RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and highly resistant to available chemotherapies. Mammalian target of rapamycin (mTOR) functions to regulate protein translation, angiogenesis and cell cycle progression in many cancers including HCC. In the present study, subcutaneous patient-derived HCC xenografts were used to study the effects of an mTOR inhibitor, RAD001 (everolimus), on tumour growth, apoptosis and angiogenesis. We report that oral administration of RAD001 to mice bearing patient-derived HCC xenografts resulted in a dose-dependent inhibition of tumour growth. RAD001-induced growth suppression was associated with inactivation of downstream targets of mTOR, reduction in VEGF expression and microvessel density, inhibition of cell proliferation, up-regulation of p27(Kip1) and down-regulation of p21(Cip1/Waf1), Cdk-6, Cdk-2, Cdk-4, cdc-25C, cyclin B1 and c-Myc. Our data indicate that the mTOR pathway plays an important role in angiogenesis, cell cycle progression and proliferation of liver cancer cells. Our study provides a strong rationale for clinical investigation of mTOR inhibitor RAD001 in patients with HCC.

Tuberculous biliary stricture.

Tuberculosis (TB) of the hepatobiliary system is not uncommon, but as a cause of biliary strictures, it is very rare. It poses difficulty in diagnosis and often requires surgical intervention to exclude underlying malignancy. To our knowledge, there are fewer than 20 reported cases in the English literature. We report a 35-year-old Filipino woman who presented with a 3-day history of obstructive jaundice, associated with significant weight loss and anorexia. Computed tomography (CT) revealed dilated intrahepatic biliary system secondary to distal stricture at the confluence of the left and right bile ducts. Magnetic resonance cholangiopancreatography characterised the lesion as an irregular stricturing at several sites in the common bile duct. Incidentally, the scans also showed indeterminate pulmonary nodules in the right lower lobes. CT thorax confirmed bilateral involvement of the lungs. She required percutaneous transhepatic drainage for biliary decompression. Tests on tissue from the lung lesions, the blood, and the bile all confirmed the presence of TB. She was treated with anti-TB medication. This report emphasizes the importance of considering TB as a possibile cause of biliary stricture, especially in South-East Asia.