Combined treatment of refractory ascites with an alfapump® plus hernia repair in the same surgical session: A retrospective, multicentre, European pilot study in cirrhotic patients.

INTRODUCTION: The treatment of symptomatic hernia in cirrhotic patients with refractory ascites is critical but challenging. The objective of this study was to assess the feasibility and safety of the implantation of alfapump® combined with concomitant hernia repair in cirrhotic patients with refractory ascites. METHODS: Using data from six European centres, we retrospectively compared patients treated with alfapump® system implantation and concomitant hernia repair [the combined treatment group (CT group, n=12)] or with intermittent paracentesis hernia repair [the standard treatment group (ST group, n=26)]. Some patients of the ST group had hernia repair in an elective setting (STel group) and others in emergency (STem group). The endpoints were requirement of peritoneal drainage, the rate of infectious complications, the in-hospital mortality, the length of stay, paracentesis-free survival. RESULTS: Postoperatively, none of the patients in the CT group and 21 patients (80%) in the ST group underwent peritoneal drainage for the evacuation of ascites fluid (P<0.0001). The overall incidence of infectious complications was not different between groups but there were fewer infections in the CT group than in the STem group (33% vs. 81%; P=0.01). There was no difference for in-hospital mortality. The length of stay was shorter in the CT group (P=0.03). Paracentesis-free survival was significantly better (P=0.0003) in the CT group than in the ST group. CONCLUSION: Implantation of alfapump combined with concomitant hernia repair seems feasible and safe in cirrhotic patients; however, larger and randomized study are required.

Allergens displayed on virus-like particles are highly immunogenic but fail to activate human mast cells.

BACKGROUND: The goal of allergen-specific immunotherapy is the induction of protective immune responses in the absence of anaphylactic reactions. We have previously shown that Fel d 1, the major cat allergen, displayed in a repetitive fashion on virus-like particles (VLPs) may fulfill these criteria. Specifically, Fel d 1 on VLPs induced strongly increased protective IgG responses compared to free allergen in mice while anaphylactic reactions were essentially abolished. Here we extend these findings to human mast cells and offer a mechanistic explanation for the reduced anaphylactic activity. METHODS: We differentiated human mast cells in vitro from blood-derived stem cell progenitors and sensitized the cells with a monoclonal Fel d 1-specific IgE. We compared the capability of Fel d 1 to induce mast cell activation in its free form versus displayed on VLPs and we performed allergen binding studies by surface plasmon resonance as well as flow cytometry. RESULTS: We show that free Fel d 1 induces degranulation of IgE-sensitized mast cells whereas Fel d 1 displayed on VLPs fails to induce mast cell activation. We demonstrate that this inability to activate mast cells is based on a biophysical as well as a biochemical mechanism. Firstly, Fel d 1 on VLPs showed a strongly impaired ability to bind to surface-bound IgE. Secondly, despite residual binding, repetitively displayed allergen on VLPs failed to cause mast cell activation. CONCLUSION: These findings indicate that repetitively displaying allergens on VLPs increases their immunogenicity while reducing their potential to cause anaphylactic reactions by essentially eliminating IgE-mediated activation of mast cells.

Treatment of refractory ascites with an automated low-flow ascites pump in patients with cirrhosis.

BACKGROUND: Refractory ascites (RA) is a frequent complication of cirrhosis, requiring large volume paracentesis or placement of a transjugular intrahepatic portosystemic shunt (TIPSS). The automated low-flow ascites pump (alfapump, Sequana Medical AG, Zurich, Switzerland) is an innovative treatment option for patients with RA. AIM: To assess safety and efficacy of this treatment in patients with a contraindication to TIPSS. METHODS: Fifty-six patients (43 males; mean age 62 years) from centres in Germany, Switzerland, UK and Spain were included and followed for up to 24 months. Complications, device deficiencies, paracentesis frequency and patient survival were recorded. RESULTS: At the time of this analysis, 3 patients completed the 24-month observation period, monitoring of 3 was ongoing, 9 underwent liver transplantation, 17 patients were withdrawn due to serious adverse events and 23 patients died. Most frequently observed technical complication was blocking of the peritoneal catheter. Twenty-three pump-related reinterventions (17 patients) and 12 pump exchanges (11 patients) were required during follow-up. The pump system was explanted in 48% of patients (in 17 patients due to serious adverse events, in 9 at the time of liver transplantation and in 1 due to recovery from RA). Median frequency of paracentesis dropped from 2.17 to 0.17 per month. CONCLUSIONS: The alfapump can expand therapeutic options for cirrhotic patients with RA. Continuous drainage of ascites in a closed loop automated system led to significant reduction in paracentesis frequency. Technical and procedural improvements are required to reduce the rate of adverse events and reinterventions. https://clinicaltrials.gov/ct2/show/NCT01532427.

A selective COX-2 inhibitor suppresses chronic pancreatitis in an animal model (WBN/Kob rats): significant reduction of macrophage infiltration and fibrosis.

INTRODUCTION: Therapeutic strategies to treat chronic pancreatitis (CP) are very limited. Other chronic inflammatory diseases can be successfully suppressed by selective cyclooxygenase 2 (COX-2) inhibitors. As COX-2 is elevated in CP, we attempted to inhibit COX-2 activity in an animal model of CP (WBN/Kob rat). We then analysed the effect of COX-2 inhibition on macrophages, important mediators of chronic inflammation. METHODS: Male WBN/Kob rats were continuously fed the COX-2 inhibitor rofecoxib, starting at the age of seven weeks. Animals were sacrificed 2, 5, 9, 17, 29, 41, and 47 weeks later. In some animals, treatment was discontinued after 17 weeks, and animals were observed for another 24 weeks. RESULTS: Compared with the spontaneous development of inflammatory injury and fibrosis in WBN/Kob control rats, animals treated with rofecoxib exhibited a significant reduction and delay (p<0.0001) in inflammation. Collagen and transforming growth factor beta synthesis were significantly reduced. Similarly, prostaglandin E(2) levels were markedly lower, indicating strong inhibition of COX-2 activity (p<0.003). If treatment was discontinued at 24 weeks of age, all parameters of inflammation strongly increased comparable with that in untreated rats. The correlation of initial infiltration with subsequent fibrosis led us to determine the effect of rofecoxib on macrophage migration. In chemotaxis experiments, macrophages became insensitive to the chemoattractant fMLP in the presence of rofecoxib. CONCLUSION: In the WBN/Kob rat, chronic inflammatory changes and subsequent fibrosis can be inhibited by rofecoxib. Initial events include infiltration of macrophages. Cell culture experiments indicate that migration of macrophages is COX-2 dependent.