diagnosis with PTC or an indeterminate thyroid nodule, many patients have strong emotional reactions and an impulse to “get it out” elicited by the word “cancer.” This reaction can persist even after receiving education about the excellent prognosis. Understanding patients' response to diagnosis is critical, because their emotional reactions likely pose a barrier to implementing guidelines recommending less extensive management for PTC.

Background: The BRAF(V600E) mutation is the most common driver mutation in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC). This mutation is considered actionable and, for BRAF(V600E)-mutated ATC, a BRAF inhibitor (dabrafenib) in combination with an MEK inhibitor (trametinib) is FDA approved. BRAF inhibitors have also shown efficacy in BRAF(V600E)-mutated PTC. However, as with all targeted therapies, resistance to these drugs eventually develops. It is essential that we understand the mechanisms of resistance to the BRAF inhibitors in thyroid cancer to develop future strategies to effectively treat these patients and improve survival. Patients: Herein, we describe four patients with thyroid cancer treated with selective BRAF inhibitors, who developed a RAS mutation in addition to the BRAF(V600E) mutation at progression. Results: Patients 1 and 3 acquired a KRAS(G12V) mutation in the progressive tumor, patient 2 acquired a NRAS(Q61K) mutation in a progressive lymph node, and patient 4 acquired NRAS(G13D) mutation on liquid biopsy performed at the time of radiographic disease progression. Conclusion: Similar to the melanoma experience, the emergence of RAS mutations appears to act as a mechanism of resistance to BRAF inhibitors in thyroid cancers.

Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease 30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6–50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: −86.8%; interquartile range [IQR]: −90.7% to −70.9%) compared with the 28 who did not (median: −69.0%; IQR: −78.1% to −27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (−23.5% [CI: −55.3 to 8.3]; Fisher's exact test p-value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.

Background: Despite advances in targeted kinase inhibitor development for patients with medullary thyroid cancer (MTC), most patients develop resistance and would benefit from alternative approaches. Immune-based therapies are now considered for patients with progressive MTC. This study is the first comprehensive assessment of the immune milieu, immune-suppressive molecules, and potential tumor antigens in patients with MTC. Methods: Primary and/or regionally metastatic tumor tissues from 46 patients with MTC were screened for immune infiltrates by using standard immunohistochemistry (IHC) and further analyzed by multispectral imaging for T cell and myeloid markers. RNASeq expression profiling was performed in parallel. RNASeq, targeted sequencing, and IHC techniques identified cancer-associated mutations and MTC-enriched proteins. Results: Organized immune infiltration was observed in 49% and 90% of primary and metastatic tumors, respectively. CD8(+) cells were the dominant T cell subtype in most samples, while CD163(+) macrophages were most frequent among myeloid infiltrates. PD-1(+) T cells were evident in 24% of patients. Myeloid subsets were largely major histocompatibility complex II (MHCII(−)), suggesting a dysfunctional phenotype. Expression profiling confirmed enrichment in T cell, macrophage, and inflammatory profiles in a subset of samples. PD-L1 was expressed at low levels in a small subset of patients, while the immune regulatory molecules CD155 and CD47 were broadly expressed. Calcitonin, GRP, HIST1H4E, NOMO3, and NPIPA2 were highly and specifically expressed in MTC. Mutations in tumor suppressors, PTEN and p53, and mismatch repair genes, MSH2 and MSH6, may be relevant to disease progression and antigenicity. Conclusions: This study suggests that MTC is a more immunologically active tumor that has been previously reported. Patients with advanced MTC should be screened for targetable antigens and immune checkpoints to determine their eligibility for current clinical trials. Additional studies are necessary to fully characterize the antigenic potential of MTC and may encourage the development of adoptive T cells therapies for this rare tumor.

Background: The association between thyroid disorders and breast cancer remains controversial, in part, due to small cohort sizes and inconsistent findings. We investigated this association in postmenopausal women to determine whether hyper- or hypothyroidism is associated with the risk of developing breast cancer and to determine whether menopausal hormone therapy (MHT) further modifies the risk. Methods: We conducted a prospective cohort study of multiethnic U.S. postmenopausal women aged 50 to 79 years enrolled in both clinical trial and observational study arms between 1993 and 1998 and followed up through February 28, 2017. Development of invasive breast cancer after enrollment was recorded and a history of hyper- or hypothyroidism before the diagnosis of breast cancer was identified. The effect modification by MHT in both study arms was analyzed. All statistical tests were two sided. Results: Among a total of 134,122 women who were included in our study, 8137 participants developed invasive breast cancer during the follow-up period. There was a significant inverse association of invasive breast cancer among women with a history of hypothyroidism (hazard ratio [HR] 0.91, confidence interval [95% CI] 0.86–0.97) and among women who had taken levothyroxine [HR 0.89, 95% CI 0.82–0.96]. Evaluating effect modification by MHT use, the inverse association between hypothyroidism treated with thyroid replacement medications and breast cancer risk was strongest in non-MHT users [HR 0.80, 95% CI 0.69–0.93]. The results did not significantly differ by race/ethnicity. Although a history of hyperthyroidism was associated with an increased risk of invasive breast cancer [HR 1.11, 95% CI 0.91–1.35], this finding did not reach statistical significance. We did not see significant differences in the breast cancer Surveillance, Epidemiology, and End Results stages, histologic types, morphologic grades, or receptor status (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) according to thyroid disorder status. Conclusions: Compared with women with no history of thyroid disorder, hypothyroidism was associated with a lower risk of breast cancer. This was mainly seen among those who received thyroid replacement therapy and had never used MHT. Among the treatment options for hypothyroidism, levothyroxine had the strongest inverse association with breast cancer risk.

Background: Whether radiation-induced thyroid cancer affects survival rates has not been clearly elucidated. Survival could be affected by the thyroid cancer itself, its treatment, or by being a sign of susceptibility to other cancers. The objective of the current study was to determine if the development of thyroid cancer is associated with a differential survival in radiation-exposed individuals. Methods: We conducted a matched prospective cohort mortality follow-up study based on data from a cohort of 4296 individuals who were irradiated predominantly for enlarged tonsils during their childhood (between 1939 and 1962) and were prospectively followed since 1974. The study matched an irradiated subject who developed (was exposed to) thyroid cancer (a “case”) and two irradiated subjects, who had not developed (were not exposed to) thyroid cancer (“controls”) by the time of case incidence. The two controls were randomly matched to cases by sex, year of birth, age at radiation treatment, and radiation dose. Then, using a stratified Cox analysis, we compared survival time from the date of thyroid cancer diagnosis or time of selection to either date of death or the end of the observation period (December 31, 2016). Vital status and causes of death were determined using the National Death Index (1979–2016), the Social Security Death Index (1974–1979), and study files. Cause of death was categorized as cardiovascular, malignancy, or other. Results: A total of 1008 subjects were included in the analysis, including 353 thyroid cancer cases. At the end of the study period, 162 of 655 (24.7%) of individuals without thyroid cancer had died compared with 100 of 353 (28.3%) of the subjects with thyroid cancer. The hazard ratio (HR) for all-cause mortality, comparing the thyroid cancer cases to controls, was close to unity (HR = 1.01 [0.77–1.33]). HRs remained insignificant after eliminating matched sets with microcarcinomas, defined as tumor size

Background: Thyroid nodules are routinely evaluated with ultrasound. Our aim was to determine if thyroid nodule location was a useful feature to predict thyroid cancer. Materials and Methods: Retrospective review of patients with thyroid nodules from six referral centers from 2006 to 2010. A total of 3313 adult patients with thyroid nodules and confirmed benign or malignant thyroid diagnoses were included. Results: Mean patient age was 54.2 (18–97) years, and the majority were women (n = 2635, 79.8%). A total of 3241 nodules were analyzed, 335 (10.3%) of which were malignant. Thyroid nodule location was an independent risk factor in predicting thyroid cancer (p = 0.005). Thyroid cancer odds were highest in the isthmus (odds ratio [OR] = 2.4, 95% confidence interval [CI] 1.6–3.6, p

Background: Hurthle cell/oncocytic change is commonly reported on thyroid fine-needle aspiration (FNA) and may be considered an "atypical cell" by clinicians. This study aims to delineate the association between Hurthle cells in preoperative cytology and subsequent pathology of the indexed thyroid nodule and to report rates of malignancy. Methods: Retrospective review of records of 300 patients with Hurthle cell/oncocytic change on FNA and final surgical pathology at a tertiary referral center between 2000 and 2013 was performed and compared with a multi-institutional FNA cohort. The degree of Hurthle cell presence was correlated with histopathologic diagnoses. Results: In the Hurthle cell FNA group, Bethesda System for Reporting Thyroid Cytopathology (BSRTC) categories were as follows: I (nondiagnostic) 14 (4.7%); II (benign) 113 (37.7%); III (atypia of undetermined significance/follicular lesion of undetermined significance) 33 (11%); IV (follicular neoplasm/suspicious for a follicular neoplasm) 125 (41.6%); V (suspicious for malignancy) 12 (4%); and VI (malignant) 3 (1%). When categorized based on the degree of Hurthle cell change, 59 (29%) were classified as mild, 13 (6%) moderate, and 131 (65%) as predominant. When comparing the results with a multi-institutional FNA cohort (all with surgical confirmation), the presence of Hurthle cells was found to be associated with a lower risk of malignancy in all BSRTC categories, with a statistically significant difference in the BSRTC IV and V groups. The sole exception was when Hurthle cell presence was classified as predominant (defined as >75% of the cellular population); the rate of malignancy was significantly elevated in FNAs interpreted as benign/Bethesda II. Conclusions: Although Hurthle cells have been considered by clinicians as an "atypical cell," their presence does not increase the risk of malignancy within BSRTC categories overall. However, when predominant Hurthle cell change is present, the risk of malignancy is increased in the benign cytology/BSRTC category II.

Background: Although most thyroid nodules with indeterminate cytology are benign, in most of the world, surgery remains as the most frequent diagnostic approach. We have previously reported a 10-gene thyroid genetic classifier, which accurately predicts benign thyroid nodules. The assay is a prototype diagnostic kit suitable for reference laboratory testing and could potentially avoid unnecessary diagnostic surgery in patients with indeterminate thyroid cytology. Methods: Classifier performance was tested in two independent, ethnically diverse, prospective multicenter trials (TGCT-1/Chile and TGCT-2/USA). A total of 4061 fine-needle aspirations were collected from 15 institutions, of which 897 (22%) were called indeterminate. The clinical site was blind to the classifier score and the clinical laboratory blind to the pathology report. A matched surgical pathology and valid classifier score was available for 270 samples. Results: Cohorts showed significant differences, including (i) clinical site patient source (academic, 43% and 97% for TGCT-1 and -2, respectively); (ii) ethnic diversity, with a greater proportion of the Hispanic population (40% vs. 3%) for TGCT-1 and a greater proportion of African American (11% vs. 0%) and Asian (10% vs. 1%) populations for TGCT-2; and (iii) tumor size (mean of 1.7 and 2.5 cm for TGCT-1 and -2, respectively). Overall, there were no differences in the histopathological profile between cohorts. Forty-one of 155 and 45 of 115 nodules were malignant (cancer prevalence of 26% and 39% for TGCT-1 and -2, respectively). The classifier predicted 37 of 41 and 41 of 45 malignant nodules, yielding a sensitivity of 90% [95% confidence interval; CI 77–97] and 91% [95% CI 79–98] for TGCT-1 and -2, respectively. One hundred one of 114 and 61 of 70 nodules were correctly predicted as benign, yielding a specificity of 89% [95% CI 82–94] and 87% [95% CI 77–94], respectively. The negative predictive values for TGCT-1 and TGCT-2 were 96% and 94%, respectively, whereas the positive predictive values were 74% and 82%, respectively. The overall accuracy for both cohorts was 89%. Conclusions: Clinical validation of the classifier demonstrates equivalent performance in two independent and ethnically diverse cohorts, accurately predicting benign thyroid nodules that can undergo surveillance as an alternative to diagnostic surgery.

Background: Thyroid cancer is an emerging health problem in the United States and worldwide. With incidence rates of thyroid cancer rapidly rising, the need to develop new treatment options is becoming a priority, and understanding the molecular mechanisms of this disease is crucial to furthering these efforts. Thyroid growth is driven by the TSH/cAMP/PKA signaling pathway, and it has previously been shown that activation of PKA through genetic ablation of the regulatory subunit Prkar1a (Prkar1a KO) is sufficient to cause follicular thyroid cancer in mouse models. cAMP also activates the Epac proteins and their downstream effectors, Rap1a and Rap1b. Methods: Previously, the authors' laboratory generated a mouse model of follicular thyroid cancer by conferring thyroid-specific deletion of Prkar1a (R1a-TpoKO). To probe the roles of other components of the PKA signaling system in the development of thyroid cancer, this study deleted Rap1 and Epac1 in the setting of the Prkar1a knockout. Results: Deletion of Rap1 significantly decreases thyroid size and cancer incidence in Prkar1a KO thyroids. Further, isoform-specific ablation of Rap1a and Rap1b implicates Rap1b as the downstream effector of PKA during thyroid carcinogenesis. In vivo modeling provides definitive evidence that Epac1 plays little role in thyroid proliferation and is dispensable for thyroid carcinogenesis arising from the deletion of Prkar1a. Conclusions: This study demonstrate that PKA signaling to Rap1b is a key signaling node for follicular thyroid carcinogenesis, while Epac1 activity is not required for tumor development. This work sheds new light on the pathways involved in FTC development and identifies a possible target for the development of new therapies in the treatment of FTC.

Background: Differentiated thyroid cancer typically has an indolent clinical course but can cause significant morbidity by local progression. Oncologic surgical resection can be technically difficult due to the proximity to critical normal structures in the neck. Our objective was to review the safety, feasibility, and outcomes of definitive-intent intensity-modulated radiation therapy (IMRT) and to analyze whether patients receiving concurrent chemotherapy (CC-IMRT) had higher rates of disease control and survival over IMRT alone in patients with unresectable or gross residual disease (GRD).Methods: Eighty-eight patients with GRD or unresectable nonanaplastic, nonmedullary thyroid cancer treated with definitive-intent IMRT between 2000 and 2015 were identified. Local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and overall survival (OS) were evaluated using the Kaplan-Meier method. Univariate and multivariate analyses using cox regression were used to determine the impact of clinical conditions and treatment on LPFS, DMFS, and OS.Results: Of the 88 patients identified, 45 (51.1%) were treated CC-IMRT and 43 (48.9%) were treated with IMRT alone. All patients treated with CC-IMRT received weekly doxorubicin (10 mg/m(2)). The median followup among surviving patients was 40.3 months and 29.2 months for all patients. The LPFS at 4 years was 77.3%. Patients receiving CC-IMRT had higher LPFS compared with IMRT alone (CC-IMRT 85.8% vs. IMRT 68.8%, p = 0.036). The 4-year OS was 56.3% for all patients. Patients treated with CC-IMRT had higher OS compared to patients treated with IMRT alone (CC-IMRT 68.0% vs. IMRT 47.0%, p = 0.043). On multivariate analysis, receipt of concurrent chemotherapy was associated with a lower risk of death (HR 0.395, p = 0.019) and lower risk of local failure (HR 0.306, p = 0.042). Grade 3+ acute toxicities occurred in 23.9% of patients, the most frequent being dermatitis (18.2%) and mucositis (9.1%). 17.1% of patients required a percutaneous endoscopic gastrostomy (PEG) tube during or shortly after completion of RT, with 10.1% of patients needing a PEG more than 12 months after therapy. The rates of acute and late toxicities were not statistically higher in the CC-IMRT cohort, although trends towards higher toxicity in the CC-IMRT were present for dermatitis and PEG requirement.Conclusions: IMRT is a safe and effective means to achieve local control in patients with unresectable or incompletely resected nonanaplastic, nonmedullary thyroid cancer. Concurrent doxorubicin was not associated with worse toxicity and should be considered in these patients given its potential to improve local control and overall survival.

Background: Rates of adverse events with sorafenib were higher in the DECISION trial in radioactive iodine-refractory, advanced differentiated thyroid cancer (DTC) than in trials of sorafenib for other tumor types. One possible explanation is that sarcopenia, a known predictive factor of toxicity in patients with cancer, is more common in patients with DTC due to hormone suppressive therapy. Methods: This retrospective exploratory analysis was performed to assess whether the risk of early toxicity leading to dose modification (DMT) with sorafenib was higher in patients with sarcopenia compared with those without sarcopenia. The data set comprised patients from the phase III DECISION trial with a computed tomography scan available to determine muscle mass. The skeletal muscle (SM) cross-sectional area was used to determine the SM index and define sarcopenia. The end points were changes in body composition, DMT, early DMT (within 1 month), severe toxic events (STEs), and early STEs. Results: Overall, 365 patients were eligible for this analysis; baseline characteristics were well balanced between patients receiving sorafenib (n = 180) versus placebo (n = 185). Using a sarcopenia definition of an SM index less than the median sex-specific SM index, approximately half of the patients receiving sorafenib were at risk of sarcopenia (89/180; 49.4%), with wide geographical variation. At 6 months, the mean weight, body mass index, and lean body mass of patients receiving sorafenib were lower than at baseline and significantly lower than for patients receiving placebo (all p

Background: The extent of initial surgical resection for low-risk papillary thyroid cancer (PTC) remains debatable. Since the 2015 American Thyroid Association (ATA) guidelines, several retrospective studies have reported that 40-60% of patients initially treated with lobectomy would require a completion thyroidectomy (CTx) due to high-risk pathological features (HRFs). These studies are limited by variable preoperative stratification and inability to quantify the value of intraoperative assessment. The study objectives were to determine whether diligent preoperative and intraoperative assessment improves the appropriateness of initial surgery for low-risk PTCs and whether varying the criteria for lobectomy reduces the need for CTx. Methods: A prospectively collected province-wide database was analyzed over a 10-year period (2008-2017) for patients who underwent a total thyroidectomy (TT) for PTC without preoperative HRFs. All patients had preoperative ultrasound and fine-needle aspirates. Unique to this database are mandatory synoptic operative fields that identify intraoperative risk factors such as positive lymph nodes and local invasion. Results: In total, 74% of patients (709/959) were deemed eligible for lobectomy. Of those eligible, 149 (21%) had intraoperative risk factors that would necessitate conversion to TT at the initial operation. A further 209 (30%) would require CTx due to HRFs on final pathology. Varying the preoperative criteria for lobectomy did not significantly affect intraoperative conversion or CTx rates. Conclusions: Although intraoperative assessment reduced the need for CTx in 21%, up to 30% of patients would still require a second operation. Altering the preoperative criteria does not influence this outcome. Patients deemed eligible for lobectomy should be informed that despite careful pre- and intraoperative assessment, there is up to a 30% risk of requiring CTx.

Background: The BRAF(V600E) mutation is the most common driver in papillary thyroid carcinoma (PTC) tumors. In recent years, gene fusions have also been recognized as important drivers of cancer in PTC. Previous studies have suggested that thyroid tumors with fusion genes frequently display an aggressive course. These observations prompted further exploration of gene fusions in PTC tumors. The aim was to search for previously unrecognized gene fusions using thyroid tissue samples from PTC patients. Methods: Gene fusions were analyzed in RNA sequencing data obtained from 12 PTC tumors and paired unaffected thyroid tissue samples. Candidate fusions were further filtered and validated using reverse transcriptase polymerase chain reaction, Sanger sequencing, and fluorescence in situ hybridization. An Ohio cohort of 148 PTC tumor samples was screened for a LMO7–BRAF fusion and the BRAF(V600E) mutation. Functional assays were performed to assess the LMO7–BRAF fusion. Results: Two coding fusions (CCDC6–RET and LMO7–BRAF) were found in one tumor sample each. The novel LMO7–BRAF fusion was validated by reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization. The LMO7–BRAF fusion was a recurrent somatic alteration with a frequency of 2.0% (3/148) in PTC tumors, while the BRAF(V600E) point mutation was found in 63.5% (94/148) of tumors. Enforced expression of LMO7–BRAF fusion protein stimulated endogenous ERK1/2 phosphorylation and promoted anchorage independent cell growth to an extent similar to BRAF(V600E). Conclusions: A novel fusion gene, LMO7-BRAF, was identified in PTC tumors. The results indicate that the LMO7–BRAF fusion behaves as an oncogenic alteration. This observation expands the spectrum of fusion genes involving kinases in thyroid cancer.

Background: Indeterminate categories of thyroid cytopathology (categories B-III and B-IV of the Bethesda system) are integrated by a heterogeneous spectrum of cytological scenarios that are generally clustered for analysis and management recommendations. It has been suggested that aspirates exhibiting nuclear atypia have a higher risk of malignancy. This study aimed to assess whether cytologically indeterminate thyroid nodules with nuclear atypia have a significantly higher cancer risk than those without nuclear atypia. Methods: On June 30, 2016, PubMed and EMBASE were searched for articles in English or Spanish using a search strategy developed by an endocrinologist and a librarian. Case reports were excluded, and no date limits were used. The references of all included studies were also screened for relevant missing studies. Studies were included if the prevalences of malignancy of cytologically indeterminate thyroid nodules with histological confirmation with and without nuclear atypia were reported. Studies were excluded if they had: (i) nodules suspicious for malignancy; (ii) nodules with non-indeterminate (B-III or B-IV) cytology on repeated biopsy, if performed; (iii) nodules not consecutively evaluated; or (iv) cohorts overlapping with another larger series. Two investigators independently assessed the eligibility and risk of bias of the studies. PRISMA and MOOSE guidelines were followed. Summary data were extracted from published reports by one investigator and independently reviewed by another. Data were pooled using a random-effects model. Heterogeneity was explored using subgroup analysis and mixed-effect model meta-regression. The odds ratio for malignancy of cytologically indeterminate thyroid nodules with nuclear atypia over cytologically indeterminate thyroid nodules without nuclear atypia was calculated. Results: Of 2571 retrieved studies, 20 were eligible. The meta-analysis was conducted on summary data of 3532 cytologically indeterminate thyroid nodules: 1162 with and 2370 without nuclear atypia. The odds ratio for malignancy in cytologically indeterminate thyroid nodules with nuclear atypia was 3.63 [confidence interval 3.06–4.35]. There was no evidence of publication bias, and heterogeneity was insignificant (I(2) < 0.01%, p = 0.40). Conclusions: Nuclear atypia is a significant indicator of malignancy in cytologically indeterminate thyroid nodules and needs to be standardized and implemented into clinical practice.

Background: This study aims to compare the seventh and eighth editions of the American Joint Commission on Cancer/Union for International Cancer Control (AJCC/UICC) tumor, node, metastasis staging system for patients with papillary thyroid cancer (PTC) in two national patient cohorts. Methods: Adult PTC patients undergoing surgery were selected from the Surveillance, Epidemiology and End Results (SEER) program (2004–2012) and the National Cancer Database (2004–2012). Staging criteria for the seventh and eighth AJCC/UICC editions were applied separately to each cohort. Survival probabilities were estimated using the Kaplan–Meier method. Multivariable Cox proportional hazards models were used to estimate the association of stage with survival in both settings. The Akaike information criterion was used to assess model performance. Results: About 23% of patients were downstaged from the seventh to the eighth edition in SEER, while 24% were downstaged in the National Cancer Database. Disease-specific survival (DSS) and overall survival (OS) were significantly related to stage at diagnosis when using both the seventh and eighth editions of the AJCC/UICC staging system (p

Management recommendations for thyroid nodules rely primarily on the cytological diagnosis. However, 25% of biopsies render an indeterminate cytology for which management decision is more challenging due to heterogeneity of the specimens. This study aimed to stratify the cancer risk through subcategorization of indeterminate cytology.The indeterminate cytological specimens (Bethesda-III or IV) of 518 thyroid nodules consecutively evaluated at our academic cancer center between October 2008 and September 2015, blinded to the histological outcome, were retrospectively reviewed. Cytological specimens were subclassified into four groups: aspirates exhibiting nuclear atypia (n = 158; 31%); architectural atypia (n = 222; 43%); oncocytic features (n = 120; 23%); or other types of atypia (n = 18; 3%). The prevalence of malignancy and odds ratio for malignancy were calculated in 323 nodules with histological confirmation.The prevalence of malignancy was 26% overall (20% in Bethesda-III and 29% in Bethesda-IV; p = 0.07), and 47%, 12%, 24%, and 25% for aspirates with nuclear atypia, architectural atypia, oncocytic features, or other types of atypia, respectively. The OR of nuclear atypia over architectural atypia was 6.4 (3.4-12.2; p 0.001), and 2.7 over oncocytic features (1.4-5.1; p = 0.01), whereas the OR of architectural atypia over oncocytic features was 0.4 (0.2-0.9; p = 0.03). Results were similar for Bethesda-III and IV aspirates when analyzed independently. Furthermore, cytological subcategories improved cytology-histology correlation, as they were associated with distinct profiles of histological diagnoses (p 0.001).Cytological subcategories can effectively stratify the risk of malignancy of thyroid nodules with indeterminate cytology and improve cytology-histology correlation.

Background: Therapeutic options for treating advanced or metastatic medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma (ATC) are still limited in Japan, even though vandetanib for MTC and lenvatinib for MTC and ATC have been approved. Sorafenib is an oral multikinase inhibitor approved for the treatment of patients with radioactive iodine-refractory differentiated thyroid cancer (DTC). An uncontrolled, open-label, multicenter, single-arm, Phase 2 clinical study was conducted to evaluate the safety and efficacy of sorafenib in Japanese patients with MTC and ATC. Methods: Japanese patients with histologically confirmed ATC and locally advanced or metastatic MTC were enrolled from April to September 2014. The primary endpoint was to evaluate the safety of sorafenib. Treatment efficacy variables including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and maximum reduction in tumor size were evaluated as secondary endpoints. Patients received sorafenib 400 mg orally twice daily on a continuous basis and then continued treatment until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent. Results: A total of 20 patients were screened, and 18 (8 with MTC and 10 with ATC) were enrolled. The most common drug-related adverse events were palmar-plantar erythrodysesthesia (72%), alopecia (56%), hypertension (56%), and diarrhea (44%). In the ATC patients, median PFS was 2.8 months [confidence interval 0.7–5.6], and median OS was 5.0 months [confidence interval 0.7–5.7]; ORR and DCR were 0% and 40%, respectively. In the MTC population, neither median PFS nor OS had been reached at the time of this analysis; ORR was 25% and DCR was 75%. Conclusions: The toxicities reported in this study were consistent with the known safety profile of sorafenib. Sorafenib seems to be effective in the treatment of advanced MTC but not ATC, and could be a new treatment option for locally advanced or metastatic MTC and radioactive iodine-refractory DTC.

Background: While there is a clear consensus for defining radioiodine-refractory differentiated thyroid cancer (RR-DTC), it is unknown whether these criteria are equally valid for determining when radioiodine (RAI) therapy is no longer beneficial and systemic treatment should be considered. Lenvatinib, a multikinase inhibitor, significantly prolonged progression-free survival (PFS) compared to placebo in a Phase 3 trial in RR-DTC (SELECT; hazard ratio [HR]: 0.21 [99% confidence interval (CI) 0.14-0.31]; p < 0.001). This sub-analysis compared clinical outcomes of lenvatinib-treated patients in SELECT stratified by RR-DTC inclusion criteria. Methods: In SELECT, patients with measurable RR-DTC and radiologic evidence of disease progression ≤13 months prior to study entry were randomized 2:1 to lenvatinib (24 mg/day; 28-day cycle) or placebo. In this analysis, patients were stratified based on the following RR-DTC inclusion criteria: no RAI uptake, disease progression within 12 months of RAI therapy despite RAI avidity at the time of treatment, and extensive (>600 mCi) cumulative RAI exposure. All had disease progression as an inclusion criterion for SELECT. Results: Of 392 patients (261 lenvatinib; 131 placebo) enrolled, 275, 235, and 73 patients met the inclusion criteria for no RAI uptake, disease progression despite RAI avidity, and extensive RAI exposure, respectively. There was significant overlap between the patient groups, with 167 (42.6%) patients meeting more than one inclusion criterion. Lenvatinib improved median PFS compared to placebo in all groups ("no RAI uptake": lenvatinib not quantifiable [NQ; CI 14.8-NQ] vs. placebo, 3.7 months [CI 2.5-5.3]; "disease progression despite RAI avidity": lenvatinib 16.5 months [CI 12.8-NQ] vs. placebo, 3.7 months [CI 1.9-5.4]; "extensive RAI exposure": lenvatinib 18.7 months [CI 10.7-NQ] vs. placebo, 3.6 months [CI 1.9-5.5]). Objective response rates were 71.8%, 60.0%, and 56.0% for patients with no RAI uptake, disease progression despite RAI avidity, and extensive RAI exposure, respectively. Lenvatinib-related adverse events were similar across groups. Conclusions: Comparable efficacy and safety profiles were observed in lenvatinib-treated patients regardless of RR-DTC criteria, possibly because of a large overlap among patients fulfilling each criterion. However, differing definitions for RR-DTC may be equally valid because both lenvatinib and placebo arms exhibited similar PFS outcomes across groups.

Background: In most of the world, diagnostic surgery remains the most frequent approach for indeterminate thyroid cytology. Although several molecular tests are available for testing in centralized commercial laboratories in the United States, there are no available kits for local laboratory testing. The aim of this study was to develop a prototype in vitro diagnostic (IVD) gene classifier for the further characterization of nodules with an indeterminate thyroid cytology. Methods: In a first stage, the expression of 18 genes was determined by quantitative polymerase chain reaction (qPCR) in a broad histopathological spectrum of 114 fresh-tissue biopsies. Expression data were used to train several classifiers by supervised machine learning approaches. Classifiers were tested in an independent set of 139 samples. In a second stage, the best classifier was chosen as a model to develop a multiplexed-qPCR IVD prototype assay, which was tested in a prospective multicenter cohort of fine-needle aspiration biopsies. Results: In tissue biopsies, the best classifier, using only 10 genes, reached an optimal and consistent performance in the ninefold cross-validated testing set (sensitivity 93% and specificity 81%). In the multicenter cohort of fine-needle aspiration biopsy samples, the 10-gene signature, built into a multiplexed-qPCR IVD prototype, showed an area under the curve of 0.97, a positive predictive value of 78%, and a negative predictive value of 98%. By Bayes' theorem, the IVD prototype is expected to achieve a positive predictive value of 64–82% and a negative predictive value of 97–99% in patients with a cancer prevalence range of 20–40%. Conclusions: A new multiplexed-qPCR IVD prototype is reported that accurately classifies thyroid nodules and may provide a future solution suitable for local reference laboratory testing.

Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes.The National Center for Biotechnology Information Gene Expression Omnibus database was searched for high-throughput gene expression microarray studies from human ATC tissue along with normal thyroid and/or papillary thyroid cancer (PTC) tissue. Gene expression levels in ATC were compared with normal thyroid or PTC using seven separate comparisons, and an ATC-specific gene set common in all seven comparisons was identified. We investigated these genes for their biological functions and pathways.There were three studies meeting inclusion criteria, (including 32 ATC patients, 69 PTC, and 75 normal). There were 259 upregulated genes and 286 downregulated genes in ATC with at least two-fold change in all seven comparisons. Using a five-fold filter, 36 genes were upregulated in ATC, while 40 genes were downregulated. Of the 10 top globally upregulated genes in ATC, 4/10 (MMP1, ANLN, CEP55, and TFPI2) are known to play a role in ATC progression; however, 6/10 genes (TMEM158, CXCL5, E2F7, DLGAP5, MME, and ASPM) had not been specifically implicated in ATC. Similarly, 3/10 (SFTA3, LMO3, and C2orf40) of the most globally downregulated genes were novel in this context, while 7/10 genes (SLC26A7, TG, TSHR, DUOX2, CDH1, PDE8B, and FOXE1) have been previously identified in ATC. We experimentally validated a significant correlation for seven transcription factors (KLF16, SP3, ETV6, FOXC1, SP1, EGFR1, and MAFK) with the ATC-specific genes using microarray analysis of ATC cell lines. Ontology clustering of globally altered genes revealed that "mitotic cell cycle" is highly enriched in the globally upregulated gene set (44% of top upregulated genes, p-value10By focusing on globally altered genes, we have identified a set of consistently altered biological processes and pathways in ATC. Our data are consistent with an important role for M-phase cell cycle genes in ATC, and may provide direction for future studies to identify novel therapeutic targets for this disease.

BACKGROUND: Germline mutations of the REarranged during Transfection (RET) proto-oncogene cause multiple endocrine neoplasia 2 (MEN2). It is unclear whether the distribution of RET mutations varies among populations. The first nationwide study of the distribution of RET mutations was conducted, and the results were compared to those of other populations.METHODS: This retrospective cohort study included 1583 patients who underwent RET gene testing in one of three centers covering all of Denmark between September 1994 and December 2014. Primary testing method was Sanger sequencing, which included exons 8-11 and 13-16. Mutations were defined according to the ARUP database July 1, 2016.RESULTS: RET mutations were identified in 163 patients from 36 apparently unrelated families. Among the 36 families 13 (36.1%) carried mutations in codon 611, four (11.1%) in codon 618, three (8.3%) in codon 620, one (2.8%) in codon 631, six (16.7%) in codon 634, one (2.8%) in codon 790, one (2.8%) in codon 804, one (2.8%) in codon 852, one (2.8%) in codon 883, and five (13.9%) in codon 918. Among the 13 families with codon 611 mutations, 12 had the p.C611Y mutation.CONCLUSIONS: The distribution of RET mutations in Denmark appears to differ from that of other populations. Mutations in codon 611 were the most prevalent, followed by more frequently reported mutations. This might be due to a possible founder effect for the p.C611Y mutation. However, further studies are needed to find possible explanations for the skewed mutational spectrum in Denmark.