Imaging and Dosimetry Study of Inter-fraction Setup Error in a Murine Xenograft Flank Tumor Radiation Model.

Modern small animal irradiation platforms provide for accurate delivery of radiation under 3D image guidance. However, leveraging these improvements currently comes at the cost of lower-throughput experimentation. Herein, we characterized setup accuracy and dosimetric robustness for mock/sham irradiation of a murine xenograft flank tumor model using the X-RAD SmART+ with the vendor-supplied Monte Carlo (MC) treatment planning system (SmART ATP). The chosen beam arrangement was parallel-opposing using a 20 mm square collimator, aligned off-axis for ipsilateral lung sparing. Using a cohort of five mice imaged with cone beam computed tomography (CBCT) over five consecutive mock-irradiation fractions, we compared inter-fraction setup variability resulting from a vendor-supplied multi-purpose bed with anesthesia nose cone with a more complicated immobilization solution with an integrated bite block with nose cone and Styrofoam platform. A hypothetical "high-throughput" image-guidance scenario was investigated, wherein the day 1 stage coordinates (resulting from CBCT guidance) were applied on days 2-5. Daily inter-fraction setup errors were evaluated per specimen (days 2-5) using CBCT-derived offsets from day 1 stage coordinates. Using the CBCT images and Monte Carlo dose calculation, 3D dosimetric plan robustness was evaluated for the vendor-supplied immobilization solution, for both the high-throughput guidance scenario as well as for use of daily CBCT-based alignment. Inter-fraction setup offset magnitude was 3.6 (±1.5) mm for the vendor-supplied immobilization compared to 3.3 (±1.8) mm for the more complicated solution. For the vendor-supplied immobilization, we found that daily CBCT was needed to adequately cover the flank tumors dosimetrically, given our chosen treatment approach.

Pharmacokinetic Assessment of Cooperative Efflux of the Multitargeted Kinase Inhibitor Ponatinib Across the Blood-Brain Barrier.

A compartmental blood-brain barrier (BBB) model describing drug transport across the BBB was implemented to evaluate the influence of efflux transporters on the rate and extent of the multikinase inhibitor ponatinib penetration across the BBB. In vivo pharmacokinetic studies in wild-type and transporter knockout mice showed that two major BBB efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), cooperate to modulate the brain exposure of ponatinib. The total and unbound (free) brain-to-plasma ratios were approximately 15-fold higher in the triple knockout mice lacking both P-gp and Bcrp [Mdr1a/b(-/-)Bcrp1(-/-)] compared with the wild-type mice. The triple knockout mice had a greater than an additive increase in the brain exposure of ponatinib when compared with single knockout mice [Bcrp1(-/-) or Mdr1a/b(-/-)], suggesting functional compensation of transporter-mediated drug efflux. Based on the BBB model characterizing the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were approximately 15-fold higher in the wild-type compared with Mdr1a/b(-/-)Bcrp1(-/-) mice, resulting in a significant increase in the mean transit time (the average time spent by ponatinib in the brain in a single passage) in the absence of efflux transporters (P-gp and Bcrp). This study characterized transporter-mediated drug efflux from the brain, a process that reduces the duration and extent of ponatinib exposure in the brain and has critical implications for the use of targeted drug delivery for brain tumors.

Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data.

The blood-brain barrier (BBB) excludes the vast majority of cancer therapeutics from normal brain. However, the importance of the BBB in limiting drug delivery and efficacy is controversial in high-grade brain tumors, such as glioblastoma (GBM). The accumulation of normally brain impenetrant radiographic contrast material in essentially all GBM has popularized a belief that the BBB is uniformly disrupted in all GBM patients so that consideration of drug distribution across the BBB is not relevant in designing therapies for GBM. However, contrary to this view, overwhelming clinical evidence demonstrates that there is also a clinically significant tumor burden with an intact BBB in all GBM, and there is little doubt that drugs with poor BBB permeability do not provide therapeutically effective drug exposures to this fraction of tumor cells. This review provides an overview of the clinical literature to support a central hypothesis: that all GBM patients have tumor regions with an intact BBB, and cure for GBM will only be possible if these regions of tumor are adequately treated.

Design and characterization of an economical (192)Ir hemi-brain small animal irradiator.

PURPOSE: To describe the design and dosimetric characterization of a simple and economical small animal irradiator. MATERIALS AND METHODS: A high dose rate (HDR) (192)Ir brachytherapy source from a commercially available afterloader was used with a 1.3 cm thick tungsten collimator to provide sharp beam penumbra suitable for hemi-brain irradiation of mice. The unit was equipped with continuous gas anesthesia to allow robust animal immobilization. Dosimetric characterization of the device was performed with Gafchromic film measurements. RESULTS: The tungsten collimator provided a sharp penumbra suitable for hemi-brain irradiation, and dose rates on the order of 200 cGy/minute were achieved. The sharpness of the penumbra attainable with this device compares favorably to those measured experimentally for 6 MV photons, and 6 and 20 MeV electron beams from a linear accelerator, and was comparable to those measured for a 300 kVp orthovoltage beam and a Monte Carlo simulated 90 MeV proton beam. CONCLUSIONS: Due to its simplicity and low cost, the apparatus described is an attractive alternative for small animal irradiation experiments requiring steep dose gradients.