Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies.

PURPOSE: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. PATIENTS AND METHODS: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. RESULTS: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P =.01 for oral dose; P =.0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P =.004%; and 51%, P =.006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. CONCLUSION: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitors, such as PTK/ZK, for further clinical development.

Gadobenate dimeglumine in MRI of acute myocardial infarction: results of a phase III study comparing dynamic and delayed contrast enhanced magnetic resonance imaging with EKG, (201)Tl SPECT, and echocardiography.

RATIONALE AND OBJECTIVES: To evaluate the safety and utility of gadobenate dimeglumine as a magnetic resonance (MR) contrast agent in patients with acute myocardial infarction (MI). METHODS: One hundred three patients with acute MI received intravenous bolus gadobenate dimeglumine (0.05 mmol/kg) during MR examination. Dynamic and delayed T1-weighted spin-echo postcontrast images were compared with precontrast images, EKG, resting (201)Tl SPECT and echocardiography. RESULTS: Gadobenate dimeglumine was well tolerated. Dynamic imaging with gadobenate dimeglumine was more sensitive (72% vs 56%) than delayed spin echo imaging (P < 0.001). No difference in specificity was seen (98% vs 99%). (201)Tl SPECT was a sensitive (96%) test, but was not specific (63%). Echocardiography was not sensitive (32%), but was specific (92%). CONCLUSION: The intravenous use of gadobenate dimeglumine, at a bolus dose of 0.05 mmol/kg, is safe in patients with an acute MI. Dynamic contrast enhanced MR imaging has moderate sensitivity and high specificity for demonstrating infarct.

Magnetic resonance perfusion imaging in patients with coronary artery disease: a qualitative approach.

UNLABELLED: Although contrast-enhanced first pass magnetic resonance imaging (MRI) has potential to quantify blood flow through extensive image post-processing, clinical utility is likely to depend on rapid qualitative analysis. AIMS: To investigate use of an on-line analytical approach for detection of coronary artery disease (CAD). METHODS AND RESULTS: Thirty subjects with CAD underwent contrast-enhanced rest/adenosine stress MRI with basal, mid-papillary and apical short-axis image acquisition. Each short axis was divided into eight regions of interest (ROI). Regional perfusion was visually classified as normal or impaired according to transmural distribution and defect reversibility. MRI and angiographic data were compared. Qualitative MRI reporting was possible for 98% ROI. Eighty-six coronary artery (CA) territories were assessed of which 71 (83%) had stenoses. Sensitivity and specificity for detection of stenoses were 93 and 60%, respectively. The proportion of hypoperfused ROI rose from 31% with < 50% stenosis to 65% with occlusion. More transmural defects were seen in infarction-related territories (75 vs. 54%, p < 0.05). More ROI demonstrated defect reversibility in occluded rather than in stenosed infarction-related vessels (89 vs. 58%, p < 0.05). Occluded vessels with grade 2-3 collaterals contained a higher proportion of normal ROI (44 vs. 25%, p < 0.05). CONCLUSIONS: Qualitative MRI analysis had high sensitivity and moderate specificity for detecting CA stenoses. Additional information was obtained relating to lesion severity, previous infarction, myocardial viability and impact of collateral circulation. The technique has potential for de novo diagnosis of CAD and as a complementary modality to angiography to assess the significance of given angiographic lesions.

Interpreting regional myocardial magnetic resonance imaging data: a new method for collation with angiographic findings in patients with coronary artery disease.

The magnetic resonance imaging (MRI) assessment of myocardial function and perfusion is a valuable complementary technique to coronary angiography. We describe a method of presenting and collating regional MRI data with the angiographic findings as annotated by the Green Lane reporting system. Routine clinical use of this approach is likely to increase the accuracy of MRI data interpretation and to influence both medical and interventional treatment strategies.

Efficacy of transmyocardial laser revascularization and thoracic sympathectomy for the treatment of refractory angina.

BACKGROUND: Transmyocardial laser revascularization (TMR) is an effective treatment for relief of refractory angina. This benefit may be mediated by increase in myocardial perfusion or by cardiac denervation. We investigate the efficacy of TMR and thoracic sympathectomy (TS) for relief of angina and whether any clinical benefit is associated with enhanced myocardial perfusion. METHODS: Twenty consecutive patients with nonrevascularizable coronary arteries and intractable angina were prospectively randomized to have TMR by holmium: yttrium aluminum garnet laser or TS. Subjects were clinically evaluated before, and for 42 months after, surgery. They underwent exercise tolerance testing and rest and stress quantitative perfusion magnetic resonance imaging (MRI) before, and 6 months after surgery. RESULTS: The demographics of the two groups were similar. There was no perioperative mortality; however, two patients died in the TS group during follow-up. The Canadian Cardiovascular Society angina score improved from 3.4 +/- 0.5 to 2.6 +/- 1.1 (p = 0.06) in the TS group at 6 months but returned to 3.2 +/- 0.7 at 42 months, while in the TMR group it improved from 3.6 +/- 0.5 to 1.9 +/- 0.7 (p = 0.008) at 6 months and deteriorated to 2.5 +/- 0.9 (p = 0.01) after 42 months of surgery. The TMR-treated patients showed significant improvements in the SF-36 scores and Seattle Angina Questionnaire only at 6 months, whereas TS-treated patients did not show amelioration at any time during follow-up. The MRI protocol was completed in 15 of 20 (TMR = 8; TS = 7) patients and no significant differences in qualitative or quantitative perfusion variables were demonstrated in either group. CONCLUSIONS: A greater clinical benefit was obtained with TMR than with TS early after surgery but this clinical effect did not seem to be associated with improvement in myocardial perfusion as assessed by MRI and part of the beneficial effect was lost by 42 months after surgery.