Analysis of multi-stage open shop processing systems

We study algorithmic problems in multi-stage open shop processing systems that are centered around reachability and deadlock detection questions. We characterize safe and unsafe system states. We show that it is easy to recognize system states that can be reached from the initial state (where the system is empty), but that in general it is hard to decide whether one given system state is reachable from another given system state. We show that the problem of identifying reachable deadlock states is hard in general open shop systems, but is easy in the special case where no job needs processing on more than two machines (by linear programming and matching theory), and in the special case where all machines have capacity one (by graph-theoretic arguments).Comment: 19 pages, no figure

Interferon and interferon inducers in the treatment of cancer : experimental studies in mice, rats and humans

Biological response modifiers are agents that · exert their antitumor effects mainly or exclusively through modulation of host immune defense mechanisms. A common feature of these agents is their capacity to induce the production of endogenous interferons and/ or other lymphokines in vivo, and their capacity to activate various subsets of lymphocytes and monocytes that can lyse tumor cells in vitro and in vivo. Antiproliferative and immunomodulative effects as well as toxicity and side-effects observed in connection with the admin

Integration of Translational Research in the European Organization for Research and Treatment of Cancer Research (EORTC) Clinical Trial Cooperative Group Mechanisms

The landscape for cancer research is profoundly different today from that only one decade ago. Basic science is moving rapidly and biotechnological revolutions in molecular targeting and immunology have completely modified the opportunities and concepts for cancer treatment. In contrast to the recent past where cytotoxic molecules were screened in the laboratory and then tested in early clinical studies with toxicity as endpoint instead of the often poorly defined mechanism for its potential anti-tumor effect, we now have entered the age of molecular therapeutics, rationally designed to target "strategic" checkpoints that underlie the malignant phenotype. Translational research in early clinical trials (Phase I and II) is an integral aspect of the development of the new generation of cancer drugs as it is necessary to implement radically different early phase clinical trial design and to validate new biological end-points if the full potential of these new agents is to be realized. The "proof of principle with mechanistic analysis" strategy will allow optimisation of therapy from the beginning, and provide important feedback to pre-clinical drug developers. Translational research is also essential in late (phase III) clinical trials in defining different patient populations that may benefit to differing degrees from new treatments, and thus provide further insight and refine clinical practice in a more and more patient-tailored approach. In this editorial we will discuss the integration of Translational Research in the Organization for Research and Treatment of Cancer (EORTC)

The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat

the feasibility of using chemosensitizers in the circumvention of P-glycoprotein-mediated multidrug resistance has been shown in many studies. We recently reported on the chemosensitizing effect of cyclosporin A (CsA) on doxorubicin in a rat solid tumour model. Using the same experimental design we investigated the side-effects of the combination treatment. During the 35-day experiment doxorubicin treatment caused dose-dependent weight loss, which was enhanced by combination treatment with CsA. The main doxorubicin-related side-effects were myelosuppression (transient leucopenia and thrombopenia) and nephrotoxicity. Damage to the kidney was severe, leading to a nephrotic syndrome and resulting in ascites, pleural effusion, hypercholesterolaemia and hypertriglyceridaemia. These toxicities were enhanced by the addition of the chemosensitizer CsA. Mild doxorubicin-related cardiomyopathy and minimal hepatotoxicity were seen on histological examination. There were no signs of enhanced toxicity of the combination treatment in tissues with known high expression levels of P-glycoprotein, like the liver, adrenal gland and large intestine. CsA had a low toxicity profile, as it only caused a transient rise in bilirubin. In conclusion, the chemosensitizer CsA enhanced the side-effects of the anticancer drug doxorubiein without altering the toxicity pattern. There was no evidence of a therapeutic gain by adding CsA to doxorubicin, compared to single-agent treatment with doxorubicin in 25%-33% higher doses, because of the enhanced toxicity of the combination treatment

Fifty tumor necrosis factor-based isolated limb perfusions for limb salvage in patients older than 75 years with limb-threatening soft tissue sarcomas and other extremity tumors

BACKGROUND: Isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan is highly effective in treating limb-threatening soft tissue sarcoma (STS) and other bulky tumors. Because of fear of TNF-associated toxicity, ILP with TNF is not offered to older patients in some cancer centers, although especially in older patients, every attempt to avoid an amputation that may end their independence must be considered. METHODS: Out of 306 TNF-based ILPs, 50 ILPs were performed for limb salvage in 43 patients >75 years old (range, 75-91 years): 29 STS and 14 melanoma patients. RESULTS: In the STS patients, a response rate of 76% and a limb-salvage rate of 76% were achieved; in the melanoma patients, a 100% response rate and a 93% limb-salvage rate were achieved. Local toxicity was mild. The three postoperative deaths that occurred in the total series of 306 TNF-based ILPs in Rotterdam (75 years old after leakage-free perfusions and were not related to TNF but to extremely high-risk profiles in these three patients. CONCLUSIONS: Older patients should not be withheld a TNF-based ILP for limb salvage, because the procedure is safe and highly effective in these patients