Non-invasive tests for liver fibrosis assessment in patients with chronic liver diseases: a prospective study.

There is an urgent need of non-invasive tests (NITs) for monitoring treatment response and disease progression in chronic liver disease. Liver stiffness (LS) evaluated by transient elastography (TE), shear wave elastography (SWE), and magnetic resonance elastography (MRE) and serum markers e.g. APRI and FIB-4 scores were assessed at baseline and the 1-year follow-up. In all, 89 chronic hepatitis C virus (HCV) patients with sustained virological response and 93 non-alcoholic fatty liver disease (NAFLD) patients were included. There was a significantly strong correlation among imaging techniques. Using MRE as the reference standard, the area under the receiver operating characteristics curves for TE, SWE, APRI, and FIB-4 in detecting stage1-4 fibrosis were 0.88-0.95, 0.87-0.96, 0.83-0.89, and 0.79-0.92, respectively. In chronic HCV patients, the values of TE, SWE, MRE, APRI and FIB-4 significantly decreased from baseline to the 1-year follow-up. Liver steatosis did not significantly change over time. In NAFLD, compared to obese patients, non-obese patients had less LS and steatosis at baseline, and these values did not show significant changes at the 1-year follow-up. Our study suggests that the current NITs have a good correlation and accuracy in monitoring the treatment outcomes in patients with chronic liver diseases.

Effect of vitamin D supplementation in patients with chronic hepatitis C after direct-acting antiviral treatment: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Replacement of vitamin D (VD) among patients with chronic hepatitis C (CHC) before viral eradication has demonstrated a protective effect on serum markers associated with hepatic fibrogenesis. We therefore hypothesized that VD may facilitate further fibrosis amelioration following curative treatment with direct-acting antivirals (DAA). METHODS: This study was a randomized, double-blind, placebo-controlled trial conducted between February 2018 and August 2018. Patients with CHC and VD deficiency were randomized in a 1:1 ratio to either receive ergicalciferol or placebo over 6 weeks. Biochemical analysis indicators, including 25-hydroxyvitamin D (25(OH)D), fibrogenic markers [(transforming growth factor beta 1 (TGF-ß1) and tissue inhibitors of matrix metalloproteinases 1 (TIMP-1)], and fibrolytic markers [matrix metalloproteinase 9 (MMP-9) and amino terminal type III procollagen peptide (P3NP)], were assessed at baseline and at 6 weeks. Serum 25(OH)D was analyzed by a chemiluminescence immunoassay. Serum hepatic fibrogenesis markers were measured using a quantitative sandwich enzyme-linked immunosorbent assay. RESULTS: Seventy-five patients with CHC and VD deficiency were randomly assigned to VD (n = 37) and placebo (n = 38) groups. At the end of the study, the mean serum 25(OH)D level had risen to a normal level in the VD group, but was still deficient in the placebo group (41.8 ±   9.1 vs. 18.1 ±  4.6 ng/mL, p < 0.001). Upon restoration of the VD level, there were no significant mean differences in the change from baseline for TGF-ß1 (-0.6 ng/mL (95% confidence interval (95% CI) [-2.8-1.7]), p = 0.63), TIMP-1 (-5.5 ng/mL (95% CI [-26.4 -15.3]), p = 0.60), MMP-9 (122.9 ng/mL (95% CI [-69.0 -314.8]), p = 0.21), and P3NP (-0.1 ng/mL (95% CI [-2.4 -2.2]), p = 0.92) between the VD and placebo groups. CONCLUSION: Short-term VD supplementation after DAA treatment in patients with CHC does not improve serum fibrogenesis markers and may not expedite the residual liver fibrosis healing process. Future studies are warranted to evaluate the long-term effect of VD supplementation on hepatic fibrosis regression.

The Prevalence of Nonalcoholic Fatty Liver Disease and Its Risk Factors in Children and Young Adults with Type 1 Diabetes Mellitus.

OBJECTIVES: To determine the prevalence of nonalcoholic fatty liver disease (NAFLD) and its associated risk factors in children and young adults with type 1 diabetes (T1D). STUDY DESIGN: A cross-sectional study was conducted at a tertiary care center in children and young adults with T1D. Liver fat quantification and hepatic fibrosis were assessed by magnetic resonance imaging proton density fat fraction and magnetic resonance elastography (MRE). Logistic regression analysis was performed to examine the associated risk factors for NAFLD. RESULTS: Fifty patients with T1D (28 females, 13 with overweight/obesity) were included. The median age and duration of T1D were 16.9 years (IQR, 13.6-20 years) and 6.5 years (IQR, 4-11 years), respectively. The prevalence of NAFLD was 10%. Four out of 5 patients with NAFLD were overweight/obese, and 2 had an and elevated alanine aminotransferase (ALT) level. None had liver fibrosis (defined as MRE >2.9 kPa). Compared with patients without NAFLD, patients with NAFLD had significantly higher body mass index standard deviation score (BMI-SDS) (median, 0.94 [IQR, 1.30-2.62] vs 0.13 [IQR, -0.69 to 0.84]; P = .01), ALT (median, 17 IU/L [IQR, 16-52 IU/L] vs 12 IU/L [IQR, 10-14 IU/L]; P = .02), and lower high-density lipoprotein cholesterol (median, 49 mg/dL [IQR, 41-51 mg/dL] vs 57 mg/dL [IQR, 52-69 mg/dL]; P = .039). Multivariate logistic regression analysis identified high BMI-SDS as the sole independent risk factor associated with NAFLD (OR, 5.79; 95% CI, 1.04-32.18). CONCLUSION: The prevalence of NAFLD in children and young adults with T1D was comparable to that in the general population. Our study suggests that routine screening for NAFLD in patients with T1D might not be necessary but should be performed in those patients with T1D who are overweight/obese.

Changes in hepatic fibrosis and vitamin D levels after viral hepatitis C eradication using direct-acting antiviral therapy.

BACKGROUND: Vitamin D (VD) is important in hepatic fibrogenesis in animal models and human studies. VD deficiency is associated with liver fibrosis progression. Metabolic dysfunction of the liver, as an intermediate organ for VD metabolism, contributes partly to this deficiency. We hypothesized that improving hepatic fibrosis and inflammation in chronic hepatitis C (CHC) patients after eradication with direct-acting antivirals (DAA) would increase 25-hydroxyVD [25(OH)VD] levels. METHODS: Eighty CHC patients (17 chronic hepatitis, and 63 cirrhosis) were enrolled. Baseline characteristics, hepatitis C viral load (VL), genotypes, liver enzymes and liver stiffness measurements (LSM) were assessed at baseline. Blood samples for 25(OH)VD and the procollagen type III N-terminal peptide (P3NP) were collected at baseline, 24 and 48 weeks. LSMs were re-evaluated at 48 weeks. Serum 25(OH)VD levels < 30 ng/mL were defined as VD insufficiency/deficiency. Paired t-tests were used for statistical analyses. RESULTS: Among 80 patients, the mean age was 57.7 ± 10.5 years, and 52.5% were men. The mean VL was 6.1 ± 0.7 logIU/mL with genotype 1 predominance (55%). All patients achieved sustained virological response. The alanine aminotransferase levels decreased from 79.9 ± 53.3 U/L at baseline to 25.7 ± 17.2 and 22.3 ± 11.0 U/L at 24 and 48 weeks, respectively (p < 0.001). The mean LSM decreased from 19.2 ± 15.3 to 11.7 ± 8.0 kPa at 48 weeks (p < 0.001). The P3NP levels decreased from 43.6 ± 22.0 ng/mL before treatment to 35.7 ± 21.1 and 29.4 ± 15.0 ng/mL at 24 and 48 weeks, respectively (p < 0.001). The proportions of VD insufficiency/deficiency were 72.5%, 91.3%, and 86.5% at baseline, 24 and 48 weeks, respectively. The 25(OH)VD levels decreased from 26.3 ± 10.7 ng/mL at baseline to 20.8 ± 8.1 and 20.8 ± 8.5 ng/mL at 24 and 48 weeks, respectively (p < 0.001). CONCLUSIONS: Curative treatment with DAA attenuated the liver stiffness and inflammation but did not improve VD levels. Over 80% of patients remained VD insufficient/deficient. Whether VD replacement during and after DAA therapy can improve hepatic fibrosis remains unclear. Trial registration The Thai Clinical Trial Registry as TCTR20161025001 (31 October 2016). http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=2136 .

Hepatopleural Fistula with Empyema Thoracis: A Rare Complication of Autosomal Dominant Polycystic Kidney Disease.

We report a 70-year-old man with autosomal dominant polycystic kidney disease (ADPKD) who presented with right-sided extended-spectrum beta-lactamases Escherichia coli empyema thoracis. Chest and abdominal computed tomography showed hepatopleural fistula. The patient refused a surgical operation and was treated with tube thoracotomy, percutaneous drainage of dominant liver cyst, and intravenous antibiotics. His symptoms improved after 2 months of nonsurgical treatment.

Electronic cleansing in computed tomography colonography using AT layer identification with integration of gradient directional second derivative and material fraction model.

BACKGROUND: In computed tomography colonography images, electronic cleansing (EC) is applied to remove opacified residual materials, called fecal-tagging materials (FTM), using positive-contrast tagging agents and laxative to facilitate polyp detection. METHODS: The proposed EC, EC prop , integrates the gradient directional second derivative into material fraction model to preserve submerged soft tissue (ST) under FTM. Three-material fraction model is used to remove FTM and artifacts at air-tagging (AT) layers and T-junctions where air, ST, and FTM material meet simultaneously. Moreover, the proposed AT layer identification is used to distinguish AT layers from air-tissue-tagging (ATT) layers in order to preserve ATT layers during cleansing. The clinical evaluation on 467 3-Dimensional band view images was conducted by the abdominal radiologist using four grading levels of cleansing quality with five causes of low quality EC. The amount of the remaining artifacts at T-junctions was approximated from the results of EC prop . The results from EC prop were compared with the results from syngo.via Client 3.0 Software, EC syngo , and the fast three-material modeling, EC prev , using the preference of the radiologist. Two-tailed paired Wilcoxon signed rank test is used to indicate statistical significance. RESULTS: The average grade on cleansing quality is 2.89 out of 4. The artifacts at T-junctions from 86.94% of the test images can be removed, whereas artifacts at T-junctions from only 13.06% of the test images cannot be removed. For 13.06% of the test images, the results from EC prop are more preferable to the results from EC syngo (p<0.008). For all the test images, the results from EC prop are more preferable to the results from EC prev (p<0.001). Finally, the visual assessment shows that EC prop can preserve ATT layers, submerged polyps and folds while EC prev can preserve only submerged folds but fails to preserve ATT layers. CONCLUSION: From our implementation, EC prop can improve the performance of the existing EC, such that it can preserve ST, especially ATT layers and remove the artifacts at T-junctions which have never been proposed by any other methods before.

Evaluation of a novel macromolecular cascade-polymer contrast medium for dynamic contrast-enhanced MRI monitoring of antiangiogenic bevacizumab therapy in a human melanoma model.

RATIONALE AND OBJECTIVES: To assess the applicability of a novel macromolecular polyethylene glycol (PEG)-core gadolinium contrast agent for monitoring early antiangiogenic effects of bevacizumab using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). MATERIALS AND METHODS: Athymic rats (n = 26) implanted with subcutaneous human melanoma xenografts underwent DCE-MRI at 2.0 T using two different macromolecular contrast agents. The PEG core cascade polymer PEG12,000-Gen4-(Gd-DOTA)16, designed for clinical development, was compared to the prototype, animal-only, macromolecular contrast medium (MMCM) albumin-(Gd-DTPA)35. The treatment (n = 13) and control (n = 13) group was imaged at baseline and 24 hours after a single dose of bevacizumab (1 mg) or saline to quantitatively assess the endothelial-surface permeability constant (K(PS), µL⋅min⋅100 cm(3)) and the fractional plasma volume (fPV,%), using a two-compartment kinetic model. RESULTS: Mean K(PS) values, assessed with PEG12,000-Gen4-(Gd-DOTA)16, declined significantly (P < .05) from 29.5 ± 10 µL⋅min⋅100 cm(3) to 10.4 ± 7.8 µL⋅min⋅100 cm(3) by 24 hours after a single dose of bevacizumab. In parallel, K(PS) values quantified using the prototype MMCM albumin-(Gd-DTPA)35 showed an analogous, significant decline (P < .05) in the therapy group. No significant effects were detected on tumor vascularity or on microcirculatory parameters in the control group between the baseline and the follow-up scan at 24 hours. CONCLUSION: DCE-MRI enhanced with the novel MMCM PEG12,000-Gen4-(Gd-DOTA)16 was able to monitor the effects of bevacizumab on melanoma xenografts within 24 hours of a single application, validated by the prototype, animal-only albumin-(Gd-DTPA)35. PEG12,000-Gen4-(Gd-DOTA)16 may be a promising candidate for further clinical development as a macromolecular blood pool contrast MRI agent.

Permeability to macromolecular contrast media quantified by dynamic MRI correlates with tumor tissue assays of vascular endothelial growth factor (VEGF).

PURPOSE: To correlate dynamic MRI assays of macromolecular endothelial permeability with microscopic area-density measurements of vascular endothelial growth factor (VEGF) in tumors. METHODS AND MATERIAL: This study compared tumor xenografts from two different human cancer cell lines, MDA-MB-231 tumors (n=5), and MDA-MB-435 (n=8), reported to express respectively higher and lower levels of VEGF. Dynamic MRI was enhanced by a prototype macromolecular contrast medium (MMCM), albumin-(Gd-DTPA)35. Quantitative estimates of tumor microvascular permeability (K(PS); µl/min × 100 cm(3)), obtained using a two-compartment kinetic model, were correlated with immunohistochemical measurements of VEGF in each tumor. RESULTS: Mean K(PS) was 2.4 times greater in MDA-MB-231 tumors (K(PS)=58 ± 30.9 µl/min × 100 cm(3)) than in MDA-MB-435 tumors (K(PS)=24 ± 8.4 µl/min × 100 cm(3)) (p<0.05). Correspondingly, the area-density of VEGF in MDA-MB-231 tumors was 2.6 times greater (27.3 ± 2.2%, p<0.05) than in MDA-MB-435 cancers (10.5 ± 0.5%, p<0.05). Considering all tumors without regard to cell type, a significant positive correlation (r=0.67, p<0.05) was observed between MRI-estimated endothelial permeability and VEGF immunoreactivity. CONCLUSION: Correlation of MRI assays of endothelial permeability to a MMCM and VEGF immunoreactivity of tumors support the hypothesis that VEGF is a major contributor to increased macromolecular permeability in cancers. When applied clinically, the MMCM-enhanced MRI approach could help to optimize the appropriate application of VEGF-inhibiting therapy on an individual patient basis.

Nephrogenic systemic fibrosis in rats treated with erythropoietin and intravenous iron.

PURPOSE: To use a rat model for nephrogenic systemic fibrosis (NSF) that was administered high-dose gadodiamide to determine whether the co-administration of erythropoietin (Epo) and intravenous iron potentiated development of skin lesions that are thought to be a marker for the development of NSF. MATERIALS AND METHODS: The local committee for animal research approved this study. High-dose gadodiamide was administered, 2.5 mmol per kilogram of body weight for 20 days, or 500 times the U.S. Food and Drug Administration-approved dose, to four groups of Hannover-Wistar rats: group A, gadodiamide only; B, gadodiamide and Epo; C, gadodiamide and intravenous iron; and D, gadodiamide, Epo, and intravenous iron. The animals were sacrificed 7 days after final injection, and the authors examined dermal histologic findings from each animal and measured metal deposition by using inductively coupled plasma mass spectrometry. To compare the effect of metal deposition and cellularity, a linear mixed effects model was used to fit the data within PROC MIXED modeled with rat-specific random effects, and subsequently a Dunnett adjustment was performed. RESULTS: Rats treated with gadodiamide and both Epo and intravenous iron (group D) had significantly worse skin lesions at gross and histologic analysis (P = .004) compared with the rate treated with gadodiamide only (group A). Group D also had increased levels of deposited gadolinium as measured by means of mass spectrometry (P = .012). CONCLUSION: With a rat model similar to those already existing in the literature, skin changes were more marked in animals exposed to gadodiamide, Epo, and intravenous iron, as opposed to those animals exposed to gadodiamide alone; this experiment suggests that great caution may be warranted when prescribing gadolinium-based contrast agents to patients receiving Epo and intravenous iron.

Magnetic resonance imaging for monitoring the effects of thalidomide on experimental human breast cancers.

Thalidomide, which inhibits angiogenesis in certain tumor types, reduced extravasation of a macromolecular contrast medium (MMCM) in a human breast cancer model as assayed by MMCM-enhanced dynamic magnetic resonance imaging (MRI) and fluorescence microscopy in the same tumors. After a 1-week, three-dose course of thalidomide, the mean MRI-assayed endothelial transfer coefficient, K(PS), decreased significantly (p < 0.05) from 19.4 +/- 9.1 to 6.3 +/- 9.1 microl/min.100 cm(3). Correspondingly, microscopic measurements of extravasated MMCM, expressed as fractional area of streptavidin staining, were significantly (p < 0.05) lower in thalidomide-treated tumors (18.6 +/- 11.9%) than in control saline-treated tumors (50.2 +/- 2.3%). On a tumor-by-tumor basis, post-treatment K(PS) values correlated significantly (r(2) = 0.55, p < 0.05) with microscopic measures of MMCM extravasation. However, no significant differences were observed between saline- and thalidomide-treated tumors with respect to rate of growth, vascular richness, or amount of VEGF-containing cells. Because of its sensitivity to the detection of changes in vascular leakage in tumors, this MMCM-enhanced MRI assay could prove useful for monitoring the effects of thalidomide on an individual patient basis. The significant correlation between MRI and fluorescence microscopic measures of MMCM extravasation supports the utility of the non-invasive MRI approach for assessing the action of thalidomide on tumor blood vessels.

Magnetic resonance imaging assays for dimethyl sulfoxide effect on cancer vasculature.

OBJECTIVES: To evaluate the potential of quantitative assays of vascular characteristics based on dynamic contrast-enhanced magnetic resonance imaging (MRI) using a macromolecular contrast medium (MMCM) to search for and measure effects of dimethyl sulfoxide (DMSO) on cancer vasculature with microscopic correlations. MATERIAL AND METHODS: Saline-treated control (n = 8) and DMSO-treated (n = 7) human breast cancer xenografts (MDA-MB-435) in rats were imaged dynamically by MMCM-enhanced MRI using albumin-(Gd-DTPA)27-(biotin)11 (molecular weight approximately 90 kDa), before and after a 1-week, 3-dose treatment course. After the posttreatment MRI examinations, tumors were perfused with lectin and fixative and subsequently stained with RECA-1 and streptavidin for quantitative fluorescent microscopy. Quantitative MRI estimates of cancer microvessel permeability (KPS; microL/min.100 cm3) and fractional plasma volume (fPV; %) were based on a 2-compartment kinetic model. Fluorescent microscopy yielded estimates of MMCM extravasation and vascular density that were compared to the MRI results. RESULTS: DMSO decreased cancer vascular endothelial permeability significantly (P < 0.05) from tumor KPSday0 = 19.3 +/- 8.8 microL/min.100 cm3 to KPSday7 = 0 microL/min.100 cm3). K values in the saline-treated tumors did not change significantly. The amount of extravasated albumin-Gd-(DTPA)27-(biotin)11, as assayed by a fluorescently labeled streptavidin stain that strongly binds to the biotin tag on the MMCM, was significantly (P < 0.05) lower in the DMSO-treated cancers than in the control cancers (57.7% +/- 5.5% vs. 34.2% +/- 4.9%). Tumor vascular richness as reflected by the MRI-assayed fPV and by the RECA-1 and lectin-stained microscopy did not change significantly with DMSO or saline treatment. CONCLUSION: Reductions in cancer microvascular leakiness induced by a 7-day course of DMSO could be detected and measured by dynamic MMCM-enhanced MRI and were confirmed by microscopic measurements of the leaked macromolecular agents in the same cancers. Results support the robustness of an MMCM-enhanced MRI approach to the characterization of cancers and providing first evidence for an in vivo effect of DMSO on cancer blood vessels.

New macromolecular polymeric MRI contrast agents for application in the differentiation of cancer from benign soft tissues.

PURPOSE: To compare three new macromolecular polyethylene glycol (PEG) -core dendrimeric gadolinium(Gd)-based MRI contrast agents for their applicability in quantitative assays of endothelial leakiness and tissue vascular density for the differentiation of cancer from normal soft tissues. MATERIALS AND METHODS: Thirty-two athymic rats with human breast cancer xenografts (MDA-MB-435) were imaged by dynamic MRI following enhancement with one of three new (Gd-DOTA)-conjugated PEG-core dendrimer contrast agents (effective molecular weights 161 to 323 kDa). Results were compared with a prototype macromolecular contrast agent, albumin (Gd-DTPA). Assays of permeabilities (K(PS); microL/min . 100 cm(3)) and tumor fractional plasma volumes (%) based on a two-compartment kinetic model were performed for skeletal muscle and tumors. RESULTS: The largest PEG-core contrast agent, PEG(20,000)-Gen4-(Gd-DOTA), leaked in breast tumors (K(PS) = 50 +/- 23 microL/min . 100 cm(3)), while exhibiting no measurable transendothelial leak (K(PS) = 0 microL/min . 100 cm(3)) in normal soft tissue microvessels allowing successful differentiation (P < 0.05) of cancers from normal muscle. PEG(12,000)-Gen4-(Gd-DOTA) leaked in tumors and in normal muscle (K(PS) = 51 +/- 26 and K(PS) = 21 +/- 18 microL/min . 100 cm(3), respectively). The smallest agent, PEG(12,000)-Gen3-(Gd-DOTA) also showed a measurable leak in both normal and malignant microvessels. CONCLUSION: MRI assays of vascular endothelial leakiness using new PEG-core, (Gd-DOTA)-conjugated macromolecular contrast agents proved applicable for the differentiation of human breast cancer from normal soft tissue. The apparent threshold in effective molecular weight for a clear differentiation of cancer from normal muscle with no measurable leak in the muscle is between 194 and 323 kDa.