Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma

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, 2×/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.     

Bidirectional interactions between bone metabolism and hematopoiesis

Interactions between hematopoiesis and bone metabolism have been described in various developmental and pathological situations. Here we review this evidence from the literature with a focus on microenvironmental regulation of hematopoiesis and bone metabolism. Our hypothesis is that this process occurs by bidirectional signaling between hematopoietic and mesenchymal cells through cell adhesion molecules, membrane-bound growth factors, and secreted matrix proteins. Examples of steady-state hematopoiesis and pathologies are presented and support our view that hematopoietic and mesenchymal cell functions are modulated by specific microenvironments in the bone marrow.     

Biomarkers for hepatocellular apoptosis in the management of liver diseases

Apoptosis is a rare event in normal hepatocytes. However, multiple signals can trigger apoptosis in hepatocytes and it plays a role in the pathogenesis of many liver diseases. This review summarizes the mechanisms of hepatocellular apoptosis and the importance of apoptosis in the pathological processes of liver disease. The potential for non-invasive biomarkers of apoptosis to gauge the extent and follow the evolution of clinical disease is emphasized.     

Deep veins of the calf: assessment with color Doppler flow imaging

The authors studied the ability of real-time ultrasound aided by color Doppler flow imaging to demonstrate the deep veins of the calf in ten healthy subjects and 49 patients (91 limbs) with suspected deep venous thrombosis. Posterior tibial and peroneal veins demonstrated flow accentuation in 98% (74 of 75) and 96% (72 of 75), respectively, of the limbs without thrombosis and in all 20 normal limbs. Sixteen legs were involved with deep venous thrombosis. Peroneal veins could not be seen in three legs with marked calf swelling due to proximal thrombosis. There were two cases of thrombosis limited to the calf, nine of popliteal thrombosis (seven with contiguous spread of thrombus), and five of thrombosis limited to above the knee (four with sparing of the deep veins of the calf). Visualization of anterior tibial veins, achieved in 65% of all legs, did not correlate with thrombosis. The authors conclude that color Doppler flow imaging can demonstrate patency of posterior tibial and peroneal veins in most patients without deep venous thrombosis and aid in detection of below-the-knee thrombosis.