Publications by Year: 2019

Miller K, Joldes GR, Bourantas G, Warfield SK, Hyde DE, Kikinis R, Wittek A. Biomechanical Modeling and Computer Simulation of the Brain during Neurosurgery. Int J Numer Method Biomed Eng. 2019 :e3250.Abstract
Computational biomechanics of the brain for neurosurgery is an emerging area of research recently gaining in importance and practical applications. This review paper presents the contributions of the Intelligent Systems for Medicine Laboratory and its collaborators to this field, discussing the modeling approaches adopted and the methods developed for obtaining the numerical solutions. We adopt a physics-based modeling approach and describe the brain deformation in mechanical terms (such as displacements, strains, and stresses), which can be computed using a biomechanical model, by solving a continuum mechanics problem. We present our modeling approaches related to geometry creation, boundary conditions, loading, and material properties. From the point of view of solution methods, we advocate the use of fully nonlinear modeling approaches, capable of capturing very large deformations and nonlinear material behavior. We discuss finite element and meshless domain discretization, the use of the total Lagrangian formulation of continuum mechanics, and explicit time integration for solving both time-accurate and steady-state problems. We present the methods developed for handling contacts and for warping 3D medical images using the results of our simulations. We present two examples to showcase these methods: brain shift estimation for image registration and brain deformation computation for neuronavigation in epilepsy treatment.
Fan G, Liu H, Wu Z, Li Y, Feng C, Wang D, Luo J, Wells WM, He S. Deep Learning-Based Automatic Segmentation of Lumbosacral Nerves on CT for Spinal Intervention: A Translational Study. AJNR Am J Neuroradiol. 2019;40 (6) :1074-81.Abstract
BACKGROUND AND PURPOSE: 3D reconstruction of a targeted area ("safe" triangle and Kambin triangle) may benefit the viability assessment of transforaminal epidural steroid injection, especially at the L5/S1 level. However, manual segmentation of lumbosacral nerves for 3D reconstruction is time-consuming. The aim of this study was to investigate the feasibility of deep learning-based segmentation of lumbosacral nerves on CT and the reconstruction of the safe triangle and Kambin triangle. MATERIALS AND METHODS: A total of 50 cases of spinal CT were manually labeled for lumbosacral nerves and bones using Slicer 4.8. The ratio of training/validation/testing was 32:8:10. A 3D U-Net was adopted to build the model SPINECT for automatic segmentations of lumbosacral structures. The Dice score, pixel accuracy, and Intersection over Union were computed to assess the segmentation performance of SPINECT. The areas of Kambin and safe triangles were measured to validate the 3D reconstruction. RESULTS: The results revealed successful segmentation of lumbosacral bone and nerve on CT. The average pixel accuracy for bone was 0.940, and for nerve, 0.918. The average Intersection over Union for bone was 0.897 and for nerve, 0.827. The Dice score for bone was 0.945, and for nerve, it was 0.905. There were no significant differences in the quantified Kambin triangle or safe triangle between manually segmented images and automatically segmented images ( > .05). CONCLUSIONS: Deep learning-based automatic segmentation of lumbosacral structures (nerves and bone) on routine CT is feasible, and SPINECT-based 3D reconstruction of safe and Kambin triangles is also validated.
Lemaire J-J, De Salles A, Coll G, El Ouadih Y, Chaix R, Coste J, Durif F, Makris N, Kikinis R. MRI Atlas of the Human Deep Brain. Front Neurol. 2019;10 :851.Abstract
Mastering detailed anatomy of the human deep brain in clinical neurosciences is challenging. Although numerous pioneering works have gathered a large dataset of structural and topographic information, it is still difficult to transfer this knowledge into practice, even with advanced magnetic resonance imaging techniques. Thus, classical histological atlases continue to be used to identify structures for stereotactic targeting in functional neurosurgery. Physicians mainly use these atlases as a template co-registered with the patient's brain. However, it is possible to directly identify stereotactic targets on MRI scans, enabling personalized targeting. In order to help clinicians directly identify deep brain structures relevant to present and future medical applications, we built a volumetric MRI atlas of the deep brain (MDBA) on a large scale (infra millimetric). Twelve hypothalamic, 39 subthalamic, 36 telencephalic, and 32 thalamic structures were identified, contoured, and labeled. Nineteen coronal, 18 axial, and 15 sagittal MRI plates were created. Although primarily designed for direct labeling, the anatomic space was also subdivided in twelfths of AC-PC distance, leading to proportional scaling in the coronal, axial, and sagittal planes. This extensive work is now available to clinicians and neuroscientists, offering another representation of the human deep brain ([] [hal-02116633]). The atlas may also be used by computer scientists who are interested in deciphering the topography of this complex region.
Patel NA, Li G, Shang W, Wartenberg M, Heffter T, Burdette EC, Iordachita I, Tokuda J, Hata N, Tempany CM, et al. System Integration and Preliminary Clinical Evaluation of a Robotic System for MRI-Guided Transperineal Prostate Biopsy. J Med Robot Res. 2019;4 (2).Abstract
This paper presents the development, preclinical evaluation, and preliminary clinical study of a robotic system for targeted transperineal prostate biopsy under direct interventional magnetic resonance imaging (MRI) guidance. The clinically integrated robotic system is developed based on a modular design approach, comprised of surgical navigation application, robot control software, MRI robot controller hardware, and robotic needle placement manipulator. The system provides enabling technologies for MRI-guided procedures. It can be easily transported and setup for supporting the clinical workflow of interventional procedures, and the system is readily extensible and reconfigurable to other clinical applications. Preclinical evaluation of the system is performed with phantom studies in a 3 Tesla MRI scanner, rehearsing the proposed clinical workflow, and demonstrating an in-plane targeting error of 1.5mm. The robotic system has been approved by the institutional review board (IRB) for clinical trials. A preliminary clinical study is conducted with the patient consent, demonstrating the targeting errors at two biopsy target sites to be 4.0 and 3.7, which is sufficient to target a clinically significant tumor foci. First-in-human trials to evaluate the system's effectiveness and accuracy for MR image-guide prostate biopsy are underway.
Machado I, Toews M, George E, Unadkat P, Essayed W, Luo J, Teodoro P, Carvalho H, Martins J, Golland P, et al. Deformable MRI-Ultrasound Registration using Correlation-based Attribute Matching for Brain Shift Correction: Accuracy and Generality in Multi-site Data. Neuroimage. 2019 :116094.Abstract
Intraoperative tissue deformation, known as brain shift, decreases the benefit of using preoperative images to guide neurosurgery. Non-rigid registration of preoperative magnetic resonance (MR) to intraoperative ultrasound (US) has been proposed as a means to compensate for brain shift. We focus on the initial registration from MR to predurotomy US. We present a method that builds on previous work to address the need for accuracy and generality of MR-iUS registration algorithms in multi-site clinical data. To improve accuracy of registration, we use high-dimensional texture attributes instead of image intensities and propose to replace the standard difference-based attribute matching with correlation-based attribute matching. We also present a strategy that deals explicitly with the large field-of-view mismatch between MR and iUS images. We optimize key parameters across independent MR-iUS brain tumor datasets acquired at three different institutions, with a total of 43 tumor patients and 758 corresponding landmarks to validate the registration algorithm. Despite differences in imaging protocols, patient demographics and landmark distributions, our algorithm was able to reduce landmark errors prior to registration in three data sets (5.37 ± 4.27, 4.18 ± 1.97 and 6.18 ± 3.38 mm, respectively) to a consistently low level (2.28 ± 0.71, 2.08 ± 0.37 and 2.24 ± 0.78 mm, respectively). Our algorithm is compared to 15 other algorithms that have been previously tested on MR-iUS registration and it is competitive with the state-of-the-art on multiple datasets. We show that our algorithm has one of the lowest errors in all datasets (accuracy), and this is achieved while sticking to a fixed set of parameters for multi-site data (generality). In contrast, other algorithms/tools of similar performance need per-dataset parameter tuning (high accuracy but lower generality), and those that stick to fixed parameters have larger errors or inconsistent performance (generality but not the top accuracy). We further characterized landmark errors according to brain regions and tumor types, a topic so far missing in the literature. We found that landmark errors were higher in high-grade than low-grade glioma patients, and higher in tumor regions than in other brain regions.
Frisken S, Luo M, Juvekar P, Bunevicius A, Machado I, Unadkat P, Bertotti MM, Toews M, Wells WM, Miga MI, et al. A Comparison of Thin-Plate Spline Deformation and Finite Element Modeling to Compensate for Brain Shift during Tumor Resection. Int J Comput Assist Radiol Surg. 2019.Abstract
PURPOSE: Brain shift during tumor resection can progressively invalidate the accuracy of neuronavigation systems and affect neurosurgeons' ability to achieve optimal resections. This paper compares two methods that have been presented in the literature to compensate for brain shift: a thin-plate spline deformation model and a finite element method (FEM). For this comparison, both methods are driven by identical sparse data. Specifically, both methods are driven by displacements between automatically detected and matched feature points from intraoperative 3D ultrasound (iUS). Both methods have been shown to be fast enough for intraoperative brain shift correction (Machado et al. in Int J Comput Assist Radiol Surg 13(10):1525-1538, 2018; Luo et al. in J Med Imaging (Bellingham) 4(3):035003, 2017). However, the spline method requires no preprocessing and ignores physical properties of the brain while the FEM method requires significant preprocessing and incorporates patient-specific physical and geometric constraints. The goal of this work was to explore the relative merits of these methods on recent clinical data. METHODS: Data acquired during 19 sequential tumor resections in Brigham and Women's Hospital's Advanced Multi-modal Image-Guided Operating Suite between December 2017 and October 2018 were considered for this retrospective study. Of these, 15 cases and a total of 24 iUS to iUS image pairs met inclusion requirements. Automatic feature detection (Machado et al. in Int J Comput Assist Radiol Surg 13(10):1525-1538, 2018) was used to detect and match features in each pair of iUS images. Displacements between matched features were then used to drive both the spline model and the FEM method to compensate for brain shift between image acquisitions. The accuracies of the resultant deformation models were measured by comparing the displacements of manually identified landmarks before and after deformation. RESULTS: The mean initial subcortical registration error between preoperative MRI and the first iUS image averaged 5.3 ± 0.75 mm. The mean subcortical brain shift, measured using displacements between manually identified landmarks in pairs of iUS images, was 2.5 ± 1.3 mm. Our results showed that FEM was able to reduce subcortical registration error by a small but statistically significant amount (from 2.46 to 2.02 mm). A large variability in the results of the spline method prevented us from demonstrating either a statistically significant reduction in subcortical registration error after applying the spline method or a statistically significant difference between the results of the two methods. CONCLUSIONS: In this study, we observed less subcortical brain shift than has previously been reported in the literature (Frisken et al., in: Miller (ed) Biomechanics of the brain, Springer, Cham, 2019). This may be due to the fact that we separated out the initial misregistration between preoperative MRI and the first iUS image from our brain shift measurements or it may be due to modern neurosurgical practices designed to reduce brain shift, including reduced craniotomy sizes and better control of intracranial pressure with the use of mannitol and other medications. It appears that the FEM method and its use of geometric and biomechanical constraints provided more consistent brain shift correction and better correction farther from the driving feature displacements than the simple spline model. The spline-based method was simpler and tended to give better results for small deformations. However, large variability in the spline results and relatively small brain shift prevented this study from demonstrating a statistically significant difference between the results of the two methods.
Canalini L, Klein J, Miller D, Kikinis R. Segmentation-based Registration of Ultrasound Volumes for Glioma Resection in Image-guided Neurosurgery. Int J Comput Assist Radiol Surg. 2019.Abstract
PURPOSE: In image-guided surgery for glioma removal, neurosurgeons usually plan the resection on images acquired before surgery and use them for guidance during the subsequent intervention. However, after the surgical procedure has begun, the preplanning images become unreliable due to the brain shift phenomenon, caused by modifications of anatomical structures and imprecisions in the neuronavigation system. To obtain an updated view of the resection cavity, a solution is to collect intraoperative data, which can be additionally acquired at different stages of the procedure in order to provide a better understanding of the resection. A spatial mapping between structures identified in subsequent acquisitions would be beneficial. We propose here a fully automated segmentation-based registration method to register ultrasound (US) volumes acquired at multiple stages of neurosurgery. METHODS: We chose to segment sulci and falx cerebri in US volumes, which remain visible during resection. To automatically segment these elements, first we trained a convolutional neural network on manually annotated structures in volumes acquired before the opening of the dura mater and then we applied it to segment corresponding structures in different surgical phases. Finally, the obtained masks are used to register US volumes acquired at multiple resection stages. RESULTS: Our method reduces the mean target registration error (mTRE) between volumes acquired before the opening of the dura mater and during resection from 3.49 mm (± 1.55 mm) to 1.36 mm (± 0.61 mm). Moreover, the mTRE between volumes acquired before opening the dura mater and at the end of the resection is reduced from 3.54 mm (± 1.75 mm) to 2.05 mm (± 1.12 mm). CONCLUSION: The segmented structures demonstrated to be good candidates to register US volumes acquired at different neurosurgical phases. Therefore, our solution can compensate brain shift in neurosurgical procedures involving intraoperative US data.
Zaffino P, Pernelle G, Mastmeyer A, Mehrtash A, Zhang H, Kikinis R, Kapur T, Spadea MF. Fully Automatic Catheter Segmentation in MRI with 3D Convolutional Neural Networks: Application to MRI-guided Gynecologic Brachytherapy. Phys Med Biol. 2019;64 (16) :165008.Abstract
External-beam radiotherapy followed by High Dose Rate (HDR) brachytherapy is the standard-of-care for treating gynecologic cancers. The enhanced soft-tissue contrast provided by Magnetic Resonance Imaging (MRI) makes it a valuable imaging modality for diagnosing and treating these cancers. However, in contrast to Computed Tomography (CT) imaging, the appearance of the brachytherapy catheters, through which radiation sources are inserted to reach the cancerous tissue later on, is often variable across images. This paper reports, for the first time, a new deep-learning-based method for fully automatic segmentation of multiple closely spaced brachytherapy catheters in intraoperative MRI. 
 Represented in the data are 50 gynecologic cancer patients treated by MRI-guided HDR brachytherapy. For each patient, a single intraoperative MRI was used. 826 catheters in the images were manually segmented by an expert radiation physicist who is also a trained radiation oncologist. The number of catheters in a patient ranged between 10 and 35. A deep 3-dimensional Convolutional Neural Network (CNN) model was developed and trained. In order to make the learning process more robust, the network was trained 5 times, each time using a different combination of shown patients. Finally, each test case was processed by the 5 networks and the final segmentation was generated by voting on the obtained 5 candidate segmentations. 4-fold validation was executed and all the patients were segmented.
 An average distance error of 2.0±3.4 mm was achieved. False positive and false negative catheters were 6.7% and 1.5% respectively. Average Dice score was equal to 0.60±0.17. The algorithm is available for use in the open source software platform 3D Slicer allowing for wide scale testing and research discussion. In conclusion, to the best of our knowledge, fully automatic segmentation of multiple closely spaced catheters from intraoperative MR images was achieved for the first time in gynecological brachytherapy.
Schwier M, van Griethuysen J, Vangel MG, Pieper S, Peled S, Tempany C, Aerts HJWL, Kikinis R, Fennessy FM, Fedorov A. Repeatability of Multiparametric Prostate MRI Radiomics Features. Sci Rep. 2019;9 (1) :9441.Abstract
In this study we assessed the repeatability of radiomics features on small prostate tumors using test-retest Multiparametric Magnetic Resonance Imaging (mpMRI). The premise of radiomics is that quantitative image-based features can serve as biomarkers for detecting and characterizing disease. For such biomarkers to be useful, repeatability is a basic requirement, meaning its value must remain stable between two scans, if the conditions remain stable. We investigated repeatability of radiomics features under various preprocessing and extraction configurations including various image normalization schemes, different image pre-filtering, and different bin widths for image discretization. Although we found many radiomics features and preprocessing combinations with high repeatability (Intraclass Correlation Coefficient > 0.85), our results indicate that overall the repeatability is highly sensitive to the processing parameters. Neither image normalization, using a variety of approaches, nor the use of pre-filtering options resulted in consistent improvements in repeatability. We urge caution when interpreting radiomics features and advise paying close attention to the processing configuration details of reported results. Furthermore, we advocate reporting all processing details in radiomics studies and strongly recommend the use of open source implementations.
Aryal M, Papademetriou I, Zhang Y-Z, Power C, McDannold N, Porter T. MRI Monitoring and Quantification of Ultrasound-Mediated Delivery of Liposomes Dually Labeled with Gadolinium and Fluorophore through the Blood-Brain Barrier. Ultrasound Med Biol. 2019;45 (7) :1733-1742.Abstract
Magnetic resonance image-guided focused ultrasound has emerged as a viable non-invasive technique for the treatment of central nervous system-related diseases/disorders. Application of mechanical and thermal effects associated with focused transcranial ultrasound has been studied extensively in pre-clinical models, which has paved the way for clinical trials. However, in vivo treatment evaluation techniques on drug delivery application via blood-brain barrier opening has not been fully explored. Current treatment evaluation techniques via magnetic resonance imaging are hindered by systemic toxicity resulting from free gadolinium delivery. Here we propose a novel treatment evaluation strategy to overcome limitations by (i) synthesizing liposomes that are dually labeled with gadolinium, a magnetic resonance imaging (MRI) contrast agent, and rhodamine, a fluorophore; (ii) applying a focused ultrasound (FUS)-mediated BBB opening technique to deliver the liposomes across vascular barriers, achieving local gadolinium enhancement while reducing systemic and unwanted regional toxic effects associated with free gadolinium; and (iii) utilizing the MRI modality to confirm the delivery as it is already included in the FUS treatment in clinic. Liposomes were secondarily labeled with a fluorescent marker to confirm results obtained by MRI quantification postmortem. Two different sizes, 77.5 nm (group A) and 140 nm (group B), of gadolinium- and fluorescence-labeled liposomes were fabricated using thin-film hydration followed by extrusion methods and determined their stability up to 6 h under physiologic conditions. Gadolinium signal was detected on contrast-enhanced T1-weighted MRI 5 h after the delivery of liposomes via the BBB opening approach with an ultrasound pulse of 0.42 MPa (estimate in water) combined with microbubbles. MRI contrast was enhanced significantly in sonicated regions compared with non-sonicated regions of the brain. This was due to the accumulation of labeled liposomes, which was confirmed by detection of rhodamine fluorescence in histologic sections. The relative increase in MRI signal intensity was greater for smaller liposomes (mean diameter = 77.5 nm) than larger liposomes (mean diameter = 140 nm), which suggested a greater accumulation of the smaller liposomes in the brain after ultrasound-mediated opening of the BBB. Our findings suggest that the dual-labeled nanocarrier platform can be established, the FUS-mediated BBB opening approach can be used to deliver it through vascular barriers and MRI can be used to evaluate the extent of nanocarrier delivery.
Basu SS, Regan MS, Randall EC, Abdelmoula WM, Clark AR, Gimenez-Cassina Lopez B, Cornett DS, Haase A, Santagata S, Agar NYR. Rapid MALDI Mass Spectrometry Imaging for Surgical Pathology. NPJ Precis Oncol. 2019;3 :17.Abstract
Matrix assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) is an emerging analytical technique, which generates spatially resolved proteomic and metabolomic images from tissue specimens. Conventional MALDI MSI processing and data acquisition can take over 30 min, limiting its clinical utility for intraoperative diagnostics. We present a rapid MALDI MSI method, completed under 5 min, including sample preparation and analysis, providing a workflow compatible with the clinical frozen section procedure.
Abdelmoula WM, Regan MS, Lopez BGC, Randall EC, Lawler S, Mladek AC, Nowicki MO, Marin BM, Agar JN, Swanson KR, et al. Automatic 3D Nonlinear Registration of Mass Spectrometry Imaging and Magnetic Resonance Imaging Data. Anal Chem. 2019;91 (9) :6206-16.Abstract
Multimodal integration between mass spectrometry imaging (MSI) and radiology-established modalities such as magnetic resonance imaging (MRI) would allow the investigations of key questions in complex biological systems such as the central nervous system. Such integration would provide complementary multiscale data to bridge the gap between molecular and anatomical phenotypes, potentially revealing new insights into molecular mechanisms underlying anatomical pathologies presented on MRI. Automatic coregistration between 3D MSI/MRI is a computationally challenging process due to dimensional complexity, MSI data sparsity, lack of direct spatial-correspondences, and nonlinear tissue deformation. Here, we present a new computational approach based on stochastic neighbor embedding to nonlinearly align 3D MSI to MRI data, identify and reconstruct biologically relevant molecular patterns in 3D, and fuse the MSI datacube to the MRI space. We demonstrate our method using multimodal high-spectral resolution matrix-assisted laser desorption ionization (MALDI) 9.4 T MSI and 7 T in vivo MRI data, acquired from a patient-derived, xenograft mouse brain model of glioblastoma following administration of the EGFR inhibitor drug of Erlotinib. Results show the distribution of some identified molecular ions of the EGFR inhibitor erlotinib, a phosphatidylcholine lipid, and cholesterol, which were reconstructed in 3D and mapped to the MRI space. The registration quality was evaluated on two normal mouse brains using the Dice coefficient for the regions of brainstem, hippocampus, and cortex. The method is generic and can therefore be applied to hyperspectral images from different mass spectrometers and integrated with other established in vivo imaging modalities such as computed tomography (CT) and positron emission tomography (PET).
Herz C, MacNeil K, Behringer PA, Tokuda J, Mehrtash A, Mousavi P, Kikinis R, Fennessy FM, Tempany CM, Tuncali K, et al. Open Source Platform for Transperineal In-bore MRI-guided Targeted Prostate Biopsy. IEEE Trans Biomed Eng. 2019.Abstract
OBJECTIVE: Accurate biopsy sampling of the suspected lesions is critical for the diagnosis and clinical management of prostate cancer (PCa). Transperineal in-bore MRI-guided prostate biopsy (tpMRgBx) is a targeted biopsy technique that was shown to be safe, efficient and accurate. Our goal was to develop an open source software platform to support evaluation, refinement and translation of this biopsy approach. METHODS: We developed SliceTracker, a 3D Slicer extension to support tpMRgBx. We followed modular design of the implementation to enable customization of the interface, and interchange of image segmentation and registration components to assess their effect on the processing time, precision and accuracy of the biopsy needle placement. The platform and supporting documentation were developed to enable the use of software by an operator with minimal technical training to facilitate translation. Retrospective evaluation studied registration accuracy, effect of the prostate segmentation approach, and re-identification time of biopsy targets. Prospective evaluation focused on the total procedure time and biopsy targeting error (BTE). RESULTS: Evaluation utilized data from 73 retrospective and 10 prospective tpMRgBx cases. Mean Landmark Registration Error (LRE) for retrospective evaluation was 1.88 ±2.63 mm and was not sensitive to the approach used for prostate gland segmentation. Prospectively, we observed target re-identification time of 4.60 ±2.40 min, and BTE of 2.40 ±0.98 mm. CONCLUSION: SliceTracker is modular and extensible open source platform for supporting image processing aspects of the tpMRgBx procedure. It has been successfully utilized to support clinical research procedures at our site.
Gao Y, Takagi K, Kato T, Shono N, Hata N. Continuum Robot with Follow the Leader Motion for Endoscopic Third Ventriculostomy and Tumor Biopsy. IEEE Trans Biomed Eng. 2019.Abstract
[Background] In a combined endoscopic third ventriculostomy (ETV) and endoscopic tumor biopsy (ETB) procedure, an optimal tool trajectory is mandatory to minimize trauma to surrounding cerebral tissue. [Objective] This paper presents wire-driven multi-section robot with push-pull driving wire. The robot is tested to attain follow-the-leader (FTL) motion to place surgical instruments through narrow passages while minimizing the trauma to tissues. [Methods] A wire-driven continuum robot with six sub-sections was developed and its kinematic model to achieve FTL motion was proposed. An accuracy test to assess the robot's ability to attain FTL motion along a set of elementary curved trajectory was performed. We also used hydrocephalus ventricular model created from human subject data to generate five ETV/ETB trajectory and conducted a study assessing the accuracy of the FTL motion along these clinically desirable trajectories. [Results] In the test with elementary curved paths, the maximal deviation of the robot was increased from 0.47 mm at 30 degrees turn to 1.78 mm at 180 degrees in a simple C-shaped curve. S-shaped FTL motion had lesser deviation ranging from 0.16 mm to 0.18 mm. In the phantom study, the greatest tip-deviation was 1.45 mm, and the greatest path deviation was 1.23 mm. [Conclusion] We present the application of a continuum robot with FTL motion to perform a combined ETV/ETB procedure. The validation study using human subject data indicated that the accuracy of FTL motion is relatively high. It is expected that may be useful combined ETV and ETB.
Price C, Gill S, Ho ZV, Davidson SM, Merkel E, McFarland JM, Leung L, Tang A, Kost-Alimova M, Tsherniak A, et al. Genome-Wide Interrogation of Human Cancers Identifies EGLN1 Dependency in Clear Cell Ovarian Cancers. Cancer Res. 2019;79 (10) :2564-79.Abstract
We hypothesized that candidate dependencies for which there are small molecules that are either approved or in advanced development for a nononcology indication may represent potential therapeutic targets. To test this hypothesis, we performed genome-scale loss-of-function screens in hundreds of cancer cell lines. We found that knockout of , which encodes prolyl hydroxylase domain-containing protein 2 (PHD2), reduced the proliferation of a subset of clear cell ovarian cancer cell lines . EGLN1-dependent cells exhibited sensitivity to the pan-EGLN inhibitor FG-4592. The response to FG-4592 was reversed by deletion of HIF1A, demonstrating that EGLN1 dependency was related to negative regulation of HIF1A. We also found that ovarian clear cell tumors susceptible to both genetic and pharmacologic inhibition of EGLN1 required intact HIF1A. Collectively, these observations identify EGLN1 as a cancer target with therapeutic potential. SIGNIFICANCE: These findings reveal a differential dependency of clear cell ovarian cancers on EGLN1, thus identifying EGLN1 as a potential therapeutic target in clear cell ovarian cancer patients.
King MT, Nguyen PL, Boldbaatar N, Yang DD, Muralidhar V, Tempany CM, Cormack RA, Hurwitz MD, Suh WW, Pomerantz MM, et al. Evaluating the Influence of Prostate-specific Antigen Kinetics on Metastasis in Men with PSA Recurrence after Partial Gland Therapy. Brachytherapy. 2019;18 (2) :198-203.Abstract
PURPOSE: Although current Delphi Consensus guidelines do not recommend a specific definition of biochemical recurrence after partial gland therapy, these guidelines acknowledge that serial prostate-specific antigen (PSA) tests remain the best marker for monitoring disease after treatment. The purpose of this study was to determine whether PSA velocity at failure per the Phoenix (nadir + 2 ng/mL) definition is associated with metastasis and prostate cancer-specific mortality (PCSM) in a cohort of patients who experienced PSA failure after partial gland therapy. METHODS: Between 1997 and 2007, 285 patients with favorable risk prostate cancer underwent partial prostate brachytherapy to the peripheral zone. PSA velocity was calculated for 94 patients who experienced PSA failure per the Phoenix (nadir + 2) definition. Fine and Gray competing risks regression was performed to determine whether PSA velocity and other clinical factors were associated with metastasis and PCSM. RESULTS: The median time to PSA failure was 4.2 years (interquartile range: 2.2, 7.9), and the median followup time after PSA failure was 6.5 years (3.5-9.7). Seventeen patients developed metastases, and five experienced PCSM. On multivariate analysis, PSA velocity ≥3.0 ng/mL/year (adjusted hazard ratio 5.97; [2.57, 13.90]; p < 0.001) and PSA nadir (adjusted hazard ratio 0.39; [0.24, 0.64]; p < 0.001) were significantly associated with metastasis. PSA velocity ≥3.0 ng/mL/year was also associated with PCSM (HR 15.3; [1.8, 128.0]; p = 0.012) on univariate analysis. CONCLUSIONS: Rapid PSA velocity at PSA failure after partial gland treatment may be prognostic for long-term outcomes.
Frisken S, Luo M, Machado I, Unadkat P, Juvekar P, Bunevicius A, Toews M, Wells WM, Miga MI, Golby AJ. Preliminary Results Comparing Thin Plate Splines with Finite Element Methods for Modeling Brain Deformation during Neurosurgery using Intraoperative Ultrasound. Proc SPIE Int Soc Opt Eng. 2019;10951.Abstract
Brain shift compensation attempts to model the deformation of the brain which occurs during the surgical removal of brain tumors to enable mapping of presurgical image data into patient coordinates during surgery and thus improve the accuracy and utility of neuro-navigation. We present preliminary results from clinical tumor resections that compare two methods for modeling brain deformation, a simple thin plate spline method that interpolates displacements and a more complex finite element method (FEM) that models physical and geometric constraints of the brain and its material properties. Both methods are driven by the same set of displacements at locations surrounding the tumor. These displacements were derived from sets of corresponding matched features that were automatically detected using the SIFT-Rank algorithm. The deformation accuracy was tested using a set of manually identified landmarks. The FEM method requires significantly more preprocessing than the spline method but both methods can be used to model deformations in the operating room in reasonable time frames. Our preliminary results indicate that the FEM deformation model significantly out-performs the spline-based approach for predicting the deformation of manual landmarks. While both methods compensate for brain shift, this work suggests that models that incorporate biophysics and geometric constraints may be more accurate.
Lampinen B, Szczepankiewicz F, Novén M, van Westen D, Hansson O, Englund E, Mårtensson J, Westin C-F, Nilsson M. Searching for the Neurite Density with Diffusion MRI: Challenges for Biophysical Modeling. Hum Brain Mapp. 2019;40 (8) :2529-45.Abstract
In vivo mapping of the neurite density with diffusion MRI (dMRI) is a high but challenging aim. First, it is unknown whether all neurites exhibit completely anisotropic ("stick-like") diffusion. Second, the "density" of tissue components may be confounded by non-diffusion properties such as T2 relaxation. Third, the domain of validity for the estimated parameters to serve as indices of neurite density is incompletely explored. We investigated these challenges by acquiring data with "b-tensor encoding" and multiple echo times in brain regions with low orientation coherence and in white matter lesions. Results showed that microscopic anisotropy from b-tensor data is associated with myelinated axons but not with dendrites. Furthermore, b-tensor data together with data acquired for multiple echo times showed that unbiased density estimates in white matter lesions require data-driven estimates of compartment-specific T2 values. Finally, the "stick" fractions of different biophysical models could generally not serve as neurite density indices across the healthy brain and white matter lesions, where outcomes of comparisons depended on the choice of constraints. In particular, constraining compartment-specific T2 values was ambiguous in the healthy brain and had a large impact on estimated values. In summary, estimating neurite density generally requires accounting for different diffusion and/or T2 properties between axons and dendrites. Constrained "index" parameters could be valid within limited domains that should be delineated by future studies.
Kocev B, Hahn HK, Linsen L, Wells WM, Kikinis R. Uncertainty-aware Asynchronous Scattered Motion Interpolation using Gaussian Process Regression. Comput Med Imaging Graph. 2019;72 :1-12.Abstract
We address the problem of interpolating randomly non-uniformly spatiotemporally scattered uncertain motion measurements, which arises in the context of soft tissue motion estimation. Soft tissue motion estimation is of great interest in the field of image-guided soft-tissue intervention and surgery navigation, because it enables the registration of pre-interventional/pre-operative navigation information on deformable soft-tissue organs. To formally define the measurements as spatiotemporally scattered motion signal samples, we propose a novel motion field representation. To perform the interpolation of the motion measurements in an uncertainty-aware optimal unbiased fashion, we devise a novel Gaussian process (GP) regression model with a non-constant-mean prior and an anisotropic covariance function and show through an extensive evaluation that it outperforms the state-of-the-art GP models that have been deployed previously for similar tasks. The employment of GP regression enables the quantification of uncertainty in the interpolation result, which would allow the amount of uncertainty present in the registered navigation information governing the decisions of the surgeon or intervention specialist to be conveyed.
Schmitt ND, Rawlins CM, Randall EC, Wang X, Koller A, Auclair JR, Kowalski J-M, Kowalski PJ, Luther E, Ivanov AR, et al. Genetically Encoded Fluorescent Proteins Enable High-Throughput Assignment of Cell Cohorts Directly from MALDI-MS Images. Anal Chem. 2019;91 (6) :3810-7.Abstract
Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) provides a unique in situ chemical profile that can include drugs, nucleic acids, metabolites, lipids, and proteins. MSI of individual cells (of a known cell type) affords a unique insight into normal and disease-related processes and is a prerequisite for combining the results of MSI and other single-cell modalities (e.g. mass cytometry and next-generation sequencing). Technological barriers have prevented the high-throughput assignment of MSI spectra from solid tissue preparations to their cell type. These barriers include obtaining a suitable cell-identifying image (e.g. immunohistochemistry) and obtaining sufficiently accurate registration of the cell-identifying and MALDI-MS images. This study introduces a technique that overcame these barriers by assigning cell type directly from mass spectra. We hypothesized that, in MSI from mice with a defined fluorescent protein expression pattern, the fluorescent protein's molecular ion could be used to identify cell cohorts. A method was developed for the purification of enhanced yellow fluorescent protein (EYFP) from mice. To determine EYFP's molecular mass for MSI studies, we performed intact mass analysis and characterized the protein's primary structure and post-translational modifications through various techniques. MALDI-MSI methods were developed to enhance the detection of EYFP in situ, and by extraction of EYFP's molecular ion from MALDI-MS images, automated, whole-image assignment of cell cohorts was achieved. This method was validated using a well-characterized mouse line that expresses EYFP in motor and sensory neurons and should be applicable to hundreds of commercially available mice (and other animal) strains comprising a multitude of cell-specific fluorescent labels.