Rue-Tsuan Liu

No correlation between BRAFV600E mutation and clinicopathological features of papillary thyroid carcinomas in Taiwan.

Objectiveu2002 Genetic alterations in four oncogenes, namely RAS point mutations, RET rearrangements (RET/PTC), NTRK1 rearrangements (TRK) and BRAF point mutations have been identified in human papillary thyroid carcinomas (PTCs). These oncogenes act along the RET/PTC(TRK)–RAS–BRAF–MEK–MAPK kinase pathway, mediating a number of cellular fates including growth, proliferation and survival in thyroid cells. In this study, we analysed mutations of BRAF in a cohort of PTCs.

Prognostic Implications of miR-146b Expression and Its Functional Role in Papillary Thyroid Carcinoma

CONTEXTnRecent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with the prognosis of a previously reported PTC cohort and reveal the underlying mechanisms via a PTC cell line model.nnnMETHODOLOGYnExpression levels of miR-146b were assessed via quantitative real-time PCR in 71 cases of PTC with distinct clinico-pathogenetic characteristics. All patients were classified into the disease-free or active disease group, based on their medical records at the end of the follow-up period. In vitro gain-of-function experiments were performed in a BCPAP human papillary thyroid cancer cell line model, which harbored the homozygous mutation of BRAF. BCPAP cells were transfected with a mimic-miR-146b and nonspecific microRNA (miRNA) control to determine whether miR-146b overexpression promotes cell migration and invasion. Proliferation assay, colony formation assay, and chemotherapy-induced apoptosis were also determined.nnnRESULTSnMultivariate logistic regression analysis demonstrated advanced tumor stage, presence of cervical lymph node metastasis, and miR-146b expression were independent risk factors for poor prognosis in PTC. Patients with higher miR-146b expression levels had significantly poorer overall survival compared with those with lower miR-146b levels. The associated hazard ratio was 3.92 (95% confidence interval, 1.73-8.86, log-rank P < .05). Overexpression of miR-146b significantly increased cell migration and invasiveness. Furthermore, miR-146b also increased resistance to chemotherapy-induced apoptosis.nnnCONCLUSIONSnOur results suggest that miR-146b is a novel prognostic factor of PTC. Furthermore, in vitro functional studies provided the mechanistic explanation for miR-146b in tumor aggressiveness. These results enhance understanding of the molecular mechanisms involved in tumor aggressiveness in PTC, provide new prognostic biomarkers, and ultimately offer new leads for developing therapies for PTC.

Long-term outcomes of distant metastasis from differentiated thyroid carcinoma

Backgroundu2002 The aim of this study was to identify the prognostic factors of long‐term survival and optimal therapeutic protocol for patients with distant metastasis secondary to differentiated thyroid carcinoma (DTC).

Genotype and Phenotype Predictors of Relapse of Graves' Disease after Antithyroid Drug Withdrawal

Background: For patients with Graves’ disease (GD), the primary goal of antithyroid drug therapy is to temporarily restore the patient to the euthyroid state and wait for a subsequent remission of the disease. This study sought to identify the predictive markers for the relapse of disease. Methods: To do this, we studied 262 GD patients with long enough follow-up after drug withdrawal to determine treatment outcome. The patients were divided into three groups by time of relapse: early relapse group (n = 91) had an early relapse within 9 months, late relapse group (n = 65) had a relapse between 10 and 36 months, and long-term remission group (n = 106) were either still in remission after at least 3 years or relapsed after 3 years of drug withdrawal. We assessed the treatment outcome of 23 SNPs of costimulatory genes, phenotype and smoking habits. We used permutation to obtain p values for each SNP as an adjustment for multiple testing. Cox proportional hazards models was performed to assess the strength of association between the treatment outcome and clinical and laboratory variables. Results: Four SNPs were significantly associated with disease relapse: rs231775 (OR 1.96, 95% CI 1.18–3.26) at CTLA-4 and rs745307 (OR 7.97, 95% CI 1.01–62.7), rs11569309 (OR 8.09, 95% CI 1.03–63.7), and rs3765457 (OR 2.60, 95% CI 1.08–6.28) at CD40. Combining risk alleles at CTLA-4 and CD40 improved the predictability of relapse. Using 3 years as the cutoff point for multivariate analysis, we found several independent predictors of disease relapse: number of risk alleles (HR 1.30, 95% CI 1.09–1.56), a large goiter size at the end of the treatment (HR 1.30, 95% CI 1.05–1.61), persistent TSH-binding inhibitory Ig (HR 1.64, 95% CI 1.15–2.35), and smoking habit (HR 1.60, 95% CI 1.05–2.42). Conclusion: Genetic polymorphism of costimulatory genes, smoking status, persistent goiter, and TSH-binding inhibitory Ig predict disease relapse.

The Influence of Self-monitoring Blood Glucose Frequency on the Oscillation of Hemoglobin A1c and Chronic Complications

BACKGROUNDnA fluctuating blood glucose level is one of the risks of chronic complications in diabetes. Previous studies indicated that hemoglobin A1c (HbA1c) values apparently improved after initiation of self-monitoring blood glucose (SMBG). The purpose of this study is to investigate the relationship between the frequency of SMBG, long-term fluctuatation of HbA1c, and risks of chronic complications in diabetes.nnnMETHODSnWe enrolled 1052 patients with type 2 diabetes. The mean follow-up was 4.7 years. The HbA1c level and frequency of SMBG were recorded every 3 months. Non-mydriatic retinal photography, semiquantitative neuropathy assessment, the lipid profile, serum creatinine level, and urine protein were measured at the beginning of the study and then every year. The fluctuation in HbA1c throughout the period was expressed as the standard deviations (SDs) of all measurements of the HbA1c.nnnRESULTSnThe frequency of SMBG was significantly and negatively correlated with the SDs of the HbA1c (r = -0.553, p < 0.001) but not with the average HbA1c. After controlling for age, sex, body mass index, duration of diabetes and comorbidities (dyslipidemia and hypertension), the correlation was still apparent (r = -0.511, p = 0.008). Patients with progression of nephropathy, neuropathy, and retinopathy, exhibited greater fluctuation of HbA1cs (2.38 ± 0.99 vs. 0.93 ± 1.16, p-value 0.002; 0.97 ± 1.59 vs. 0.90 ± 0.56, p-value 0.04; 0.99 ± 1.33 vs. 0.90 ± 0.56, p-value 0.04, respectively) and less frequent SMBG (3.2 ± 2.6 vs. 4.3 ± 3.1, p-value 0.02; 3.2 ± 2.6 vs. 4.1 ± 3.9, p-value 0.05; 3.0 ± 3.1 vs. 4.2 ± 2.8, p-value 0.01, respectively) than patients without progression of these complications.nnnCONCLUSIONnThis study shows that frequent SMBG decreased the fluctuation of HbA1c and decreased microvascular complications. Decreasing fluctuation of HbA1c may play an important role in diabetes treatment.

MicroRNA-146b: A Novel Biomarker and Therapeutic Target for Human Papillary Thyroid Cancer

Papillary thyroid cancer (PTC) is the most common tumor subtype of thyroid cancer. However, not all PTCs are responsive to current surgical and radioiodine treatment. The well-established clinical prognostic factors include tumor size, lymph node/distal metastasis, and extrathyroidal invasion. The RET/PTC-RAS-BRAF linear molecular signaling cascade is known to mediate PTC pathogenesis. However, whether presence of BRAF mutation, the most common genetic alteration in PTC, can affect PTC behavior and prognosis is controversial. MicroRNAs (miRNAs) have been labeled as promising molecular prognostic markers in several tumor types. Our recent studies demonstrated that microRNA-146b (miR-146b) deregulation is associated with PTC aggressiveness and prognosis. Here we summarize the current knowledge related to the functional roles, regulated target genes, and clinical applications of miR-146b in PTC and discuss how these studies provide insights into the key role of miR-146b as an oncogenic regulator promoting cellular transformation as well as a prognosis marker for tumor recurrence in PTC. In conjunction with the current perspectives on miRNAs in a wide variety of human cancers, this review will hopefully translate these updated findings on miR-146b into more comprehensive diagnostic or prognostic information regarding treatment in PTC patients before surgical intervention and follow up strategies.

Contents Vol. 1, 2012

Maria Alevizaki, Athens Ana Aranda, Madrid Rebecca Bahn, Rochester, Minn. Paul Banga, London Luigi Bartalena, Varese Bernadette Biondi, Naples Anita Boelen, Amsterdam Georg Brabant, Lubeck Henning Dralle, Halle Murat Erdogan, Ankara Creswell J. Eastman, Westmead, N.S.W. Valentin Fadeyev, Moscow Ulla Feldt-Rasmussen, Copenhagen Laszlo Hegedus, Odense George J. Kahaly, Mainz Rui Maciel, São Paolo Ana Luiza Maia, Porto Alegre Jens Mittag, Stockholm Ralf Paschke, Leipzig Simon Pearce, Newcastle-upon-Tyne Robin Peeters, Rotterdam Kris Poppe, Bruxelles Samuel Refetoff , Chicago, Ill. Jacques Samarut, Lyon Pilar Santisteban, Madrid YoungKee Shong, Seoul Jan Smit, Leiden Mark Vanderpump, London Th eo Visser, Rotterdam Paolo Vitti, Pisa Graham Williams, London Shunichi Yamashita, Nagasaki Mariastella Zannini, Naples Luca Persani, Milan (Translational Th yroidology)