Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a european organization for research and treatment of cancer head and neck cancer cooperative group sty

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Water accounting for (agro)industrial operations and its application to energy pathways

Discussions about the water needed for the provision of goods and services have been hampered by a lack of a generic water-accounting methodology from the industrial operations perspective. We propose a methodology based on the concept of “economic water stress” that enables the assessment of water-related risks at the level of an industrial site and the level of an industrial supply chain or pathway. We then rigorously apply it to quantify the freshwater withdrawal and consumption needed for fuel and electricity supply chains. Those data make it possible to present, in comparable source-to-service terms, estimates of the freshwater intensities of mobility. Most of the estimated supply-chain and pathway freshwater intensities range over orders of magnitude on account of the variety of technologies and geographic locations. On average, fuels from unconventional fossil resources and biofuels derived from irrigated crops have higher freshwater withdrawal and consumption than conventional fossil fuels. Cooling in thermal power generation can also make severe demands on freshwater withdrawal and consumption, but technological options are available for most levels of freshwater scarcity. The mobility results reveal that vehicles with internal-combustion engines and electric motors have biofuel and power-generation technology options that lie roughly within the same freshwater-intensity ranges as that of conventional transport based on refined oil. In any case, the local context is critical: industrial sites with high freshwater withdrawal and consumption may be sustainable if there is ample water supply. Conversely, low freshwater withdrawal and consumption may be unsustainable in water-stressed regions

Influence of concomitant infusion of thymidine and inosine on methotrexate activity in normal and P388-bearing mice

Combinations of thymidine and inosine (ranging from 0 to 7.5 mg/hr) were co-administered during a 72-hr continuous i.v. infusion of 3 μg/hr methotrexate in normal and P388 solid tumor-bearing DBA/2 mice. Methotrexate alone was lethal to all normal mice. Inosine at 1.0–7.5 mg/hr could reverse toxicity up to 100% while thymidine at 0.5–7.5 mg/hr was less effective (86% survival). Combinations of the nucleosides averted toxicity more effectively than either compound alone and in a synergistic manner. From P388 tumor-bearing mice 27% survived methotrexate and eventually died of tumor. Co-infusion of thymidine or inosine decreased the percentage of toxic deaths and caused an increase in life span of more than 50% as compared to untreated tumor-bearing mice. However, the diminishing effect on survival with thymidine and inosine doses above 0.5 mg/hr indicated loss of the antitumor effect of methotrexate. This was also observed with combinations of the nucleosides. The influence of thymidine on the antitumor effect of methotrexate was compared in L1210- and P388-bearing mice (both in ascites) with 13 μg/hr methotrexate for 48 hr and 4 mg/hr thymidine for 96 hr. The increase in life span for L1210-bearing mice (8.6 days, 96%) was significantly longer than that with P388-bearing mice (6.1 days, 56%), probably due to biochemical differences between these tumors. It is concluded that co-administration of inosine and/or thymidine allows the use of methotrexate doses otherwise not tolerated, though with loss of anti-tumor effect. The choice of the tumor model may greatly influence the outcome of in-vivo studies on the modulation of methotrexate action by nucleosides

High dose chemotherapy in breast cancer reviewed

Laboratory and experimental data show a dose response curve for cytostatic drugs, especially for alkylating agents. For many malignancies, clinical evidence of a dose response relationship is limited. The dose limiting toxicity of most cytostatic drugs is myelosuppression, which can be circumvented by the use of haematopoietic growth factors and/or autologous hone marrow or peripheral stem cell support. Clinical data derived from studies in patients with metastatic breast cancer, show that dose escalations of 1.5-2 x standard dosages, possible without autologous bone marrow or peripheral stem cell transport can induce higher remission rates, which did not, however, correspond to a significant survival advantage. Despite promising results from small trials with high dose intensity treatment in combination with peripheral stem cell or bone marrow support (depending on the schedule used, dose escalations possible of 5-10 x the standard dosages) in a selected patient population with high risk or metastatic breast cancer, they do not justify the use of this approach outside the setting of clinical studies. We have to gain more knowledge of selecting the patients who are likely to profit from high dose chemotherapy as well as to continue focusing on improvement of efficacy, reduction of the considerable morbidity and costs of this treatment