PTK787/ZK222584 Combined with Interferon Alpha and 5-Fluorouracil Synergistically Inhibits VEGF Signaling Pathway in Hepatocellular Carcinoma

Background

The prognosis of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus remains poor. We previously reported the beneficial effects of interferon alpha (IFN) and 5-fluorouracil (5-FU) combination therapy for these patients. We showed that the mechanism of therapy was regulation of vascular endothelial growth factor (VEGF). Here, we combined IFN/5-FU therapy with the VEGF receptor–selective inhibitor PTK787/ZK222584 (PTK/ZK) and examined the antitumor effects and the mechanism of action.

Methods

We studied two HCC cell lines, PLC/PRF/5 and HuH7, and a human umbilical vein endothelial cell line, HUVEC. We studied the effects of IFN/5-FU with or without PTK/ZK in growth inhibition assays, immunohistochemistry, Western blot analysis, and immunocytochemistry.

Results

In a HuH7 xenograft model, the combination of PTK/ZK and IFN/5-FU significantly inhibited proliferation, induced apoptosis, decreased microvessel density, reduced the number of tumor cells that expressed VEGF receptor 2 (VEGFR-2), and repressed the phosphorylation of Akt in vivo. In HCC cells and HUVECs in vitro, IFN/5-FU plus PTK/ZK repressed the expression of VEGFR-2 and repressed the phosphorylation of VEGFR, Akt, Erk, and p38MAPK.

Conclusions

VEGF signaling inhibition enhanced the antitumor effects of IFN/5-FU therapy on HCC cells and endothelial cells via Erk, Akt, and p38MAPK pathways.

     

Aortic arch thrombosis in the neonate

Aortic arch thrombosis (AAT) of the neonate is rare but life-threatening by fatal compromise associated with thrombotic obstruction of the ascending aorta. We report a neonate with AAT who demonstrated a severe coarctation of the aorta and cerebral hypo-perfusion immediately after birth. Echocardiography confirmed the diagnosis of AAT on the findings of a large thrombus located on the transverse arch and blocking the cervical arterial branches. Low-molecular-weight heparin reduced the size of the thrombus and improved the hemodynamics of coarctation and cerebral perfusion. Echocardiography is a powerful tool to make a diagnosis and to monitor the size and regression of AAT.     

Patient-prosthesis mismatch in patients with aortic valve replacement

Objective

Patient-prosthesis mismatch (PPM) may affect clinical outcomes in patients with aortic valve replacement (AVR). We retrospectively examined the PPM in patients with isolated AVR in the Japan Adult Cardiovascular Surgery Database (JACVSD).

Methods

We examined all patients with isolated AVR between January 1, 2008 and December 31, 2009. The JACVSD data collection form has a total of 255 variables. We defined PPM as an effective orifice area index of ≤0.85 m²/cm².

Results

PPM was observed in 306 of 3,609 cases analyzed, PPM rate was 8.5 %. Body surface area was larger and body mass index was higher in the PPM group than the non-PPM group (P < 0.001). Patients with PPM were older (P = 0.001) and had a higher prevalence of diabetes (P = 0.004), dyslipidemia (P < 0.001), hypertension (P < 0.001), cerebrovascular disease (P = 0.031), old myocardial infarction (P = 0.006), previous percutaneous coronary artery intervention (P = 0.001), coronary artery disease (P = 0.018), and aortic valve stenosis (P < 0.001). Perioperative blood transfusion (P < 0.001) and dialysis (P = 0.005) were more frequent in the PPM group. Postoperative ventilation (P = 0.004) and intensive care unit stay (P = 0.004) were significantly longer in the PPM group.

Conclusions

Age, aortic valve stenosis, dyslipidemia, hypertension, old myocardial infarction, previous percutaneous coronary artery intervention, diabetes mellitus, cerebrovascular disease, and high body mass index were the risk factors for PPM. PPM was not an independent risk factor for short-term mortality.     

Isolated pyramidal tract impairment in the central nervous system of adult-onset Krabbe disease with novel mutations in the GALC gene

This report describes a 60-year-old female patient with Krabbe disease who presented with slowly progressive gait disturbance due to mild spastic paraplegia. Brain magnetic resonance imaging showed high-intensity lesions along the upper parts of the bilateral pyramidal tracts in fluid-attenuated inversion recovery images. Central motor conduction time was prolonged both in the upper and the lower extremities, while central sensory conduction time was normal. The reduced lymphocyte galactocerebrosidase (GALC) activity and two novel mutations in the GALC gene, p.G496S and p.G569S, proved the diagnosis of Krabbe disease. Our findings show that adult-onset Krabbe disease is characterized by isolated pyramidal tract impairment in the central nervous system, both neurophysiologically and radiologically.