Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma

Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses ⩾12.5 mg kg⁻¹ day⁻¹ (P<0.05), but higher doses (50 mg kg⁻¹ day⁻¹, P<0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg⁻¹ day⁻¹) also significantly (P=0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma.     

Attenuation of Ischaemia-Induced Regional Myocardial Acidosis by Bevantolol,a β1-Adrenoceptor Antagonist,in Dogs

Abstract: In dogs anaesthetized with pentobarbital, the left anterior descending coronary artery (LAD) was occluded for 90 min. so that about 1/2 of the original flow was allowed to flow (partial occlusion). Bevantolol (a β₁-adrenoceptor antagonist) or propranolol (a reference drug) was injected intravenously 30 min. after partial occlusion. Regional myocardial pH was measured by a micro glass pH electrode inserted in the LAD area. Partial occlusion decreased myocardial pH by 0.62 to 0.74. Bevantolol (1.0 mg/kg) or propranolol (1.0 mg/kg) significantly increased myocardial pH, that had been decreased by partial occlusion, within 60 min. after the injection. Restoration of myocardial [H⁺] (defined as return towards a lower [H⁺] to the preocclusion level) (calculated from the pH data) induced by bevantolol and that induced by propranolol were 64.0 and 66.4% (measured 60 min. after the injection), respectively. Bevantolol or propranolol decreased heart rate also. Even in the paced heart, bevantolol restored the myocardial [H⁺] that had been increased by partial occlusion. These results suggest that bevantolol has a favorable effect on the ischaemic myocardium as has propranolol, and that the pH effect of bevantolol is not primarily due to a decrease in heart rate.     

Dyschromatosis symmetrica hereditaria associated with neurological disorders

Dyschromatosis symmetrica hereditaria (DSH) is a pigmentary genodermatosis of autosomal dominant inheritance caused by a mutation of adenosine deaminase acting on the RNA 1 gene (ADAR1). It is characterized by a mixture of hyper‐ and hypopigmented macules on the back of the hands and feet. The pathomechanism by which the ADAR1 gene mutation induces DSH has not been clarified yet. We experienced an 11‐year‐old male DSH patient associated with dystonia, mental deterioration and brain calcification, who had a mutation of p.G1007R in the ADAR1 gene. This mutation had already been reported in a patient with similar neurological symptoms by Tojo et al. Additionally, a patient with DSH associated with torsion dystonia was reported by Patrizi et al., but gene analysis was not carried out. Only three cases with neurological disorders have been reported, although more than 50 mutations of the ADAR1 gene causing DSH have been reported and none of them had any neurological symptoms. Therefore, we suggest that neurological disorders rarely develop in DSH.     

Focal cortical dysplasia with calcification: a case report

Case report Focal cortical dysplasia (FCD) with calcification is rare. We presented a 13-year-old epileptic patient with FCD and calcification in the left frontal lobe. At age 24, the FCD lesion and the surrounding epileptogenic cortex and underlying subcortex were removed after chronic subdural electrode recording. Histological examination showed that the calcified lesion was not independent of the FCD lesion but located in the subcortical area of the FCD lesion. A neoplastic nature was ruled out for the lesion. Discussion The pathophysiological mechanism involved in the coexistence of FCD and calcification is discussed.     

Left atrial myxoma associated with acute myocardial infarction

We describe a patient with left atrial myxoma associated with acute myocardial infarction. Since hemodynamics were impaired even with the support of an intra-aortic balloon pump, the patient underwent removal of the tumor concomitant with coronary artery bypass grafting to the right coronary artery on the fifth day from infarction onset. In circumstances of life-threatening of myxoma associated with acute myocardial infarction, removal of myxoma with coronary artery bypass should be performed in an acute phase of myocardial infarction.     

Accumulation of L-type Bovine Prions in Peripheral Nerve Tissues

We recently reported the intraspecies transmission of L-type atypical bovine spongiform encephalopathy (BSE). To clarify the peripheral pathogenesis of L-type BSE, we studied prion distribution in nerve and lymphoid tissues obtained from experimentally challenged cattle. As with classical BSE prions, L-type BSE prions accumulated in central and peripheral nerve tissues.     

IMPORTANCE OF THE FISTULA TRACT ANGLE IN FISTULA TRACT DISRUPTION IN PERCUTANEOUS ENDOSCOPIC GASTROSTOMY

Background : The fistula tract angle formed by percutaneous endoscopic gastrostomy (PEG) was examined. Also, the previous literature on fistula tract disruption is reviewed and the possible influence of the fistula tract angle on fistula tract disruption by non‐endoscopic catheter change is discussed. Methods : A total of 15 patients aged 24–80 years were examined.The fistula tract angle was measured as the angle of elevation between the tangent line at the orifice of the PEG stoma and the longitudinal axis of the catheter. Results : Values of the angle ranged from 56 to 90° (mean 77.6°), with four cases (27%) having angles below 70°.With one case of pan‐peritonitis after catheter insertion at 90°, laparotomy revealed that the angle of the fistula tract was low at 62° and that the catheter had broken through the tract just below the abdominal wall. Conclusion : This study suggests that the fistula tract angle might be a potential risk factor for fistula tract disruption by non‐endoscopic catheter change.