Immunotherapy in patients with brain metastasis: advances and challenges for the treatment and the application of circulating biomarkers.

The central nervous system (CNS) is one of the most frequent metastatic sites of various cancers, including lung cancer, breast cancer and melanoma. The development of brain metastases requires a specific therapeutic approach and is associated with high mortality and morbidity in cancer patients. Advances in precision medicine and the introduction in recent years of new drugs, such as immunotherapy, have made it possible to improve the prognosis of these patients by improving survival and quality of life. New diagnostic techniques such as liquid biopsy allow real-time monitoring of tumor evolution, providing molecular information on prognostic and predictive biomarkers of response to treatment in blood or other fluids. In this review, we perform an exhaustive update of the clinical trials that demonstrate the utility of immunotherapy in patients with brain metastases and the potential of circulating biomarkers to improving the results of efficacy and toxicity in this subgroup of patients.

miRNAs in liquid biopsy for oral squamous cell carcinoma diagnosis: Systematic review and meta-analysis.

Oral squamous cell carcinoma (OSCC) is often diagnosed at advanced stages and is associated with poor survival rates. Increasing evidence suggests that microRNAs (miRNAs) present in liquid biopsies could be potential biomarkers for non-invasive OSCC diagnosis. Here, we performed a comprehensive meta-analysis to evaluate the overall diagnostic accuracy of blood and salivary miRNAs in detecting OSCC. A literature search using PubMed EMBASE, Web of Science, LILACS, Scopus, and the Cochrane Library was undertaken up to February 2019. Study quality was assessed with the Quality Assessment for Studies of Diagnostic Accuracy-2, and sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and their corresponding 95% confidence intervals (CIs) were calculated using a bivariate random-effect meta-analysis model. Meta-regression and subgroup analyses were performed to assess the heterogeneity. Twenty-five study units from 16 articles with 2562 subjects were included in this meta-analysis. The pooled sensitivity and specificity of blood and salivary miRNAs in the diagnosis of OSCC were 0.78 (95% CI: 0.76-0.80) and 0.82 (95% CI: 0.79-0.84), respectively, and the pooled positive and negative likelihood ratios were 4.31 (95% CI: 3.38-5.51) and 0.25 (95% CI: 0.20-0.32), respectively. The overall area under the curve was 0.91 (95% CI: 0.88-0.93), with a diagnostic odds ratio of 21.46 (95% CI: 13.37-34.45). These findings provide evidence regarding the potential clinical application of blood and salivary miRNAs as a novel, non-invasive, and accurate diagnostic tool for OSCC.

EPAC-lung: pooled analysis of circulating tumour cells in advanced non-small cell lung cancer.

INTRODUCTION: We assessed the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with advanced non-small cell lung cancer (NSCLC) by undertaking a pooled analysis of individual patient data. METHODS: Nine European NSCLC CTC centres were asked to provide reported/unreported pseudo-anonymised data for patients with advanced NSCLC who participated in CellSearch CTC studies from January 2003 to March 2017. We used Cox regression models, stratified by centres, to establish the association between CTC count and survival. We assessed the added value of CTCs to prognostic clinicopathological models using likelihood ratio (LR) statistics and c-indices. RESULTS: Seven out of nine eligible centres provided data for 550 patients with prognostic information for overall survival. CTC counts of ≥2 and ≥ 5 per 7·5 mL were associated with reduced progression-free survival (≥2 CTCs: hazard ratio [HR] = 1.72, p < 0·001; ≥5 CTCs: HR = 2.21, p < 0·001) and overall survival (≥2 CTCs: HR = 2·18, p < 0·001; ≥5 CTCs: HR = 2·75, p < 0·001), respectively. Survival prediction was significantly improved by addition of baseline CTC count to LR clinicopathological models (log-transformed CTCs p < 0·001; ≥2 CTCs p < 0·001; ≥5 CTCs p ≤ 0·001 for both survival end-points), whereas moderate improvements were observed with the use of c-index models. There was some evidence of between-centre heterogeneity, especially when examining continuous counts of CTCs. CONCLUSIONS: These data confirm CTCs as an independent prognostic indicator of progression-free survival and overall survival in advanced NSCLC and also reveal some evidence of between-centre heterogeneity. CTC count improves prognostication when added to full clinicopathological predictive models.

Tumor invasion and oxidative stress: biomarkers and therapeutic strategies.

Tumor invasion is paradigmatic of the complex interactions connecting a carcinoma with its environment, and a reflex of the cellular and molecular heterogeneity that defines the initiation of dissemination and metastasis. The hostile situation generated by a growing carcinoma and a reactive stroma is at the basis of the promotion of carcinoma invasion and metastasis, with oxidative stress emerging as a main player in the acquisition of an aggressive tumor phenotype. In this review, we present this complex scenario with a focus on the contribution of the reactive environment and the oxidative stress to the cellular and molecular events associated with carcinoma invasion and metastasis. We also discuss the potential of oxidative stress as a source of biomarkers of advance disease, and as supplier of a therapeutic armamentarium against the initial steps of metastatic dissemination.

ETV5 cooperates with LPP as a sensor of extracellular signals and promotes EMT in endometrial carcinomas.

Endometrial carcinoma (EC) is the most frequent among infiltrating tumors of the female genital tract, with myometrial invasion representing an increase in the rate of recurrences and a decrease in survival. We have previously described ETV5 transcription factor associated with myometrial infiltration in human ECs. In this work, we further investigated ETV5 orchestrating downstream effects to confer the tumor the invasive capabilities needed to disseminate in the early stages of EC dissemination. Molecular profiling evidenced ETV5 having a direct role on epithelial-to-mesenchymal transition (EMT). In particular, ETV5 modulated Zeb1 expression and E-Cadherin repression leading to a complete reorganization of cell-cell and cell-substrate contacts. ETV5-promoted EMT resulted in the acquisition of migratory and invasive capabilities in endometrial cell lines. Furthermore, we identified the lipoma-preferred partner protein as a regulatory partner of ETV5, acting as a sensor for extracellular signals promoting tumor invasion. All together, we propose ETV5-transcriptional regulation of the EMT process through a crosstalk with the tumor surrounding microenvironment, as a principal event initiating EC invasion.

α(1,6)Fucosyltransferase expression is an independent prognostic factor for disease-free survival in colorectal carcinoma.

We previously reported that α(1,6)fucosyltransferase (Enzyme class 2.4.1.68) activity and expression are increased in colorectal cancer, suggesting a role for this enzyme in tumor development and progression. However, the possible impact of α(1,6)fucosyltransferase activity or expression on clinical outcomes in colorectal cancer patients has never been studied. Thus, the present study was conducted to determine the value of α(1,6)fucosyltransferase as a prognostic factor for colorectal cancer. α(1,6)Fucosyltransferase expression was analyzed using immunohistochemistry in 141 colorectal tumors, and α(1,6)fucosyltransferase activity was determined in 39 tumors. A complete standardized follow-up of patients was documented until the end of the observation period of 5 years or patient death. Univariate analysis demonstrated the absence of a correlation between enzyme activity and disease evolution. However, in patients with moderate or strong α(1,6)fucosyltransferase expression, a significant decrease in the overall (P = .04) and disease-free (P = .03) survival rates was observed. In addition, when local and distant disease recurrence were considered separately, enzyme expression was found to correlate with local tumor recurrences (P = .01). Furthermore, multivariate analysis showed that α(1,6)fucosyltransferase expression has independent value for predicting tumor recurrences and, specifically, local recurrences. These findings suggest that α(1,6)fucosyltransferase expression may be a good indicator of poor prognosis in colorectal cancer and, therefore, a helpful tool to choose the most effective treatment.

α(1,2)fucosylation in human colorectal carcinoma.

Lewis(b) and Lewis(y) (Le) antigens are known to be elevated in colorectal tumours. Alterations in the catalytic behaviour of GDP-L-fucose:ß-D-galactoside α(1,2)fucosyltransferase [α(1,2)FT, EC: 2.4.1.69], the key enzyme in their synthesis, have been suggested as being responsible for these changes. In particular, an aberrant tumour-specific α(1,2)FT activity that converts Le(a) and Le(x) to Le(b) and Le(y) determinants, respectively, has been reported in colorectal cancer tissues. To clarify the catalytic function of this enzyme during colorectal tumorigenesis, we analyzed α(1,2)FT activity levels in healthy and tumour colon specimens using different acceptor substrates and determined the kinetic properties of the enzyme. To complete the study, the aberrant Le(a)/Le(x) α(1,2)fucosylation was determined in healthy and tumour colorectal tissues. A correlation analysis between the activity levels and various standard clinicopathological features, such as tumour stage, was also carried out to elucidate the role of these activities in tumour progression. The results obtained confirm the enhanced α(1,2)fucosylation in colorectal neoplastic tissues and the importance of the aberrant Le(a)/Le(x) α(1,2)FT activity in this increase. However, taking into account the high levels of Le(a)/Le(x) fucosylation observed in healthy control tissues, we must rule out the idea of a colorectal tumour-specific α(1,2)FT. On the other hand, no significant association was observed between α(1,2)FT activity levels and the clinicopathological characteristics. Overall, our results suggest that α(1,2)FT activity plays a critical role in the accumulation of Le(b) and Le(y) antigens in human colorectal carcinoma.