Radio-sensitizing effect of MEK inhibition in glioblastoma in vitro and in vivo.

INTRODUCTION: Glioblastoma (GBM) is an incurable cancer type. New therapeutic options are investigated, including targeting the mitogen-activated protein kinase (MAPK) pathway using MEK inhibitors as radio-sensitizers. In this study, we investigated whether MEK inhibition via PD0325901 leads to radio-sensitization in experimental in vitro and in vivo models of GBM. MATERIALS AND METHODS: In vitro, GBM8 multicellular spheroids were irradiated with 3 fractions of 2 Gy, during 5 consecutive days of incubation with either PD0325901 or MEK-162. In vivo, we combined PD0325901 with radiotherapy in the GBM8 orthotopic mouse model, tumor growth was measured weekly by bioluminescence imaging and overall survival and toxicity were assessed. RESULTS: Regrowth and viability of spheroids monitored until day 18, showed that both MEK inhibitors had an in vitro radio-sensitizing effect. In vivo, PD0325901 concentrations were relatively constant throughout multiple brain areas and temporal PD0325901-related adverse events such as dermatitis were observed in 4 out of 14 mice (29%). Mice that were treated with radiation alone or combined with PD0325901 had significantly better survival compared to vehicle (both P < 0.005), however, no significant interaction between PD0325901 MEK inhibition and irradiation was observed. CONCLUSION: The difference between the radiotherapy-enhancing effect of PD0325901 in vitro and in vivo urges further pharmacodynamic/pharmacokinetic investigation of PD0325901 and possibly other candidate MEK inhibitors.

Free-running cardiac magnetic resonance fingerprinting: Joint T1/T2 map and Cine imaging.

PURPOSE: To develop and evaluate a novel non-ECG triggered 2D magnetic resonance fingerprinting (MRF) sequence allowing for simultaneous myocardial T1 and T2 mapping and cardiac Cine imaging. METHODS: Cardiac MRF (cMRF) has been recently proposed to provide joint T1/T2 myocardial mapping by triggering the acquisition to mid-diastole and relying on a subject-dependent dictionary of MR signal evolutions to generate the maps. In this work, we propose a novel "free-running" (non-ECG triggered) cMRF framework for simultaneous myocardial T1 and T2 mapping and cardiac Cine imaging in a single scan. Free-running cMRF is based on a transient state bSSFP acquisition with tiny golden angle radial readouts, varying flip angle and multiple adiabatic inversion pulses. The acquired data is retrospectively gated into several cardiac phases, which are reconstructed with an approach that combines parallel imaging, low rank modelling and patch-based high-order tensor regularization. Free-running cMRF was evaluated in a standardized phantom and ten healthy subjects. Comparison with reference spin-echo, MOLLI, SASHA, T2-GRASE and Cine was performed. RESULTS: T1 and T2 values obtained with the proposed approach were in good agreement with reference phantom values (ICC(A,1) > 0.99). Reported values for myocardium septum T1 were 1043 ± 48 ms, 1150 ± 100 ms and 1160 ± 79 ms for MOLLI, SASHA and free-running cMRF respectively and for T2 of 51.7 ± 4.1 ms and 44.6 ± 4.1 ms for T2-GRASE and free-running cMRF respectively. Good agreement was observed between free-running cMRF and conventional Cine 2D ejection fraction (bias = -0.83%). CONCLUSION: The proposed free-running cardiac MRF approach allows for simultaneous assessment of myocardial T1 and T2 and Cine imaging in a single scan.

Towards predicting the encoding capability of MR fingerprinting sequences.

Sequence optimization and appropriate sequence selection is still an unmet need in magnetic resonance fingerprinting (MRF). The main challenge in MRF sequence design is the lack of an appropriate measure of the sequence's encoding capability. To find such a measure, three different candidates for judging the encoding capability have been investigated: local and global dot-product-based measures judging dictionary entry similarity as well as a Monte Carlo method that evaluates the noise propagation properties of an MRF sequence. Consistency of these measures for different sequence lengths as well as the capability to predict actual sequence performance in both phantom and in vivo measurements was analyzed. While the dot-product-based measures yielded inconsistent results for different sequence lengths, the Monte Carlo method was in a good agreement with phantom experiments. In particular, the Monte Carlo method could accurately predict the performance of different flip angle patterns in actual measurements. The proposed Monte Carlo method provides an appropriate measure of MRF sequence encoding capability and may be used for sequence optimization.

Aperture weighted cardiac reconstruction for cone-beam CT.

Multi-row detectors together with fast rotating gantries made cardiac imaging possible for CT. Due to the cardiac motion, ECG gating has to be integrated into the reconstruction of the data measured on a low pitch helical trajectory. Since the first multi-row scanners were introduced, it has been shown that approximative true cone-beam reconstruction methods are most suitable for the task of retrospectively gated cardiac volume CT. In this paper, we present the aperture weighted cardiac reconstruction (AWCR), which is a three-dimensional reconstruction algorithm of the filtered back-projection type. It is capable of handling all illumination intervals of an object point, which occur as a consequence of a low pitch helical cone-beam acquisition. Therefore, this method is able to use as much redundant data as possible, resulting in an improvement of the image homogeneity, the signal to noise ratio and the temporal resolution. Different optimization techniques like the heart rate adaptive cardiac weighting or the automatic phase determination can be adopted to AWCR. The excellent image quality achieved by AWCR is presented for medical datasets acquired with both a 40-slice and a 64-slice cone-beam CT scanner.

Helical cardiac cone beam CT reconstruction with large area detectors: a simulation study.

Retrospectively gated cardiac volume CT imaging has become feasible with the introduction of heart rate adaptive cardiac CT reconstruction algorithms. The development in detector technology and the rapid introduction of multi-row detectors has demanded reconstruction schemes which account for the cone geometry. With the extended cardiac reconstruction (ECR) framework, the idea of approximate helical cone beam CT has been extended to be used with retrospective gating, enabling heart rate adaptive cardiac cone beam reconstruction. In this contribution, the ECR technique is evaluated for systems with an increased number of detector rows, which leads to larger cone angles. A simulation study has been carried out based on a 4D cardiac phantom consisting of a thorax model and a dynamic heart insert. Images have been reconstructed for different detector set-ups. Reconstruction assessment functions have been calculated for the detector set-ups employing different rotation times, relative pitches and heart rates. With the increased volume coverage of large area detector systems, low-pitch scans become feasible without resulting in extensive scan times, inhibiting single breath hold acquisitions. ECR delivers promising image results when being applied to systems with larger cone angles.

Helical cardiac cone beam reconstruction using retrospective ECG gating.

In modern computer tomography (CT) systems, the fast rotating gantry and the increased detector width enable 3D imaging of the heart. Cardiac volume CT has a high potential for non-invasive coronary angiography with high spatial resolution and short scan time. Due to the increased detector width, true cone beam reconstruction methods are needed instead of adapted 2D reconstruction schemes. In this paper, the extended cardiac reconstruction method is introduced. It integrates the idea of retrospectively gated cardiac reconstruction for helical data acquisition into a cone beam reconstruction framework. It leads to an efficient and flexible algorithmic scheme for the reconstruction of single- and multi-phase cardiac volume datasets. The method automatically adapts the number of cardiac cycles used for the reconstruction. The cone beam geometry is fully taken into account during the reconstruction process. Within this paper, results are presented on patient datasets which have been acquired using a 16-slice cone beam CT system.

Direct comparison of 3D spiral vs. Cartesian gradient-echo coronary magnetic resonance angiography.

While 3D thin-slab coronary magnetic resonance angiography (MRA) has traditionally been performed using a Cartesian acquisition scheme, spiral k-space data acquisition offers several potential advantages. However, these strategies have not been directly compared in the same subjects using similar methodologies. Thus, in the present study a comparison was made between 3D coronary MRA using Cartesian segmented k-space gradient-echo and spiral k-space data acquisition schemes. In both approaches the same spatial resolution was used and data were acquired during free breathing using navigator gating and prospective slice tracking. Magnetization preparation (T(2) preparation and fat suppression) was applied to increase the contrast. For spiral imaging two different examinations were performed, using one or two spiral interleaves, during each R-R interval. Spiral acquisitions were found to be superior to the Cartesian scheme with respect to the signal-to-noise ratio (SNR) and contrast-to-noise-ratio (CNR) (both P < 0.001) and image quality. The single spiral per R-R interval acquisition had the same total scan duration as the Cartesian acquisition, but the single spiral had the best image quality and a 2.6-fold increase in SNR. The double-interleaf spiral approach showed a 50% reduction in scanning time, a 1.8-fold increase in SNR, and similar image quality when compared to the standard Cartesian approach. Spiral 3D coronary MRA appears to be preferable to the Cartesian scheme. The increase in SNR may be "traded" for either shorter scanning times using multiple consecutive spiral interleaves, or for enhanced spatial resolution.

Impact of simple tissue inhomogeneity correction algorithms on conformal radiotherapy of lung tumours.

BACKGROUND AND PURPOSE: Conformal radiotherapy requires accurate dose calculation at the dose specification point, at other points in the planning target volume (PTV) and in organs at risk. To assess the limitations of treatment planning of lung tumours, errors in dose values, calculated by some simple tissue inhomogeneity correction algorithms available in a number of currently applied treatment planning systems, have been quantified. MATERIALS AND METHODS: Single multileaf collimator-shaped photon beams of 6, 8, 15 and 18 MV nominal energy were used to irradiate a 50 mm diameter spherical solid tumour, simulated by polystyrene, which was located centrally inside lung tissue, simulated by cork. The planned dose distribution was made conformal to the PTV, which was a 15 mm three-dimensional expansion of the tumour. Values of both the absolute dose at the International Commission on Radiation Units and Measurement (ICRU) reference point and relative dose distributions inside the PTV and in the lung were calculated using three inhomogeneity correction algorithms. The algorithms investigated in this study are the pencil beam algorithm with one-dimensional corrections, the modified Batho algorithm and the equivalent path length algorithm. The calculated data were compared with measurements for a simple beam set-up using radiographic film and ionization chambers. RESULTS: For this specific configuration, deviations of up to 3.5% between calculated and measured values of the dose at the ICRU reference point were found. Discrepancies between measured and calculated beam fringe values (distance between the 50 and 90% isodose lines) of up to 14 mm have been observed. The differences in beam fringe and penumbra width (20-80%) increase with increasing beam energy. Our results demonstrate that an underdosage of the PTV up to 20% may occur if calculated dose values are used for treatment planning. The three algorithms predict a considerably higher dose in the lung, both along the central beam axis and in the lateral direction, compared with the actual delivered dose values. CONCLUSIONS: The dose at the ICRU reference point of such a tumour in lung geometry is calculated with acceptable accuracy. Differences between calculated and measured dose distributions are primarily due to changes in electron transport in the lung, which are not adequately taken into account by the simple tissue inhomogeneity correction algorithms investigated in this study. Particularly for high photon beam energies, clinically unacceptable errors will be introduced in the choice of field sizes employed for conformal treatments, leading to underdosage of the PTV. In addition, the dose to the lung will be wrongly predicted which may influence the choice of the prescribed dose level in dose-escalation studies.

A straightforward implantation method of radioactive sources by means of the Leksell frame.

Stereotactic brachytherapy of cerebral gliomas often involves insertion of catheters through the tumor bed. We adopted the hexagonal tube configuration around a central tube. Such a configuration is applicable to most commonly occurring brain tumors. In order to perform a low-cost, accurate and straightforward implantation, a robust mathematical derivation of all relevant formulas is used to transform CT coordinates to Leksell frame coordinates, including derivations for the two stereotactic angles. The coordinates of the seven tubes (which are essential if no template is available) and the length of the radioactive source are also derived, and an example is presented. The calculations have been implemented on a personal computer (Intel processor 386 or higher). Additional options, such as choosing other stereotactic angles than the calculated ones and rotating the tube configuration around the central tube, are integrated into the program.

Simultaneous hand tracking does not affect human vergence pursuit.

In order to find out whether human vergence eye movements are influenced by simultaneous hand tracking movements, vergence was studied when sinusoidal (expressed in vergence angles) target movements were tracked. The target motion was externally generated and the target actually moved in depth. Tracking was done by the eyes alone or by the eyes and hand together, in both light and dark viewing conditions. Our data show that the target motion was tracked by the eyes with a short delay (on average 48 ms), independent of the tracking condition. This suggests that vergence modeling should include some predictive mechanism similar to that proposed for the smooth pursuit subsystem. Furthermore, in contrast to effects on smooth pursuit, simultaneous hand tracking movements did not influence vergence eye movements. From this, we argue that the balance between smooth pursuit and saccadic eye movements is adjustable and can be adapted to the requirements of different tasks.

Influences of hand movements on eye movements in tracking tasks in man.

We investigated horizontal smooth pursuit eye movements and hand movements in tracking tasks in order to find out whether hand movements influence eye movements and if so, in what ways. Externally controlled target movements were tracked either by the eyes alone or by the eyes and right hand together. Because a possible influence might depend on the stimulus, we used two classes of target movements: sinusoidal target movements (predictable target movements) and pseudo-random target movements (unpredictable target movements). Our data show that the eye movements contained only a few small saccades when sinusoidal target movements with frequencies higher than about 1 Hz were tracked by eyes and hand together. More and larger saccades were made when the same target movements were tracked by the eyes alone. The difference in smoothness of eye movements was highly significant between the two tracking conditions. Such a difference was not found during the tracking of a pseudo-random target motion. This suggests that the influence of hand movements is related to the predictability of the stimulus. In contrast to the gain of the smooth pursuit eye movements and the maximum of the cross-correlation function, the gain of the composite eye movements did not depend on the tracking condition. The delay of the eye movements with respect to the (sinusoidal) target movements also showed no dependence on the tracking condition. Visual feedback from the tracking hand was found not to play a role in the difference in eye movements for the two tracking conditions.

Quantitative fluorodensitometric determination and survey of aflatoxins in nutmeg.

A study is presented for the quantitative fluorodensitometric analysis of aflatoxins in spices, in particular nutmeg (Semen myristicae). Samples were extracted with chloroform, followed by silica gel column cleanup according to the AOAC officail first action method, 26.019(a), and by 2-dimensional thin layer chromatography according to the antidiagonal technique. The method includes a confirmatory test for aflatoxins by hemiacetal formation. The concentrations of aflatoxins in samples were determined by measurement of the fluorescent intensities of the separated aflatoxin spots from sample and standards on the same chromato-plate with a reflectance flying-spot sensitometer. With such a technique, a coefficient of variation value of 5.22 plus or minus 1.24% (P = 99%) was calculated for a series of 5 standard B-1 spots and averaged for 13 TLC plates, demonstrating the precision of the chromatographic and densitometric procedures. An average recovery of 108.4 plus or minus 5.8% (P = 95%) was obtained for 11 spiked nutmeg extracts (5.0-20.0 mu-g B-1 added/kg), whereas an average recovery of 92.6 plus or minus 4.9 (P = 95%) was established for 13 spiked nutmeg samples (5.0-20.0 mu-g B-1 added/kg). The coefficient of variation of the complete analytical procedure for ground nutmeg was 8.80%. In a survey on the occurrence of aflatoxins in 40 commercial nutmeg samples (covering 12 different brands) in The Netherlands, aflatoxins were detected in 30 ground samples (32 ground samples analyzed) in concentrations ranging from 1.0 to 23.2 mu-g B-1/kg or 2.7 to 36.5 mu-g B-1 + B-2 + G-1 + G-2/kg, whereas no aflatoxins were present in whole nutmeg kernels (8 samples analyzed). The lowest level of detection was 1.0 mu-g B-1/kg. In addition, 50 commercial spices consisting of 19 different types of commodities other than nutmeg wer assayed for aflatoxins according to the same procedure. No aflatoxins were detected in these samples, with the exception of 1 sample of bay leaf which contained 5.1 mu-g B-1/kg.