HMGB1 is an architectural chromatin-binding protein that can be released actively by activated cells or passively by dying cells and can serve as a DAMP molecule to drive the pathogenesis of inflammatory and angiogenic diseases. Through TLR4 and RAGE signaling pathways, HMGB1 could regulate vascular growth in vivo and in vitro through diverse mechanisms, including induction of proangiogenic cytokine release and activation of ECs, macrophages, EPCs, and mesoangioblasts, all of which could contribute to vessel formation. Accordingly, HMGB1 plays a significant role in many angiogenesis-related conditions, such as tumors, PDR, wound-healing, and ischemia-induced angiogenesis. In this review, we focus on the regulatory role of HMGB1 in angiogenesis and recent progress in therapeutic strategies targeting HMGB1.

4511 Background: Patients (pts) with advanced esophageal squamous cell carcinoma (ESCC) refractory to first-line chemotherapy have limited treatment options. The study aims to evaluate the efficacy and safety of sintilimab, a PD-1 inhibitor, versus chemotherapy in these pts, and explore predictive value of PD-L1 and neutrophil-to-lymphocyte ratio (NLR) on efficacy of sintilimab. Methods: The open-label, multi-center phase 2 trial (NCT03116152) enrolled advanced ESCC pts refractory to first-line chemotherapy, and randomly assigned (1:1) them to receive sintilimab (200mg, Q3W) or chemotherapy (paclitaxel, 175mg/m2, Q3W; or irinotecan, 180mg/m2, Q2W), intravenously. The primary endpoint was overall survival (OS). Explorative endpoint were effects of PD-L1 and NLR on efficacy of sintilimab. Results: From May 16, 2017 to Aug 30, 2018, 190 pts were randomly assigned to sintilimab or chemotherapy (n = 95 per group). With the median follow-up of 7.2 months for sintilimab group and 6.2 months for chemotherapy group, the median OS in sintilimab was significantly higher than chemotherapy (7.2m vs. 6.2m, hazard ratio [HR] 0.70, P = 0.034). The objective response rate (ORR) was greater in sintilimab than chemotherapy with 12.6% vs. 6.3%, and the median duration of response was longer (8.3m vs. 6.2m). Incidences of treatment-related adverse events (TRAEs) of any grade (54.3% vs. 90.8%) and of grade 3-5 (20.2% vs. 39.1%) were both numerically less in sintilimab than in chemotherapy. The ORR in sintilimab versus chemotherapy in pts with tumor PD-L1 tumor proportion score (TPS) ≥1% and with TPS ≥10% were 20.2% vs. 0%, and 35.7% vs. 0%, respectively. In sintilimab group, pts with low NLR ( < 3) had a significant longer median OS (HR 0.54, P = 0.019) than with high NLR. Conclusions: Sintilimab was superior to chemotherapy with a significantly prolonged survival benefit and a favorable safety profile in pts with advanced ESCC refractory to first-line chemotherapy. High tumor PD-L1 expression (TPS ≥1% or ≥10%) might indicate more response benefit to sintilimab for these pts, and low NLR might be a positive predictive factor for sintilimab. Clinical trial information: NCT03116152 .

Retinal image analysis is a challenging problem due to the precise quantification required and the huge numbers of images produced in screening programs. This paper describes a series of innovative brain-inspired algorithms for automated retinal image analysis, recently developed for the B Bart M. ter Haar Romeny B.M.terHaarRomeny@tue.nl 123 B. M. ter Haar Romeny et al.optic nerve head detection, crossing-preserving enhancement and segmentation of retinal vasculature, arterio-venous ratio, fractal dimension, and vessel tortuosity and bifurcations. Many of these algorithms outperform state-of-the-art techniques. The methods are currently validated in collaborating hospitals, with a rich accompanying base of metadata, to phenotype and validate the quantitative algorithms for optimal classification power.