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 p27Kip1 and down-regulation of p21Cip1/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.

Gemcitabine has moderate activity in NPC with minimal toxicity, and is also an effective salvage agent for patients who have failed or progressed after treatment with other agents.

Background and AimsSurgery is the primary curative option in patients with hepatocellular carcinoma (HCC). Current prognostic models for HCC are developed on datasets of primarily patients with advanced cancer, and may be less relevant to resectable HCC. We developed a postoperative nomogram, the Singapore Liver Cancer Recurrence (SLICER) Score, to predict outcomes of HCC patients who have undergone surgical resection.MethodsRecords for 544 consecutive patients undergoing first-line curative surgery for HCC in one institution from 1992–2007 were reviewed, with 405 local patients selected for analysis. Freedom from relapse (FFR) was the primary outcome measure. An outcome-blinded modeling strategy including clustering, data reduction and transformation was used. We compared the performance of SLICER in estimating FFR with other HCC prognostic models using concordance-indices and likelihood analysis.ResultsA nomogram predicting FFR was developed, incorporating non-neoplastic liver cirrhosis, multifocality, preoperative alpha-fetoprotein level, Child-Pugh score, vascular invasion, tumor size, surgical margin and symptoms at presentation. Our nomogram outperformed other HCC prognostic models in predicting FFR by means of log-likelihood ratio statistics with good calibration demonstrated at 3 and 5 years post-resection and a concordance index of 0.69. Using decision curve analysis, SLICER also demonstrated superior net benefit at higher threshold probabilities.ConclusionThe SLICER score enables well-calibrated individualized predictions of relapse following curative HCC resection, and may represent a novel tool for biomarker research and individual counseling.

BACKGROUND Patients with nasopharyngeal carcinoma (NPC) are treated primarily with radiotherapy. In the disseminated state, platinum‐based, 2‐drug combination regimens yielded response rates of 55–75%, achieving a median survival of 10–12 months. With the proven efficacy of second‐generation cytotoxics like paclitaxel and gemcitabine in patients with metastatic NPC, the authors hypothesized that a triplet combination incorporating these newer cytotoxics may improve treatment results. METHODS Thirty‐two patients with metastatic NPC were treated with combination chemotherapy that included paclitaxel 70 mg/m2 on Days 1 and 8, carboplatin dosed to area under curve of 5 on Day 1, and gemcitabine 1000 mg/m2 on Days 1 and 8 every 21 days for a maximum of 8 cycles. RESULTS Two patients achieved a complete response, and 23 patients achieved a partial response, for an overall response rate of 78%. The main toxicities were hematologic, with 41% of patients experiencing Grade 3 or 4 anemia, 41% of patients experiencing Grade 3 or 4 thrombocytopenia, and 78% of patients experiencing Grade 3 or 4 neutropenia. The median time to disease progression was 8.1 months, and the median overall survival was 18.6 months. CONCLUSIONS The combination of paclitaxel, carboplatin, and gemcitabine showed promising efficacy against metastatic NPC but at the expense of considerable toxicity. Cancer 2005. © 2004 American Cancer Society.

Pretreatment with amifostine showed a trend toward reducing the severity of esophagitis associated with concurrent chemoradiotherapy, but it did not reach statistical significance. There was no significant protective effect on hematologic or neurologic toxicities induced by paclitaxel and carboplatin.