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Background: Extracellular volume (ECV) correlates with the degree of liver fibrosis. Purpose: To analyze the performance of liver MRI‐based ECV evaluations with different blood pool measurements at different time points. Study Type: Prospective. Sample: 73 consecutive patients (n = 31 females, mean age 56 years) with histopathology‐proven liver fibrosis. Field Strength/Sequence: 3T acquisition within 90 days of biopsy, including shortened modified look–locker inversion recovery T1 mapping. Assessment: Polygonal regions of interest were manually drawn in the liver, aorta, vena cava, and in the main, left and right portal vein on four slices before and after Gd‐DOTA administration at 5/10/15 minutes. ECV was calculated 1) on one single slice on portal bifurcation level, and 2) averaged over all four slices. Statistical Tests: Parameters were compared between patients with fibrosis grades F0‐2 and F3‐F4 with the Mann–Whitney U and fishers exact test. ROC analysis was used to assess the performance of the parameters to predict F3‐4 fibrosis. A P‐value <0.05 was considered statistically significant. Results: ECV was significantly higher in F3‐4 fibrosis (35.4% [33.1%–37.6%], 36.1% [34.2%–37.5%], and 37.0% [34.8%–39.2%] at 5/10/15 minutes) than in patients with F0‐2 fibrosis (33.3% [30.8%–34.8%], 33.7% [31.6%–34.7%] and 34.9% [32.2%–36.0%]; AUC = 0.72–0.75). Blood pool T1 relaxation times in the aorta and vena cava were longer on the upper vs. lower slices at 5 minutes, but not at 10/15 minutes. AUC values were similar when measured on a single slice (AUC = 0.69–0.72) or based on blood pool measurements in the cava or portal vein (AUC = 0.63–0.67 and AUC = 0.65–0.70). Data Conclusion: Liver ECV is significantly higher in F3‐4 fibrosis compared to F0‐2 fibrosis with blood pool measurements performed in the aorta, inferior vena cava, and portal vein at 5, 10, and 15 minutes. However, a smaller variability was observed for blood pool measurements between slices at 15 minutes. Level of Evidence: 1 Technical Efficacy: Stage 3 [ABSTRACT FROM AUTHOR]

Introduction: The standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection. Methods: To prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus. Results: Repeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both Tcellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62– 84% reduction in NETs after stimulated neutrophils were treated with tacrolimus. Conclusion: Our data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target. [ABSTRACT FROM AUTHOR]