Characterization of the Thyroid Cancer Genomic Landscape by Plasma-Based Circulating Tumor DNA Next-Generation Sequencing.

Background: The limited availability of targeted therapies in thyroid cancer (TC) has challenged conventional treatment algorithms and has established urgency for the identification of targetable genomic abnormalities. In addition to widely adopted tissue-based next-generation sequencing (NGS), plasma-based circulating tumor DNA (ctDNA) NGS is rapidly emerging as a genomic biomarker detection method and is steadily gaining utility across solid tumors. To date, plasma-based genomic alterations in TC have not been determined. Herein, we profile potential actionable mutations detected through ctDNA in patients with TC subtypes. Methods: A retrospective data analysis of the Guardant Health, Inc. database was performed using the commercially available Guardant360® plasma-NGS test on TC samples from adult patients collected between 2016 and 2021. The landscape of genomic alterations and blood tumor mutation burden (bTMB) were analyzed in patients with different types of TC: anaplastic TC (ATC), papillary TC (PTC), follicular TC (FTC), oncolytic carcinoma of the thyroid (OCA), poorly differentiated TC (PDTC), medullary TC (MTC), and TC not otherwise specified (TC NOS). Results: Of the 1094 patients included most of the patients n = 876 had TC NOS, and 20% had a specific diagnosis (92 ATC, 62 PTC, 14 FTC, 16 OCA, 2 PDTC, and 32 MTC patients). The median age was 65 (range 10-98) and 47.3% were male. 78.3% of patients had one or more genomic alteration detected by ctDNA NGS. TP53 (46.9%) was the most common mutation detected among all TC. BRAFV600E was detected in 27.2% of ATC, 35.7% of PTC, and in none of FTC. RAS was detected in 18.5% of ATC, 11.9% of PTC, and 62.5% of FTC. RET, ALK, and NTRK fusions were seen in 1.1%, 0.5%, and 0.2% of all TC, respectively. RET mutations were detected in 66.7% of MTC. bTMB analysis was performed on 159 patients. The mean bTMB was higher in ATC compared with other types of TC (p = 0.0011, 0.0557, and <0.0001, respectively). Conclusions: Plasma-based comprehensive NGS is a promising NGS method in TC; however, future validation of the clinical utility by analysis of paired tumor and plasma samples is needed.

Genetically engineered mouse models of head and neck cancers.

The head and neck region is one of the anatomic sites commonly afflicted by cancer, with ~1.5 million new diagnoses reported worldwide in 2020 alone. Remarkable progress has been made in understanding the underlying disease mechanisms, personalizing care based on each tumor's individual molecular characteristics, and even therapeutically exploiting the inherent vulnerabilities of these neoplasms. In this regard, genetically engineered mouse models (GEMMs) have played an instrumental role. While progress in the development of GEMMs has been slower than in other major cancer types, several GEMMs are now available that recapitulate most of the heterogeneous characteristics of head and neck cancers such as the tumor microenvironment. Different approaches have been employed in GEMM development and implementation, though each can generally recapitulate only certain disease aspects. As a result, appropriate model selection is essential for addressing specific research questions. In this review, we present an overview of all currently available head and neck cancer GEMMs, encompassing models for head and neck squamous cell carcinoma, nasopharyngeal carcinoma, and salivary and thyroid gland carcinomas.

Outcomes of repeat fineneedle aspiration biopsy for AUS/FLUS thyroid nodules.

OBJECTIVE: To determine the proportion of aspirates reclassified into each Bethesda category and to assess the rates of malignancy in each of them on repeat fine-needle aspiration biopsy (RFNA) following an AUS/FLUS diagnosis. DESIGN: Systematic review and meta-analysis. METHODS: On February 2019, Pubmed/MEDLINE, EMBASE, WoS, and the Cochrane Library were searched for articles published from January 1, 2007. All studies published in English describing RFNA outcomes in AUS/FLUS nodules were included. PRISMA and MOOSE guidelines were followed. Five investigators independently assessed the eligibility of the studies. Two investigators extracted summary data and assessed the risk of bias. Data were pooled using a random-effects model. The rate of malignancy was calculated on resected nodules only (upper limit of true value); and considering all unresected nodules were benign (lower limit of true value). The protocol was registered in PROSPERO (CRD42019123114). RESULTS: Of 2937 retrieved studies, 27 were eligible. The meta-analysis was conducted on summary data of 3932 AUS/FLUS thyroid nodules with RFNA. RFNA cytology would reclassify into categories I through VI of Bethesda: 4% (3%, 5%), 48% (43%, 54%), 26% (20%, 32%), 4% (3%, 6%), 5% (3%, 6%), and 2% (1%, 2%) of AUS/FLUS nodules. Malignancy rates of resected nodules were 24% (9%, 38%), 4% (1%, 7%), 40% (28%, 52%), 37% (27%, 47%), 79% (69%, 90%), and 99% (95%, 100%) for categories I through VI of Bethesda. There was high heterogeneity in these data. CONCLUSIONS: RFNA reclassified two-thirds of the AUS/FLUS specimens into a more definitive cytological category, with a benign call rate of nearly 50% and a negative predictive value greater than 96%.

Molecular Determinants of Thyroid Nodules with Indeterminate Cytology and RAS Mutations.

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 < 0.0001). Conclusions: The gene expression analysis of RAS-mutant thyroid nodules suggests increasing upregulation of key oncogenic pathways depending on their degree of malignancy and supports the concept of a stepwise progression. The utility of ANGPT2 expression as a potential diagnostic biomarker warrants further evaluation.

Criterion of Existence of Power-Law Memory for Economic Processes.

In this paper, we propose criteria for the existence of memory of power-law type (PLT) memory in economic processes. We give the criterion of existence of power-law long-range dependence in time by using the analogy with the concept of the long-range alpha-interaction. We also suggest the criterion of existence of PLT memory for frequency domain by using the concept of non-integer dimensions. For an economic process, for which it is known that an endogenous variable depends on an exogenous variable, the proposed criteria make it possible to identify the presence of the PLT memory. The suggested criteria are illustrated in various examples. The use of the proposed criteria allows apply the fractional calculus to construct dynamic models of economic processes. These criteria can be also used to identify the linear integro-differential operators that can be considered as fractional derivatives and integrals of non-integer orders.

Cancer Risk Associated with Nuclear Atypia in Cytologically Indeterminate Thyroid Nodules: A Systematic Review and Meta-Analysis.

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 (I2 < 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.

A Risk-adapted Approach to Follow-up in Differentiated Thyroid Cancer.

The last 10 years have seen a renewed interest in a risk-adapted approach to the management of differentiated thyroid cancer. This review outlines a state-of-the-art approach to individualized management in which the original follow-up plan that was developed based on initial risk stratification is modified over time as new data become available. This risk-adapted follow-up approach allows clinicians to determine the intensity of follow-up and management recommendations in response to real-time dynamic risk assessments which may change over time.

Painful acute radiation thyroiditis induced by 131I treatment of Graves' disease.

A 44-year-old woman, chronic smoker with Graves' disease was treated with radioactive iodine ablation (RAI). One week after the treatment, she presented with severe pain in the anterior neck with radiation to the angle of the jaw associated with fatigue, tremor and odynophagia. Physical examination demonstrated an asymmetric and exquisitely tender thyroid gland. There was no laboratory evidence of thyrotoxicosis. Acute radiation thyroiditis was diagnosed. Non-steroidal anti-inflammatory drugs and hydrocodone-acetaminophen started initially were ineffective for pain control. Prednisone provided relief and was continued for 1 month with a tapering dose. Symptoms completely resolved after 1 month at which time the thyroid remained diffusely enlarged and non-tender. Three months following RAI ablation she developed hypothyroid symptoms. Levothyroxine was initiated. The patient has remained asymptomatic on continued follow-up care.

Successful treatment of tumor-induced osteomalacia due to an intracranial tumor by fractionated stereotactic radiotherapy.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome, characterized by tumor secretion of fibroblast growth factor-23 (FGF23) causing hypophosphatemia due to renal phosphate wasting. TIO is usually caused by small, benign, difficult-to-localize, mesenchymal tumors. Although surgery with wide excision of tumor borders is considered the "gold standard" for definitive therapy, it can be associated with considerable morbidity depending on the location. To date, radiation therapy has not been considered as an effective treatment modality in TIO. OBJECTIVE: A 67-year-old female presented with multiple nontraumatic fractures, progressive bone pain, and muscle weakness for 4 years. She was found to have biochemical evidence of urinary phosphate wasting with low serum phosphorus, low-normal serum calcium, normal 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and high serum FGF23 levels. TIO was diagnosed. Selective venous sampling for FGF23 confirmed that a 1.7-cm left frontal mass, radiographically similar to a meningioma, was the causative tumor. She declined surgery due to fear of complications and instead underwent fractionated stereotactic radiotherapy for 6 weeks. RESULTS: In less than 4 years after radiation therapy, she was successfully weaned off phosphorus and calcitriol, starting from 2 g of oral phosphorus daily and 1 µg of calcitriol daily. Her symptoms have resolved, and she has not had any new fractures. CONCLUSIONS: Stereotactic radiotherapy was an effective treatment modality for TIO in our patient. Fractionated stereotactic radiation therapy represents an alternative to surgery for patients with TIO who are not surgical candidates or who decline surgery.