Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial

This randomised, double-blind, placebo-controlled study was designed to evaluate the ability of the orally administered matrix metalloproteinase inhibitor, marimastat, to prolong survival in patients with non-resectable gastric and gastro-oesophageal adenocarcinoma. Three hundred and sixty-nine patients with histological proof of adenocarcinoma, who had received no more than a single regimen of 5-fluorouracil-based chemotherapy, were randomised to receive either marimastat (10 mg b.d.) or placebo. Patients were treated for as long as was tolerable. The primary endpoint was overall survival with secondary endpoints of time to disease progression and quality of life. At the point of protocol-defined study completion (85% mortality in the placebo arm) there was a modest difference in survival in the intention-to-treat population in favour of marimastat (P=0.07 log-rank test, hazard ratio=1.23 (95% confidence interval 0.98–1.55)). This survival benefit was maintained over a further 2 years of follow-up (P=0.024, hazard ratio=1.27 (1.03–1.57)). The median survival was 138 days for placebo and 160 days for marimastat, with 2-year survival of 3% and 9% respectively. A significant survival benefit was identified at study completion in the pre-defined sub-group of 123 patients who had received prior chemotherapy (P=0.045, hazard ratio=1.53 (1.00–2.34)). This benefit increased with 2 years additional follow-up (P=0.006, hazard ratio=1.68 (1.16–2.44)), with 2-year survival of 5% and 18% respectively. Progression-free survival was also significantly longer for patients receiving marimastat compared to placebo (P=0.009, hazard ratio=1.32 (1.07–1.63)). Marimastat treatment was associated with the development of musculoskeletal pain and inflammation. Events of anaemia, abdominal pain, jaundice and weight loss were more common in the placebo arm. This is one of the first demonstrations of a therapeutic benefit for a matrix metalloproteinase inhibitor in cancer patients. The greatest benefit was observed in patients who had previously received chemotherapy. A further randomised study of marimastat in these patients is warranted

Inhibition of tumour growth by marimastat in a human xenograft model of gastric cancer: relationship with levels of circulating CEA

Inhibition of matrix metalloproteinases (MMPs) is an attractive approach to adjuvant therapy in the treatment of cancer. Marimastat is the first orally administered, synthetic MMP inhibitor to be evaluated, in this capacity, in the clinic. Measurement of the rate of change of circulating tumour antigens was used for evaluating biological activity and defining optimum dosage in the early clinical trials of marimastat. Although tumour antigen levels have been used in the clinical management of cancer for many years, they have not been validated as markers of disease progression. In order to investigate the relationship between the effects of marimastat on tumour growth and circulating tumour antigen levels, mice bearing the human gastric tumour, MGLVA1, were treated with marimastat. The MMP inhibitor exerted a significant therapeutic effect, reducing tumour growth rate by 48% (P = 0.0005), and increasing median survival from 19 to 30 days (P = 0.0001). In addition, carcinoembryonic antigen (CEA) levels were measured in serum samples from animals sacrificed at regular intervals, and correlated with excised tumour weight. It was shown that the natural log of the CEA concentration was linearly related to the natural log of the tumour weight and that treatment was not a significant factor in this relationship (P = 0.7). In conclusion, circulating CEA levels were not directly affected by marimastat, but did reflect tumour size. These results support the use of cancer antigens as markers of biological activity in early phase trials of non-cytotoxic anticancer agents. © 1999 Cancer Research Campaig

Protein tyrosine phosphatases expression during development of mouse superior colliculus

Protein tyrosine phosphatases (PTPs) are key regulators of different processes during development of the central nervous system. However, expression patterns and potential roles of PTPs in the developing superior colliculus remain poorly investigated. In this study, a degenerate primer-based reverse transcription-polymerase chain reaction (RT-PCR) approach was used to isolate seven different intracellular PTPs and nine different receptor-type PTPs (RPTPs) from embryonic E15 mouse superior colliculus. Subsequently, the expression patterns of 11 PTPs (TC-PTP, PTP1C, PTP1D, PTP-MEG2, PTP-PEST, RPTPJ, RPTPε, RPTPRR, RPTPσ, RPTPκ and RPTPγ) were further analyzed in detail in superior colliculus from embryonic E13 to postnatal P20 stages by quantitative real-time RT-PCR, Western blotting and immunohistochemistry. Each of the 11 PTPs exhibits distinct spatiotemporal regulation of mRNAs and proteins in the developing superior colliculus suggesting their versatile roles in genesis of neuronal and glial cells and retinocollicular topographic mapping. At E13, additional double-immunohistochemical analysis revealed the expression of PTPs in collicular nestin-positive neural progenitor cells and RC-2-immunoreactive radial glia cells, indicating the potential functional importance of PTPs in neurogenesis and gliogenesis

Evolution of stress and morphology in thermal barrier coatings

Residual stress in the thermally grown oxide (TGO) in thermal barrier coatings (TBCs) was measured by photoluminescence piezospectroscopy (PLPS) and stress maps created to track local stress changes as a function of thermal cycling. The local stress images were observed to be correlated with morphological features on the metal surface that were purposely introduced during specimen preparation. Local stress relaxation and morphological evolution with thermal cycling were studied using the stress maps combined by post-mortem SEM examination. It was found that the morphology in the specimen having an initial polished surface was quite stable, while that in the specimen with a rough surface was unstable. The average residual stress in the specimen with the unstable morphology decreased with thermal cycling and it eventually failed along TGO/YSZ interface. The specimen with stable morphology maintained a high TGO stress throughout the thermal cycling process and failed along TGO/bond coat interface. The rough surface was also found to give rise to the formation of transition alumina (theta-Al2O3) in the TGO which was correlated with a reduced TGO stress. (C) 2010 Elsevier B.V. All rights reserved

Projective normality of complete symmetric varieties

We prove that in characteristic zero the multiplication of sections of dominant line bundles on a complete symmetric variety X=\overline{G/H} is a surjective map. As a consequence the cone defined by a complete linear system over X, or over a closed G stable subvariety of X is normal. This gives an affirmative answer to a question raised by Faltings in [F]. A crucial point of the proof is a combinatorial property of root systems

A NOTE ON THE PAPER "ON NORMALITY OF CONES OVER SYMMETRIC VARIETIES"

Let G be a semisimple and simply connected algebraic group, and let H_0 be the subgroup of points fixed by an involution of G. Let V be an irreducible representation of G with a nonzero vector v fixed by H_0. In this article, we prove a property of the normalization of the coordinate ring of the closure of G·[v] in P(V)

A note on the normality of cones over symmetric varieties

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Equations Defining Symmetric Varieties and Affine Grassmannians

Suppose sigma be a simple involution of a semisimple algebraic group G, and suppose H is the subgroup of G of points fixed by sigma. If the restricted root system is of type A, C, or BC and G is simply connected, or if the restricted root system is of type B and G is of adjoint type, then we describe a standard monomial theory and the equations for the coordinate ring k[G/H] using the standard monomial theory and the Plucker relations of an appropriate (maybe infinite-dimensional) Grassmann variety