Solutions must include the community hospitals.

The authors of this commentary acknowledge that Academic Health Sciences Centres(AHSCs) will need to change, but they assert that the need for change and urgency are even more dramatic than presented by Lozon and Fox. While the AHSCs are likely to survive, their form and fabric are likely to change dramatically in the new order. Any solutions to the problems of the AHSCs have to include the community hospital stakeholders, especially the evolving regional teaching hospitals. This applies not only to patient care but also to the potential teaching and research (clinical trials) contributions of the community/regional players. There must also be more involvement by non-medical faculties in defining the vision, mission and values of the AHSC. Federal funding should be available not only to enhance the research activity of the AHSCs and the regional partners but also to provide the informatic linkages between players. Alternative funding programs for academic physicians along with enhanced productivity measures in areas of patient care, education and research are important in order to level the playing field not only with respect to remuneration but also with respect to other incentives such as recognition and promotion.

Phase I study of ONO-4007, a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide.

ONO-4007 is a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide, which exhibits antitumor activity by the induction of intratumoral tumor necrosis factor alpha, the potentiation of tumor-infiltrating macrophages, and the inhibition of angiogenesis. Interleukin (IL)-1 alpha, IL-6, and IL-12 induction by ONO-4007 activates cytotoxic natural killer cells to up-regulate IFN-gamma and nitric oxide synthase activity. ONO-4007 was given to 24 patients (13 males and 11 females; median age, 53 years) as a 30-min i.v. infusion on day 1, followed on day 15 by a first treatment cycle consisting of three weekly infusions at the same dose, followed by a rest period of 1 week. Cohorts of six patients received up to a maximum of four treatment cycles at increasing dose levels (75, 100, and 125 mg). The maximum tolerated dose was 125 mg, with grade 3 National Cancer Institute Common Toxicity Criteria toxicity (rigors with cyanosis) occurring in two of six patients at this dose level. An additional six patients were treated at 100 mg, the dose below the maximum tolerated dose. Other toxicities included grade 2 National Cancer Institute Common Toxicity Criteria myalgia, nausea, and hypotension. The pharmacokinetics of ONO-4007 appeared to be independent of dose and showed linearity with respect to time. ONO-4007 has a low systemic clearance (approximately 1.3 ml/min) and a small volume of distribution (5-8 liters) with a long t1/2 of 74-95 h. The administration of ONO-4007 was shown to result in a significant increase in circulating levels of tumor necrosis factor alpha and IL-6. No objective antitumor responses were observed. Seven patients maintained stable disease for at least two cycles, whereas five patients maintained stable disease for the full four-cycle duration of the study. Additional studies are required to determine the antitumor activity of ONO-4007.