Sorafenib-Related Adverse Events in Predicting the Early Radiologic Responses of Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) has a poor prognosis with low chemotherapeutic efficiency to medications except to sorafenib. Previous studies showed that adverse events (AEs) of sorafenib can predict therapy efficacy to HCC. The aim of the study is to evaluate the early efficacy and AEs of sorafenib therapy. METHODS: The database of HCC patients receiving sorafenib at Taichung Veterans General Hospital during the period from June 2012 to October 2016 was analyzed. All HCC cases were Barcelona Clinic Liver Cancer (BCLC) classification stage C. The early efficacy of sorafenib was classified according to the mRECIST criteria as either partial response (PR), stable disease (SD) or progressive disease (PD). Responses were recorded within 6 weeks after the start of sorafenib treatment. AEs were defined as the appearance of hand-foot skin reaction (HFSR), hypertension (HTN) and diarrhea. Exclusion criteria were poor performance status, poor drug compliance, discontinued follow-up or mortality occurring within 1 day after medication. RESULTS: From a total of 222 subjects, eight cases (3.6%) were classified as PR, 82 cases (36.9%) SD, and 132 cases (59.5%) PD. The PR group had the highest ratio of HFSR (62.4%) and hypertension (37.5%). Pooling cases of PR and SD together, the presence of HFSR adjusted odd ratio (aOR) 2.80, 95% confidence interval (CI) 1.52 - 5.16) and diarrhea (aOR 3.42, 95% CI 1.67 - 7.01) were good predictors of favorable responses to sorafenib therapy. CONCLUSIONS: HFSR and diarrhea are good predictors of early therapy efficacy to the sorafenib treatment.

Impact of real-time shedding on binding kinetics of membrane-remaining L-selectin to PSGL-1.

L-selectin shedding induced by various cytokines is crucial in activating neutrophils (PMNs) in inflammatory cascade. While the real-time shedding in vivo lasts ~10 min after PMN activation, the impact of time-dependent shedding on binding kinetics of membrane-remaining L-selectins to its ligands is poorly understood at transient or steady state. Here, we developed an in vitro L-selectin shedding dynamics approach, together with competitive assays of cell adhesion, and proposed a theoretical model for quantifying the impact of real-time shedding on the binding kinetics of membrane-remaining L-selectins to P-selectin glycoprotein ligand-1 (PSGL-1). Our data indicated that the extent of L-selectin shedding on PMA activation is higher, but the terminating time is longer for Jurkat cells than those for human PMNs. Meanwhile, fMLF or IL-8 stimulation yields the longer terminating time than that on PMA stimulation but results in a similar shedding extent for PMNs. L-selectin shedding reduces L-selectin-PSGL-1-mediated cell adhesion in three ways: decreasing membrane-anchored L-selectins, increasing soluble L-selectins competitively binding to ligands, and presenting conformational alteration of membrane-remaining L-selectins themselves. Compared with those on intact cells, the binding affinities of membrane-remaining L-selectin-PSGL-1 pairs were all enhanced at initial and lowered at the late shedding phase for both PMN and Jurkat cells even with varied transition time points. The rolling velocities of both PMNs and Jurkat cells were increased following mechanically or biochemically induced shedding of L-selectin under shear flow. These findings help to further our understanding of the function of time-dependent L-selectin shedding during the inflammation cascade.

Binding of intercellular adhesion molecule 1 to ß2-integrin regulates distinct cell adhesion processes on hepatic and cerebral endothelium.

Flowing polymorphonuclear neutrophils (PMNs) are forced to recruit toward inflamed tissue and adhere to vascular endothelial cells, which is primarily mediated by the binding of ß2-integrins to ICAM-1. This process is distinct among different organs such as liver and brain; however, the underlying kinetic and mechanical mechanisms regulating tissue-specific recruitment of PMNs remain unclear. Here, binding kinetics measurement showed that ICAM-1 on murine hepatic sinusoidal endothelial cells (LSECs) bound to lymphocyte function-associated antigen-1 (LFA-1) with higher on- and off-rates but lower effective affinity compared with macrophage-1 antigen (Mac-1), whereas ICAM-1 on cerebral endothelial cells (BMECs or bEnd.3 cells) bound to LFA-1 with higher on-rates, similar off-rates, and higher effective affinity compared with Mac-1. Physiologically, free crawling tests of PMN onto LSEC, BMEC, or bEnd.3 monolayers were consistent with those kinetics differences between two ß2-integrins interacting with hepatic sinusoid or cerebral endothelium. Numerical calculations and Monte Carlo simulations validated tissue-specific contributions of ß2-integrin-ICAM-1 kinetics to PMN crawling on hepatic sinusoid or cerebral endothelium. Thus, this work first quantified the biophysical regulation of PMN adhesion in hepatic sinusoids compared with cerebral endothelium.