RESUMEN

INTRODUCTION: We evaluated the clinical performance of an expanded mutation panel in combination with microRNA classification (MPTX) for the management of indeterminate thyroid nodules. MATERIALS AND METHODS: MPTX included testing of fine-needle aspirates from multiple centers with a combination of ThyGeNEXT mutation panel for strong and weak driver oncogenic changes and ThyraMIR microRNA risk classifier (both from Interpace Diagnostics; Pittsburgh, PA). MPTX test status (positive or negative) and MPTX clinical risk classifications (low, moderate, or high risk) were determined blind to patient outcomes. Surgical pathology and clinical follow-up records of patients from multiple centers were used to determine patient outcomes. MPTX performance was assessed by Kaplan Meier analysis for cancer-free survival of patients, with risk of malignancy determined by hazard ratio (HR). RESULTS: Our study included 140 patients with AUS/FLUS or FN/SFN nodules, of which 13% had malignancy. MPTX negative test status and MPTX low risk results conferred a high probability (94%) that patients would remain cancer-free. MPTX positive test status (HR 11.2, P < 0.001) and MPTX moderate-risk results (HR 8.5, P = 0.001) were significant risk factors for malignancy, each conferring a 53% probability of malignancy. MPTX high-risk results elevated risk of malignancy even more so, conferring a 70% probability of malignancy (HR 38.5, P < 0.001). CONCLUSIONS: MPTX test status accurately stratifies patients for risk of malignancy. Further classification using MPTX clinical risk categories enhances utility by accurately identifying patients at low, moderate, or high risk of malignancy at the low rate of malignancy encountered when clinically managing patients with indeterminate thyroid nodules.

Asunto(s)

Adenocarcinoma Folicular/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , MicroARNs/genética , Mutación , Neoplasias de la Tiroides/diagnóstico , Nódulo Tiroideo/diagnóstico , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biopsia con Aguja Fina , Exactitud de los Datos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Oncogenes , Medición de Riesgo , Factores de Riesgo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/genética , Nódulo Tiroideo/patología , Adulto Joven

RESUMEN

Cytologically indeterminate thyroid nodules are associated with a broad range (5%-75%) of malignant risk and accurately informing definitive management poses a challenge. Advancements in molecular testing of fine-needle aspiration biopsies have improved preoperative diagnostic accuracy and prognostication. For indeterminate nodules, such testing ideally will reduce the need for surgery for benign nodules and potentially guide appropriate extent of initial surgery for malignancy.

Asunto(s)

Biomarcadores de Tumor/análisis , Toma de Decisiones , Neoplasias de la Tiroides/diagnóstico , Nódulo Tiroideo/diagnóstico , Biopsia con Aguja Fina , Diagnóstico Diferencial , Humanos , Neoplasias de la Tiroides/metabolismo , Nódulo Tiroideo/metabolismo

RESUMEN

BACKGROUND: We report results of a multicenter clinical experience study examining the likelihood of patients with indeterminate thyroid nodules to undergo surgery or have malignant outcome based on multiplatform combination mutation and microRNA testing (MPT). METHODS: MPT assessed mutations in BRAF, HRAS, KRAS, NRAS, and PIK3CA genes, PAX8/PPARγ, RET/PTC1, and RET/PTC3 gene rearrangements, and the expression of 10 microRNAs. Baseline clinical information at the time of MPT and clinical follow-up records were reviewed for 337 patients, of which 80% had negative MPT results. Kaplan Meier analysis for cumulative probability of survival without having a surgical procedure or malignant diagnosis over the course of patient follow-up was determined for MPT results of 180 patients, among which only 14% had malignancy. RESULTS: A negative MPT result in nodules with Bethesda III or IV cytology (2009) conferred a high probability of non-surgical treatment, with only 11% expected to undergo surgery and a high probability of survival without malignancy (92%) for up to 2 years follow up. A positive MPT result conferred a 57% probability of malignancy and was an independent risk factor for undergoing surgical treatment (Hazard Ratio [HR] 9.2, 95% confidence intervals 5.4-15.9, P < .0001) and for malignancy (HR 13.4, 95% confidence intervals 4.8-37.2, P < .0001). For nodules with weak driver mutations, positive microRNA test results supported high risk of cancer while negative results downgraded cancer risk. CONCLUSION: MPT results are predictive of real-world decisions to surgically treat indeterminate thyroid nodules, with those decisions being appropriately aligned with a patient's risk of malignancy over time.

Asunto(s)

MicroARNs/genética , Mutación/genética , Nódulo Tiroideo/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Probabilidad , Sensibilidad y Especificidad , Adulto Joven

RESUMEN

BACKGROUND: Owing to the importance of early treatment, simple and reliable methods for monitoring inflammatory bowel disease (IBD) are needed. AIMS: To determine whether circulating microRNAs are reliable biomarkers for IBD monitoring. METHODS: Serum levels of 17 candidate microRNAs were measured by quantitative real-time polymerase chain reaction in a discovery cohort (n = 120). Differentially expressed serum microRNAs were further investigated in an independent training cohort (n = 341). Correlations between relative microRNA levels and disease activity were evaluated. A disease control group was included to investigate the specificity of microRNA. Logistical regression was used to construct a microRNA classifier to identify endoscopic activity. Its predictive value was explored in the validation cohort (n = 66) using the area under the receiver operating characteristic curve (AUC). RESULTS: Serum microRNA146b-5p (miR-146b-5p) expression was 2.87- and 2.72-fold higher in patients with Crohn's disease and ulcerative colitis, respectively, than in healthy controls. Serum miR-146b-5p was significantly correlated with disease activity and was more specific than C-reactive protein (CRP). A classifier was built for Crohn's disease, ie P [Endoscopically active] = 11+e2.937-0.737(miR-146b-5p)-0.008PLT , with a greater AUC of 0.869 [0.764-0.940] than that for CRP (0.680 [0.554-0.790]) (P = 0.0043). CONCLUSIONS: MiR-146b-5p may better reflect mucosal inflammation in IBD than CRP. The Crohn's disease classifier developed in this study may be valuable for identifying endoscopic activity in patients with Crohn's disease.

Asunto(s)

Proteína C-Reactiva/metabolismo , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/diagnóstico , MicroARNs/sangre , Adulto , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos

RESUMEN

BACKGROUND: Molecular testing of thyroid fine-needle aspirates has demonstrated value in cases of indeterminate cytology (Bethesda categories III, IV, and V) enabling optimized individual patient management leading to better outcomes with health economic benefits. For most molecular testing modalities, including mutational panels and classifier analyses, part or all of a dedicated needle aspiration pass is required to obtain an adequate sample for testing. Our analysis, which is based on a combination approach (mutation detection and microRNA classifier status), has documented clinical validity and utility when performed on thyroid fine-needle aspirates placed directly into RNA preservative fluid. Here we show that the combination approach can be extended to microdissected stained cytology slides provides the physician greater opportunity to resolve cytological indeterminacy. METHODS: Extracted nucleic acid from needle aspirate and corresponding cytology preparations of 47 thyroid nodules were analyzed using identical methodology and results were compared. RESULTS: Of 94 molecular analyses (47 mutational analyses, 47 microRNA classifier assessments based on a validated 10 marker panel) only 5 samples showed discordant results. CONCLUSION: These findings, together with supplementary work using archival specimens shows that the combination approach can be effectively applied to both direct aspirated thyroid nodule aspirates or to nucleic acid extracted from macrodissected and microdissected cytology slide smears, with the expectation of equivalent results. The advantages of both specimen sources, direct aspirate, and cytology slide smears are discussed.

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Biomarcadores de Tumor/genética , Microdisección/métodos , Neoplasias de la Tiroides/diagnóstico , Humanos , MicroARNs/clasificación , MicroARNs/genética , Mutación , Neoplasias de la Tiroides/genética