Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast.

Since a detailed inventory of endothelial cell (EC) heterogeneity in breast cancer (BC) is lacking, here we perform single cell RNA-sequencing of 26,515 cells (including 8433 ECs) from 9 BC patients and compare them to published EC taxonomies from lung tumors. Angiogenic ECs are phenotypically similar, while other EC subtypes are different. Predictive interactome analysis reveals known but also previously unreported receptor-ligand interactions between ECs and immune cells, suggesting an involvement of breast EC subtypes in immune responses. We also identify a capillary EC subtype (LIPEC (Lipid Processing EC)), which expresses genes involved in lipid processing that are regulated by PPAR-γ and is more abundant in peri-tumoral breast tissue. Retrospective analysis of 4648 BC patients reveals that treatment with metformin (an indirect PPAR-γ signaling activator) provides long-lasting clinical benefit and is positively associated with LIPEC abundance. Our findings warrant further exploration of this LIPEC/PPAR-γ link for BC treatment.

In-depth characterization of the tumor microenvironment in central nervous system lymphoma reveals implications for immune-checkpoint therapy.

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma with an aggressive clinical course. To investigate the potential of immune-checkpoint therapy, we retrospectively studied the tumor microenvironment (TME) using high-plex immunohistochemistry in 22 PCNSL and compared to 7 secondary CNS lymphomas (SCNSL) and 7 "other" CNSL lymphomas with the presence of the Epstein-Barr virus and/or compromised immunity. The TME in PCNSL was predominantly composed of CD8+ cytotoxic T cells and CD163+ phagocytes. Despite molecular differences between PCNSL and SCNSL, the cellular composition and the functional spectrum of cytotoxic T cells were similar. But cytotoxic T cell activation was significantly influenced by pre-biopsy corticosteroids intake, tumor expression of PD-L1 and the presence of EBV. The presence of low numbers of CD8+ T cells and geographic-type necrosis each predicted inferior outcome in PCNSL. Both M1-like (CD68 + CD163low) and M2-like (CD68 + CD163high) phagocytes were identified, and an increased ratio of M1-like/M2-like phagocytes was associated with a better survival. PD-L1 was expressed in lymphoma cells in 28% of cases, while PD1 was expressed in only 0.4% of all CD8+ T cells. TIM-3, a marker for T cell exhaustion, was significantly more expressed in CD8posPD-1pos T cells compared to CD8posPD-1neg T cells, and a similar increased expression was observed in M2-like pro-tumoral phagocytes. In conclusion, the clinical impact of TME composition supports the use of immune-checkpoint therapies in PCNSL. Based on observed differences in immune-checkpoint expression, combinations that boost cytotoxic T cell activation (by blocking TIM-3 or TGFBR1) prior to the administration of PD-L1 inhibition could be of interest.

Metal debris after dental implant placement: A proof-of-concept study in fresh frozen cadavers using MRI and histological analysis.

PURPOSE: This report originated from the finding of metal artefacts on magnetic resonance images (MRI) which were not detected on panoramic radiography or cone beam computed tomography (CBCT) imaging. It was hypothesised that drills or implants might release metal particles during surgical procedures in the jawbones. Therefore, the aim was to assess whether dental implants or surgical drills might cause metal debris in the surrounding tissues. MATERIALS AND METHODS: The experiment consisted of a postmortem and an antemortem model. A split-mouth design was carried out in a postmortem fresh frozen cadaver head. In the left mandible only the drill preparation sequence was performed, whereas in the right mandible, the drill sequence was followed by implant placement. Before surgery, the postmortem model underwent a baseline MRI acquisition. A second MRI (MRI2) was acquired after performing the osteotomies on both sides and implant placement on the right side. Finally, the implants were carefully removed, and a final MRI (MRI3) was acquired. Bone blocks containing the implant and osteotomy sites were isolated. For the antemortem model, a fresh frozen cadaver head was selected that already had implants in place. An implant in the anterior maxilla was removed and the surrounding bone block was isolated as well. A histological analysis was prepared for both models. RESULTS: In the antemortem model, histological analysis showed irregular-shaped dark particles near the bone-implant interface consistent with metal debris. Additionally, in the postmortem model, both sites showed metal artefacts on MRI2 and MRI3, and by using a balanced fast field echo sequence, and histological analysis, the suspected particles of metal debris were confirmed on both sides of the mandible. CONCLUSIONS: Further studies should investigate the origin and extent of the metal debris following implant placement, as well as its clinical significance, possible risk factors and preventive measures.