High Diagnostic Accuracy of Epigenetic Imprinting Biomarkers in Thyroid Nodules.

PURPOSE: To explore the novel diagnostic value of epigenetic imprinting biomarkers in thyroid nodules. PATIENTS AND METHODS: A total of 550 patients with fine-needle aspiration (FNA)-evaluated and histopathologically confirmed thyroid nodules were consecutively recruited from eight medical centers. Quantitative chromogenic imprinted gene in situ hybridization (QCIGISH) was used to assess the allelic expression of imprinted genes SNRPN and HM13, on the basis of which a diagnostic grading model for thyroid nodules was developed. The model was retrospectively trained on 124 postsurgical thyroid samples, optimized on 32 presurgical FNA samples, and prospectively validated on 394 presurgical FNA samples. Blinded central review-based cytopathologic and histopathologic diagnoses were used as the reference standard. RESULTS: For thyroid malignancy, the QCIGISH test achieved an overall diagnostic sensitivity of 100% (277/277), a specificity of 91.5% (107/117; 95% CI, 86.4 to 96.5), a positive predictive value (PPV) of 96.5% (95% CI, 94.4 to 98.6), and a negative predictive value (NPV) of 100% in the prospective validation, with a diagnostic accuracy of 97.5% (384/394; 95% CI, 95.9 to 99.0). QCIGISH demonstrated a PPV of 97.8% (95% CI, 94.7 to 100) and NPV of 100%, with a diagnostic accuracy of 98.2% (111/113; 95% CI, 95.8 to 100), for indeterminate Bethesda III-V thyroid nodules. QCIGISH demonstrated a PPV of 96.6% (95% CI, 91.9 to 100) and a NPV of 100%, with a diagnostic accuracy of 97.5% (79/81; 95% CI, 94.2 to 100), for Bethesda III-IV. For Bethesda VI, QCIGISH showed a 100% (184/184) accuracy. CONCLUSION: This imprinting biomarker-based test can effectively distinguish malignant from benign thyroid nodules. The high PPV and NPV make the test both an excellent rule-in and rule-out diagnostic tool. With such a diagnostic performance and its technical simplicity, this novel thyroid molecular test is clinically widely applicable.

Epigenetic imprinting alterations as effective diagnostic biomarkers for early-stage lung cancer and small pulmonary nodules.

BACKGROUND: Early lung cancer detection remains a clinical challenge for standard diagnostic biopsies due to insufficient tumor morphological evidence. As epigenetic alterations precede morphological changes, expression alterations of certain imprinted genes could serve as actionable diagnostic biomarkers for malignant lung lesions. RESULTS: Using the previously established quantitative chromogenic imprinted gene in situ hybridization (QCIGISH) method, elevated aberrant allelic expression of imprinted genes GNAS, GRB10, SNRPN and HM13 was observed in lung cancers over benign lesions and normal controls, which were pathologically confirmed among histologically stained normal, paracancerous and malignant tissue sections. Based on the differential imprinting signatures, a diagnostic grading model was built on 246 formalin-fixed and paraffin-embedded (FFPE) surgically resected lung tissue specimens, tested against 30 lung cytology and small biopsy specimens, and blindly validated in an independent cohort of 155 patients. The QCIGISH diagnostic model demonstrated 99.1% sensitivity (95% CI 97.5-100.0%) and 92.1% specificity (95% CI 83.5-100.0%) in the blinded validation set. Of particular importance, QCIGISH achieved 97.1% sensitivity (95% CI 91.6-100.0%) for carcinoma in situ to stage IB cancers with 100% sensitivity and 91.7% specificity (95% CI 76.0-100.0%) noted for pulmonary nodules with diameters ≤ 2 cm. CONCLUSIONS: Our findings demonstrated the diagnostic value of epigenetic imprinting alterations as highly accurate translational biomarkers for a more definitive diagnosis of suspicious lung lesions.

A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti-PD-1 Agent Pembrolizumab.

Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.3M to 60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T cells were detected in peripheral blood for >100 days in 39% of patients. Following our demonstration that PD-1 blockade enhances CAR T-cell function in mice, 18 patients with MPM also received pembrolizumab safely. Among those patients, median overall survival from CAR T-cell infusion was 23.9 months (1-year overall survival, 83%). Stable disease was sustained for ≥6 months in 8 patients; 2 exhibited complete metabolic response on PET scan. Combination immunotherapy with CAR T cells and PD-1 blockade agents should be further evaluated in patients with solid tumors. SIGNIFICANCE: Regional delivery of mesothelin-targeted CAR T-cell therapy followed by pembrolizumab administration is feasible, safe, and demonstrates evidence of antitumor efficacy in patients with malignant pleural diseases. Our data support the investigation of combination immunotherapy with CAR T cells and PD-1 blockade agents in solid tumors.See related commentary by Aldea et al., p. 2674.This article is highlighted in the In This Issue feature, p. 2659.

Novel visualized quantitative epigenetic imprinted gene biomarkers diagnose the malignancy of ten cancer types.

BACKGROUND: Epigenetic alterations are involved in most cancers, but its application in cancer diagnosis is still limited. More practical and intuitive methods to detect the aberrant expressions from clinical samples using highly sensitive biomarkers are needed. In this study, we developed a novel approach in identifying, visualizing, and quantifying the biallelic and multiallelic expressions of an imprinted gene panel associated with cancer status. We evaluated the normal and aberrant expressions measured using the imprinted gene panel to formulate diagnostic models which could accurately distinguish the imprinting differences of normal and benign cases from cancerous tissues for each of the ten cancer types. RESULTS: The Quantitative Chromogenic Imprinted Gene In Situ Hybridization (QCIGISH) method developed from a 1013-case study which provides a visual and quantitative analysis of non-coding RNA allelic expressions identified the guanine nucleotide-binding protein, alpha-stimulating complex locus (GNAS), growth factor receptor-bound protein (GRB10), and small nuclear ribonucleoprotein polypeptide N (SNRPN) out of five tested imprinted genes as efficient epigenetic biomarkers for the early-stage detection of ten cancer types. A binary algorithm developed for cancer diagnosis showed that elevated biallelic expression (BAE), multiallelic expression (MAE), and total expression (TE) measurements for the imprinted gene panel were associated with cell carcinogenesis, with the formulated diagnostic models achieving consistently high sensitivities (91-98%) and specificities (86-98%) across the different cancer types. CONCLUSIONS: The QCIGISH method provides an innovative way to visually assess and quantitatively analyze individual cells for cancer potential extending from hyperplasia and dysplasia until carcinoma in situ and invasion, which effectively supplements standard clinical cytologic and histopathologic diagnosis for early cancer detection. In addition, the diagnostic models developed from the BAE, MAE, and TE measurements of the imprinted gene panel GNAS, GRB10, and SNRPN could provide important predictive information which are useful in early-stage cancer detection and personalized cancer management.

Dolor abdominal crónico orgánico y funcional en niños: prevalencia en la consulta especializada / CHRONIC ABDOMINAL PAIN, ORGANIC AND FUNCTIONAL IN CHILDREN: PREVALENCE IN THE SPECIALIZED CONSULTATION

Introducción: El dolor abdominal crónico se presenta en forma frecuente e interfiere en la calidad de vida del niño; conocer su verdadera prevalencia en la consulta, contribuye a mejorar el abordaje diagnóstico y esclarecer la causa orgánica o funcional para indicar tratamiento específico. Objetivo: determinar la prevalencia de dolor abdominal crónico orgánico y funcional en la consulta de gastroenterología. Pacientes y Método: estudio descriptivo, retrospectivo y longitudinal (enero 2014-marzo 2015). Definición de dolor crónico, orgánico y funcional. Criterios de Roma III. Variables: edad, sexo, clínica, laboratorio, ecografía y endoscopia. Resultados: 137 niños con dolor abdominal crónico de un total de 1194 pacientes evaluados, para una prevalencia general en la consulta de 11,45% (IC 99%: 9,10-13,85). Edad promedio 9,8 años (rango 4-19), femenino 56,20% y masculino 43,8%; el grupo más afectado entre 10-15 años. En la identificación de la causa se realizó videogastroscopia al 64,96%, hallazgos anormales en ultrasonido abdominal en 11,67%. El dolor abdominal de origen orgánico se encontró en 92/137(67,15%) para una prevalencia real de 7,71% (IC 99%: 5,72-9,69), las causas: Gastroduodenitis con o sin infección Helicobacter pylori 71/92(77,17%), Enteropatía alérgica 12/92(13,04%), Parasitosis 5/92(5,43%), otras causas 4/92 (4,36%). Origen funcional 45/137(32,85%) con una prevalencia 3,77% (IC99%: 2,32-5,19), siendo el estreñimiento lo más frecuente, 30/45(66,66%), dispepsia 8/45(17,78%) y Síndrome de intestino irritable 7/45(15,56%). Conclusiones: el dolor abdominal crónico tiene una prevalencia importante en la consulta, la causa orgánica fue más frecuente que la funcional, y la utilización de definiciones claras permitió una mejor evaluación del paciente, identificar la causa e indicar el tratamiento específico.

Introduction: Chronic abdominal pain occurs on a frequent basis and interferes with the quality of life of the child; know its true prevalence in the consultation helps to improve the diagnostic approach and clarify the organic or functional cause to indicate specific treatment. Objective: determine the prevalence of organic and functional chronic abdominal pain in gastroenterology consultation. Patients and methods: A descriptive, retrospective and longitudinal study (January 2014-March 2015). Defintion of chronic abdominal pain, organic and functional. Rome III criteria. Variables: age, sex, clinical features, laboratory, ultrasound and upper endoscopy. Results: 137 children with chronic abdominal pain of a total of 1194 patients evaluated, for an overall prevalence in the consultation of 11.45% (99% CI: 9.10 to 13.85). Average age 9.8 years (range 4-19), 56.20% female and 43.8% male; the most affected age group 10-15. Upper endoscopy was performed at 64.96%, an abdominal ultrasound was altered in 11.67%. Abdominal pain of organic origin was found in 92/137 (67.15%) for a real prevalence of 7.71% (99% CI: 5.72 to 9.69), causes: gastroduodenitis with or without Helicobacter pylori infection 71/92 (77.17%), allergic enteropathyn 12/92 (13.04%), parasitosis 5/92 (5.43%), other causes 4/92 (4.36%). Functional abdominal pain 45/137 (32.85%) with a prevalence 3.77% (IC99%: 2.32 to 5.19), the most frequent was constipation, 30/45 (66.66%), dyspepsia 8/45 (17.78%) and irritable bowel syndrome 7/45 (15.56%). Conclusions: chronic abdominal pain is a significant prevalence in the consultation, the organic cause was more common than functional, and use of clear definitions allowed for better patient assessment, identify the cause and indicate the specific treatment.

Bird Diversity and Structure in Different Land-use Types in Lowland South-Central Mindanao, Philippines.

Birds are crucial to maintaining the balance of many ecosystems by providing various ecological services. The diversity of birds and their feeding guilds in different land-use types were investigated in south-central Mindanao to elucidate the effect of disturbance and habitat modification on bird communities. Point count method was employed to identify birds in three habitat types: i) agroforests; ii) ricefields; iii) roads and heavily disturbed areas. A total of 1114 bird sightings were recorded that included 33 species of 24 families; of these, 3 were Philippine endemics, and 5 were migrant species. Among all of the habitat types, the highest species diversity was found in agroforests (1/D = 16.148), and the lowest was recorded from roads and heavily disturbed habitats. The species composition of agroforests was more similar to ricefields than to areas with high levels of disturbance, such as roads. The characteristic of the vegetation and the availability of food resources may be vital to the diversity of birds in every habitat as evidenced by the high species richness of frugivores and insectivores in agroforests and ricefields, respectively, where food source is largely available. The observation of Streptopelia tranquebarica was a new record for Mindanao, and it was particularly sighted in ricefields. Therefore, this study indicates that land-use change and modification may alter bird diversity structure, and the maintenance of the vegetation in land-use types as food and resource, and as habitat is essential to the conservation of the native and ecologically-important bird species in south-central Mindanao.

Impact of clinical predictors and routine coronary artery disease testing on outcome of patients admitted to chest pain decision unit.

BACKGROUND: Chest pain decision unit (CDU) evaluation of patients with acute chest pain (ACP) and nondiagnostic electrocardiogram (ECG) usually includes noninvasive testing for coronary artery disease (CAD). HYPOTHESIS: CAD evaluation will not improve clinical outcome in low-risk ACP patients. METHODS: We studied 459 adults admitted to CDU with ACP and no troponin release who underwent noninvasive CAD testing (stress testing in 396 and coronary computed tomographic angiography in 63). Multivariate logistic regression was used to determine predictors of adverse outcome over a 3-year follow-up period. RESULTS: Initial noninvasive test was normal in 367 (80%) and abnormal (positive or indeterminate) in 92 (20%). A total of 42 (9%) patients underwent invasive coronary angiography, and 16 (3.5%) underwent revascularization. During follow-up, 33 patients had a total of 36 major clinical events: 12 revascularizations, 9 myocardial infarctions, and 15 deaths. Multivariate logistic regression analysis identified abnormal ECG (odds ratio [OR]: 2.7, P = 0.03), typical chest pain (OR: 3.8, P = 0.002), diabetes (OR: 4.1, P = 0.001), and known CAD (OR: 2.3, P = 0.03) as independent predictors for adverse outcome, but not noninvasive test result. Thus, in 187 patients with no high-risk features (41% of the cohort), the annualized event rate was 0.5%. In 272 patients with at least 1 high-risk feature, annualized event rates were 2.8% and 5.7% when noninvasive test was normal or abnormal, respectively (P = 0.04). CONCLUSIONS: Clinical risk stratification allows identification of patients at low risk of adverse outcome over an intermediate period of follow-up. Noninvasive testing is not warranted in such patients.