Efficacy and safety of different PD-1 inhibitors in combination with lenvatinib in the treatment of unresectable primary liver cancer: a multicentre retrospective study.

Immune checkpoint inhibitors (ICIs) are safe and efficacious treatments for advanced primary liver cancer (PLC). The efficacy of different ICIs in the treatment of liver cancer remains unclear. The purpose of this study was to explore whether there is a difference in the efficacy and safety of various programmed cell death protein 1 (PD-1) inhibitors in combination with lenvatinib in the treatment of unresectable PLC. Patients with PLC treated with lenvatinib in combination with PD-1 inhibitors (camrelizumab, tislelizumab, sintilimab, or pembrolizumab) between January 2018 and December 2021 were retrospectively enrolled. Tumor response, adverse events, and grades were evaluated. Kaplan-Meier analysis and log-rank test were used to compare the overall survival and progression-free survival of patients treated with different PD-1 inhibitors. Cox regression analysis was used for univariate and multivariate analyses to identify clinical variables related to treatment efficacy. This study included a total of 176 patients who received a combination of lenvatinib and PD-1 inhibitors. Of these, 103 patients received camrelizumab, 44 received tislelizumab, 20 received sintilimab, and 9 received pembrolizumab. There was no significant difference in the pairwise comparison of camrelizumab, tislelizumab, sintilimab, and pembrolizumab using Kaplan-Meier survival analysis. Adverse events occurred in 40 (22.7%) patients (grade ≥ 3, 2.3%). The incidence of grade 3 adverse events among the four PD-1 inhibitor groups was below 5%. Camrelizumab, tislelizumab, sintilimab, and pembrolizumab are viable options for patients with unresectable PLC. These PD-1 inhibitors in combination with lenvatinib showed good safety profiles. The results guide selecting treatment for patients with unresectable PLC.

Predictive Value of the Hepatic Immune Predictive Index for Patients with Primary Liver Cancer Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved survival outcomes and resulted in long-term responses in primary liver cancer in some patients. Nevertheless, not all patients with PLC could benefit from immunotherapy. Therefore, it is necessary to identify patients suitable for such therapy. METHODS: 215 patients with primary liver cancer with immunotherapy from Nanfang Hospital were screened between August 2018 and October 2020 as a training set and our validation set included 71 patients of hepatocellular carcinoma from Jiangxi Cancer Hospital from May 2019 to July 2021. The primary endpoint was the disease control rate (DCR), and the secondary endpoints were overall survival (OS) and progression-free survival. RESULTS: In the training set, neutrophil-lymphocyte ratio (NLR) ≥3 and alpha-fetoprotein (AFP) level ≥20 ng/mL were independently associated with non-DCR in the training set after adjusting for distant metastasis at baseline and targeted therapy combination. Furthermore, a hepatic immune predictive index (HIPI) based on NLR and AFP level was developed and patients with poor HIPI associated with worse clinical outcomes. In validation set, high HIPI was associated with poor OS. CONCLUSION: HIPI, based on NLR and AFP level, is an effective indicator in ICI-treated patients with primary liver cancer. Our findings may help guide the selection and on-treatment strategies for immunotherapies for primary liver cancer patients.

Use of computed tomography-derived body composition to determine the prognosis of patients with primary liver cancer treated with immune checkpoint inhibitors: a retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been used to successfully treat primary liver cancer (PLC); however, identifying modifiable patient factors associated with therapeutic benefits is challenging. Obesity is known to be associated with increased survival after ICI treatment; however, the relationship between body composition (muscle, fat) and outcomes is unclear. This study aimed to evaluate the association between sarcopenia and CT-derived fat content and the prognosis of ICIs for the treatment of PLC. METHODS: In this retrospective cohort study of 172 patients with PLC, we measured the skeletal muscle index (SMI), skeletal muscle density, visceral adipose tissue index, subcutaneous adipose tissue index, total adipose tissue index (TATI), and visceral-to-subcutaneous adipose tissue area ratio using CT. In addition, we analyzed the impact of body composition on the prognosis of the patients. Multivariate Cox regression analysis was used to screen for influencing factors. RESULTS: Among the seven body composition components, low SMI (sarcopenia) and low TATI were significantly associated with poor clinical outcomes. Multivariate analysis revealed that sarcopenia (hazard ratio [HR], 5.39; 95% confidence interval [CI], 1.74-16.74; p = 0.004) was a significant predictor of overall survival (OS). Kaplan-Meier curves showed that sarcopenia and TATI were significant predictors of OS. Body mass index was not associated with survival outcomes. CONCLUSIONS: Sarcopenia and fat tissue content appear to be independently associated with reduced survival rates in patients with PLC treated with ICIs.

Splenomegaly in predicting the survival of patients with advanced primary liver cancer treated with immune checkpoint inhibitors.

BACKGROUND & AIMS: Immune checkpoint inhibitors (ICIs) play an increasingly important role in the treatment of primary liver cancer (PLC). Some patients with PLC experience symptoms of splenomegaly. Splenomegaly may affect the efficacy of ICIs due to an imbalance of the immune microenvironment. Currently, there is a lack of evidence on the relationship between splenomegaly and prognosis in patients with PLC treated with ICIs. This study analyzed the relationship between splenomegaly and prognosis in patients with PLC treated with ICIs. METHODS: In this retrospective cohort study of 161 patients with PLC treated with ICIs, splenomegaly was diagnosed using computed tomography or magnetic resonance imaging and the impact of splenomegaly on patient survival was analyzed. RESULTS: Through univariate and multivariate Cox regression analyses, we determined that splenomegaly was associated with shortened overall survival (p = 0.002) and progression-free survival (p = 0.013) in patients with PLC treated with ICIs. Kaplan-Meier analysis further validated our results. The overall survival and progression-free survival of patients with splenomegaly were significantly shorter than those of patients without splenomegaly (p < 0.01 and p = 0.02, respectively). CONCLUSIONS: We concluded that splenomegaly was a predictor of prognosis in patients with PLC treated with ICIs. This is the first study to report this important finding.

Breakfast consumption frequency is associated with dyslipidemia: a retrospective cohort study of a working population.

BACKGROUND: Dyslipidemia is a significant contributor to cardiovascular and cerebrovascular diseases. Research on the relationship between breakfast consumption frequency and dyslipidemia in the working population is lacking. Therefore, we aimed to investigate this relationship based on a retrospective cohort study of a large working population in China. METHODS: This retrospective cohort study used data from the physical examinations and questionnaire survey of working participants at Nanfang Hospital from January 20, 2015 to October 16, 2020. Univariate and multivariate analyses were conducted to explore the relationship between breakfast consumption frequency and dyslipidemia in this working population (n = 7644). RESULTS: The prevalence of dyslipidemia among the participants was 26.4%. The univariate logistic regression test showed that the breakfast consumption frequency was inversely correlated with dyslipidemia. After adjusting for multiple factors, such as sex, age, body mass index, hypertension, hyperuricaemia, diabetes, smoking status, alcohol consumption, education level, marital status, long-term exposure to kitchen oil fumes, attending business dinners, and sleep time, it was found that breakfast consumption remained inversely associated with dyslipidaemia. The odds ratio for daily breakfast consumption was 0.466 (95% confidence interval 0.283-0.770, P = 0.003). After adjusting for confounding factors, we found that the higher the frequency of breakfast consumption, the lower the odds ratios for hypertriglyceridaemia. CONCLUSIONS: This study demonstrated that breakfast consumption frequency was inversely correlated with dyslipidemia. The higher the frequency of breakfast, the lower the risk of hypertriglyceridaemia. This study provides a basis on which dietary suggestions for the working population and lifestyle guidance for patients with a clinical need to prevent dyslipidemia can be made.

Lung metastasis and lymph node metastasis are risk factors for hyperprogressive disease in primary liver cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: At present, some cancer patients experience hyperprogressive disease (HPD) after receiving immunotherapy. This study used the Response Evaluation Criteria in Solid Tumors 1.1 to evaluate the incidence of HPD in patients receiving immune checkpoint inhibitors (ICIs) for treating primary liver cancer (PLC) and to explore the risk factors for HPD. METHODS: This retrospective, single-center study included patients with PLC who were treated with ICIs. The RECIST 1.1 was used to determine patients with HPD. Univariate and multivariate regression analyses were performed to explore the risk factors for HPD, and clinical variables with prognostic significance for HPD were included to establish a risk model. RESULTS: Among 129 patients with PLC treated with ICIs, HPD occurred in 13 patients (10.1%). In the multivariate regression analysis, lymph node metastasis and lung metastasis were risk factors for HPD. The area under the curve of the risk model, established by including lymph node metastasis, lung metastasis, neutrophil-lymphocyte ratio, albumin, and performance status, was 0.801 (P<0.001). The progression-free survival of HPD patients was significantly worse than that of non-HPD patients (P<0.001). CONCLUSIONS: In this study, 10.1% of patients with PLC had HPD. Compared with the non-HPD patients, lung metastasis and lymph node metastasis were independent risk factors of HPD.

Astragaloside IV-loaded nanoparticle-enriched hydrogel induces wound healing and anti-scar activity through topical delivery.

This study aims to investigate the novel preparation of solid lipid nanoparticle-enriched hydrogel (SLN-gel) for the topical delivery of astragaloside IV and to determine the effects of astragaloside IV-based SLN-gel on wound healing and anti-scar formation. Solid lipid nanoparticles (SLNs) were prepared through the solvent evaporation method. The particle size, polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), drug release, and morphological properties of the SLNs were characterized. The optimized SLNs were incorporated in carbomer hydrogel to form an SLN-enriched gel (SLN-gel) carrier. The effects of astragaloside IV-enriched SLNs on wound healing were determined using the wound scratch test, and their uptake by skin cells was tested in vitro. With the rat full-skin excision model, the in vivo regulation of astragaloside IV-based SLN-gel in the wound stages of re-epithelization, angiogenesis, and extracellular matrix remodeling was investigated. The best formulation of astragaloside IV-based SLNs had high EE (93% ± 5%) and ZP (-23.6 mV ± 1.5 mV), with a PDI of 0.18 ± 0.03 and a drug loading percentage of 9%. Astragaloside IV-based SLNs and SLN-gel could release drug sustainably. Astragaloside IV-based SLNs enhanced the migration and proliferation of keratinocytes and increased drug uptake on fibroblasts in vitro (P<0.01) through the caveolae endocytosis pathway, which was inhibited by methyl-ß-cyclodextrin. Astragaloside IV-based SLN-gel strengthened wound healing and inhibited scar formation in vivo by increasing wound closure rate (P<0.05) and by contributing to angiogenesis and collagen regular organization. SLN-enriched gel is a promising topical drug delivery system. Astragaloside IV-loaded SLN-enriched gel was proven as an excellent topical preparation with wound healing and anti-scar effects.

The healing and anti-scar effects of astragaloside IV on the wound repair in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragaloside IV is the chief ingredient of Radix Astragali, which has been used in the Traditional Chinese Medicine as a major component of many polyherbal formulations for the repair and regeneration of injured organ and tissues. This study is to investigate the influence of astragaloside IV on both of the wound healing and scar formation. MATERIALS AND METHODS: For the in vitro evaluation, the influence of the astragaloside IV in the wound scratch test of keratinocytes and the secretion of transforming growth factor-ß1, a key factor contributing to scar formation were determined. With the rat skin excision model, the in vivo regulation of astragaloside IV on wound closure, angiogenesis and collagen disposition were also evaluated. RESULTS: Astragaloside IV was shown to significantly promote the migration of keratinocytes in wound scratching assay. The superior effect of Astragaloside IV was observed at 100 µmol/L, in which the recover rates was increased with 2 and 3 folds after 48 h and 96 h respectively than that of blank control (P<0.01). Animal skin closure measurement showed that astragaloside IV could stimulate the wound healing, e.g. with 21% recover in contrast to the 8% of blank control at the 6th day. Biomechanic and Masson's trichrome stain analysis indicated that astragaloside IV may improve the strength of the repaired skin and promoted the angiogenesis and collagen synthesis. Meanwhile, the picrosirius-sirus red stain and Elisa test definitely showed the anti-scar effects of astragaloside IV by decreasing the levels of collagen I/III and TGF-ß1 secretion by firbroblasts with a dose-dependent manner (25-100 µmol/L). CONCLUSIONS: Astragaloside IV was shown a promising natural product with both healing and anti-scar effects for wound treatment. These results give the evidence for the application of astragaloside IV in the treatment of injury.