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Purpose: Target delineation using only CT information introduces large geometric uncertainties in radiotherapy for lung cancer. Therefore, a reduction of the delineation variability is needed. The impact of including a matched CT scan with 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and adaptation of the delineation protocol and software on target delineation in lung cancer was evaluated in an extensive multi-institutional setting and compared with the delineations using CT only., Methods and Materials: The study was separated into two phases. For the first phase, 11 radiation oncologists (observers) delineated the gross tumor volume (GTV), including the pathologic lymph nodes of 22 lung cancer patients (Stages I-IIIB) on CT only. For the second phase (1 year later), the same radiation oncologists delineated the GTV of the same 22 patients on a matched CT-FDG-PET scan using an adapted delineation protocol and software (according to the results of the first phase). All delineated volumes were analyzed in detail. The observer variation was computed in three dimensions by measuring the distance between the median GTV surface and each individual GTV. The variation in distance of all radiation oncologists was expressed as a standard deviation. The observer variation was evaluated for anatomic regions (lung, mediastinum, chest wall, atelectasis, and lymph nodes) and interpretation regions (agreement and disagreement; i.e., >80% vs. <80% of the radiation oncologists delineated the same structure, respectively). All radiation oncologist-computer interactions were recorded and analyzed with a tool called "Big Brother.", Results: The overall three-dimensional observer variation was reduced from 1.0 cm (SD) for the first phase (CT only) to 0.4 cm (SD) for the second phase (matched CT-FDG-PET). The largest reduction in the observer variation was seen in the atelectasis region (SD 1.9 cm reduced to 0.5 cm). The mean ratio between the common and encompassing volume was 0.17 and 0.29 for the first and second phases, respectively. For the first phase, the common volume was 0 in 4 patients (i.e., no common point for all GTVs). In the second phase, the common volume was always >0. For all anatomic regions, the interpretation differences among the radiation oncologists were reduced. The amount of disagreement was 45% and 18% for the first and second phase, respectively. Furthermore, the mean delineation time (12 vs. 16 min, p<0.001) and mean number of corrections (25 vs. 39, p<0.001) were reduced in the second phase compared with the first phase., Conclusion: For high-precision radiotherapy, the delineation of lung target volumes using only CT introduces too great a variability among radiation oncologists. Implementing matched CT-FDG-PET and adapted delineation protocol and software reduced observer variation in lung cancer delineation significantly with respect to CT only. However, the remaining observer variation was still large compared with other geometric uncertainties (setup variation and organ motion).

Background and Purpose: To evaluate the process of target volume delineation in lung cancer for optimization of imaging, delineation protocol and delineation software., Patients and Methods: Eleven radiation oncologists (observers) from five different institutions delineated the Gross Tumor Volume (GTV) including positive lymph nodes of 22 lung cancer patients (stages I-IIIB) on CT only. All radiation oncologist-computer interactions were recorded with a tool called 'Big Brother'. For each radiation oncologist and patient the following issues were analyzed: delineation time, number of delineated points and corrections, zoom levels, level and window (L/W) settings, CT slice changes, use of side windows (coronal and sagittal) and software button use., Results: The mean delineation time per GTV was 16 min (SD 10 min). The mean delineation time for lymph node positive patients was on average 3 min larger (P = 0.02) than for lymph node negative patients. Many corrections (55%) were due to L/W change (e.g. delineating in mediastinum L/W and then correcting in lung L/W). For the lymph node region, a relatively large number of corrections was found (3.7 corr/cm2), indicating that it was difficult to delineate lymph nodes. For the tumor-atelectasis region, a relative small number of corrections was found (1.0 corr/cm2), indicating that including or excluding atelectasis into the GTV was a clinical decision. Inappropriate use of L/W settings was frequently found (e.g. 46% of all delineated points in the tumor-lung region were delineated in mediastinum L/W settings). Despite a large observer variation in cranial and caudal direction of 0.72 cm (1 SD), the coronal and sagittal side windows were not used in 45 and 60% of the cases, respectively. For the more difficult cases, observer variation was smaller when the coronal and sagittal side windows were used., Conclusions: With the 'Big Brother' tool a method was developed to trace the delineation process. The differences between observers concerning the delineation style were large. This study led to recommendations on how to improve delineation accuracy by adapting the delineation protocol (guidelines for L/W use) and delineation software (double window with lung and mediastinum L/W settings at the same time, enforced use of coronal and sagittal views) and including FDG-PET information (lymph nodes and atelectasis).

Purpose: The prostate is known to translate and rotate under influence of rectal filling changes and many studies have addressed the magnitude of these motions. However, prostate shape variations also have been reported. For image-guided radiotherapy, it is essential to know the relative magnitude of translations, rotations, and shape variation so that the most appropriate correction strategy can be chosen. However, no quantitative analysis of shape variation has been performed. It is, therefore, the purpose of this article to develop a method to determine shape variation of complex organs and apply it to determine shape variation during external beam radiotherapy of a GTV (gross tumor volume) consisting of prostate and seminal vesicles., Methods and Materials: For this study, the data of 19 patients with prostate cancer were used. Each patient received a planning computed tomography (CT) scan and 8-12 (11 on average) repeat CT scans that were made during the course of conformal radiotherapy. One observer delineated the GTV in all scans, and volume variations were measured. After matching the GTVs for each patient for translation and rotation, a coverage probability matrix was constructed and the 50% isosurface was taken to determine the average GTV surface. Perpendicular distances between the average GTV and the individual GTVs were calculated for each point of the average GTV, and their variation was expressed in terms of local standard deviation (SD). The local SDs of the shape variation of all 19 patients were mapped onto a reference case by matching and morphing of the individual average GTVs. Repeated delineation of the GTV was done for 6 patients to determine intraobserver variation. Finally, the measured shape variation was corrected for intraobserver variation to estimate the "real" shape variation., Results: No significant variations in GTV volume were observed. The measured shape variation (including delineation variation) was largest at the tip of the vesicles (SD = 2.0 mm), smallest at the left and right side of the prostate (SD = 1.0 mm), and average elsewhere (SD = 1.5 mm). At the left, right, and cranial sides of the prostate, the intraobserver variation was of the same order of magnitude as the measured shape variation; elsewhere it was smaller. However, the accuracy of the estimated SD for intraobserver variation was about half of the accuracy of the estimated SD for the measured shape variation, giving an overall uncertainty of maximum 0.6 mm SD in the estimate of the "real" shape variation. The "real" shape variation was small at the left, right, and cranial side of the prostate (SD <0.5 mm) and between 0.5 mm and 1.6 mm elsewhere., Conclusions: We developed a method to quantify shape variation of organs with a complex shape and applied it to a GTV consisting of prostate and seminal vesicles. Deformation of prostate and seminal vesicles during the course of radiotherapy is small (relative to organ motion). Therefore, it is a valid approximation in image-guided radiotherapy of prostate cancer, in first order, to correct only for setup errors and organ motion. Prostate and seminal vesicles deformation can be considered as a second-order effect.

Purpose: The prostate volume delineated on MRI is smaller than on CT. The purpose of this study was to determine the influence of MRI- vs. CT-based prostate delineation using multiple observers on the dose to the target and organs at risk during external beam radiotherapy., Materials and Methods: CT and MRI scans of the pelvic region were made of 18 patients and matched three-dimensionally on the bony anatomy. Three observers delineated the prostate using both modalities. A fourth observer delineated the rectal wall and the bulb of the penis. The planning treatment volume (PTV) was generated from the delineated prostates with a margin of 10 mm in three-dimensions. A three-field treatment plan with a prescribed dose of 78 Gy to the International Commission on Radiation Units and Measurements point was automatically generated from each PTV. Dose-volume histograms were calculated of all PTVs, rectal walls, and penile bulbs. The equivalent uniform dose was calculated for the rectal wall using a volume exponent (n = 0.12)., Results: The equivalent uniform dose of the CT rectal wall in plans based on the CT-delineated prostate was, on average, 5.1 Gy (SEM 0.5) greater than in the plans based on the MRI-delineated prostate. For the MRI rectal wall, this difference was 3.6 Gy (SEM 0.4). Allowing for the same equivalent uniform dose to the CT rectal wall, the prescribed dose to the PTV could be raised from 78 to 85 Gy when using the MRI-delineated prostate for treatment planning. The mean dose to the bulb of the penis was 11.6 Gy (SEM 1.8) lower for plans based on the MRI-delineated prostate. The mean coverage (volume of the PTV receiving > or =95% of the prescribed dose) was 99.9% for both modalities. The interobserver coverage (coverage of the PTV by a treatment plan designed for the PTV delineated by another observer in the same modality) was 97% for both modalities. The MRI rectum was significantly more ventrally localized than the CT rectum, probably because of the rounded tabletop and no knee support on the MRI scanner., Conclusions: The dose delivered to the rectal wall and bulb of the penis is significantly reduced with treatment plans based on the MRI-delineated prostate compared with the CT-delineated prostate, allowing a dose escalation of 2.0-7.0 Gy for the same rectal wall dose. The interobserver coverage was the same for CT and MRI delineation of the prostate. A statistically significant difference in position between the CT- and MRI-delineated rectum was observed, probably owing to a different tabletop and use of knee support.

The performance of cathode-anode configurations in a cuff electrode to stimulate a single fascicle in a nerve trunk has been investigated theoretically. A three-dimensional volume conductor model of a nerve trunk with four fascicles in a cuff electrode and a model of myelinated nerve fiber stimulation were used to calculate the recruitment of 15 m fibers in each fascicle. The effect of a monopole, a transverse bipole (anode opposite the cathode), and a narrow transverse tripole (guarded cathode) in selectively stimulating 15 m fibers in each fascicle has been quantified and presented as recruitment curves. It is predicted that selective fascicle stimulation is advanced most by stimulation with a bipole in a plane perpendicular to the axis of the nerve trunk. Monopoles and conventional longitudinal tripoles perform less well, as does a longitudinal tripole with an additional "steering" anode. Apart from transverse bipolar stimulation an additional anode may be used to maximally fit the area of excitation to the topography of the fascicle to be recruited. As compared to monopolar and longitudinal tripolar stimulation, the slope of the recruitment curves in transverse bipolar stimulation is reduced considerably, thus allowing improved fine tuning of nerve (and thus force) recruitment. Another advantage of this method is a minimal number of cable connections to the cuff electrode. The cost of the improved selectivity is an increased stimulation current.

The influence of subthreshold depolarizing prepulses on the threshold current-to-distance and the threshold current-to-diameter relationship of myelinated nerve fibers has been investigated. A nerve fiber model was used in combination with both a simple, homogeneous volume conductor model with a point source and a realistic, inhomogeneous volume conductor model of a monofascicular nerve trunk surrounded by a cuff electrode. The models predict that a subthreshold depolarizing prepulse will desensitize Ranvier nodes of fibers in the vicinity of the cathode and thus cause an increase in the threshold current of a subsequent pulse to activate these fibers. If the increase in threshold current of the excited node is large enough, the excitation will be accompanied by a strong hyperpolarization of adjacent nodes, preventing the propagation of action potentials in these fibers. As fibers close to the electrode are more desensitized by prepulses than more distant ones, it is possible to stimulate distant fibers without stimulating such fibers close to the electrode. Moreover, as larger fibers are more desensitized than smaller ones, smaller fibers have lower threshold currents than larger fibers up to a certain distance from the electrode. The realistic model has provided an additional condition for the application of this method to invert nerve fiber recruitment, i.e., real or virtual anodes should be close to the cathode. When using a cuff electrode for this purpose, in the case of monopolar stimulation the cuff length (determining the position of the virtual anodes) should not exceed twice the internodal length of the fibers to be blocked. Similarly, the distance between cathode and anodes should not exceed the internodal length of these fibers when stimulation is to be applied tripolarly.

The recruitment characteristics of muscle selective nerve stimulation by a multi-contact nerve cuff electrode, as predicted by computer modeling, have been investigated in acute experiments on rabbits. A nerve cuff containing five or six dot electrodes was placed around the sciatic nerve in five rabbits. M-waves were recorded with wire electrodes from the lateral gastrocnemius, soleus, tibialis anterior, and extensor digitorum longus muscles. The muscle recruitment performances of three contact configurations (monopole, transverse bipole, transverse tripole) were compared. The selectivity was quantified by the recruitment of two muscles (one extensor and one flexor) in response to a particular stimulus. The results showed that only in a few cases, transverse bi- and tripolar stimulation provided a better selectivity than monopolar stimulation. Neither of the two extensors, nor of the two flexors could be stimulated separately. In accordance with the results of the modeling studies, bi- and tripolar stimulation required higher stimulus currents than monopolar stimulation, whereas maximum recruitment and slopes of recruitment curves were lower. The rabbit sciatic nerve appears to be a less suitable preparation for reproducible selectivity experiments, due to the variability in the number and size of the fascicles and their position in this nerve.

Various anode-cathode configurations in a nerve cuff are modelled to predict their spatial selectivity characteristics for functional nerve stimulation. A 3D volume conductor model of a monofascicular nerve is used for the computation of stimulation-induced field potentials, whereas a cable model of myelinated nerve fibre is used for the calculation of the excitation thresholds of fibres. As well as the usual configurations (monopole, bipole, longitudinal tripole, 'steering' anode), a transverse tripolar configuration (central cathode) is examined. It is found that the transverse tripole is the only configuration giving convex recruitment contours and therefore maximises activation selectivity for a small (cylindrical) bundle of fibres in the periphery of a monofascicular nerve trunk. As the electrode configuration is changed to achieve greater selectivity, the threshold current increases. Therefore threshold currents for fibre excitation with a transverse tripole are relatively high. Inverse recruitment is less extreme than for the other configurations. The influences of several geometrical parameters and model conductivities of the transverse tripole on selectivity and threshold current are analysed. In chronic implantation, when electrodes are encapsulated by a layer of fibrous tissue, threshold currents are low, whereas the shape of the recruitment contours in transverse tripolar stimulation does not change.

Flow cytometric measurements of light scattering of polystyrene calibration beads revealed remarkable Lissajous-like loops in two-parameter scatter plots. The existence of such loops is shown to be in qualitative agreement with Lorenz-Mie scattering theory of homogeneous spheres. The occurrence of these patterns reflects the extreme particle size dependency of perpendicular light scattering of homogeneous spheres. These effects may give an explanation for the frequently observed phenomenon that polystyrene spheres reveal a relatively large CV in the perpendicular light scattering signals, whereas the CV of the forward light scattering signal is small. We conclude that one should be careful to optimize the perpendicular light scattering channel by minimizing the CV, because there is no linear relationship between instrument alignment quality and the CV of the perpendicular light scattering signals of calibration beads.

The complete scattering matrix S of spheres was measured with a flow cytometer. The experimental equipment allows simultaneous detection of two scattering-matrix elements for every sphere in the distribution. Two-parameter scatterplots with x and y coordinates determined by the S(ll) + S(ij) and S(ll)-S(ij) values are measured. Samples of spheres with very narrow size distributions (< 1%) were analyzed with a FlowCytometer, and they produced unexpected two-parameter scatterplots. Instead of compact distributions we observed Lissajous-like loops. Simulation of the scatterplots, using Lorenz-Mie theory, shows that these loops are due not to experimental errors but to true Lorenz-Mie scattering. It is shown that the loops originate from the sensitivity of the scattered field on the radius of the spheres. This paper demonstrates that the interpretation of rare events and hidden features in flow cytometry needs reconsideration.