Vascular endothelial growth factor A amplification in colorectal cancer is associated with reduced M1 and M2 macrophages and diminished PD-1-expressing lymphocytes

<div><p>VEGFA is an angiogenic factor secreted by tumors, in particular those with <i>VEGFA</i> amplification, as well as by macrophages and lymphocytes in the tumor microenvironment. Here we sought to define the presence of M1/M2 macrophages, PD-1-positive lymphocytes and PD-L1 tumoral and stromal expression in colorectal cancers harboring <i>VEGFA</i> amplification or chromosome 6 polysomy. 38 CRCs of which 13 harbored <i>VEGFA</i> amplification, 6 with Chr6 polysomy and 19 with neutral <i>VEGFA</i> copy number were assessed by immunohistochemistry for CD68 (marker for M1/M2 macrophages), CD163 (M2 macrophages), programmed death 1(PD-1)- tumor infiltrating and stromal lymphocytes as well as tumoral and stromal PD-1 ligand (PD-L1) expression. CRCs with <i>VEGFA</i> amplification or Chr6 polysomy were associated with decreased M1/M2 macrophages, reduced PD-1-expressing lymphocyte infiltration, as well as reduced stromal expression of PD-L1 at the tumor front. Compared to intermediate-grade CRCs, high-grade CRCs were associated with increased M1/M2 macrophages and increased tumoral expression of PD-L1. Our results suggest that <i>VEGFA</i> amplification or Chr6 polysomy is associated with an altered tumor immune microenvironment.</p></div

Number of macrophages in colorectal cancers, using CD68 and CD163 markers.

<p>Boxplots depict the number of (A, C) CD68+ and (B, D) CD163+ cells (A, B) in CRCs with and without <i>VEGFA</i> amplification/polysomy and (C, D) in CRCs of intermediate and high grade.</p

<i>VEGFA</i> copy number status in colorectal cancers measured by fluorescent <i>in situ</i> hybridization.

<p>Representative micrographs of (A) diploid, (B) polysomic and (C) amplified <i>VEGFA</i> using fluorescent <i>in situ</i> hybridization (FISH). FISH analysis was performed using two-color probes for <i>VEGFA</i> (red) and internal control (green). Scale bar 20 μm.</p

PD-1-positive tumor infiltrating and stromal lymphocytes and PD-L1 tumoral and stromal expression in colorectal cancers.

<p>Barplots depict the number of samples with high, low and negative expression of (A, B) PD-1 and (C, D) PD-L1 in (A, C) tumoral and (B, D) stromal areas of CRCs.</p

Distribution of macrophages in colorectal cancers, using CD68 and CD163 markers.

<p>Representative micrographs of (A, C) CD68+ cells and (B, D) CD163+ cells (A, B) at the invasive tumor front (T) and (C, D) in the surrounding tumor tissue (S). Magnification 40X. Scale bar 20 μm.</p

Uncertainties and controversies in axillary management of patients with breast cancer

The aims of this Oncoplastic Breast Consortium and European Breast Cancer Research Association of Surgical Trialists initiative were to identify uncertainties and controversies in axillary management of early breast cancer and to recommend appropriate strategies to address them. By use of Delphi methods, 15 questions were prioritized by more than 250 breast surgeons, patient advocates and radiation oncologists from 60 countries. Subsequently, a global virtual consensus panel considered available data, ongoing studies and resource utilization. It agreed that research should no longer be prioritized for standardization of axillary imaging, de-escalation of axillary surgery in node-positive cancer and risk evaluation of modern surgery and radiotherapy. Instead, expert consensus recommendations for clinical practice should be based on current evidence and updated once results from ongoing studies become available. Research on de-escalation of radiotherapy and identification of the most relevant endpoints in axillary management should encompass a meta-analysis to identify knowledge gaps, followed by a Delphi process to prioritize and a consensus conference to refine recommendations for specific trial designs. Finally, treatment of residual nodal disease after surgery was recommended to be assessed in a prospective register.</p