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Importance Unresected locally advanced non–small cell lung cancer (LA-NSCLC) shows poor survival outcomes even after aggressive concurrent chemoradiotherapy. Whether metformin, a diabetes agent that inhibits the mitochondria oxidative phosphorylation chain, could improve radiotherapy and chemotherapy response in LA-NSCLC remains to be studied. Objective To examine whether metformin, given concurrently with chemoradiotherapy and as consolidation treatment, could improve outcomes in patients with LA-NSCLC. Design, Setting, and Participants The Ontario Clinical Oncology Group Advanced Lung Cancer Treatment With Metformin and Chemoradiotherapy (OCOG-ALMERA) study was a multicenter phase 2 randomized clinical trial. Patients were stratified for stage IIIA vs IIIB LA-NSCLC and use of consolidation chemotherapy. The trial was designed to enroll 96 patients with unresected LA-NSCLC who did not have diabetes. The trial was conducted from September 24, 2014, to March 8, 2019. Interventions Patients were randomized to platinum-based chemotherapy, concurrent with chest radiotherapy (60-63 Gy), with or without consolidation chemotherapy or the same treatment plus metformin, 2000 mg/d, during chemoradiotherapy and afterward for up to 12 months. Main Outcomes and Measures The primary outcome was the proportion of patients who experienced a failure event (ie, locoregional disease progression, distant metastases, death, and discontinuation of trial treatment or planned evaluations for any reason within 12 months). Proportions were compared using a 2-sided Fisher exact test. Conventional progression-free and overall survival were estimated using the Kaplan-Meier method. Adverse events were graded with Common Terminology Criteria for Adverse Events, version 4.03. All randomized patients were included in an intention-to-treat analysis. Results The trial was stopped early due to slow accrual. Between 2014 and 2019, 54 patients were randomized (26 in experimental arm and 28 in control arm). Participants included 30 women (55.6%); mean (SD) age was 65.6 (7.6) years. Treatment failure was detected in 18 patients (69.2%) receiving metformin within 1 year vs 12 (42.9%) control patients (P = .05). The 1-year progression-free survival rate was 34.8% (95% CI, 16.6%-53.7%) in the metformin arm and 63.0% (95% CI, 42.1%-78.1%) in the control arm (hazard ratio, 2.42; 95% CI, 1.14-5.10) The overall survival rates were 47.4% (95% CI, 26.3%-65.9%) in the metformin arm and 85.2% (95% CI, 65.2%-94.2%) in the control arm (hazard ratio, 3.80; 95% CI, 1.49-9.73). More patients in the experimental arm vs control arm (53.8% vs 25.0%) reported at least 1 grade 3 or higher adverse event. Conclusions and Relevance In this randomized clinical trial, the addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with combined modality therapy alone. Metformin is not recommended in patients with LA-NSCLC who are candidates for chemoradiotherapy. Trial Registration ClinicalTrials.gov Identifier:NCT02115464

In external beam radiation therapy (EBRT), skin dose measurement is important to evaluate dose coverage of superficial target volumes. Treatment planning systems (TPSs) are often inaccurate in this region of the patient, so in vivo measurements are necessary for skin surface dose estimation. In this work, superficial dose distributions were measured using radiochromic translucent poly(vinyl alcohol) cryogels. The cryogels simultaneously served as bolus material, providing the necessary buildup to achieve the desired superficial dose. The relationship between dose to the skin surface and dose measured with the bolus was established using a series of oblique irradiations with gantry angles ranging from 0° to 90°. EBT‐2 Gafchromic film was placed under the bolus, and the ratio of bolus‐film dose was determined ranging from 0.749 ± 0.005 to 0.930 ± 0.002 for 0° and 90° gantry angles, respectively. The average ratio over 0–67.5° (0.800 ± 0.064) was used as the single correction factor to convert dose in bolus to dose to the skin surface. The correction factor was applied to bolus measurements of skin dose from head and neck intensity‐modulated radiation therapy (IMRT) treatments delivered to a RANDO phantom. The resulting dose distributions were compared to film measurements using gamma analysis with a 3%/3 mm tolerance and a 10% threshold. The minimum gamma pass rate was 95.2% suggesting that the radiochromic bolus may provide an accurate estimation of skin surface dose using a simple correction factor. This study demonstrates the suitability of radiochromic cryogels for superficial dose measurements in megavoltage photon beams.

Lung stereotactic-body radiotherapy (SBRT) places additional requirements on targeting accuracy over standard approaches. In treatment planning, a tumour volume is geometrically expanded and the resulting planning target volume (PTV) is covered with the prescribed dose. This ensures full dose delivery despite various uncertainties encountered during treatment. We developed a retrospective technique for optimizing the PTV expansion for a patient population. The method relies on deformable image registration (DIR) of the planning CT to a treatment cone-beam CT (CBCT). The resulting transformation is used to map the planned target onto the treatment geometry, allowing the computation of the achieved target/PTV overlap. Basic validation of the method was performed using an anthropomorphic respiratory motion phantom. A self-validation technique was also implemented to allow estimation of the DIR error for the data being analyzed. Our workflow was used to retrospectively optimize PTV margin for 25 patients treated over 93 fractions. Targets for these patients were contoured on 4D CT images. SBRT delivery followed CBCT acquisition and a couch correction. A post-treatment CBCT was also acquired in some cases. Our basic validation demonstrated that the DIR-based technique is capable of transforming target volumes from planning CTs to treatment CBCTs with sub-mm accuracy. Our clinical analysis showed that the minimum percentages of target volumes covered for 3, 4, and 5 mm PTV margins were 92.1, 97.6, and 99.2, respectively. Analyzing data acquired before and just after treatment demonstrated that margins exceeding 5 mm did not significantly improve coverage. Finally, a 5 mm PTV margin achieved ⩾95% target volume coverage with ⩾95% probability. Our technique is accurate, automated, self-validating, and incorporates complex ITV shapes/deformations to allow PTV margin optimization. The analysis of clinical data indicates a 5 mm PTV margin is optimal for our process. This approach is generalizable to other disease sites and treatment strategies.

Intensity modulated radiation therapy (IMRT) is an advanced technique used to concentrate the prescribed dose in the tumour while minimizing exposure to healthy tissues. Success in IMRT is greatly dependent upon the localization of the target volume and normal tissue, thus accurate contouring is crucial. In this paper, we describe an automated atlas-based image contouring system and our approach for improving the system by performing a full-scale optimization of registration parameters using high-performance computing. To achieve this, we use manually pre-contoured CT images of ten head and neck patients. For any parameter set, each patient data is registered with the remaining patients. Accuracy of the resulting contours is determined automatically by comparing their overlap with manually defined targets using Dice's similarity coefficient (DSC). This allows us to compare all permutations of the image registration parameter sets and input data to investigate their impact on final contour accuracy. Investigating the parameter space required 27,000 image registrations and 216,000 DSC computations. To perform these registrations we introduced a large cluster of high-performance computers and developed a parallel testing harness. The metrics collected from the tests show a wide range of performance, indicating that parameter selection is crucial in our contouring system. By selecting an optimized parameter set, we increased the mean overlap of the automatically contoured regions of interest by 50% and reduced registration time by 50% compared to the original parameters. Our findings illustrate that full-scale optimization is an effective method for improving the performance of the automated image contouring system.

Stereotactic body radiation therapy (SBRT) requires precise delivery of radiation to the target; intra- and inter-fraction lung tumour motion may adversely impact local tumour control. The purpose of this study was to retrospectively evaluate the impact of planning target volume (PTV) margin size on the coverage of the internal target volume (ITV) as localized in pre- and post-treatment cone-beam computed tomography (CBCT) images. Data from two patients undergoing SBRT were evaluated. For planning, free-breathing and 4DCT scans were performed, and used to contour the ITV. A 5mm margin was added to create the PTV. During treatment, 14 CBCTs were collected pre- and post-beam delivery. A data set comprising the average 4DCT intensities where available and treatment planning CT intensities for voxels that were beyond the field of view of the 4DCT was constructed. Registration of the combined planning image to each CBCT was performed using a deformable image registration algorithm. The transformations aligning the combined planning image with the CBCTs were applied to the planning ITV to obtain the treatment ITVs. For each CBCT, the fraction of treatment ITV within the PTV was determined using Boolean logic. This was repeated for various PTV margins ranging from 0 to 10 mm at 1mm intervals. The 3 and 5 mm PTV margins covered 95.1 ± 5.9% and 99.0 ± 2.0% of the ITV, respectively. Analysis of additional patients will be performed to confirm these preliminary results, which reinforce the use of a 5mm PTV margin for lung SBRT.

Linac-mounted cone beam computed tomography (CBCT) using Varian's On Board Imager (OBI) currently delivers significant imaging dose and lacks automatic methods for clinical target volume (CTV) registration. In this work, we address these two issues to enable frequent treatment corrections during a course of prostate intensity modulated radiation therapy (IMRT). The process starts by acquiring a low dose (low mAs) CBCT image after patient setup. The image is then used in one of two automatic image guidance strategies. The "global" technique provides the couch corrections necessary to improve patient setup by registering the CBCT to the planning CT. The "local" method involves non-rigid registration of the planning CT to the CBCT followed by automatic treatment re-optimization using the deformed planning CT and contours. Thus, the global method attempts to correct patient setup to match the planned treatment, while the local method corrects the treatment to match the patient setup. Both techniques were evaluated using images of an anthropomorphic male pelvis phantom. Global image guidance resulted in a registration error of 3.6 ± 1.3 mm (imaging dose independent) and high treatment doses to the bladder and rectum for large magnitude motion. The local technique always resulted in clinically acceptable treatment doses due to a reduced registration error of 2.3 ± 0.8 mm, obtained at 15% of the OBI's default dose (125 kVp, 2 mAs per projection). These preliminary results show that our automatic local image guidance technique reduces imaging dose and is sufficiently accurate and robust for application in prostate IMRT.

Purpose: Varian’s On-Board Imager is a linac-integrated cone-beam CT(CBCT) system used at the authors’ institution to acquire images prior to delivering each fraction of prostate intensity modulated radiotherapy. The images are used to determine a couch shift that realigns the tumor with the position obtained in the planning CT. However, this manual image-guided radiotherapy (IGRT) technique is operator dependent, time consuming, offers limited degrees of freedom, and requires significant imagingdose over the course of treatment. To overcome these problems, the authors propose two fully automatic IGRT techniques that require significantly less imagingdose. Methods: Dose is reduced by lowering the x-ray tube mA s during CBCT acquisition at the cost of increasing imagenoise. In “forward” IGRT, the CBCTimage is automatically registered to the planning CT to obtain the necessary couch shift. The “reverse” technique offers additional degrees of freedom as it involves nonrigid registration of the planning CT to the CBCT. Both techniques were evaluated using images of an anthropomorphic phantom with simulated motion and by retrospectively analyzing data from ten prostate cancer patients. Results: IGRT error for the phantom data at 100% relative imagingdose was 8.2 ± 3.7 , 3.5 ± 1.2 , and 2.1 ± 0.6 mm for setup only, forward, and reverse techniques, respectively. For patient images acquired at 100% relative imagingdose, the errors were 5.4 ± 1.7 , 5.0 ± 1.6 , 5.0 ± 2.0 , and 4.0 ± 1.6 mm for setup only, manual forward (performed clinically), automatic forward, and reverse IGRT, respectively. Furthermore, imagingdose could be reduced to 20% without a significant loss in image guidance accuracy. Conclusions: The presented image guidance methods are accurate while requiring only 20% of the standard imagingdose. The combination of low dose, automation, and accuracy enables frequent corrections during treatment, possibly leading to reduced margins and improved treatment outcomes.

This work presents the initial development and implementation of a novel 3D biomechanics-based approach to measure the mechanical activity of myocardial tissue, as a potential non-invasive tool to assess myocardial function. This technique quantifies the myocardial contraction forces developed within the ventricular myofibers in response to electro-physiological stimuli. We provide a 3D finite element formulation of a contraction force reconstruction algorithm, along with its implementation using magnetic resonance (MR) data. Our algorithm is based on an inverse problem solution governed by the fundamental continuum mechanics principle of conservation of linear momentum, under a first-order approximation of elastic and isotropic material conditions. We implemented our technique using a subject-specific ventricle model obtained by extracting the left ventricular anatomical features from a set of high-resolution cardiac MR images acquired throughout the cardiac cycle using prospective electrocardiographic gating. Cardiac motion information was extracted by non-rigid registration of the mid-diastole reference image to the remaining images of a 4D dataset. Using our technique, we reconstructed dynamic maps that show the contraction force distribution superimposed onto the deformed ventricle model at each acquired frame in the cardiac cycle. Our next objective will consist of validating this technique by showing the correlation between the presence of low contraction force patterns and poor myocardial functionality.

Two reasons for the recent rise in radiation exposure from CT are increases in its clinical applicability and the desire to maintain high SNR while acquiring smaller voxels. To address this emerging dose problem, several strategies for reducing patient exposure have already been proposed. One method employed in cardiacimaging is ECG-driven modulation of the tube current between 100% at one time point in the cardiac cycle and a reduced fraction at the remaining phases. In this paper, we describe how images obtained during such acquisition can be used to reconstruct 4D data of consistent high quality throughout the cardiac cycle. In our approach, we assume that the mid-diastole (MD) phase is imaged with full dose. The MD image is then independently registered to lower dose images (lower SNR) at other frames, resulting in a set of transformations. Finally, the transformations are used to warp the MD frame through the cardiac cycle to generate the full 4D image. In addition, the transformations may be interpolated to increase the temporal sampling or to generate images at arbitrary time points. Our approach was validated using various data obtained with simulated and scanner-implemented dose modulation. We determined that as little as 10% of the total dose was required to reproduce full quality images with a 1 mm spatial error and an error in intensity values on the order of the imagenoise. Thus, our technique offers considerable dose reductions compared to standard imaging protocols, with minimal effects on the quality of the final data.

Intensity Modulated Radiation Therapy (IMRT) has been used in lung cancer treatment to deliver dose distributions with steep gradients and exquisite target volume conformality. While many benefits of IMRT exist, significant challenges are involved when unpredictable intrafraction movement is combined with the highly optimized nature of IMRT. The National Cancer Institute (NCI) Guidelines for the Use of IMRT state that there is potential for significant dosimetric consequences if the target volume moves while treatment is being administered. Thus, lung IMRT is especially challenging due to breathing motion. Furthermore, tissue density differences at the lung-tumor interface contribute to disagreements between the administered and planned doses. These inhomogeneities may allow for a relatively large portion of the planning target volume (PTV) to be left without coverage and the target will still receive the prescribed dose during treatment. For example, the Radiation Therapy Oncology Group (RTOG) 0617 study requires that 95% of the PTV is to be covered by 95% (93% is a minor violation) of the prescription dose during planning.

Lung tumor metabolism is severely altered involving enhanced levels of glucose uptake, glycolysis, lipogenesis and protein synthesis. These events are essential for the support of enhanced energy demands and increased need for ribonucleotides, proteins and membrane biogenesis that are required for rapid proliferation. Combined treatment with cytotoxic therapy and metabolism modulating agents may improve outcomes in NSCLC. We observed that radiotherapy (RT) alone activates the metabolic stress sensor AMP-activated kinase (AMPK) within an Ataxia Telengiectasia Mutated (ATM) – AMPK – p53/p21 pathway to mediate the RT-induced G2-M checkpoint and cytotoxicity. Further, inhibition of biosynthetic pathways and energy production through blockade of OxPhos inhibits tumor growth. In human NSCLC cells and xenografts, we combined RT with the anti-diabetic agent metformin, which blocks OxPhos complex I, and showed that metformin activates the ATM-AMPK-p53/p21 axis and inhibits the AktmTOR-4EBP1 pathway, tumor growth and angiogenesis and induces apoptosis and radio-sensitization. Based on these observations and supporting retrospective clinical evidence from locally advanced lung cancer patients treated with Chemo-RT, we launched phase II studies combiningmetforminwith chemo-RT. NRG-LU001 (NCT02186847) and OCOG ALMERA (NCT02186847) are on-going randomized phase II studies investigating whether targeting metabolism with metformin can improve progression free survival in stage III NSCLC. In recent studies we observed that combined treatment with metabolism modulating agents can enhance anti-tumor activity in NSCLC. Combined treatment with Metformin and Salicylate, which activate AMPK through different mechanisms, mediated increased inhibition of clonogenic survival in part through AMPK and suppression of de-novo lipogenesis. Further, in earlier studies we showed that blockade of the cholesterol synthesis pathway with lovastatin (HMG-CoA reductase inhibitor) mediated activation of AMPK, suppression of the Akt-PI3k pathways and radio-sensitization of NSCLC. In current studies we observe that lovastatin also activates the ATM-AMPK-p53 axis, inhibit the Akt-mTOR pathway and mediate tumor suppression in an AMPKdependent manner through suppression of de novo lipogenesis along both the mevalonate and the fatty acid synthesis pathways. Further, in retrospective clinical studies we find that in locally advanced NSCLC patients treated with Chemo-RT, statin treatment is associated with increased survival. These observations suggest that targeting tumor metabolism is promising in NSCLC to improve outcomes of standard cytotoxic therapy. Completion of on-going trials with metformin will provide the first prospective evidence on this concept. We plan to investigate combinations of well-tolerated metabolism modulating agents that show promising pre-clinical activity in future rolling phase II studies.

Background Despite improved staging and surgical techniques, the rate of incomplete resection (R1) of non–small-cell lung cancer (NSCLC) has not significantly decreased. Patients with R1 resection have worse survival compared with those with complete resection (R0). Stereotactic body radiotherapy (SBRT) is a rapid and convenient radiotherapy treatment that delivers high-dose radiotherapy to tumors with high precision while sparing normal organs. Although its efficacy in treating small lung tumors is documented, its use as neoadjuvant therapy for locally advanced (LA) NSCLC has not been examined. We hypothesized that a short course of preoperative SBRT is feasible and can be delivered safely as a neoadjuvant therapy in patients at risk for incomplete resection. Methods In this phase I study, 20 patients with cT3 to 4, N0 to 1, M0 NSCLC at risk for incomplete resection will be treated with neoadjuvant SBRT followed by surgery and adjuvant chemotherapy. Four groups of 5 patients will be treated with escalating doses (35, 40, 45, and 50 Gy) in 10 daily fractions. The primary outcome is feasibility (ie, the ability to complete SBRT and surgery as planned; within 7 weeks). Secondary outcomes include acute and late adverse events; R0, R1, and R2 rates; and secondary surrogates of feasibility and safety. Relevance This study is an important first step in introducing a new therapeutic modality to patients with LA NSCLC that could improve surgical outcomes in the future. If neoadjuvant SBRT is found to be feasible and safe for LA NSCLC, its effect in achieving R0 resection could be investigated in randomized trials.

Superficial dose distributions were measured using radiochromic translucent poly(vinyl alcohol) cryogels. The relationship between dose to the skin surface and dose measured with the bolus (cryogel) was established using a series of oblique irradiations. Gafchromic film was placed under the bolus, and the ratio of bolus-film dose was determined for angle ranging from 0o to 90o. The average ratio over 0-67.5 degrees (0.800 ± 0.064) was used as the single correction factor to convert dose in bolus to dose to the skin surface, and applied to bolus measurements of skin dose from head and neck intensity modulated radiation therapy (IMRT) treatments delivered to a RANDO phantom. The resulting dose distributions were compared to film measurements using gamma analysis with a 3%/3mm tolerance and a 10% threshold. The minimum gamma pass rate was 95.2%. This study is the first report on the use of a poly(vinyl alcohol) cryogels based dosimeter to provide an accurate estimation of superficial dose distributions in megavoltage photon beams.

Atlas based-segmentation has recently been evaluated for use in prostate radiotherapy. In a typical approach, the essential step is the selection of an atlas from a database that the best matches of the target image. This work proposes an atlas selection strategy and evaluate it impacts on final segmentation accuracy. Several anatomical parameters were measured to indicate the overall prostate and body shape, all of these measurements obtained on CT images. A brute force procedure was first performed for a training dataset of 20 patients using image registration to pair subject with similar contours; each subject was served as a target image to which all reaming 19 images were affinity registered. The overlap between the prostate and femoral heads was quantified for each pair using the Dice Similarity Coefficient (DSC). Finally, an atlas selection procedure was designed; relying on the computation of a similarity score defined as a weighted sum of differences between the target and atlas subject anatomical measurement. The algorithm ability to predict the most similar atlas was excellent, achieving mean DSCs of 0.78 ± 0.07 and 0.90 ± 0.02 for the CTV and either femoral head. The proposed atlas selection yielded 0.72 ± 0.11 and 0.87 ± 0.03 for CTV and either femoral head. The DSC obtained with the proposed selection method were slightly lower than the maximum established using brute force, but this does not include potential improvements expected with deformable registration. The proposed atlas selection method provides reasonable segmentation accuracy.

Purpose: In lung radiotherapy, breathing motion may be encompassed by contouring the internal target volume (ITV). Remaining uncertainties are included in a geometrical expansion to the planning target volume (PTV). In IMRT, the treatment is then optimized until a desired PTV fraction is covered by the appropriate dose. The resulting beams often carry high fluence in the PTV margin to overcome low lung density and to generate steep dose gradients. During treatment, the high density tumour can enter the PTV margin, potentially increasing target dose. Thus, planning lung IMRT with a reduced PTV dose may still achieve the desired ITV dose during treatment. Methods: A retrospective analysis was carried out with 25 IMRT plans prescribed to 63 Gy in 30 fractions. The plans were re-normalized to cover various fractions of the PTV by different isodose lines. For each case, the isocentre was moved using 125 shifts derived from all 3D combinations of 0 mm, (PTV margin - 1 mm), and PTV margin. After each shift, the dose was recomputed to approximate the delivered dose. Results and Conclusion: Our plans typically cover 95% of the PTV by 95% of the dose. Reducing the PTV covered to 94% did not significantly reduce the delivered ITV doses for (PTV margin - 1 mm) shifts. Target doses were reduced significantly for all other shifts and planning goals studied. Thus, a reduced planning goal will likely deliver the desired target dose as long as the ITV rarely enters the last mm of the PTV margin.

Three-dimensional visualization for planning and guidance is still not routinely available for minimally invasive cardiac surgery (MICS). This can be addressed by providing the surgeon with subject-specific geometric models derived from 3D preoperative images for planning of port locations or to rehearse the procedure. For guidance purposes, these models can also be registered to the subject using intraoperative images. In this paper, we present a method for extracting subject-specific heart geometry from preoperative MR images. The main obstacle we face is the low quality of clinical data in terms of resolution, signal-to-noise ratio, and presence of artefacts. Instead of using these images directly, we approach the problem in three steps: (1) generate a high quality template model, (2) register the template with the preoperative data, and (3) animate the result over the cardiac cycle. Validation of this approach showed that dynamic subject-specific models can be generated with a mean error of 3.6 ± 1.1 mm from low resolution target images (6 mm slices). Thus, the models are sufficiently accurate for MICS training and procedure planning. In terms of guidance, we also demonstrate how the resulting models may be adapted to the operating room using intraoperative ultrasound imaging.

As part of an ongoing theme in our laboratory on reducing morbidity during minimally-invasive intracardiacprocedures, we developed a computer-assisted interventi on system that provides safe access inside the beatingheart and sucient visualization to deliver therapy to intracardiac targets while maintaining the ecacy of theprocedure. Integrating pre-operative information, 2D trans-esophageal ultrasound for real-time intra-operativeimaging, and surgical tool tracking using the NDI Aurora TM magnetic tracking system in an augmented virtualenvironment, our system allows the surgeons to navigate instruments inside the heart in spite of the lack ofdirect target visualization. This work focuses on further enhancing intracardiac visualization and navigation bysupplying the surgeons with detailed 3D dynamic cardiac models constructed from high-resolution pre-operativeMR data and overlaid onto the intra-operative imaging environment. Here we report our experience during an invivo porcine study. A feature-based registration technique previously explored and validated in our laboratorywas employed for the pre-operative to intra-operative mapping. This registration method is suitable for invivo interventional applications as it involves the selection of easily identi“able landmarks, while ensuring a goodalignment of the pre-operative and intra-operative surgical targets. The resulting augmented reality environmentfuses the pre-operative cardiac model with the intra-operative real-time US images with approximately 5 mmaccuracy for structures located in the vicinity of the valvular region. Therefore, we strongly believe that ouraugmented virtual environment signi“cantly enhances intracardiac navigation of surgical instruments, while on-target detailed manipulations are performed under real-time US guidance.Keywords: Image-Guided Cardiac Procedures, Pre-operative Modeling, Intra-operative Imaging, AugmentedVirtual Reality, Data Integration for the Clinic/OR.

Surgeons need a robust interventional system capable of providing reliable, real-time information regarding the position and orientation of the surgical targets and tools to compensate for the lack of direct vision and to enhance manipulation of intracardiac targets during minimally-invasive, off-pump cardiac interventions. In this paper, we describe a novel method for creating dynamic, pre-operative, subject-specific cardiac models containing the surgical targets and surrounding anatomy, and how they are used to augment the intra-operative virtual environment for guidance of valvular interventions. The accuracy of these pre-operative models was established by comparing the target registration error between the mitral valve annulus characterized in the pre-operative images and their equivalent structures manually extracted from 3D US data. On average, the mitral valve annulus was extracted with a 3.1 mm error across all cardiac phases. In addition, we also propose a method for registering the pre-operative models into the intra-operative virtual environment.

This work presents the first steps towards the development and implementation of a novel 3D biomechanical- based method for assessing the viability of myocardial tissue, with particular interest for its application in myocardial infarction (MI) diagnosis. This assessment technique quantifies the myocardial contraction forces developed within the ventricular myofibrils in response to the electrophysiological stimulus. In this manuscript we provide a 3D finite element (FE) formulation of a contraction force reconstruction algorithm based on an inverse problem solution of linear elasticity, along with its implementation using clinical data. This algorithm has been applied to patient-specific models obtained by extracting anatomical features from high- resolution, high-contrast magnetic resonance (MR) cardiac images. The input consists of motion information extracted by nonrigid registration of the mid-diastole reference image to the remaining images of the 4D data set, acquired using ECG- gating throughout the cardiac cycle. The result consists of a display-map of the contraction force distribution superimposed on the anatomical ventricle model, which allows the clinician to identify regions of low contractility in the myocardium.

Surgeons need a robust interventional system capable of providing reliable, real-time information regarding the position and orientation of the surgical targets and tools to compensate for the lack of direct vision and to enhance manipulation of intracardiac targets during minimally-invasive, off-pump cardiac interventions. In this paper, we describe a novel method for creating dynamic, pre-operative, subject-specific cardiac models containing the surgical targets and surrounding anatomy, and how they are used to augment the intra-operative virtual environment for guidance of valvular interventions. The accuracy of these pre-operative models was established by comparing the target registration error between the mitral valve annulus characterized in the pre-operative images and their equivalent structures manually extracted from 3D US data. On average, the mitral valve annulus was extracted with a 3.1 mm error across all cardiac phases. In addition, we also propose a method for registering the pre-operative models into the intraoperative virtual environment.

In an effort to reduce morbidity during minimally- invasive cardiac procedures, we have recently developed an interventional technique targeted towards off-pump cardiac interventions. To compensate for the absence of direct visualization, our system employs a virtual reality environment for image guidance, that integrates pre-operative information with real-time intra-operative imaging and surgical tool tracking. This work focuses on enhancing intracardiac visualization and navigation by overlaying pre-operative cardiac models onto the intra-operative virtual space, to display surgical targets within their specific anatomical context. Our method for integrating pre-operative data into the intra-operative environment is accurate within ~5.0 mm. Thus, we feel that our virtually-augmented surgical space is accurate enough to improve spatial orientation and intracardiac navigation.

Two reasons for the recent rise in radiation exposure from CT are increases in its clinical applicability and the desire to maintain high SNR while acquiring smaller voxels. To address this emerging dose problem, several strategies for reducing patient exposure have already been proposed. One method employed in cardiac imaging is ECG-driven modulation of the tube current between 100% at one time point in the cardiac cycle and a reduced fraction at the remaining phases. In this paper, we describe how images obtained during such acquisition can be used to reconstruct 4D data of consistent high quality throughout the cardiac cycle. In our approach, we assume that the middiastole (MD) phase is imaged with full dose. The MD image is then independently registered to lower dose images (lower SNR) at other frames, resulting in a set of transformations. Finally, the transformations are used to warp the MD frame through the cardiac cycle to generate the full 4D image. In addition, the transformations may be interpolated to increase the temporal sampling or to generate images at arbitrary time points. Our approach was validated using various data obtained with simulated and scanner-implemented dose modulation. We determined that as little as 10% of the total dose was required to reproduce full quality images with a 1 mm spatial error and an error in intensity values on the order of the image noise. Thus, our technique offers considerable dose reductions compared to standard imaging protocols, with minimal effects on the quality of the final data.

High quality images have many uses, such as the testing of image processing algorithms and serving as templates for registration in image guided surgery. This work describes the creation of four high quality images or "appearance models", for 1. myocardium, 2. right atrium and ventricle, 3. left atrium and aorta, and 4. epicardial surface. The appearance models are created by registering and averaging together a series of high-resolution MR images of the same volunteer. These are then corrected to represent the average shape as determined from MR data of ten other volunteers. Thus, we show how single volunteer imaging can be combined with image registration to generate average-shape appearance models with high resolution and signal-to-noise ratio. Our final data consist of four 3D average shape appearance models (each depicting one of the sub-heart components) with 1.5 times 1.5 times 1.5 mm voxels and a signal-to-noise ratio increase of 6.6 versus raw data

Current minimally invasive techniques for beating heart surgery are associated with three major limitations: the shortage of realistic and safe training methods, the process of selecting port locations for optimal target coverage from X-rays and angiograms, and the sole use of the endoscope for instrument navigation in a dynamic and confined 3D environment. To supplement the current surgery training, planning and guidance methods, we continue to develop our Virtual Cardiac Surgery Planning environment (VCSP) – a virtual reality, patient-specific, thoracic cavity model derived from 3D pre-procedural images. In this work, we create and validate dynamic models of the heart and its components. A static model is first generated by segmenting one of the image frames in a given 4D data set. The dynamics of this model are then extracted from the remaining image frames using a non-linear, intensity-based registration algorithm with a choice of six different similarity metrics. The algorithm is validated on an artificial CT image set created using an excised porcine heart, on CT images of canine subjects, and on MR images of human volunteers. We found that with the appropriate choice of similarity metric, our algorithm extracts the motion of the epicardial surface in CT images, or of the myocardium, right atrium, right ventricle, aorta, left atrium, pulmonary arteries, vena cava and epicardial surface in MR images, with a root mean square error in the 1 mm range. These results indicate that our method of modeling the motion of the heart is easily adaptable and sufficiently accurate to meet the requirements for reliable cardiac surgery training, planning, and guidance.

While most currently available minimally invasive robotically assisted cardiac surgical systems do not employ 3D image guidance, such support can be generated using pre operative images such as CT. Previously we demonstrated a virtual model of the thorax with simulated surgical instruments, and a pulsating virtual model of the coronary arteries. In this paper we report the overlay of optical endoscopic images of a beating heart phantom with CT-based dynamic volumetric images of the phantom. Spatial matching is obtained through optical tracking of the endoscope and of the phantom, while time synchronization of the display of the model utilizes ECG gating. The spatial accuracy between the optical and virtual images varies from about 0.8 mm to -2.6 mm, while the time discrepancy depends on the frame-rate at which the virtual model is refreshed, and is typically 50-100 ms. Although the CT-based dynamic images are sufficient for animation of the model, artefacts associated with the image registration prevent seamless animation. Instead, to reconstruct the various phases of heart pulsation, we used a high-quality semi-static image of the diastolic phase of the phantom, and warped it to match the CT-based images corresponding to other phases of the heart pulsation.

Our image-guided radiation therapy (IGRT) protocol for post-prostatectomy patients involves acquiring a kV cone beam computed tomography (CBCT) dataset at each fraction and shifting the treatment couch to align the surgical clips. This IGRT strategy requires significant resources, and delivers non-negligible dose to normal tissues. The objective of this work is to evaluate this IGRT protocol against two alternative strategies in terms of the dose-volume statistics for target and organ at risk regions. Our method involves deforming the planning CT to the CBCT dataset acquired at each fraction, computing dose on the deformed dataset, and inversely transforming the dose back onto the original planning CT dataset. The treatments of six patients were evaluated assuming three IGRT scenarios: no IGRT, daily IGRT using the clinically employed couch shifts, and alternating day IGRT. The doses delivered to the clinical target volumes are within approximately 3.2, 1.3, and 2.1% of the plan for the non-IGRT, daily, and alternating day IGRT protocols, respectively. Doses to relevant portions of the organs at risk deviate from the plan by up to 10.5, 13.1 and 10.7% for non-IGRT, daily IGRT, and alternating day IGRT protocols, respectively. Some cases do not differ significantly between IGRT and non-IGRT protocols in terms of cumulative DVHs, highlighting the difficult task of correcting prostate bed deformations via the treatment couch translations. In general, the alternating day IGRT protocol was found to result in a clinically insignificant deviation in delivered dose while providing a significant reduction in resource use and patient imaging dose.

A four dimensional computed tomography (4DCT) image is acquired for all radically treated, lung cancer patients to define the internal target volume (ITV), which encompasses tumour motion due to breathing and subclinical disease. Patient set-up error and anatomical motion that is not due to breathing is addressed through an additional 1 cm margin around the ITV to obtain the planning target volume (PTV). The objective of this retrospective study is to find the minimum PTV margin that provides an acceptable probability of delivering the prescribed dose to the ITV. Acquisition of a kV cone beam computed tomography (CBCT) image at each fraction was used to shift the treatment couch to accurately align the spinal cord and carina. Our method utilized deformable image registration to automatically position the planning ITV on each CBCT. We evaluated the percentage of the ITV surface that fell within various PTVs for 79 fractions across 18 patients. Treatment success was defined as a situation where at least 99% of the ITV is covered by the PTV. Overall, this is to be achieved in at least 90% of the treatment fractions. The current approach with a 1cm PTV margin was successful ∼96% of the time. This analysis revealed that the current margin can be reduced to 0.8cm isotropic or 0.6×0.6×1 cm3 non-isotropic, which were successful 92 and 91 percent of the time respectively. Moreover, we have shown that these margins maintain accuracy, despite intrafractional variation, and maximize CBCT image guidance capabilities.

Automated atlas-based segmentation has recently been evaluated for use in planning prostate cancer radiotherapy. In the typical approach, the essential step is the selection of an atlas from a database that best matches the target image. This work proposes an atlas selection strategy and evaluates its impact on the final segmentation accuracy. Prostate length (PL), right femoral head diameter (RFHD), and left femoral head diameter (LFHD) were measured in CT images of 20 patients. Each subject was then taken as the target image to which all remaining 19 images were affinely registered. For each pair of registered images, the overlap between prostate and femoral head contours was quantified using the Dice Similarity Coefficient (DSC). Finally, we designed an atlas selection strategy that computed the ratio of PL (prostate segmentation), RFHD (right femur segmentation), and LFHD (left femur segmentation) between the target subject and each subject in the atlas database. Five atlas subjects yielding ratios nearest to one were then selected for further analysis. RFHD and LFHD were excellent parameters for atlas selection, achieving a mean femoral head DSC of 0.82 ± 0.06. PL had a moderate ability to select the most similar prostate, with a mean DSC of 0.63 ± 0.18. The DSC obtained with the proposed selection method were slightly lower than the maximums established using brute force, but this does not include potential improvements expected with deformable registration. Atlas selection based on PL for prostate and femoral diameter for femoral heads provides reasonable segmentation accuracy.

Purpose: A 2D/3D registration algorithm is proposed for registering orthogonal x-ray images with a diagnostic CT volume for high dose rate (HDR) lung brachytherapy. Methods: The algorithm utilizes a rigid registration model based on a pixel/voxel intensity matching approach. To achieve accurate registration, a robust similarity measure combining normalized mutual information, image gradient, and intensity difference was developed. The algorithm was validated using a simple body and anthropomorphic phantoms. Transfer catheters were placed inside the phantoms to simulate the unique image features observed during treatment. The algorithm sensitivity to various degrees of initial misregistration and to the presence of foreign objects, such as ECG leads, was evaluated. Results: The mean registration error was 2.2 and 1.9 mm for the simple body and anthropomorphic phantoms, respectively. The error was comparable to the interoperator catheter digitization error of 1.6 mm. Preliminary analysis of data acquired from four patients indicated a mean registration error of 4.2 mm. Conclusions: Results obtained using the proposed algorithm are clinically acceptable especially considering the complications normally encountered when imaging during lung HDR brachytherapy.

Purpose: Characterization of the accuracy of the dose delivery for pelvic adaptive radiotherapy using cone‐beam CT for post‐planning. Methods: A commercially available phantom (CIRS 062) was modified to allow for full scatter conditions in a cone‐beam CT radiation field. Various density inserts were used to calibrate the Hounsfield Unit (HU) to electron density (ED) for all of our Varian linacs with installed On‐Board Imagers (OBI). Different insert arrangements were explored. The calibration stability of six machines was monitored weekly over a time period of four to six weeks. The effect of different induced shifts from isocentre on the HU to ED calibration was examined along with different scan ranges (6 cm, 10.3 cm, and 20.8 cm). In order to test the dose calculation accuracy, a pelvic phantom with a hypothetical target and sensitive structures was used and identical plans were generated on a diagnostic quality, fan‐beam CT (FBCT) image and the CBCTimages using the Pinnacle treatment planning software. A number of prostate patients were selected for dosimetric comparisons using the FBCT and CBCTimages acquired for patient positioning. Results: We found that reproducible HU to ED numbers were obtained for the density inserts situated in the inner circular section of the phantom when additional tissue equivalent material was added to CIRS 062 phantom. The variance in HU to ED numbers across the six linacs was less than the spatial variation observed on a single unit, even for the high density bone insert. Therefore, a common calibration curve can be used across all OBI linacs at our institute. There were no significant changes in the HU to ED calibration curve over the observed period. The dosimetric analysis is in progress. Conclusions: The performance of CBCT on Varian linacs is adequate to support a post‐planning dosimetric study.