Background To investigate vascular-related pathophysiological characteristics of two human lung cancers with modifiable vascularisation using MRI and CT. Methods Tumour xenografts with modifiable vascularisation were established in 71 rats (approval by the Animal Care Committee was obtained) by subcutaneous transplantation of two human non-small-cell lung cancer (NSCLC) cells (A549, H1299) either alone or co-transplanted with vascular growth promoters. The vascularity of the tumours was assessed noninvasively by MRI diffusion-weighted-imaging (DWI), T2-weighted, and time-of-flight (TOF) sequences) as well as contrast-enhanced CT (CE-CT), using clinical scanners. As a reference standard, histological examinations (CD-31, fluorescent beads) were done after explantation. Results Microvessel density (MVD) was higher in co-transplanted tumours (171 ± 19 number/mm2) than in non-co-transplanted tumours (111 ± 11 number/mm2; p = 0.002). Co-transplanted tumours showed higher growth rates and larger tumour vessels at TOF-MRI as well as larger necrotic areas at CE-CT. In co-transplanted tumours, DWI revealed higher cellularity (lower minimal ADCdiff 166 ± 15 versus 346 ± 27 mm2/s × 10−6; p < 0.001), highly necrotic areas (higher maximal ADCdiff 1695 ± 65 versus 1320 ± 59 mm2/s × 10−6; p < 0.001), and better-perfused tumour stroma (higher ADCperf 723 ± 36 versus 636 ± 51 mm2/s × 10−6; p = 0.005). Significant correlations were found using qualitative and quantitative parameters: maximal ADCperf and MVD (r = 0.326); maximal ADCdiff and relative necrotic volume on CE-CT (r = 0.551); minimal ADCdiff and MVD (r = −0.395). Conclusions Pathophysiological differences related to vascular supply in two human lung cancer cell lines with modifiable vascularity are quantifiable with clinical imaging techniques. Imaging parameters of vascularisation correlated with the results of histology. DWI was able to characterise both the extent of necrosis and the level of perfusion.

Background To investigate vascular-related pathophysiological characteristics of two human lung cancers with modifiable vascularisation using MRI and CT. Methods Tumour xenografts with modifiable vascularisation were established in 71 rats (approval by the Animal Care Committee was obtained) by subcutaneous transplantation of two human non-small-cell lung cancer (NSCLC) cells (A549, H1299) either alone or co-transplanted with vascular growth promoters. The vascularity of the tumours was assessed noninvasively by MRI diffusion-weighted-imaging (DWI), T2-weighted, and time-of-flight (TOF) sequences) as well as contrast-enhanced CT (CE-CT), using clinical scanners. As a reference standard, histological examinations (CD-31, fluorescent beads) were done after explantation. Results Microvessel density (MVD) was higher in co-transplanted tumours (171 ± 19 number/mm2) than in non-co-transplanted tumours (111 ± 11 number/mm2; p = 0.002). Co-transplanted tumours showed higher growth rates and larger tumour vessels at TOF-MRI as well as larger necrotic areas at CE-CT. In co-transplanted tumours, DWI revealed higher cellularity (lower minimal ADCdiff 166 ± 15 versus 346 ± 27 mm2/s × 10−6; p < 0.001), highly necrotic areas (higher maximal ADCdiff 1695 ± 65 versus 1320 ± 59 mm2/s × 10−6; p < 0.001), and better-perfused tumour stroma (higher ADCperf 723 ± 36 versus 636 ± 51 mm2/s × 10−6; p = 0.005). Significant correlations were found using qualitative and quantitative parameters: maximal ADCperf and MVD (r = 0.326); maximal ADCdiff and relative necrotic volume on CE-CT (r = 0.551); minimal ADCdiff and MVD (r = −0.395). Conclusions Pathophysiological differences related to vascular supply in two human lung cancer cell lines with modifiable vascularity are quantifiable with clinical imaging techniques. Imaging parameters of vascularisation correlated with the results of histology. DWI was able to characterise both the extent of necrosis and the level of perfusion.

Cancer cells use the interaction between immune-checkpoint receptor programmed cell death protein 1 (PD-1) on activated T cells and programmed cell death ligand 1 (PD-L1) on tumor cells and various cell types of the tumor microenvironment to evade immune surveillance. Blocking the interaction between PD-1 and PD-L1 with checkpoint inhibitors can improve T-cell reactions and mediate efficient antitumor activity in a variety of solid tumors including melanoma. However, clinical data from patients with myeloid diseases that are treated with these agents are limited to clinical trials in advanced disease. Pembrolizumab (PEM) is a humanized monoclonal antibody of the immunoglobulin G4/κ isotype designed to block PD-1/PD-L1 interactions and is approved for various solid tumors including advanced melanoma.

Die pädiatrische Akute Lymphatische Leukämie ist heutzutage gut behandelbar. Trotzdem ist die Prognose im Falle eines Rezidives weiterhin schlecht. Die häufigsten extramedullären Orte für Rezidive sind das zentrale Nervensystem und der Hoden. Um ein Rezidiv im Hoden zu verhindern, ist es nötig die zellulären und molekularen Vorgänge zu verstehen. Dafür wurde Patientenmaterial auf seine Expression bestimmter Oberflächenmoleküle analysiert. Verglichen wurden Proben von Patienten mit verschiedenen Rezidiv-Arten. Um die funktionellen Aspekte der Hodenphysiologie auf die Leukämiezellmigration und -lokalisation zu untersuchen wurde ein PDX-ALL Mausmodel mit Hodenbeteiligung etabliert. Um potenziell involvierte Chemokin-Chemokinrezeptor-Achsen zu identifizieren, wurden 55 Knochenmarksproben von Patienten untersucht. Die Expressionsmuster der Rezeptoren wurde mittels Durchflusszytometrie analysiert. Es wurde festgestellt, dass CXCR4 meistens sehr hoch exprimiert wird. Deshalb wurde anschließend der Einfluss der CXCR4-CXCL12 Achse in in vitro Versuchen mit Hilfe primären Hodenstromas untersucht. Um verschiedene Subpopulationen zu untersuchen, wurde die Isolation von Hodenmakrophagen, Sertoli Zellen und Peritubulären Zellen aus der Maus etabliert und ihr Einfluss auf ALL Zellen untersucht. Es wurde festgestellt, dass Hodenmakrophagen bei Tumorkontakt ihren Phänotyp zugunsten einer tumorfördernden Subpopulation verändern. Zu guter Letzt wurde ein adaptives PDX-ALL Mausmodel mit Hodenbeteiligung entwickelt. Dabei wurden die Hoden von vorpubertären Mäusen bevorzugt infiltriert. Die Bedeutung der CXCR4-CXCL12 Achse für die Hodeninfiltration wurde in einem in vivo Versuch validiert. Während Knochenmark und Milz nach einer anti-CXCR4 Gabe kleine ALL Populationen aufwiesen, war der Hoden komplett Tumor-frei. Das Model kann für Versuche genutzt werden, um weitere Signalwege zu identifizieren, welche in die Hoden gerichtete Migration und das Überleben der Zellen involviert sind. / Advancing therapy strategies led to event-free-survival increase of paediatric acute lymphoblastic leukaemia (ALL). Relapses that occur are often drug resistant and come with poor prognosis. Extramedullary sites for relapse are the central nervous system (CNS) and the testis. To prevent testicular relapse, factors responsible for the infiltration and survival need to be discovered. Primary patient material was analysed with regard to differential expression of surface molecules on leukemic cells from BM. To analyse functional aspects of testis physiology on leukemic cell migration and localisation an adoptive PDX-ALL mouse model with testicular involvement was established. To identify potential chemokine-chemokine receptor axes responsible for the leukaemia cell migration towards the testis, a characterization of 55 patient BM samples was performed. The expression pattern of chemokine receptors on BM derived leukaemia cells was compared by flow cytometry. CXCR4 was identified to be highly expressed on patients cells, regardless of the subclass of relapse. Relevance of the CXCR4-CXCL12 axis was studied in vitro. Primary testicular stroma cultures were available, which provided a useful tool to examine testis directed migration. Isolation of testicular macrophages, Sertoli cells and peritubular cells was established and their impact on ALL cell survival was analysed. The macrophages were found to alter their phenotype upon ALL cell contact towards a tumour favourable subtype. Most importantly, a murine adoptive patient-derived xenograft (PDX)-ALL cell transfer model with testicular involvement was established. Testes of pre-puberty mice were preferentially infiltrated. Blocking CXCR4 with an antibody validated relevance of the CXCR4-CXCL12 signalling axis. The testis showed no infiltration in anti-CXCR4 treated animals. The mouse model will be useful to identify and validate further signalling pathways, participating in testis directed migration and survival.