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De Gottardi A.,University of Geneva | De Gottardi A.,University of Bern | De Gottardi A.,University Clinic of Visceral Surgery and Medicine | Keller P.-F.,University of Geneva | And 3 more authors.
BMC Research Notes

Background: The evaluation of the hepatic parenchyma in patients with chronic liver disease is important to assess the extension, localization and relationship with adjacent anatomical structures of possible lesions. This is usually performed with conventional abdominal ultrasound, CT-scan or magnetic resonance imaging. In this context, the feasibility and the safety of intravascular ultrasound in the liver have not been assessed yet. Methods. We tested the safety and performance of an intracardiac echography (ICE) catheter applied by a transjugular approach into the hepatic veins in patients with chronic liver disease undergoing hepatic hemodynamic measurements. Results: Five patients were enrolled in this pilot study. The insertion of the ICE catheter was possible into the right and middle, but not into the left hepatic vein. The position of the ICE was followed using fluoroscopy and external conventional ultrasound. Accurate imaging of focal hepatic parenchymal lesions, Doppler ultrasound of surrounding blood vessels and assessment of liver surface and ascites were achieved without complications. Conclusions: This study demonstrated that a diagnostic approach using an ICE device inserted in the hepatic veins is feasible, safe and well tolerated. However, it remains for the moment only an experimental investigative tool. Whether ICE adds further information regarding parenchymal lesions and associated vascular alterations as compared to other techniques, needs additional investigation. © 2012 De Gottardi et al; licensee BioMed Central Ltd. Source

Piguet A.-C.,University of Bern | Saran U.,University of Bern | Simillion C.,University of Bern | Keller I.,University of Bern | And 4 more authors.
Journal of Hepatology

Background & Aims Unhealthy lifestyles predispose people to non-alcoholic steatohepatitis (NASH), which may further result in the development of hepatocellular carcinoma (HCC). Although NASH patients benefit from physical activity, it is unknown whether regular exercise reduces the risk of developing HCC. Therefore, we studied the effect of regular exercise on the development of HCC in male hepatocyte-specific PTEN-deficient mice (AlbCrePtenflox/flox), which develop steatohepatitis and HCC spontaneously. Methods Mice were fed a standardized 10% fat diet and were randomly divided into exercise or sedentary groups. The exercise group ran on a motorized treadmill for 60 min/day, 5 days/week during 32 weeks. Results After 32 weeks of regular exercise, 71% of exercised mice developed nodules larger than 15 mm3 vs. 100% of mice in the sedentary group. The mean number of tumors per liver was reduced by exercise, as well as the total tumoral volume per liver. Exercise did not affect steatosis and had no effect on the non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS). Exercise decreased tumor cell proliferation. Mechanistically, exercise stimulated the phosphorylation of AMPK and its substrate raptor, which decreased the kinase activity of mTOR. Conclusions These data show a beneficial effect of regular exercise on the development of HCC in an experimental model of NASH and offer a rationale for encouraging predisposed patients to increase their physical activity for the prevention of HCC. © 2015 European Association for the Study of the Liver. Source

Saran U.,University of Bern | Saran U.,University Clinic of Visceral Surgery and Medicine | Foti M.,University of Geneva | Dufour J.-F.,University of Bern | Dufour J.-F.,University Clinic of Visceral Surgery and Medicine
Clinical Science

mTOR (mechanistic target of rapamycin) functions as the central regulator for cell proliferation, growth and survival. Up-regulation of proteins regulating mTOR, as well as its downstream targets, has been reported in various cancers. This has promoted the development of anti-cancer therapies targeting mTOR, namely fungal macrolide rapamycin, a naturally occurring mTOR inhibitor, and its analogues (rapalogues). One such rapalogue, everolimus, has been approved in the clinical treatment of renal and breast cancers. Although results have demonstrated that these mTOR inhibitors are effective in attenuating cell growth of cancer cells under in vitro and in vivo conditions, subsequent sporadic response to rapalogues therapy in clinical trials has promoted researchers to look further into the complex understanding of the dynamics of mTOR regulation in the tumour environment. Limitations of these rapalogues include the sensitivity of tumour subsets to mTOR inhibition. Additionally, it is well known that rapamycin and its rapalogues mediate their effects by inhibiting mTORC (mTOR complex) 1, with limited or no effect on mTORC2 activity. The present review summarizes the pre-clinical, clinical and recent discoveries, with emphasis on the cellular and molecular effects of everolimus in cancer therapy. © 2015 Authors. Source

Berzigotti A.,University Clinic of Visceral Surgery and Medicine | Saran U.,University of Bern | Dufour J.-F.,University Clinic of Visceral Surgery and Medicine | Dufour J.-F.,University of Bern

Regular physical activity beneficially impacts the risk of onset and progression of several chronic diseases. However, research regarding the effects of exercising on chronic liver diseases is relatively recent. Most researchers focused on nonalcoholic fatty liver disease (NAFLD), in which increasing clinical and experimental data indicate that skeletal muscle crosstalking to the adipose tissue and the liver regulates intrahepatic fat storage. In this setting, physical activity is considered to be required in combination with calories restriction to allow an effective decrease of intrahepatic lipid component, and despite that evidence is not conclusive, some studies suggest that vigorous activity might be more beneficial than moderate activity to improve NAFLD/nonalcoholic steatohepatitis. Evidence regarding the effects of exercise on the risk of hepatocellular carcinoma is scarce; some epidemiological studies indicate a lower risk in patients regularly and vigorously exercising. In compensated cirrhosis, exercise acutely increases portal pressure, but in the longer term it has been proved safe and probably beneficial. Decreased aerobic capacity (VO2) correlates with mortality in patients with decompensated cirrhosis, who are almost invariably sarcopenic. In these patients, VO2 is improved by physical activity, which might also reduce the risk of hepatic encephalopathy through an increase in skeletal muscle mass. In solid organ transplantation recipients, exercise is able to improve lean mass, muscle strength, and, as a consequence, aerobic capacity. Few data exist in liver transplant recipients, in whom exercise should be an object of future studies given its high potential of providing long-term beneficial effects. Conclusions: Despite that evidence is far from complete, physical activity should be seen as an important part of the management of patients with liver disease in order to improve their clinical outcome. © 2016 by the American Association for the Study of Liver Diseases. Source

Piguet A.-C.,University of Bern | Saar B.,Institute for Diagnostic Radiology | Hlushchuk R.,University of Fribourg | St-Pierre M.V.,University of Bern | And 7 more authors.
Molecular Cancer Therapeutics

Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2x/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI quantified tumor volumes. Erk1/2, 4E-BP1, and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85%, and 55%, relative to controls, in everolimus, the combination, and sequential groups, respectively (P < 0.01). Survival was longest in the combination group (P < 0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (P < 0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib, and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib. ©2011 AACR. Source

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