Bryce Kerlin | PubMed Health

PubMed2005

Temozolomide and radiation for aggressive pediatric central nervous system malignancies.

This study describes the outcomes of children treated with combinations of temozolomide and radiation therapy for various aggressive central nervous system malignancies. Their age at diagnosis ranged from 1 to 15 years. Patients with focal disease were treated with concomitant temozolomide (daily 75 mg/m) and three-dimensional conformal radiotherapy in a dose that ranged from 50 to 54 Gy, followed by temozolomide (200 mg/m/d x 5 days/month in three patients, 150 mg/m x 5 days/ month in one patient). Patients with disseminated disease were treated with craniospinal radiation (39.6 Gy) before conformal boost. One patient received temozolomide (200 mg/m x 5 days/month) before craniospinal radiation, and one patient received temozolomide (daily 95 mg/m) concomitant with craniospinal radiation and a radiosurgical boost, followed by temozolomide (200 mg/m x 5 days/month). Three patients achieved a partial response during treatment, with two of these patients dying of progressive disease after treatment. One patient has no evidence of disease. Three patients achieved stable disease, with one of these patients dying of progressive disease after treatment. Toxicities observed included low-grade neutropenia, thrombocytopenia, and lymphopenia. The combination of temozolomide and radiotherapy appears to be well tolerated in a variety of treatment schemas for aggressive pediatric central nervous system malignancies. This information is of particular use in designing future studies, given the recent positive results in a randomized study examining the use of temozolomide concomitant with radiation in the treatment of adult glioblastoma.

Adolescent↗

PubMed2004

Factor V Leiden polymorphism modifies sepsis outcome: evidence from animal studies.

OBJECTIVE: The high prevalence of the factor V Leiden mutation in certain populations has prompted speculation that the mutation may have been subject to positive selection during evolution, either by providing a survival benefit or by directly enhancing reproductive performance. We investigated the hypothesis that heterozygous factor V Leiden carrier status might protect against the lethal consequences of severe inflammatory disease. DATA SOURCE: Two mouse models (thrombomodulin-deficient TMPro mice and factor V Leiden mice), in which the endogenous protein C anticoagulant pathway is disrupted either at the level of protein C activation (TMPro mice) or at the level of factor V proteolysis by activated protein C (factor V Leiden mice), were employed. The mutant mouse strains were subjected to lethal doses of bacterial lipopolysaccharide. The effects of these two mutations on coagulation activation and inflammatory cytokine elaboration were observed and compared with those in wild-type mice. DATA SUMMARY: As has already been shown, heterozygous factor V Leiden carrier status improves the survival of mice subjected to endotoxemia induced by bacterial lipopolysaccharide. The survival of homozygous factor V Leiden mice did not differ from that of normal mice. The survival benefit derived from heterozygous factor V Leiden carrier status was only evident at doses of lipopolysaccharide producing death in approximately 50% of wild-type animals. At higher (LD90) or lower (LD10) doses of lipopolysaccharide, the survival of heterozygous factor V Leiden mice did not differ from that of wild-type mice. Concomitant administration of an LD90 dose of lipopolysaccharide and therapeutic heparin abolished the relative survival advantage of heterozygous factor V Leiden mice. Analysis of systemic coagulation and cytokine variables failed to provide conclusive evidence for altered coagulation activation or inflammatory cytokine production as the basis for the survival advantage associated with heterozygous factor V Leiden carrier status. CONCLUSIONS: The improved survival of mice heterozygous for the factor V Leiden mutation complements results from the analysis of the factor V Leiden subgroup of patients enrolled in the PROWESS trial. Such convergent findings in two different species strongly suggest that the factor V Leiden mutation is indeed a potent modifier of the response to severe inflammatory disease. The striking magnitude of the factor V Leiden survival benefit in the initial PROWESS population, and in mice, suggests that the as-yet unknown mechanism conferring this benefit is a rather potent endogenous modifier of the pathogenic pathways engaged in sepsis. Delineation of this pathway will be important for understanding the therapeutic mechanisms, or absence thereof, of agents designed to act at the interface of coagulation and inflammation.

Animals↗

PubMed2003

Cause-effect relation between hyperfibrinogenemia and vascular disease.

Elevated plasma levels of fibrinogen are associated with the presence of cardiovascular disease, but it is controversial whether elevated fibrinogen causally imparts an increased risk, and as such is a true modifier of cardiovascular disease, or is merely associated with disease. By investigating a transgenic mouse model of hyperfibrinogenemia, we show that elevated plasma fibrinogen concentration (1) elicits augmented fibrin deposition in specific organs, (2) interacts with an independent modifier of hemostatic activity to regulate fibrin turnover/deposition, (3) exacerbates neointimal hyperplasia in an experimental model of stasis-induced vascular remodeling, yet (4) may suppress thrombin generation in response to a procoagulant challenge. These findings provide direct experimental evidence that hyperfibrinogenemia is more than a by-product of cardiovascular disease and may function independently or interactively to modulate the severity and/or progression of vascular disease.

Animals↗