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Objectives To analyze revision rates after transjugular intrahepatic portosystemic shunt (TIPS) using expanded polytetrafluoroethylene-covered stentgrafts and to identify predictors of shunt revisions. Materials and methods This single-center retrospective study included 514 consecutive patients (mean age 56.9 ± 12.7 years; 194 females) with TIPS placement between 2003 and 2021. Follow-up included clinical assessment, laboratory testing, ultrasound, and computed tomography. Reinterventions were categorized by type and technique. Univariable and multivariable Cox regression analyses were performed to identify predictors of shunt dilation and reduction. Results A total of 149 patients (28.9%) required TIPS revision: 95 (18.5%) shunt dilation, 42 (8.2%) shunt reduction, and 12 (2.3%) others. Median time to first revision was 2.8 months (3.2 months for dilation, 1.9 months for reduction). Indications for first shunt dilation were persistent or recurrent refractory ascites ( n  = 61), recurrent variceal bleeding ( n  = 7), and asymptomatic stenosis or occlusion of the TIPS tract ( n  = 27). Indications for shunt reduction were hepatic encephalopathy refractory to conservative measures ( n  = 39) and acute liver failure following TIPS ( n  = 3). Forty-seven patients (9.1%) underwent two or more reinterventions. Multivariable Cox analysis identified immediate post-TIPS portosystemic pressure gradients > 8 mmHg, prior hepatic encephalopathy, and hepatorenal syndrome prior to TIPS as predictors of mandatory shunt dilation. In contrast, age ≥ 65 years, female gender, serum sodium levels, and a pre-TIPS hepatic hydrothorax were predictive of shunt reduction during revision. Conclusion Around one in three patients requires shunt revision. Predictive factors for revision varied by intervention type: shunt dilation was linked to disease severity and portal pressure, whereas reduction was more closely related to the patient’s age and gender. Critical relevance statement Patients who undergo TIPS require structured, long-term follow-up to identify clinical situations that may necessitate shunt adaptation or other secondary interventions. Key Points Shunt revision after TIPS occurs in one-third of patients, with prognostic significance. Several independent prognostic factors for both shunt dilation and reduction were identified. Structured long-term follow-up is crucial to identify patients needing shunt revision. Graphical Abstract

Background Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC). Methods OCT1 ( SLC22A1 ) and OCT3 ( SLC22A3 ) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by real time PCR (n = 53). Protein expression was determined by western blot analysis and immunofluorescence. Data were correlated with the clinicopathological parameters of HCCs. Results Real time PCR showed a downregulation of SLC22A1 and SLC22A3 in HCC compared to TST (p ≤ 0.001). A low SLC22A1 expression was associated with a worse patient survival (p < 0.05). Downregulation was significantly associated with advanced HCC stages, indicated by a higher number of T3 tumors (p = 0.025) with a larger tumor diameter (p = 0.035), a worse differentiation (p = 0.001) and higher AFP-levels (p = 0.019). In accordance, SLC22A1 was less frequently downregulated in tumors with lower stages who underwent transarterial chemoembolization (p < 0.001) and liver transplantation (p = 0.001). Tumors with a low SLC22A1 expression (< median) showed a higher SLC22A3 expression compared to HCC with high SLC22A1 expression (p < 0.001). However, there was no significant difference in tumor characteristics according to the level of the SLC22A3 expression. In the western blot analysis we found a different protein expression pattern in tumor samples with a more diffuse staining in the immunofluorescence suggesting that especially OCT1 is not functional in advanced HCC. Conclusion The downregulation of OCT1 is associated with tumor progression and a worse patient survival.

The CD95 (APO–1/Fas) system is an important mediator of T–cell cytotoxicity. We investigated this system in 22 hepatocellular carcinomas (HCCs) from patients. All HCCs had partially or completely lost the expression of the CD95 receptor constitutively expressed by normal liver cells and might thus evade CD95–mediated killing. We also considered a new mechanism of immune evasion, namely, the active destruction of T–lymphocytes by tumor cells expressing CD95 ligand (CD95L). CD95L messenger RNA and protein could be detected in the HCCs. In coculture experiments, HepG2 hepatoblastoma cells, expressing CD95L mRNA after treatment with cytostatic drugs, killed CD95 + Jurkat lymphocytes. Our data suggest that tumor cells can evade immune attack by down–regulation of the CD95 receptor and killing of lymphocytes through expression of CD95L.

Osteoporosis and related fractures are a major complication after organ transplantation. The aim of this study was to find out the frequency and predictors of osteoporotic fractures after cardiac or liver transplantation. 235 consecutive patients who had a cardiac transplant (n=105; 88 men, 17 women) or a liver transplant (130; 75 men, 55 women) were followed. Vertebral fractures were assessed by a standardised analysis of spinal radiographs before and annually after transplantation. Clinical and non-vertebral fracture data were noted from hospital records. In the first and second years after transplantation, the proportion of patients (Kaplan-Meier estimates) who had at least one vertebral fracture was slightly higher in the cardiac group (first year 21%, second year 27%) than in the liver group (first year 14%, second year 21%). In the third and fourth years, one third of patients from both groups had had one or more vertebral fractures. Non-vertebral fractures occurred in nine patients (7%) after liver transplantation and avascular necrosis of the hip head in three patients (3%) after cardiac transplantation. In both groups, no dose dependent effect of immunosuppressive therapy on fracture development could be identified. Independent predictors assessed by multivariate analysis were age (hazard ratio [95% CI] increase of 5 years, 1·71 [1·1–2·7]) and lumbar bone-mineral density (decrease of 1 SD t score, 1·97 [1·2–3·2]) in cardiac transplantation patients, and vertebral fractures before transplantation (6·07 [1·7–21·7]) in the liver group. The high frequency of osteoporotic fractures in the 2 years after transplantation and the limitations of reliable fracture-risk predictions, show the need to investigate preventive therapies.

Wilson's disease can result in fulminant liver failure due to hepatic copper overload. The CD95 system mediates apoptosis and has been demonstrated to be involved in liver disease. In this study CD95 mediated apoptosis was investigated in patients with fulminant hepatic failure in the course of Wilson's disease and in an in vitro model of copper treated human hepatoma cells. In patients, hepatic expression of CD95 and CD95L mRNA and apoptosis were detected. Copper overload in vitro resulted in hepatocytic apoptosis which could be reduced with a neutralizing anti-CD95L antibody. Copper treatment of hepatocytes results in activation of the CD9S system and induction of apoptosis which is operative during the course of hepatic failure in acute Wilson's disease.

PurposePorto-systemic pressure gradient is used to prognosticate rebleeding and resolution of ascites after TIPS. This study investigates the reliability of portal pressure characteristics as quantified immediately after TIPS placement and at short-term control.Patients and MethodsPortal venous pressure (PVP) and right atrial pressure (RAP) were prospectively obtained before and after TIPS as well as ≥ 48 h after TIPS procedure. Porto-systemic pressure gradients (PSG) and pressure changes were calculated. A multivariate regression analysis was performed to predict portal hemodynamics at short-term control.ResultsThe study included 124 consecutive patients. Indications for TIPS were refractory ascites, variceal bleeding or combinations of both. Pre- and post-interventional PSG yielded 16.4 ± 5.3 mmHg and 5.9 ± 2.7 mmHg, respectively. At that time, 105/124 patients (84.7%) met the target (PSG ≤ 8 mmHg). After 4 days (median), PSG was 8.5 ± 3.5 mmHg and only 66 patients (53%) met that target. In patients exceeding the target PSG at follow-up, PVP was significantly higher and RAP was lower resulting in the increased PSG. The highly variable changes of RAP were the main contributor to different pressure gradients. In the multivariate regression analysis, PVP and RAP immediately after TIPS were predictors for PSG at short-term control with moderately predictive capacity (AUC = 0.75).ConclusionBesides the reduction of portal vein pressure, the highly variable right atrial pressure was the main contributor to different pressure gradients. Thus, immediate post-TIPS measurements do not reliably predict portal hemodynamics during follow-up. These findings need to be further investigated with respect to the corresponding clinical course of the patients.

Background The incidence of non-alcoholic steatohepatitis (NASH) is increasing worldwide and a poorly defined subset of patients develops end-stage liver disease and hepatocellular carcinoma (HCC). Differences in the biological behaviour, tumour characteristics, associated risk factors, treatment outcomes and overall survival of patients with NASH-HCC remain poorly defined. The aim of this study was to determine and analyze these differences in a large clinical cohort to guide treatment decisions. Methods 1119 patients with HCC treated in an 11 year period at the University Medical Centre of the Johannes Gutenberg University Mainz were retrospectively analyzed. Results Patients with NASH-HCC (n = 45) were older (67.6 vs. 65 years), had an increased frequency of the metabolic syndrome and complications with a higher incidence of obesity (31.1% vs. 14.7%), type II diabetes mellitus (66.7% vs. 37.85%), a higher rate of myocardial infarction (13.3% vs. 4.8%) and apoplectic stroke (8.9% vs. 2.1%) (all p < 0.05). Interestingly, liver function was preserved to a higher extent and MELD scores were significantly lower in NASH-HCC. Nonetheless, resection or orthotopic liver transplantation was performed only in 17.8% and 4.4% of NASH-HCC respectively. Overall survival was lower compared to HCC of other aetiologies. Independent of the underlying aetiology BMI exhibited a positive correlation with overall survival. Conclusion Despite retained liver function, patients with NASH-associated HCC showed a decreased overall survival. With regards to the expected increasing prevalence of NASH, it will be necessary to improve screening and surveillance strategies to identify HCC in NASH early and improve survival.

Purpose To prospectively compare SIRT and DEB-TACE for treating hepatocellular carcinoma (HCC). Methods From 04/2010–07/2012, 24 patients with histologically proven unresectable N0, M0 HCCs were randomized 1:1 to receive SIRT or DEB-TACE. SIRT could be repeated once in case of recurrence; while, TACE was repeated every 6 weeks until no viable tumor tissue was detected by MRI or contraindications prohibited further treatment. Patients were followed-up by MRI every 3 months; the final evaluation was 05/2013. Results Both groups were comparable in demographics (SIRT: 8males/4females, mean age 72 ± 7 years; TACE: 10males/2females, mean age 71 ± 9 years), initial tumor load (1 patient ≥25 % in each group), and BCLC (Barcelona Clinic Liver Cancer) stage (SIRT: 12×B; TACE 1×A, 11×B). Median progression-free survival (PFS) was 180 days for SIRT versus 216 days for TACE patients ( p  = 0.6193) with a median TTP of 371 days versus 336 days, respectively ( p  = 0.5764). Median OS was 592 days for SIRT versus 788 days for TACE patients ( p  = 0.9271). Seven patients died in each group. Causes of death were liver failure ( n  = 4 SIRT group), tumor progression ( n  = 4 TACE group), cardiovascular events, and inconclusive ( n  = 1 in each group). Conclusions No significant differences were found in median PFS, OS, and TTP. The lower rate of tumor progression in the SIRT group was nullified by a greater incidence of liver failure. This pilot study is the first prospective randomized trial comparing SIRT and TACE for treating HCC, and results can be used for sample size calculations of future studies.

Ischemic-type biliary lesions (ITBL) belong to a group of biliary disorders that are regarded as the major complication in patients with orthotopic liver transplantation (OLT). We performed histological evaluation of donor common bile ducts received during OLT to find morphological clues to the pathomechanisms of ITBL. We investigated 93 grafts of 92 patients (recipients: mean age, 56.5 years; underlying disease: hepatocellular carcinoma ( n  = 45), alcoholic cirrhosis ( n  = 16), viral hepatitis with cirrhosis ( n  = 9), retransplantations ( n  = 9), others ( n  = 14); donors: mean age, 53.2 years). Donor common bile ducts were received after recirculation of the hepatic artery prior to biliary end-to-end anastomosis and routinely processed. Statistical evaluation was performed by chi-square analysis and multivariate analysis using a logistic regression model. With regard to ITBL (observed in 19.4 %), the following phenomena were found to be statistically relevant: necrosis of the bile duct wall, arteriolonecrosis, vascular lesions (such as subintimal edema), and intramural bleeding ( P  < 0.001, P  < 0.001, P  = 0.029, and P  = 0.031, respectively). In logistic regression analysis, arteriolonecrosis was the only parameter with significance ( P  = 0.001). Based on these results on the morphology of the donor common bile duct, we conclude that these phenomena of vascular damage, reflecting microangiopathy, play a major role in the pathogenesis of ITBL.