Background: Small-for-size syndrome looms over patients needing liver resection or living-donor transplantation. Hypoxia has been shown to be crucial for the successful outcome of liver resection in the very early postoperative phase. While poorly acceptable as such in real-world clinical practice, hypoxia responses can still be simulated by pharmacologically raising levels of its transducers, the hypoxia-inducible factors (HIF). We aimed to assess the potential role of a selective inhibitor of HIF degradation in 70% hepatectomy (70%Hx). Methods: In a pilot study, we tested the required dose of roxadustat to stabilize liver HIF1α. We then performed 70%Hx in 8-week-old male Lewis rats and administered 25 mg/kg of roxadustat (RXD25) at the end of the procedure. Regeneration was assessed: ki67 and EdU immunofluorescent labeling, and histological parameters. We also assessed liver function via a blood panel and functional gadoxetate-enhanced magnetic resonance imaging, up to 47 hours after the procedure. Metabolic results were analyzed by means of RNA sequencing. Results: Roxadustat effectively increased early HIF1α transactivity. Liver function did not appear to be improved nor liver regeneration to be accelerated by the experimental compound. However, treated livers showed a mitigation in hepatocellular steatosis and ballooning, known markers of cellular stress after liver resection. RNA sequencing confirmed that roxadustat unexpectedly increases lipid breakdown and cellular respiration. Conclusions: Selective HIF stabilization did not result in an enhanced liver function after standard liver resection, but it induced interesting metabolic changes that are worth studying for their possible role in extended liver resections and fatty liver diseases.

BackgroundMicrostructure analyses are gaining interest in cancer MRI as an alternative to the conventional apparent diffusion coefficient (ADC), of which the determinants remain unclear.PurposeTo assess the sensitivity of parameters calculated from a double diffusion encoding (DDE) sequence to changes in a tumor's microstructure early after radiotherapy and to compare them with ADC and histology.Study TypeCohort study on experimental tumors.Animal ModelSixteen WAG/Rij rats grafted with one rhabdomyosarcoma fragment in each thigh. Thirty‐one were imaged at days 1 and 4, of which 17 tumors received a 20 Gy radiation dose after the first imagery.Field Strength/Sequence3T. Diffusion‐weighted imaging, DDE with flow compensated, and noncompensated measurements.Assessments1) To compare, after irradiation, DDE‐derived parameters (intracellular fraction, cell size, and cell density) to their histological counterparts (fraction of stained area, minimal Feret diameter, and nuclei count, respectively). 2) To compare percentage changes in DDE‐derived parameters and ADC. 3) To evaluate the evolution of DDE‐derived parameters describing perfusion.Statistical TestsWilcoxon rank sum test.Results1) Intracellular fraction, cell size, and cell density were respectively lower (−24%, P < 0.001), higher (+7.5%, P < 0.001) and lower (−38%, P < 0.001) in treated tumors as compared to controls. Fraction of stained area, minimal Feret diameter, and nuclei count were respectively lower (−20%, P < 0.001), higher (+28%, P < 0.001), and lower (−34%, P < 0.001) in treated tumors. 2) The magnitude of ADC's percentage change due to irradiation (16.4%) was superior to the one of cell size (8.4%, P < 0.01) but inferior to those of intracellular fraction (35.5%, P < 0.001) and cell density (42%, P < 0.001). 3) After treatment, the magnitude of the vascular fraction's decrease was higher than the increase of flow velocity (33.3%, vs. 13.3%, P < 0.001).Data ConclusionThe DDE sequence allows quantitatively monitoring the effects of radiotherapy on a tumor's microstructure, whereas ADC only reveals global changes.Evidence Level2.Technical EfficacyStage 4. J. Magn. Reson. Imaging 2020;52:941–951.