Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial

Background The prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical setting. While it has similar activity when compared to other anti-EGFR antibodies, it does not induce skin toxicity or hypomagnesemia. Methods A randomized, double blind, multicentric clinical trial was conducted in high grade glioma patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-balanced for the most important prognostic variables. Patients received 6 weekly doses of 200 mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance treatment was given for 1 year with subsequent doses administered every 3 weeks. The objectives of this study were to assess the comparative overall survival, progression free survival, response rate, immunogenicity and safety. Results The median cumulative dose was 3200 mg of nimotuzumab given over a median number of 16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration. No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. Conclusions In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation.

Design of an optimised wheel profile for rail vehicles operating on two track gauges

This paper sets out an optimum synthesis methodology for wheel profiles of railway vehicles in order to secure good dynamic behaviour with different track configurations. Specifically, the optimisation process has been applied to the case of rail wheelsets mounted on double gauge bogies, that move over two different gauges, which also have different types of rail: the Iberian gauge (1668 mm) and the UIC gauge (1435 mm). Optimisation is performed using Genetic Algorithms and traditional optimisation methods in a complementary way. The objective function used is based on an ideal equivalent conicity curve which ensures good stability on straight sections and also proper negotiation of curves. To this end the curve is constructed in such a way that it is constant with a low value for small lateral wheelset displacements (with regard to stability), and increases as the displacements increase (to facilitate negotiation of curved sections). Using this kind of ideal conicity curve also enables a wheel profile to be secured where the contact points have a larger distribution over the active contact areas, making wear more homogeneous and reducing stresses. The result is a wheel profile with a conicity that is closer to the target conicity for both gauges studied, producing better curve negotiation while maintaining good stability on straight sections of track. The paper shows the resultant wheel profile, the contact curves it produces, and a number of dynamic analyses demonstrating better dynamic behaviour of the synthesised wheel on curved sections with respect to the original wheel.