Hemodynamic response to primary prophylactic therapy with nonselective ß-blockers is related to a reduction of first variceal bleeding risk in liver cirrhosis: a meta-analysis.

The current primary prophylaxis for esophageal variceal bleeding in cirrhotic patients consists of nonselective ß-blocker (NSBB) therapy. However, only approximately half of the patients achieve a sufficient hemodynamic response to NSBB therapy. Clinical application of hemodynamic response monitoring is still under debate. The aim of this meta-analysis is to assess the potential clinical value of monitoring the hemodynamic response to NSBB therapy using hepatic venous pressure gradient (HVPG) measurements in the primary prophylaxis for variceal bleeding. A systematic literature search was performed in PubMed, Embase, Web of Science, and the COCHRANE Library. Randomized-controlled trials and case series that included cirrhotic patients receiving primary prophylaxis for variceal bleeding with NSBBs and hemodynamic response monitoring using HVPG measurements were included for analysis. The primary outcome measure was variceal bleeding. A fixed-effect analysis was carried out using the Mantel-Haenszel method for relative risks. Six of the 1172 papers found were selected on the basis of stringent selection criteria. Hemodynamic response (HVPG ≤12 mmHg and/or a reduction of ≥20%, or ≥10% in one study, from baseline) to ß-blocker therapy was associated significantly with a lower risk of variceal bleeding (relative risk=0.13, 95% confidence interval=0.06-0.29) compared with a nonresponse. Patients achieving a hemodynamic response to NSBB therapy have a lower risk of variceal bleeding than hemodynamic nonresponders. Hemodynamic monitoring in primary prophylaxis is of potential clinical value and requires further assessment in large cohort randomized-controlled trials.

Genome-scale discovery of DNA-methylation biomarkers for blood-based detection of colorectal cancer.

BACKGROUND: There is an increasing demand for accurate biomarkers for early non-invasive colorectal cancer detection. We employed a genome-scale marker discovery method to identify and verify candidate DNA methylation biomarkers for blood-based detection of colorectal cancer. METHODOLOGY/PRINCIPAL FINDINGS: We used DNA methylation data from 711 colorectal tumors, 53 matched adjacent-normal colonic tissue samples, 286 healthy blood samples and 4,201 tumor samples of 15 different cancer types. DNA methylation data were generated by the Illumina Infinium HumanMethylation27 and the HumanMethylation450 platforms, which determine the methylation status of 27,578 and 482,421 CpG sites respectively. We first performed a multistep marker selection to identify candidate markers with high methylation across all colorectal tumors while harboring low methylation in healthy samples and other cancer types. We then used pre-therapeutic plasma and serum samples from 107 colorectal cancer patients and 98 controls without colorectal cancer, confirmed by colonoscopy, to verify candidate markers. We selected two markers for further evaluation: methylated THBD (THBD-M) and methylated C9orf50 (C9orf50-M). When tested on clinical plasma and serum samples these markers outperformed carcinoembryonic antigen (CEA) serum measurement and resulted in a high sensitive and specific test performance for early colorectal cancer detection. CONCLUSIONS/SIGNIFICANCE: Our systematic marker discovery and verification study for blood-based DNA methylation markers resulted in two novel colorectal cancer biomarkers, THBD-M and C9orf50-M. THBD-M in particular showed promising performance in clinical samples, justifying its further optimization and clinical testing.