The PerPAIN trial: a pilot randomized controlled trial of personalized treatment allocation for chronic musculoskeletal pain-a protocol.

BACKGROUND: The therapy of chronic musculoskeletal pain (CMSP) is complex and the treatment results are often insufficient despite numerous therapeutic options. While individual patients respond very well to specific interventions, other patients show no improvement. Personalized treatment assignment offers a promising approach to improve response rates; however, there are no validated cross-disease allocation algorithms available for the treatment of chronic pain in validated personalized pain interventions. This trial aims to test the feasibility and safety of a personalized pain psychotherapy allocation with three different treatment modules and estimate initial signals of efficacy and utility of such an approach compared to non-personalized allocation. METHODS: This is a randomized, controlled assessor-blinded pilot trial with a multifactorial parallel arm design. CMSP patients (n = 105) will be randomly assigned 1:1 to personalized or non-personalized treatment based on a cluster assignment of the West Haven-Yale Multidimensional Pain Inventory (MPI). In the personalized assignment condition, patients with high levels of distress receive an emotional distress-tailored intervention, patients with pain-related interference receive an exposure/extinction-tailored treatment intervention and patients who adapt relatively well to the pain receive a low-level smartphone-based activity diary intervention. In the control arm, patients receive one of the two non-matching interventions. Effect sizes will be calculated for change in core pain outcome domains (pain intensity, physical and emotional functioning, stress experience, participant ratings of improvement and satisfaction) after intervention and at follow-up. Feasibility and safety outcomes will assess rates of recruitment, retention, adherence and adverse events. Additional data on neurobiological and psychological characteristics of the patients are collected to improve treatment allocation in future studies. CONCLUSION: Although the call for personalized treatment approaches is widely discussed, randomized controlled trials are lacking. As the personalization of treatment approaches is challenging, both allocation and intervention need to be dynamically coordinated. This study will test the feasibility and safety of a novel study design in order to provide a methodological framework for future multicentre RCTs for personalized pain psychotherapy. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00022792 ( https://www.drks.de ). Prospectively registered on 04/06/2021.

Auto-calibration by locally consistent contours for dental CBCT.

The image quality of dental cone-beam computed tomography (CBCT) is limited by the accuracy of device calibration. Inaccurate calibration introduces errors in the reconstruction process, which may lead to severe artifacts in the reconstructed volume. Patient motion during scan acquisition induces similar effects. This paper introduces a novel auto-calibration approach calculating geometrical projection parameters from unknown patient geometry. We formulate consistency conditions linking the information of consecutive projection images and a regularization technique to prevent overall distortions. Implemented as a global optimization problem we present an efficient greedy optimizer as well. Our strategy turns out to be robust towards inaccurate initialization. As our method does not rely on consistency between projection data and tomography reconstruction it is robust towards reconstruction artifacts such as e.g. truncation. Applying our approach for auto-calibration shows a relative improvement of sharpness up to [Formula: see text] of in a standard dental CBCT setup. Evaluation is performed on digital reconstructed radiographs (DRRs) of a CT head-scan. In particular different motion types are considered and the number of anatomical structures used for calibration is varied to achieve an understanding of the behavior of the approach.

Pharmacokinetic Modeling of Intra-arterial Nimodipine Therapy for Subarachnoid Hemorrhage-Related Cerebral Vasospasm.

PURPOSE: Intra-arterial (IA) administration of nimodipine has been shown to be an effective treatment for subarachnoid hemorrhage-related cerebral vasospasm. The concentrations achieved in cerebral arteries during this procedure, though, are unknown. Therefore, there are no clinical studies investigating dose-dependent effects of nimodipine. We aimed at providing a pharmacokinetic model for IA nimodipine therapy for this purpose. METHODS: A two-compartment pharmacokinetic model for intravenous nimodipine therapy was modified and used to assess cerebral arterial nimodipine concentration during IA nimodipine infusion into the internal carotid artery (ICA). RESULTS: According to our simulations, continuous IA nimodipine infusion at 2 mg/h and 1 mg/h resulted in steady-state cerebral arterial concentrations of about 200 ng/ml and 100 ng/ml assuming an ICA blood flow of 200 ml/min and a clearance of 70 l/h. About 85 % of the maximal concentration is achieved within the first minute of IA infusion independent on the infusion dose. Within the range of physiological and pharmacokinetic data available in the literature, ICA blood flow has more impact on cerebral arterial concentration than nimodipine clearance. CONCLUSION: The presented pharmacokinetic model is suitable for estimations of cerebral arterial nimodipine concentration during IA infusion. It may, for instance, assist in dose-dependent analyses of angiographic results.

Optimization of Single Voxel MR Spectroscopy Sequence Parameters and Data Analysis Methods for Thermometry in Deep Hyperthermia Treatments.

OBJECTIVE: The difference in the resonance frequency of water and methylene moieties of lipids quantifies in magnetic resonance spectroscopy the absolute temperature using a predefined calibration curve. The purpose of this study was the investigation of peak evaluation methods and the magnetic resonance spectroscopy sequence (point-resolved spectroscopy) parameter optimization that enables thermometry during deep hyperthermia treatments. MATERIALS AND METHODS: Different Lorentz peak-fitting methods and a peak finding method using singular value decomposition of a Hankel matrix were compared. Phantom measurements on organic substances (mayonnaise and pork) were performed inside the hyperthermia 1.5-T magnetic resonance imaging system for the parameter optimization study. Parameter settings such as voxel size, echo time, and flip angle were varied and investigated. RESULTS: Usually all peak analyzing methods were applicable. Lorentz peak-fitting method in MATLAB proved to be the most stable regardless of the number of fitted peaks, yet the slowest method. The examinations yielded an optimal parameter combination of 8 cm3 voxel volume, 55 millisecond echo time, and a 90° excitation pulse flip angle. CONCLUSION: The Lorentz peak-fitting method in MATLAB was the most reliable peak analyzing method. Measurements in homogeneous and heterogeneous phantoms resulted in optimized parameters for the magnetic resonance spectroscopy sequence for thermometry.

Real-time inverse high-dose-rate brachytherapy planning with catheter optimization by compressed sensing-inspired optimization strategies.

This paper demonstrates that optimization strategies derived from the field of compressed sensing (CS) improve computational performance in inverse treatment planning (ITP) for high-dose-rate (HDR) brachytherapy. Following an approach applied to low-dose-rate brachytherapy, we developed a reformulation of the ITP problem with the same mathematical structure as standard CS problems. Two greedy methods, derived from hard thresholding and subspace pursuit are presented and their performance is compared to state-of-the-art ITP solvers. Applied to clinical prostate brachytherapy plans speed-up by a factor of 56-350 compared to state-of-the-art methods. Based on a Wilcoxon signed rank-test the novel method statistically significantly decreases the final objective function value (p < 0.01). The optimization times were below one second and thus planing can be considered as real-time capable. The novel CS inspired strategy enables real-time ITP for HDR brachytherapy including catheter optimization. The generated plans are either clinically equivalent or show a better performance with respect to dosimetric measures.

A new optimization method using a compressed sensing inspired solver for real-time LDR-brachytherapy treatment planning.

This work discusses a novel strategy for inverse planning in low dose rate brachytherapy. It applies the idea of compressed sensing to the problem of inverse treatment planning and a new solver for this formulation is developed. An inverse planning algorithm was developed incorporating brachytherapy dose calculation methods as recommended by AAPM TG-43. For optimization of the functional a new variant of a matching pursuit type solver is presented. The results are compared with current state-of-the-art inverse treatment planning algorithms by means of real prostate cancer patient data. The novel strategy outperforms the best state-of-the-art methods in speed, while achieving comparable quality. It is able to find solutions with comparable values for the objective function and it achieves these results within a few microseconds, being up to 542 times faster than competing state-of-the-art strategies, allowing real-time treatment planning. The sparse solution of inverse brachytherapy planning achieved with methods from compressed sensing is a new paradigm for optimization in medical physics. Through the sparsity of required needles and seeds identified by this method, the cost of intervention may be reduced.

Low-cost flexible thin-film detector for medical dosimetry applications.

The purpose of this study is to characterize dosimetric properties of thin film photovoltaic sensors as a platform for development of prototype dose verification equipment in radiotherapy. Towards this goal, flexible thin-film sensors of dose with embedded data acquisition electronics and wireless data transmission are prototyped and tested in kV and MV photon beams. Fundamental dosimetric properties are determined in view of a specific application to dose verification in multiple planes or curved surfaces inside a phantom. Uniqueness of the new thin-film sensors consists in their mechanical properties, low-power operation, and low-cost. They are thinner and more flexible than dosimetric films. In principle, each thin-film sensor can be fabricated in any size (mm² - cm² areas) and shape. Individual sensors can be put together in an array of sensors spreading over large areas and yet being light. Photovoltaic mode of charge collection (of electrons and holes) does not require external electric field applied to the sensor, and this implies simplicity of data acquisition electronics and low power operation. The prototype device used for testing consists of several thin film dose sensors, each of about 1.5 cm × 5 cm area, connected to simple readout electronics. Sensitivity of the sensors is determined per unit area and compared to EPID sensitivity, as well as other standard photodiodes. Each sensor independently measures dose and is based on commercially available flexible thin-film aSi photodiodes. Readout electronics consists of an ultra low-power microcontroller, radio frequency transmitter, and a low-noise amplification circuit implemented on a flexible printed circuit board. Detector output is digitized and transmitted wirelessly to an external host computer where it is integrated and processed. A megavoltage medical linear accelerator (Varian Tx) equipped with kilovoltage online imaging system and a Cobalt source are used to irradiate different thin-film detector sensors in a Solid Water phantom under various irradiation conditions. Different factors are considered in characterization of the device attributes: energies (80 kVp, 130 kVp, 6 MV, 15 MV), dose rates (different ms × mA, 100-600 MU/min), total doses (0.1 cGy-500 cGy), depths (0.5 cm-20 cm), irradiation angles with respect to the detector surface (0°-180°), and IMRT tests (closed MLC, sweeping gap). The detector response to MV radiation is both linear with total dose (~1-400 cGy) and independent of dose rate (100-600 Mu/min). The sensitivity per unit area of thin-film sensors is lower than for aSi flat-panel detectors, but sufficient to acquire stable and accurate signals during irradiations. The proposed thin-film photodiode system has properties which make it promising for clinical dosimetry. Due to the mechanical flexibility of each sensor and readout electronics, low-cost, and wireless data acquisition, it could be considered for quality assurance (e.g., IMRT, mechanical linac QA), as well as real-time dose monitoring in challenging setup configurations, including large area and 3D detection (multiple planes or curved surfaces).

High throughput film dosimetry in homogeneous and heterogeneous media for a small animal irradiator.

PURPOSE: We have established a high-throughput Gafchromic film dosimetry protocol for narrow kilovoltage beams in homogeneous and heterogeneous media for small-animal radiotherapy applications. The kV beam characterization is based on extensive Gafchromic film dosimetry data acquired in homogeneous and heterogeneous media. An empirical model is used for parameterization of depth and off-axis dependence of measured data. METHODS: We have modified previously published methods of film dosimetry to suit the specific tasks of the study. Unlike film protocols used in previous studies, our protocol employs simultaneous multi-channel scanning and analysis of up to nine Gafchromic films per scan. A scanner and background correction were implemented to improve accuracy of the measurements. Measurements were taken in homogeneous and inhomogeneous phantoms at 220 kVp and a field size of 5 × 5 mm(2). The results were compared against Monte Carlo simulations. RESULTS: Dose differences caused by variations in background signal were effectively removed by the corrections applied. Measurements in homogeneous phantoms were used to empirically characterize beam data in homogeneous and heterogeneous media. Film measurements in inhomogeneous phantoms and their empirical parameterization differed by about 2%-3%. The model differed from MC by about 1% (water, lung) to 7% (bone). Good agreement was found for measured and modelled off-axis ratios. CONCLUSIONS: EBT2 films are a valuable tool for characterization of narrow kV beams, though care must be taken to eliminate disturbances caused by varying background signals. The usefulness of the empirical beam model in interpretation and parameterization of film data was demonstrated.

A fast analytic dose calculation method for arc treatments for kilovoltage small animal irradiators.

Arc treatments require calculation of dose for collections of discrete gantry angles. The sampling of angles must balance between short computation time of small angle sets and the better calculation reliability of large sets. In this paper, an analytical formula is presented that allows calculation of dose delivered during continuous rotation of the gantry. The formula holds valid for continuous short arcs of up to about 30° and is derived by integrating a dose formula over gantry angles within a small angle approximation. Doses for longer arcs may be obtained in terms of doses for shorter arcs. The formula is derived with an empirical beam model in water and extended to inhomogeneous media. It is validated with experimental data obtained by applying arc treatment using kV small animal irradiator to a phantom of solid water and lung-equivalent material. The results are a promising step towards efficient 3D dose calculation and inverse planning purposes. In principle, this method also applies to VMAT dose calculation and optimization but requires extensions.

Evaluation of robustness of maximum likelihood cone-beam CT reconstruction with total variation regularization.

The objective of this paper is to evaluate an iterative maximum likelihood (ML) cone-beam computed tomography (CBCT) reconstruction with total variation (TV) regularization with respect to the robustness of the algorithm due to data inconsistencies. Three different and (for clinical application) typical classes of errors are considered for simulated phantom and measured projection data: quantum noise, defect detector pixels and projection matrix errors. To quantify those errors we apply error measures like mean square error, signal-to-noise ratio, contrast-to-noise ratio and streak indicator. These measures are derived from linear signal theory and generalized and applied for nonlinear signal reconstruction. For quality check, we focus on resolution and CT-number linearity based on a Catphan phantom. All comparisons are made versus the clinical standard, the filtered backprojection algorithm (FBP). In our results, we confirm and substantially extend previous results on iterative reconstruction such as massive undersampling of the number of projections. Errors of projection matrix parameters of up to 1° projection angle deviations are still in the tolerance level. Single defect pixels exhibit ring artifacts for each method. However using defect pixel compensation, allows up to 40% of defect pixels for passing the standard clinical quality check. Further, the iterative algorithm is extraordinarily robust in the low photon regime (down to 0.05 mAs) when compared to FPB, allowing for extremely low-dose image acquisitions, a substantial issue when considering daily CBCT imaging for position correction in radiotherapy. We conclude that the ML method studied herein is robust under clinical quality assurance conditions. Consequently, low-dose regime imaging, especially for daily patient localization in radiation therapy is possible without change of the current hardware of the imaging system.

Kilovoltage beam model for flat panel imaging system with bow-tie filter for scatter prediction and correction.

PURPOSE: Kilovoltage flat-panel imaging systems are used for cone-beam Computed Tomography (CBCT) and digital Tomosynthesis (DTS). Hereby, the presence of scatter and relatively large dose from imaging are challenging factors. In this study a phenomenological beam model was developed to characterize imager response to imaging beams with a bow-tie filter (Varian OBI system). MATERIALS AND METHOD: The kilovoltage beam model was based on dose ratio formalism and thus was using standard concepts of megavoltage dose calculation such as scatter factors, tissue maximum ratio and off-axis ratio. Primary and scatter (head and phantom scatter) were modeled with three Gaussian kernels. Parameters were based on measured transmission images for slabs of solid water of different total thickness and various jaw settings. RESULTS: The beam model was used to evaluate contributions from primary, secondary and tertiary contributions for different geometrical objects such as cylinders and step-like phantoms. Theoretical predictions of radiographs using the model for known objects are consistent with the measurements. CONCLUSION: Secondary and tertiary contributions were interpreted as scatter and can be subtracted from CBCT projections based on the analytical model. Therefore our model can provide a basis for improvement of image quality (less artifacts due to scatter, better contrast and resolution) in CBCT reconstruction.

SU-E-T-163: Thin-Film Organic Photocell (OPV) Properties in MV and KV Beams for Dosimetry Applications.

PURPOSE: To characterize dosimetric properties of low-cost thin film organic-based photovoltaic (OPV) cells to kV and MV x-ray beams for their usage as large area dosimeter for QA and patient safety monitoring device. METHODS: A series of thin film OPV cells of various areas and thicknesses were irradiated with MV beams to evaluate the stability and reproducibility of their response, linearity and sensitivity to absorbed dose. The OPV response to x-rays of various linac energies were also characterized. Furthermore the practical (clinical) sensitivity of the cells was determined using IMRT sweeping gap test generated with various gap sizes. To evaluate their potential usage in the development of low cost kV imaging device, the OPV cells were irradiated with kV beam (60-120 kVp) from a fluoroscopy unit. Photocell response to the absorbed dose was characterized as a function of the organic thin film thickness and size, beam energy and exposure for kV beams as well. In addition, photocell response was determined with and without thin plastic scintillator. RESULTS: Response of the OPV cells to the absorbed dose from kV and MV beams are stable and reproducible. The photocell response was linearly proportional to the size and about slightly decreasing with the thickness of the organic thin film, which agrees with the general performance of the photocells in visible light. The photocell response increases as a linear function of absorbed dose and x-ray energy. The sweeping gap tests performed showed that OPV cells have sufficient practical sensitivity to measured MV x-ray delivery with gap size as small as 1 mm. CONCLUSIONS: With proper calibration, the OPV cells could be used for online radiation dose measurement for quality assurance and patient safety purposes. Their response to kV beam show promising potential in development of low cost kV radiation detection devices.

Stochastic formulation of patient positioning using linac-mounted cone beam imaging with prior knowledge.

PURPOSE: In this work, a novel stochastic framework for patient positioning based on linac-mounted CB projections is introduced. Based on this formulation, the most probable shifts and rotations of the patient are estimated, incorporating interfractional deformations of patient anatomy and other uncertainties associated with patient setup. METHODS: The target position is assumed to be defined by and is stochastically determined from positions of various features such as anatomical landmarks or markers in CB projections, i.e., radiographs acquired with a CB-CT system. The patient positioning problem of finding the target location from CB projections is posed as an inverse problem with prior knowledge and is solved using a Bayesian maximum a posteriori (MAP) approach. The prior knowledge is three-fold and includes the accuracy of an initial patient setup (such as in-room laser and skin marks), the plasticity of the body (relative shifts between target and features), and the feature detection error in CB projections (which may vary depending on specific detection algorithm and feature type). For this purpose, MAP estimators are derived and a procedure of using them in clinical practice is outlined. Furthermore, a rule of thumb is theoretically derived, relating basic parameters of the prior knowledge (initial setup accuracy, plasticity of the body, and number of features) and the parameters of CB data acquisition (number of projections and accuracy of feature detection) to the expected estimation accuracy. RESULTS: MAP estimation can be applied to arbitrary features and detection algorithms. However, to experimentally demonstrate its applicability and to perform the validation of the algorithm, a water-equivalent, deformable phantom with features represented by six 1 mm chrome balls were utilized. These features were detected in the cone beam projections (XVI, Elekta Synergy) by a local threshold method for demonstration purposes only. The accuracy of estimation (strongly varying for different plasticity parameters of the body) agreed with the rule of thumb formula. Moreover, based on this rule of thumb formula, about 20 projections for 6 detectable features seem to be sufficient for a target estimation accuracy of 0.2 cm, even for relatively large feature detection errors with standard deviation of 0.5 cm and spatial displacements of the features with standard deviation of 0.5 cm. CONCLUSIONS: The authors have introduced a general MAP-based patient setup algorithm accounting for different sources of uncertainties, which are utilized as the prior knowledge in a transparent way. This new framework can be further utilized for different clinical sites, as well as theoretical developments in the field of patient positioning for radiotherapy.

Live-wires using path-graphs.

OBJECTIVES: This article discusses our new Path-Graph approach for the interactive Live-Wire segmentation method in 2D applied to pre-segmented data. Furthermore, we examine whether or not the Live-Lane extension provides advantages in combination with pre-segmentation. METHODS: We automatically over-segment the image data in a preprocessing step, using region growing with an automatic seed point generation. The Live-Wire algorithm is applied on this mosaic data by using the outlines of the homogeneous regions as the basis for graph building. We present a new definition of this underlying graph where the edges of the standard graphs are turning into vertices and the vertices of the new graph are defined by the edge connectivity in the standard graph. For better differentiation we name our new graph Path-Graph and the original defined graph Node-Graph. RESULTS: The quality evaluation is done by comparing our segmentation results with existing model data. We show that using the Path-Graph as basis for the Live-Wire algorithm instead of the Node-Graph allows for a finer segmentation. We achieve a reduction of incorrectly classified pixels by 20.66 per cent and a decrease of the mean boundary deviation by 11.61 per cent. Since savings on cost tree calculations are compensated by additional computation time required to compute the Live-Lanes, a performance loss of 2.41 per cent is measured. CONCLUSIONS: Our redefinition of the underlying graph increases the quality of the Live-Wire segmentation. The Live-Lane extension in combination with pre-segmentation is not justified for our data.

Operation planning of correction osteotomies in 3D.

This paper discusses an operation planning system for correction osteotomies. It is based on 3D data obtained from CT/MR of the bone and it allows to perform a 3D planning. The physician can individually determine anatomical landmarks for measuring geometric parameters of the bone like length, angle and torsion angle. In a virtual scene he or she can set a single cut or can remove/insert a wedge, dissecting the bones. The bone parts can be rearranged in 3D space. Optimization routines allow that the physician only defines the position of the cut, the orientation of the cut plane, the rearrangement of the bone and the optimization for the maximal overlap of the cortical bone can be processed automatically. The system is currently in use at the Trauma department at the University of Ulm. A case study shows the results by applying this system.

[Cathi-training on virtual patients for catheter interventions]. / Cathi-training on virtual patients for catheter interventions.

In this paper we present a trainings system for catheter interventions, especially PCTAs also called ballon dilatation. Despite the large number of such interventions the education of the cardiologist is still based on learning on the patient. This means risk to the patient and additional cost. To overcome these problems we developed the CathI system (Catheter Instruction System), a realistic computerbased training system. It provides the physician with the same equipment found in a catheter laboratory, e.g. original control instruments for the flouroscopy system, syringes, catheters, and guide wires. CathI only replaces patient and C-arm by a virtual patient and a virtual x-ray system.

[Computer assisted surgery, 2001 development and prospects. Results of a congress at Reisensburg Castle, 23-24 November 2000]]. / Computer assistierte Chirurgie, Entwicklung und Perspektiven 2001. Ergebnisse einer Arbeitstagung auf Schloss Reisensburg, 23./24.11.2000.

The progress in computer assisted surgery (CAS) is influenced by new technologies in imaging as well as by the input of the users. At present, CAS procedures are established in dorsal spine instrumentation, prosthetics and long bone surgery. Present status and future of CAS was a topic of an expert meeting at the Reisensburg castle. Imaging will speed up in the future using multi-detector techniques. C-arm navigation will gain more information using the 3D technology intraoperatively. CT based navigation procedures are standard in spine and will be established in pelvic surgery. CAS in robotics at the moment means the use of robot-assistance. A new concept is the modality-based navigated surgery, which can be used at various skeletal locations. Visualization of patient data will improve using 3D semi-transparencies with real time update. In the future it will be mandatory to find algorithms to fuse the different possibilities and techniques. A new concept of surgical training is necessary to teach CAS procedures. Therefore discussion must go on to improve these systems.

[Computer-assisted surgery: developments and prospects in 2001. Results of a workshop at Schloss Reisenburg, 23-24 November 2000]. / Computer assistierte Chirurgie, Entwicklung und Perspektiven 2001. Ergebnisse einer Arbeitstagung auf Schloss Reisenburg, 23./24.11.2000.

The progress in computer assisted surgery (CAS) is influenced by new technologies in imaging as well as by the input of the users. At present, CAS procedures are established in dorsal spine instrumentation, prosthetics and long bone surgery. Present status and future of CAS was a topic of an expert meeting at the Reisensburg castle. Imaging will speed up in the future using multi-detector techniques. C-arm navigation will gain more information using the 3D technology intraoperatively. CT based navigation procedures are standard in spine and will be established in pelvic surgery. CAS in robotics at the moment means the use of robot-assistance. A new concept is the modality-based navigated surgery, which can be used at various skeletal locations. Visualization of patient data will improve using 3D semi-transparencies with real time update. In the future it will be mandatory to find algorithms to fuse the different possibilities and techniques. A new concept of surgical training is necessary to teach CAS procedures. Therefore discussion must go on to improve these systems.

Computer assisted treatment of pelvis fractures.

The presented approach is the realization of a minimal invasive treatment of pelvis fractures using the computer aided surgery (CAS). Main problem of tracking of major bone fragments after reposition is solved by implementing of 3D ultrasound to obtain intraoperative bone surfaces. Preoperative and intraoperative data sets are matched. Major fragments are tracked. The real time navigation is possible.