Reactive cutaneous capillary endothelial proliferation following camrelizumab monotherapy or combination therapy for multi-cancers: a large-scale pooled analysis of 10 studies in China.

Background: Skin toxicities are the most common adverse events related to immunotherapy, such as reactive cutaneous capillary endothelial proliferation (RCCEP) following treatment with the anti-programmed cell death-1 antibody camrelizumab. Objective: This study aimed to comprehensively analyze the clinical features and prognostic value of RCCEP in patients with malignancies who received camrelizumab alone (Camre) or in combination with the angiogenesis-targeted agent apatinib (Camre-Apa) or chemotherapy (Camre-Chemo). Design: A large-scale pooled analysis. Methods: Individual patient-level data were derived from 10 clinical trials of camrelizumab monotherapy, camrelizumab plus apatinib, or camrelizumab plus chemotherapy (n = 1305). Results: RCCEP occurred in 77.0% (516/670) of patients with Camre, 23.6% (70/296) with Camre-Apa, and 67.8% (230/339) with Camre-Chemo. Most RCCEP lesions were grade 1 or 2 in severity. The median time to onset was 0.8 months [interquartile range (IQR), 0.6-1.2] with Camre, 5.0 months (IQR, 2.7-8.0) with Camre-Apa, and 1.6 months (IQR, 1.0-4.2) with Camre-Chemo; and the median duration was 4.8 months (IQR, 2.6-8.8), 4.4 months (IQR, 1.7-8.9), and 7.2 months (IQR, 4.1-14.3), respectively. In all the three groups, patients with RCCEP showed significantly better clinical outcomes compared with those without [objective response rate: 23.8% versus 1.9% with Camre, 48.6% versus 21.2% with Camre-Apa, and 78.7% versus 54.1% with Camre-Chemo; median progression-free survival: 3.2 versus 1.7 months (hazard ratio (HR) = 0.36), 10.2 versus 4.5 months (HR = 0.39), and 12.7 versus 7.3 months (HR = 0.38); median overall survival: 13.3 versus 3.8 months (HR = 0.34), 29.2 versus 13.5 months (HR = 0.46), and not reached versus 12.8 months (HR = 0.19); all p < 0.0001]. Conclusion: Although RCCEP occurred frequently with camrelizumab, most lesions were mild and self-limiting. The occurrence of RCCEP was strongly associated with the antitumor activity and survival of camrelizumab, both as monotherapy and in combination therapy.

Efficacy and safety of hepatic arterial infusion chemotherapy combined with immune checkpoint inhibitors and tyrosine kinase inhibitors in advanced hepatocellular carcinoma: A systematic review and meta­analysis.

At present, hepatic arterial infusion chemotherapy (HAIC) for the treatment of hepatocellular carcinoma (HCC) is often applied to patients who are not suitable or are unwilling to undergo surgical treatment. However, to the best of our knowledge, the efficacy and safety of HAIC combined with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in HCC have not been fully demonstrated. Published studies involving the treatment of patients with HCC with HAIC, ICIs and TKIs were searched from public databases, including PubMed, Embase, the Cochrane Library and Sinomed. Efficacy and safety data for each study, including progression-free survival (PFS), overall survival (OS) and adverse events (AEs) were collected. The present study included 17 treatment groups from 15 studies, including 1,987 patients with HCC in the systematic review. The target population was dominated by those unsuitable for surgical treatment, with Barcelona Clinic Liver Cancer stage B or C, Eastern Cooperative Oncology Group performance status ≤2 and Child-Pugh score A or B. The results showed that the longest estimated median PFS (95% CI) in the HAIC + ICI/TKI therapy group (group C) was 9.37 months (95% CI, 6.81-11.93); in the HAIC therapy group (group B) was 7.45 months (95% CI, 6.45-8.46); and in the ICIs + other systemic therapies group (group A) was 5.92 months (95% CI, 5.31-6.54). There was no significant difference in the expected OS among the three groups, which may be because OS events were not reached in numerous studies during the follow-up time. The incidence of treatment-related adverse effects, such as increased AST [14/221 (6.33%)], increased ALT [13/221 (5.88%)], and decreased platelet count [13/221 (5.88%)], was not significantly increased in group C when compared with groups A or B (P>0.05). In conclusion, the effectiveness of HAIC + ICI/TKI for the treatment of advanced HCC was better than that of ICIs + other systemic therapies or HAIC alone. In addition, the incidence of AEs above grade 3 was not significantly higher compared with that in the other treatment groups, and the safety profile was good.

Peperomin E and its orally bioavailable analog induce oxidative stress-mediated apoptosis of acute myeloid leukemia progenitor cells by targeting thioredoxin reductase.

The early immature CD34+ acute myeloid leukemia (AML) cell subpopulation-acute myeloid leukemia progenitor cells (APCs), is often resistant to conventional chemotherapy, making them largely responsible for the relapse of AML. However, to date, the eradication of APCs remains a major challenge. We previously reported a naturally occurring secolignan- Peperomin E (PepE) and its analog 6-methyl (hydroxyethyl) amino-2, 6-dihydropeperomin E (DMAPE) that selectively target and induce oxidative stress-mediated apoptosis in KG-1a CD34+ cells (an APCs-like cell line) in vitro. We therefore further evaluated the efficacy and the mechanism of action of these compounds in this study. We found that PepE and DMAPE have similar potential to eliminate primary APCs, with no substantial toxicities to the normal cells in vitro and in vivo. Mechanistically, these agents selectively inhibit TrxR1, an antioxidant enzyme aberrantly expressed in APCs, by covalently binding to its selenocysteine residue at the C-terminal redox center. TrxR1 inhibition mediated by PepE (DMAPE) leads to the formation of cellular selenium compromised thioredoxin reductase-derived apoptotic protein (SecTRAP), oxidation of Trx, induction of oxidative stress and finally activation of apoptosis of APCs. Our results demonstrate a potential anti-APCs molecular target - TrxR1 and provide valuable insights into the mechanism underlying PepE (DMAPE)-induced cytotoxicity of APCs, and support the further preclinical investigations on PepE (DMAPE)-related therapies for the treatment of relapsed AML.

Inhibitory effect of endostar on specific angiogenesis induced by human hepatocellular carcinoma.

To investigate the effect of endostar on specific angiogenesis induced by human hepatocellular carcinoma, this research systematically elucidated the inhibitory effect on HepG2-induced angiogenesis by endostar from 50 ng/mL to 50000 ng/mL. We employed fluorescence quantitative Boyden chamber analysis, wound-healing assay, flow cytometry examination using a coculture system, quantitative analysis of tube formation, and in vivo Matrigel plug assay induced by HCC conditioned media (HCM) and HepG2 compared with normal hepatocyte conditioned media (NCM) and L02. Then, we found that endostar as a tumor angiogenesis inhibitor could potently inhibit human umbilical vein endothelial cell (HUVEC) migration in response to HCM after four- to six-hour action, inhibit HCM-induced HUVEC migration to the lesion part in a dose-dependent manner between 50 ng/mL and 5000 ng/mL at 24 hours, and reduce HUVEC proliferation in a dose-dependent fashion. Endostar inhibited HepG2-induced tube formation of HUVECs which peaked at 50 ng/mL. In vivo Matrigel plug formation was also significantly reduced by endostar in HepG2 inducing system rather than in L02 inducing system. It could be concluded that, at cell level, endostar inhibited the angiogenesis-related biological behaviors of HUVEC in response to HCC, including migration, adhesion proliferation, and tube formation. At animal level, endostar inhibited the angiogenesis in response to HCC in Matrigel matrix.