Clinical and Prognostic Impact of the Warburg Effect in Esophageal Carcinoma: Monocarboxylate Transporters as Candidates for Therapeutic Targeting.

INTRODUCTION: Esophageal cancer (EC) seems to display increased glycolytic activity, but clinical studies on the expression/prognostic significance of glycometabolism-related proteins, as well as functional assays, are missing. METHODS: Expression of 10 glycolytic biomarkers was evaluated by immunohistochemistry in tissue sections from 95 patients. Two esophageal squamous cell carcinoma (ESCC) cell lines were used to assess the effect of monocarboxylate transporter (MCT) downregulation on cell viability and extracellular lactate/glucose accumulation. RESULTS: Expression of MCT1, MCT4, CD147, and GLUT1 was significantly associated with an ESCC histopathology, while a poor clinicopathological profile was seen in GLUT1- and LDHA-positive EC cases. In the ESCC group, MCT1 immunoreactivity is associated with high TNM stage and metastasis. The 3-year overall survival (OS) rate was significantly influenced by MCT4 and CAIX positivity and HKII negativity. Those biomarkers were considered independent prognostic factors of OS in multivariate analysis. Dual inhibition of MCT1/4 expression decreased cell viability and extracellular lactate accumulation in ESCC cells. CONCLUSION: Elevated glycolytic rates correlate with a poor clinicopathological profile in EC patients. MCT4 and CAIX positivity independently predict a worse prognosis. Due to the lack of information on treatment modalities, we could not further infer the role of these biomarkers in predicting response to therapy, which needs to be assessed in future studies. In addition, MCT1/4 targeting should be performed both "in vitro" and "in vivo" to further explore its impact on tumor growth and response to classical therapies. HKII expression and function, particularly in the tumor stroma, should be investigated.

Comparison of the very long term (>1 year) outcomes of drug-eluting stents for the treatment of bare-metal and drug-eluting stent restenosis.

AIMS: Drug-eluting stents (DES) have become the first choice to treat BMS restenosis (ISR), replacing brachytherapy and all other available percutaneous approaches. Although markedly reduced, DES ISR still occurs and has been frequently treated with another DES, despite the lack of robust data supporting the safety and efficacy of this approach. We sought to compare the long term clinical outcomes of patients with BMS and DES ISR treated with another DES deployment. METHODS AND RESULTS: Between May 2002 and January 2008 a total of 158 patients with BMS restenosis and 58 patients with DES restenosis were treated with a DES and enrolled in this registry. Primary endpoint included the cumulative occurrence of major adverse cardiac events (MACE=cardiac death, myocardial infarction and target-vessel revascularisation) and stent thrombosis. Baseline clinical aspects did not significantly differ between the groups. There was a trend toward a higher incidence of DM in the DES cohort (36.1% vs. 32.9%, p=0.1). Mean time between first procedure and restenosis was significant longer in the DES population (178+/-61 days vs. 140+/-38 days, p=0.02). At the end of the follow-up period, 92.6% of the patients with BMS-ISR and 86.3% of those with DES-ISR were free of MACE (p<0.001). Patients with DES ISR had significant more recurrence of ISR but equivalent rates of cardiac death, MI and stent thrombosis. CONCLUSIONS: Percutaneous treatment of BMS or DES ISR with the implant of a DES represents a simple and safe approach with sustained long term results. However, the relatively high rate of ISR recurrence among patients with prior DES ISR demand the developing of more effective strategies for that subset of individuals.