Clinical development directions in oncolytic viral therapy.

Oncolytic virotherapy is an emerging experimental treatment platform for cancer therapy. Oncolytic viruses are replicative-competent viruses that are engineered to replicate selectively in cancer cells with specified oncogenic phenotypes. Multiple DNA and RNA viruses have been clinically tested in a variety of tumors. This review will provide a brief description of these novel anticancer biologics and will summarize the results of clinical investigation. To date oncolytic virotherapy has shown to be safe, and has generated clinical responses in tumors that are resistant to chemotherapy or radiotherapy. The major challenge for researchers is to maximize the efficacy of these viral therapeutics, and to establish stable systemic delivery mechanisms.

Phase II trial of talabostat and docetaxel in advanced non-small cell lung cancer.

AIMS: Currently available therapies do improve survival in advanced stage non-small cell lung cancer (NSCLC), but only to a limited degree. Talabostat mesilate (PT-100) is an orally available amino boronic dipeptide that specifically inhibits dipeptidyl peptidases (including fibroblast activation protein) and enhances an immune response. The aim of this study was to determine the efficacy and safety of talabostat in NSCLC patients. MATERIALS AND METHODS: A phase II trial was conducted to evaluate talabostat in combination with docetaxel in patients with advanced NSCLC after failure of previous platinum-based chemotherapy. In total, 42 patients were enrolled. RESULTS: Talabostat was well tolerated. Two patients achieved a partial response and one achieved a complete response. CONCLUSION: There was no evidence that talabostat enhanced the clinical activity of docetaxel in patients with NSCLC.

Validation study of a transcutaneous carbon dioxide monitor in patients in the emergency department.

BACKGROUND: Transcutaneous carbon dioxide tension (TcPco(2)) monitors offer a non-invasive method of continuously measuring arterial carbon dioxide tensions. The concordance between the TcPco(2) measurement and the value obtained from arterial blood gas sampling (Paco(2)) was measured in patients attending the emergency department. METHODS: A prospective observational cohort study was performed in 49 adult patients who were undergoing arterial blood gas sampling as part of their assessment. Blood gas sampling and recording of the TcPco(2) level from the monitor was done simultaneously. Concordance between the two values (Paco(2) and TcPco(2)) was demonstrated using the method described by Bland and Altman. RESULTS: The mean difference was 0.02 kPa (95% CI -0.11 to 0.15). The Pearson's correlation coefficient was 0.94 (p<0.001) and the Bland-Altman limits of agreement were +/-0.9 kPa. CONCLUSIONS: In adult patients, concordance between carbon dioxide measurements by transcutaneous monitor and arterial blood sampling is good. Using the transcutaneous method, patients may be monitored non-invasively which may reduce the need for repeated blood gas sampling.

Current practice relating to equine castration in the UK.

This study aimed to characterise current practice relating to equine castration in the UK. A questionnaire was posted to all 655 veterinary practices specified to provide veterinary care for horses, or classified as specialist equine practices. Respondents were asked to cite the number of equine castrations performed annually by the practice, describe techniques used for castration, outline anaesthetic/sedative/analgesic drug protocols used and provide details of post-operative medication. There was a 43% response rate to the questionnaire. Considerable variation in techniques and analgesia provision was identified, with the majority of respondents using a number of sedation/anaesthetic protocols rather than a single technique. This characterisation of current practice provides a useful platform from which subsequent investigations into welfare implications of current equine castration techniques can be directed.

Recording of ECG signals on a portable MiniDisc recorder for time and frequency domain heart rate variability analysis.

Analysis of heart rate variability (HRV) is a non-invasive technique useful for investigating autonomic function in both humans and animals. It has been used for research into both behaviour and physiology. Commercial systems for human HRV analysis are expensive and may not have sufficient flexibility for appropriate analysis in animals. Some heart rate monitors have the facility to provide inter-beat interval (IBI), but verification following collection is not possible as only IBIs are recorded, and not the raw electrocardiogram (ECG) signal. Computer-based data acquisition and analysis systems such as Po-Ne-Mah and Biopac offer greater flexibility and control but have limited portability. Many laboratories and veterinary surgeons have access to ECG machines but do not have equipment to record ECG signals for further analysis. The aim of the present study was to determine whether suitable HRV data could be obtained from ECG signals recorded onto a MiniDisc (MD) and subsequently digitised and analysed using a commercial data acquisition and analysis package. ECG signals were obtained from six Thoroughbred horses by telemetry. A split BNC connecter was used to allow simultaneous digitisation of analogue output from the ECG receiver unit by a computerised data acquisition system (Po-Ne-Mah) and MiniDisc player (MZ-N710, Sony). Following recording, data were played back from the MiniDisc into the same input channel of the data acquisition system as previously used to record the direct ECG. All data were digitised at a sampling rate of 500 Hz. IBI data were analysed in both time and frequency domains and comparisons between direct recorded and MiniDisc data were made using Bland-Altman analysis. Despite some changes in ECG morphology due to loss of low frequency content (primarily below 5 Hz) following MiniDisc recording, there was minimal difference in IBI or time or frequency domain analysis between the two recording methods. The MiniDisc offers a cost-effective approach to intermediate recording of ECG signals for subsequent HRV analysis and also provides greater flexibility than use of human Holter systems.

Phase I assessment of the pharmacokinetics, metabolism, and safety of emitefur in patients with refractory solid tumors.

PURPOSE: To determine the toxicities, dose-limiting toxicities (DLT), maximum-tolerated dose, and pharmacokinetic profile of emitefur (BOF-A2) in patients with advanced solid tumors. METHODS: This was a phase I dose-escalating trial in which cohorts of patients received BOF-A2 (cohort 1, 300 mg/m(2) orally [PO] tid; cohort 2, 200 mg/m(2) PO tid; cohort 3, 200 mg/m(2) bid; and cohort 4, 250 mg/m(2) bid) for 14 consecutive days followed by 1 week of rest (cycle 1). Pharmacokinetics, toxicity, and tumor response were monitored. RESULTS: Nineteen patients received 110 cycles (three patients in cohort 1, three patients in cohort 2, 10 patients in cohort 3, and three patients in cohort 4). DLT (grade 3 stomatitis, diarrhea, leukopenia) was observed in cohorts 1, 2, and 4. Pharmacokinetics indicated that prolonged systemic expression of fluorouracil (5-FU) is maintained after administration of BOF-A2 at a dose of 200 mg bid for 14 days. The mean steady-state concentration of plasma 5-FU was > or = 24 ng/mL, which was 184-fold greater than the minimum effective cytotoxic concentration in vitro. Lack of variation of 5-FU trough levels within a day at steady-state indicates suppression of circadian variation. One patient in cohort 3 achieved a partial response and five patients maintained stable disease in excess of 6 months. CONCLUSION: BOF-A2 at a dose of 200 mg PO bid for 14 days followed by 7 days of rest is well tolerated. Prolonged exposure to 5-FU above the predicted preclinical minimum effective concentration is maintained, without evidence of circadian variation. Furthermore, evidence of antitumor activity is suggested.

Glial responses to degenerating cerebellar cortico-nuclear pathways in the cat.

Astrocytic changes in regions of long-term, cerebellar corticonuclear degeneration are characterized by large increases in cytoplasmic volume, as well as by formation of vacuoles and fibrils. Lipids are demonstrable in the vacuoles with oil red-O staining.