Indeterminate Thyroid Nodules: From Cytology to Molecular Testing

Thyroid cancer is the most common malignancy of the endocrine system. Fine-needle aspiration (FNA) biopsy of thyroid nodules has become the gold standard procedure, in terms of cost and efficacy, for guiding clinicians towards appropriate patients’ management. One challenge for cytopathologists is to accurately classify cytological specimens as benign or malignant based on cytomorphological features. In fact, with a frequency ranging from 10% to 30%, nodules are diagnosed as indeterminate. In recent years, the mutational landscape of thyroid tumors has been extensively described, and two molecular profiles have been identified: RAS-like (NRAS, HRAS, and KRAS mutations; EIF1AX mutations; BRAF K601E mutation; and PPARG and THADA fusions) and BRAFV600E-like (including BRAFV600E mutation and RET and BRAF fusions). The purpose of this review is to discuss the latest molecular findings in the context of indeterminate thyroid nodules, highlighting the role of molecular tests in patients’ management

pre treatment egfr t790m subclones in lung adenocarcinoma harboring activating mutation of egfr a positive prognostic factor for survival

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Plio-quaternary geology of L’Aquila-Scoppito basin (Central Italy)

We present a geological map at 1: 25,000 scale of the Plio-Quaternary L'Aquila-Scoppito intermontane basin (central Italy), which corresponds to the epicentral area of the 6th April 2009 L'Aquila earthquake (Mw: 6.29). The map is derived from geological field surveys at 1: 5000 scale and takes into account previously published maps. It is supported by a fine-scale LiDAR digital elevation model, paleontological analyses, C-14 dating, well log analyses of deep boreholes, and geophysical data interpretation. By taking into account that the remarkable historical and present-day seismicity of the area is the result of its PlioQuaternary geological evolution, the aim of this study is to produce a fine-scale geological map of the study area through a comprehensive analysis of the occurring Plio-Quaternary synthems and the tectonic processes that are taking place within it

MicroRNA expression profiling of RAS-mutant thyroid tumors with follicular architecture: microRNA signatures to discriminate benign from malignant lesions

Purpose: RAS mutations represent common driver alterations in thyroid cancer. They can be found in benign, low-risk and malignant thyroid tumors with follicular architecture, which are often diagnosed as indeterminate nodules on preoperative cytology. Therefore, the detection of RAS mutations in preoperative setting has a suboptimal predictive value for malignancy. In this study, we investigated differentially expressed microRNA (miRNA) in benign and malignant thyroid tumors with follicular architecture carrying mutations in RAS genes. Methods: Total RNA was purified from 60 RAS-mutant follicular-patterned thyroid tumors, including follicular adenoma (FA), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), papillary and follicular thyroid carcinoma cases (PTC, FTC); 22 RAS-negative FAs were used as controls. The expression analysis of 798 miRNAs was performed by digital counting (nCounter nanoString platform). Results: Comparing RAS-mutant and RAS-negative FAs, 12 miRNAs showed significant deregulation, which was likely related to the oncogenic effects of RAS mutations. Twenty-two miRNAs were differentially expressed in RAS-mutant benign versus malignant tumors. Considering the tumor type, 24 miRNAs were deregulated in PTC, 19 in NIFTP, and seven in FTC and compared to FA group; among these, miR-146b-5p, miR-144-3p, and miR-451a showed consistent deregulation in all the comparisons with the highest fold change. Conclusions: The miRNA expression analysis of follicular-patterned thyroid tumors demonstrated that RAS mutations influences miRNA profile in benign tumors. In addition, several miRNAs showed a histotype-specific deregulation and could discriminate between RAS-mutant benign and RAS-mutant malignant thyroid lesions, thus deserving further investigation as potential diagnostic markers

Web Based Postgraduate Thesis/Dessertation System - A Prototype

With the advancement of information communication technology in Malaysia, education field should take advantage to upgrade their learning and management techniques. Students should be allowed to learn anytime, anywhere and at their own place. However administration and lecture should be able to manage their work more effective and flexible. The web-based system is effective way to learning and managing education works. This report outlines the development of a web-based postgraduate thesis/dissertation management system (WPTS), which aimed to assist thesis/dissertation administration, supervisor and students in the better integration during students doing the thesis/dissertation works. This prototype system base on case study with a group of MSC(IT), administration, lecturer and students who participate in thesis/dissertation management activities. This report also presenting the tests conducted with users, it also contributed some perspective regarding benefits that gain by administration, supervisor and students, and recommends future application of the approach

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

NanoString in the screening of genetic abnormalities associated with thyroid cancer

In the setting of cancer pathology, molecular characterization of tumors providing diagnostic and predictive information is acquiring more and more relevance. Moreover, the advent of innovative technologies continuously improves the knowledge of the molecular landscape of tumors and strengthens the links between clinics, tumor pathology and molecular features. In the clinical management of patients with thyroid nodules and thyroid tumors, the aid of molecular testing is encouraged but still not strongly recommended by current guidelines. Also for this reason this field of study is attracting much interest. The nCounter system is a relatively new technology based on a direct hybridization of fluorescent probes to specific nucleic acid targets, followed by digital measurement of signals; the reaction is highly multiplexable and results are robust and reproducible. This review reports and discusses the available data related to the application of this specific technique to thyroid nodules and thyroid tumors samples. The available data indicate that nCounter system represents a solid approach for the research of relevant diagnostic and prognostic biomarkers in thyroid pathology

Tailored surgery according to molecular analysis in differentiated thyroid carcinomas

Papillary thyroid carcinoma (PTC) is an often indolent disease implying a long survival and in most of the cases an excellent prognosis, but there is still a limited percentage of cases where, in spite of their pre-operative conventional staging, these tumors could better be treated through a more selective surgical approach. Small PTC in fact are generally considered as "low risk" tumors but using simply a TNM classification might lead to a limited surgery such as unilateral hemithyroidectomy, in particular according to the most recent guidelines of the American Thyroid Association. On the other hand though, an absence of the mutation could allow simplifying the follow-up of these patients, for example avoiding unnecessary radioactivated iodine therapy after surgery or even limiting to a unilateral thyroidectomy the operative procedure for these cases. Molecular testing has a peculiar interest for surgeons in two different ways: (I) with respect to diagnosis, in order to reduce the number of indeterminate citologies; (II) with respect to prognosis after both cytology and histology, in order to improve risk stratification and help the surgeon in developing a tailored surgical therapy. The aim of this review is the second issue: how to implement the concept of a tailored surgery according to molecular analysis in differentiated thyroid carcinomas (DTC)

The mutational analysis in the diagnostic work-up of thyroid nodules: the real impact in a center with large experience in thyroid cytopathology

Purpose: Fine-needle aspiration (FNA) cytology is a mainstay in the evaluation of thyroid nodules, but fails to reach reliable results in 25–30% of cases. The role of molecular markers in helping clinical decisions has been investigated for the last years, but their clinical usefulness is still unsettled. Methods: Mutation analysis of BRAF, RAS genes and TERT promoter was performed in a series of 617 consecutive cytological specimens undergoing FNA. Results: The 617 nodules had the following cytological diagnosis: non diagnostic 22 (3.6%), benign 425 (68.9%), indeterminate 114 (18.5%), suspicious 11 (1.8%) and malignant 45 (7.3%). BRAF mutations were found in 31 cases (5.0%), all but two in suspicious and malignant nodules. RAS mutations were detected in 47 samples (7.6%): 25 benign (5.9%) and 19 indeterminate nodules (16.7%). TERT promoter mutation alone was detected in three samples. Histological outcome was available for 167 nodules, 81 of which proved malignant: all the 48 with suspicious or malignant cytology; 25 out of 56 (44.6%) with indeterminate and 8 out of 57 (14%) with benign cytology. BRAF mutations were associated with worse tumors pathological features. The presence of RAS mutations was indicative of follicular-patterned malignancies in 5 out of 8 benign nodules and 9 out of 11 indeterminate nodules. Conclusions: Our study established mutational rates for BRAF and RAS genes in a large series of FNA specimens. BRAF mutations were confirmed as highly specific but not able to improve cytological diagnosis, while RAS testing proved effective in assessing malignancy in nodules with indeterminate and benign cytology