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Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization. We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC). Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs were BRAF-like irrespective of driver mutation. These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality. This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.

Abstract Context Age at diagnosis has been identified as a major determinant of thyroid cancer–specific survival, with older patients being at higher risk for mortality, but the association of age with risk of recurrence has not been studied to date. Objective To examine the effect of a patient’s age on response to therapy and disease-specific mortality in a cohort of thyroid cancer patients at high risk of recurrence, as defined by the American Thyroid Association (ATA) risk stratification system. Design Retrospective cohort study of 320 patients, median age 49.3 years, with follicular cell-derived thyroid carcinoma classified at ATA high risk and followed for a median of 7 years. Main Outcome Measures Association of age with response to therapy, overall mortality, disease-specific mortality, and timing of metastases. Results Age was a major determinant of response to therapy. There was a significantly larger percentage of excellent responders among young patients (age <55) than among old patients (age ≥55), 40.3% vs 27.5%, P = 0.002, respectively, whereas the proportion of structural incomplete responders was higher in the old group compared with the young group, 53% vs 33%, P = 0.002, respectively. ATA high-risk young patients with a structural incomplete response to therapy had a significantly better disease-specific survival than old patients (74% vs 12%, P < 0.001, respectively). Conclusions Age was a key predictor of response to therapy and disease-specific survival in ATA high-risk thyroid cancer patients. Its incorporation as a variable in the ATA risk stratification system would improve its power to predict response to therapy as well as mortality. We found that age at diagnosis significantly predicts response to therapy and disease-specific mortality in ATA high-risk thyroid cancer patients.

Increased endogenous glucose production (EGP) is a hallmark of type 2 diabetes mellitus. While there is evidence for central regulation of EGP by activation of hypothalamic ATP-sensitive potassium (KATP) channels in rodents, whether these central pathways contribute to regulation of EGP in humans remains to be determined. Here we present evidence for central nervous system regulation of EGP in humans that is consistent with complementary rodent studies. Oral administration of the KATP channel activator diazoxide under fixed hormonal conditions substantially decreased EGP in nondiabetic humans and Sprague Dawley rats. In rats, comparable doses of oral diazoxide attained appreciable concentrations in the cerebrospinal fluid, and the effects of oral diazoxide were abolished by i.c.v. administration of the KATP channel blocker glibenclamide. These results suggest that activation of hypothalamic KATP channels may be an important regulator of EGP in humans and that this pathway could be a target for treatment of hyperglycemia in type 2 diabetes mellitus.

Hypoglycemia is a common problem in hospitalized patients, particularly the elderly, frail, and severely ill. Hypoglycemia has been implicated in the development of adverse clinical outcomes, including increased mortality. Fear of iatrogenic hypoglycemia remains an obstacle to adequate inpatient glycemic control. However, evidence from large clinical trials is mixed: several intensive care unit studies have shown either reduced or no change in mortality with intensive glycemic control, despite high rates of iatrogenic hypoglycemia, and only 1 large study showed higher mortality. In the general ward setting, the association of hypoglycemia with worse outcomes and mortality has been frequently reported, but after multivariate adjustment for comorbidities this association disappears. Spontaneous hypoglycemia, rather than iatrogenic hypoglycemia, is strongly associated with mortality suggesting that hypoglycemia behaves as a biomarker rather than a causative factor of adverse outcomes. Inpatient glycemic management should be patient-centered, follow the current guidelines, and aimed at preventing hypoglycemia.

Radioactive iodine (RAI) has been associated with hematologic abnormalities. Previous research has shown that even a single dose of RAI can cause changes in the peripheral complete blood count (CBC). It is unclear if the use of dosimetry guidance would prevent the effects of high doses of RAI on bone marrow suppression. CBC at baseline was compared to a CBC obtained 1 year after the last RAI treatment in 50 thyroid cancer patients that received ≥250 mCi RAI during the course of their disease. Cumulative dose, number of treatments, patients' age, and the use of external beam radiation therapy (EBRT) were considered in the analysis. We observed a small but statistically significant decrease in hemoglobin (Hb), hematocrit (Hct), and platelet (Plt) counts at 1 year in 50 patients who had received ≥250 mCi RAI. We did not find a significant change in white blood cell count (WBC). Approximately 60% of patients who developed anemia had concomitant WBC and Plt abnormalities. RAI dose, number of treatments, and age at diagnosis did not confer a higher risk of bone marrow suppression. High cumulative activities of RAI administered under dosimetric guidance are associated with a small but statistically significant decreases in Hb, Hct, and Plt counts. The clinical implications of these changes, if any, are unclear. The benefits obtained with high doses of RAI, when indicated, are likely to outweigh the minimal hematologic risks observed in the present study.

The use of radioactive iodine (RAI) after total thyroidectomy for patients at the American Thyroid Association (ATA) who are at intermediate risk of recurrence is controversial. This is due to the lack of prospective randomized trials proving a benefit to recurrence or survival of RAI therapy in this group. In the absence of such evidence, clinicians struggle to recommend for or against this therapeutic approach which frequently results in overtreatment. This review describes key elements in the decision-making process that help clinicians more comprehensively evaluate the need for RAI therapy in patients with thyroid cancer at intermediate risk of recurrence. A clear definition of the purpose of RAI therapy should be conveyed to patients. In this sense, adjuvant RAI therapy intends to decrease recurrence, and ablation therapy is used to facilitate surveillance. Better stratification of the intermediate risk category into a low–intermediate subgroup and an intermediate–high-risk subgroup results in less heterogeneity and a more precise prediction of recurrence risk. The evaluation of post-operative thyroglobulin levels may prevent the overtreatment of low–intermediate-risk patients when their thyroglobulin level is <2.5 ng/mL. the integration of tumor genomics (when available) alongside pathologic features can enhance the ability of the clinician to predict iodine concentration in thyroid cancer cells. Finally, a detailed consideration of the adverse effects of RAI, patients’ comorbidities, and patient preferences will result in a patient-centered personalized approach. Systematic examination of these variables will ultimately provide a framework for making more educated decisions on the use of RAI in patients at intermediate risk of recurrence that will prevent overtreatment and minimize harm.

Abstract Context BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI). Objectives To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). Design This was a pilot trial that enrolled from June 2014 to January 2016. Setting Academic cancer center. Patients Patients with RAIR, BRAF mutant thyroid cancer. Intervention Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation. Main Outcome Measure The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I. Results Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048). Conclusions Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit. The BRAF inhibitor vemurafenib increased radioiodine uptake in a subset of patients with BRAF mutant, radioiodine-refractory thyroid cancer.

Radioactive iodine (RAI) has been epidemiologically associated with the development of hematologic malignancies. Clonal hematopoiesis (CH) is a precursor clonal state that confers increased risk of leukemia and occurs at an elevated rate in patients with thyroid cancer relative to other solid tumors. We explore if the high prevalence of CH may be a result of RAI exposure and whether CH may be a surrogate in the association between RAI and leukemia. CH, CH-potential driver (CH-PD), and overall survival were evaluated in 279 patients with advanced thyroid carcinoma. The prevalence of CH in patients with thyroid cancer was 37%, and that of CH-PD was 5.2%. Age was the strongest predictor of CH and CH-PD. For every year increase in age, there was a 5% and 13% increase in the odds of CH and CH-PD, respectively. RAI dose was significantly associated with CH and CH-PD, even after adjustment for age, external beam radiation therapy, and chemotherapy. For every 10 mCi increase in the dose of RAI administered, there was a 2% and 4% increase in the odds of CH and CH-PD, respectively. Patients with CH-PD previously exposed to RAI had a significantly poorer survival, even when stratified by age (heart rate = 3.75, 95% CI = 1.23 to 11.5, P = 0.02). RAI was associated with a high prevalence of CH, and CH is a precursor state of hematologic malignancies. The implications of this study may favor identification of CH in patients where the risks might outweigh the benefits of receiving RAI therapy for thyroid cancer.

Abstract Context Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as effective therapies for diabetes mellitus and obesity. Their effect on nonmedullary thyroid malignancies remains unclear. Objective To evaluate the impact of GLP-1RA exposure on tumor kinetics of patients with low-risk papillary thyroid carcinoma undergoing active surveillance (AS). Design Retrospective observational cohort study of 18 patients with 19 papillary thyroid carcinomas (≤1.5 cm) exposed to GLP-1RA matched 1:2 by body mass index and tumor size to 37 patients with 38 carcinomas never exposed to GLP-1RA and undergoing AS at a single tertiary center for a median of 5.5 years. Main outcome Tumor growth/shrinkage was considered significant when any diameter changed by ≥3 mm and/or volume changed >72%. Tumor volume doubling time was calculated in a subset of patients off and on GLP-1RA therapy. Results After a median GLP-1RA exposure of 25 months [interquartile range: 14-34] and a median follow-up of 5.5 years, 2/19 (10.5%) tumors exposed to GLP-1RA exhibited significant volume growth, 1 (5.3%) decreased, and 16 (84.2%) remained stable, whereas 1/38 (2.6%) carcinomas not exposed to GLP-1RA showed >72% volume increase, 2/38 (5.3%) decreased, and 35/38 (92.1%) remained stable, P = .53. GLP-1RA exposure did not alter tumor volume growth kinetics in either of the 2 tumors that increased over time. Conclusion GLP-1RA therapy does not affect tumor growth kinetics in patients with low-risk papillary thyroid carcinoma on AS. Further studies with larger cohorts and extended follow-up are warranted to validate the safety of GLP-1RA use in patients with thyroid carcinomas undergoing active surveillance.

Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T cells that contribute to the antitumor response. We found that mouse BrafV600E-driven anaplastic thyroid cancers (ATCs) responded markedly to the RAF plus MEK inhibitors dabrafenib and trametinib (dab/tram) and that this was associated with upregulation of MhcII in cancer cells and increased CD4+ T cell infiltration. A subset of recurrent tumors lost MhcII expression due to silencing of Ciita, the master transcriptional regulator of MhcII, despite preserved IFN-γ signal transduction, which could be rescued by EZH2 inhibition. Orthotopically implanted Ciita-/- and H2-Ab1-/- ATC cells into immune-competent mice became unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+, T cells also abrogated the response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.