bluuebunny/crossref_metadata_2025 huggingface dataset:
WE‐E‐BRB‐07: EPID Based Verification of Delivered Fluence for VMAT with High Angular Resolution
Authors: Adamson J , Wu Q
Published: November 2011

Purpose: In VMAT, the dose rate, MLC position, and gantry angle change simultaneously, it is important they follow their predefined trajectories to ensure correct dose delivery. Our purpose is to develop an efficient VMAT QA strategy using EPID that is capable of quantifying delivery errors per gantry angle. Methods: For the QA procedure, portal images are acquired continuously during VMAT delivery. The plan is modified automatically so that the two most inferior MLC leaf pairs are open at all control points. A custom built phantom is positioned via image guidance to be visible in all projections of the opened leaf pairs, and is used to measure the angular fraction through which each portal image is acquired. Expected values of delivered MU and beginning and ending MLC positions are calculated from the plan using the measured start and stop gantry angles per image. They are used to compute a predicted detector response using the treatment planning software (Portal Dosimetry, Varian). The calculated portal response is further analyzed against the EPID images in 3D. We performed the QA procedure for a clinical VMAT 170° arc. Results: The mean gantry angle and angular width of each portal image measured using the phantom was shown to be accurate to within 0.06°±0.14° and 0.59°±0.36°, respectively. Conversely, the angle recorded with each portal image had a larger error of 1.04°±0.84°. QA analysis consisted of projecting the measured and predicted data into 3 planes: leaf motion axis vs. cross leaf axis, leaf motion vs. gantry angle, and cross leaf vs. gantry. In each plane intensities are defined by dose, dose rate, MLC positioning, and gantry angle, thereby allowing verification of all essential machine parameters. Conclusions: Accurate and efficient VMAT QA can be performed using EPID and customized phantom and software that provides verification of all plan parameters.
WE‐E‐BRB‐08: Commissioning and Benchmarking a 3D Dosimetry System for Clinical Use
Authors: Thomas A , Newton J , Adamovics J , Oldham M
Published: November 2011

Purpose: To commission and benchmark a 3D dosimetry system for clinical use, in particular, for verification and commissioning of complex radiation treatments like VMAT, IMRT and gated treatments. The system is composed of two parts: a radiochromic plastic dosimeter Presage, which responds to absorbed dose with a linear change in optical‐density; and the Duke Large field of view Optical‐CT Scanner (DLOS). Methods: DLOS commissioning involved creating stray light and spectral corrections, determining the dynamic range, spatial resolution, and noise, and characteristics of source and imaging components. The benchmarking tests were performed on the combined DLOS/Presage system to establish baseline capabilities. These tests consisted of delivering 6 treatments of gradually increasing complexity, and comparing the measured distributions with a gold standard (e.g. machine beam‐data). All studies used standard‐ procedures to ensure consistency. Results: Commissioning: isotropic spatial resolution was sub‐mm (MTF >0.5 for frequencies of 1.5;p/mm) and the dynamic range was ∼ 60dB . Flood field uniformity was 10% and stable after 45minutes. Stray light is small, due to telecentricity, but even the residual can be removed through deconvolution. Benchmarking: the mean 3D passing gamma rate (3%, 3mm, 5% dose threshold) over the 6 benchmark data sets was 97.3% ± 0.6% (range 96%–98%), indicating excellent ability to perform 3D dosimetry. Noise was low at ∼2% for 2mm reconstructions. Conclusions: The DLOS/Presage benchmark tests show consistently excellent performance, with very good agreement to simple known distributions. The telecentric design was critical to enabling fast (∼15mins) imaging with minimal stray light artifacts. The system produces accurate isotropic 2mm3 dose data over clinical volumes (e.g. 16cm diameter phantoms, 12 cm height), and represents a uniquely useful and versatile new tool for commissioning complex therapy techniques. The system also has wide versatility, and has successfully been used in preliminary tests with protons, and kV irradiations.
WE‐E‐BRB‐09: TLD‐100, Alanine, and Ionization Chamber Dosimetric Measurements in Small Megavoltage Photon Fields
Authors: Junell S , Sharpe P , Palmans H , DeWerdl L
Published: November 2011

Purpose: To derive beam quality correction factors for ionization chambers in small and nonstandard field calibration conditions to compare with a NIST‐traceable Cobalt‐60 standard. Methods: Beam quality correction factors for three ionization chambers were determined with thermoluminescent dosimeter and alanine absorbed dose to water measurements. These measurements were performed for ten different calibration conditions ranging from the standards labsˈ Cobalt‐60 reference conditions to small static and composite 6 MV fields, based on the proposed formalism for small and non‐standard fields (Alfonso et al; 2008). The composite field was created using the Pinnacle treatment planning system and mimicked a typical IMRT head and neck treatment with one treatment volume and one organ at risk. Measurements were performed in a specially developed cylindrical acrylic phantom and a standard water phantom. Results: The TLD‐determined beam quality correction factors remained statistically within unity under most of the calibration conditions. The only exception was for the Exradin A19 in a 2 cm × 2 cm field for which it amounted to 1.30. The estimated relative combined standard uncertainty is around 2% (k=1). The alanine‐determined absorbed dose to water yielded beam quality correction factors statistically significantly different from unity. The alanine‐determined beam quality correction factors varied from 0.990 to 1.031 for most situations except again for the Exradin A19 in a 2 cm × 2 cm field for which it amounted up to 1.303. The estimated combined relative standard uncertainty is about 1% (k=1). Conclusions: The results of this work indicate that the calibration coefficient from an ADCL can be applied to the proposed small field and nonstandard field formalism using beam quality correction factors with acceptably small uncertainties. Application of these beam quality correction factors offers improved uncertainty in small and nonstandard treatment techniques.
WE‐E‐BRB‐10: Can 2D and 3D Detector Arrays Identify Multileaf Collimator (MLC) Positional Errors during Smart‐Arc Pre‐Treatment Verification Plan Delivery?
Authors: Calvo O , Kim S , Lei Y , Gutierrez A , Stathakis S , Papanikolaou N
Published: November 2011

Purpose: Evaluate the sensitivity of 2D and 3D dose arrays in detecting multileaf collimator (MLC) positional errors during Smart‐Arc pre‐treatment verification delivery. Materials and Methods: Four Smart‐Arc patient treatment plans of different tumor sites were delivered on three different phantoms: 1) Delta4, 2) Seven29 OCTAVIUS and 3) MatriXX. MLC files for each plan were exported to an in‐house MATLAB program and two set of errors were introduced: 1) Systematic error: MLC bank shifted 1.0, 3.0 and 5.0mm and 2) Random error: Selected MLCs (ten leaf pairs) shifted 1.0, 3.0 and 5.0mm. The new sets of MLCs were used to create six additional plans. A total of seven plans were delivered for each of the patients. The original delivered plans were compared to the TPS plans and statistics acquired. After which, each of the error MLC plans were compared against the original TPS plan and statistics acquired. Finally, each of the error plans were compared against each other and statistics acquired. Results: When the original plan was compared against the error plans, the 1.0mm and 3mm systematic error plans were not detected by any of the arrays: gamma analysis >95% (3%/3mm), 3.0mm gamma analysis >90% (3%,3mm) but bigger errors than 3mm were detected: 5mm <80% (3mm/3%). When comparing the original plan and random error plans all detector arrays failed all plans with gamma analysis <50% (3%/3mm). Finally, when comparing error plans against each other, all detector arrays were not able to differentiate between plans with systematic errors on it showing gamma analysis >97% (3%/3mm), but significant differences were observed between errors plans when random error plans were compared showing gamma analysis <60% (3%/3mm). Conclusions: Detector arrays are able to detect randomized MLC type of error as well as large (>3.0mm) systematic type of error introduced in the MLC.
WE‐E‐BRC‐02: Real‐Time Deformable Registration Using Multi‐Pixel X‐Ray Technology for Image‐Guided Lung Radiotherapy
Authors: Chou C , Frederick B , Chang S , Pizer S
Published: November 2011

Purpose: To study the feasibility of a novel method, CLARET (correction in limited‐angle residues in external beam radiation), for supporting the Nanotube Stationary Tomosynthesis (NST) device to perform real‐time deformable registration in lung IGRT. Methods: We designed a method called CLARET that uses a machine learning strategy. CLARET is a two‐step process: training and IGRT. In the training stage it performs a patient‐specific training that generates sample images from a range of potential treatment deformations. Potential treatment deformations are generated from the principal variations of deformation, which are calculated between the respiratory‐correlated CTs (RCCTs) and their Fréchet mean image by diffeomorphic registration. For each such sample image it generates 2D projections by re‐projecting on the image volume. It computes multi‐scale linear regressions between the deformation parameters and the differences between the projections of the deformed CTs and those of the Fréchet mean CT. In the IGRT stage, the learned regressions are applied iteratively to the successive residues between the radiographs and those of the current estimated CT deformed by the previously predicted parameters. This iteration yields an accurate deformation field for treatment‐time 3D image generation. Results: We tested CLARET using four patientsˈ lung RCCTs with two types of NST geometries: 1) the single‐source projection geometry and 2) the multiple‐source projection geometry. For each patient and geometry a total of 40 simulated treatment‐time NST projections were generated by reprojecting on the target CTs deformed from the patientˈs Fréchet mean RCCT. The mean and standard deviation of the tumor CoG location difference before registration is 0.6792±0.3267 cm. After CLARET registration, results in all geometries yielded sub‐milimeter accuracy. The average computation time is 5 seconds. Conclusions: We have demonstrated the potential of our CLARET method in supporting the NST device to provide real‐time lung IGRT with few limited‐angle projection images.

This research is partially sponsored by Siemens Medical Solutions.
WE‐E‐BRC‐03: Interactive Anatomy Editing: Implicit Function Reshaping via RBF Management
Authors: Hibbard L
Published: November 2011

Purpose: To efficiently visualize and accurately edit presegmented anatomies for radiotherapy planning in a fully 3D setting. Methods: Anatomy representations (contours, surfaces) derived from prior segmentations are recreated as implicit surfaces‐‐the zero level sets of implicit functions f(x,y,z)=k whose shapes are defined by radial basis functions (RBFs) centered on, and along normals to, the zero level (k=0). These smooth and continuous surfaces are re‐shaped by altering the number and arrangement of the RBFs. Using a standard contouring program, the user overdraws the surface profiles in any combination of transverse, sagittal, or coronal views, and the 2D curves comprising the differences between the original surface profiles and the user edit‐contours determine the arrangement of the new RBFs. Constructing smooth shape transitions between the new and old portions of the surface is a challenge‐‐several methods were developed to define that portion of the surface spanned by the edit curves and to insure that the geometric transition from the old to the new surface is smooth and accurately renders the intended change. The surface reconstructed between the user‐drawn edit contours is a form of spline interpolation, so that a few inputs can smoothly redefine a large surface. Extensive parallelization enables this expensive computation to run in nearly real time. Results: The management of RBFs removed from the original shape and added to the new shape is essential to obtain a comprehensible and correct updated surface. Such surfaces are smooth and continuous and accurately represent the anatomy viewed in the drawing program single plane views. The updates are computed in 1–3 s and the user can operate in those views that provide the greatest shape information. Conclusions: We present a novel method to efficiently edit 3D anatomic shapes by operating directly on the implicit surface representing the anatomy.

This work was supported by Elekta.
WE‐E‐BRC‐04: Quantitative Endoscopy for Improved Target Delineation in Planning Radiation Therapy
Authors: Weersink R , Qiu J , Daly M , Cho J , Breen S , Hope A , Sharpe M , Jaffray D
Published: November 2011

Purpose: To improve target delineation in the radiation therapy planning process by quantitatively registering endoscopic contours traced on endoscopic images to volumetric imaging. This method is especially useful for target delineation in head and neck and esophageal cancers. Methods: We have developed technology that registers endoscopic images to CT images by tracking and registering the position and orientation of the endoscope relative to the CT image set using electromagnetic sensors embedded in the endoscope. After 2D to 3D image registration, users can contour regions‐of‐interest visible in the 2D endoscopic view. A mesh is created on the interior of the ROI and projected onto the 3D image data, registering the ROI with the volumetric image. This 3D ROI can be exported into the treatment planning software (TPS).The technology was tested on an anatomical head phantom based on a subject image with test “lesion” created by soaking a pad with CT contrast agent so that the lesion was visible in the TPS images. The contouring accuracy was tested by comparing the average minimum distance between the endoscopy‐derived and TPS contours. Results: A CT image of the head phantom was acquired followed by endoscopic imaging. The lesion was contoured in the endoscopic image and the resulting mesh contour imported imported into Pinnacle. The lesion was contoured in Pinacle using CT# threshold. The average minimum distance between the endoscopy and TPS contours was 0.96mm with 93% of all points in the endoscopy ROI within 1.5 mm of any point within the TPS ROI. This accuracy is limited by the CT imaging resolution and the EM sensor accuracy. Conclusions: We have demonstrated that lesions can be contoured from 2D endoscopic images and registered to 3D volumetric data sets with an accuracy of ±1 mm.
WE‐E‐BRC‐05: Voxel Based Four Dimensional Tissue Deformation Reconstruction (4DTDR) Validation Using a Real Tissue Phantom
Authors: Szegedi M , Hinkle J , Joshi S , Sarkar V , Rassiah‐Szegedi P , Wang B , Salter B
Published: November 2011

Purpose: Calculation of four dimensional (4D) dose distributions requires the remapping of dose calculated on each available binned phases of the 4DCT onto a reference phase for summation. Deformable image registration (DIR) is usually used for this task. This project validates a type of new algorithm, using 4D tissue deformation reconstruction (4DTDR) from all 4DCT generated images (or projections) to confirm voxel to voxel accuracy for the complete motion path and future 4D dose calculations. Methods: Three electro‐magnetic‐tracking (EMT) fiducial were implanted into fresh porcine liver and animated in a clinically realistic phantom with highly reproducible hysteresis motion pattern previously reported on. After 4DCT acquisition, all data was copied and fiducial locations were masked in the copied set. All images were sent to the 4DTDR for reconstruction. The original 4DCT data (with fiducials) was sampled in 20 CT phase sets and fiducialsˈ coordinates were recorded, resulting in time‐resolved fiducial motion paths. Measured values of fiducial location were compared to that measured through EMT and those calculated by 4DTDR. Results: The performance of the 4DTDR was measured to have average accuracy of 1.86 mm over all 20 phases (4.54 mm max error) in time and location, calculating a motion path that correctly represents measured hysteresis. EMT measurement confirms 4DCT and 4DTDR values. Conclusion: Accuracy of deformation within tissue necessitates the understanding of motion accuracy over the whole motion path of deformation. Validation of the actual voxel path over the period adds a higher level of accuracy, leading away from typically quoted end‐to‐end accuracy to a definition that includes all motion locations at any moment or any location.
WE‐E‐BRC‐07: Evaluate Reproducibility of 4DCT Registration‐Based Lung Ventilation Measurement with Gamma Comparison Method
Authors: Du K , Ding K , Cao K , Reinhardt J , Christensen G , Bayouth J
Published: November 2011

Purpose: The regional lung pulmonary function can be calculated by computing the Jacobian of image registration deformation field. Radiation‐induced pulmonary function changes are assessed by comparing pulmonary function before and after radiation therapy (RT). Due to the probably different breath pattern and effort, uncertainties from 4DCT imaging and registration error, we need to first establish the measurement reproducibility. We also introduce gamma comparison method to compensate space disalignment in two distributions. Methods: Two repeated 4DCT data sets scanned with 30 minutes interval before RT from two patients are used in this study. Tissue volume preserving nonrigid registration algorithm with Laplacian regularization constraints was applied to register the maximum exhalation image to the maximum inhalation image for the calculation of local lung expansion as a measurement of regional pulmonary function in two scans. We compared the two pulmonary functions and analyzed the pulmonary function ratio map. Gamma comparison method is introduced to tolerate possible error in image acquisition and image registration. Mean and standard deviation of pulmonary function ratio map and gamma pass percent are calculated to measure reproducibility. Results: The registration accuracy analysis indicated our registration error is on the order of 1.0 mm. Most lung tissue has a reproducible pulmonary function. Reproducibility near the diaphragm is worse than other regions. The standard deviation of function ratio map is respectively 0.0352 and 0.0495. The gamma comparison pass percent is respectively 84% and 87%. Further plots suggest most of the lung function is reproducible in 2 scans. Conclusions: We analyzed the reproducibility to measure regional pulmonary function using 4DCT and image registration. We compared the regional lung function in two repeated 4DCT scan and discussed the function ratio map. We also introduced a gamma comparison method to quantify reproducibility.

This work was supported in part by NIH grant HL079406 and EB004126.
WE‐E‐BRC‐08: Evaluation of a Probabilistic Non‐Rigid Registration Method for Improved Intra‐Operative Target Definition in 125‐I Permanent Prostate Implants
Authors: Pursley J , Risholm P , Fedorov A , Tuncali K , Fennessy F , Wells W
Published: November 2011

Purpose: To evaluate the use of a non‐rigid registration method for improved intra‐operative target definition in 125‐I permanent prostate implants. Methods: The validation dataset was created from 10 MRI‐guided prostate biopsy patients with both diagnostic (with endorectal coil) and intra‐procedural (without endorectal coil) 3 Tesla MRI scans under an IRB approved protocol. A biomechanical‐based probabilistic non‐rigid registration method was adapted to register diagnostic to intra‐procedural images by matching the contoured prostate boundaries. The probabilistic framework provides a collection of prostate configurations under deformation, or a marginal probability map for a given location to be identified as inside the prostate by the registration. The marginal probability map was compared to the intra‐procedural prostate contour. 125‐I treatment plans were generated for the intra‐procedural scans. Results: In two cases we find that ∼5% of the prostate volume within the 50th percentile of the marginal deformed probability is not included in the intra‐procedural contour, and 3–4% of the intra‐procedural prostate volume is not included in any of the deformed configurations. Different regions of the prostate have varying uncertainties; preliminary results show margins of 1–2 mm near mid‐gland and 3–4 mm around the apex. We present geometric uncertainties and the resulting variation of dosimetric quantities in the base, mid‐gland, apex and peripheral zone of the prostate. Conclusions: We study the feasibility of using a probabilistic non‐rigid registration method for supplementing intra‐procedural images with diagnostic MR images. The method is evaluated geometrically and dosimetrically, which quantifies the methodˈs ability to provide intra‐procedural estimation of the accuracy of the deformed configurations. This method will be applied to registration of diagnostic MR with intra‐procedural transrectal ultrasound images to improve visualization of the prostate apex and substructure, which could provide improved prostate boundary definitions with uncertainty margins to guide the development of intra‐operative brachytherapy treatment plans.

This work was supported by NIH grants 1U41RR019703‐01A2, 1R01CA111288‐01A1,P01‐CA67165,andU01CA151261.
WE‐E‐BRC‐09: 4D CT Image Based Bifurcation Trajectory Tracking in the Lung
Authors: Xiong G , Xing L
Published: November 2011

Purpose: Vessel and bronchial bifurcations are ubiquitous in the lungs and their motions caused by respiration are detectable in 4D CT and serve as valuable internal fiducial markers for studying and monitoring the respiratory motion patterns of the lungs. Bifurcations also serve as reliable landmarks for validation of deformable registration models. In this work, we report the first systematic investigation of motion patterns of a large collection of lung bifurcations. Methods: More than 500 bifurcations are identified automatically on a reference image. Each bifurcation is tracked separately. Trajectory of a bifurcation is defined by a B‐spline space curve with 5 control points with imposed cyclic constraints. A metric is defined as the combination of the correlation coefficients from all images with respect to the reference image. It is used to measure how well the image intensities on the trajectory match. Correlation coefficient is employed since it is bounded and straightforward to indicate the reliability of a tracked trajectory. Finally, an optimization strategy based on the L‐BFGS method is employed to optimize the metric parameterized by the coordinates of control points. Local extrema, if found, are suppressed by improving the initial conditions by random walks from pair‐wise optimizations. Results: We successfully tested our method in 5 cases. With automatically detected bifurcations, the tracked trajectories correspond to image intensities of high correlation coefficients. Non‐homogeneous and hysteretic motion is clearly observable in all cases. For validation, the tracking error is measured by computing the distance between the tracked and manual bifurcations. On average, the error is within the voxel size in all cases. Conclusions: We have shown that our approach can track the motion of the bifurcations in 4D CT images of the lung accurately. It may substitute the invasive fiducial markers as noninvasive counterparts for future real‐time volumetric imaging guided radiation therapy.
WE‐E‐BRC‐10: Quality Assurance of Deformation Algorithms Using a Two‐Dimensional Deformable Phantom
Authors: Kirby N , Chuang C , Pouliot J
Published: November 2011

Purpose: Clinical implementation of deformation algorithms requires dependable quality assurance techniques. A two‐dimensional deformable phantom that can objectively verify the accuracy of the algorithms throughout an entire slice of the anatomy is proposed. Methods: The phantom represents a single plane of the anatomy for a head and neck patient. Inflation of a balloon catheter inside the phantom simulates tumor growth. CT and camera images of the phantom are acquired before and after its deformation. Non‐radiopaque markers reside on the surface of the deformable anatomy and are visible through an acrylic plate, which enables an optical camera to measure their positions; thus, establishing the ground truth deformation. This measured deformation can be directly compared to the predictions of deformation algorithms, using several similarity metrics, and it can be applied to create a simulated deformation for a patient CT, which can also be used to test algorithm accuracy. The ratio of the number of points with more than a 3 mm deformation error over those that are deformed by more than 3 mm was used for an error metric. A comparison of the deformation algorithm accuracy for the phantom CTs and the simulated CTs evaluates the adequacy of the phantom electron density heterogeneity. Results: The balloon catheter deforms 32 out of the 54 surface markers by more than 3 mm. Different deformation errors result from the different similarity metrics. The most accurate deformation results for the phantom CTs had an error of 75%, compared to 25% for the simulated CTs. Conclusions: The developed phantom demonstrates its utility for verifying deformation algorithms and determining which is the most accurate. The reduction of the deformable anatomy to a two‐dimensional system allows for the use of non‐radiopaque markers, which do not influence deformation algorithms. This is the fundamental advantage of this verification technique.
WE‐E‐214‐03: Biology and Physiology of Targeted Radionuclide Therapy (TRT)
Authors: Williams L
Published: November 2011

Radiolabeled agents are being developed for TRT (Targeted Radionuclide Therapy). Included in the 50 to 200 nm scale of this project are liposomes, short segments of DNA or RNA, nanoparticles and proteins. Because of possibly multiple lesion sites, these radiopharmaceuticals (RPs) are usually given by IV injection. Targeting, which requires a number of hours to days to accomplish, is effected by various means. The simplest method is to have the agent pass out of the blood and into the tumor space using the fenestrations in tumor capillaries. Liposomes are one such example whose membranes are dissolved in the lesion so as to release vesicle contents. Among the most specific localization processes is protein binding to a molecular marker on ‐ or near ‐ the tumor cell. Among such markers are Carcinoembryonic Antigen (CEA) and human epidermal growth factor receptor 2 (HER2). CEA is associated with colon, lung and some breast cancers, while HER2 is a breast cancer marker in approximately 25% of patients. These antigens are found in normal colon lumen and heart muscle respectively. A protein used in finding a molecular target may be something as simple as a mouse‐derived antibody or an engineered protein construct. One constraint is that proteins from alien species eventually generate their own human antibodies when repeatedly used in a given patient. This effect can be moderated by DNA manipulation of the alien antibody to change its structure to a more human‐like amino‐acid sequence. Use of a blood‐injection for the RP may result in sequestration by a normal tissue such as the liver or kidneys. In the renal case, small proteins (<25 kDa) would be very rapidly taken out of circulation so as to prevent significant tumor targeting. Various strategies have been developed to minimize sequestration; e.g., blocking or use of polyethylene glycol covering molecules (“stealth”) to prolong protein circulation. Because of the large numbers of possible RPs, it is necessary that preselection be done on any putative clinical RP. A figure of merit (FOM) may be used to choose one of a series of agents dedicated to the same tumor type; e.g., cognate antibodies to CEA. Both imaging and therapeutic FOMs have been developed. These indicators are used to differentiate RPs using animal data. This preferential ordering process is needed since the number of agents is large while volunteers for research studies are only a small fraction (2 to 5%) of the total patient population. One is still left with the question of the relationship between animal and clinical biodistribution data.

Learning Objectives:

1. Know the types of agents presently being studied for TRT.

2. Understand the reasons for tumor targeting by engineered pharmaceuticals (RPs).

3. Realize the importance of the RP blood curve for the targeting process.

4. Use of Figures of Merit to select an optimal imaging or therapy agent.
WE‐E‐220‐01: Focused‐Ultrasound Mediated Blood‐Brain Barrier Disruption
Authors: McDannold N
Published: November 2011

Purpose: Numerous studies have shown that ultrasound bursts combined with an ultrasound contrast agent results in a temporary disruption of the blood‐brain barrier (BBB). Combined with focused ultrasound systems that can precisely focus ultrasound through the human skull, a noninvasive means for targeted drug delivery becomes possible. As the BBB, which normally serves to protect the central nervous system, prevents most substances from being delivered to the brain from the circulation, this approach could have a large impact on treatments for brain tumors and other disorders. This talk will review recent results from recent studies testing the safety and efficacy of this approach. Methods: Ongoing studies at our institution are testing repeated BBB disruption sessions in nonhuman primates using a clinical MR‐guided focused ultrasound system (ExAblate 4000, InSightec). Additional studies are being performed to test whether combining BBB disruption with Herceptin, an antibody‐based drug for HER2‐positive breast cancer that often fails with brain metastases, can improve outcomes in rats implanted with human breast cancer cells. Relevant works on safety and efficacy of this technique from other research groups will also be presented. Results: We have found that BBB disruption can be achieved repeatedly in nonhuman primates without MRI‐based evidence of tissue damage or functional deficits. Furthermore, the disruption has been found to only occur at targeted locations in the brain. Tests in the breast cancer brain metastases model have shown improvement in tumor growth rate, with tumors in 4/10 animals in the Herceptin+BBB disruption group disappearing. This result was not achieved in the control groups. Conclusion: These and other similar studies, while still ongoing, are encouraging and supportive of preparing for initial human tests of this technique. Methods to control and monitor the procedure, however, are currently lacking and will be necessary for widespread use of the technique.

Learning objectives:

1. Learn how ultrasound and ultrasound contrast agents are applied for blood‐brain barrier disruption

2. Learn about ongoing safety and efficacy studies of the technique

3. Learn about need for methods to guide and monitor the ultrasound exposures
WE‐E‐220‐05: On‐Thermal Pulsed Focused Ultrasound for Cancer Therapy
Authors: Ma C , Cvetkovic D , Chen X , Chen L
Published: November 2011

Purpose: MR guided focused ultrasound (MRgFUS) has been investigated for ablative therapy and drug enhancement for gene therapy and chemotherapy in our institution. The aim of this work is to explore the feasibility of pulsed focused ultrasound (pFUS) for non‐thermal cancer therapy using an in vivo animal model. Methods: An InSightec ExAblate 2000 with a 1.5T GE MR scanner was used in this study. Suitable ultrasound parameters were investigated to perform non‐thermal sonications, keeping the temperature below 42C as measured in real time by MR thermometry. LNCaP cells (106) were injected into the prostates of male mice (n=20). When tumors reached the volume of 100±50mm3 on MRI, the tumor‐bearing mice (n=8) were treated with pFUS (US frequency 1MHz; 25W acoustic power; pulse frequency 1Hz; 0.1 duty cycle) for 60sec. A total of 4–6 sonications were used to cover the entire tumor volume under MR image guidance. The animals were allowed to survive for 4 weeks after the treatment. The tumor growth was monitored on MRI and compared with the control group (n=12). Results: Significant tumor growth delay was observed in the tumor‐bearing mice treated with pFUS. The mean tumor volume for the pFUS treated mice remained the same 1 week after the pFUS treatment while the mean tumor volume of the control mice grew 42% over the same time. Two weeks after the pFUS treatment the cont Conclusions: Our results demonstrated that non‐thermal pFUS has a great potential for cancer therapy. Further experiments are needed to derive optimal ultrasound parameters and fractionation schemes to maximize the therapeutic effect. This work is supported by Focused Ultrasound Surgery Foundation, Varian Medical Systems, DOD PC073127 and DOD BC102806. Technical support from InSightec is acknowledged.
WE‐G‐224‐01: History Symposium ‐ Historical Aspects of Brachytherapy
Authors: Rothenberg L , Hilaris B , Germain J St.
Published: November 2011

This presentation will review some of the historic developments in brachytherapy treatment. The early history of brachytherapy is primarily the history of radium and its daughter products, particularly 222Rn. Much of this history is interwoven with the histories of institutions in North America and Europe, such as the Memorial Hospital, Harvard Medical School, the Huntington Memorial Hospital, closed in 1941, with its activities transferred to the Massachusetts General Hospital, M.D. Anderson Hospital, the Mayo Clinic, the Radium Institute of Paris, the Radium Hemmet in Stockholm and the Holt Radium Institute in Manchester. Noted personalities such as William Duane, Gioacchino Failla, Robert Abbe, Henry Janeway, Victor Hess and Enrico Fermi all worked with “radium cows” which supplied radon gas in seeds and tubes for treatment. Edith Quimby and Herbert Parker made significant advances in dosimetry, developing systems for planar implants and more complex geometries. Noted physicians such as Gilbert Fletcher, Ulrich Henschke, Luis Delclos and Nisar Syed developed applicators and procedures for using radioactive sources for treatment. Modern brachytherapy techniques were developed in the 1960ˈs with the search for radium‐substitute materials including 125I and 192Ir. This time period also saw the development of remote afterloading by Henschke and his associates and the adaptation of computer technology which facilitated the development of more accurate, user friendly techniques of dosimetry. In the modern era, remote afterloading in conjunction with high dose rate radioactive sources (HDR) and the use of 125I and 103Pd seeds have become staples of modern treatment.
WE‐G‐BRA‐01: A Framework to Determine Risk of Pneumonitis Following Radiotherapy for Lung Cancer
Authors: Chawla A , Marks L , Deasy J , Bradley J , Das S
Published: November 2011

Purpose: To assess external validity of a framework, which was previously developed to predict the incidence of radiation‐induced pneumontis in patients following radiotherapy for lung cancer, by testing it on an alternate dataset (other than the one used to develop it). Methods: The study employed two independent datasets: 1) a Duke University dataset of 219 patients, of whom 34 were diagnosed with post‐radiotherapy pneumonitis; and 2) a Washington University (WashU) dataset of 219 patients, of whom 52 developed pneumonitis post‐radiotherapy. While the Duke dataset was used to develop the framework, the WashU dataset was used to assess its validity. The framework was based on a predictive model that combined results from four machine learning models into a single fused model using a Bayesian decision fusion methodology. The results of testing the framework on the WashU dataset was measured in terms of the area under ROC curve (AUC) and compared to the AUC value obtained by Mean Lung Dose (MLD) — a metric commonly used to discriminate between patients with and without pneumonitis. Results: The framework yielded an overall AUC of 0.84 for cross‐validated testing on Duke data. Six patient features were identified as most significant. They consisted of two dose features: EUD (a=1.3) and V30; and four non‐dose features: female gender, tumor in central lung location, adenocarcinoma, and chemotherapy prior to radiotherapy. Most notably, when tested on the WashU dataset, the framework yielded an AUC value of 0.73. In comparison, the AUC value obtained by employing MLD values was only 0.68. Conclusions: Based on testing with an independent dataset, the framework to predict the incidence of radiation‐induced pneumonitis appears to be fairly robust. The framework may potentially be used in the clinic to improve the treatment decision‐making process.
WE‐G‐BRA‐02: Model for Time‐Dependent Radiation‐Induced Lung Disease Risk Based on Systematic Image‐Based Scoring and Monte‐Carlo Dose Calculations
Authors: Lee S , Stroian G , Seuntjens J , El Naqa I
Published: November 2011

Purpose: To construct an analytical model for radiation‐induced lung injury (RILD) risk using computed tomography (CT) image analysis correlated to Monte Carlo (MC) dose calculations along with investigation of the modelˈs post‐RT dependency. Methods: The extent of RILD was segmented on the difference CT image between a planning CT image and registered post‐RT diagnostic CT image. Radiation dose was calculated using the anisotropic analytical algorithm (AAA) and MC methods. The segmented RILD was spatially correlated with the dose distribution to generate a dose‐response curve for each of 39 follow‐up studies from 12 subjects. The response curves were grouped into 6 follow‐up periods with 3 months intervals according to the time elapsed since the completion of RT. For each period, a probit function derived from the Lyman‐Kutcher‐Burman (LKB) model was fit to the patient data with the two adjustable parameters: TD50 (dose at 50% chances of complication) and m (steepness of the curve). Results: TD50 demonstrated a monotonic increase from its initial level (73 Gy/77 Gy for AAA/MC dose) to its peak (130 Gy/116 Gy) at 9∼12 months post‐RT after which it fell to 85 Gy/80 Gy beyond 15 months post‐ RT. The change in TD50 occurred coincidently with the decrease in the proportion of injured lung volume, demonstrating the association between TD50 and the severity of RILD. The value of m significantly decreased in time from its initial values (0.51/0.55) to 0.24/0.25 beyond 15 months post‐RT. This suggests a transition in the dose‐response from a linear‐no‐threshold to nonlinear‐threshold type behavior. Replacement of AAA calculation by MC did not yield a significant difference in the fitting parameters. Conclusions: Time‐dependent results from the analytical modeling of RILD dose response indicates the transition from early to late radiation effects and the necessity to incorporate a temporal factor into the current time‐static RILD risk models.
WE‐G‐BRA‐04: Bootstrapping Guards against Overfitting in Multivariate NTCP Modeling with Automated Variable Selection
Authors: van der Schaaf A , Xu CJ , van ˈt Veld AA , Langendijk JA , Schilstra C
Published: November 2011

Purpose: The use of multivariate normal tissue complication probability (NTCP) models applying logistic regression and automated variable selection has increased in recent years. The extensive data exploration in this methodology to find an optimal subset of predicting factors is often effective. However, the main risk of this approach is overfitting, resulting in lower true prediction power than initially estimated. Bootstrapping is an accepted method to reduce the risk of overfitting. The main purpose of the current study was to quantify its effectiveness for data with typical characteristics for multivariate NTCP modeling and various set sizes by measuring overfitting in simulations. Methods: A method was developed to generate simulated data with statistical properties similar to real clinical data sets, enabling repeated modeling and cross‐validation with independent data sets. Characteristics of three clinical data sets from radiotherapy treatment of head and neck cancer patients were used to simulate data with set sizes between 50 and 1000 patients. We implemented a bootstrapping method using forward variable selection. We measured for each resulting model the estimated and true prediction power, and the selected and true optimal number of included variables. Results: Bootstrapping selects on average the true optimal number of variables for all different data characteristics and set sizes (mean deviation: −0.32±0.20 SEM), but with considerable spread. Both the true and estimated prediction power converge asymptotically towards a maximum prediction power for large data sets, indicating that, despite the spread around the optimal number of selected variables, the bootstrapping technique is not overfitting for data sets of sufficient size. Severe overfitting (true prediction power worse than random guessing) was found in our analysis only for small data sets (95% of cases had <33 events). Conclusions: Bootstrapping guards multivariate NTCP modeling against overfitting for data sets of sufficient size (typically >32 events in our simulations).
WE‐G‐BRA‐06: Radiotherapy Planning for Glioma Based on a Computational Tumor Growth Model
Authors: Unkelbach J , Menze B , Konukoglu E , Shih H , Ayache N , Bortfeld T
Published: November 2011

Purpose: We investigate treatment planning for intensity‐modulated radiotherapy (IMRT) for glioma based on a computational tumor growth model. Currently, the target consists of the tumor mass visible on MRI plus a 1–2 centimeter isotropic expansion to account for tumor cell infiltration into adjacent brain tissue. Observations suggest that glioma primarily grow along white matter fiber tracts. Accounting for the anisotropic infiltration pattern may potentially improve the efficacy of radiotherapy and prolong survival. Methods: We assume that tumor growth is characterized by local proliferation of tumor cells and diffusion into neighboring tissue. Mathematically, this can be described via a partial differential equation of reaction‐diffusion type (Fisher‐Kolmogoroff‐Equation). Diffusion‐Tensor‐Imaging provides the spatial distribution of the diffusion tensor. Solution of the model equations yields a spatial distribution of the tumor cell density. Radiation‐induced cell kill is described via the linear‐quadratic cell survival model. Modification of current treatment planning procedures can be approached in three steps: 1) the target contour is adaped to match an isoline of the tumor cell density while keeping the total volume constant; 2) dose within the target can be redistributed to maximize overall cell kill while keeping the integral dose constant; 3) unavoidable dose outside the target can be redistributed to affect brain tissue more likely to be infiltrated by tumor cells. Results: Treatment planning studies suggest that overall cell survival can be reduced by 1–3 orders of magnitude compared to the isotropic margin approach — depending on model parameters. Accounting for uncertainties in model parameters reduces the expected benefit, but a sensitivity analysis over a range of realistic parameters suggests that substantial improvements can be expected. Conclusions: Since current planning procedures based on isotropic margins do not reflect known growth characteristics of glioma, computational tumor growth models have the potential to improve radiotherapy efficacy despite uncertainties in model parameters.

J Unkelbach receives funding from Philips Medical Systems; E Konukoglu receives funding from Microsoft Research.
WE‐G‐BRA‐08: Evaluation of Dosimetric Parameters by ROC Curve with Radiation Induced Pneumonitis and Esophagitis of Non‐Small Cell Lung Cancer(NSCLC) Treated by Three‐Dimensional Conformal Radiotherapy(3DCRT)
Authors: Zhu S , Liu Z , Su J , Li J , Shen W , Wang Y
Published: November 2011

Purpose: To understand the correlation between radiation induced pneumonitis (RIP) and esophagitis (RIE) with dosimetric parameters for patients treated using 3‐D conformal radiation therapy (3DCRT) for non‐small cell lung cancers (NSCLC). Methods: Dosimetric parameters of dose‐volume histograms from 3DCRT plans for 104 NSCLC patients treated between 2000 to 2004 from our hospital were retrospectively analyzed. The prescription doses ranged from 60–78Gy with a median dose of 66Gy. The RIP and RIE were assessed for each patient during the treatment and follow‐up within 3 months after treatment completion. The correlation between dosimetric parameters with RIP and RIE were evaluated by univariate and multivariate analysis using Logistic Regression Model of SPSS 11.0 software. The predictive ability of parameters was assessed with receiver operating characteristic (ROC)curves. The area under the curve (AUC) was used to filter cut‐off values for predictive RIP and RIE. Results: The rate of RIP>=2 grade was 38.3% for patients. Univariate analysis showed that the lung mean dose and volumes receiving doses from 5 to 40Gy (V5–V40)were important factors for predicting RIP. Multivariable analysis indicated that lung V35 was likely to be an independent factor. The optimal cut‐off value for lungV35 was 20.75%, corresponding to sensitivity of 66.10% and specificity of 81.00% in ROC curve. The rate of RIE was 46.2%. Multivariate analysis showed that both GTV and PTV of NSCLC, and esophagus V60 were the independent parameters for predicting RIE. The optimal cut‐off value for esophagus V60 was 12.50%, corresponding to sensitivity of 81.30% and specificity of 69.60% in ROC curve. It was found that there was significantly difference between AUC of ROC curve for esophagus V60 and those for GTVˈs and PTVˈs of NSCLC (P<0.05). Conclusions: lung V35 and esophagus V60 were likely to be the independent factors predicting of RIP and RIE, respectively.

Our funding support received from National Natural Science Foundation of China (30870743).