Assessment of dual-energy computed tomography derived virtual monoenergetic imaging for target volume delineation of brain metastases.

BACKGROUND: Objective and subjective assessment of image quality of brain metastases on dual-energy computed tomography (DECT) virtual monoenergetic imaging (VMI) and its impact on target volume delineation. MATERIALS AND METHODS: 26 patients with 37 brain metastases receiving Magnetic Resonance Imaging (MRI) and DECT for stereotactic radiotherapy planning were included in this retrospective analysis. Lesion contrast (LC), contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) were assessed for reconstructed VMI at 63 keV and artificial 120 kV Computed Tomography (CT). Image contrast and demarcation of metastases between 120 kV CT, VMI and MRI were subjectively assessed. Brain metastases were delineated by four radiation oncologists on VMI with a fixed or free brain window and contours were compared to solely MRI-based delineation using the Dice similarity coefficient. RESULTS: LC, CNR and SNR were significantly higher in VMI than in 120 kV CT (p < 0.0001). Image contrast and lesion demarcation were significantly better on VMI compared to 120 kV CT (p < 0.0001). Mean gross tumor volume (GTV)/planning target volume (PTV) Dice similarity coefficients were 0.87/0.9 for metastases without imaging uncertainties (no artifacts, calcification or impaired visibility with MRI) but worse for metastases with imaging uncertainties (0.71/0.74). Target volumes delineated on VMI were around 5-10% smaller compared to MRI. CONCLUSION: Image quality of VMI is objectively and subjectively superior to conventional CT. VMI provides significant advantages in stereotactic radiotherapy planning with improved visibility of brain metastases and geometrically distortion-free representation of brain metastases. Beside a plausibility check of MRI-based target volume delineation, VMI might improve reliability and accuracy in target volume definition particularly in cases with imaging uncertainties with MRI.

MEK-inhibitor PD184352 enhances the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922: the role of cell type and drug-irradiation schedule.

Targeting MEK protein in cancer cells usually leads to acquired resistance to MEK inhibitors and activation of the prosurvival protein Akt. Since both MEK and Akt are clients of the Hsp90 chaperone system, the present study explores the responses of irradiated lung carcinoma A549 and glioblastoma SNB19 cell lines to combined MEK and Hsp90 inhibition. Unexpectedly, the MEK inhibitor PD184352 administered 24 h prior to irradiation, enhanced cell survival through upregulation of not only MEK and Erk1/2 but also of Akt. In contrast, PD184352 added 1 h before irradiation strongly reduced the expression of Erk and did not upregulate Akt in both cell lines. As a result, the MEK inhibitor increased the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in glioblastoma SNB19 cells. Possible reasons for the enhanced cell killing under this short-term pretreatment schedule may be a down-regulation of Erk during or directly after irradiation, increased DNA damage and/or a strong G2/M arrest 24 h after irradiation. In addition, an 1-h pretreatment with PD184352 and/or NVP-AUY922 under schedule II induced neither G1 arrest nor up-regulation of p-Akt in both cell lines as it did under schedule I. Yet, a long-term treatment with the MEK inhibitor alone caused a strong cytostatical effect. We conclude that the duration of drug pretreatment before irradiation plays a key role in the targeting of MEK in tumor cells. However, due to an aberrant activation of prosurvival proteins, the therapeutic window needs to be carefully defined, or a combination of inhibitors should be considered.