MRI Extracellular Volume Fraction in Liver Fibrosis-A Comparison of Different Time Points and Blood Pool Measurements.

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.

Uptake of Gadolinium-Based Contrast Agents by Blood Cells During Contrast-Enhanced MRI Examination.

OBJECTIVES: Gadolinium-based contrast agents (GBCAs) are routinely used in magnetic resonance imaging (MRI) examinations. However, there is limited knowledge about the interaction with and distribution of the drug in human cells. This lack of knowledge is surprising, given that the first interaction of the drug occurs with blood cells. Moreover, recent studies reported gadolinium (Gd) deposition within organs, such as the brain. Hence, this study is aiming to determine the uptake of GBCA in blood cells of patients undergoing contrast-enhanced MRI (ce-MRI) examination. MATERIALS AND METHODS: Human blood was exposed to either gadoterate meglumine (Gd-DOTA) or Eu-DOTA in vitro or was collected from patients undergoing ce-MRI with Gd-DOTA. Uptake of contrast agents (CAs) by blood cells was quantified by Gd measurements using single-cell inductively coupled plasma mass spectrometry (SC-ICP-MS) or, to confirm Gd-DOTA uptake, by a complementary method using Eu-DOTA by time-resolved fluorescence spectroscopy, respectively. RESULTS: Uptake of Gd-DOTA or Eu-DOTA into white blood cells (WBCs) ex vivo was detectable by SC-ICP-MS and time-resolved fluorescence spectroscopy. The intracellular concentrations were estimated to be in the range of 1-3 µM. However, no CA uptake into erythrocytes was detected with either method. In total, 42 patients between 30 and 84 years old (24 men, 18 women) were enrolled. White blood cells' uptake of Gd was measured by SC-ICP-MS. Isolated WBCs from patients who underwent ce-MRI examination showed substantial Gd uptake; however, the studied patient group showed an inhomogeneous distribution of Gd uptake. Measurements immediately after MRI examination indicated 21-444 attogram/WBC, corresponding to an intracellular Gd concentration in the range from 0.2 to 5.5 µM. CONCLUSIONS: This study confirms the ex vivo uptake of GBCA by WBCs and provides the first evidence that GBCA is indeed taken up by WBCs in vivo by patients undergoing ce-MRI examination. However, the observed Gd uptake in WBCs does not follow a log-normal distribution commonly observed in the fields of environmental studies, biology, and medicine. Whether cellular uptake of GBCA is linked to the observed deposition of Gd remains unclear. Therefore, studying the interaction between GBCA and human cells may clarify crucial questions about the effects of Gd on patients after MRI examinations.

Obstetrical and Fertility Outcomes Following Transcatheter Pelvic Arterial Embolization for Postpartum Hemorrhage: A Cohort Follow-Up Study.

Objectives: Management of severe postpartum hemorrhage (PPH) includes transcatheter pelvic arterial embolization (TAE). Data regarding subsequent fertility and obstetrical outcomes is limited, as most fertility outcomes derive from TAE in uterine fibroma. The purpose of our study was to evaluate the long-term outcomes of patients undergoing TAE, particularly concerning subsequent fertility and following pregnancies. Material and methods: We included 28 patients who underwent TAE for PPH at our institution between 2009 and 2018 in a retrospective cohort study. Data were assessed by reviewing patients' charts and by contacting the patients. Results: Ten patients had prophylactic balloon occlusion before cesarean section because of anticipated PPH, with planned hysterectomy by placenta increta/percreta. All these patients were excluded from the analysis regarding fertility. 16 (73%) patients reported having regular menstruation after TAE. In total, 11 women had no desire for subsequent pregnancy. Seven of the remaining 11 patients (63.6%) had a total of 13 spontaneous pregnancies, nine of these resulted in miscarriages. Four patients delivered a live baby (36.4%). Two of these (50%) had recurrent PPH and treatment was conservative. Of the patients with infertility (n = 4, 36.4%), two (18.1%) underwent assisted infertility treatment without success. Conclusion: Our study suggests that the fertility of patients undergoing TAE due to PPH is limited. In women who conceive, the risk for first trimester miscarriage as well as recurrent PPH seems to be increased. If this is a consequence of the underlying cause of PPH or the TAE remains unknown. Larger follow-up cohorts are needed. In the meantime, patients who desire pregnancy after TAE should be counseled accordingly.

T1 reduction rate with Gd-EOB-DTPA determines liver function on both 1.5 T and 3 T MRI.

Magnetic resonance T1 mapping before and after Gd-EOB-DTPA administration allows quantification of the T1 reduction rate as a non-invasive surrogate marker of liver function. A major limitation of T1 relaxation time measurement is its dependency on MRI field strengths. Since T1 reduction rate is calculated as the relative shortening of T1 relaxation time before and after contrast administration, we hypothesized that the T1 reduction rate is comparable between 1.5 and 3 T. We thus compared liver T1 relaxation times between 1.5 and 3 T in a total of 243 consecutive patients (124, 1.5 T and 119, 3 T) between 09/2018 and 07/2019. T1 reduction rates were compared between patients with no cirrhosis and patients with cirrhosis Child-Pugh A-C. There was no significant difference of T1 reduction rate between 1.5 and 3 T in any patient group (p-value 0.126-0.861). On both 1.5 T and 3 T, T1 reduction rate allowed to differentiate between patients with no cirrhosis and patients with liver cirrhosis Child A-C (p < 0.001). T1 reduction rate showed a good performance to predict liver cirrhosis Child A (AUC = 0.83, p < 0.001), Child B (AUC = 0.83, p < 0.001) and Child C (AUC = 0.92, p < 0.001). In conclusion, T1 reduction rate allows to determine liver function on Gd-EOB-DTPA MRI with comparable values on 1.5 T and 3 T.

Noninvasive assessment of clinically significant portal hypertension using ΔT1 of the liver and spleen and ECV of the spleen on routine Gd-EOB-DTPA liver MRI.

PURPOSE: To analyze the predictive value of ΔT1 of the liver and spleen as well as the extracellular volume fraction (ECV) of the spleen as noninvasive biomarkers for the determination of clinically significant portal hypertension (CSPH) on routine Gd-EOB-DTPA liver MRI. METHOD: 195 consecutive patients with known or suspected chronic liver disease from 9/2018 to 7/2019 with Gd-EOB-DTPA liver MRI and abdominal T1 mapping were retrospectively included. Based on the presence of splenomegaly with thrombocytopenia, ascites and portosystemic collaterals, the patients were divided into noCSPH (n = 113), compensated CSPH (cCSPH, ≥1 finding without ascites; n = 55) and decompensated CSPH (dCSPH, ascites ± other findings; n = 27). T1 times were measured in the liver, spleen and abdominal aorta in the unenhanced and contrast-enhanced T1 maps. Native T1 times and ΔT1 of the liver and spleen as well as ECV of the spleen were compared between groups using the Kruskal-Wallis test with Dunn's post hoc test. Furthermore, cutoff values for group differentiation were calculated using ROC analysis with Youden's index. RESULTS: ΔT1 of the liver was significantly lower in patients with cCSPH and dCSPH (p < 0.001) compared to patients with noCSPH. In the ROC analyses for differentiation between noCSPH and CSPH (cCSPH + dCSPH), a cutoff of < 0.67 for ΔT1 of the liver (AUC = 0.79) performed better than ΔT1 (AUC = 0.69) and ECV (AUC = 0.63) of the spleen with cutoffs of > 0.29 and > 41.9, respectively. CONCLUSION: ΔT1 of the liver and spleen in addition to ECV of the spleen allow for determination of CSPH on routine Gd-EOB-DTPA liver MRI.

Beyond Single-Cell Analysis of Metallodrugs by ICP-MS: Targeting Cellular Substructures.

Platinum compounds such as cisplatin (cisPt) embody the backbone of combination chemotherapy protocols against advanced lung cancer. However, their efficacy is primarily limited by inherent or acquired platinum resistance, the origin of which has not been fully elucidated yet, although of paramount interest. Using single cell inductively coupled plasma mass spectrometry (SC-ICP-MS), this study quantifies cisPt in single cancer cells and for the first time in isolated nuclei. A comparison of cisPt uptake was performed between a wild type (wt) cancer cell line and related resistant sublines. In both, resistant cells, wt cells, and their nuclei, cisPt uptake was measured at different incubation times. A lower amount of cisPt was found in resistant cell lines and their nuclei compared to wt cells. Moreover, the abundance of internalized cisPt decreased with increasing resistance. Interestingly, concentrations of cisPt found within the nuclei were higher than compared to cellular concentrations. Here, we show, that SC-ICP-MS allows precise and accurate quantification of metallodrugs in both single cells and cell organelles such as nuclei. These findings pave the way for future applications investigating the potency and efficacy of novel metallodrugs developed for cancer treatment.

T1 mapping of the liver and the spleen in patients with liver fibrosis-does normalization to the blood pool increase the predictive value?

PURPOSE: To analyze whether the T1 relaxation time of the liver is a good predictor of significant liver fibrosis and whether normalization to the blood pool improves the predictive value. METHODS: This prospective study was conducted between 03/2016 and 02/2018. One hundred seventy-three patients underwent multiparametric liver MRI at 3 T. The T1 relaxation time was measured in the liver and the spleen, in the aorta, the portal vein, and the inferior vena cava (IVC). T1 relaxation times with and without normalization to the blood pool were compared between patients with (n = 26) and without (n = 141) significant liver fibrosis, based on a cutoff value of 3.5 kPa in MRE as the noninvasive reference standard. For statistics, Student's t test, receiver operating characteristic (ROC) curve analysis, and Pearson's correlation were used. RESULTS: The T1 relaxation time of the liver was significantly longer in patients with liver fibrosis, both with and without blood pool normalization (p < 0.001). T1 relaxation time of the liver allowed prediction of significant liver fibrosis (AUC = 0.88), while normalization to the IVC resulted in a slightly lower performance (AUC = 0.82). The lowest performance was achieved when the T1 relaxation times of the liver were normalized to the aorta (AUC = 0.66) and to the portal vein (AUC = 0.62). The T1 relaxation time of the spleen detected significant liver fibrosis with an AUC of 0.68, and 0.51-0.64 with normalization to the blood pool. CONCLUSION: The T1 relaxation time of the liver is a good predictor of significant liver fibrosis. However, normalization of the blood pool did not improve the predictive value. KEY POINTS: • The T1 relaxation time of the liver is a good predictor of significant liver fibrosis. • Normalization to the blood pool did not improve the predictive value of T1 mapping. • If the blood pool normalization was weighted 30% to the aorta and 70% to the portal vein, the performance was better than normalization to the aorta alone but still lower than normalization to the IVC.

Conjugates Containing Two and Three Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Units as In Vitro Antiparasitic and Anticancer Agents.

The synthesis, characterization, and in vitro antiparasitic and anticancer activity evaluation of new conjugates containing two and three dinuclear trithiolato-bridged ruthenium(II)-arene units are presented. Antiparasitic activity was evaluated using transgenic Toxoplasmagondii tachyzoites constitutively expressing ß-galactosidase grown in human foreskin fibroblasts (HFF). The compounds inhibited T.gondii proliferation with IC50 values ranging from 90 to 539 nM, and seven derivatives displayed IC50 values lower than the reference compound pyrimethamine, which is currently used for treatment of toxoplasmosis. Overall, compound flexibility and size impacted on the anti-Toxoplasma activity. The anticancer activity of 14 compounds was assessed against cancer cell lines A2780, A2780cisR (human ovarian cisplatin sensitive and resistant), A24, (D-)A24cisPt8.0 (human lung adenocarcinoma cells wild type and cisPt resistant subline). The compounds displayed IC50 values ranging from 23 to 650 nM. In A2780cisR, A24 and (D-)A24cisPt8.0 cells, all compounds were considerably more cytotoxic than cisplatin, with IC50 values lower by two orders of magnitude. Irrespective of the nature of the connectors (alkyl/aryl) or the numbers of the di-ruthenium units (two/three), ester conjugates 6-10 and 20 exhibited similar antiproliferative profiles, and were more cytotoxic than amide analogues 11-14, 23, and 24. Polynuclear conjugates with multiple trithiolato-bridged di-ruthenium(II)-arene moieties deserve further investigation.

Generation of Stable cisPt Resistant Lung Adenocarcinoma Cells.

Platinum compounds represent the backbone of combined chemotherapy protocols for advanced lung cancer. The mechanisms responsible for its frequent primary or acquired resistance to cisplatin (cisPt)-based chemotherapy remains enigmatic. The availability of two cell lines of the same origin, one resistant and the other sensitive, will facilitate research to reveal the mechanism of resistance formation. Lung adenocarcinoma cells, A240286S (A24), were cultivated in increasing cisPt concentrations over a prolonged time. After a significant increase in IC50 was measured, cultivation of the cells was continued in absence of cisPt and IC50s determined over a long period (>7 months). As a result, a cell line with lasting, high-level cisPt resistance, designated (D-)A24cisPt8.0, was obtained. The cells were cross-resistant to oxaliplatin and to pemetrexed at a low level. Previous publications have claimed that Leucine-rich repeat-containing protein 8 (LRRC8A and LRRC8D) of the volume-regulated anion channels (VRACs) affect cellular resistance to cisPt. Even though cisPt decreased LRRC8D expression levels, we showed by knockdown and overexpression experiments with LRRC8A and D that these proteins do not govern the observed cisPt resistance. The tumor cell sublines described here provide a powerful model to study the mechanisms of resistance to cisPt in lung cancer cells and beyond.

General anaesthesia for patients with a history of a contrast medium-induced anaphylaxis: a useful prophylaxis?

Contrast-enhanced radiological examinations are important diagnostic tools in modern medicine. Currently, all approved and available iodinated and gadolinium-based contrast agents are safe and well-tolerated by most patients. However, approximately 2% of patients receiving iodinated contrast media exhibit hypersensitivity reactions. Patients with a history of such a reaction are at increased risk upon reexposure. Therefore, they are subjected to a prophylaxis such as injection of antiallergy drugs or general anaesthesia. The latter procedure is expensive, can burden the patients organism, and besides lacks objective verification. Therefore, the purpose of our review paper is to present and discuss the background and the previous practice, as well as to provide a proposal for a safe individual patient management.