Purpose: This study aimed to investigate the biomarkers of sintilimab (anti-PD-1) plus IBI305 (a bevacizumab biosimilar) in advanced HCC, as well as their safety and efficacy. Experimental Design: A total of 50 patients with advanced HCC received sintilimab (200 mg) plus IBI305 (7.5 or 15 mg/kg), treated every 3 weeks in a phase 1b clinical study. We performed baseline serum cytokine analysis using bead-based multiplex immunoassay and multiplex immunofluorescence on tissue specimens to discover novel biomarkers of response to VEGF/PD-1 combination therapy in HCC. Results: The overall response rate was 34.0% (17/50). The median progression-free survival (PFS) and the median overall survival were 10.5 and 20.2 months, respectively. The incidence of grade 3-5 adverse events was lower in the 7.5 mg/kg (13.8%) than in the 15 mg/kg (28.6%) dose groups. Biomarker analysis showed that the serum CD137 concentration was significantly higher in patients with clinical benefit (CB) than in those without CB (median, 32.8 vs 19.8 pg/mL, P = 0.034). A markedly longer PFS was observed in patients with high CD137 concentrations compared to those with low concentrations (median, 14.2 vs 4.1 months, P = 0.001). The higher density of M1 macrophages (CD68+CD163-) in the stroma was also associated with higher efficacy (P = 0.033) and a longer PFS (P = 0.024). Conclusion: Sintilimab plus IBI305 was well tolerated and was effective therapy for advanced HCC. Both serum concentrations of CD137 and tumor infiltration of M1 macrophages may serve as potential predictive biomarkers.

The role of anti-epithelial growth factor receptor monoclonal antibodies (anti-EGFR MoAbs) in treatment-related electrolyte disorders is still controversial. Therefore, we conducted a meta-analysis of published randomized controlled trials (RCTs) to evaluate the incidences and overall risks of all-grade and grade 3/4 electrolyte disorder events. We searched relevant clinical trials from PubMed, EMBASE, and Web of Knowledge databases, meeting proceedings of American Society of Clinical Oncology and the European Society of Medical Oncology, as well as ClinicalTrials.gov. Eligible studies included phases II, III, and IV RCTs. Statistical analysis was performed to calculate the summary incidence, relative risk (RR), and 95 % confidence intervals (CIs) using fixed effects or random effects models based on the heterogeneity of included studies. A total of 16,411 patients from 25 RCTs were included in this meta-analysis. The all-grade incidence of hypomagnesemia related to anti-EGFR MoAbs was 34.0 % (95 % CI 28.0–40.5 %), and that for hypokalemia and hypocalcemia were 14.5 % (95 % CI 8.2–24.4 %) and 16.8 % (95 % CI 14.2–19.7 %), respectively. Compared with chemotherapy alone in colorectal cancer, addition of cetuximab increased the risk of grade 3/4 hypomagnesemia and grade 3/4 hypokalemia with RRs of 7.14 (95 % CI 3.13–16.27, p < 0.001) and 2.19 (95 % CI 1.14–4.23, p = 0.019). Additionally, colorectal cancer patients in panitumumab cases were more vulnerable to grade 3/4 hypomagnesemia and hypokalemia (RR 18.29, 95 % CI 7.29–48.41, p < 0.001, and RR 3.3, 95 % CI 1.32–8.25, p = 0.011). Treatment with anti-EGFR MoAbs is associated with significantly higher risks of electrolyte disorders such as hypomagnesemia, hypomagnesemia, and hypocalcemia, especially in colorectal cancer. Rigorous monitoring and early treatment of electrolyte disorders are proposed.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-014-2983-9) contains supplementary material, which is available to authorized users.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the progress of new treatments, the risk of recurrence, morbidity, and death remains important. The neuropilin-1 (NRP-1) receptor has recently been implicated in tumor progression of MB, which seems to play an important role in the phenotype of cancer stem cells. Targeting this receptor appears as an interesting strategy to promote MB stem cells differentiation. Cancer stem-like cells of 3 MB cell lines (DAOY, D283-Med and D341-Med), classified in the more pejorative molecular subgroups, were obtained by in vitro enrichment. These models were characterized by an increase of NRP-1 and cancer stem cell markers (CD15, CD133 and Sox2), meanwhile a decrease of the differentiated cell marker Neurofilament-M (NF-M) was observed. Our previous work investigated potential innovative peptidomimetics that specifically target NRP-1 and showed that MR438 had a good affinity for NRP-1. This small molecule decreased the self-renewal capacity of MB stem cells for the 3 cell lines and reduced the invasive ability of DAOY and D283 stem cells while NRP-1 expression and cancer stem cell markers decreased at the same time. Possible molecular mechanisms were explored and showed that the activation of PI3K/AKT and MAPK pathways significantly decreased for DAOY cells after treatment. Finally, our results highlighted that targeting NRP-1 with MR438 could be a potential new strategy to differentiate MB stem cells and could limit medulloblastoma progression.

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is now a serious public health problem. Angiotensin-converting enzyme 2 (ACE2) recognized as the receptor of SARS-CoV is also necessary for SARS-CoV-2. However, the impact of ACE2 on SARS-CoV-2 susceptibility and the situation of malignant tumor patients in this outbreak are unclear. So, it is important to understand the expressions of ACE2 in different normal tissues and cancers. The results showed that the kidneys, duodenum, intestine, gallbladder and testis had the highest ACE2 expressions, followed by the colon, rectum and seminal vesicles. The lungs had a very low expression. ACE2 expressions were upregulated in renal cancer, gastrointestinal tumor and lung cancer. ACE2 expression levels may affect SARS-CoV-2 infection and severity. A total of 3,421 cases with COVID-19 have been collected. Among them, 43 cases (1.26%) had malignant tumor coexisting conditions. The rate of severe events for malignant tumor patients was 39.02% (16/41), while the rate of severe events for all patients was 10.79% (194/1,798). The clinical symptoms and signs were studied for the following three systems: respiratory (31–92%), digestive (10–13%) and urinary systems (3.38%). It seems that symptom severity is not related to protein expression levels. This might be the reason for SARS-CoV-2 showing higher regeneration index and susceptibility. More research is needed to explore the mechanisms and treatments.