A phase II study of ispinesib (SB-715992) in patients with metastatic or recurrent malignant melanoma: a National Cancer Institute of Canada Clinical Trials Group trial

Summary To assess the response rate and toxicity of the kinesin spindle protein (KSP) inhibitor, ispinesib, in malignant melanoma. Seventeen patients were enrolled from April to November 2005. Ispinesib was administered as a 1-hour infusion at a dose of 18 mg/m² once every 3 weeks until disease progression. No objective responses were seen. Six patients (35%) had a best response of stable disease for a median duration of 2.8 months. Disease progression was documented in 9 (53%) after 1 or 2 cycles. Eighty-eight percent of patients received ≥90% of planned dose intensity. Grade 3 non-hematologic toxicities included dizziness (1) and blurred vision (1). There was one episode of febrile neutropenia, but no grade 3 or 4 biochemical adverse events. Pharmacokinetics was consistent with prior studies. KSP immunoreactivity was seen in 14 of 16 available archival tissue samples (88%). Ispinesib can be safely administered using the dose and schedule employed, with mild hematologic and non-hematologic toxicity. No objective responses were observed, and further development of single-agent ispinesib in malignant melanoma is not recommended. Although KSP expression appears to be common in melanoma, KSP may not be a suitable target for its treatment.     

Apparent diffusion coefficient histograms may predict low-grade glioma subtype

The subtypes of glioma are known to have different prognosis and response to treatment. The purpose of this work was to investigate whether apparent diffusion coefficient (ADC) histograms of untreated low-grade astrocytomas and oligodendrogliomas exhibit different characteristics due to their biological differences, and whether a diagnosis of tumour subtype can be made at presentation using the histogram alone, which, if possible, would have an impact on clinical practise. Fifteen patients with astrocytoma (AC) [11 male (mean age +/- standard deviation) 40 +/- 11 years], nine with oligodendroglioma (OD) (four male, 45 +/- 13 years) and three with oligoastrocytoma (OA) (two male, 60 +/- 11 years) were recruited and diffusion-weighted images (b = 0 and 1000 s mm(-2)) were acquired every 6 months to date or until malignant transformation. Whole tumour ADC histograms were calculated, a multiple discriminant analysis was performed and quantitative morphological parameters extracted, the AC and OD subtypes were then compared using Student's unpaired t-test. Classification of the histograms was also performed. ODs had significantly lower group ADC values than ACs and up to 83% of the subjects could be correctly classified into the OD and AC groups by reference to the histogram. The group differences were most significant for the multiple discriminant analysis (p = 1 x 10(-5)) and at the 10th centile point [AC = 1170 +/- 170, OD = (1030 +/- 80) x 10(-6) mm(2) s(-1)] (p = 0.01). ODs have a lower ADC than ACs with differences throughout the histogram. Both tumour types show similar intra-tumour heterogeneity, as seen from the equal group peak heights, but ACs shows more intra-group heterogeneity. ADC histogram analysis may aid non-invasive sub-classification of low-grade glioma histological subtypes.     

Hormonal contraception update

Unintended pregnancy continues to be a serious public health issue in the United States. Of the 3 million unplanned pregnancies per year, 60% occur in women using some form of contraception. Educating and helping women choose a contraceptive agent that best suits their needs will improve compliance and contraceptive efficacy. A multitude of new contraceptive agents are now available. We review new hormonal contraceptive options and discuss newer oral agents, extended-cycle contraception, and innovative delivery methods.     

Towards magnetic detection electrical impedance tomography: data acquisition and image reconstruction of current density in phantoms and in vivo

The objective of magnetic detection electrical impedance tomography (MD-EIT) is to reconstruct in vivo images of conductivity from magnetic field measurements taken around the body. MD-EIT is performed by applying an alternating current, at one of a range of frequencies, to a conducting object through a pair of electrodes fixed to the surface of the object. Magnetic field measurements recorded by search coils at a number of positions around the object are used to determine the current distribution that is generating the magnetic field. From this distribution, a conductivity map of a cross-section of the object can be reconstructed. This paper describes the development of an MD-EIT data acquisition system and discusses the related image reconstruction issues. The ill-conditioned nature of the inverse problem is examined and a number of image reconstruction methods are compared. The technical feasibility of MD-EIT data collection and image reconstruction is demonstrated with example images of current density from both phantom and human data.     

CCK(2) receptor antagonists containing the conformationally constrained phenylalanine derivatives,including the new amino acid Xic

The conformationally constrained analogues of phenylalanine, tetrahydroisoquinoline-3-carboxylic acid (Tic), Sic, Hic and Nic, and the new amino acid Xic have been incorporated into a potent and highly selective cholecystokinin-2 (CCK(2)) receptor antagonist (2) in place of the phenylalanine residue, producing compounds 15a-e. High selectivities for CCK(2) over CCK(1) were observed for compounds 15a-e. The in vitro profile of the analogue containing the Nic residue (15d) was identical to that of compound 2, whereas the alternative conformational constraints resulted in a significant loss of affinity. The apparent advantage of Nic in the context of these CCK(2) ligands was subsequently demonstrated to be statistically significant.     

Disrupting tumour blood vessels

Low-molecular-weight vascular-disrupting agents (VDAs) cause a pronounced shutdown in blood flow to solid tumours, resulting in extensive tumour-cell necrosis, while they leave the blood flow in normal tissues relatively intact. The largest group of VDAs is the tubulin-binding combretastatins, several of which are now being tested in clinical trials. DMXAA (5,6-dimethylxanthenone-4-acetic acid) - one of a structurally distinct group of drugs - is also being tested in clinical trials. A full understanding of the action of these and other VDAs will provide insights into mechanisms that control tumour blood flow and will be the basis for the development of new therapeutic drugs for targeting the established tumour vasculature for therapy.     

Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability

The tumor vascular effects of the tubulin destabilizing agent disodium combretastatinA-4 3-O-phosphate (CA-4-P) were investigated in the rat P22 tumor growing in a dorsal skin flap window chamber implanted into BD9 rats. CA-4-P is in clinical trial as a tumor vascular targeting agent. In animal tumors, it can cause the shut-down of blood flow, leading to extensive tumor cell necrosis. However, the mechanisms leading to vascular shut-down are still unknown. Tumor vascular effects were visualized and monitored on-line before and after the administration of two doses of CA-4-P (30 and 100 mg/kg) using intravital microscopy. The combined effect of CA-4-P and systemic nitric oxide synthase (NOS) inhibition using N(omega)-nitro-L-arginine (L-NNA) was also assessed, because this combination has been shown previously to have a potentiating effect. The early effect of CA-4-P on tumor vascular permeability to albumin was determined to assess whether this could be involved in the mechanism of action of the drug. Tumor blood flow reduction was extremely rapid after CA-4-P treatment, with red cell velocity decreasing throughout the observation period and dropping to <5% of the starting value by 1 h. NOS inhibition alone caused a 50% decrease in red cell velocity, and the combined treatment of CA-4-P and NOS inhibition was approximately additive. The mechanism of blood flow reduction was very different for NOS inhibition and CA-4-P. That of NOS inhibition could be explained by a decrease in vessel diameter, which was most profound on the arteriolar side of the tumor circulation. In contrast, the effects of CA-4-P resembled an acute inflammatory reaction resulting in a visible loss of a large proportion of the smallest blood vessels. There was some return of visible vasculature at 1 h after treatment, but the blood in these vessels was static or nearly so, and many of the vessels were distended. The hematocrit within larger draining tumor venules tended to increase at early times after CA-4-P, suggesting fluid loss from the blood. The stacking of red cells to form rouleaux was also a common feature, coincident with slowing of blood flow; and these two factors would lead to an increase in viscous resistance to blood flow. Tumor vascular permeability to albumin was increased to approximately 160% of control values at 1 and 10 min after treatment. This could lead to an early decrease in tumor blood flow via an imbalance between intravascular and tissue pressures and/or an increase in blood viscosity as a result of increased hematocrit. These results suggest a mechanism of action of CA-4-P in vivo. Combination of CA-4-P with a NOS inhibitor has an additive effect, which it may be possible to exploit therapeutically.     

European consumer exposure to cosmetic products, a framework for conducting population exposure assessments.

Access to reliable exposure data is essential to evaluate the toxicological safety of ingredients in cosmetic products. This study was carried out by European cosmetic manufacturers acting within the trade association Colipa, with the aim to construct a probabilistic European population model of exposure. The study updates, in distribution form, the current exposure data on daily quantities of six cosmetic products. Data were collected using a combination of market information databases and a controlled product use study. In total 44,100 households and 18,057 individual consumers in five European countries provided data using their own products. All product use occasions were recorded, including those outside of home. The raw data were analysed using Monte Carlo simulation and a European Statistical Population Model of exposure was constructed. A significant finding was an inverse correlation between frequency of product use and quantity used per application for body lotion, facial moisturiser, toothpaste and shampoo. Thus it is not appropriate to calculate daily exposure to these products by multiplying the maximum frequency value by the maximum quantity per event value. The results largely confirm the exposure parameters currently used by the cosmetic industry. Design of this study could serve as a model for future assessments of population exposure to chemicals in products other than cosmetics.