IL-6 Trans-Signaling Is Increased in Diabetes, Impacted by Glucolipotoxicity, and Associated With Liver Stiffness and Fibrosis in Fatty Liver Disease.

Many people living with diabetes also have nonalcoholic fatty liver disease (NAFLD). Interleukin-6 (IL-6) is involved in both diseases, interacting with both membrane-bound (classical) and circulating (trans-signaling) soluble receptors. We investigated whether secretion of IL-6 trans-signaling coreceptors are altered in NAFLD by diabetes and whether this might associate with the severity of fatty liver disease. Secretion patterns were investigated with use of human hepatocyte, stellate, and monocyte cell lines. Associations with liver pathology were investigated in two patient cohorts: 1) biopsy-confirmed steatohepatitis and 2) class 3 obesity. We found that exposure of stellate cells to high glucose and palmitate increased IL-6 and soluble gp130 (sgp130) secretion. In line with this, plasma sgp130 in both patient cohorts positively correlated with HbA1c, and subjects with diabetes had higher circulating levels of IL-6 and trans-signaling coreceptors. Plasma sgp130 strongly correlated with liver stiffness and was significantly increased in subjects with F4 fibrosis stage. Monocyte activation was associated with reduced sIL-6R secretion. These data suggest that hyperglycemia and hyperlipidemia can directly impact IL-6 trans-signaling and that this may be linked to enhanced severity of NAFLD in patients with concomitant diabetes. ARTICLE HIGHLIGHTS: IL-6 and its circulating coreceptor sgp130 are increased in people with fatty liver disease and steatohepatitis. High glucose and lipids stimulated IL-6 and sgp130 secretion from hepatic stellate cells. sgp130 levels correlated with HbA1c, and diabetes concurrent with steatohepatitis further increased circulating levels of all IL-6 trans-signaling mediators. Circulating sgp130 positively correlated with liver stiffness and hepatic fibrosis. Metabolic stress to liver associated with fatty liver disease might shift the balance of IL-6 classical versus trans-signaling, promoting liver fibrosis that is accelerated by diabetes.

Intravoxel incoherent motion diffusion-weighted MRI for the characterization of inflammation in chronic liver disease.

OBJECTIVE: To evaluate the diagnostic performance of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) for grading hepatic inflammation. METHODS: In this retrospective cross-sectional dual-center study, 91 patients with chronic liver disease were recruited between September 2014 and September 2018. Patients underwent 3.0-T MRI examinations within 6 weeks from a liver biopsy. IVIM parameters, perfusion fraction (f), diffusion coefficient (D), and pseudo-diffusion coefficient (D*), were estimated using a voxel-wise nonlinear regression on DWI series (10 b-values from 0 to 800 s/mm2). The reference standard was histopathological analysis of hepatic inflammation grade, steatosis grade, and fibrosis stage. Intraclass correlation coefficients (ICC), univariate and multivariate correlation analyses, and areas under receiver operating characteristic curves (AUC) were assessed. RESULTS: Parameters f, D, and D* had ICCs of 0.860, 0.839, and 0.916, respectively. Correlations of f, D, and D* with inflammation grade were ρ = - 0.70, p < 0.0001; ρ = 0.10, p = 0.35; and ρ = - 0.27, p = 0.010, respectively. When adjusting for fibrosis and steatosis, the correlation between f and inflammation (p < 0.0001) remained, and that between f and fibrosis was also significant to a lesser extent (p = 0.002). AUCs of f, D, and D* for distinguishing inflammation grades 0 vs. ≥ 1 were 0.84, 0.53, and 0.70; ≤ 1 vs. ≥ 2 were 0.88, 0.57, and 0.60; and ≤ 2 vs. 3 were 0.86, 0.54, and 0.65, respectively. CONCLUSION: Perfusion fraction f strongly correlated, D very weakly correlated, and D* weakly correlated with inflammation. Among all IVIM parameters, f accurately graded inflammation and showed promise as a biomarker of hepatic inflammation. KEY POINTS: • IVIM parameters derived from DWI series with 10 b-values are reproducible for liver tissue characterization. • This retrospective two-center study showed that perfusion fraction provided good diagnostic performance for distinguishing dichotomized grades of inflammation. • Fibrosis is a significant confounder on the association between inflammation and perfusion fraction.

Impact of temporal resolution and motion correction for dynamic contrast-enhanced MRI of the liver using an accelerated golden-angle radial sequence.

This paper presents a prospective study evaluating the impact on image quality and quantitative dynamic contrast-enhanced (DCE)-MRI perfusion parameters when varying the number of respiratory motion states when using an eXtra-Dimensional Golden-Angle Radial Sparse Parallel (XD-GRASP) MRI sequence. DCE acquisition was performed using a 3D stack-of-stars gradient-echo golden-angle radial acquisition in free-breathing with 100 spokes per motion state and temporal resolution of 6 s/volume, and using a non-rigid motion compensation to align different motion states. Parametric analysis was conducted using a dual-input single-compartment model. Nonparametric analysis was performed on the time-intensity curves. A total of 22 hepatocellular carcinomas (size: 11-52 mm) were evaluated. XD-GRASP reconstructed with increasing number of spokes for each motion state increased the signal-to-noise ratio (SNR) (p < 0.05) but decreased temporal resolution (0.04 volume/s vs 0.17 volume/s for one motion state) (p < 0.05). A visual scoring by an experienced radiologist show no change between increasing number of motion states with same number of spokes using the Likert score. The normalized maximum intensity time ratio, peak enhancement ratio and tumor arterial fraction increased with decreasing number of motion states (p < 0.05) while the transfer constant from the portal venous plasma to the surrounding tissue significantly decreased (p < 0.05). These same perfusion parameters show a significant difference in case of tumor displacement more than 1 cm (p < 0.05) whereas in the opposite case there was no significant variation. While a higher number of motion states and higher number of spokes improves SNR, the resulting lower temporal resolution can influence quantitative parameters that capture rapid signal changes. Finally, fewer displacement compensation is advantageous with lower number of motion state due to the higher temporal resolution. XD-GRASP can be used to perform quantitative perfusion measures in the liver, but the number of motion states may significantly alter some quantitative parameters.

MRI cine-tagging of cardiac-induced motion for noninvasive staging of liver fibrosis.

BACKGROUND: MR elastography is a noninvasive technique that provides high diagnostic accuracy for the staging of liver fibrosis; however, it requires external hardware and mainly assesses the right lobe. PURPOSE: To evaluate the diagnostic performance of MRI cine-tagging for staging fibrosis in the left liver lobe, using biopsy as the reference standard. STUDY TYPE: Institutional Review Board (IRB)-approved two-center prospective study. POPULATION: Seventy-six patients with chronic liver disease who underwent an MRI cine-tagging examination and a liver biopsy within a 6-week interval. FIELD STRENGTH/SEQUENCE: 2D-GRE multislice sequence at 3.0T with spatial modulation of the magnetization preparation sequence and peripheral pulse-wave triggering on two coronal slices chosen underneath the heart apex to capture maximal deformation with consecutive breath-holds adapted to patient cardiac frequency. ASSESSMENT: A region of interest was selected in the liver close to the heart apex. Maximal strain was evaluated with the harmonic phase (HARP) technique. STATISTICAL TESTS: Spearman's correlation, Kruskal-Wallis test, Mann-Whitney U-test, and receiver operating characteristic (ROC) analysis were performed. RESULTS: Liver strain measured on tagged images decreased with higher histological fibrosis stage (ρ = -0.68, P < 0.0001). Strain values were significantly different between all fibrosis stages (P < 0.0001), and between groups of fibrosis stages ≤F3 vs. F4 (P < 0.05). Areas under the ROC curves were 0.95 (95% confidence interval: 0.89-1.00) to distinguish fibrosis stages F0 vs. F4, 0.81 (0.70-0.92) for stages F0 vs. ≥F1, 0.84 (0.76-0.93) for stages ≤F1 vs. ≥F2, 0.86 (0.78-0.94) for stages ≤F2 vs. ≥F3, and 0.87 (0.77-0.96) for stages ≤F3 vs. F4. DATA CONCLUSION: MRI cine-tagging is a promising technique for measuring liver strain without additional elastography hardware. It could be used to assess the left liver lobe as a complement to current techniques assessing the right lobe. LEVEL OF EVIDENCE: 1 Technical Efficacy: 3 J. Magn. Reson. Imaging 2020;51:1570-1580.

Dynamic contrast-enhanced MRI to assess hepatocellular carcinoma response to Transarterial chemoembolization using LI-RADS criteria: A pilot study.

PURPOSE: To identify quantitative dynamic contrast-enhanced (DCE)-MRI perfusion parameters indicating tumor response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE). MATERIALS AND METHODS: This prospective pilot study was approved by our institutional review board; written and informed consent was obtained for each participant. Patients underwent DCE-MRI examinations before and after TACE. A variable flip-angle unenhanced 3D mDixon sequence was performed for T1 mapping. A dynamic 4D mDixon sequence was performed after contrast injection for assessing dynamic signal enhancement. Nonparametric analysis was conducted on the time-intensity curves. Parametric analysis was performed on the time-concentration curves using a dual-input single-compartment model. Treatment response according to Liver Reporting and Data System (LI-RADS) v2018 was used as the reference standard. The comparisons within groups (before vs. after treatment) and between groups (nonviable vs. equivocal or viable tumor) were performed using nonparametric bootstrap taking into account the clustering effect of lesions in patients. RESULTS: Twenty-eight patients with 52 HCCs (size: 10-104 mm) were evaluated. For nonviable tumors (n = 27), time to peak increased from 62.5 ±â€¯18.2 s before to 83.3 ±â€¯12.8 s after treatment (P< 0.01). For equivocal or viable tumors (n = 25), time to peak and mean transit time significantly increased (from 54.4 ±â€¯24.1 s to 69.5 ±â€¯18.9 s, P < 0.01 and from 14.2 ±â€¯11.8 s to 33.9 ±â€¯36.8 s, P= 0.01, respectively) and the transfer constant from the extracellular and extravascular space to the central vein significantly decreased from 14.8 ±â€¯14.1 to 8.1 ±â€¯9.1 s-1 after treatment (P= 0.01). CONCLUSION: This prospective pilot DCE-MRI study showed that time to peak significantly changed after TACE treatment for both groups (nonviable tumors and equivocal or viable tumors). In our cohort, several perfusion parameters may provide an objective marker for differentiation of treatment response after TACE in HCC patients.

Risk-adapted stereotactic ablative radiotherapy for central and ultra-central lung tumours.

BACKGROUND: SABR is a widely accepted treatment for early-stage lung cancer but there are safety concerns for central and ultra-central tumours. Herein we report our experience using risk-adapted fractionation (prescribed doses: 40-60 Gy in 3-8 fractions) with prioritization of dose to organs at risk. METHODS: Patient declining or unsuitable for surgery with primitive or recurrent lung cancer were included. Tumours inside a 2 cm area around proximal bronchial tree (PBT) were classified as central while tumours with PTV overlapping PBT, oesophagus, great vessels and pericardial pleura were classified as ultra-central. We assessed overall survival (OS), disease-free survival (DFS), local control (LC) and toxicities. RESULTS: From 2009 to 2016, 137 patients were treated (median age: 75 years), with 60 central and 77 ultra-central tumours. Median follow-up was 36 months. Median tumour size, GTV and PTV were 2.5 cm (0.9-7), 7.8 cm3 (0.7-94.2) and 30.6 cm3 (6.5-274.3), respectively. For the whole population, median OS and DFS were 46 months and 33 months. One- and 2-years LC rates were 95% and 81%. Median OS between central and ultra-central tumours was statistically different with 57 vs 37 months (HR 0.48, p = 0.017), but LC was not different among them. We observed 4 Grade 3 and 6 Grade 5 toxicities (no grade 4). CONCLUSIONS: SABR for central and ultra-central tumours is associated with good OS, DFS and LC rates, with 7.3% grade 3-5 toxicities. Central tumours had a better prognosis in our cohort.

Central3D: A Computer Tool to Help Clinicians Differentiate Central and Peripheral Lung Tumors.

PURPOSE: We present a concise description of an in-house decision aid software called "Central3D" that allows a quick and robust lung tumor classification between central and peripheral as defined by the Radiation Therapy Oncology Group (RTOG) 0813. METHODS AND MATERIALS: Twenty cases of lung tumors were selected for this study and four radiation oncologists blindly classified them as peripheral versus central without assistance of our software. All discordant cases were reviewed using Central3D and prompt consensus was obtained. RESULTS: Many authors have stressed the importance of adopting risk adaptive fractionation schedule with lower biological equivalent dose when treating centrally-located high risks lesions. Central3D addresses the limitation of current treatment planning systems to represent image data in fixed planes and can help radiation oncologists to fully characterize these pulmonary lesions.