Angiogenesis and immune checkpoint dual blockade: Opportunities and challenges for hepatocellular carcinoma therapy.

The disease burden related to hepatocellular carcinoma (HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the approval of immune checkpoint inhibitors (ICIs) has provided a new therapeutic strategy for HCC. It is noteworthy that the positive outcomes of the phase III clinical trial IMBrave150 [atezolizumab (anti-programmed cell death ligand 1 antibody) combined with bevacizumab (anti-vascular endothelial growth factor monoclonal antibody)], showed that overall survival and progression-free survival were significantly better with sorafenib. This combination therapy has become the new standard therapy for advanced HCC and has also attracted more attention in the treatment of HCC with anti-angiogenesis-immune combination therapy. Currently, the synergistic antitumor efficacy of this combination has been shown in many preclinical and clinical studies. In this review, we discuss the mechanism and clinical application of anti-angiogenics and immunotherapy in HCC, outline the relevant mechanism and rationality of the combined application of anti-angiogenics and ICIs, and point out the existing challenges of the combination therapy.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

Association of phenotypic transformation of circulating tumor cells and early recurrence in patients with hepatocellular carcinoma following liver transplantation.

BACKGROUND: CTCs play a critical role in the diagnosis and prognosis of liver cancer. However, there are few studies on whether different types of CTCs can predict the prognosis in patients with HCC following LT. METHODS: Retrospective data including CTCs detected by the CanPatrolTM platform combined with RNA-ISH were collected and analyzed on 56 patients from December 2016 to December 2019 at the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China. RESULTS: During the study period, fifty-six patients (51 males, 5 females) were included with an mean age of 52 ± 9 years. The 1-, 2- and 3-year recurrence rates of postoperative interstitial CTC-positive and CTC-negative groups were 21.7% vs 10.8%, 37.5% vs 10.8% and 55.5% vs 10.8%, confirming a statistically significant difference between the 2 groups (p = 0.044). The 1-, 2- and 3-year recurrence rates of the increasing interstitial CTCs group were 25.2%, 36.9% and 66.9%, while 12.6%, 24.4% and 24.4% in the decreasing and unchanged group, indicating a significant difference (p = 0.038). CONCLUSION: CanPatrolTM platform presents a superior analytical sensitivity, and may be used as a dynamic monitoring tool for CTCs. And interstitial CTCs which are more aggressive and metastatic caused by EMT can be regarded as a predictor of post-transplant tumor recurrence after LT for HCC.

Effect of Hepatic Artery Spasm on a Rat Model of Hepatic Ischemia-Reperfusion Injury.

OBJECTIVES: To investigate hemodynamic changes in the hepatic artery after hepatic ischemia-reperfusion injury (IRI) in rats via ultrasound (US) imaging and to discuss the protective effect of phentolamine (PHT) pretreatment on hepatic IRI. METHODS: Fifty rats were randomly divided into 3 groups: a sham operation group (n = 10), a control ischemia-reperfusion group (n = 20), and a PHT pretreatment group (n = 20). Color Doppler flow imaging and contrast-enhanced US examinations were performed in each group at 30 minutes (n = 10) and 90 minutes (n = 10) after reperfusion. Blood samples were obtained to analyze serum alanine aminotransferase and aspartate aminotransferase levels, and liver tissue specimens were collected for pathologic analysis. RESULTS: Using US, we found that hepatic artery resistance at 30 minutes after reperfusion in the control group was higher than that in the sham group (mean resistive index [RI] ± SD, 0.65 ± 0.09 versus 0.50 ± 0.09; P < .01), which was higher at 30 than 90 minutes (RI, 0.65 ± 0.09 versus 0.50 ± 0.08; P < .01) after reperfusion in the control group. However, the hepatic artery resistance and liver microcirculation in the PHT group were better than those in the control group at 30 minutes after reperfusion (RI, 0.54 ± 0.09 versus 0.65 ± 0.09; P < .05; time to peak, 31.94 ± 2.02 versus 48.34 ± 4.74 seconds; P < .01). Compared to the control group, the aspartate aminotransferase and alanine aminotransferase levels were significantly lower at 30 minutes after reperfusion in the PHT group (P < .05). A pathologic examination revealed a smaller hepatic artery diameter and a depressed vessel wall in the control group. CONCLUSIONS: The hepatic artery can undergo a transient spasm during the hepatic IRI process, which can exacerbate liver damage. Phentolamine treatment can alleviate hepatic artery spasms, improve liver perfusion, and reduce liver injury by ameliorating the hepatic microcirculation.