Hepatocyte KLF6 expression affects FXR signalling and the clinical course of primary sclerosing cholangitis

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic cholestasis and inflammation, which promotes cirrhosis and an increased risk of cholangiocellular carcinoma (CCA). The transcription factor Krueppel-like-factor-6 (KLF6) is a mediator of liver regeneration, steatosis, and hepatocellular carcinoma (HCC), but no data are yet available on its potential role in cholestasis. Here, we aimed to identify the impact of hepatic KLF6 expression on cholestatic liver injury and PSC and identify potential effects on farnesoid-X-receptor (FXR) signalling. Methods: Hepatocellular KLF6 expression was quantified by immunohistochemistry (IHC) in liver biopsies of PSC patients and correlated with serum parameters and clinical outcome. Liver injury was analysed in hepatocyte-specific Klf6-knockout mice following bile duct ligation (BDL). Chromatin-immunoprecipitation-assays (ChIP) and KLF6-overexpressing HepG2 cells were used to analyse the interaction of KLF6 and FXR target genes such as NR0B2. Results: Based on IHC, PSC patients could be subdivided into two groups showing either low (80%) hepatocellular KLF6 expression. In patients with high KLF6 expression, we observed a superior survival in Kaplan-Meier analysis. Klf6-knockout mice showed reduced hepatic necrosis following BDL when compared to controls. KLF6 suppressed NR0B2 expression in HepG2 cells mediated through binding of KLF6 to the NR0B2 promoter region. Conclusion: Here, we show an association between KLF6 expression and the clinical course and overall survival in PSC patients. Mechanistically, we identified a direct interaction of KLF6 with the FXR target gene NR0B2

Prospektive randomisierte Untersuchung der Neointimaproliferation in goldbeschichteten Koronarstents im Vergleich zu herkömmlichen Edelstahlstents mittels intravaskulären Ultraschalls

In-stent restenosis is a major limitation of percutaneous coronary interventions and occurs due to neointimal hyperplasia after stent implantation. Gold coating of stainless stell stents showed an in-vitro-reduction of neointimal formation, an effect attributed to an assumed favourable biocompatibility and reduced thrombogenicity of the element gold. The presented prospective randomised and multicentric study compared the quantitative formation of neointima in diseased human coronary arteries of 204 patients (stainless steel stents n=101, gold coated stents n=103) after placement of stainless steel stents and gold coated stents of identical design, respectively. Evaluation of the anatomical changes of the stented vessel segments was done using intravascular ultrasound (IVUS), a valuable tool for tomographic assessment of vascular stuctures. Baseline parameters did not differ between the groups and procedural success of stent implantation was similar, but after six months IVUS revealed significant differences in neointimal proliferation. By ultrasound, the neointimal volume within the gold coated stents was higher (47 ± 25 vs. 41 ± 23 mm3, p>0,05) as well as the neointimal volume-to-stent volume (0.45 ± 0.12 vs. 0.40 ± 0,12, p>0,01). Thus, gold coating of the tested stent type resulted in mor neointima proliferation

Prospektive randomisierte Untersuchung der Neointimaproliferation in goldbeschichteten Koronarstents im Vergleich zu herkömmlichen Edelstahlstents mittels intravaskulären Ultraschalls

In-stent restenosis is a major limitation of percutaneous coronary interventions and occurs due to neointimal hyperplasia after stent implantation. Gold coating of stainless stell stents showed an in-vitro-reduction of neointimal formation, an effect attributed to an assumed favourable biocompatibility and reduced thrombogenicity of the element gold. The presented prospective randomised and multicentric study compared the quantitative formation of neointima in diseased human coronary arteries of 204 patients (stainless steel stents n=101, gold coated stents n=103) after placement of stainless steel stents and gold coated stents of identical design, respectively. Evaluation of the anatomical changes of the stented vessel segments was done using intravascular ultrasound (IVUS), a valuable tool for tomographic assessment of vascular stuctures. Baseline parameters did not differ between the groups and procedural success of stent implantation was similar, but after six months IVUS revealed significant differences in neointimal proliferation. By ultrasound, the neointimal volume within the gold coated stents was higher (47 ± 25 vs. 41 ± 23 mm3, p>0,05) as well as the neointimal volume-to-stent volume (0.45 ± 0.12 vs. 0.40 ± 0,12, p>0,01). Thus, gold coating of the tested stent type resulted in mor neointima proliferation

Photochemical internalization and gemcitabine combined with first-line chemotherapy in perihilar cholangiocarcinoma: observations in three patients

Photochemical internalization (PCI) is a technology to induce a localized, intracellular enhancement of therapeutics that are processed through endosomal pathways, including gemcitabine in malignant cells. In addition to a direct phototoxic and tumoricidal effect, PCI specifically disrupts endosomal membranes and, thereby, the compartmentalization of certain cytotoxic compounds to enhance a drug’s intended intracellular target reach within the tissue treated. Non-resectable extrahepatic cholangiocarcinoma (eCCA) is a common primary tumor and gemcitabine/cisplatin chemotherapy is widely considered standard of care for it. PCI is well suited as an endoscopic intervention, and clinical observations in three subjects participating in a phase I/IIa dose escalation safety trial are described. The trial included patients with perihilar, non-resectable CCA suitable for standard-of-care chemotherapy. Per protocol, a single endoscopic PCI procedure with gemcitabine was conducted at the initiation of standard gemcitabine/cisplatin therapy. Sixteen patients enrolled in the initial dose escalation phase of the trial, which later was extended to explore the safety of a second PCI procedure during chemotherapy. While limited to a case series, the various clinical observations described here serve to illustrate the effects of localized, perihilar tumor targeting in appropriate patients by any safe methodology, including PCI. As previously indicated by clinical data using other localized treatment modalities, adding a directed, tumor-targeting treatment to systemic therapy to ameliorate the progressively expanding extrahepatic tumor burden can have important effects on the overall outcome of systemic treatment in many patients who have incurable eCCA

ERCP in babies: Low risk of post-ERCP pancreatitis – results from a multicentre survey

Background and aims: Endoscopic retrograde cholangiopancreatography (ERCP) is rarely performed in newborns, and the risk of post-ERCP pancreatitis (PEP) has not been defined in this age group. We therefore performed a European multicentre analysis of PEP rates and risk factors in children aged ≤1 year. Patients and methods: Based on a sample size estimation, 135 consecutive ERCPs in 126 children aged ≤1 year were evaluated from five European centres, and the first ERCP per child analysed. All ERCPs and clinical reports were reviewed manually for PEP and associated risk factors. All ERCPs were performed by endoscopists with high ERCP expertise. Results: No PEP was observed (0/126, 0.0%, CI 0–2.9%) despite the formal presence of multiple risk factors and despite lack of PEP prophylaxis (except one patient having received a pancreatic duct stent). The PEP rate was significantly lower than the PEP rate expected in adults with similar risk factors. Conclusions: ERCP in children aged ≤1 year is safe in terms of PEP. The PEP risk is significantly lower in children aged ≤1 year than in adults, therefore no PEP prophylaxis seems to be needed in young children. Risk factors from adults may not apply to children under 1 year. Reluctance to perform diagnostic ERCP in suspected biliary anomalies should not be based on presumed PEP risk

Novel implications in the treatment of hepatocellular carcinoma

Abstract Worldwide hepatocellular carcinoma remains one of the leading causes of cancer-related death, associated with a poor prognosis due to late diagnosis in the majority of cases. Physicians at care are frequently confronted with patients who are ineligible for curative treatment such as liver resection, transplantation or radiofrequency ablation. Besides established palliative locoregional therapies, such as ablation or chemoembolization, new treatment options, such as microwave ablation, drug-eluting bead transarterial chemoembolization or selective internal radiation therapy, are emerging; however, data from randomized controlled trials are still lacking. In order to achieve optimal tumor control, patients should receive tailored treatment concepts, considering their tumor burden, liver function and performance status, instead of strictly assigning patients to treatment modalities following algorithms that may be partly very restrictive. Palliative locoregional pretreatment might facilitate downstaging to ensure later curative resection or transplantation. In addition, the combined utilization of diff erent locoregional treatment options or systemic co-treatment has been the subject of several trials. In cases where local tumor control cannot be achieved, or in the scenario of extrahepatic spread, sorafenib remains the only approved systemic therapy option. Alternative targeted therapies, such as immune checkpoint inhibitors have shown encouraging preliminary results, while data from phase III studies are pending

Absolute (presented as median and range) and relative volumetric liver lobe changes (presented as mean, standard deviation, and range) after RE.

<p>Absolute (presented as median and range) and relative volumetric liver lobe changes (presented as mean, standard deviation, and range) after RE.</p

Factors associated with contralateral liver hypertrophy after unilateral radioembolization for hepatocellular carcinoma

<div><p>Introduction</p><p>Radioembolization for the treatment of hepatocellular carcinoma (HCC) induces liver volume changes referred to as “atrophy-hypertrophy complex”. The aim of this study was to investigate lobar liver volume changes after unilateral radioembolization and to search for factors associated with hypertrophy of the untreated lobe.</p><p>Materials and methods</p><p>Seventy-five patients were retrospectively evaluated. Inclusion criteria were: (1) right-lobar radioembolization for unresectable unilateral HCC, (2) available liver computed tomography scans before, 1, 3, and at least 6 months after radioembolization. Baseline patient characteristics included clinical features, laboratory results, spleen volume, and liver computed tomography. Absolute and relative (referred to the whole liver volume) liver lobe volumes (LLV) as well as relative LLV (rLLV) change per month were evaluated and compared.</p><p>Results</p><p>Absolute and relative contralateral LLV continuously increased after radioembolization (p<0.001). Mean relative contralateral LLV increased from 36±11.6% before radioembolization to 50±15.3% 6 months after radioembolization. Median contralateral rLLV increase/month (within first 6 months) was 2.5%. Contralateral rLLV increase/month was significantly lower in patients with ascites (p = 0.017) or platelet count <100/nl (p = 0.009). An inverse correlation of contralateral rLVV increase/month with spleen volume (p = 0.017), patient age (p = 0.024), Child Pugh score (p = 0.001), and tumor burden (p = 0.001) was found.</p><p>Conclusions</p><p>Significant contralateral hypertrophy and ipsilateral atrophy were common after unilateral radioembolization. Small spleen volume, low patient age, low Child Pugh score, absence of ascites, platelet count ≥100/nl, and low tumor burden were associated with increased contralateral hypertrophy, indicating that younger patients with compensated cirrhosis might benefit most from radioembolization in a “bridge-to-resection” setting.</p></div