TERT Promoter Mutations Are a Major Indicator of Poor Outcome in Differentiated Thyroid Carcinomas

Context: Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. Objectives: We aimed to evaluate the frequency of TERT promoter mutations in thyroid lesions and to investigate the prognostic significance of such mutations in a large cohort of patients with differentiated thyroid carcinomas (DTCs). Design: This was a retrospective observational study. Setting and Patients: We studied 647 tumors and tumor-like lesions. A total of 469 patients with FCDTC treated and followed in five university hospitals were included. Mean follow-up (±SD) was 7.8 ± 5.8 years. Main Outcome Measures: Predictive value of TERT promoter mutations for distant metastasization, disease persistence at the end of follow-up, and disease-specific mortality. Results: TERT promoter mutations were found in 7.5% of papillary carcinomas (PTCs), 17.1% of follicular carcinomas, 29.0% of poorly differentiated carcinomas, and 33.3% of anaplastic thyroid carcinomas. Patients with TERT-mutated tumors were older (P < .001) and had larger tumors (P = .002). In DTCs, TERT promoter mutations were significantly associated with distant metastases (P < .001) and higher stage (P < .001). Patients with DTC harboring TERT promoter mutations were submitted to more radioiodine treatments (P = .009) with higher cumulative dose (P = .004) and to more treatment modalities (P = .001). At the end of follow-up, patients with TERT-mutated DTCs were more prone to have persistent disease (P = .001). TERT promoter mutations were significantly associated with disease-specific mortality [in the whole FCDTC (P < .001)] in DTCs (P < .001), PTCs (P = .001), and follicular carcinomas (P < .001). After adjusting for age at diagnosis and gender, the hazard ratio was 10.35 (95% confidence interval 2.01–53.24; P = .005) in DTC and 23.81 (95% confidence interval 1.36–415.76; P = .03) in PTCs. Conclusions: TERT promoter mutations are an indicator of clinically aggressive tumors, being correlated with worse outcome and disease-specific mortality in DTC. TERT promoter mutations have an independent prognostic value in DTC and, notably, in PTC.

Implementação da técnica Silver In Situ Hibridization para avaliação do status do gene EGFR em doentes com CPNPC

Avaliação do estado do gene Epidermal Growth Factor Receptor (EGFR), por Silver In Situ Hibridization (SISH), tem-se destacado como biomarcador preditivo na resposta à terapêutica. O principal objectivo foi optimizar a etapa de recuperação por calor da metodologia automatizada SISH Dual-Colour, em carcinomas pulmonares fixados em formol durante 24 e 72 horas. A optimização levou a um aumento da preservação do contorno nuclear e da intensidade e contraste dos sinais para os dois tempos de fixação, permitindo avaliar o estado do EGFR em 83,3% dos casos em estudo. A SISH Dual-Colour é uma alternativa para avaliar o estado do EGFR.

Enoxacin inhibits growth of prostate cancer cells and effectively restores microRNA processing

Prostate cancer (PCa) is one of the most incident malignancies worldwide. Although efficient therapy is available for early-stage PCa, treatment of advanced disease is mainly ineffective and remains a clinical challenge. microRNA (miRNA) dysregulation is associated with PCa development and progression. In fact, several studies have reported a widespread downregulation of miRNAs in PCa, which highlights the importance of studying compounds capable of restoring the global miRNA expression. The main aim of this study was to define the usefulness of enoxacin as an anti-tumoral agent in PCa, due to its ability to induce miRNA biogenesis in a TRBP-mediated manner. Using a panel of five PCa cell lines, we observed that all of them were wild type for the TARBP2 gene and expressed TRBP protein. Furthermore, primary prostate carcinomas displayed normal levels of TRBP protein. Remarkably, enoxacin was able to decrease cell viability, induce apoptosis, cause cell cycle arrest, and inhibit the invasiveness of cell lines. Enoxacin was also effective in restoring the global expression of miRNAs. This study is the first to show that PCa cells are highly responsive to the anti-tumoral effects of enoxacin. Therefore, enoxacin constitutes a promising therapeutic agent for PCa.

Predictive Biomarkers of Bacillus Calmette-Gu´erin Immunotherapy Response in Bladder Cancer: Where AreWe Now?

The most effective therapeutic option for managing nonmuscle invasive bladder cancer (NMIBC), over the last 30 years, consists of intravesical instillations with the attenuated strain Bacillus Calmette-Gu´erin (the BCG vaccine). This has been performed as an adjuvant therapeutic to transurethral resection of bladder tumour (TURBT) and mostly directed towards patients with highgrade tumours, T1 tumours, and in situ carcinomas. However, from 20% to 40% of the patients do not respond and frequently present tumour progression. Since BCG effectiveness is unpredictable, it is important to find consistent biomarkers that can aid either in the prediction of the outcome and/or side effects development. Accordingly, we conducted a systematic critical review to identify themost preeminent predictive molecular markers associated with BCG response. To the best of our knowledge, this is the first review exclusively focusing on predictive biomarkers for BCG treatment outcome. Using a specific query, 1324 abstracts were gathered, then inclusion/exclusion criteria were applied, and finally 87 manuscripts were included. Several molecules, including CD68 and genetic polymorphisms, have been identified as promising surrogate biomarkers. Combinatory analysis of the candidate predictive markers is a crucial step to create a predictive profile of treatment response.