Ruptured aneurysm of the ulnar artery in a woman with neurofibromatosis

A 61-year-old woman with neurofibromatosis type 1 (Recklinghausen's disease) was referred for massive swelling of the right forearm, pain, increasing numbness, and impaired movement of the fingers. Angiography demonstrated a 13- × 11-mm aneurysm and a capped rupture of the ulnar artery. Because of the complicated soft-tissue condition, interventional treatment was indicated. Two 360° coils were placed for embolization of the ruptured aneurysm. Arterial involvement in neurofibromatosis is a well known but infrequent occurrence. Stenotic lesions predominate. Aneurysmal defects are less common, and rupture of peripheral arteries is exceptional

Functional integration of natural killer cells in a microfluidically perfused liver on-a-chip model.

OBJECTIVE The liver acts as an innate immunity-dominant organ and natural killer (NK) cells, are the main lymphocyte population in the human liver. NK cells are in close interaction with other immune cells, acting as the first line of defense against pathogens, infections, and injury. A previously developed, three-dimensional, perfused liver-on-a-chip comprised of human cells was used to integrate NK cells, representing pivotal immune cells during liver injury and regeneration. The objective of this study was to integrate functional NK cells in an in vitro model of the human liver and assess utilization of the model for NK cell-dependent studies of liver inflammation. RESULTS NK cells from human blood and liver specimen were isolated by Percoll separation with subsequent magnetic cell separation (MACS), yielding highly purified blood and liver derived NK cells. After stimulation with toll-like-receptor (TLR) agonists (lipopolysaccharides, Pam3CSK4), isolated NK cells showed increased interferon (IFN)-gamma secretion. To study the role of NK cells in a complex hepatic environment, these cells were integrated in the vascular compartment of a microfluidically supported liver-on-a-chip model in close interaction with endothelial and resident macrophages. Successful, functional integration of NK cells was verified by immunofluorescence staining (NKp46), flow cytometry analysis and TLR agonist-dependent secretion of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. Lastly, we observed that inflammatory activation of NK cells in the liver-on-a-chip led to a loss of vascular barrier integrity. Overall, our data shows the first successful, functional integration of NK cells in a liver-on-a-chip model that can be utilized to investigate NK cell-dependent effects on liver inflammation in vitro

Living Donor Liver Transplantation for Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma is in most transplant regions a contraindication for liver transplantation, even ruling out an active waiting list registration. However, recent studies showed that well-selected patients after a neo-adjuvant treatment benefit from liver transplantation with good long-term outcomes. The role of living donor liver transplantation is unclear for this indication. The current study focuses on LDLT for intrahepatic cholangiocarcinoma

Transarterial chemoembolization with drug-eluting beads in patients with hepatocellular carcinoma: response analysis with mRECIST

PURPOSEAccording to the Barcelona Clinic Liver Cancer (BCLC) staging classification, transarterial chemoembolization (TACE) is the treatment of choice for intermediate hepatocellular carcinoma (HCC). Thereby, the use of drug-eluting beads (DEB) as embolic agents has been recently established in clinical practice. The aim of this study was to evaluate tumor response after DEB-TACE.METHODSThis retrospective study was approved by the institutional ethics committee. Overall, 89 patients with HCC (Child Pugh A or B) receiving DEB-TACE as palliative treatment option or as bridging before liver transplantation were included in the study. Tumor response was assessed by modified response evaluation criteria in solid tumors (mRECIST) and a tumor growth rate. Survival analysis was performed using Kaplan-Meier estimator with log-rank testing and Cox proportional hazards.RESULTSA total of 188 TACE procedures were performed between 2006 and 2010. After the last intervention, 18% achieved complete response, 45% achieved partial response, 28% had stable disease and 9% had progressive disease. Using the tumor growth rate, 90% of all patients showed a tumor reduction between first and final response evaluation. The 6-month, 1-, 2- and 3-year overall survival rates were 86.5%, 67.4%, 47.2%, and 33.7%, with a median survival of 45, 24, 15, and 14 months for complete response, partial response, stable disease, and progressive disease, respectively. Tumor reduction showed a positive effect on survival.CONCLUSIONDEB-TACE offers conclusive response results with mRECIST and proves a strong tendency of tumor reduction on survival benefits. Therefore, tumor growth rate represents a possible parameter to predict survival

Identification of Proteins Interacting with Cytoplasmic High-Mobility Group Box 1 during the Hepatocellular Response to Ischemia Reperfusion Injury

Ischemia/reperfusion injury (IRI) occurs inevitably in liver transplantations and frequently during major resections, and can lead to liver dysfunction as well as systemic disorders. High-mobility group box 1 (HMGB1) plays a pathogenic role in hepatic IRI. In the normal liver, HMGB1 is located in the nucleus of hepatocytes; after ischemia reperfusion, it translocates to the cytoplasm and it is further released to the extracellular space. Unlike the well-explored functions of nuclear and extracellular HMGB1, the role of cytoplasmic HMGB1 in hepatic IRI remains elusive. We hypothesized that cytoplasmic HMGB1 interacts with binding proteins involved in the hepatocellular response to IRI. In this study, binding proteins of cytoplasmic HMGB1 during hepatic IRI were identified. Liver tissues from rats with warm ischemia reperfusion (WI/R) injury and from normal rats were subjected to cytoplasmic protein extraction. Co-immunoprecipitation using these protein extracts was performed to enrich HMGB1-protein complexes. To separate and identify the immunoprecipitated proteins in eluates, 2-dimensional electrophoresis and subsequent mass spectrometry detection were performed. Two of the identified proteins were verified using Western blotting: betaine–homocysteine S-methyltransferase 1 (BHMT) and cystathionine γ-lyase (CTH). Therefore, our results revealed the binding of HMGB1 to BHMT and CTH in cytoplasm during hepatic WI/R. This finding may help to better understand the cellular response to IRI in the liver and to identify novel molecular targets for reducing ischemic injury

Proteinase-activated receptor 2 (PAR2) in hepatic stellate cells – evidence for a role in hepatocellular carcinoma growth in vivo

Background Previous studies have established that proteinase-activated receptor 2 (PAR2) promotes migration and invasion of hepatocellular carcinoma (HCC) cells, suggesting a role in HCC progression. Here, we assessed the impact of PAR2 in HCC stromal cells on HCC growth using LX-2 hepatic stellate cells (HSCs) and Hep3B cells as model. Methods PAR2 expression and function in LX-2 cells was analysed by RT-PCR, confocal immunofluorescence, electron microscopy, and [Ca2+]i measurements, respectively. The impact of LX-2-expressed PAR2 on tumour growth in vivo was monitored using HCC xenotransplantation experiments in SCID mice, in which HCC-like tumours were induced by coinjection of LX-2 cells and Hep3B cells. To characterise the effects of PAR2 activation in LX-2 cells, various signalling pathways were analysed by immunoblotting and proteome profiler arrays. Results Following verification of functional PAR2 expression in LX-2 cells, in vivo studies showed that these cells promoted tumour growth and angiogenesis of HCC xenografts in mice. These effects were significantly reduced when F2RL1 (encoding PAR2) was downregulated by RNA interference (RNAi). In vitro studies confirmed these results demonstrating RNAi mediated inhibition of PAR2 attenuated Smad2/3 activation in response to TGF-β1 stimulation in LX-2 cells and blocked the pro-mitotic effect of LX-2 derived conditioned medium on Hep3B cells. Furthermore, PAR2 stimulation with trypsin or a PAR2-selective activating peptide (PAR2-AP) led to activation of different intracellular signalling pathways, an increased secretion of pro-angiogenic and pro-mitotic factors and proteinases, and an enhanced migration rate across a collagen- coated membrane barrier. Silencing F2RL1 by RNAi or pharmacological inhibition of Src, hepatocyte growth factor receptor (Met), platelet-derived growth factor receptor (PDGFR), p42/p44 mitogen activated protein kinase (MAPK) or matrix-metalloproteinases (MMPs) blocked PAR2-AP-induced migration. Conclusion PAR2 in HSCs plays a crucial role in promoting HCC growth presumably by mediating migration and secretion of pro-angiogenic and pro-mitotic factors. Therefore, PAR2 in stromal HSCs may have relevance as a therapeutic target of HCC