Background Volumetric modulated arc therapy (VMAT) has been shown feasible for radiosurgical treatment of multiple cranial lesions with a single isocenter. Objective To investigate whether equivalent radiosurgical plan quality and reduced delivery time could be achieved in VMAT for patients with multiple intracranial targets previously treated with Gamma Knife (GK) radiosurgery. Methods We identified 28 Gamma Knife treatments of multiple metastases. These were replanned for multi-arc (MA) and single-arc (SA), single-isocenter VMAT (RapidArc) in Eclipse. The prescription for all targets was standardized to 18 Gy. Each plan was normalized for 100% prescription dose to 99–100% of target volume. Plan quality was analyzed by target conformity (RTOG, Paddick CI), dose fall-off (area under DVH curve), as well as the V4.5, V9, V12, and V18 isodose volumes. Other endpoints included beam-on and treatment time. Results Compared to Gamma Knife, multi-arc VMAT improved median plan conformity (CIVMAT = 1.14, CIGK = 1.65; p<0.001) with no significant difference in median dose fall-off (p=0.269), 12Gy isodose volume (p=0.500), or low isodose spill (p=0.49). Multi-arc VMAT plans were associated with markedly reduced treatment time. A predictive model of the 12Gy isodose volume as a function of tumor number and volume was also developed. Conclusion For multiple target SRS, 4-arc VMAT produced clinically equivalent conformity, dose fall-off, 12 Gy isodose volume, and low isodose spill, and reduced treatment time compared to GK. Due to its similar plan quality and increased delivery efficiency, single-isocenter VMAT radiosurgery may constitute an attractive alternative to multi-isocenter radiosurgery for some patients.

The mechanical property of extracellular matrix and cell-supporting substrates is known to modulate neuronal growth, differentiation, extension and branching. Here we show that substrate stiffness is an important microenvironmental cue, to which mouse hippocampal neurons respond and integrate into synapse formation and transmission in cultured neuronal network. Hippocampal neurons were cultured on polydimethylsiloxane substrates fabricated to have similar surface properties but a 10-fold difference in Young's modulus. Voltage-gated Ca2+ channel currents determined by patch-clamp recording were greater in neurons on stiff substrates than on soft substrates. Ca2+ oscillations in cultured neuronal network monitored using time-lapse single cell imaging increased in both amplitude and frequency among neurons on stiff substrates. Consistently, synaptic connectivity recorded by paired recording was enhanced between neurons on stiff substrates. Furthermore, spontaneous excitatory postsynaptic activity became greater and more frequent in neurons on stiff substrates. Evoked excitatory transmitter release and excitatory postsynaptic currents also were heightened at synapses between neurons on stiff substrates. Taken together, our results provide compelling evidence to show that substrate stiffness is an important biophysical factor modulating synapse connectivity and transmission in cultured hippocampal neuronal network. Such information is useful in designing instructive scaffolds or supporting substrates for neural tissue engineering.

We have implemented a three-dimensional dose calculation technique accounting for dose inhomogeneity within the liver and tumor of a patient treated with 90Y microspheres. Single-photon emission computed tomography (SPECT) images were used to derive the activity distribution within liver. A Monte Carlo calculation was performed to create a voxel dose kernel for the 90Y source. The activity distribution was convolved with the voxel dose kernel to obtain the three-dimensional (3D) radiation absorbed dose distribution. An automated technique was developed to accurately register the computed tomography (CT) and SPECT scans in order to display the 3D dose distribution on the CT scans. In addition, dose-volume histograms were generated to fully analyze the tumor and liver doses. The calculated dose-volume histogram indicated that although the patient was treated to the nominal whole liver dose of 110 Gy, only 16% of the liver and 83% of the tumor received a dose higher than 110 Gy. The mean tumor and liver doses were 163 and 58 Gy, respectively.

We propose a new method for selecting importance factors (for regions of interest like organs at risk) used to plan conformal radiotherapy. Importance factors, also known as weighting factors or penalty factors, are essential in determining the relative importance of multiple objectives or the penalty ratios of constraints incorporated into cost functions, especially in dealing with dose optimization in radiotherapy treatment planning. Researchers usually choose importance factors on the basis of a trial-and-error process to reach a balance between all the objectives. In this study, we used a genetic algorithm and adopted a real-number encoding method to represent both beam weights and importance factors in each chromosome. The algorithm starts by optimizing the beam weights for a fixed number of iterations then modifying the importance factors for another fixed number of iterations. During the first phase, the genetic operators, such as crossover and mutation, are carried out only on beam weights, and importance factors for each chromosome are not changed or 'frozen'. In the second phase, the situation is reversed: the beam weights are 'frozen' and the importance factors are changed after crossover and mutation. Through alternation of these two phases, both beam weights and importance factors are adjusted according to a fitness function that describes the conformity of dose distribution in planning target volume and dose-tolerance constraints in organs at risk. Those chromosomes with better fitness are passed into the next generation, showing that they have a better combination of beam weights and importance factors. Although the ranges of the importance factors should be set in advance by using this algorithm, it is much more convenient than selecting specific numbers for importance factors. Three clinical examples are presented and compared with manual plans to verify this method. Three-dimensional standard displays and dose-volume histograms are shown to demonstrate that this method is feasible, automatic and convenient.

Purpose To evaluate the accuracy of monitoring intrafraction motion during stereotactic radiotherapy with the optical surface monitoring system. Prior studies showing a false increase in the magnitude of translational offsets at non‐coplanar couch positions prompted the vendor to implement software changes. This study evaluated two software improvements intended to address false offsets. Methods The vendor implemented two software improvements: a volumetric (ACO) rather than planar calibration and, approximately 6 months later, an improved calibration workflow (CIB) designed to better compensate for thermal drift. Offsets relative to the reference position, obtained at table angle 0 following image‐guided setup, were recorded before beam‐on at each table position and at the end of treatment the table returned to 0° for patients receiving SRT. Results Prior to ACO, between ACO and CIB, and after CIB, 223, 155, and 436 fractions were observed respectively. The median magnitude of translational offsets at the end of treatment was similar for all three intervals: 0.29, 0.33, and 0.27 mm. Prior to ACO, the offset magnitude for non‐zero table positions had a median of 0.79 mm and was found to increase with increasing distance from isocenter to the anterior patient surface. After ACO, the median magnitude was 0.74 mm, but the dependence on surface‐to‐isocenter distance was eliminated. After CIB, the median magnitude for non‐zero table positions was reduced to 0.57 mm. Conclusion Ongoing improvements in software and calibration procedures have decreased reporting of false offsets at non‐zero table angles. However, the median magnitude for non‐zero table angles is larger than that observed at the end of treatment, indicating that accuracy remains better when the table is not rotated.

Repolarization and termination of the ventricular cardiac action potential is highly dependent on the activation of the slow delayed-rectifier potassium IKs channel. Disruption of the IKs current leads to the most common form of congenital long QT syndrome (LQTS), a disease that predisposes patients to ventricular arrhythmias and sudden cardiac death. We previously demonstrated that polyunsaturated fatty acid (PUFA) analogues increase outward K+ current in wild type and LQTS-causing mutant IKs channels. Our group has also demonstrated the necessity of a negatively charged PUFA head group for potent activation of the IKs channel through electrostatic interactions with the voltage-sensing and pore domains. Here, we test whether the efficacy of the PUFAs can be tuned by the presence of different functional groups in the PUFA head, thereby altering the electrostatic interactions of the PUFA head group with the voltage sensor or the pore. We show that PUFA analogues with taurine and cysteic head groups produced the most potent activation of IKs channels, largely by shifting the voltage dependence of activation. In comparison, the effect on voltage dependence of PUFA analogues with glycine and aspartate head groups was half that of the taurine and cysteic head groups, whereas the effect on maximal conductance was similar. Increasing the number of potentially negatively charged moieties did not enhance the effects of the PUFA on the IKs channel. Our results show that one can tune the efficacy of PUFAs on IKs channels by altering the pKa of the PUFA head group. Different PUFAs with different efficacy on IKs channels could be developed into more personalized treatments for LQTS patients with a varying degree of IKs channel dysfunction.

PurposeThe study aimed to develop and demonstrate a standardized linear accelerator multileaf collimator-based method of delivering small, spherical dose distributions suitable for radiosurgical treatment of small targets such as the trigeminal nerve.Methods and materialsThe virtual cone is composed of a multileaf collimator–defined field with the central 2 leaves set to a small gap. For 5 table positions, clockwise and counter-clockwise arcs were used with collimator angles of 45 and 135 degrees, respectively. The dose per degree was proportional to the sine of the gantry angle. The dose distribution was calculated by the treatment planning system and measured using radiochromic film in a skull phantom for leaf gaps of 1.6, 2.1, and 2.6 mm. Cones with a diameter of 4 mm and 5 mm were measured for comparison. Output factor constancy was investigated using a parallel-plate chamber.ResultsThe mean ratio of the measured-to-calculated dose was 0.99, 1.03, and 1.05 for 1.6, 2.1, and 2.6 mm leaf gaps, respectively. The diameter of the measured (calculated) 50% isodose line was 4.9 (4.6) mm, 5.2 (5.1) mm, and 5.5 (5.5) mm for the 1.6, 2.1, and 2.6 mm leaf gap, respectively. The measured diameter of the 50% isodose line was 4.5 and 5.7 mm for the 4 mm and 5 mm cones, respectively. The standard deviation of the parallel-plate chamber signal relative to a 10 cm × 10 cm field was less than 0.4%. The relative signal changed 32% per millimeter change in leaf gap, indicating that the parallel-plate chamber is sensitive to changes in gap width.ConclusionsThe virtual cone is an efficient technique for treatment of small spherical targets. Patient-specific quality assurance measurements will not be necessary in routine clinical use. Integration directly into the treatment planning system will make planning using this technique extremely efficient.

Purpose To measure dosimetric and spatial accuracy of stereotactic radiosurgery (SRS) delivered to targets as small as the trigeminal nerve (TN) using a standard external beam treatment planning system (TPS) and multileaf collimator‐(MLC) equipped linear accelerator without cones or other special attachments or modifications. Methods Dosimetric performance was assessed by comparing computed dose distributions to film measurements. Comparisons included the γ‐index, beam profiles, isodose lines, maximum dose, and spatial accuracy. Initially, single static 360° arcs of MLC‐shaped fields ranging from 1.6 × 5 to 30 × 30 mm2 were planned and delivered to an in‐house built block phantom having approximate dimensions of a human head. The phantom was equipped with markings that allowed accurate setup using planar kV images. Couch walkout during multiple‐arc treatments was investigated by tracking a ball pointer, initially positioned at cone beam computed tomography (CBCT) isocenter, as the couch was rotated. Tracks were mapped with no load and a 90 kg stack of plastic plates simulating patient treatment. The dosimetric effect of walkout was assessed computationally by comparing test plans that corrected for walkout to plans that neglected walkout. The plans involved nine 160° arcs of 2.4 × 5 mm2 fields applied at six different couch angles. For end‐to‐end tests that included CT simulation, target contouring, planning, and delivery, a cylindrical phantom mimicking a 3 mm lesion was constructed and irradiated with the nine‐arc regimen. The phantom, lacking markings as setup aids was positioned under CBCT guidance by registering its surface and internal structures with CTs from simulation. Radiochromic film passing through the target center was inserted parallel to the coronal and the sagittal plane for assessment of spatial and dosimetric accuracy. Results In the single‐arc block phantom tests computed maximum doses of all field sizes agreed with measurements within 2.4 ± 2.0%. Profile widths at 50% maximum agreed within 0.2 mm. The largest targeting error was 0.33 mm. The γ‐index (3%, 1 mm) averaged over 10 experiments was >1 in only 1% of pixels for field sizes up to 10 × 10 mm2 and rose to 4.4% as field size increased to 20 × 20 mm2. Table walkout was not affected by load. Walkout shifted the target up to 0.6 mm from CBCT isocenter but, according to computations shifted the dose cloud of the nine‐arc plan by only 0.16 mm. Film measurements verified the small dosimetric effect of walkout, allowing walkout to be neglected during planning and treatment. In the end‐to‐end tests average and maximum targeting errors were 0.30 ± 0.10 and 0.43 mm, respectively. Gamma analysis of coronal and sagittal dose distributions based on a 3%/0.3 mm agreement remained <1 at all pixels. To date, more than 50 functional SRS treatments using MLC‐shaped static field arcs have been delivered. Conclusion Stereotactic radiosurgery (SRS) can be planned and delivered on a standard linac without cones or other modifications with better than...