Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma.

There is increasing experimental evidence to suggest that expression of O6-alkylguanine-DNA-alkyltransferase (ATase) is a major factor in resistance to dacarbazine (DTIC). We recently demonstrated a progressive ATase depletion in human peripheral lymphocytes with nadir levels occurring at 4-6 h after DTIC administration (Lee et al., 1991). Therefore in an attempt to improve the clinical response rate of DTIC, fotemustine was administered 4 h after DTIC administration; since in the case of fotemustine, ATase removes the chloroethyl lesions from the O6-position of guanine, thereby preventing the formation of the cytotoxic cross-links. Sixty patients with widely metastatic melanoma received DTIC at 400, 500 or 800 mg m-2 followed by fotemustine (100 mg m-1) at 4 h after DTIC administration. Treatment was repeated every 28 days with a total of 169 cycles of chemotherapy administered; 75, 57 and 37 treatment cycles with 400, 500 and 800 mg m-2 DTIC groups respectively. Eighteen of the 60 patients responded (with three complete response); response rates were linearly related to dose, being 24%, 30% and 40% in patients receiving 400, 500 and 800 mg m-2 of DTIC respectively and the overall response rate was 30%. Median survival was 3.6 months (range, 1-15 months) with no statistically significant difference between the different DTIC treatment groups (P = 0.67). Nine patients are alive at 5 to 26 months (median 10 months); three patients with no tumour and five patients with stable disease. A statistically significant relationship was seen between the development of severe haematological toxicity (WHO > or = 3) with increasing dosage of DTIC and significant subclinical pulmonary damage was seen in 11 patients where the lung function was monitored during the course of treatment. In conclusion, it appears that with this small group of patients, escalation of DTIC dosage might not significantly affect response rates but does increase haematological toxicity. The present study provides a framework for other studies in an attempt to modulate ATase-mediated drug resistance in tumour tissues but the associated toxicity will need careful monitoring

A randomized phase II trial of interleukin 2 and interleukin 2-interferon alpha in advanced renal cancer.

A randomized phase II trial was performed to compare the efficacy and toxicity of interleukin 2 (IL-2) with an IL-2 and interferon alpha (IFN-alpha) regimen for the treatment of metastatic renal carcinoma. Sixty patients with recurrent renal cell carcinoma (RCC) who had previously undergone a nephrectomy were randomized to receive three cycles of IL-2 or IL-2 with IFN-alpha2b. Eighteen MU of IL-2 were administered subcutaneously on Mondays-Fridays for 3 weeks out of 4. Those patients randomized to receive the combination received the same regimen of IL-2 with 9 MU of IFN-alpha2b subcutaneously on Mondays, Wednesdays and Fridays for 3 weeks out of 4. Thirty patients were randomized to receive each arm. Twenty-nine were evaluable in each arm. Twenty-two patients received three cycles of IL-2 but only 14 patients received three cycles of IL-2/IFN-alpha because of the greater toxicity of the combination. The principal toxicities included nausea, fatigue and fever. There were no complete responses in either arm and only two patients who were treated with IL-2 attained a partial response. Twelve patients in each arm had stable disease and 15 patients in the IL-2 arm and 16 patients in the IL-2/IFN-alpha arm progressed through treatment. There were no significant differences in survival. Ten patients who received IL-2 are alive with a median follow-up of 266 days, whereas six patients who received IL-2/IFN-alpha are alive after a median of 278 days. The median survival from the time of identification of metastatic disease is 444 days in the IL-2 arm and 381 days in the IL-2/IFN-alpha arm. The IL-2/IFN-alpha combination is more toxic than IL-2 alone and this resulted in a reduced number of cycles of treatment. However, the median survival of the two groups was the same, suggesting that further evaluation of the IL-2/IFN-alpha combination should be confined to large prospective randomized clinical trials

Logics for Unranked Trees: An Overview

Labeled unranked trees are used as a model of XML documents, and logical languages for them have been studied actively over the past several years. Such logics have different purposes: some are better suited for extracting data, some for expressing navigational properties, and some make it easy to relate complex properties of trees to the existence of tree automata for those properties. Furthermore, logics differ significantly in their model-checking properties, their automata models, and their behavior on ordered and unordered trees. In this paper we present a survey of logics for unranked trees

Segment-based spatial analysis for assessing road infrastructure performance using monitoring observations and remote sensing data

Road infrastructure is important to the well-being and economic health of all nations. The performance of road pavement infrastructure is sophisticated and affected by numerous factors and varies greatly across different roads. Large scale spatial analysis for assessing road infrastructure performance is increasingly required for road management, therefore multi-source factors, including satellite remotely sensed climate and environmental data, and ground-monitored vehicles observations, are collected as explanatory variables. Different from the traditional point or area based geospatial attributes, the performance of pavement infrastructure is the line segment based spatial data. Thus, a segment-based spatial stratified heterogeneitymethod is utilized to explore the comprehensive impacts of vehicles, climate, properties of road and socioeconomic conditions on pavement infrastructure performance. Segment-based optimal discretization is applied on discretizing segment-based pavement data, and a segment-based geographical detector is utilized to assess the spatial impacts of variables and their interactions. Results show that the segment-based methods can more reasonably and accurately describe the characteristics of line segment based spatial data and assess the spatial associations. The two major categories of factors associated with pavement damage are the variables of traffic vehicles and heavy vehicles in particular, and climate and environmental conditions. Meanwhile, the interactions between the explanatory variables in these two categories have much more influence than the single explanatory variables, and the interactions can explain more than half of the pavement damage. This study highlights the great potential of remote sensing based large scale spatial analysis of road infrastructures. The approach in this study provides new ideas for spatial analysis for segmented geographical data. The findings indicate that the quantified comprehensive impacts of variables are practical for wise decision-making for road design, construction and maintenance

Shaping the global communications milieu : the EU's influence on internet and telecommunications governance

This article evaluates the European Union's (EU) influence in shaping the global governance for telecommunications and the Internet. Through analysing EU behaviour within an actorness framework, we demonstrate how the external opportunity structure and the EU's internal environment has impacted on its ability to exert and maximize its presence in order to meet its goals and aims in these two very different sub-sectors of global communications in terms of evolution and development. Such a comparison of EU actorness, we argue, is revealing in terms of uncovering the underlying factors and conditions that allow the EU to influence two important and dynamic communications sub-sectors