Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme.

BACKGROUND: Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study. PATIENTS AND METHODS: 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0-2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks+1-week rest followed by once 3-weeks+1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA). RESULTS: Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P=0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P=0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P=0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRß expression correlated with longer PFS. CONCLUSION: The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.

Three-question dementia screening. Development of the Salzburg Dementia Test Prediction (SDTP).

BACKGROUND: To date, short dementia screenings are often limited by poor specificity or still take too much time with respect to the restricted resources of primary care physicians and the increasing number of dementia disorders. As a new instrument, the three-question dementia screening (SDTP, Salzburg Dementia Test Prediction) should be compared with the eight-item screening of Chen et al. and the CERAD battery (Consortium to Establish a Registry for Alzheimer's Disease), focusing on specificity and economy of time. MATERIALS AND METHODS: We tested 404 patients (243 women). The mean age of the subjects was 80.1 years (SD = 6.8) for men and 83.2 years (SD = 6.0) for women. The mean Mini-Mental State Examination (MMSE) score was 21.9 (SD = 5.8) for men and 21.1 (SD = 6.3) for women. Artificial neural networks (ANNs) were used to find a mathematical model that allows the total MMSE to be predicted with only three questions of the MMSE. This is achieved by multiplying the outcome of the three best predictor questions with a weighting coefficient, which was delineated by using ANNs. RESULTS: The Salzburg Dementia Test Prediction (SDTP) had a sensitivity of 94% (95% CI: 87-97%) for screening of possible dementia, when the MMSE (MMSE < 25/30) was used as the reference test method and 96% when the CERAD was used. The specificity was 68% (95% CI: 57-77%) if the MMSE was used and 70% if the whole test battery (CERAD) was used, which is as sensitive as and more specific than the eight-item screening. CONCLUSION: The SDTP is a time-saving instrument for screening of dementia, which is as sensitive as and more specific than the eight-item screening of Chen et al. and provides a prediction of the MMSE with high accuracy.