ABSTRACT
OBJECTIVE: The aim of this study was to identify the prognostic factors in patients with advanced hepatocellular carcinoma (HCC) who are refractory or intolerant to sorafenib and to exclude unsuitable candidates from subsequent therapy. METHODS: The study cohort consisted of 111 patients who had discontinued sorafenib therapy. Uni- and multivariate analyses were conducted to identify the prognostic factors for survival after discontinuation of sorafenib therapy. RESULTS: The median age of the patients was 70 years, and 96 of them (86%) were male. The Eastern Cooperative Oncology Group performance status was 0-1 in 94 patients (85%). Forty patients (36%) were classified as Child-Pugh class A and 57 (51%) as Child-Pugh class B. The median survival time after discontinuation of sorafenib therapy was 146 days. Hepatitis C viral antibody negativity, presence of ascites, absence of a history of previous treatment excluding sorafenib, elevated serum total bilirubin level, and elevated serum α-fetoprotein level were identified as the independent unfavorable prognostic factors by multivariate analysis. The median survival time of the patients with 4 or 5 unfavorable prognostic factors was 59 days. CONCLUSIONS: We should judge the indication of any subsequent therapy carefully in patients with 4 or 5 of the aforementioned factors.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Drug Resistance, Neoplasm , Liver Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Cohort Studies , Female , Follow-Up Studies , Humans , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Niacinamide/therapeutic use , Prognosis , Sorafenib , Survival RateABSTRACT
BACKGROUND: Therapeutic gene transfer is currently being evaluated as a potential therapy for inflammatory bowel disease. This study investigates the safety and therapeutic benefit of a locally administered lentiviral vector encoding murine interleukin-10 in altering the onset and relapse of dextran sodium sulfate induced murine colitis. METHODS: Lentiviral vectors encoding the reporter genes firefly-luciferase and murine interleukin-10 were administered by intrarectal instillation, either once or twice following an ethanol enema to facilitate mucosal uptake, on Days 3 and 20 in Balb/c mice with acute and relapsing colitis induced with dextran sulfate sodium (DSS). DSS colitis was characterized using clinical disease activity, macroscopic, and microscopic scores. Bioluminescence optical imaging analysis was employed to examine mucosal lentiviral vector uptake and transgene expression. Levels of tumor necrosis factor-α and interleukin-6 in homogenates of rectal tissue were measured by ELISA. Biodistribution of the lentiviral vector to other organs was evaluated by real time quantitative PCR. RESULTS: Mucosal delivery of lentiviral vector resulted in significant transduction of colorectal mucosa, as shown by bioluminescence imaging analysis. Lentiviral vector-mediated local expression of interleukin-10 resulted in significantly increased levels of this cytokine, as well as reduced levels of tumor necrosis factor-α and interleukin-6, and significantly reduced the clinical disease activity, macroscopic, and microscopic scores of DSS colitis. Systemic biodistribution of locally instilled lentiviral vector to other organs was not detected. CONCLUSIONS: Topically-delivered lentiviral vectors encoding interleukin-10 safely penetrated local mucosal tissue and had therapeutic benefit in this DSS model of murine colitis.
Subject(s)
Colitis/therapy , Genetic Therapy/methods , Genetic Vectors , Interleukin-10/genetics , Lentivirus , Administration, Mucosal , Administration, Rectal , Animals , Colitis/chemically induced , Colitis/prevention & control , Dextran Sulfate/toxicity , Disease Models, Animal , Gene Transfer Techniques , Mice , Mice, Inbred BALB C , RecurrenceABSTRACT
BACKGROUND: The efficacy of sorafenib for hepatocellular carcinoma (HCC) patients refractory to transcatheter arterial chemoembolization (TACE) has not yet been clarified. We investigated the efficacy of sorafenib in HCC patients who were refractory to TACE (sorafenib group) and retrospectively compared the results with those of patients treated with hepatic arterial infusion chemotherapy using cisplatin (cisplatin group). METHODS: We evaluated the anti-tumor effect, the time to progression, and the overall survival in 48 patients in the sorafenib group and 66 patients in the cisplatin group. RESULTS: The disease control rate to sorafenib was 60.4 %, the median time to progression was 3.9 months, and the median survival time was 16.4 months in patients who were refractory to TACE. When compared with the cisplatin group, significant differences in the patient characteristics were not observed between the two groups with the exception of patient age; however, the disease control rate (cisplatin group 28.8 %, P = 0.001), time to progression (cisplatin group: median 2.0 months, hazard ratio 0.44, P < 0.01), and overall survival (cisplatin group: median 8.6 months, hazard ratio 0.57, P < 0.001) were significantly superior in the sorafenib group. The multivariate analysis also showed the sorafenib treatment to be the most significant factor contributing to prolongation of time to progression and overall survival. CONCLUSIONS: Sorafenib showed favorable treatment results in patients refractory to TACE. When compared with hepatic arterial infusion chemotherapy using cisplatin, sorafenib demonstrated a significantly higher disease control rate, a longer time to progression and increased overall survival.