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The aim of this study was to determine if, at a national level, diabetes mellitus is associated with worse perioperative outcomes after open lower extremity arterial reconstruction. Using Current Procedural Terminology codes, the National Surgical Quality Improvement Program database was queried to identify diabetic and nondiabetic patients who underwent open lower extremity arterial reconstruction from January 1, 2005, to December 31, 2007. These 2 groups were then compared using bivariate and multivariate analyses. There was no difference in mortality between the 2 groups (3.3% in diabetics and 3.5% in nondiabetics, P = .618). On multivariate analysis, there was no difference in the incidence of cardiac, pulmonary, or renal complications between the 2 groups. Diabetics, though, were more likely to develop infectious complications postoperatively. After lower extremity arterial reconstruction, diabetes is not associated with an increased risk for mortality or an increased rate of major postoperative complications. Diabetics, however, have an increased rate of certain perioperative infections.

Purpose Programmed death receptor ligand-1 (PD-L1) expression and tumor mutational burden (TMB) are approved screening biomarkers for immune checkpoint inhibition (ICI) in advanced triple negative breast cancer. We examined these biomarkers along with characterization of the tumor microenvironment (TME) between breast tumors (BrTs), axillary metastases (AxMs), liver metastases (LvMs), non-axillary lymph node metastases, and non-liver metastases to determine differences related to site of metastatic disease. Methods 3076 unpaired biopsies from breast cancer patients were analyzed using whole transcriptome sequencing and NextGen DNA depicting TMB within tumor sites. The PD-L1 positivity was determined with VENTANA PD-L1 (SP142) assay. The immune cell fraction within the TME was calculated by QuantiSeq and MCP-counter. Results Compared to BrT, more LvM samples had a high TMB (≥ 10 mutations/Mb) and fewer LvM samples had PD-L1 + expression. Evaluation of the TME revealed that LvM sites harbored lower infiltration of adaptive immune cells, such as CD4 + , CD8 + , and regulatory T-cells compared with the BrT foci. We saw differences in innate immune cell infiltration in LvM compared to BrT, including neutrophils and NK cells. Conclusions LvMs are less likely to express PD-L1 + tumor cells but more likely to harbor high TMB as compared to BrTs. Unlike AxMs, LvMs represent a more immunosuppressed TME and demonstrate lower gene expression associated with adaptive immunity compared to BrTs. These findings suggest biopsy site be considered when interpreting results that influence ICI use for treatment and further investigation of immune composition and biomarkers expression by metastatic site.

BackgroundA major cause of death in patients with breast cancer is complications resulting from metastasis. Immune checkpoint inhibitors (ICIs) activate T cells and B cells to mount anti-tumor responses, but they have proved ineffective against metastatic breast cancer as single-agent therapies. Myeloid cell-T cell interactions contribute to this treatment inefficacy, as macrophages and myeloid-derived suppressor cells (MDSCs) are abundant in breast tumors, which suppress anti-tumoral responses by T cells. Our group has demonstrated that the histone deacetylase inhibitor, entinostat, decreases the immunosuppression by MDSCs, and when combined with anti-PD-1 and anti-CTLA-4, increases survival in HER2+ and triple-negative breast cancer (TNBC) primary tumor models.MethodsNeuN mice harboring spontaneous HER2+ breast-to-lung metastases were treated with combinations of entinostat, anti-PD-1, and anti-CTLA-4 and assessed for survival. Lung metastases were analyzed using single-cell RNA-sequencing (scRNA-seq), and tumor-targeting antibodies were determined via immunostaining of cancer cells. Immune cell proportions within lung metastases from HER2+ and TNBC models were determined via flow cytometry. Myeloid immunosuppression and validation of treatment targets identified via scRNA-seq were assessed via T cell proliferation in ex-vivo co-cultures between macrophages/G-MDSCs isolated from lung metastases with CD8+ T cells. Tissues from metastatic patients treated with the triple combination from our phase 1b trial (NCI-9844) were analyzed using imaging mass cytometry (IMC).ResultsTriple combination of entinostat, anti-PD-1, and anti-CTLA-4 increased survival in the NT2.5-LM model of HER2+ breast cancer, which was associated with an increase in plasma cell proportions, tumor-targeting antibodies, and Th2 activation, as determined by scRNA-seq and flow cytometry using HER2+ and TNBC models. CellChat analysis revealed a decrease in ligand-receptor interactions associated with immunosuppression in myeloid cells, including Icam1_Itgam_Itgb2 and Ifng_Ifngr1_Ifngr2, in mice treated with either entinostat or triple-combination. Macrophages and G-MDSCs suppressed T cell proliferation, and blockade of ICAM1 or IFNγ receptor increased T cell proliferation, respectively. IMC results demonstrated increased proportions of CD8+ T cells, expression of pro-inflammatory marker CD137 in B cells and CD8+ T cells, and distances between CD8+ T cells and macrophages with triple combination treatment in responders. In addition, only responders had detectable germinal centers or mature tertiary lymphoid structures and increased proportions of B cells and plasma cells post-treatment.ConclusionsOverall, our results suggest that B cell activation and the amelioration of myeloid immunosuppression increase the efficacy of checkpoint inhibition in metastatic breast cancer; these mechanisms should be carefully considered when using ICIs in clinical settings.Ethics ApprovalAll mice were housed under pathogen-free conditions and handled according to protocol 21770 approved by the USC Institutional Animal Care and Use Committee, following guidelines by the American Association of Laboratory Animal Committee policies. The use of patient samples for this study was approved by the Institutional Review Boards of participating institutions (Johns Hopkins, Yale, University of Pittsburgh Medical Center and City of Hope), and participants signed a written informed consent before enrollment. The trial was conducted according to the principles of Good Clinical Practice and the Declaration of Helsinki. The NCI Central Institutional Review Board (9844) also reviewed the clinical protocol. The Sidney Kimmel Comprehensive Cancer Center Clinical Research Review Committee and Safety Monitoring Committee were responsible for reviewing accrual and safety data for this trial at least twice a year. The Protocol Chair and the study statistician reviewed the study as needed based on rate of accrual for toxicity monitoring during the dose expansion phase at least quarterly.

Sensitization of the immune-suppressed tumor microenvironment (TME) of breast cancer by histone deacetylase inhibition shows promise, but the mechanisms of sensitization are unknown. We investigated the TME of breast-to-lung metastases by combining experimental and clinical data with theory. Knowledge-guided subclustering of single-cell RNA-sequencing data and cell circuits analysis identified 39 cell states and salient interactions, of which myeloid, T cell and B cell subpopulations were most affected by treatment. Using functional immunologic assays, we verified that inhibition of the ICAM pathway partially recapitulated treatment effects. Mathematical modeling of tumor-immune dynamics confirmed that tumor reduction required simultaneous modulation of multiple TME interactions. We found evidence that treatment affected anti-tumor antibody production. Analysis of patient biopsies via spatial proteomics corroborated preclinical findings: in responders we observed increased B cell activation, mature tertiary lymphoid structures, and increased CD8+ T cell-macrophage distances with treatment. Overall, this study provides a framework for the discovery of cell-cell interactions that govern responses in complex TMEs.