The treatment landscape for advanced hepatocellular carcinoma (HCC) has recently changed and become relatively confusing. Head-to-head comparisons between most of the available agents have not been performed and are less likely to be examined in a prospective fashion in the future. Therefore, a network meta-analysis (NMA) is helpful to compare different agents from across different trials.OBJECTIVE To evaluate comparative effectiveness of different systemic treatments in advanced patients with HCC across lines of therapy.DATA SOURCES We searched various databases for abstracts and full-text articles published from database inception through March 2020.STUDY SELECTION We included phase 3 trials evaluating different vascular endothelial growth factor inhibitors (VEGFis), checkpoint inhibitors (CPIs), or their combinations in advanced HCC, in the first-line or refractory setting. DATA EXTRACTION AND SYNTHESISThe reporting of this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The overall effect was pooled using the random effects model. MAIN OUTCOMES AND MEASURES Outcomes of interest included overall (OS) and progression-free survival (PFS).FINDINGS Fourteen trials (8 in the first-line setting and 6 in the second-line setting) at low risk of bias were included. The 8 trials in the first-line setting encompassed a total of 6290 patients, with an age range of 18 to 89 years. The 5 trials included in the second-line analysis encompassed a total of 2653 patients, with an age range of 18 to 91 years. Network meta-analysis showed the combination of atezolizumab and bevacizumab was superior in patients with HCC treated in the first-line setting compared with lenvatinib (HR, 0.63; 95% CI, 0.44-0.89), sorafenib (HR, 0.58; 95% CI, 0.42-0.80), and nivolumab (HR, 0.68; 95% CI, 0.48-0.98). In the refractory setting, NMA showed that all studied drugs had PFS benefit compared with placebo. However, this only translated into OS benefit with regorafenib (HR, 0.62; 95% CI, 0.51-0.75) and cabozantinib (HR, 0.76; 95% CI, 0.63-0.92) compared with placebo. In the NMA of patients with α-fetoprotein (AFP) levels of 400 ng/mL or greater, regorafenib, cabozantinib, and ramucirumab showed PFS and OS benefit compared with placebo with no superiority of an active drug compared with any others.CONCLUSIONS AND RELEVANCE This systematic review and NMA of 14 trials found that atezolizumab and bevacizumab in combination is now considered the standard of care in the first-line setting in patients with advanced HCC. Regorafenib and cabozantinib are preferred options in refractory patients, with ramucirumab as an additional option in those with levels of AFP of 400 ng/mL or higher. Future trials should focus on other potential combinations and best treatment strategy in patients with prior VEGFi/CPI exposure.

We report the in vitro and in vivo characteristics of a new molecular conjugate vector for targeting and imaging of tumors. Its core is a cyclodecapeptide platform named RAFT, onto which two spatially independent functional domains can be covalently and stereospecifically linked: a cell-targeting domain for tumor targeting and a labeling domain able to carry two drugs and/or labeling agents. To prove the interest of this carrier, we used a well-known cRGD cyclopeptide, a ligand for the alphavbeta3 integrin. We demonstrate that this vector presenting four cRGD motifs very efficiently prevents alphavbeta3-mediated cell adhesion to vitronectin. Furthermore, it is actively endocytosed because of the multivalent cRGD presentation, a major advantage for drug delivery. In vivo experiments in nude mice reveal that repeated intratumoral injections of low doses of RAFT(cRGD)4 reduce tumor growth. Furthermore, RAFT(cRGD)4 significantly improves the targeting specificity of subcutaneous tumor masses as well as that of disseminated metastasis after intravenous injection. Thus, RAFT(cRGD)4 is specific, internalized, and perfectly controlled and can carry multiple biological functions on a single, spatially defined backbone, making it a powerful and versatile synthetic vector for drug delivery, molecular imaging, or both.

Psoriasis is a common autoimmune and chronic inflammatory skin disorder globally affecting 0.51–11.43% of adults. Inflammation-associated cell death in keratinocytes plays a key role in the process of integrate inflammatory cascade in psoriasis. Necroptosis is a regulated necrotic cell death mediated by receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL), which participates in many human inflammatory diseases. However, the mechanism and function of programmed necrosis in psoriasis is not well-illustrated. In the current study, we provide evidence for the involvement of necroptosis in psoriasis. RIPK1 and MLKL were significantly upregulated and localized in all layers of the epidermis in human psoriatic lesions, while RIPK3 and phosphorylated MLKL were mainly expressed in keratinocytes, which located in the upper layers. Increased tendency of necroptosis was also found in IMQ-induced psoriasiform skin of mice. Further, we discovered that both the inhibitor of RIPK1 R-7-Cl-O-Necrostatin-1 (Nec-1s) and MLKL-inhibitor necrosulfonamide (NSA) suppressed necroptosis in HaCaT cells and IMQ mouse models, powerfully blocked IMQ-induced inflammatory responses in vivo, and significantly downregulated the production of inflammatory factors like IL-1β, IL-6, IL-17A, IL-23a, CXCL1, and CCL20. These findings promote the development of new therapies for the treatment of necroptosis-activated pathologies for psoriasis.