Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab

Background Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2).Methods Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed.Results Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6–12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354–0.574; p < 0.0001).Conclusions AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab.Clinical Trial Registration ClinicalTrials.gov, REACH ({"type":"clinical-trial","attrs":{"text":"NCT01140347","term_id":"NCT01140347"}}NCT01140347) and REACH-2 ({"type":"clinical-trial","attrs":{"text":"NCT02435433","term_id":"NCT02435433"}}NCT02435433).Subject terms: Oncology, Biomarkers     

Transport of amino acids by the human placenta: Predicted effects thereon of maternal hyperphenylalaninaemia

Summary Brush border and basal plasma membrane vesicles prepared from normal term human placental syncytiotrophoblast have been used to study amino acid transport. Such studies are reviewed and novel results presented which confirm that saturation of placental transport by phenylalanine is unlikely to limit delivery of this amino acid to the fetus even with grossly raised maternal concentrations. Such raised maternal levels of phenylalanine are, however, likely to severely embarrass the delivery to the fetus across the placental brush border membrane ofl-tyrosine and, to a lesser extent, ofl-tryptophan. Reasons for thinking that this may be relevant to the fetal damage found in maternal PKU are discussed.     

Molecular mechanisms of portal vein tolerance

The liver has been considered as a tolerogenic organ in the sense that favors the induction of peripheral tolerance. The administration of antigens (Ags) via the portal vein causes tolerance, which is termed portal vein tolerance and can explain the occurrence of tolerogenic responses in the liver. Here we discuss the fundamental mechanisms accounting for portal vein tolerance. Antigen-presenting cells (APCs) in the liver, especially dendritic cells and sinusoidal endothelial cells, have limited the ability to produce pro-inflammatory cytokines upon stimulation with endotoxin, an effect that could be due to the continuous exposure to bacterial Ags derived from intestinal microflora. Ag presentation by liver APCs results in T cell tolerance through clonal deletion and selection of regulatory T cells. Thus, APCs with immunosuppressive functions are associated with the achievement of portal vein tolerance via the induction of clonal deletion and generation of regulatory T cells.     

Fully automated diagnostic system with artificial intelligence using endocytoscopy to identify the presence of histologic inflammation associated with ulcerative colitis (with video)

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