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BACKGROUND Partial prostate treatment has emerged as a potential method for treating patients with favorable-risk prostate cancer while minimizing toxicity. The authors previously demonstrated poor rates of biochemical disease control for patients with National Comprehensive Cancer Network (NCCN) intermediate-risk disease using partial gland treatment with brachytherapy. The objective of the current study was to estimate the rates of distant metastasis and prostate cancer-specific mortality (PCSM) for this cohort. METHODS Between 1997 and 2007, a total of 354 men with clinical T1c disease, a prostate-specific antigen (PSA) level

BACKGROUND Phase 3 trials have demonstrated a benefit from adjuvant radiation therapy (ART) for men who have adverse factors at radical prostatectomy (RP). However, some patients have a high risk of progression despite ART. The role of systemic therapy with ART in this high-risk group remains to be defined. METHODS Patients who had either a post-RP prostate-specific antigen (PSA) nadir > 0.2 ng/mL and a Gleason score ≥7 or a PSA nadir ≤0.2 ng/mL, a Gleason score ≥8, and a pathologic tumor (pT) classification ≥ pT3 received 6 months of androgen-deprivation therapy (ADT) plus radiotherapy and 6 cycles of docetaxel. The primary objective was to assess whether the addition of ADT and docetaxel to ART resulted in a freedom from progression (FFP) rate ≥ 70% compared with an expected rate of 50%. Multivariate logistic and Cox regression analyses were used to model associations between factors and outcomes. RESULTS In total, 74 patients were enrolled. The median follow-up was 4.4 years. The pathologic tumor classification was pT2 in 4% of patients, pT3 in 95%, and pT4 in 1%. The Gleason score was 7 in 18% of patients and ≥8 in 82%. Post-RP PSA levels were ≤0.2 ng/mL in 53% of patients and >0.2 ng/mL in 47%. The 3-year FFP rate was 73% (95% confidence interval, 61%-83%), and the 3-year cumulative incidence of biochemical, distant, and local failure was 26%, 7%, and 0%, respectively. In multivariate models, postprostatectomy PSA nadir was associated with 3-year FFP, Gleason score, and PSA with biochemical failure. Grade 3 and 4 neutropenia was common; however, only 3 episodes of febrile neutropenia occurred. Late toxicities were not impacted by the addition of systemic therapy. CONCLUSIONS Combined ADT, docetaxel, and ART for men with high-risk prostate cancer after prostatectomy exceeded the prespecified study endpoint of 70% 3-year FFP. Phase 3 trials assessing combined local and systemic therapies for these high-risk patients are warranted. Cancer 2017;123:2489–96. © 2017 American Cancer Society.

Men treated for prostate cancer often have unexpected outcomes despite predictive models based on stage, grade and prostate-specific antigen (PSA). Previous results have indicated that nuclear morphometry can predict patient outcome in urologic malignancies. Application of this analytical method in prostate cancer treated with radiation therapy is limited. We have evaluated the predictive ability of nuclear morphometry in such patients. Histologic sections from 23 men with clinically localized adenocarcinoma of the prostate treated with radiation therapy were studied. Nuclear morphometric parameters were assessed using a previously described and validated system. Univariate and multivariate logistic regression analyses and a Cox proportional hazards model were used to assess the ability of nuclear morphometric parameters to predict recurrence and disease-free interval. Ten patients had no recurrence with median follow-up of 47.5 months, while 13 had recurrence. Gleason grade was not predictive of treatment outcome. Pre-treatment PSA data, available for only 11 patients, were predictive of treatment outcome. Several nuclear morphometric parameters predicted recurrence, including upper quartile of suboptimal circle fit and upper quartile of feret-diameter ratio. A prognostic factor score incorporating these 2 parameters was derived, which predicted disease-free interval (p = 0.0014). Int. J. Cancer (Pred. Oncol.) 84:594–597, 1999. © 1999 Wiley-Liss, Inc.

Purpose: Respiratory motion can vary significantly over the course of simulation and treatment. Our goal is to use volumetric images generated with a respiratory motion model to improve the definition of the internal target volume (ITV) and the estimate of delivered dose. Methods: Ten irregular patient breathing patterns spanning 35 seconds each were incorporated into a digital phantom. Ten images over the first five seconds of breathing were used to emulate a 4DCT scan, build the ITV, and generate a patient-specific respiratory motion model which correlated the measured trajectories of markers placed on the patients’ chests with the motion of the internal anatomy. This model was used to generate volumetric images over the subsequent thirty seconds of breathing. The increase in the ITV taking into account the full 35 seconds of breathing was assessed with ground-truth and model-generated images. For one patient, a treatment plan based on the initial ITV was created and the delivered dose was estimated using images from the first five seconds as well as ground-truth and model-generated images from the next 30 seconds. Results: The increase in the ITV ranged from 0.2 cc to 6.9 cc for the ten patients based on ground-truth information. The model predicted this increase in the ITV with an average error of 0.8 cc. The delivered dose to the tumor (D95) changed significantly from 57 Gy to 41 Gy when estimated using 5 seconds and 30 seconds, respectively. The model captured this effect, giving an estimated D95 of 44 Gy. Conclusion: A respiratory motion model generating volumetric images of the internal patient anatomy could be useful in estimating the increase in the ITV due to irregular breathing during simulation and in assessing delivered dose during treatment. This project was supported, in part, through a Master Research Agreement with Varian Medical Systems, Inc. and Radiological Society of North America Research Scholar Grant #RSCH1206.

Purpose: We develop a method to generate time varying volumetric images (3D fluoroscopic images) using patient-specific motion models derived from four-dimensional cone-beam CT (4DCBCT). Methods: Motion models are derived by selecting one 4DCBCT phase as a reference image, and registering the remaining images to it. Principal component analysis (PCA) is performed on the resultant displacement vector fields (DVFs) to create a reduced set of PCA eigenvectors that capture the majority of respiratory motion. 3D fluoroscopic images are generated by optimizing the weights of the PCA eigenvectors iteratively through comparison of measured cone-beam projections and simulated projections generated from the motion model. This method was applied to images from five lung-cancer patients. The spatial accuracy of this method is evaluated by comparing landmark positions in the 3D fluoroscopic images to manually defined ground truth positions in the patient cone-beam projections. Results: 4DCBCT motion models were shown to accurately generate 3D fluoroscopic images when the patient cone-beam projections contained clearly visible structures moving with respiration (e.g., the diaphragm). When no moving anatomical structure was clearly visible in the projections, the 3D fluoroscopic images generated did not capture breathing deformations, and reverted to the reference image. For the subset of 3D fluoroscopic images generated from projections with visibly moving anatomy, the average tumor localization error and the 95th percentile were 1.6 mm and 3.1 mm respectively. Conclusion: This study showed that 4DCBCT-based 3D fluoroscopic images can accurately capture respiratory deformations in a patient dataset, so long as the cone-beam projections used contain visible structures that move with respiration. For clinical implementation of 3D fluoroscopic imaging for treatment verification, an imaging field of view (FOV) that contains visible structures moving with respiration should be selected. If no other appropriate structures are visible, the images should include the diaphragm. This project was supported, in part, through a Master Research Agreement with Varian Medical Systems, Inc, Palo Alto, CA.

Purpose: High-density materials used in dental restoration can cause significant localized dose enhancement due to electron backscatter in head-and-neck radiotherapy, increasing the risk of mucositis. The materials used in prosthetic dentistry have evolved in the last decades from metal alloys to ceramics. We aim to determine the dose enhancement caused by backscatter from currently-used dental materials. Methods: Measurements were performed for three different dental materials: lithium disilicate (Li2Si2O5), zirconium dioxide (ZrO2), and gold alloy. Small thin squares (2×2×0.15 cm3) of the material were fabricated, and placed into a phantom composed of tissue-equivalent material. The phantom was irradiated with a single 6 MV photon field. A thin-window parallel-plate ion chamber was used to measure the dose at varying distances from the proximal interface between the material and the plastic. Results: The dose enhancement at the interface between the high-density and tissue-equivalent materials, relative to a homogeneous phantom, was 54% for the gold alloy, 31% for ZrO2, and 9% for Li2Si2O5. This enhancement decreased rapidly with distance from the interface, falling to 11%, 5%, and 0.5%, respectively, 2 mm from the interface. Comparisons with the modeling of this effect in treatment planning systems are performed. Conclusion: While dose enhancement due to dental restoration is smaller with ceramic materials than with metal alloys, it can still be significant. A spacer of about 2–3 mm would be effective in reducing this enhancement, even for metal alloys.

REM sleep behaviour disorder (RBD) is an injurious clinical disorder of attempted dream-enactment ('oneirism') in humans which has a corresponding experimental animal model involving dorsolateral pontine tegmental lesions in cats. To date, our sleep disorders centre has collected data on 96 chronic RBD cases which can be compared with pooled data on 70 chronic RBD cases from other centres contained in 26 reports published in the world literature since 1985, when our initial cases were first reported. The data from our centre and from other centres demonstrate a male predominance in RBD (87.5% vs 63.5%); indicate a similar mean age of RBD onset (52.4 y vs 55.9 y); contain substantial numbers of diverse central nervous system disorders causally associated with RBD (47.9% vs 60.0%); and identify clonazepam treatment as being very effective in controlling both the (violent) dream and sleep behavioural disturbances of RBD. Our centre's data additionally reveal an 80% prevalence of elevated stage 3/4 (slow-wave) sleep% for age in RBD, and reveal a frequent presence of periodic and aperiodic limb movements during NREM sleep. Thus, RBD in humans is a complex syndrome in which there is generalized REM and NREM sleep motor dyscontrol, as was originally observed in the animal RBD model by Jouvet and Delorme in 1965.

In an examination of the language used by expert witnesses during actual courtroom testimony, it was expected that experts who exhibited content themes related to their credentials or experience (expertise) and to objectivity (trustworthiness) would be perceived as being more credible. Forty-three segments of expert testimony were taken from actual court transcripts and content analyzed. Two-factor analytically derived factors predicted expert witness membership into low- and high-credibility groups, defined a priori by credibility judgments of undergraduate raters (n = 348). These factors were (a) the use of passive voice and (b) the witnesses' background and qualifications. Further analyses revealed that perceptions of expert witness credibility were also a function of the usage of words that connote power (an expert's official status, degree of prominence and/or recognition) or negative (suffering or damage). Results are discussed in terms of dimensions of source credibility and their parallels to past research in persuasion.

Purpose: To design a comprehensive open-source, publicly available, graphical user interface (GUI) to facilitate the configuration, generation, processing and use of the 4D Extended Cardiac-Torso (XCAT) phantom. Methods: The XCAT phantom includes over 9000 anatomical objects as well as respiratory, cardiac and tumor motion. It is widely used for research studies in medical imaging and radiotherapy. The phantom generation process involves the configuration of a text script to parameterize the geometry, motion, and composition of the whole body and objects within it, and to generate simulated PET or CT images. To avoid the need for manual editing or script writing, our MATLAB-based GUI uses slider controls, drop-down lists, buttons and graphical text input to parameterize and process the phantom. Results: Our GUI can be used to: a) generate parameter files; b) generate the voxelized phantom; c) combine the phantom with a lesion; d) display the phantom; e) produce average and maximum intensity images from the phantom output files; f) incorporate irregular patient breathing patterns; and f) generate DICOM files containing phantom images. The GUI provides local help information using tool-tip strings on the currently selected phantom, minimizing the need for external documentation. The DICOM generation feature is intended to simplifymore » the process of importing the phantom images into radiotherapy treatment planning systems or other clinical software. Conclusion: The GUI simplifies and automates the use of the XCAT phantom for imaging-based research projects in medical imaging or radiotherapy. This has the potential to accelerate research conducted with the XCAT phantom, or to ease the learning curve for new users. This tool does not include the XCAT phantom software itself. We would like to acknowledge funding from MRA, Varian Medical Systems Inc.« less

Purpose: Respiratory-correlated cone-beam CT (4DCBCT) images acquired immediately prior to treatment have the potential to represent patient motion patterns and anatomy during treatment, including both intra- and inter-fractional changes. We develop a method to generate patient-specific motion models based on 4DCBCT images acquired with existing clinical equipment and used to generate time varying volumetric images (3D fluoroscopic images) representing motion during treatment delivery. Methods: Motion models are derived by deformably registering each 4DCBCT phase to a reference phase, and performing principal component analysis (PCA) on the resulting displacement vector fields. 3D fluoroscopic images are estimated by optimizing the resulting PCA coefficients iteratively through comparison of the cone-beam projections simulating kV treatment imaging and digitally reconstructed radiographs generated from the motion model. Patient and physical phantom datasets are used to evaluate the method in terms of tumor localization error compared to manually defined ground truth positions. Results: 4DCBCT-based motion models were derived and used to generate 3D fluoroscopic images at treatment time. For the patient datasets, the average tumor localization error and the 95th percentile were 1.57 and 3.13 respectively in subsets of four patient datasets. For the physical phantom datasets, the average tumor localization error and the 95th percentile were 1.14 and 2.78 respectively in two datasets. 4DCBCT motion models are shown to perform well in the context of generating 3D fluoroscopic images due to their ability to reproduce anatomical changes at treatment time. Conclusion: This study showed the feasibility of deriving 4DCBCT-based motion models and using them to generate 3D fluoroscopic images at treatment time in real clinical settings. 4DCBCT-based motion models were found to account for the 3D non-rigid motion of the patient anatomy during treatment and have the potential to localize tumor and other patient anatomical structures at treatment time even when inter-fractional changes occur. This project was supported, in part, through a Master Research Agreement with Varian Medical Systems, Inc., Palo Alto, CA. The project was also supported, in part, by Award Number R21CA156068 from the National Cancer Institute.

Purpose: To develop a 4DCBCT-based dose assessment method for calculating actual delivered dose for patients with significant respiratory motion during the course of SBRT or anatomical changes between treatment days. Methods: To address the limitation of 4DCT-based dose assessment, we propose to calculate the delivered dose using time varying (‘fluoroscopic’) 3D patient images generated from a 4DCBCT-based motion model. The method includes four steps: (1) before each treatment, 4DCBCT data is acquired with the patient in treatment position, based on which a patient-specific motion model is created using a principal components analysis (PCA) algorithm. (2) During treatment, 2D time-varying kV projection images are continuously acquired, from which time-varying ‘fluoroscopic’ 3D images of the patient are reconstructed using the motion model. (3) Lateral truncation artifacts are corrected using planning 4DCT images. (4) the 3D dose distribution is computed for each timepoint in the set of 3D fluoroscopic images, from which the total effective 3D delivered dose is calculated by accumulating deformed dose distributions. This approach is validated using six modified XCAT phantoms with lung tumors and different respiratory motions derived from patient data. The estimated doses are compared to that calculated using ground-truth XCAT phantoms. Results: For each XCAT phantom, the delivered tumor dose values generally follow the same trend as that of the ground truth and at most timepoints the difference is less than 5%. For the overall delivered dose, the normalized error of calculated 3D dose distribution is generally less than 3% and the tumor D95 error is less than 1.5%. Conclusions: XCAT phantom studies indicate the potential of the proposed method to accurately estimate 3D tumor dose distributions for SBRT lung treatment based on 4DCBCT imaging and motion modeling. Further research is necessary to investigate its performance for clinical patients data.

Purpose: The goal of this study is to quantify the interfraction reproducibility of patient-specific motion models derived from 4DCBCT acquired on the day of treatment of lung cancer stereotactic body radiotherapy (SBRT) patients. Methods: Motion models are derived from patient 4DCBCT images acquired daily over 3–5 fractions of treatment by 1) applying deformable image registration between each 4DCBCT image and a reference phase from that day, resulting in a set of displacement vector fields (DVFs), and 2) performing principal component analysis (PCA) on the DVFs to derive a motion model. The motion model from the first day of treatment is compared to motion models from each successive day of treatment to quantify variability in motion models generated from different days. Four SBRT patient datasets have been acquired thus far in this IRB approved study. Results: Fraction-specific motion models for each fraction and patient were derived and PCA eigenvectors and their associated eigenvalues are compared for each fraction. For the first patient dataset, the average root mean square error between the first two eigenvectors associated with the highest two eigenvalues, in four fractions was 0.1, while it was 0.25 between the last three PCA eigenvectors associated with the lowest three eigenvalues.more » It was found that the eigenvectors and eigenvalues of PCA motion models for each treatment fraction have variations and the first few eigenvectors are shown to be more stable across treatment fractions than others. Conclusion: Analysis of this dataset showed that the first two eigenvectors of the PCA patient-specific motion models derived from 4DCBCT were stable over the course of several treatment fractions. The third, fourth, and fifth eigenvectors had larger variations.« less

Purpose: To develop a clinically feasible method of calculating actual delivered dose for patients with significant respiratory motion during the course of SBRT. Methods: This approach can be specified in three steps. (1) At planning stage, a patient-specific motion model is created from planning 4DCT using a principal components analysis (PCA) algorithm. (2) During treatment, 2D time-varying projection images (either kV or MV projections) are acquired, from which time-varying ‘fluoroscopic’ 3D images of the patient are reconstructed using the motion model. (3) A 3D dose distribution is computed for each timepoint in the set of 3D fluoroscopic images, from which the total effective 3D delivered dose is calculated by accumulating dose distributions onto a reference image. This approach was validated using two modified XCAT phantoms with lung tumors and different respiratory motions. The estimated doses were compared to the dose that would be calculated for 4DCT-based planning and to the actual delivered dose that was calculated using “ground truth” XCAT phantoms. The approach was also tested using one set of patient data. Results: For the XCAT phantom with a regular breathing pattern, the errors in D95 are 0.11% and 0.83% respectively for kV and MV reconstructions compared to the ground truth, which is comparable to 4DCT (0.093%). For the XCAT phantom with an irregular breathing pattern, the errors are 0.81% and 1.75% for kV and MV reconstructions, both better than that of 4DCT (4.01%). For real patient, the dose estimation is clinically reasonable and demonstrates differences between 4DCT and MV reconstruction-based estimation. Conclusions: Using kV or MV projections, the proposed approach is able to assess delivered doses for all respiratory phases during treatment. Compared to the 4DCT dose, the dose estimation using reconstructed 3D fluoroscopic images is as good for regular respiratory pattern and better for irregular respiratory pattern.

Purpose: To estimate the dose delivered to a physical anthropomorphic phantom based on: 1) CT scans representing each phase of respiration; and 2) 3D images generated from a respiratory motion model and an external surrogate signal. OSLDs are used to measure doses delivered to the phantom. Methods: A commercially available physical phantom was modified, replacing the lung system with foam rubber of lung-equivalent density and placing a tumor made of bolus within the lung. A wooden diaphragm driven by a programmable motor compressed the foam with a realistic breathing pattern based on patient measurements. CT scans of the phantom were taken at several phases of a breathing cycle, and the dose delivered by a nine-field treatment at each phase was calculated with Monte Carlo. Dose distributions at each phase were mapped to a reference phase with vectors from deformable image registration performed on the original CT images. A second estimate of the delivered dose was performed replacing the CT scans and associated vectors with images and deformations generated by a motion model. Finally, with a one-field treatment plan, the estimated delivered dose was compared to measurements with OSLDs placed in the phantom. Results: The estimated dose delivered to the tumor using CT scans agreed with the estimate using model-generated images, and the difference in the D95 for the two approaches was less than 2%. This demonstrates that images generated by the motion model can be used for dose estimates. Dose measured with OSLDs at nine points within the tumor and foam lung of the phantom agreed with predictions within measurement uncertainties. Conclusion: The images generated from a motion model based on an external surrogate trace can be used to estimate dose delivered during treatment. Dose estimates were validated with measurements.

A theoretical treatment is presented for an electrochemical cell in which a suspension of catalytically active particles and fuel stream through the anodic compartment. The overall rate of discharge of the particles at the collector electrode is supposedly controlled either by electrochemical oxydation of chemisorbed species on the particle surface (case of hydrogen reaction) or by charge transfer through a resistance at the contact-making spot between the collector electrode and the catalyst particle. Special emphasis is given to hydrodynamic determination of collision frequencies with the collector electrode of suspended particles, as a function of their dimension and of the state of turbulency, in order to derive current efficiencies of slurry electrodes under various experimental conditions. Fur den Fall einer elektrochemischen Zelle, in der aufgewirbelte Katalysatorteilchen und Brennstoff durch den Anodenraum stromen, wird eine theoretische Behandlung vorgeschlagen. Die Bruttogeschwindigkeit der Entladung der Teilchen auf der Abnehmerelektrode wird entweder durch elektrochemische Oxidation des auf den aktiven Teilchen chemisorbierten Stoffes (Fall der Wasserstoffreaktion) oder durch Ladungsubergang durch den Ubergangswiderstand an der Kontaktflache zwischen Abnehmerelektrode und aktiven Teilchen kontrolliert. Besonderer Wert wird auf die hydrodynamische Bestimmung der Kollisionsfrequenz der aktiven Teilchen mit der Abnehmerelektrode in Abhangigkeit von der Teilchengrose und dem Turbulenzzustand gelegt, um die Stromleistung des Systems unter verschiedenen experimentellen Bedingungen abschatzen zu konnen. On traite theoriquement le cas d'une cellule electrochimique dans laquelle on force l'ecoulement d'une suspension de particules catalytiquement actives et de combustible au travers du compartiment anodique. La vitesse globale de decharge des particules sur l'electrode collectrice est cǒntrollee soit par l'etape d'oxydation electrochimique des especes chemisorbees a la surface des particules actives (cas de la reaction de l'hydrogene) soit par le transfert de charge au travers d'une resistance s'etablissant au point de contact entre l'electrode collectrice et la particule catalytique. Une attention toute speciale est accordee a la determination hydrodynamique des frequences de collision, avec l'electrode collectrice, des particules en suspension, en fonction des dimensions de ces dernieres et de l'etat de turbulence du systeme. Ceci permet d'evaluer les rendements en courant de ce type d'electrode sous differentes conditions experimentales.