Functional MRI for anticancer therapy assessment.

Anticancer drug discovery and development are experiencing a paradigm shift from cytotoxic therapies to more selective therapies that target underlying oncogenic abnormalities. Many newer therapies are cytostatic, for which objective tumour shrinkage is an inappropriate response parameter. There is a growing need to develop surrogate endpoints of drug efficacy to speed up the process of finding effective drug combinations for phase III trials. This review focuses on the developing field of functional magnetic resonance imaging (MRI) and its potential applications in the pharmacodynamic evaluation of existing and new cancer therapeutics. Dynamic contrast enhanced MRI, which is currently being used to evaluate anti-angiogenic, and anti-vascular agents in human trials will be reviewed in detail. The requirements that must be met before incorporating functional MRI techniques into clinical protocols are also discussed.

Angiogenic activity of cervical carcinoma: assessment by functional magnetic resonance imaging-based parameters and a histomorphological approach in correlation with disease outcome.

Angiogenesis plays a fundamental role in tumor growth and metastasis. What is needed is a quantitative, noninvasive, and repeatable assay to estimate functional angiogenic activity of the entire tumor. The aims of the present study were to: (a) examine the relationship between functional magnetic resonance imaging (MRI)-based parameters with established histomorphological markers of tumor angiogenesis [histological microvessel density (HMVD) and vascular endothelial growth factor expression (VEGF)]; and (b) determine the ultimate value of both approaches to assess functional angiogenic active hotspots as markers of disease outcome in patients with cancer of the uterine cervix. Pharmacokinetic parameters (amplitude A, tissue exchange rate constant k21) were calculated from contrast-enhanced dynamic MRI series in 57 patients (mean age, 49 +/- 14 years) with biopsy proven uterine cervical cancer. Both pharmacokinetic parameters were correlated to histomorphologically determined areas of high HMVD and VEGF expression obtained from the operative specimens after radical surgery. In addition, the functional MRI and histomorphological data were used to assess disease outcome. A significant association was found between HMVD and the amplitude A (P < 0.001) and a less pronounced association with k21, (P < 0.05), respectively. No significant associations were found between the pharmacokinetic parameters (A, k21) and VEGF expression. When stratified into high and low median k21 groups, median k21 values >5.4 min(-1) were the only significant (P < 0.05) factors in predicting poor patient survival. None of the histomorphological markers of angiogenesis (HMVD or VEGF expression) showed any predictive power. We have found that: (a) focal hotspots of HMVD are the pathophysiological basis for differences in functional MRI; (b) areas of high microvessel density and microvessel permeability do not necessarily coincide, as demonstrated by the histomorphological and functional MRI findings; (c) the functional angiogenic activity of a tumor may not be sufficiently characterized by a histomorphological approach but rather by a functional MRI-based approach; and (d) functional MRI-based analysis may assess tumor angiogenic activity in terms of disease outcome more comprehensively than the histomorphological approach.

Assessment of c-erbB2 and vascular endothelial growth factor mRNA expression in fine-needle aspirates from early breast carcinomas: pre-operative determination of malignant potential.

AIMS: Although axillary lymph nodes status, tumour size, hormonal-receptor status and histological grade at diagnosis are frequently used to orient the treatment of breast cancer patients, some tumours recur in patients with early stage disease. Pre-operative assessment of individual tumour characteristics, based on oncogenes and growth factors related to tumour growth, invasion or metastasis, may guide the treatment for patients with breast carcinomas. METHODS: We examine here the prognostic significance of cyclin D1, urokinase type plasminogen activator, vascular endothelial growth factor (VEGF), platelet-derived growth factor, and c-erbB2 expression in pre-operatively obtained fine-needle aspirates from breast carcinomas less than or equal to 3 cm in size. Correlation between mRNA expression of these factors and clinicopathological characteristics was analysed. RESULTS: The level of c-erbB2 mRNA expression was significantly higher in tumours with lymph node metastases than in those without lymph node metastases. VEGF mRNA expression positively correlated with the degree of angiogenesis as quantitated by immunohistological staining with a CD31 monoclonal antibody. CONCLUSIONS: Analysis of c-erbB2 and VEGF mRNA expression in fine-needle aspirates may be useful in assessing the malignant potential of individual breast carcinomas, leading to a pre-operative discrimination of a high-risk group.

Lymphokine production by peripheral blood leucocytes: quantitation of T-cell growth factor activity for assessment of immune response capability.

Mitogen stimulation of as few as 200,000 human peripheral blood leucocytes (PBL) in 0.2 ml volumes produces highly active lymphokine supernatants. The lymphokine activity measured is T-cell growth factor. Under optimum conditions of PHA-P concentration, serum source and concentration, and time, activity is detectable to a dilution of between 1/250 and 1/700 for lymphokine supernatants from PBL of normal donors. Lymphokine supernatants prepared from PBL of donors previously treated with the immunosuppressive regimes of radiotherapy and/or chemotherapy had activities that were between 13% and 66% of normal controls. Lymphokine production as a quantitative measure of immune capability is discussed.