Publications by Year: 2019

2019
Fan Zhang, Nico Hoffmann, Suheyla Cetin Karayumak, Yogesh Rathi, Alexandra J Golby, and Lauren J O'Donnell. 10/2019. “Deep White Matter Analysis: Fast, Consistent Tractography Segmentation Across Populations and dMRI Acquisitions.” Med Image Comput Comput Assist Interv, 11766, Pp. 599-608.Abstract
We present a deep learning tractography segmentation method that allows fast and consistent white matter fiber tract identification across healthy and disease populations and across multiple diffusion MRI (dMRI) acquisitions. We create a large-scale training tractography dataset of 1 million labeled fiber samples (54 anatomical tracts are included). To discriminate between fibers from different tracts, we propose a novel 2D multi-channel feature descriptor (FiberMap) that encodes spatial coordinates of points along each fiber. We learn a CNN tract classification model based on FiberMap and obtain a high tract classification accuracy of 90.99%. The method is evaluated on a test dataset of 374 dMRI scans from three independently acquired populations across health conditions (healthy control, neuropsychiatric disorders, and brain tumor patients). We perform comparisons with two state-of-the-art white matter tract segmentation methods. Experimental results show that our method obtains a highly consistent segmentation result, where over 99% of the fiber tracts are successfully detected across all subjects under study, most importantly, including patients with space occupying brain tumors. The proposed method leverages deep learning techniques and provides a much faster and more efficient tool for large data analysis than methods using traditional machine learning techniques.
Pelin Aksit Ciris, Jr-yuan George Chiou, Daniel I Glazer, Tzu-Cheng Chao, Clare M Tempany-Afdhal, Bruno Madore, and Stephan E. Maier. 2019. “Accelerated Segmented Diffusion-Weighted Prostate Imaging for Higher Resolution, Higher Geometric Fidelity, and Multi-b Perfusion Estimation.” Invest Radiol, 54, 4, Pp. 238-46.Abstract
PURPOSE: The aim of this study was to improve the geometric fidelity and spatial resolution of multi-b diffusion-weighted magnetic resonance imaging of the prostate. MATERIALS AND METHODS: An accelerated segmented diffusion imaging sequence was developed and evaluated in 25 patients undergoing multiparametric magnetic resonance imaging examinations of the prostate. A reduced field of view was acquired using an endorectal coil. The number of sampled diffusion weightings, or b-factors, was increased to allow estimation of tissue perfusion based on the intravoxel incoherent motion (IVIM) model. Apparent diffusion coefficients measured with the proposed segmented method were compared with those obtained with conventional single-shot echo-planar imaging (EPI). RESULTS: Compared with single-shot EPI, the segmented method resulted in faster acquisition with 2-fold improvement in spatial resolution and a greater than 3-fold improvement in geometric fidelity. Apparent diffusion coefficient values measured with the novel sequence demonstrated excellent agreement with those obtained from the conventional scan (R = 0.91 for bmax = 500 s/mm and R = 0.89 for bmax = 1400 s/mm). The IVIM perfusion fraction was 4.0% ± 2.7% for normal peripheral zone, 6.6% ± 3.6% for normal transition zone, and 4.4% ± 2.9% for suspected tumor lesions. CONCLUSIONS: The proposed accelerated segmented prostate diffusion imaging sequence achieved improvements in both spatial resolution and geometric fidelity, along with concurrent quantification of IVIM perfusion.
Lauren J O'Donnell, Alessandro Daducci, Demian Wassermann, and Christophe Lenglet. 2019. “Advances in Computational and Statistical Diffusion MRI.” NMR Biomed., 32, 4, Pp. e3805.Abstract
Computational methods are crucial for the analysis of diffusion magnetic resonance imaging (MRI) of the brain. Computational diffusion MRI can provide rich information at many size scales, including local microstructure measures such as diffusion anisotropies or apparent axon diameters, whole-brain connectivity information that describes the brain's wiring diagram and population-based studies in health and disease. Many of the diffusion MRI analyses performed today were not possible five, ten or twenty years ago, due to the requirements for large amounts of computer memory or processor time. In addition, mathematical frameworks had to be developed or adapted from other fields to create new ways to analyze diffusion MRI data. The purpose of this review is to highlight recent computational and statistical advances in diffusion MRI and to put these advances into context by comparison with the more traditional computational methods that are in popular clinical and scientific use. We aim to provide a high-level overview of interest to diffusion MRI researchers, with a more in-depth treatment to illustrate selected computational advances.
Jie Luo, Alireza Sedghi, Karteek Popuri, Dana Cobzas, Miaomiao Zhang, Frank Preiswerk, Matthew Toews, Alexandra Golby, Masashi Sugiyama, William III M Wells, and Sarah Frisken. 2019. “On the Applicability of Registration Uncertainty.” In MICCAI 2019, LNCS 11765: Pp. 410-9. Shenzhen, China: Springer.Abstract
Estimating the uncertainty in (probabilistic) image registration enables, e.g., surgeons to assess the operative risk based on the trustworthiness of the registered image data. If surgeons receive inaccurately calculated registration uncertainty and misplace unwarranted confidence in the alignment solutions, severe consequences may result. For probabilistic image registration (PIR), the predominant way to quantify the registration uncertainty is using summary statistics of the distribution of transformation parameters. The majority of existing research focuses on trying out different summary statistics as well as means to exploit them. Distinctively, in this paper, we study two rarely examined topics: (1) whether those summary statistics of the transformation distribution most informatively represent the registration uncertainty; (2) Does utilizing the registration uncertainty always be beneficial. We show that there are two types of uncertainties: the transformation uncertainty, Ut, and label uncertainty Ul. The conventional way of using Ut to quantify Ul is inappropriate and can be misleading. By a real data experiment, we also share a potentially critical finding that making use of the registration uncertainty may not always be an improvement.
Luo MICCAI 2019
Wenya Linda Bi, Ahmed Hosny, Matthew B Schabath, Maryellen L Giger, Nicolai J Birkbak, Alireza Mehrtash, Tavis Allison, Omar Arnaout, Christopher Abbosh, Ian F Dunn, Raymond H Mak, Rulla M Tamimi, Clare M Tempany, Charles Swanton, Udo Hoffmann, Lawrence H Schwartz, Robert J Gillies, Raymond Y Huang, and Hugo JWL Aerts. 2019. “Artificial Intelligence in Cancer Imaging: Clinical Challenges and Applications.” CA Cancer J Clin, 69, 2, Pp. 127-57.Abstract
Judgement, as one of the core tenets of medicine, relies upon the integration of multilayered data with nuanced decision making. Cancer offers a unique context for medical decisions given not only its variegated forms with evolution of disease but also the need to take into account the individual condition of patients, their ability to receive treatment, and their responses to treatment. Challenges remain in the accurate detection, characterization, and monitoring of cancers despite improved technologies. Radiographic assessment of disease most commonly relies upon visual evaluations, the interpretations of which may be augmented by advanced computational analyses. In particular, artificial intelligence (AI) promises to make great strides in the qualitative interpretation of cancer imaging by expert clinicians, including volumetric delineation of tumors over time, extrapolation of the tumor genotype and biological course from its radiographic phenotype, prediction of clinical outcome, and assessment of the impact of disease and treatment on adjacent organs. AI may automate processes in the initial interpretation of images and shift the clinical workflow of radiographic detection, management decisions on whether or not to administer an intervention, and subsequent observation to a yet to be envisioned paradigm. Here, the authors review the current state of AI as applied to medical imaging of cancer and describe advances in 4 tumor types (lung, brain, breast, and prostate) to illustrate how common clinical problems are being addressed. Although most studies evaluating AI applications in oncology to date have not been vigorously validated for reproducibility and generalizability, the results do highlight increasingly concerted efforts in pushing AI technology to clinical use and to impact future directions in cancer care.
Walid M Abdelmoula, Michael S Regan, Begona GC Lopez, Elizabeth C Randall, Sean Lawler, Ann C Mladek, Michal O Nowicki, Bianca M Marin, Jeffrey N Agar, Kristin R Swanson, Tina Kapur, Jann N Sarkaria, William Wells, and Nathalie YR Agar. 2019. “Automatic 3D Nonlinear Registration of Mass Spectrometry Imaging and Magnetic Resonance Imaging Data.” Anal Chem, 91, 9, Pp. 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).
J Nitsch, J Klein, P Dammann, K Wrede, O Gembruch, JH Moltz, H Meine, U Sure, R. Kikinis, and D Miller. 2019. “Automatic and Efficient MRI-US Segmentations for Improving Intraoperative Image Fusion in Image-guided Neurosurgery.” Neuroimage Clin, 22, Pp. 101766.Abstract
Knowledge of the exact tumor location and structures at risk in its vicinity are crucial for neurosurgical interventions. Neuronavigation systems support navigation within the patient's brain, based on preoperative MRI (preMRI). However, increasing tissue deformation during the course of tumor resection reduces navigation accuracy based on preMRI. Intraoperative ultrasound (iUS) is therefore used as real-time intraoperative imaging. Registration of preMRI and iUS remains a challenge due to different or varying contrasts in iUS and preMRI. Here, we present an automatic and efficient segmentation of B-mode US images to support the registration process. The falx cerebri and the tentorium cerebelli were identified as examples for central cerebral structures and their segmentations can serve as guiding frame for multi-modal image registration. Segmentations of the falx and tentorium were performed with an average Dice coefficient of 0.74 and an average Hausdorff distance of 12.2 mm. The subsequent registration incorporates these segmentations and increases accuracy, robustness and speed of the overall registration process compared to purely intensity-based registration. For validation an expert manually located corresponding landmarks. Our approach reduces the initial mean Target Registration Error from 16.9 mm to 3.8 mm using our intensity-based registration and to 2.2 mm with our combined segmentation and registration approach. The intensity-based registration reduced the maximum initial TRE from 19.4 mm to 5.6 mm, with the approach incorporating segmentations this is reduced to 3.0 mm. Mean volumetric intensity-based registration of preMRI and iUS took 40.5 s, including segmentations 12.0 s.
Alireza Mehrtash, Mohsen Ghafoorian, Guillaume Pernelle, Alireza Ziaei, Friso G Heslinga, Kemal Tuncali, Andriy Fedorov, Ron Kikinis, Clare M Tempany, William M Wells, Purang Abolmaesumi, and Tina Kapur. 2019. “Automatic Needle Segmentation and Localization in MRI with 3D Convolutional Neural Networks: Application to MRI-targeted Prostate Biopsy.” IEEE Trans Med Imaging., 38, 4, Pp. 1026-36.Abstract
Image-guidance improves tissue sampling during biopsy by allowing the physician to visualize the tip and trajectory of the biopsy needle relative to the target in MRI, CT, ultrasound, or other relevant imagery. This paper reports a system for fast automatic needle tip and trajectory localization and visualization in MRI that has been developed and tested in the context of an active clinical research program in prostate biopsy. To the best of our knowledge, this is the first reported system for this clinical application, and also the first reported system that leverages deep neural networks for segmentation and localization of needles in MRI across biomedical applications. Needle tip and trajectory were annotated on 583 T2-weighted intra-procedural MRI scans acquired after needle insertion for 71 patients who underwent transperenial MRI-targeted biopsy procedure at our institution. The images were divided into two independent training-validation and test sets at the patient level. A deep 3-dimensional fully convolutional neural network model was developed, trained and deployed on these samples. The accuracy of the proposed method, as tested on previously unseen data, was 2.80 mm average in needle tip detection, and 0.98° in needle trajectory angle. An observer study was designed in which independent annotations by a second observer, blinded to the original observer, were compared to the output of the proposed method. The resultant error was comparable to the measured inter-observer concordance, reinforcing the clinical acceptability of the proposed method. The proposed system has the potential for deployment in clinical routine.
Karol Miller, Grand R Joldes, George Bourantas, Simon K Warfield, Damon E Hyde, Ron Kikinis, and Adam Wittek. 2019. “Biomechanical Modeling and Computer Simulation of the Brain during Neurosurgery.” Int J Numer Method Biomed Eng, Pp. 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.
G Fan, H Liu, Z. Wu, Y. Li, C Feng, D Wang, J Luo, WM Wells, and S He. 2019. “Deep Learning-Based Automatic Segmentation of Lumbosacral Nerves on CT for Spinal Intervention: A Translational Study.” AJNR Am J Neuroradiol, 40, 6, Pp. 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.
Inês Machado, Matthew Toews, Elizabeth George, Prashin Unadkat, Walid Essayed, Jie Luo, Pedro Teodoro, Herculano Carvalho, Jorge Martins, Polina Golland, Steve Pieper, Sarah Frisken, Alexandra Golby, William Wells, and Yangming Ou. 2019. “Deformable MRI-Ultrasound Registration using Correlation-based Attribute Matching for Brain Shift Correction: Accuracy and Generality in Multi-site Data.” Neuroimage, 202, Pp. 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.
Sanjay S Yengul, Paul E Barbone, and Bruno Madore. 2019. “Dispersion in Tissue-Mimicking Gels Measured with Shear Wave Elastography and Torsional Vibration Rheometry.” Ultrasound Med Biol, 45, 2, Pp. 586-604.Abstract
Dispersion, or the frequency dependence of mechanical parameters, is a primary confounding factor in elastography comparisons. We present a study of dispersion in tissue-mimicking gels over a wide frequency band using a combination of ultrasound shear wave elastography (SWE), and a novel torsional vibration rheometry which allows independent mechanical measurement of SWE samples. Frequency-dependent complex shear modulus was measured in homogeneous gelatin hydrogels of two different bloom strengths while controlling for confounding factors such as temperature, water content and material aging. Furthermore, both techniques measured the same physical samples, thereby eliminating possible variation caused by batch-to-batch gel variation, sample geometry differences and boundary artifacts. The wide-band measurement, from 1 to 1800 Hz, captured a 30%-50% increase in the storage modulus and a nearly linear increase with frequency of the loss modulus. The magnitude of the variation suggests that accounting for dispersion is essential for meaningful comparisons between SWE implementations.
Martin T King, Paul L Nguyen, Ninjin Boldbaatar, David D Yang, Vinayak Muralidhar, Clare M Tempany, Robert A Cormack, Mark D Hurwitz, Warren W Suh, Mark M Pomerantz, Anthony V D'Amico, and Peter F Orio. 2019. “Evaluating the Influence of Prostate-specific Antigen Kinetics on Metastasis in Men with PSA Recurrence after Partial Gland Therapy.” Brachytherapy, 18, 2, Pp. 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.
Paolo Zaffino, Guillaume Pernelle, Andre Mastmeyer, Alireza Mehrtash, Hongtao Zhang, Ron Kikinis, Tina Kapur, and Maria Francesca Spadea. 2019. “Fully Automatic Catheter Segmentation in MRI with 3D Convolutional Neural Networks: Application to MRI-guided Gynecologic Brachytherapy.” Phys Med Biol, 64, 16, Pp. 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. &#13; 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.&#13; 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.
Prashin Unadkat, Luca Fumagalli, Laura Rigolo, Mark G Vangel, Geoffrey S Young, Raymond Huang, Srinivasan Mukundan, Alexandra Golby, and Yanmei Tie. 2019. “Functional MRI Task Comparison for Language Mapping in Neurosurgical Patients.” J Neuroimaging, 29, 3, Pp. 348-56.Abstract
BACKGROUND AND PURPOSE: Language task-based functional MRI (fMRI) is increasingly used for presurgical planning in patients with brain lesions. Different paradigms elicit activations of different components of the language network. The aim of this study is to optimize fMRI clinical usage by comparing the effectiveness of three language tasks for language lateralization and localization in a large group of patients with brain lesions. METHODS: We analyzed fMRI data from a sequential retrospective cohort of 51 patients with brain lesions who underwent presurgical fMRI language mapping. We compared the effectiveness of three language tasks (Antonym Generation, Sentence Completion (SC), and Auditory Naming) for lateralizing language function and for activating cortex within patient-specific regions-of-interest representing eloquent language areas, and assessed the degree of spatial overlap of the areas of activation elicited by each task. RESULTS: The tasks were similarly effective for lateralizing language within the anterior language areas. The SC task produced higher laterality indices within the posterior language areas and had a significantly higher agreement with the clinical report. Dice coefficients between the task pairs were in the range of .351-.458, confirming substantial variation in the components of the language network activated by each task. CONCLUSIONS: SC task consistently produced large activations within the dominant hemisphere and was more effective for lateralizing language within the posterior language areas. The low degree of spatial overlap among the tasks strongly supports the practice of using a battery of tasks to help the surgeon to avoid eloquent language areas.
Nicholas D Schmitt, Catherine M Rawlins, Elizabeth C Randall, Xianzhe Wang, Antonius Koller, Jared R. Auclair, Jane-Marie Kowalski, Paul J. Kowalski, Ed Luther, Alexander R Ivanov, Nathalie YR Agar, and Jeffrey N Agar. 2019. “Genetically Encoded Fluorescent Proteins Enable High-Throughput Assignment of Cell Cohorts Directly from MALDI-MS Images.” Anal Chem, 91, 6, Pp. 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.
Colles Price, Stanley Gill, Zandra V Ho, Shawn M Davidson, Erin Merkel, James M McFarland, Lisa Leung, Andrew Tang, Maria Kost-Alimova, Aviad Tsherniak, Oliver Jonas, Francisca Vazquez, and William C Hahn. 2019. “Genome-Wide Interrogation of Human Cancers Identifies EGLN1 Dependency in Clear Cell Ovarian Cancers.” Cancer Res, 79, 10, Pp. 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.
Wei Huang, Yiyi Chen, Andriy Fedorov, Xia Li, Guido H Jajamovich, Dariya I Malyarenko, Madhava P Aryal, Peter S LaViolette, Matthew J Oborski, Finbarr O'Sullivan, Richard G Abramson, Kourosh Jafari-Khouzani, Aneela Afzal, Alina Tudorica, Brendan Moloney, Sandeep N Gupta, Cecilia Besa, Jayashree Kalpathy-Cramer, James M Mountz, Charles M Laymon, Mark Muzi, Paul E Kinahan, Kathleen Schmainda, Yue Cao, Thomas L Chenevert, Bachir Taouli, Thomas E Yankeelov, Fiona Fennessy, and Xin Li. 2019. “The Impact of Arterial Input Function Determination Variations on Prostate Dynamic Contrast-Enhanced Magnetic Resonance Imaging Pharmacokinetic Modeling: A Multicenter Data Analysis Challenge, Part II.” Tomography, 5, 1, Pp. 99-109.Abstract
This multicenter study evaluated the effect of variations in arterial input function (AIF) determination on pharmacokinetic (PK) analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data using the shutter-speed model (SSM). Data acquired from eleven prostate cancer patients were shared among nine centers. Each center used a site-specific method to measure the individual AIF from each data set and submitted the results to the managing center. These AIFs, their reference tissue-adjusted variants, and a literature population-averaged AIF, were used by the managing center to perform SSM PK analysis to estimate K (volume transfer rate constant), v (extravascular, extracellular volume fraction), k (efflux rate constant), and τ (mean intracellular water lifetime). All other variables, including the definition of the tumor region of interest and precontrast T values, were kept the same to evaluate parameter variations caused by variations in only the AIF. Considerable PK parameter variations were observed with within-subject coefficient of variation (wCV) values of 0.58, 0.27, 0.42, and 0.24 for K, v, k, and τ, respectively, using the unadjusted AIFs. Use of the reference tissue-adjusted AIFs reduced variations in K and v (wCV = 0.50 and 0.10, respectively), but had smaller effects on k and τ (wCV = 0.39 and 0.22, respectively). k is less sensitive to AIF variation than K, suggesting it may be a more robust imaging biomarker of prostate microvasculature. With low sensitivity to AIF uncertainty, the SSM-unique τ parameter may have advantages over the conventional PK parameters in a longitudinal study.
Mehdi Taghipour, Alireza Ziaei, Francesco Alessandrino, Elmira Hassanzadeh, Mukesh Harisinghani, Mark Vangel, Clare M Tempany, and Fiona M Fennessy. 2019. “Investigating the Role of DCE-MRI, over T2 and DWI, in accurate PI-RADS v2 Assessment of Clinically Significant Peripheral Zone Prostate Lesions as Defined at Radical Prostatectomy.” Abdom Radiol (NY), 44, 4, Pp. 1520-7.Abstract
PURPOSE: PI-RADS v2 dictates that dynamic contrast-enhanced (DCE) imaging be used to further classify peripheral zone (PZ) cases that receive a diffusion-weighted imaging equivocal score of three (DWI3), a positive DCE resulting in an increase in overall assessment score to a four, indicative of clinically significant prostate cancer (csPCa). However, the accuracy of DCE in predicting csPCa in DWI3 PZ cases is unknown. This study sought to determine the frequency with which DCE changes the PI-RADS v2 DWI3 assessment category, and to determine the overall accuracy of DCE-MRI in equivocal PZ DWI3 lesions. MATERIALS AND METHODS: This is a retrospective study of patients with pathologically proven PCa who underwent prostate mpMRI at 3T and subsequent radical prostatectomy. PI-RADS v2 assessment categories were determined by a radiologist, aware of a diagnosis of PCa, but blinded to final pathology. csPCa was defined as a Gleason score ≥ 7 or extra prostatic extension at pathology review. Performance characteristics and diagnostic accuracy of DCE in assigning a csPCa assessment in PZ lesions were calculated. RESULTS: A total of 271 men with mean age of 59 ± 6 years mean PSA 6.7 ng/mL were included. csPCa was found in 212/271 (78.2%) cases at pathology, 209 of which were localized in the PZ. DCE was necessary to further classify (45/209) of patients who received a score of DWI3. DCE was positive in 29/45 cases, increasing the final PI-RADS v2 assessment category to a category 4, with 16/45 having a negative DCE. When compared with final pathology, DCE was correct in increasing the assessment category in 68.9% ± 7% (31/45) of DWI3 cases. CONCLUSION: DCE increases the accuracy of detection of csPCa in the majority of PZ lesions that receive an equivocal PI-RADS v2 assessment category using DWI.
Sankha S Basu, Madison H McMinn, Begoña Giménez-Cassina Lopéz, Michael S Regan, Elizabeth C Randall, Amanda R Clark, Christopher R Cox, and Nathalie YR Agar. 2019. “Metal Oxide Laser Ionization Mass Spectrometry Imaging (MOLI MSI) Using Cerium(IV) Oxide.” Anal Chem, 91, 10, Pp. 6800-7.Abstract
Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is a powerful technique for spatially resolved metabolomics. A variation on MALDI, termed metal oxide laser ionization (MOLI), capitalizes on the unique property of cerium(IV) oxide (CeO) to induce laser-catalyzed fatty acyl cleavage from lipids and has been utilized for bacterial identification. In this study, we present the development and utilization of CeO as an MSI catalyst. The method was developed using a MALDI TOF instrument in negative ion mode, equipped with a high frequency laser. Instrument parameters for MOLI MS fatty acid catalysis with CeO were optimized with phospholipid standards and fatty acid catalysis was confirmed using lipid extracts from reference bacterial strains, and sample preparation was optimized using mouse brain tissue. MOLI MSI was applied to the imaging of normal mouse brain revealing differentiable fatty acyl pools in myelinated and nonmyelinated regions. Similarly, MOLI MSI showed distinct fatty acyl composition in tumor regions of a patient derived xenograft mouse model of glioblastoma. To assess the potential of MOLI MSI to detect pathogens directly from tissue, a pseudoinfection model was prepared by spotting Escherichia coli lipid extracts on mouse brain tissue sections and imaged by MOLI MSI. The spotted regions were molecularly resolved from the supporting mouse brain tissue by the diagnostic odd-chained fatty acids and reflected control bacterial MOLI MS signatures. We describe MOLI MSI for the first time and highlight its potential for spatially resolved fatty acyl analysis, characterization of fatty acyl composition in tumors, and its potential for pathogen detection directly from tissue.

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