No abstract

Patients with triple-negative breast cancer (TNBC) suffer an unfavorable prognosis. Carboplatin (CBDCA) as a cytotoxic reagent has been widely administered to patients with cancer including TNBC. Programmed cell death protein 1 (PD-1) is an immune checkpoint, blockade of which unleashes T cell functions that kill cancer cells. However, the efficacy of CBDCA combined with anti-PD-1 antibodies in TNBC has not been determined. Patient-derived xenografts (PDX) were implanted to immune-deficient mice. Three mouse TNBC cell lines (4T1, EMT6, and E0771) were seeded to immune-competent mice. Tumor volumes and survival rates were monitored. CBDCA and anti-PD-1 antibodies were administered by intra-peritoneal injection at designated time points. Total CD8 + T cells, memory CD8 + T cells, and CD103 + dendritic cells (DC) in the tumor were measured by flow cytometry. Tumor-specific CD8 + T cells were quantified by the ELISpot assay. Administration of CBDCA to PDX-bearing mice induced increased levels of tumor cell necrosis and reduced tumor size. Treatment with CBDCA and anti-PD-1 antibodies reduced TNBC tumor volumes and slightly improved survival rates. More importantly, therapy with CBDCA and anti-PD-1 antibodies before surgery showed a remarkably improved, sustainable protection against a secondary tumor after surgery by a CD8 +-T-cell-dependent manner, which required CCL4 expressed in the tumor and subsequently CD103 + DC recruited to the tumor microenvironment. Immunochemotherapy with CBDCA and anti-PD-1 antibodies before surgery improves the outcome of a secondary tumor after surgery via increasing the number of tumor-specific CD8 + T cells in the tumor microenvironment of murine TNBC. These results highlight the possibility to utilize this regimen in clinical practice.

Surgical EGJ carcinoma patients with elevated CRP at Day 2 after surgery should be excluded the possibility of anastomotic leakage.

Capsular contracture is an important complication after silicone mammary implant surgery. Fibroblasts and macrophages play critical roles in the pathogenesis of capsular contracture, making these two cell types therapeutic targets. It has been reported that inhibiting histamine receptors results attenuates fibrosis, but the role of roxatidine (a histamine receptor 2 inhibitor) in preventing fibrosis caused by breast implant materials remains unknown. The aim of the present study was to assess the hypothesis that roxatidine might have a prophylactic effect in capsular contracture induced by implant material. Inflammation induced by breast implant materials was mimicked by co-culturing macrophages or fibroblasts with these materials in vitro. Capsular contracture was modeled in mice by planting breast implant materials in a subcutaneous pocket. Roxatidine was added in the culture medium or administered to mice bearing breast implant materials. By co-culturing macrophages or fibroblasts with common breast implant materials (micro-textured or smooth breast implants), the present study demonstrated that macrophages respond to these materials by producing pro-inflammatory cytokines, a process that was abolished by addition of roxatidine to the culture medium. Although fibroblasts did not respond to implant surface materials in the same way as macrophages, the conditioned media of macrophages induced proliferation of fibroblasts. Mechanistically, administration of roxatidine inhibited activation of NF-κB and p38/mitogen-activated protein kinase (MAPK) signaling in macrophages. Furthermore, treatment with roxatidine in implant-bearing mice reduced serum concentrations of transforming growth factor-β and the abundance of fibroblasts around the implant. The present study concluded that roxatidine plays an important role in preventing fibrosis by inhibiting activation of NF-κB and p38/MAPK signaling in macrophages.