Aaron Fenster

Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans

The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.

A review of electronic portal imaging devices (EPIDs)

On-line electronic portal imaging devices are beginning to come into clinical service in support of radiotherapy. A variety of technologies are being explored to provide real-time or near real-time images of patient anatomy within x-ray fields during treatment on linear accelerators. The availability of these devices makes it feasible to verify treatment portals with much greater frequency and clarity than with film. This article reviews the physics of high-energy imaging and describes the operation principles of the electronic portal imaging devices that are under development or are beginning to be used clinically.

Poly(vinyl alcohol) cryogel phantoms for use in ultrasound and MR imaging.

Poly(vinyl alcohol) cryogel, PVA-C, is presented as a tissue-mimicking material, suitable for application in magnetic resonance (MR) imaging and ultrasound imaging. A 10% by weight poly(vinyl alcohol) in water solution was used to form PVA-C, which is solidified through a freeze-thaw process. The number of freeze-thaw cycles affects the properties of the material. The ultrasound and MR imaging characteristics were investigated using cylindrical samples of PVA-C. The speed of sound was found to range from 1520 to 1540 m s(-1), and the attenuation coefficients were in the range of 0.075-0.28 dB (cm MHz)(-1). T1 and T2 relaxation values were found to be 718-1034 ms and 108-175 ms, respectively. We also present applications of this material in an anthropomorphic brain phantom, a multi-volume stenosed vessel phantom and breast biopsy phantoms. Some suggestions are made for how best to handle this material in the phantom design and development process.

Intraoperative ultrasound for guidance and tissue shift correction in image-guided neurosurgery

We present a surgical guidance system that incorporates pre-operative image information (e.g., MRI) with intraoperative ultrasound (US) imaging to detect and correct for brain tissue deformation during image-guided neurosurgery (IGNS). Many interactive IGNS implementations employ pre-operative images as a guide to the surgeons throughout the procedure. However, when a craniotomy is involved, tissue movement during a procedure can be a significant source of error in these systems. By incorporating intraoperative US imaging, the target volume can be scanned at any time, and two-dimensional US images may be compared directly to the corresponding slice from the pre-operative image. Homologous points may be mapped from the intraoperative to the pre-operative image space with an accuracy of better than 2 mm, enabling the surgeon to use this information to assess the accuracy of the guidance system along with the progress of the procedure (e.g., extent of lesion removal) at any time during the operation. Anatomical features may be identified on both the pre-operative and intraoperative images and used to generate a deformation map, which can be used to warp the pre-operative image to match the intraoperative US image. System validation is achieved using a deformable multi-modality imaging phantom, and preliminary clinical results are presented.

Prostate boundary segmentation from 2D ultrasound images

Outlining, or segmenting, the prostate is a very important task in the assignment of appropriate therapy and dose for cancer treatment; however, manual outlining is tedious and time-consuming. In this paper, an algorithm is described for semiautomatic segmentation of the prostate from 2D ultrasound images. The algorithm uses model-based initialization and the efficient discrete dynamic contour. Initialization requires the user to select only four points from which the outline of the prostate is estimated using cubic interpolation functions and shape information. The estimated contour is then deformed automatically to better fit the image. The algorithm can easily segment a wide range of prostate images, and contour editing tools are included to handle more difficult cases. The performance of the algorithm with a single user was compared to manual outlining by a single expert observer. The average distance between semiautomatically and manually outlined boundaries was found to be less than 5 pixels (0.63 mm), and the accuracy and sensitivity to area measurements were both over 90%.

3D Ultrasound Measurement of Change in Carotid Plaque Volume A Tool for Rapid Evaluation of New Therapies

Background and Purpose— New therapies are being developed that are antiatherosclerotic but that lack intermediate end points, such as changes in plasma lipids, which can be measured to test efficacy. To study such treatments, it will be necessary to directly measure changes in atherosclerosis. The study was designed to determine sample sizes needed to detect effects of treatment using 3D ultrasound (US) measurement of carotid plaque. Methods— In 38 patients with carotid stenosis >60%, age±SD 69.42±7.87 years, 15 female, randomly assigned in a double-blind fashion to 80 mg atorvastatin daily (n=17) versus placebo (n=21), we measured 3D plaque volume at baseline and after 3 months by disc segmentation of voxels representing carotid artery plaque, after 3D reconstruction of parallel transverse duplex US scans into volumetric 3D data sets. Results— There were no significant differences in baseline risk factors. The rate of progression was 16.81±74.10 mm3 in patients taking placebo versus regression of −90.25±85.12 mm3 in patients taking atorvastatin (P<0.0001) Conclusions— 3D plaque volume measurement can show large effects of therapy on atherosclerosis in 3 months in sample sizes of ≈20 patients per group. Sample sizes of 22 per group would be sufficient to show an effect size of 25% that of atorvastatin in 6 months. This technology promises to be very useful in evaluation of new therapies.

A wall-less vessel phantom for Doppler ultrasound studies

Doppler ultrasound flow measurement techniques are often validated using phantoms that simulate the vasculature, surrounding tissue and blood. Many researchers use rubber tubing to mimic blood vessels because of the realistic acoustic impedance, robust physical properties and wide range of available sizes. However, rubber tubing has a very high acoustic attenuation, which may introduce artefacts into the Doppler measurements. We describe the construction of a wall-less vessel phantom that eliminates the highly attenuating wall and reduces impedance mismatches between the vessel lumen and tissue mimic. An agar-based tissue mimic and a blood mimic are described and their acoustic attenuation coefficients and velocities are characterised. The high attenuation of the latex rubber tubing resulted in pronounced shadowing in B-mode images; however, an image of a wall-less vessel phantom did not show any shadowing. We show that the effects of the highly attenuating latex rubber vessels on Doppler amplitude spectra depend on the vessel diameter and ultrasound beam width. In this study, only small differences were observed in spectra obtained from 0.6 cm inside diameter thin-wall latex, thick-wall latex and wall-less vessel phantoms. However, a computer model predicted that the spectrum obtained from a 0.3-cm inside diameter latex-wall vessel would be significantly different than the spectrum obtained from a wall-less vessel phantom, thus resulting in an overestimation of the average fluid velocity. These results suggest that care must be taken to ensure that the Doppler measurements are not distorted by the highly attenuating wall material. In addition, the results show that a wall-less vessel phantom is preferable when measuring flow in small vessels.

Three-dimensional imaging system

A three-dimensional ultrasound imaging system includes an ultrasound probe to direct ultrasound waves to and to receive reflected ultrasound waves from a target volume of a subject under examination. The ultrasound probe is swept over the target volume along a linear scanning path and the reflected ultrasound waves are conveyed to a computer wherein successive two-dimensional images of the target volume are digitized. The digitized two-dimensional images can be used to generate a three-dimensional image with virtually no delay. A user interface allows a user to manipulate the displayed image. Specifically, the entire displayed image may be rotated about an arbitrary axis, a surface of the displayed image may be translated to provide different cross-sectional views of the image and a selected surface of the displayed image may be rotated about an arbitrary axis. All of these manipulations can be achieved via a single graphical input device such as a mouse connected to the computer.

Image Guided Photothermal Focal Therapy for Localized Prostate Cancer: Phase I Trial

PURPOSE We ascertained the feasibility and safety of image guided targeted photothermal focal therapy for localized prostate cancer. MATERIALS AND METHODS Twelve patients with biopsy proven low risk prostate cancer underwent interstitial photothermal ablation of the cancer. The area of interest was confirmed and targeted using magnetic resonance imaging. Three-dimensional ultrasound was used to guide a laser to the magnetic resonance to ultrasound fused area of interest. Target ablation was monitored using thermal sensors and real-time Definity contrast enhanced ultrasound. Followup was performed with a combination of magnetic resonance imaging and prostate biopsy. Validated quality of life questionnaires were used to assess the effect on voiding symptoms and erectile function, and adverse events were solicited and recorded. RESULTS Interstitial photothermal focal therapy was technically feasible to perform. Of the patients 75% were discharged home free from catheter the same day with the remainder discharged home the following day. The treatment created an identifiable hypovascular defect which coincided with the targeted prostatic lesion. There were no perioperative complications and minimal morbidity. All patients who were potent before the procedure maintained potency after the procedure. Continence levels were not compromised. Based on multicore total prostate biopsy at 6 months 67% of patients were free of tumor in the targeted area and 50% were free of disease. CONCLUSIONS Image guided focal photothermal ablation of low risk and low volume prostate cancer is feasible. Early clinical, histological and magnetic resonance imaging responses suggest that the targeted region can be ablated with minimal adverse effects. It may represent an alternate treatment approach to observation or delayed standard therapy in carefully selected patients. Further trials are required to demonstrate the effectiveness of this treatment concept.

X‐ray sources of medical linear accelerators: Focal and extra‐focal radiation

A computerized tomography (CT) reconstruction technique has been used to make quantitative measurements of the size and shape of the focal spot in medical linear accelerators. Using this technique, we have measured the focal spots in a total of nine accelerators, including (i) two Varian Clinac 2100cs, (ii) two Atomic Energy of Canada Ltd. (AECL) Therac-25s, (iii) two AECL Therac 6s, (iv) a Siemens KD-2, (v) a Varian Clinac 600c (4 MV), and (vi) an AECL Therac-20. Some of these focal spots were monitored for changes over a 2-yr period. It has been found that (i) the size and shape of the source spot varies greatly between accelerators of different design ranging from 0.5 to 3.4 mm in full width at half maximum (FWHM); and (ii) for accelerators of the same design, the focal spots are very similar. In addition to the measurements of the focal spot, a new technique for measuring the magnitude and distribution of extra-focal radiation originating from the linear accelerator head (flattening filter, primary collimator) has also been developed. The extra-focal radiation produced by a Varian Clinac 2100c accelerator was measured using this technique and it was found that the extra-focal radiation accounts for as much as 8% of the total photon fluence reaching the isocenter. The majority (75%) of this extra-focal radiation originates from within a circle 6 cm in diameter at the target plane. The source MTFs for each of the measured focal spots have been calculated in order to assess their influence on the spatial resolution of verification images. The limiting spatial resolution (i.e., 10% modulation) for all the source MTFs is 1.8 mm-1 or greater when used for transmission radiography at a magnification of 1.2. The extra-focal radiation, which produces a low-frequency drop in the source MTFs of up to 8%, changes with field size. As a result, the source MTFs of linear accelerators depend not only on the design of individual accelerators and image magnification, but also on the field size used when forming an image.