DCE-MRI biomarkers of tumour heterogeneity predict CRC liver metastasis shrinkage following bevacizumab and FOLFOX-6.

BACKGROUND: There is limited evidence that imaging biomarkers can predict subsequent response to therapy. Such prognostic and/or predictive biomarkers would facilitate development of personalised medicine. We hypothesised that pre-treatment measurement of the heterogeneity of tumour vascular enhancement could predict clinical outcome following combination anti-angiogenic and cytotoxic chemotherapy in colorectal cancer (CRC) liver metastases. METHODS: Ten patients with 26 CRC liver metastases had two dynamic contrast-enhanced MRI (DCE-MRI) examinations before starting first-line bevacizumab and FOLFOX-6. Pre-treatment biomarkers of tumour microvasculature were computed and a regression analysis was performed against the post-treatment change in tumour volume after five cycles of therapy. The ability of the resulting linear model to predict tumour shrinkage was evaluated using leave-one-out validation. Robustness to inter-visit variation was investigated using data from a second baseline scan. RESULTS: In all, 86% of the variance in post-treatment tumour shrinkage was explained by the median extravascular extracellular volume (v(e)), tumour enhancing fraction (E(F)), and microvascular uniformity (assessed with the fractal measure box dimension, d(0)) (R(2)=0.86, P<0.00005). Other variables, including baseline volume were not statistically significant. Median prediction error was 12%. Equivalent results were obtained from the second scan. CONCLUSION: Traditional image analyses may over-simplify tumour biology. Measuring microvascular heterogeneity may yield important prognostic and/or predictive biomarkers.

Cross-visit tumor sub-segmentation and registration with outlier rejection for dynamic contrast-enhanced MRI time series data.

Clinical trials of anti-angiogenic and vascular-disrupting agents often use biomarkers derived from DCE-MRI, typically reporting whole-tumor summary statistics and so overlooking spatial parameter variations caused by tissue heterogeneity. We present a data-driven segmentation method comprising tracer-kinetic model-driven registration for motion correction, conversion from MR signal intensity to contrast agent concentration for cross-visit normalization, iterative principal components analysis for imputation of missing data and dimensionality reduction, and statistical outlier detection using the minimum covariance determinant to obtain a robust Mahalanobis distance. After applying these techniques we cluster in the principal components space using k-means. We present results from a clinical trial of a VEGF inhibitor, using time-series data selected because of problems due to motion and outlier time series. We obtained spatially-contiguous clusters that map to regions with distinct microvascular characteristics. This methodology has the potential to uncover localized effects in trials using DCE-MRI-based biomarkers.

Candidate biomarkers of extravascular extracellular space: a direct comparison of apparent diffusion coefficient and dynamic contrast-enhanced MR imaging--derived measurement of the volume of the extravascular extracellular space in glioblastoma multiforme.

BACKGROUND AND PURPOSE: ADC measurements have been shown to have an inverse relationship with tumor cell density. DCE-MR imaging modeling techniques can produce a measurement of the v(e), which would also be expected to have an inverse relationship with cell density. The objective of this study was to test the hypothesis that areas of increased cellularity, and therefore low ADC, would be expected to have a small EES (low v(e)). MATERIALS AND METHODS: Nineteen patients with GBM were recruited. All imaging was performed before surgery on a 3T MR imaging scanner. Imaging included diffusion tensor imaging, T1-weighted DCE-MR imaging, and anatomic sequences. Tumor VOIs were defined on the anatomic images and modified to contain only enhancing voxels. Parametric maps of ADC and v(e) were generated. Statistical analysis of ADC and v(e) was performed on both a voxel-by-voxel basis and comparison of median values. RESULTS: No correlation was demonstrated between ADC and v(e) in either a voxel-by-voxel analysis or comparison of median values (P = .124). CONCLUSIONS: This study failed to demonstrate a correlation between ADC and v(e). This is important because it suggests that though the mechanisms underlying these parameters are theoretically similar, they actually reflect different aspects of tumor microenvironment. Consequently ADC and v(e) should be considered to provide independent information about the properties of the EES.

Enhancing fraction in glioma and its relationship to the tumoral vascular microenvironment: A dynamic contrast-enhanced MR imaging study.

BACKGROUND AND PURPOSE: EnF is a newly described measure of proportional tumor enhancement derived from DCE-MR imaging. The aim of this study was to assess the relationship between EnF and the more established DCE-MR imaging parameters: K(trans), v(e), and v(p). MATERIALS AND METHODS: Forty-two patients with 43 gliomas (16 grade II, 3 grade III, and 24 grade IV) were studied. Imaging included pre- and postcontrast T1-weighted sequences through the lesion and T1-weighted DCE-MR imaging. Parametric maps of EnF, K(trans), v(e), and v(p) were generated. Voxels were classified as enhancing if the IAUC was positive (EnF(IAUC)(60>0)). A threshold of IAUC > 2.5 mmol.s was used to generate EnF(IAUC)(60>2.5). Both measures of EnF were compared with the DCE-MR imaging parameters (K(trans), v(e), and v(p)). RESULTS: In grade II gliomas, EnF(IAUC60>0) and EnF(IAUC60>2.5) correlated with v(p) (R(2) = 0.6245, P < .0005; and R(2) = 0.4727, P = .003) but not with K(trans) or v(e). In grade IV tumors, both EnF(IAUC60>0) and EnF(IAUC60>2.5) correlated with K(trans) (R(2) = 0.3501, P = .001; and R(2) = 0.4699, P < .0005) and v(p) (R(2) = 0.1564, P = .01; and R(2) = 0.2429, P = .007), but not with v(e). Multiple regression analysis showed K(trans) as the only independent correlate of both EnF(IAUC60>0) and EnF(IAUC60>2.5) for grade IV tumors. CONCLUSIONS: This study suggests that in grade II tumors, EnF reflects v(p) and varies due to changes in vascular density. In grade IV gliomas, EnF is affected by K(trans) with secondary associated changes in v(p).

Effects of a short-term improvement in glycaemic control on skin microvascular dysfunction in Type 1 and Type 2 diabetic patients.

AIMS: To investigate whether Type 1 and Type 2 diabetic patients differ in the effects of short-term improvement in glycaemic control on skin microvascular dysfunction. METHODS: Fourteen Type 1 and 14 Type 2 diabetic patients admitted to hospital to improve glycaemic control were investigated. Two age- and sex-matched groups of non-diabetic subjects served as controls. Capillary blood cell velocity (CBV) was assessed at the dorsal middle phalangeal area of the ring finger at rest and after 3-min arterial occlusion using laser Doppler anemometry. RESULTS: Comparing the measurements before and after improvement in glycaemic control, there were no significant changes in peak CBV, time to peak CBV and vasomotion amplitudes in Type 1 and Type 2 diabetic patients. On admission to hospital, time to peak CBV was prolonged in Type 1 (20.9 +/- 2.9 vs. 12.3 +/- 1.6 s, P = 0.003) and Type 2 diabetic patients (20.6 +/- 2.6 vs. 11.9 +/- 1.3 s, P = 0.021) compared with control subjects. After improvement in glycaemic control, there was no significant difference in time to peak CBV between Type 1 diabetic patients and their control subjects (17.8 +/- 4.2 vs. 12.3 +/- 1.6 s, P = 0.535). In Type 2 diabetic patients, the time to peak CBV increased non-significantly. CONCLUSIONS: Short-term improvement in glycaemic control did not appear to reverse microcirculatory dysfunction in Type 1 and Type 2 diabetes. However, there was an improvement of the delayed reactive hyperaemia in Type 1 diabetic patients.

Quantifying heterogeneity in dynamic contrast-enhanced MRI parameter maps.

Simple summary statistics of Dynamic Contrast-Enhanced MRI (DCE-MRI) parameter maps (e.g. the median) neglect the spatial arrangement of parameters, which appears to carry important diagnostic and prognostic information. This paper describes novel statistics that are sensitive to both parameter values and their spatial arrangement. Binary objects are created from 3-D DCE-MRI parameter maps by "extruding" each voxel into a fourth dimension; the extrusion distance is proportional to the voxel's value. The following statistics are then computed on these 4-D binary objects: surface area, volume, surface area to volume ratio, and box counting (fractal) dimension. An experiment using 4 low and 5 high grade gliomas showed significant differences between the two grades for box counting dimension computed for extruded v(e) maps, surface area of extruded K(trans) and v(e) maps and the volume of extruded v(e) maps (all p < 0.05). An experiment using 18 liver metastases imaged before and after treatment with a vascular endothelial growth factor (VEGF) inhibitor showed significant differences for surface area to volume ratio computed for extruded K(trans) and v(e) maps (p = 0.0013 and p = 0.045 respectively).

Impairment of cutaneous arteriolar 0.1 Hz vasomotion in diabetes.

Arteriolar vasomotion, the cyclic contraction/dilation of terminal arterioles, is disordered in diabetes. The aim of the present study was to characterize the impairment of cutaneous vasomotion in type 1 and type 2 diabetes, especially with regard to the influence of metabolic control and to the response to shear stress. Twenty type 1 and 23 type 2 diabetic patients were investigated. Vasomotion waves were recorded in single capillaries at the dorsal middle phalangeal area of the left ring finger during rest, after warming the skin temperature to 33 degrees C, and after 3-min arterial occlusion by means of laser Doppler anemometry. Suprasystolic occlusion caused an increase in amplitudes of vasomotion only in type 1 diabetic patients (0.12 +/- 0.04 mm/s vs. 0.36 +/- 0.06 mm/s, p = 0.001). In type 1 but not in type 2 diabetic patients, both systolic and diastolic blood pressure correlated positively with amplitudes of resting vasomotion (r = 0.62, p = 0.002 and r = 0.65, p = 0.001, respectively). Amplitudes of vasomotion after warming up at frequencies of 5 - 8 cycles per minute (0.08 - 0.13 Hz) correlated inversely with the levels of glycated hemoglobin (HbA 1c ) (r = - 0.56, p = 0.005) only in type 1 diabetic patients. In conclusion, we found suprasystolic occlusion and increasing blood pressure to provoke vasomotion with a concomitant decrease in effective vascular resistance only in type 1 diabetic patients. The impaired vasomotion response to shear stress in type 2 diabetes might favour the development of skin lesions and arterial hypertension. Insufficient glycemic control seems to be an important factor in the pathogenesis of impaired vasomotion in type 1 diabetes.

Impaired 0.1-Hz vasomotion assessed by laser Doppler anemometry as an early index of peripheral sympathetic neuropathy in diabetes.

Impairment of 0.1-Hz vasomotion, which was found in diabetic patients, was suggested to be an early index of sympathetic dysfunction. We studied the relationships between alterations in vasomotion and both cardiac autonomic and sensory neuropathy. Twenty type 1 and 22 type 2 diabetic patients were investigated. Vasomotion was recorded in single capillaries at the dorsal middle phalangeal area of the left ring finger by means of laser Doppler anemometry. Cardiac autonomic neuropathy was assessed by spectral analysis of heart rate variation during rest and recording heart rate responses to deep breathing and Valsalva manoeuvre. Sensory neuropathy was investigated by measuring heat pain, vibration, and thermal sensory thresholds. Impaired vasomotion was more often (82.4%) found in diabetic patients with at least one altered cardiac autonomic test, but also in 47.1% of those with all of these tests being normal (P = 0.035). Both heart rate variation coefficient during rest (r = 0.40, P = 0.045) and Valsalva ratio (r = 0.41, P = 0.037) correlated positively with amplitudes of vasomotion in type 1 diabetic patients. The prevalence of impaired vasomotion was not higher in patients with sensory neuropathy compared to those with normal sensory functions. A disturbed warm sensation was only found in 2 patients and none had an abnormal heat pain threshold. Our data indicate that impairment of 0.1-Hz vasomotion precedes parasympathetic neuropathy, assessed by heart rate variation tests, and abnormalities in warm and heat pain sensation. Reduction of arteriolar vasomotion, detected by laser Doppler anemometry, might be an early index of sympathetic dysfunction, because it correlates with disturbances in those cardiac autonomic tests, which are at least in part under sympathetic control.

Duration of complete response to chemotherapy in advanced breast cancer.

Twenty-seven patients with advanced breast cancer with complete response (CR) to chemotherapy have been analysed and observed for up to 8 years. Median time to attainment of CR was 8.1 months (range, 1-19.5) and median duration of CR was 27.5 months (1-97 + months). Most (16) recurrences occurred in the first 2 years. In 12 patients (63%) relapse was at sites initially involved. No clear relationship between the duration of CR and a variety of prognostic factors or the dose of cytotoxic drugs given was found, although there was a tendency to longer duration of CR when fewer sites were involved. The presence of visceral disease did not preclude a prolonged CR. It seems that despite some patients surviving many years, relapse is inevitable and cure of the disease is unlikely with presently available chemotherapy.

Cerebral sodium extraction in the dog: a test for extracerebral contamination.

The single-pass extraction of sodium was measured with and without sympathetic stimulation in dogs anesthetized with alpha-chloralose. A mixture of the test (24Na) and reference ([125I]RISA) substances was injected as a bolus into the common carotid artery. Single-drop samples were taken at approximately 1-s intervals from the sagittal sinus and the temporal sinus while cerebral blood flow was continuously measured at the temporal sinus by the venous outflow technique. The extraction measurements were used to test for extracerebral contamination of venous outflow. The mean integral extraction determined from sagittal sinus samples was 2.2% during control conditions and 3.0% during sympathetic stimulation. The mean temporal sinus extraction of sodium was 6.9% during control and 2.7% during sympathetic stimulation. If true cerebral sodium extraction is assumed to be 1.4% and extracerebral sodium extraction is 60%, then these data indicate that extracerebral contamination is less than 10%.

Sympathetic modulation of hypercapnic cerebral vasodilation in dogs.

We measured cerebral blood flow using both the radioactive microsphere technique and the cerebral venous outflow technique in dogs anesthetized with chloralase. The effect of sympathetic stimulation on cerebral blood flow was observed during both normocapnia and prolonged hypercapnia using both blood flow techniques. The increase in blood flow with hypercapnia was the same with both methods. During hypercapnia the venous outflow method showed a 38% decrease and microspheres an 18% decrease in cerebral blood flow with sympathetic stimulation. At normal CO2, stimulation caused a decrease in cerebral venous flow: no change was observed with the microsphere method. Analysis of the blood flow patterns to extracerebral tissues and evaluation of extracerebral arterial reference samples failed to prove the existence of axial streaming and subsequent skimming of microspheres within the cephalic circulation. It is concluded that direct electrical stimulation of the sympathetic innervation of the cerebral vessels is capable of reducing cerebral blood flow even during a profound hypercapnic vasodilation.

4-(6-Methoxy-2-naphthyl)butan-2-one and related analogues, a novel structural class of antiinflammatory compounds.

A series of compounds related to 4-(6-methoxy-2-naphthyl)butan-2-one has been prepared and tested for antiinflammatory activity by the cotton pellet granuloma method. Compounds possessing a small lipophilic group such as methoxyl, methyl, or chloro in the 6 position in conjunction with a butan-2-one side chain in the 2 position of the naphthalene ring were most active. The indtroduction of a methyl group along the side chain was invariably deleterious. Good activity was generally retained by forming esters of a butan-2-ol side chain.