Treating cisplatin-resistant cancer: a systematic analysis of oxaliplatin or paclitaxel salvage chemotherapy

Objective: To examine the pre-clinical and clinical evidence for the use of oxaliplatin or paclitaxel salvage chemotherapy in patients with cisplatin-resistant cancer. Methods: Medline was searched for 1) Cell models of acquired resistance reporting cisplatin, oxaliplatin and paclitaxel sensitivities and 2) Clinical trials of single agent oxaliplatin or paclitaxel salvage therapy for cisplatin/carboplatin-resistant ovarian cancer. Results: Oxaliplatin - Oxaliplatin is widely regarded as being active in cisplatin-resistant cancer. In contrast, data in cell models suggests that there is cross-resistance between cisplatin and oxaliplatin in cellular models with resistance levels which reflect clinical resistance (<10 fold). Oxaliplatin as a single agent had a poor response rate in patients with cisplatin-resistant ovarian cancer (8%, n=91). Oxaliplatin performed better in combination with other agents for the treatment of platinum-resistant cancer suggesting that the benefit of oxaliplatin may lie in its more favourable toxicity and ability to be combined with other drugs rather than an underlying activity in cisplatin resistance. Oxaliplatin therefore should not be considered broadly active in cisplatin-resistant cancer. Paclitaxel – Cellular data suggests that paclitaxel is active in cisplatin-resistant cancer. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel. Paclitaxel as a single agent had a response rate of 22% in patients with platinum-resistant ovarian cancer (n = 1918), a significant increase from the response of oxaliplatin (p<0.01). Paclitaxel-resistant cells were also sensitive to cisplatin, suggesting that alternating between agents may be beneficial. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously received paclitaxel had an improved response rate of 35.3% n=232 (p<0.01), suggesting that pre-treatment with paclitaxel improves the response of salvage paclitaxel therapy. Conclusions: Cellular models reflect the resistance observed in the clinic as the cross resistant agent oxaliplatin has a lower response rate compared to the non-cross resistant agent paclitaxel in cisplatin-resistant ovarian cancer. Alternating therapy with cisplatin and paclitaxel may therefore lead to an improved response rate in ovarian cancer

How to Resolve an Ethical Dilemma Concerning Randomized Clinical Trials

An apparent ethical dilemma arises when physicians consider enrolling their patients in randomized clinical trials. Suppose that a randomized clinical trial comparing two treatments is in progress, and a physician has an opinion about which treatment is better. The physician has a duty to promote the patient's best medical interests and therefore seems to be obliged to advise the patient to receive the treatment that the physician prefers. This duty creates a barrier to the enrollment of patients in randomized clinical trials.1-10 Two strategies are often used to resolve the dilemma in favor of enrolling patients in clinical trials

Whither structured representation?

The perceptual symbol system view assumes that perceptual representations have a role-argument structure. A role-argument structure is often incorporated into amodal symbol systems in order to explain conceptual functions like abstraction and rule use. The power of perceptual symbol systems to support conceptual functions is likewise rooted in its use of structure. On Barsalou's account, this capacity to use structure (in the form of frames) must be innate.</jats:p

Extending the classical view of representation.

Summary Representation is a central part of models in cognitive science, but recently this idea has come under attack. Researchers advocating perceptual symbol systems, situated action, embodied cognition, and dynamical systems have argued against central assumptions of the classical representational approach to mind. We review the core assumptions of the dominant view of representation and the four suggested alternatives. We argue that representation should remain a core part of cognitive science, but that the insights from these alternative approaches must be incorporated into models of cognitive processing

Rethinking Supply Chains as Neighborhoods

This paper explores the implication of a neighborhood model for interfirm interactions that explicitly tries to create an equality matching relationship among firms in an industry. The aim is to examine what would happen if these firms worked to gain trust with each other with an eye toward maximizing the value of the collaboration across projects rather than just maximizing revenues in individual projects. A review of extant literature and an analysis of in-depth interviews yielded three actionable strategies that support the creation of a sustainable neighborhood in the construction industry: 1) Hub Strategy, 2) Trust Exercise Strategy, and 3) Sustainable Neighborhood Strategy. As envisioned in this study, the hub is a concentrated, inter-organizational structure for supply chain participants in large, complex projects. Importantly, hub members engage in a variety of technical activities that infuse ongoing and future projects with innovation, scope optimization, and operational efficiencies. Additionally, other activities within the hub are designed to purposefully allow participants to develop trust through collaboration before or outside of their primary contractual engagements. At present, this model has been examined for construction megaprojects, but the general neighborhood concept could be applied to many different industries and settings including manufacturing supply chains and collaborations among communities engaging in economic development. Future work will explore whether mechanisms like the hub and trust exercises can be applied in these other settings as well.IC2 Institut

Curve classes on irreducible holomorphic symplectic varieties

We prove that the integral Hodge conjecture holds for 1-cycles on irreducible holomorphic symplectic varieties of K3 type and of Generalized Kummer type. As an application, we give a new proof of the integral Hodge conjecture for cubic fourfolds.Comment: 15 page