M. Waleed Gaber

Radiation-induced permeability and leukocyte adhesion in the rat blood–brain barrier: modulation with anti-ICAM-1 antibodies

We assessed the acute effects of radiation on the rat blood-brain barrier. A cranial window model and intravital microscopy were used to measure changes in permeability and leukocyte adhesion in pial vessels after a localized, single dose of 20 Gy. Permeability was assessed using five sizes of fluorescein isothiocyanate (FITC)-dextran molecules (4.4-, 10-, 38.2-, 70-, and 150-kDa) with measurements performed before and 2, 24, 48, 72 and 96 h after irradiation for the 4.4 and 38.2-kDa molecules and before and 24 h after irradiation for the other three molecules. To demonstrate the nature of blood-brain barrier permeability, we concurrently studied the permeability of microvessels in the cremaster muscle. In both tissues, permeability to FITC-dextran was significantly greater 24 h after irradiation than before (P<0.05). The exception was that radiation did not affect the permeability of pial vessels to the 150-kDa molecule. The particle-size dependence of the permeability changes in the brain were indicative of altered integrity of endothelial tight junctions and occurred concomitantly with an increase in cell adhesion which was determined by fluorescent labeling of leukocytes with rhodamine 6G. An early inflammatory response to irradiation was apparent in the brain 2 h after irradiation. The numbers of rolling and adherent leukocytes increased significantly and peaked at 24 h. Injection with the anti-ICAM-1 mAb significantly reduced leukocyte adhesion and permeability thereby linking the two processes. These findings provide a target to reduce radiation-related permeability and cell adhesion and potentially the side effects of radiation in the CNS.

Radiation dose-volume effects on growth hormone secretion.

PURPOSEnGrowth hormone (GH) deficiency is a known consequence of central nervous system irradiation. The relationship between the dose to the hypothalamus and the time to onset of clinically significant GH deficiency is unknown. Conformal radiotherapy (CRT) techniques allow for a more accurate determination of hypothalamic dosimetry. We correlated the dosimetry of the hypothalamus and the peak GH value after CRT in children with localized primary brain tumors.nnnMETHODS AND MATERIALSnThe arginine tolerance/L-dopa test was performed before (baseline) and repeated 6 and 12 months after CRT in 25 children (median age 4.8 years) with ependymoma (n = 15) or low-grade (n = 8) or high-grade (n = 2) astrocytoma. None had evidence of GH deficiency (arginine tolerance/L-dopa peak GH level >10 ng/mL [10 microg/L]) at baseline. Peak GH levels were modeled as a function of time after CRT and volume of the hypothalamus receiving a dose within the specified intervals of 0-20 Gy, 20-40 Gy, and 40-60 Gy. The model was used to predict the change in the peak GH levels over time (0-12 months) and fit under the assumption that the integral effect of irradiation was a linear sum of the products of the volume receiving a particular dose and the impact of that dose.nnnRESULTSnThe peak GH level declined during the 0-12 months after CRT (p < 0.0001). GH deficiency was observed in 11 children at 6 months and a total of 20 children at 12 months. As expected, the effect of the dose interval 0-20 Gy was smaller than the 20-40-Gy dose interval; the largest effect was noted with the dose interval 40-60 Gy. The peak GH level may be predicted using the following estimating equation within the time limit of 0-12 months: GH(t)=Exp[ln(bGH)-(0.00058V(0-20 Gy)+0.00106V(20-40 Gy)+0.00156V(40-60 Gy))x t], where bGH is the baseline peak GH level, V(0-20 Gy), V(20-40 Gy), and V(40-60 Gy) is the percent-volume of the hypothalamus irradiated from 0 to 20 Gy, 20 to 40 Gy, and 40 to 60 Gy, respectively, and t is time after irradiation. When included in the model, the rate of decline in the peak GH response also was influenced by hydrocephalus and tumor location.nnnCONCLUSIONnThe peak GH response within 12 months after CRT depends on hypothalamic dose-volume effects and may be predicted on the basis of a linear model that sums the effects of the entire distribution of dose. The modeled effects may be used to optimize radiotherapy and minimize and treat GH deficiency.

Targeting microparticles to select tissue via radiation induced upregulation of endothelial cell adhesion molecules

AbstractPurpose. Certain endothelial cell adhesion molecules are up regulated in tissue that has been irradiated for therapeutic purposes. This up-regulation of adhesion molecules provides a potential avenue for targeting drugs to select tissues.nMethods. Microspheres were coated with a mAb to ICAM-1 and the level of adhesion of the anti-ICAM-1 microspheres to irradiated tissue in vitro and in vivo was quantified.nResults. Under in vitro flow conditions, the number of adherent microspheres on irradiated HUVEC was 4.8 ± 0.9 times that of control; the adhesion of anti-ICAM-1 microspheres on irradiated HUVEC could be enhanced by more than 170% in the presence of RBC (20% hematocrit) in the medium. In vivo in a rat cranial window model, the number of adherent anti-ICAM-1 microspheres in locally irradiated cerebral tissue was 8 and 13 times that of IgG microspheres at 24 h and 48 h post-irradiation, respectively and returned to baseline 7 days post-irradiation. In locally irradiated animals, the number of adhering microspheres in unirradiated tissue remained at the basal level.nConclusions. Radiation-induced up-regulation of endothelial cell adhesion molecules may be exploited to target drugs and/or genes to select segments of the endothelium.

Anti-TNFA (TNF-α) Treatment Abrogates Radiation-Induced Changes in Vascular Density and Tissue Oxygenation

Abstract Ansari, R., Gaber, M. W., Wang, B., Pattillo, C. B., Miyamoto, C. and Kiani, M. F. Anti-TNFA (TNF-α) Treatment Abrogates Radiation-Induced Changes in Vascular Density and Tissue Oxygenation. Radiat. Res. 167, 80–86 (2007). Ionizing radiation significantly alters the structure and function of microvasculature, which regulates delivery of oxygen to brain tissue. Previous experimental and modeling studies have shown that tissue oxygenation patterns are significantly different in irradiated normal tissue compared to age-matched controls, and the differences are apparent as early as 3 days postirradiation. However, oxygen delivery to irradiated tissue recovers within 6 months postirradiation. Changes in perfusion and oxygenation were studied in a bilaterally (both cerebral hemispheres) and unilaterally (only one hemisphere) irradiated mouse brain model at 6 and 24 h as well as 3, 7, 30, 60 and 120 days postirradiation. The results indicate that significant changes in the number of perfused vessels (as measured by fluorescent DiOC7 staining) and anatomical vessels (as indicated by CD31 immunohistochemical staining) and tissue oxygenation (by immunohistochemical detection of a fluorescently conjugated monoclonal antibody to EF5) are most pronounced at 3 days postirradiation, while a degree of recovery is observed at later times. However, in the unilaterally irradiated animals, both irradiated and unirradiated (out-of-field) cerebral hemispheres showed similarly significant changes in oxygenation and/or perfusion compared to unirradiated controls. Anti-TNFA treatment inhibited radiation-induced local as well as abscopal effects in the brain tissue.

COMPARISON OF TWO IMMOBILIZATION TECHNIQUES USING PORTAL FILM AND DIGITALLY RECONSTRUCTED RADIOGRAPHS FOR PEDIATRIC PATIENTS WITH BRAIN TUMORS

PURPOSEnTo compare the accuracy of two immobilization techniques for pediatric brain tumor patients.nnnMETHODS AND MATERIALSnWe analyzed data from 128 treatments involving 22 patients. Patients were immobilized with either a relocatable head frame (12 patients) or a vacuum bag (10 patients). Orthogonal portal films were used as verification images. Errors in patient positioning were measured by comparing verification images with digitally reconstructed radiographs generated by a three-dimensional treatment-planning system.nnnRESULTSnWith the head frame, systematic errors ranged from 1.4 mm to 2.1 mm; random errors, from 1.7 mm to 2.1 mm. With the vacuum bag, systematic errors ranged from 2.1 mm to 2.5 mm; random errors, from 2.0 mm to 2.6 mm. For the head frame, the mean length of the radial displacement was 4.4 mm; 90% of the total three-dimensional deviation was less than 6.8 mm. The corresponding values for the vacuum bag were 5.0 and 6.6 mm, respectively.nnnCONCLUSIONSnThe head frame and vacuum bag techniques limit the random and systematic errors in each of the three directions to within +/- 5 mm. We have used these results to determine the margin used to create the planning target volume for conformal radiation therapy.

CT reconstruction by using the MLS-ART technique and the KCD imaging system. I. Low-energy X-ray studies

The authors investigated the use of the kinestatic charge detector (KCD) combined with the multilevel scheme algebraic reconstruction technique (MLS-ART) for X-ray computer tomography (CT) reconstruction. The KCD offers excellent detective quantum efficiency and contrast resolution. These characteristics are especially helpful for applications in which a limited number of projections are used. In addition, the MLS-ART algorithm offers better contrast resolution than does the conventional convolution backprojection (CBP) technique when the number of projections is limited. Here, the authors present images of a Rando-head phantom that was reconstructed by using the KCD and MLS-ART. The authors also present, for comparison, the images reconstructed by using the CBP technique. The combination of MLS-ART and the KCD yielded satisfactory images after just one or two iterations.

Dysfunctional microvascular conducted response in irradiated normal tissue.

Ionizing radiation is used widely to treat many conditions including cancer, arteriovenous malformations (AVM), macular degeneration, and intimai hyperplasia. Damage to the microvasculature constitutes one of the most important components of the late effects of radiation damage to many organs in clinical applications. While the effects of ionizing radiation on microvascular structure and function of normal tissue have been studied, the mechanisms by which ionizing radiation interferes with the normal microvascular control processes are not well understood. An important question is why normal microvasculature is not able to repair radiation damage as efficiently as it is able to repair other forms of damage (e.g. wounds). Understanding the mechanisms by which ionizing radiation damages the microvasculature has important clinical implications.

Portal CT reconstruction using the CsI(Tl) transparent scintillator x-ray detector and the MLS-ART technique

In this paper, we report our investigation using a CsI(Tl) transparent scintillator x-ray detector together with the multi-level scheme algebraic reconstruction technique (MLS- ART) for megavoltage computed tomography (CT) reconstructions. The reconstructed CT images may be useful for positional verification in radiotherapy. The CsI(Tl) imaging system consists of a scintillator screen coupled to a liquid- nitrogen-cooled slow-scan CCD-TV camera. This system provides better contrast resolution than the standard electronic portal imaging system (EPID), which is especially useful given the low number of projections we are aiming at. The geometry of the imaging system has also been optimized to achieve high spatial resolution (1 lp/mm) in spite of the thickness of the screen. We present the images reconstructed using a pediatric head phantom using a total of 99 projections, and a combined phantom using 50 projections. Image reconstruction was carried out using the MLS-ART technique. We also present the CT images obtained using the back projection technique for comparison purposes.

Development of portal CT reconstruction using MLS-ART technique and the kinestatic charge detector imaging system: I. Low-energy x-ray studies

We investigate the use of the kinestatic charge detector (KCD) together with the multi-level scheme algebraic reconstruction technique (MLS-ART) for computer tomography (CT) reconstruction, to be used in position verification in radiotherapy. The KCD offers very good contrast resolution, which is especially useful given the low number of projections we are aiming at. We present the images reconstructed using a head phantom (Rando-phantom) using a total of 95 projections, and a standard low contrast CT phantom using 63 projections. The reconstruction was carried out using MLS-ART technique, in this technique satisfactory images are generally obtained after one or two iteration, which in effect makes ART a noniterative algorithm. We also present the CT images obtained using the back projection technique for comparison purposes.