BACKGROUND AND PURPOSE: Assuming that the dose-response curve for T3N0M0 glottic carcinoma is steep and that the rate of occult lymph node metastases is low, it should be possible to employ high biological tumour doses to modest target volumes and thereby maximise laryngeal control without compromising final neck control. Within the constraints of a retrospective study we aim to examine this policy with respect to local control, incidence of nodal relapse and late complications. MATERIALS AND METHODS: One hundred and fourteen patients with T3N0M0 glottic carcinoma who received a 3-week schedule of radical radiotherapy between 1986 and 1994 were analysed. The median age was 67 years (range, 34-85 years) and the median follow-up for living patients was 4.8 years (1.9-8.9 years). There were no strict selection criteria for those patients treated with radiotherapy. RESULTS: The 5-year overall survival was 54%. The 5-year local control with radiotherapy and the ultimate loco-regional control following salvage laryngectomy were 68 and 80%, respectively. Nine patients (8%) suffered a regional nodal relapse but only three of these (3% overall) occurred in the absence of local failure. Four patients (3.5%) developed serious late complications requiring surgical intervention (three received 55 Gy and one 52.5 Gy). CONCLUSIONS: It is possible to employ maximum tolerable doses to specific target volumes and thereby exploit the dose response demonstrated and minimise major late effects. The use of modest target volumes resulted in only 3% of patients requiring surgery that might have been avoided had prophylactic neck irradiation been employed.

PURPOSE: The aim of this study was to investigate changes in tumor oxygenation, assessed by polarographic needle electrode measurements, following fractionated external beam radiotherapy in carcinoma of the cervix. METHODS AND MATERIALS: Normal and tumor tissue oxygenation was measured in 19 patients prior to radiotherapy and after 40-45 Gy of external beam radiotherapy delivered in 20 fractions over 4 weeks. All measurements were performed during anesthesia. RESULTS: There was no significant difference in the level of normal tissue oxygenation pre- and post radiotherapy. The individual patient median tumor pO2 values ranged from 0 to 31 mmHg pre-radiotherapy and 1 to 61 mmHg post-radiotherapy. The mean of the 19 median pO2 values increased from 8 (SD +/- 10) mmHg to 20 (+/- 20) mmHg following external beam radiotherapy. The increase was significant by paired Wilcoxon test (p = 0.011). There was also a significant fall in the proportion of values < 5 mmHg (p = 0.040). Although this value remained constant, or fell, in the majority of patients (15/19), it increased in 4 tumors. Tumor size pre- and postradiotherapy did not correlate with the level of pretreatment oxygenation; neither did the change in tumor size and change in level of oxygenation. CONCLUSION: The level of tumor oxygenation increased in the majority of patients (15/19) following 40-45 Gy of radiotherapy in carcinoma of the cervix.

The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.

The discovery of novel targets that can be pharmacologically exploited to lead to a better disease outcome has long been an aim of biomedical research. At present, the technology and robotisation available have pushed the search for novel molecules to a high-throughput screening (HTS) context, making it possible to screen several hundreds of compounds or genes in a single day. High-content screenings (HCS) have added a refined complexity to the screening processes, as the information drawn from an image- based assay is more complete than the monoparametric readouts obtained in classical HTS assays. Here, we review the development of HCS platforms to identify molecules influencing FOXO nuclear relocation and activation as pharmacological targets, their applicability and the future directions of the screening field.

Evaluation of the safety and efficacy of pazopanib, a multikinase angiogenesis inhibitor, in a single-arm, open-label, extension study (VEG107769/NCT00387764) for placebo-treated patients with advanced renal cell carcinoma (RCC) from a randomized, double-blind, placebo-controlled phase III study (VEG105192/NCT00334282).

The microcolony assay technique has been used to test the validty of summing equivalent doses per fraction of 14 MeV neutrons and gamma rays for mouse intestinal damage. For a 4-daily fraction schedule, in which the first one or two fractions are given as neutrons and the remainder as gamma rays, combined dose fractions calculated from a 4-fraction schedule of either radiation type alone produce the same level of damage within the limits of accuracy of the experiment.

To compare trends in ovarian cancer incidence in the USA and Australia in relation to changes in oral contraceptive pill (OCP) and menopausal hormone therapy (MHT) use.