BackgroundNeutrophils play a controversial role in tumor development. The function of programmed cell death-1 ligand (PD-L1+) neutrophils, however, may inhibit the cytotoxicity of anti-tumor immunity. In this study, we elucidate the stimulators of PD-L1+ neutrophils in tumor microenvironment (TME) and explore the optimal combination to enhance the effect of lenvatinib by inhibiting PD-L1+ neutrophils in hepatocellular carcinoma.MethodsNeutrophil infiltration after lenvatinib treatment was examined with RNA sequencing and multicolor flow cytometry analysis in patient samples, subcutaneous and orthotopic mouse models. Neutrophils and T cells were isolated from peripheral blood and tumor tissues and purified with magnetic beads for cytotoxicity assay. Metabolites and cytokines were detected by a biochemical analyzer manufactured by Yellow Springs Instrument (YSI) and proteome profiler cytokines array. In vitro screening of pathway inhibitors was used to identify possible candidates that could reduce PD-L1+ neutrophil infiltration. Further in vivo assays were used for verification.ResultsLenvatinib increased neutrophil recruitment by inducing CXCL2 and CXCL5 secretion in TME. After entering TME, neutrophils polarized toward N2 phenotype. PD-L1 expression was simultaneously upregulated. Thus, lenvatinib efficacy on tumor cells hindered. The increasing PD-L1+ neutrophils positively corelated with a suppressive T cell phenotype. Further investigation indicated that JAK/STAT1 pathway activated by immune-cell-derived interferon γ and MCT1/NF-kB/COX-2 pathway activated by high concentrations of tumor-derived lactate could induce PD-L1+ neutrophils. The latter could be significantly inhibited by COX-2 inhibitor celecoxib. Further in vivo assays verified that Celecoxib decreased the survival of lactate-stimulated PD-L1+ neutrophil and promoted the antitumor effect of lenvatinib.ConclusionsPD-L1+ neutrophils decrease T cell cytotoxicity. Tumor-derived lactate induces PD-L1 expression on neutrophils via MCT1/NF-κB/COX-2 pathway. Thus, COX-2 inhibitor could reduce PD-L1+ neutrophil and restore T cell cytotoxicity. This may provide a potent addition to lenvatinib.
ObjectiveTo meta-analytically compare combined transarterial chemoembolization (TACE) plus radiofrequency ablation (RFA) and surgical resection (SR) for the treatment of hepatocellular carcinoma (HCC) within the Milan criteria.Materials and MethodsPubMed, Medline, Embase, and Cochrane Library were searched for studies comparing these two therapies that were published between January 2006 and August 2017. Overall survival rate (OS), recurrence-free survival rate (RFS), major complications and the average length of hospital stay were compared between these two therapies. Meta-analytic pooled odds ratio (OR) was calculated using TACE plus RFA as the base category.ResultsSeven case-control studies and one randomized trial were identified. Meta-analytic results revealed that, compared with SR, TACE plus RFA had significantly higher 1-year OS (OR for survival = 0.50, p = 0.009) and lower major complications (OR = 1.88, p = 0.02) after therapy. Three studies reported on the length of hospital stay. The average length ± standard deviation reported in individual studies for SR and TACE plus RFA groups was 19.8 ± 8.4 days and 7.4 ± 2.2 days, respectively; 18.7 ± 4.9 days and 11.5 ± 6.9 days, respectively; and 16.6 ± 6.7 days and 8.5 ± 4.1 days, respectively (p < 0.0001 for all studies). Three or 5-year OS and 1-, 3-, or 5-year RFS did not significantly differ between the two therapies.ConclusionCombined TACE plus RFA may be an alternative to SR for the treatment of patients with HCC within Milan the criteria. Non-randomized design in most of the original studies was a limitation.
BackgroundTo evaluate the effectiveness and feasibility of high-intensity focused ultrasound (HIFU) for the treatment of bone metastases. MethodsA single-center prospective study was made involving 17 consecutive patients with symptomatic bone metastases. Patients were treated by Focused Ultrasound (FUs) performed with magnetic resonance (MR) guidance. Surgical treatment or radiotherapy treatment was not indicated for patients who underwent FUs. Lesions were located in the appendicular and axial skeleton and consisted of secondary symptomatic lesions. The clinical course of pain was evaluated using the Visual Analog Scale (VAS) before treatment, at 1 week, and at 1 month after treatment and the Oral Morphine Equivalent Daily Dose (OMEDD) was also recorded. We used Wilcoxon signed rank test to assess change in patient pain (R CRAN software V 3.1.1).ResultsWe observed a significant decrease in the pain felt by patients between pre- procedure and 1 week post-procedure (p = 2.9.10–4), and pre-procedure and 1 month post-procedure (p = 3.10–4). The proportion of responders according to the International Bone Metastases Consensus Working Party was: Partial Response 50% (8/16) and Complete Response 37.5% (6/16).ConclusionsHIFU under MR-guidance seems to be an effective and safe procedure in the treatment of symptomatic bone lesions for patients suffering from metastatic disease. A significant decrease of patient pain was observed.Trial registrationNCT01091883. Registered 24 March 2010. Level of evidence: Level 3.
Superior performance status, MWA treatment and targeted drug were favorable factors, and large HCC, PVTT and advanced BCLC stage were risk factors for survival after TACE-MWA for HCC.
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