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.

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.