Evaluation of a new hybrid VMAT-IMRT multi-criteria optimization plan generation algorithm.

To evaluate the Varian 'Fast hybrid multi-criteria optimization (MCO) volumetric modulated arc therapy (VMAT)' (H-VMAT) tool for both its dosimetric accuracy and calculation time. This is a new function within V15.6 of the Varian Eclipse treatment planning system that allows VMAT optimization and dose calculation using the graphical processing unit (GPU). In versions prior to V15.6 VMAT MCO calculations were only possible using central processing unit (CPU) not GPU. We termed this approach as native VMAT (N-VMAT). The study consisted of a cohort of 53 patients representing a range of anatomical treatment sites; bladder (5), brain (6), gynaecological (5), head & neck (5), lung (7), mediastinum (7) prostate (6), oesophagus (7), and rectum (5). Each case was planned to that of a clinical standard (Base) which was compared to a H-VMAT and N-VMAT approach. The study analyzed plan calculation time data, dose to organ at risk (OAR) and target coverage for each approach. Negligible dosimetric differences were found between the H-VMAT and N-VMAT approach for the cohort of patients evaluated. The largest dosimetric changes where observed in the optic chiasm and lacrimal gland where the H-VMAT achieved a max dose of 50.9 ± 7.7 Gy and 8.0 ± 0.5 Gy in comparison to the N-VMAT 53.1 ± 6.3 Gy and 10.2 ± 2.9 Gy, respectively. Several OAR's provided indistinguishable dose outcomes, namely; brainstem, heart, kidney's, lens, parotid, and spinal cord. Large time savings were found using the H-VMAT technique when compared to N-VMAT, being 5 to 40 times faster or up to 75 minutes time saving (average of 25 minutes). Negligible dosimetric change between the 2 techniques and large time savings were observed with the GPU enabled H-VMAT approach. We have shown that the H-VMAT technique has been safely implemented and is ready for clinical use.

Acute laminar shear stress reversibly increases human glomerular endothelial cell permeability via activation of endothelial nitric oxide synthase.

Laminar shear stress is a key determinant of systemic vascular behavior, including through activation of endothelial nitric oxide synthase (eNOS), but little is known of its role in the glomerulus. We confirmed eNOS expression by glomerular endothelial cells (GEnC) in tissue sections and examined effects of acute exposure (up to 24 h) to physiologically relevant levels of laminar shear stress (10-20 dyn/cm(2)) in conditionally immortalized human GEnC. Laminar shear stress caused an orientation of GEnC and stress fibers parallel to the direction of flow and induced Akt and eNOS phosphorylation along with NO production. Inhibition of the phophatidylinositol (PI)3-kinase/Akt pathway attenuated laminar shear stress-induced eNOS phosphorylation and NO production. Laminar shear stress of 10 dyn/cm(2) had a dramatic effect on GEnC permeability, reversibly decreasing the electrical resistance across GEnC monolayers. Finally, the laminar shear stress-induced reduction in electrical resistance was attenuated by the NOS inhibitors l-N(G)-monomethyl arginine (l-NMMA) and l-N(G)-nitroarginine methyl ester (l-NAME) and also by inhibition of the PI3-kinase/Akt pathway. Hence we have shown for GEnC in vitro that acute permeability responses to laminar shear stress are dependent on NO, produced via activation of the PI3-kinase/Akt pathway and increased eNOS phosphorylation. These results suggest the importance of laminar shear stress and NO in regulating the contribution of GEnC to the permeability properties of the glomerular capillary wall.