Gregory D. Lapin

Permeability of Different Experimental Brain Tumor Models to Horseradish Peroxidase

The permeability of different brain tumor models to horseradish peroxidase (HRP) was examined by determining the fraction of tumor that contained HRP after intravenous administration. The intracerebral tumor models studied were Avian Sarcoma Virus (ASV)-induced tumors and tumors from transplanted RG-2, S69-C1-5, and 9L cell lines. The average fraction of RG-2 tumors permeable to HRP was .95; of S69-C1-5 tumors, .699; of ASV-induced tumors, .63; and of 9L tumors, .52. Except for the RG-2 tumors, there was considerable regional variation in HRP permeability, which was most marked in the ASV-induced tumors. In ASV-induced tumors, HRP permeability did not correlate with tumor histo ogical classification, size, or anatomic location within the brain. The subcutaneous tumor models studied were RG-2-, S69-C1-5, and 9L-transplanted tumors in rats, and human glioblastoma cell lines transplanted into nude mice. All were completely permeable to HRP. These results indicate that significant differences in permeability to HRP exist among brain tumor models when the tumors are intracerebral, and that all subcutaneous tumors from transplanted glial cell lines are completely permeable to HRP. These variables must be considered in future studies of permeability in experimental brain tumors. Care must be exercised in extrapolating results about permeability from one brain tumor model to another

A Method to Quantitatively Measure Transcapillary Transport of Iodinated Compounds in Canine Brain Tumors with Computed Tomography

We present a quantitative method for determining a blood-to-tissue influx constant (K1), a tissue-to-blood efflux constant (k2), and tissue plasma vascular space (Vp) that uses a computed tomographic (CT) scanner to make tissue and plasma measurements of the concentration of an iodinated compound. Meglumine iothalamate was infused intravenously over time periods of 0.5–5 min, up to 49 CT scans were obtained at one brain level, and arterial plasma was sampled over a 30- to 40-min period. K1, k2, and Vp were calculated for each voxel of the 320 × 320 matrix, using a two-compartment pharmacokinetic model and nonlinear least-squares regression. The method was used in dogs with avian sarcoma virus–induced brain tumors. As many as four studies on different days were done in the same animal. In tumor-free cortex, K1 of meglumine iothalamate was 2.4 ± 1.7 μl g−1 min−1 (mean ± SD) and Vp was 3.4 ± 0.5 ml 100 g−1. Mean whole-brain tumor K1 values ranged from 3.3 to 97.9 μl g−1 min−1; k2 ranged from 0.032 to 0.27 min−1; and Vp ranged from 1.1 to 11.4 ml 100 g−1. These values were reproducible in serial experiments in single animals. Independent verification of K1 values was obtained with quantitative autoradiographic measurements of α-aminoisobutyric acid, which has similar physicochemical properties to meglumine iothalamate. The CT methodology is capable of demonstrating regional variation of trans-capillary transport in brain tumors and may be of value in the study of human brain tumors.

Two-Dimensional Echocardiographic Measurement of Right Pulmonary Artery Diameter in Infants and Children

Two-dimensional suprasternal notch echocardiograms of the right pulmonary artery were obtained in 50 normal infants and children to determine the right pulmonary artery diameter. An excellent nonlinear correlation between the right pulmonary artery diameter (RPA) in cm and body surface area (BSA) in m2was observed: RPA (systole) = 1.41 (BSA)051, r = 0.94 and RPA (diastole) = 1.28 (BSA)0.52, r = 0.93. These data were utilized to calculate the normal range (3rd and 97th percentiles) of right pulmonary artery diameter as a function of body surface area. The right pulmonary artery diameter was also measured in 37 patients with tetralogy of Fallot, 30 patients with a secundum atrial septal defect and 12 patients with pulmonary valve insufficiency of various causes. Pulmonary artery diameter was less than the 3rd percentile for body surface area in 16 of the 37 patients with tetralogy of Fallot, but it exceeded the 97th percentile in 17 of the 30 patients with an atrial septal defect and 8 of the 12 patients with pulmonary insufficiency. In 20 patients undergoing both angiography (Angio) and echocardiography (Echo), then was excellent agreement of right pulmonary artery di-ameter measurements by the two methods: Angio = 1.06 (Echo), r = 0.93. Thus, accurate measurement of the right pulmonary artery diameter can be achieved by echocardiography, This important information, which provides quantitative and serial assessment of right pulmonary artery diam-eter in pathologic conditions that affect its caliber, may facilitate decisions about the selection of the appropriate initial surgical procedure and the timing of subsequent angiography in patients with tetralogy of Fallot.

Measurement of mitral valve orifice area in infants and children by two-dimensional echocardiography

Two-dimensional echocardiograms of the mitral valve orifice area were obtained in 50 normal pediatric subjects, 15 patients with congenital mitral stenosis and 7 patients with tricuspid atresia. The mitral area was measured near the tips of the mitral valve leaflets from a diastolic cross-sectional image of the left ventricle. The cardiac images were recorded on videotape and later transferred to video disc for high resolution contour tracing. Contour analysis was performed by a special purpose microcomputer system for calculation of the enclosed calibrated area. In normal patients, there was an excellent correlation (r = 0.95) between mitral valve area (MVA) (in cm2) and body surface area (BSA) (in m2) described by MVA = 4.83 X BSA - 0.07. Each patient with mitral stenosis had a mitral valve area that measured less than the third percentile predicted from the normal regression formula. In eight patients in whom the Gorlin formula could be applied, there was excellent correlation (r = 0.95) between echocardiographic and hemodynamic measurements of mitral valve area. Each patient with tricuspid atresia had a very large mitral valve area (greater than 99th percentile of normal). It is concluded that noninvasive measurement of mitral valve orifice area can be accurately achieved by two-dimensional echocardiography in pediatric patients with congenital mitral stenosis, allowing serial measurement of their mitral valve area.

The effects of dexamethasone on experimental brain tumors : I: Transcapillary transport and blood flow in RG-2 rat gliomas

SummaryDexamethasone dramatically improves cerebral edema associated with malignant gliomas. Although the pathophysiology of this effect is not clearly understood, many investigators have postulated that tumor capillary permeability is reduced by dexamethasone. We studied blood-to-tissue transport and blood flow in 178 RG-2 transplanted gliomas in a control group and four groups given dexamethasone at doses of 3, 6, 9, and 12 mg/kg for four days.14C-α aminoisobutyric acid (AIB) was used to study blood-to-tissue transport in 31 animals; in an additional 27 animals14C-AIB and131I-iodoantipyrine (IAP) were used in double label experiments to study blood-to-tissue transport and blood flow. Regional measurements of the transfer constant (K) of AIB and blood flow (F) were made with quantitative autoradiography. There were significant differences between the control and dexamethasone-treated groups with regard to weight loss and plasma glucose. However, there wasno significant effect of dexamethasone on values of K or F, regardless of the tumor or brain region examined, and regardless of the dose of dexamethasone administered. Analysis of the profiles of the transfer constant of AIB in the brain around tumor showed that the K of AIB decreased within 0.5 mm of the tumor edge in direct relationship to the dexamethasone dose. These results do not support the hypothesis that dexamethasone reduces brain tumor capillary permeability, and suggest that dexamethasone may decrease tumor-associated cerebral edema by effects on bulk flow away from the tumor margin.

The effects of dexamethasone on transcapillary transport in experimental brain tumors: II. Canine brain tumors

SummaryWe studied the effect of dexamethasone on transcapillary transport in ten Avian Sarcoma Virus (ASV)-induced canine brain tumors, before and one week after administration of dexamethasone, 2.5 mg/kg/day. A computed tomographic (CT) method was used to measure regional values of K1 (blood-to-tissue transfer constant), k2 (tissue-to-blood efflux constant), and Vp (tissue plasma vascular space) of meglumine iothalamate (Conray-60TM); the values were reconstructed for each 0.8 × 0.8 x 5 mm volume element of the CT data. For all tumors considered together, there was a decrease in the whole tumor K1 value of meglumine iothalamate from 26 ± 2.2 (SE) before dexamethasone to 24 ± 2.9 μl/g/min after dexamethasone. Vp decreased from 7.2 ± 0.7 to 6.7 ± 0.9 ml/100 g, and the size of the tumor extracellular space (Ve) decreased from 0.30 to 0.26 ml/g. These changes were not statistically significant. However, when each tumor was used as its own control, k1 significantly decreased after dexamethasone in four tumors, significantly increased in two and was unchanged in four. These results suggest that decreased blood-to-tissue transport may be one mechanism underlying resolution of tumor associated cerebral edema in some brain tumors and that the effects of dexamethasone on blood-to-tissue transport in brain tumors are variable from one tumor to the next. Decreased ‘permeability’ may not be the sole mechanism by which dexamethasone reduces tumor-associated cerebral edema.

Noninvasive CT determination of arterial blood concentration of meglumine iothalamate

A quantity that often must be determined in physiological imaging studies is the blood concentration of the tracer over time. This is usually performed by direct arterial or venous blood sampling. We studied the relationship between the concentration of meglumine iothalamate in arterial blood and values determined from voxels containing large blood vessels in a series of CT images at the same location over time. After correction for volume averaging based on a single venous blood sample, there was an excellent correlation between the two blood curves. Differences between the curves were shown to be inconsequential by a simulation of transcapillary transport determinations. We thus conclude that determination of plasma concentration from CT images is a reliable technique for CT transcapillary transport studies.

Spatially adaptive image restoration for autoradiography

In this paper, we present a model that is used to improve the resolution of autoradiographic images. The model involves a point spread function (PSF) due to the radiated pattern of emitted photons combined with a signal-dependent noise source due to the granularity of x-ray recording film. A theoretical expression for the PSF is presented, and experimental measurements are performed using 51Cr microspheres. An iterative regularized image restoration algorithm is developed using a weighting matrix to incorporate the signal- dependent nature of the noise. Since information about the original undegraded image is not completely available, we make use of a regualtization functional that is updated at each iteration to optimize the solution process. Our experimental results indicate that the resolution of autoradiographic images is improved by 43% using this algorithm.

Noninvasive measurement of arterial blood plasma concentration of iodinated contrast agents from CT scans of human brain

Objective Our goal was to assess the accuracy of estimating the time course of the arterial plasma concentration of meglumine iothalamate from cranial CT images of different vascular structures in the brain. Materials and Methods Dynamic CT studies of transcapillary transport in various brain lesions were analyzed. Vascular structures in the brain were identified and classified in three categories: arteries, veins, and venous sinuses. Systemic venous blood samples were taken prior to the infusion of meglumine iothalamate and 10 min after completion of the infusion and used as a calibration for the volume averaging fraction of the image of each vascular structure. A time course of plasma meglumine iothalamate concentration for each of the vascular categories in the CT images was obtained and compared with a variety of methods. Results Significant differences were found for measurement of plasma meglumine iothalamate concentration from different vascular categories. There was also a disparity between the volume averaging fraction that we calculated and what would be expected due to the measured systemic hematocrit for all vascular structures. Conclusion The use of images of veins and venous sinuses consistently underestimated the arterial concentration around the peak values. Correcting the imaged venous sinus values with the measured systemic hematocrit was even less reliable. The most accurate method of determining arterial plasma concentration of meglumine iothalamate from CT images of brain was to correct the identified arterial vessels for volume averaging.

A new head holder for reducing axial movement and repositioning errors during physiological CT imaging

Objective We designed a new head holder for immobilization and repositioning in dynamic CT studies of the brain. Materials and Methods A customized thermoplastic face mask and foam head rest were made to restrict movement of the head in all directions, but particularly out of the axial plane (z-movement). Results This design provided a rigid, detailed mold of the face and back of the head that minimized motion during lengthy CT studies and enabled accurate repositioning of the head for follow-up studies. Markers applied directly to the skin were used to quantify z-movement. Conclusion When tested on 12 subjects, immobilization was limited to <2.0 mm under worst-case conditions when the subject was asked to attempt forced movements. Repositioning was accurate to <1.5 mm when the subject was removed from the head holder and then placed back into it.